Epilepsy Currents

Resective surgery for drug-resistant temporal lobe epilepsy remains underutilized in the United States. While anteromesial temporal lobectomy consistently achieves the highest rates of long-term seizure freedom, it comes with greater risks for memory and language decline. Magnetic resonance imaging-guided laser interstitial thermal therapy and neuromodulation have gained popularity due to perceived lower surgical risk and faster recovery, although they yield lower rates of sustained seizure freedom. Neuromodulation with vagus nerve, deep brain, or responsive neurostimulation provides an option for patients ineligible for resection or ablation, but overall seizure outcomes remain modest. Balancing improved seizure control with open resection against the potential cognitive advantages of less invasive treatments is complex, requiring careful patient selection. Future research must refine these approaches to optimize results. Thoughtful, individualized decision-making, guided by each patient's clinical scenario and goals, is paramount for achieving the best balance between seizure freedom, cognitive preservation, and overall patient outcome.

Artificial intelligence (ChatGPT 4.0) vs. Human expertise for epileptic seizure and epilepsy diagnosis and classification in Adults: An exploratory study.

Francesco Brigo, Serena Broggi, Gionata Strigaro, Sasha Olivo, Valentina Tommasini, Magdalena Massar, Gianni Turcato, Arian Zaboli. Epilepsy Behav. 2025 May;166:110364. doi: 10.1016/j.yebeh.2025.110364. Epub 2025 Mar 12.

Aims: Artificial intelligence (AI) tools like ChatGPT hold promise for enhancing diagnostic accuracy and efficiency in clinical practice. This exploratory study evaluates ChatGPT's performance in diagnosing and classifying epileptic seizures, epilepsy, and underlying etiologies in adult patients compared to epileptologists and neurologists. Methods: A prospective simulation study assessed 37 clinical vignettes based on real adult patient cases. ChatGPT was “trained” using official International League Against Epilepsy documents on epilepsy diagnosis and classification. Diagnoses and classifications by ChatGPT, two epileptologists, and two neurologists were compared against a reference standard set by a senior epileptologist. Diagnostic accuracy was evaluated using sensitivity, specificity, positive predictive value, and negative predictive value. Cohen's kappa (κ) was calculated to assess agreement. Results: ChatGPT demonstrated high sensitivity (≥96.9%) in identifying epileptic seizures and diagnosing epilepsy, ensuring no cases were missed. However, its specificity was lower, particularly for distinguishing acute symptomatic from unprovoked seizures (33.3%) and diagnosing epilepsy (26.7%), leading to frequent false positives. ChatGPT excelled in diagnosing epileptic syndromes (κ = 1.00) and structural etiologies (accuracy = 90.0%) but struggled with ambiguous cases such as unknown seizure onset (accuracy = 12.5%) and rare etiologies. Human experts consistently outperformed ChatGPT with near-perfect accuracy and higher κ values. Conclusion: ChatGPT shows potential as a supplementary diagnostic tool but requires human oversight due to reduced specificity and limitations in nuanced clinical judgment. Further development with diverse datasets and targeted training is necessary to improve AI performance. Integrating AI with expert clinicians can optimize diagnostic workflows in epilepsy care.

Late-Onset Unexplained Seizures Are Associated With Cognitive Impairment and Lower Amygdala Volumes

Sarkis RA, Orozco J, Lemus HN, Hankerson A, Liu L, Lam AD, Johnson E, Stufflebeam S, Viswanathan A, Amariglio RE, Purandare M, Trouten P, Young GS, Locascio JJ, Pennell PB, Marshall GA. Brain Commun. 2025 Jan 31;7(1):fcaf050. doi:10.1093/braincomms/fcaf050. PMID: 39944741; PMCID: PMC11815171.

Late-onset epilepsy has been linked with accelerated cognitive decline and a higher risk of dementia. In this study, we sought to characterize the cognitive profile of participants with late-onset unexplained epilepsy and compare their MRI findings to healthy controls, to better understand underlying disease mechanisms. We recruited participants with at least one new-onset unexplained seizure at age 55 or later, without cortical lesions on MRI, within 5 years of the first seizure. We administered a neuropsychological battery to generate Preclinical Alzheimer Cognitive Composite and composite scores for delayed verbal recall, processing speed and executive function. We held a consensus meeting to determine whether the participants fulfilled criteria for mild cognitive impairment. An MRI volumetric analysis of hippocampal, amygdalae, and white matter hyperintensity volume was performed and compared to 353 healthy controls from the Harvard Aging Brain Study. On late-onset unexplained epilepsy participants, we also obtained 24-h EEG recording. Seventy participants were recruited, mean age 71.0 ± 7.0 years, 49% female, 15.6 ± 3.0 years of education. Impaired cognition (z-score ≤ −1.5) for late-onset unexplained epilepsy included the following: 15.9% for Preclinical Alzheimer Cognitive Composite −5, 23.2% for delayed verbal recall, 15.6% for processing speed, and 7.5% for executive function. Seventeen percent were found to have mild cognitive impairment. Late-onset unexplained epilepsy participants who were drug resistant were more likely to have cognitive impairment (50% vs. 9%). When controlling for age, sex, and race, late-onset unexplained epilepsy group had lower left AV (%; β = −0.003, P = 0.0016), right AV (%) (β = −0.003, P = 0.01), and log-transformed WMV (mm³; β = −0.21, P = 0.03) compared with Harvard Aging Brain Study (HABS); there were no differences in left or right HV between groups. EEG captured epileptiform abnormalities in 49% late-onset unexplained epilepsy participants, with a left temporal predominance (54%). In this single-site study of prospectively enrolled participants with late-onset unexplained epilepsy, we show that individuals with late-onset unexplained epilepsy exhibit cognitive impairments, mostly in verbal memory, and temporal dysfunction with left-sided predominance. Neuroimaging, when compared with healthy controls, shows lower amygdalae and white matter hyperintensity but not hippocampal volumes suggesting that the amygdalae is one of the earliest sites involved in the disease. The results also highlight the importance of seizure control given the association between mild cognitive impairment and drug-resistant epilepsy. Future studies extending these findings to Alzheimer's disease biomarkers and longitudinal follow-up will inform predictors of cognitive decline.

