Epilepsia

Objective To test a hypothesis that acutely regulated plasma microRNAs (miRNAs) can serve as prognostic biomarkers for the development of post‐traumatic epilepsy (PTE). Methods Adult male Sprague–Dawley rats (n = 245) were randomized to lateral fluid‐percussion–induced traumatic brain injury (TBI) or sham operation at three study sites (Finland, Australia, United States). Video‐electroencephalography (vEEG) was performed on the seventh post‐injury month to detect spontaneous seizures. Tail vein plasma collected 48 h after TBI for miRNA analysis was available from 209 vEEG monitored animals (45 sham, 164 TBI [32 with epilepsy]). Based on small RNA sequencing and previous data, the seven most promising brain enriched miRNAs (miR‐183‐5p, miR‐323‐3p, miR‐434‐3p, miR‐9a‐3p, miR‐124‐3p, miR‐132‐3p, and miR‐212‐3p) were validated by droplet digital polymerase chain reaction (ddPCR). Results All seven plasma miRNAs differentiated between TBI and sham‐operated rats. None of the seven miRNAs differentiated TBI rats that did and did not develop epilepsy (p > .05), or rats with ≥3 vs <3 seizures in a month (p > .05). However, miR‐212‐3p differentiated rats that developed epilepsy with seizure clusters (i.e., ≥3 seizures within 24 h) from those without seizure clusters (.34 ± .14 vs .60 ± .34, adj. p < .05) with an area under the curve (AUC) of .81 (95% confidence interval [CI] .65–.97, p < .01, 64% sensitivity, 95% specificity). Lack of elevation in miR‐212‐3p also differentiated rats that developed epilepsy with seizure clusters from all other TBI rats (n = 146, .34 ± .14 vs .55 ± .31, p < .01) with an AUC of .74 (95% CI .61–.87, p < .01, 82% sensitivity, 62% specificity). Glmnet analysis identified a combination of miR‐212‐3p and miR‐132‐3p as an optimal set to differentiate TBI rats with vs without seizure clusters (cross‐validated AUC .75, 95% CI .47–.92, p < .05). Significance miR‐212‐3p alone or in combination with miR‐132‐3p shows promise as a translational prognostic biomarker for the development of severe PTE with seizure clusters.

Objective This study was undertaken to explore the experiences and concerns of people living with epilepsy by analyzing discussions in an online epilepsy community, using large language models (LLMs) to identify themes, demographic patterns, and associations with emotional distress, substance use, and suicidal ideation. Methods We analyzed 56 970 posts and responses to them from 21 906 users on the epilepsy forum (subreddit) of Reddit and 768 504 posts from the same users in other subreddits, between 2010 and 2023. LLMs, validated against human labeling, were used to identify 23 recurring themes, assess demographic differences, and examine cross‐posting to depression‐ and suicide‐related subreddits. Hazard ratios (HRs) were calculated to assess the association between specific themes and activity in mental health forums. Results Prominent topics included seizure descriptions, medication management, stigma, drug and alcohol use, and emotional well‐being. The posts on topics less likely to be discussed in clinical settings had the highest engagement. Younger users focused on stigma and emotional issues, whereas older users discussed medical treatments. Posts about emotional distress (HR = 1.3), postictal state (HR = 1.4), surgical treatment (HR = .7), and work challenges (HR = 1.6) predicted activity in a subreddit associated with suicidal ideation, whereas emotional distress (HR = 1.5), surgical treatment (HR = .6), and stigma (HR = 1.3) predicted activity in the depression subreddit. Substance use discussions showed a temporal pattern of association with seizure descriptions, implying possible opportunities for intervention. Significance LLM analysis of online epilepsy communities provides novel insights into patient concerns often overlooked in clinical settings. These findings may improve patient–provider communication, inform personalized interventions, and support the development of patient‐reported outcome measures. Additionally, hazard models can help identify at‐risk individuals, offering opportunities for early mental health interventions.

Objective This study was undertaken to anatomically categorize insulo‐opercular focal cortical dysplasia (FCD) lesions according to their location and extent, and to summarize corresponding stereoelectroencephalographic (SEEG) patterns to guide preoperative evaluation and surgical planning. Methods Patients who underwent epilepsy surgery for insulo‐opercular FCD between 2015 and 2022 were enrolled. FCD lesions were categorized into insular, peri‐insular, opercular, and complex types based on their location and extent, as ascertained from electroclinical and neuroimaging data. SEEG signals from the seizure onset electrodes were collected for quantitative analysis. The normalized interictal spike counts, high‐frequency oscillation (HFO) counts, and ictal epileptogenicity index (EI) values of the insular and opercular channels were calculated. The spatial patterns of the spike counts, HFO counts, and EI values were analyzed. Cluster analyses utilizing spike counts, HFO counts, and EI values were performed for automatic categorization, and the results were compared with the manual categorization from the preoperative evaluations. Results A total of 53 patients were included, comprising 10 insular, 17 peri‐insular, 24 opercular, and two complex cases. Thirty‐eight patients were included in the quantitative SEEG analysis. Spike, HFO, and EI analyses indicated that in insular FCDs, the values of the three parameters were higher in insular channels than in opercular channels. In peri‐insular FCDs, the values in insular and opercular channels were comparable, whereas in opercular FCDs, the values were higher in opercular channels than in insular channels. The accuracies of the cluster analysis based on the spike counts, HFO counts, and EI values were 71.05% (27/38), 76.32% (29/38), and 86.84% (33/38), respectively. Surgical strategies were proposed according to the anatomical categorization, achieving a favorable postoperative seizure‐free rate of 84.91%. Significance Insulo‐opercular FCDs can be categorized into insular, peri‐insular, opercular, and complex types. SEEG patterns can facilitate the automatic categorization of insulo‐opercular FCDs, thereby enhancing preoperative planning and surgical outcomes.

Objective Although traumatic brain injury (TBI) and posttraumatic epilepsy (PTE) are common, there are no prospective models quantifying individual epilepsy risk after moderate‐to‐severe TBI (msTBI). We generated parsimonious prediction models to quantify individual epilepsy risk between acute inpatient rehabilitation for individuals 2 years after msTBI. Methods We used data from 6089 prospectively enrolled participants (≥16 years) in the TBI Model Systems National Database. Of these, 4126 individuals had complete seizure data collected over a 2‐year period post‐injury. We performed a case‐complete analysis to generate multiple prediction models using least absolute shrinkage and selection operator logistic regression. Baseline predictors were used to assess 2‐year seizure risk (Model 1). Then a 2‐year seizure risk was assessed excluding the acute care variables (Model 2). In addition, we generated prognostic models predicting new/recurrent seizures during Year 2 post‐msTBI (Model 3) and predicting new seizures only during Year 2 (Model 4). We assessed model sensitivity when keeping specificity ≥.60, area under the receiver‐operating characteristic curve (AUROC), and AUROC model performance through 5‐fold cross‐validation (CV). Results Model 1 (73.8% men, 44.1 ± 19.7 years, 76.1% moderate TBI) had a model sensitivity = 76.00% and average AUROC = .73 ± .02 in 5‐fold CV. Model 2 had a model sensitivity = 72.16% and average AUROC = .70 ± .02 in 5‐fold CV. Model 3 had a sensitivity = 86.63% and average AUROC = .84 ± .03 in 5‐fold CV. Model 4 had a sensitivity = 73.68% and average AUROC = .67 ± .03 in 5‐fold CV. Cranial surgeries, acute care seizures, intracranial fragments, and traumatic hemorrhages were consistent predictors across all models. Demographic and mental health variables contributed to some models. Simulated, clinical examples model individual PTE predictions. Significance Using information available, acute‐care, and year‐1 post‐injury data, parsimonious quantitative epilepsy prediction models following msTBI may facilitate timely evidence‐based PTE prognostication within a 2‐year period. We developed interactive web‐based tools for testing prediction model external validity among independent cohorts. Individualized PTE risk may inform clinical trial development/design and clinical decision support tools for this population.