Association of Cognitive and Structural Correlates of Brain Aging and Incident Epilepsy. The Framingham Heart Study

Stefanidou M, Himali JJ, Bernal R, Satizabal C, Devinsky O, Romero JR, Beiser AS, Seshadri S, Friedman D. Epilepsia. 2025;66(1):160–169. doi:10.1111/epi.18160. Epub Nov 18, 2024. PMID: 39555677; PMCID: PMC11875459.

Objectives: Late-onset epilepsy has the highest incidence among all age groups affected by epilepsy and often occurs in the absence of known clinical risk factors such as stroke and dementia. There is increasing evidence that brain changes contributing to epileptogenesis likely start years before disease onset, and we aim to relate cognitive and imaging correlates of subclinical brain injury to incident late-onset epilepsy in a large, community-based cohort. Methods: We studied Offspring Cohort of the Framingham Heart Study participants 45 years or older, who were free of prevalent stroke, dementia, or epilepsy, and had neuropsychological (NP) evaluation and brain magnetic resonance imaging (MRI). Cognitive measures included Visual Reproduction Delayed Recall, Logical Memory Delayed Recall, Similarities, Trail Making Test B minus A (TrTB-TrTA; attention and executive function), and a global measure of cognition derived from principal component analysis. MRI measures included total cerebral brain volume, cortical gray matter volume (CGMV), white matter hyperintensity volume (WMHV), and hippocampal volume. Incident epilepsy was identified through a review of administrative data and medical records. Cox proportional hazards regression models were used for the analyses. All analyses were adjusted for age, sex, and educational level (cognition only). Results: Among participants who underwent NP testing (n = 2349, 45.81% male), 31 incident epilepsy cases were identified during follow-up. Better performance on the TrTB-TrTA was associated with a lower risk of developing epilepsy (hazard ratio [HR] .25, 95% confidence interval [CI] .08–.73; p = .011). In the subgroup of participants with MRI (n = 2056, 46.01% male), 27 developed epilepsy. Higher WMHV was associated with higher epilepsy risk (HR 1.5, 95% CI 1.01–2.20; p = .042), but higher CGMV (HR .73, 95% CI .57–.93; p = .001) was associated with lower incidence of epilepsy. Significance: Better performance on the (TrTB-TrTA), a measure of executive function and attention, and higher cortical volumes are associated with lower risk of developing epilepsy. Conversely, higher WMHV, a measure of occult vascular injury, increases the risk. Our study shows that non-invasive tests performed in mid-life may help identify people at risk for developing epilepsy later in life.

Original Article Citation

Mithani K, Niazi F, Suresh H, Alrumayyan Y, Rayco ER, Ochi A, Otsubo H, Kerr E, Breitbart S, LeBlanc-Millar A, Gadgil N, Raskin JS, Weil AG, Hadjinicolaou A, Iorio-Morin C, Weiss S, Jain P, Sham L, Donner E, Fasano A, Gorodetsky C, Ibrahim GM. Deep brain stimulation of the centromedian nucleus for drug-resistant epilepsy in children: Quality-of-life and functional outcomes from the CHILD-DBS registry. Epilepsia. 2025 Apr 1. doi: 10.1111/epi.18393. Epub ahead of print. PMID: 40167366.

Objective: Deep brain stimulation of the centromedian nucleus of the thalamus (CM-DBS) is an investigational, off-label treatment for drug-resistant epilepsy (DRE) in children. Although emerging evidence supports its safety and efficacy for select indications, the effect of CM-DBS on quality of life and functional outcomes such as school attendance has not been studied. Here, we analyzed data from the prospective CHILD-DBS (Child and Youth Comprehensive Longitudinal Database for Deep Brain Stimulation) to examine the impact of CM-DBS on patient- and caregiver-reported outcomes. Methods: Twenty-two children and youth underwent bilateral CM-DBS. Caregiver–child dyads completed surveys related to seizure frequency, seizure severity, quality of life, and school attendance at baseline, 6 months, and 1 year postsurgery. Simulated volumes of tissue activation were analyzed to identify optimal stimulation targets associated with treatment outcome. Results: Of 22 children, 10 experienced ≥50% reduction in seizure frequency (mean reduction = 66.7 ± 17.3%), one exhibited a modest benefit (37.5% reduction), and the remaining 11 experienced no change. The majority (73% of patients) exhibited a clinically important reduction in seizure severity, including six children who did not demonstrate any change in seizure frequency. Only those who experienced a reduction in seizure frequency demonstrated significant improvements in general health and overall quality of life. Furthermore, we observed an increase in school attendance across participants 1 year after CM-DBS. Significance: CM-DBS can lead to reduction in seizure burden concurrent with improvements in quality of life and relevant functional outcomes in children with DRE. These findings further our understanding of the impact of CM-DBS on meaningful outcomes for children and caregivers.

Accumulated Seizure Burden Predicts Neurodevelopmental Outcome at 36 Months of Age in Patients with Tuberous Sclerosis Complex.