Objective The piriform cortex (PC) plays a critical role in ictogenesis, where an excitation/inhibition imbalance contributes to epilepsy etiology. However, the epileptic dynamics of the gamma‐aminobutyric acid (GABA) system and the precise role of GABAergic neurons within the PC in epilepsy remain unclear. Methods We combined Ca²⁺ and GABA sensors to investigate the dynamics of Gad2‐expressing neurons and GABA levels, and selectively manipulated GABAergic neurons in the PC through chemogenetic inhibition and caspase3‐mediated apoptosis targeting Gad2 interneurons. Results GABAergic system dynamics in the PC were bidirectional and asymmetric, accompanied by PC optokindling‐induced seizures, notably characterized by a robust response of Gad2 neurons but a rapid descent of GABA content during seizures. Chemogenetic inhibition of PC Gad2 neurons induced seizure‐like behavior, with a discrepancy between the GABAergic neuron activities and GABA levels, signifying a transition from interictal to ictal states. Surprisingly, selective inhibition of Gad2 neurons in the PC produced paradoxical activation in a subset of Gad2 neurons. Moreover, the chronic deficiency of PC Gad2 neurons triggered spontaneous recurrent seizures. Significance Our findings uncover the dynamic interplay within PC inhibitory components and elaborate counteractive mechanisms in seizure regulation. These insights could inform future therapeutic strategies targeting GABAergic neurons to control epileptic activity.

Objective Previous retrospective studies have reported vigabatrin‐associated brain abnormalities on magnetic resonance imaging (VABAM), although clinical impact is unknown. We evaluated the association between vigabatrin and predefined brain magnetic resonance imaging (MRI) changes in a large homogenous tuberous sclerosis complex (TSC) cohort and assessed to what extent VABAM‐related symptoms were reported in TSC infants. Methods The Dutch TSC Registry and the EPISTOP cohort provided retrospective and prospective data from 80 TSC patients treated with vigabatrin (VGB) before the age of 2 years and 23 TSC patients without VGB. Twenty‐nine age‐matched non‐TSC epilepsy patients not receiving VGB were included as controls. VABAM, specified as T2/fluid‐attenuated inversion recovery hyperintensity or diffusion restriction in predefined brain areas, were examined on brain MRI before, during, and after VGB, and once in the controls (at approximately age 2 years). Additionally, the presence of VABAM accompanying symptoms was evaluated. Results Prevalence of VABAM in VGB‐treated TSC patients was 35.5%. VABAM‐like abnormalities were observed in 13.5% of all patients without VGB. VGB was significantly associated with VABAM (risk ratio [RR] = 3.57, 95% confidence interval [CI] = 1.43–6.39), whereas TSC and refractory epilepsy were not. In all 13 VGB‐treated patients with VABAM for whom posttreatment MRIs were available, VABAM entirely resolved after VGB discontinuation. The prevalence of symptoms was 11.7% in patients with VABAM or VABAM‐like MRI abnormalities and 4.3% in those without, implicating no significant association (RR = 2.76, 95% CI = .68–8.77). Significance VABAM are common in VGB‐treated TSC infants; however, VABAM‐like abnormalities also occurred in children without either VGB or TSC. The cause of these MRI changes is unknown. Possible contributing factors are abnormal myelination, underlying etiology, recurrent seizures, and other antiseizure medication. Furthermore, the presence of VABAM (or VABAM‐like abnormalities) did not appear to be associated with clinical symptoms. This study confirms that the well‐known antiseizure effects of VGB outweigh the risk of VABAM and related symptoms.

Objective Intracranial single‐pulse electrical stimulation (SPES) can elicit cortico‐cortical evoked potentials. Their investigation with intracranial EEG is biased by the limited number and selected location of electrodes, which could be circumvented by simultaneous non‐invasive whole‐scalp recording. This study aimed at investigating the ability of magnetoencephalography (MEG) to characterize cortico‐cortical evoked fields (CCEFs) and effective connectivity between the epileptogenic zone (EZ) and non‐epileptogenic zone (i.e., non‐involved [NIZ]). Methods A total of 301 SPES trains (at 0.9 Hz during 120 s) were performed in 10 patients with refractory focal epilepsy. MEG signals were denoised, epoched, averaged, and decomposed using independent component analysis. Significant response deflections and significant source generators were detected. Peak latency/amplitude were compared between each different cortical/subcortical structure of the NIZ containing more than five SPES, and then between the EZ and corresponding brain structures in the NIZ. Results MEG detected and localized polymorphic/polyphasic CCEFs, including one to eight significant consecutive deflections. The latency and amplitude of CCEFs within the NIZ differed significantly depending on the stimulated brain structure. Compared with the corresponding NIZ, SPES within the extratemporal EZ demonstrated delayed CCEF latency, whereas SPES within the temporal EZ showed decreased CCEF amplitude. SPES within the EZ elicited a significantly higher rate of CCEFs within the stimulated lobe compared with those within the NIZ. Significance This study reveals polymorphic CCEFs with complex spatiotemporal dynamics both within the NIZ and EZ. It highlights significant differences in effective connectivity of the epileptogenic network. These cortico‐cortical evoked responses could thus contribute to increasing the yield of intracranial recordings.