S. K. Z. Ihnen, S. Alperin, J. K. Capal, A. L. Cohen, J. M. Peters, E. M. Bebin, et al. Epilepsia 2025;66(1): 117-133.DOI: 10.1111/epi.18172; https://pmc.ncbi.nlm.nih.gov/articles/PMC11742629

Objective: Epilepsy and intellectual disability are common in tuberous sclerosis complex (TSC). Although early life seizures and intellectual disability are known to be correlated in TSC, the differential effects of age at seizure onset and accumulated seizure burden on development remain unclear. Methods: Daily seizure diaries, serial neurodevelopmental testing, and brain magnetic resonance imaging were analyzed for 129 patients with TSC followed from 0 to 36 months. We used machine learning to identify subgroups of patients based on neurodevelopmental test scores at 36 months of age and assessed the stability of those subgroups at 12 months. We tested the ability of candidate biomarkers to predict 36-month neurodevelopmental subgroup using univariable and multivariable logistic regression. Candidate biomarkers included age at seizure onset, accumulated seizure burden, tuber volume, sex, and earlier neurodevelopmental test scores. Results: Patients clustered into 2 neurodevelopmental subgroups at 36 months of age, higher and lower scoring. Subgroup was mostly (75%) the same at 12 months. Significant univariable effects on subgroup were seen only for accumulated seizure burden (largest effect), earlier test scores, and tuber volume. Neither age at seizure onset nor sex significantly distinguished 36-month subgroups, although for girls but not boys there was a significant effect of age at seizure onset. In the multivariable model, accumulated seizure burden and earlier test scores together predicted 36-month neurodevelopmental group with 82% accuracy and an area under the curve of .86. Significance: These results untangle the contributions of age at seizure onset and accumulated seizure burden to neurodevelopmental outcomes in young children with TSC. Accumulated seizure burden, rather than the age at seizure onset, most accurately predicts neurodevelopmental outcome at 36 months of age. These results emphasize the need to manage seizures aggressively during the first 3 years of life for patients with TSC, not only to promote seizure control but to optimize cognitive function.

Original Article Citation

Tao AK, Rivero-Guerra J, McFarlane KN, Kerr WT, Pennell PB, Chang JC, Kazmerski TM, Harrison EI, Kirkpatrick L. Anticipatory guidance and care in pediatric and adult neurology for people with epilepsy who became pregnant. Epilepsy Behav. 2025 Apr; 165:110292. doi: 10.1016/j.yebeh.2025.110292. Epub 2025 Feb 20. PMID: 39983588.

Objective: To assess documentation of pregnancy-related counseling and care for people with epilepsy of childbearing potential (PWECP) in pediatric and adult neurology who became pregnant. Methods: We reviewed health records for primigravida PWECP prescribed an antiseizure medication (ASM) who delivered between June 2014 and May 2024 within one academic medical center. We used chi-squared tests to compare counseling, ASM prescriptions, and recommendations for supplemental folic acid between individuals in pediatric and adult neurology care before pregnancy. We performed logistic regression for these outcomes of prepregnancy counseling associated with type of neurology care, race, ethnicity, intellectual disability (ID), teratogenic profile of ASMs prescribed, and ASM polytherapy. Results: One hundred seventy-three PWECP (84% White non-Hispanic, 9% with ID were included. Twenty-one (12%) transferred from pediatric to adult neurology care due to pregnancy (“pediatric group”) and 152 (88%) were previously established with adult neurology (“adult group”). PWECP in the pediatric group compared to the adult group had lower rates of documentation of clinician discussion of ASM teratogenicity (43% vs 66%, P = .041) and folic acid use (24% vs 63%, P = .001) before pregnancy. PWECP established with adult neurology prior to pregnancy were significantly more likely to have been taking folic acid before pregnancy (OR 5.21, 95% CI [1.78-15.3]). Individuals with ID were significantly less likely to have documentation of discussion of ASM teratogenicity (OR 0.18, 95% CI [0.05-0.62]). Conclusion: Our findings suggest a need for improvement in providing prepregnancy guidance and care for PWECP, especially for PWECP in pediatric neurology care and those with ID.

Global, regional, and national burden of epilepsy, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021.

GBD Epilepsy Collaborators. Lancet Public Health. 202;10(3):e203-e227. doi: 10.1016/S2468-2667(24)00302-5

Background: Epilepsy is one of the most common serious neurological disorders and affects individuals of all ages across the globe. The aim of this study is to provide estimates of the epilepsy burden on the global, regional, and national levels for 1990-2021. Methods: Using well established Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) methodology, we quantified the prevalence of active idiopathic (epilepsy of genetic or unknown origin) and secondary epilepsy (epilepsy due to an underlying abnormality of the brain structure or chemistry), as well as incidence, death, and disability-adjusted life-years (DALYs) by age, sex, and location (globally, 21 GBD regions and seven super-regions, World Bank country income levels, Socio-demographic Index [SDI], and 204 countries) and their trends from 1990 to 2021. Vital registrations and verbal autopsies provided information about deaths, and data on the prevalence and severity of epilepsy, largely came from population representative surveys. All estimates were calculated with 95% uncertainty intervals (UIs). Findings: In 2021, there were 51.7 million (95% UI 44.9–58.9) people with epilepsy (idiopathic and secondary combined) globally, with an age-standardized prevalence of 658 per 100 000 (569–748). Idiopathic epilepsy had an age-standardized prevalence of 307 per 100 000 (235–389) globally, with 24.2 million (18.5–30.7) prevalent cases, and secondary epilepsy had a global age-standardized prevalence of 350 per 100 000 (322–380). In 2021, 0.7% of the population had active epilepsy (0.3% attributed to idiopathic epilepsy and 0.4% to secondary epilepsy), and the age-standardized global prevalence of epilepsy from idiopathic and secondary epilepsy combined increased from 1990 to 2021 by 10.8% (1.1–21.3), mainly due to corresponding changes in secondary epilepsy. However, age-standardized death and DALY rates of idiopathic epilepsy reduced from 1990 to 2021 (decline of 15.8% [8.8–22.8] and 14.5% [4.2–24.2], respectively). There were three-fold to four-fold geographical differences in the burden of active idiopathic epilepsy, with the bulk of the burden residing in low-income to middle-income countries: 82.1% (81.1–83.4) of incident, 80.4% prevalent (79.7–82.7), 84.7% (83.7–85.1) fatal epilepsy, and 87.9% (86.2–89.2) epilepsy DALYs. Interpretation: Although the global trends in idiopathic epilepsy deaths and DALY rates have improved in the preceding decades, in 2021 there were almost 52 million people with active epilepsy (24 million from idiopathic epilepsy and 28 million from secondary epilepsy), with the bulk of the burden (>80%) residing in low-income to middle-income countries. Better treatment and prevention of epilepsy are required, along with further research on risk factors of idiopathic epilepsy, good-quality long-term epilepsy surveillance studies, and exploration of the possible effect of stigma and cultural differences in seeking medical attention for epilepsy. Funding: Bill and Melinda Gates Foundation.

Vestibular Epilepsy: Clinical and Electroencephalographic Characteristics With the Proposed Diagnostic Criteria

Perriguey M, Elziere M, Lopez C, Bartolomei F. J Neurol. 2024;272(1):68. doi:10.1007/s00415-024-12796-1. PMID: 39680238.

Background: Focal seizures may encompass vestibular sensations in their symptomatology. When these manifestations occur in isolation or constitute the predominant symptom, they prompt consideration for diagnosing recurrent paroxysmal vertigo. However, the characterization of “vestibular epilepsy” remains debated and underexplored. Our objective is to characterize the clinical and electrophysiological criteria of vestibular epilepsy. Methods: We retrospectively analyzed data from a cohort of outpatients treated in the epileptology department of Marseille University Hospital. The study focused on patients presenting with vestibular symptoms without focal abnormalities on brain magnetic resonance imaging and with interictal epileptic abnormalities on wake or sleep EEG. Results: 31 patients (15 men and 16 women) were included in the study. Visual, auditory, and dysautonomic symptoms were frequently associated with vestibular symptoms. The mean time to diagnosis was 3 years. The duration of attacks was generally short, ranging from a few seconds to a few minutes, with variable frequency. Most patients responded well to antiseizure medication. Some patients showed interictal phenomena, such as permanent instability, raising the possibility of inter/postictal disturbances. Seizures could be triggered by peripheral vestibular stimuli. Interictal EEG abnormalities were observed only during sleep in 25% of patients and predominated in the posterior temporoparietal regions. Discussion: We propose clinical–electro-radiological criteria for defining vestibular epilepsy. These diagnostic criteria overlap with the criteria for vestibular paroxysmia, suggesting the possibility of a single nosological entity.

Emerging translocator protein–positron emission tomographic imaging improves detection of focal cortical dysplasia

Zichen Qiao, Yingxue Yang, Yuanhong Chen, Linai Guo, Qing Xue, Lehong Gao, Jia Chen, Bixiao Cui, Jinghui Liu, Haoxun Yang, Xueyuan Wang, Yihe Wang, Huaqiang Zhang, Cuiping Xu, Yicong Lin, Tao Yu, Yuping Wang, Yueshan Piao, Jie Lu, Liankun Ren

Objective: The identification of epileptic lesions is crucial for improving surgical outcomes. Nevertheless, substantial focal cortical dysplasia (FCD) may be invisible on magnetic resonance imaging (MRI). We aimed to characterize the expression pattern of 18-kDa translocator protein (TSPO) in FCD and to evaluate the effectiveness of this inflammation-reflective molecular imaging technique for detecting FCD. Methods: Patients clinically diagnosed with FCD, based on clinical features, interictal electroencephalographic (EEG) findings, and MRI characteristics, underwent positron emission tomography (PET) imaging using ¹⁸F-DPA714 and ¹⁸F-fluorodeoxyglucose (FDG) tracers. TSPO-PET activation patterns were qualitatively evaluated. Semiquantitative analysis using the highlight index (HI) was further performed to investigate its correlation with clinical characteristics. For patients who underwent stereo-EEG (SEEG) monitoring, the site of high-level TSPO-PET activation was compared with the seizure onset zone identified by SEEG. For patients who underwent resection surgery, the relationship between TSPO-PET uptake and histopathological findings was studied. Results: Twenty-four patients were enrolled. Three groups were identified: MRI-positive with visible high-level TSPO-PET activation (6 patients), MRI-negative with visible high-level TSPO-PET activation (13 patients), and MRI-positive with invisible low-level TSPO-PET activation (5 patients). Regions of high-level TSPO-PET activation showed concordance with ictal discharges in five patients who underwent SEEG. Compared with FDG-PET, TSPO-PET exhibited a more prominent signal against the background (p = .0158). HI was correlated with seizure frequency (p = .0362) and the occurrence of focal to bilateral tonic–clonic seizures (p = .0294), and shorter interval between the TSPO-PET scan and the last seizure was associated with higher TSPO-PET HI (R = −.4323, p = .0349). Postoperative histopathological examination confirmed high-level TSPO-PET activation rates of 3/3 for FCD type IIb and 1/3 for FCD type IIa. Significance: TSPO-PET activation patterns offer clinical significance for improving surgical outcomes by enhancing FCD detection during presurgical evaluation. Also, our observations offer new insights into the histopathological basis for increased TSPO uptake in humans.

Altered Gut Microbiome Profiles in Epileptic Children Are Associated With Spectrum of Anti-Seizure Medication Responsiveness

Yuwattana R, Suparan K, Kerdphoo S, Arunsak B, Sanguansermsri C, Katanyuwong K, Chattipakorn N, Wiwattanadittakul N, Chattipakorn SC. Brain Res. 2025;1849:149367. doi: 10.1016/j.brainres.2024.149367. Epub 2024 Dec 1. PMID: 39626831.

Gut microbiota plays a role in epilepsy. However, current knowledge of how gut dysbiosis is associated with a response to anti-seizure medications (ASMs) in epileptic children is still limited. We aimed to characterize the gut microbiota profiles in epileptic children based on response to ASMs. Eighty-six children aged 3–18 years old with a regular oral diet were enrolled onto the study and divided into three groups in accordance with ILAE definitions: 26 healthy controls, 31 drug-sensitive epilepsy (DSE) patients, and 29 drug-resistant epilepsy (DRE) patients. Based on ASM responsiveness, defined as a reduction in seizure frequency of at least 75% over one year, DRE individuals were subclassified into 13 drug responsive (DRE-DR) and 16 drug non-responsive (DRE-DNR) patients. Feces were collected at the time of enrollment for gut microbiota analysis using 16S rRNA sequencing. Epileptic patients exhibited distinctive gut dysbiotic profiles. Differential abundance investigation revealed that CAG-56 was significantly increased in epileptic patients compared to controls. Saccharimonadales and Peptoclostridium significantly increased in the DSE group, compared to the DRE group. Vibrionaceae, especially Grimontia, Rhodobacteraceae, and Enterobacter were significantly abundant in the DRE-DNR group, followed by abundance in the DRE-DR and DSE groups. Outcomes from PICRUSt2 analysis predicted that epileptic patients, especially those in the DRE group, had increased metabolic pathways responsible for vanillin and taurine degradation, compared to controls. These findings suggest that gut dysbiosis could play roles in epileptogenesis and ASM resistance. Notably, the identified gut microbes could serve as predictive biomarkers for the DRE condition.

Medication-Resistant Epilepsy is Associated With a Unique Gut Microbiota Signature

Riva A, Sahin E, Volpedo G, Catania NT, Venara I, Biagioli V, Balagura G, Amadori E, De Caro C, Cerulli Irelli E, Di Bonaventura C, Zara F, Sezerman OU, Russo E, Striano P. Epilepsia. 2025. doi: 10.1111/epi.18367. Epub ahead of print. PMID: 40119849.

Objective: Dysfunction of the microbiota-gut-brain axis is emerging as a new pathogenic mechanism in epilepsy, potentially impacting on medication response and disease outcome. We investigated the composition of the gut microbiota in a cohort of medication-resistant (MR) and medication-sensitive (MS) pediatric patients with epilepsy. Methods: Children with epilepsy of genetic and presumed genetic etiologies were evaluated clinically and subgrouped into MR and MS. Age-matched healthy controls (HCs) were also recruited. A food diary was used to evaluate nutritional habits, and the Rome IV questionnaire was used to record gastrointestinal symptoms. The microbiota composition was assessed in stool samples through 16S rRNA. α-Diversity (AD) and β-diversity (BD) were calculated, and differential abundance analysis was performed using linear multivariable models (significance: p.adj < .05). Results: Forty-one patients (MR:MS = 20:21) with a mean age of 7.2 years (±4.6 SD) and 27 age-matched HCs were recruited. No significant differences in AD were found when comparing patients and HCs. Significant positive correlation was found between AD and age (Chao1 p.adj = .0004, Shannon p.adj = .0004, Simpson p.adj = .0028). BD depicted a different bacterial profile in the epilepsy groups compared to HCs (MS vs HC: Bray-Curtis F = 1.783, p = .001; Jaccard F = 1.24, p = .001; MR vs HC: Bray-Curtis F = 2.24, p = .001; Jaccard F = 1.364, p = .001). At the genus level, the epilepsy groups were characterized by a significant increase in Hungatella (MS vs HC: + 4.95 log2 change; MR vs HC: + 6.72 log2 change); the [Eubacterium] siraeum group changed between the MR and MS subgroups. Significance: Epileptic patients display unique gut metagenomic signatures compared to HCs. Moreover, a different ratio of the butyrate-producing [Eubacterium] siraeum group suggests dissimilarities between patients based on the response to antiseizure medications.

Ramadan Fasting in Adolescents With Epilepsy: Seizure Control and Behavioral Outcome.

Magdy R, Kishk N, Al-Azayem SA, Hussein M, Yassine IA, Tarek MA, Elsebaie EH, Abdeltwab MA, Othman AS. Seizure. 2025;124:85-88. doi:10.1016/j.seizure.2024.12.007

Data about the effect of Ramadan fasting on seizure control among adolescents with epilepsy (AWE) is scarce. Several psychobehavioral problems have also been encountered in this teenage group. This study aimed to assess seizure frequency and behavioral outcomes after Ramadan fasting in a sample of AWE. Methods: In this prospective study, AWE who completed fasting during Ramadan 2024 were evaluated regarding the seizure frequency of each type during Shaban (the month immediately preceding Ramadan) and Ramadan. Three questionnaires were requested to be answered at the end of two months. They were Patient Health Questionnaire (PHQ-9), Modified Overt Aggression Scale (MOAS), and Barratt Impulsiveness Scale-Short Form (BIS-11-SF) for assessment of depression, aggression, and impulsivity, respectively. Results: One hundred twenty AWE, with a median age of 15 and interquartile range: 13-17, were evaluated. There was a statistically significant reduction in seizure frequency regarding focal onset seizures during Ramadan compared to Shaaban (P .009), as well as generalized nonmotor (absence) seizures (P .027). The MOAS-total scores significantly reduced during Ramadan than Shaaban (P .003), as well as the scores of nonplanning impulsivity of BIS-11-SF (P 0.005). On the other hand, depression assessed by PHQ-9 did not significantly differ between the two months. Conclusion: Fasting Ramadan is associated with better control of multiple seizure types, including focal and generalized-onset nonmotor (absence) seizures, besides psychobehavioral aspects of aggression & nonplanning impulsivity, without worsening of other seizure types nor depression, among AWE.

Prescribing Errors in Hospitalized Patients on the Ketogenic Diet

Yen CY, Kronisch L, Whitley K, Carew B, Zaldana A, Diaz-Medina G, Katyayan A, Cokley JA. American Journal of Health-System Pharmacy. 2025.

Purpose: A ketogenic diet (KD) is recommended as a nonpharmacological treatment option in pediatric patients with epilepsy. Prescribing errors for these patients can result in inadvertent carbohydrate exposure, increasing the risk of loss of ketosis and breakthrough seizures. The objective of this study was to evaluate the incidence of inadvertent carbohydrate exposure in hospitalized children on the traditional KD. Methods: This was a retrospective cohort study of patients with epilepsy receiving KD therapy while admitted to the hospital. Patients 18 years of age or younger diagnosed with epilepsy and/or intractable epilepsy, receiving antiseizure medications on the traditional KD or KD total parenteral nutrition, or with GLUT-1 genetic disorder were included. The primary endpoint was the incidence of patient admissions with unintended orders for carbohydrate-containing medications during hospitalization. Results: A total of 42 patients accounting for 66 inpatient admissions were included in this study. The total incidence of admissions with an inadvertent carbohydrate-containing medication order placed was 52% for intravenous (IV) medications and 64% for oral medications. Patients averaged 2 carbohydrate-containing orders per admission for both IV and oral medications. The most commonly prescribed carbohydrate-containing medications were given at least once before being discontinued. Of the IV medications documented in this study, 6 were premix products diluted in carbohydrate-containing solutions and did not have an alternative file built to facilitate dilution in normal saline. Conclusion: Because of their restricted carbohydrate allowance and the possibility of carbohydrate-containing product excipients, patients on the KD are at increased risk for receiving inappropriate carbohydrate containing medications during hospital admissions.

High-Frequency Oscillations in Epileptic and Non-Epileptic Alzheimer’s Disease Patients and the Differential Effect of Levetiracetam on the Oscillations

Shandilya MCV, Addo-Osafo K, Ranasinghe KG, Shamas M, Staba R, Nagarajan SS, Vossel K. Brain Commun. 2025;7(1):fcaf041. doi:10.1093/braincomms/fcaf041

Alzheimer's disease increases the risk of developing epilepsy together with cognitive decline. Early diagnosis or prediction of parameters associated with epileptic activity can greatly help in managing disease outcomes. Network hyperexcitability is a candidate of interest as a neurophysiological biomarker of Alzheimer's disease. High-frequency oscillations are increasingly recognized as potential biomarkers of hyperexcitability and epileptic activity. However, they have not yet been identified in Alzheimer's disease. In this study, we measured high-frequency oscillations via magnetoencephalography recordings in Alzheimer's disease patients with and without epileptic activity, as part of a Phase 2a randomized, double blind clinical trial of the efficacy of levetiracetam to improve cognitive functions in Alzheimer's disease. To measure the high-frequency oscillations, we used 10-min magnetoencephalography recordings (275-channel and sampling rate 1200-4000 Hz) during awake resting periods in participants with Alzheimer's disease and healthy controls. Recordings from 14 Alzheimer's disease participants, with six having non-epileptic Alzheimer's disease (median age: 60.8, 2 M/4 F), eight having sub-clinical epileptic activity (median age: 54.9, 5 M/3 F) and eight as control (median age: 71, 5 M/3 F), were analysed using two software scripts: Delphos and a custom-made script, for detecting high-frequency oscillations. Levetiracetam 125 mg twice-a-day or placebo was administered for 4 weeks in between two magnetoencephalography recordings, and 4 weeks of washout before switching levetiracetam/placebo phases for each participant. High-frequency oscillations were categorized into ripples (80 to 250 Hz) and fast ripples (250 to 500 Hz). At baseline, Alzheimer's disease participants, both epileptic and non-epileptic had higher rate of ripples and fast ripples than controls in several left/right hemispheric sensor regions (P < 0.05). Additionally, compared to epileptic, non-epileptic had higher rate of ripples in left-frontal, left-temporal and cerebral fissure regions and higher rate of fast ripples in left-frontal regions (P < 0.05). In epileptic type, levetiracetam decreased ripples in bilateral-frontal, bilateral-occipital regions and cerebral fissure, whereas in non-epileptic type, levetiracetam increased both ripples and fast ripples in right central and left parietal regions, and ripples in the right parietal region (P < 0.05). Additionally, we found hemisphere asymmetry in epileptic type, with right temporal/occipital having more high-frequency oscillations than their counterpart region. Overall, Alzheimer's disease had a high level of high-frequency oscillations, with higher numbers observed in non-epileptic type. Levetiracetam decreased high-frequency oscillations in epileptic but increased high-frequency oscillations in non-epileptic. Thus, high-frequency oscillations can function as a biomarker of hyperexcitability in Alzheimer's disease and may be more pathological when asymmetric and coinciding with presence of epileptic activity. Levetiracetam has the potential for treating hyperactivity in patients with epileptic Alzheimer's disease.

Sleep Spindles as a Predictor of Cognitive Motor Dissociation and Recovery of Consciousness After Acute Brain Injury

Carroll EE, Shen Q, Kansara V, Casson N, Michalak A, Niesvizky-Kogan I, Lim J, Postelnik A, Viereck MJ, Egawa S, Kahan J, Carmona JC, Kruger L, Song YL, Velazquez A, Schevon CA, Connolly ES, Ghoshal S, Agarwal S, Roh D, Park S, Kent P, Claassen J. Nat Med. 2025 May;31(5):1578–1585. doi: 10.1038/s41591-025-03578-x. Epub 2025 Mar 3. PMID: 40033114.

Cognitive motor dissociation (CMD) can improve the accuracy to predict recovery of behaviorally unresponsive patients with acute brain injury, but acquisition and analysis of task-based electroencephalography (EEG) are technically challenging. N2 sleep patterns, such as sleep spindles on EEG, have been associated with good outcomes, rely on similar thalamocortical networks as consciousness and could provide less technically challenging complementary outcome predictors. In this prospective observational cohort study of 226 acutely brain injured patients, well-formed sleep spindles (WFSS) were more likely present in those with CMD than in those without CMD, often preceding the detection of CMD. WFSS were associated with a shorter time to recovery of consciousness, and both CMD and WFSS independently predicted recovery of independence, controlling for age, admission neurological status and injury type. WFSS are seen in approximately every third behaviorally unresponsive patient after acute brain injury, frequently precede detection of CMD and are a promising complementary predictor for recovery of consciousness and functional independence.

Like Janus, the Roman god of beginnings, transitions, and endings, spreading depolarizations (SDs) can be depicted with two faces: one looking backward, waving a symbolic farewell to the end of a cortical seizure; the other forward looking, opening a darker door for a fatal wave in the brainstem that ends life. There is good agreement on the distinct electrical nature of both events, but neither role is yet proven in patients. SD is a slow-moving wave of cellular depolarization that steadily silences neuronal networks and depresses EEG amplitude, whereas seizures represent fast, intermittent synchronization of neural networks with highly variable EEG activation patterns. However, the thresholds triggering both events are neither fixed nor inseparable; indeed, their co-occurrence and interaction depend on dimly-lit intrinsic brain pathophysiology. New insights into single gene control of SD and seizure thresholds are beginning to illuminate the darkness. Here, we review recent data and consider the title's question at the end.

Seizures and Premature Death in Mice with Targeted Kv1.1 Deficiency in Corticolimbic Circuits

Kelsey Paulhus, Edward Glasscock, Brain Commun. 2025; 7(1:fcae444. https://doi.org/10.1093/braincomms/fcae444

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related death, likely stemming from seizure activity disrupting vital brain centers controlling heart and breathing function. However, understanding of SUDEP's anatomical basis and mechanisms remains limited, hampering risk evaluation and prevention strategies. Prior studies using a neuron-specific Kcna1 conditional knockout mouse model of SUDEP identified the primary importance of brain-driven mechanisms contributing to sudden death and cardiorespiratory dysregulation; yet, the underlying neurocircuits have not been identified. Using the Emx1-Cre driver, we generated a new conditional knockout mouse model lacking Kcna1 in excitatory neurons of the cortex, hippocampus, amygdala, and select vagal afferents. To test whether the absence of Kv1.1 in forebrain corticolimbic circuits is sufficient to induce spontaneous seizures, premature mortality and cardiorespiratory dysfunction, we performed survival studies and electroencephalogram, electrocardiogram, and plethysmography (EEG-ECG-Pleth) recordings. We demonstrate premature death and epilepsy in corticolimbic conditional knockout mice. During monitoring, we fortuitously captured one SUDEP event, which showed a generalized tonic-clonic seizure that initiated respiratory dysfunction culminating in cardiorespiratory failure. In addition, we observed that cardiorespiratory abnormalities are common during nonfatal seizures in conditional knockout mice, but mostly absent during interictal periods, implying ictal, not interictal, cardiorespiratory impairment as a more reliable indicator of SUDEP risk. These results point to corticolimbic excitatory neurons as critical neural substrates in SUDEP and affirm seizure-related respiratory and cardiac failure as a likely cause of death.

Enriched Environment Reduces Seizure Susceptibility via EC Circuit Augmented Adult Neurogenesis

Li Z, Chen L, Fei F, Wang W, Yang L, Wang Y, Cheng H, Xu Y, Xu C, Wang S, Gu Y, Han F, Chen Z, Wang Y. Adv. Sci. 2024; 11: 2410927. doi: 10.1002/advs.202410927.

Enriched environment (EE), characterized by multi-sensory stimulation, represents a non-invasive alternative for alleviating epileptic seizures. However, the mechanism by which EE exerts its therapeutic impact remains incompletely understood. Here, it is elucidated that EE mitigates seizure susceptibility through the augmentation of adult neurogenesis within the EC circuit. A substantial upregulation of adult hippocampal neurogenesis concomitant with a notable reduction in seizure susceptibility has been found following exposure to EE. EE-enhanced adult-born dentate granule cells (abDGCs) are functionally activated during seizure events. Importantly, the selective activation of abDGCs mimics the anti-seizure effects observed with EE, while their inhibition negates these effects. Further, whole-brain c-Fos mapping demonstrates increased activity in DG-projecting EC CaMKIIα+ neurons in response to EE. Crucially, EC CaMKIIα+ neurons exert bidirectional modulation over the proliferation and maturation of abDGCs that can activate local GABAergic interneurons; thus, they are essential components for the anti-seizure effects mediated by EE. Collectively, this study provides compelling evidence regarding the circuit mechanisms underlying the effects of EE treatment on epileptic seizures, shedding light on the involvement of the EC-DG circuit in augmenting the functionality of abDGCs. This may help for the translational application of EE for epilepsy management.

Interneuron-Specific Dual-AAV SCN1A Gene Replacement Corrects Epileptic Phenotypes in Mouse Models of Dravet Syndrome

Mich JK, Ryu J, Wei AD, Gore BB, Guo R, Bard AM, Martinez RA, Luber EM, Liu J, Bishaw YM, Christian RJ. Sci Transl Med. 2025;17(790):p.eadn5603.

Dravet syndrome (DS) is a severe developmental epileptic encephalopathy marked by treatment-resistant seizures, developmental delay, intellectual disability, motor deficits, and a 10% to 20% rate of premature death. Most patients with DS harbor loss-of-function mutations in 1 copy of SCN1A, which encodes the voltage-gated sodium channel (NaV)1.1 alpha subunit and has been associated with inhibitory neuron dysfunction. Here, we generated a split-intein form of SCN1A and used a dual-vector delivery approach to circumvent adeno-associated virus (AAV) packaging limitations. In addition, we applied previously developed enhancer technology to produce an interneuron-specific gene replacement therapy for DS, called DLX2.0-SCN1A. The split-intein SCN1A vectors produced full-length NaV1.1 protein, and functional sodium channels were recorded in HEK293 cells in vitro. Administration of dual DLX2.0-SCN1A AAVs to wild-type mice produced full-length, reconstituted human protein by Western blot and telencephalic interneuron-specific and dose-dependent NaV1.1 expression by immunohistochemistry. These vectors also conferred strong dose-dependent protection against postnatal mortality and seizures in Scn1a_612/+;Meox2-Cre and Scn1a_+/R613X DS mouse models. Injection of single or dual DLX2.0-SCN1A AAVs into wild-type mice did not result in increased mortality, weight loss, or gliosis as measured by immunohistochemistry. In contrast, expression of SCN1A in all neurons driven by the human SYNAPSIN I promoter caused an adverse effect marked by increased mortality in the preweaning period, before disease onset. These findings demonstrate proof of concept that interneuron-specific AAV-mediated SCN1A gene replacement can rescue DS phenotypes in mouse models and suggest that it could be a therapeutic approach for patients with DS.

The Severity of SLC1A2-Associated Neurodevelopmental Disorders Correlates With Transporter Dysfunction

Kovermann P, Bayat A, Fenger CD, Leeuwen L, Borovikov A, Sharkov A, Levrat V, Lesca G, Perrin L, Levy J, Fahlke C, Møller RS, Jensen AA. EBioMedicine. 2025;114:105648.

Background: Excitatory amino acid transporter 2 (EAAT2) is the predominant glutamate transporter and a key mediator of excitatory neurotransmission in the human brain. Here we present a cohort of 18 individuals harbouring 13 different SLC1A2 variants, who all present with neurodevelopmental impairment with variable symptoms and disease severities, and we delineate the impact of these variants on EAAT2 function. Methods: The consequences of 9 novel missense SLC1A2 variants for expression, transport, and anion channel properties of EAAT2 expressed in mammalian cells were characterized by confocal microscopy, enzyme-linked immunosorbent and [3H]-D-aspartate uptake assays, and electrophysiological recordings. Findings: Ten of the 13 SLC1A2 variants mediated significant changes to EAAT2 expression and/or function. These molecular phenotypes were classified into 3 categories: overall loss-of-function (F249Sfs∗17, A432D, A439V, c.1421+1G > C), mild gain-of-anion-channel function (I276S, G360A), and mixed loss-of-transport/gain-of-anion-channel function (G82R, L85R, L85P, P289R). In contrast, L37P, H542R, and I546T did not mediate significant changes to EAAT2 expression or function. Although specific clinical outcomes in individuals carrying variants within each category varied somewhat, the 3 categories overall translated into distinct clinical phenotypes in terms of phenotypic traits and severity. Interpretation: The observed associations between functional effects and clinical phenotypes produced by these variants offer valuable insights for future predictions of progression and severity of SLC1A2-associated neurodevelopmental disorders. Furthermore, these associations between variant-induced changes in EAAT2 function and phenotypic traits could assist in tailoring personalized treatments of these disorders.

Disease Modification Upon 2 Weeks of Tofacitinib Treatment in a Mouse Model of Chronic Epilepsy

Hoffman OR, Koehler JL, Espina JEC, Patterson AM, Gohar ES, Coleman EM, Schoenike BA, Espinosa-Garcia C, Paredes F, Varvel NH, Dingledine RJ, Maguire JL, Roopra AS. Sci Transl Med. 2025;17(790):eadt0527.

All current drug treatments for epilepsy, a neurological disorder affecting more than 50 million people, merely treat symptoms, and a third of patients with epilepsy do not respond to medication. There are no disease-modifying treatments that may be administered briefly to patients to enduringly eliminate spontaneous seizures and reverse cognitive deficits. Applying network approaches to whole tissue and single-nucleus transcriptomic data collected from mouse models of temporal lobe epilepsy and publicly available transcriptomic data from human temporal lobectomy samples, we confirmed a previously described pattern of rapid and transient induction of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway within days of epileptogenic insult. This was followed by a resurgent activation of the JAK/STAT pathway weeks to months later with the onset of spontaneous seizures. Targeting the first wave of JAK/STAT activation after epileptic insult did not prevent seizures. However, inhibition of the second wave with CP690550 (tofacitinib) over a 2-week period enduringly suppressed seizures, rescued deficits in spatial memory, and alleviated epilepsy-associated histopathological alterations. Seizure suppression lasted for at least 2 months after the final dose. These results indicate that reignition of inflammatory JAK/signal transducer and activator of transcription 3 signaling in chronic epilepsy opens a window for disease modification with the US Food and Drug Administration-approved, orally available drug CP690550.

Dysregulation of mTOR signalling is a converging mechanism in lissencephaly

Zhang C, Liang D, Ercan-Sencicek AG, Bulut AS, Cortes J, Cheng IQ, Henegariu O, Nishimura S, Wang X, Peksen AB, Takeo Y, Caglar C, Lam TT, Koroglu MN, Narayanan A, Lopez-Giraldez F, Miyagishima DF, Mishra-Gorur K, Barak T, Yasuno K, Erson-Omay EZ, Yalcinkaya C, Wang G, Mane S, Kaymakcalan H, Guzel A, Caglayan AO, Tuysuz B, Sestan N, Gunel M, Louvi A, Bilguvar K (2025). Nature. 2025;638(8049):172-181. doi: 10.1038/s41586-024-08341-9. PMID: 39743596

Cerebral cortex development in humans is a highly complex and orchestrated process that is under tight genetic regulation. Rare mutations that alter gene expression or function can disrupt the structure of the cerebral cortex, resulting in a range of neurological conditions. Lissencephaly ('smooth brain”) spectrum disorders comprise a group of rare, genetically heterogeneous congenital brain malformations commonly associated with epilepsy and intellectual disability. However, the molecular mechanisms underlying disease pathogenesis remain unknown. Here we establish hypoactivity of the mTOR pathway as a clinically relevant molecular mechanism in lissencephaly spectrum disorders. We characterized 2 types of cerebral organoid derived from individuals with genetically distinct lissencephalies with a recessive mutation in p53-induced death domain protein 1 (PIDD1) or a heterozygous chromosome 17p13.3 microdeletion leading to Miller–Dieker lissencephaly syndrome (MDLS). PIDD1-mutant organoids and MDLS organoids recapitulated the thickened cortex typical of human lissencephaly and demonstrated dysregulation of protein translation, metabolism and the mTOR pathway. A brain-selective activator of mTOR complex 1 prevented and reversed cellular and molecular defects in the lissencephaly organoids. Our findings show that a converging molecular mechanism contributes to 2 genetically distinct lissencephaly spectrum disorders.