Objective White matter abnormalities in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) are well known. Peak width of skeletonized mean diffusivity (PSMD) is a novel marker for quantifying white matter integrity that may reflect small vessel disease. In this study, we aimed to quantify the extent of white matter damage in patients with TLE and HS by using PSMD. Methods We enrolled 52 patients with TLE with HS and 54 age‐ and sex‐matched healthy controls. Diffusion tensor imaging (DTI) was performed using a 3‐T magnetic resonance imaging scanner. We measured PSMD using DTI findings and compared PSMD between patients with TLE with HS and healthy controls. We also evaluated the correlation between PSMD and clinical factors in patients with TLE and HS. Results PSMD differed significantly between healthy controls and patients with TLE and HS, and it was higher in the patients (2.375 × 10⁻⁴ mm²/s vs. 2.108 × 10⁻⁴ mm²/s, p < .001). Furthermore, PSMD in the ipsilateral hemisphere of the HS was higher than in the contralateral hemisphere of the HS (2.472 × 10⁻⁴ mm²/s vs. 2.258 × 10⁻⁴ mm²/s, p = .040). PSMD was positively correlated with age (r = .512, p < .001) and age at seizure onset (r = .423, p = .002) in patients with TLE and HS. Significance Patients with TLE and HS had higher PSMD values than healthy controls, and PSMD was positively correlated with age. These findings provide evidence of white matter damage probably due to small vessel disease in patients with TLE and HS and support the feasibility of PSMD as a promising imaging marker for epileptic disorders.

Joseph Conrad's epilepsy is well documented but has received little attention as he had convulsive seizures only in childhood and adolescence. The type of epilepsy has never been discussed. His biography reveals that his condition was decidedly neuropsychiatric with depression, a suicidal attempt, and prominent signs of frontal lobe dysfunction, as is seen typically in juvenile myoclonic epilepsy. This diagnosis is supported by a congruent family history and probable lifelong myoclonic seizures including reflex myocloni that were misunderstood as nervosity. It is impressive to see how he disciplined himself to become a great writer against the odds of neuropsychological impairment.

Objective Magnetic resonance imaging (MRI) is a crucial tool for identifying brain abnormalities in a wide range of neurological disorders. In focal epilepsy, MRI is used to identify structural cerebral abnormalities. For covert lesions, machine learning and artificial intelligence (AI) algorithms may improve lesion detection if abnormalities are not evident on visual inspection. The success of this approach depends on the volume and quality of training data. Methods Herein, we release an open‐source data set of pre‐processed MRI scans from 442 individuals with drug‐refractory focal epilepsy who had neurosurgical resections and detailed demographic information. We also share scans from 100 healthy controls acquired on the same scanners. The MRI scan data include the preoperative three‐dimensional (3D) T1 and, where available, 3D fluid‐attenuated inversion recovery (FLAIR), as well as a manually inspected complete surface reconstruction and volumetric parcellations. Demographic information includes age, sex, age a onset of epilepsy, location of surgery, histopathology of resected specimen, occurrence and frequency of focal seizures with and without impairment of awareness, focal to bilateral tonic–clonic seizures, number of anti‐seizure medications (ASMs) at time of surgery, and a total of 1764 patient years of post‐surgical followup. Crucially, we also include resection masks delineated from post‐surgical imaging. Results To demonstrate the veracity of our data, we successfully replicated previous studies showing long‐term outcomes of seizure freedom in the range of ~50%. Our imaging data replicate findings of group‐level atrophy in patients compared to controls. Resection locations in the cohort were predominantly in the temporal and frontal lobes. Significance We envisage that our data set, shared openly with the community, will catalyze the development and application of computational methods in clinical neurology.

Objective Area tempestas, a functionally defined region in the anterior piriform cortex, was identified as a crucial ictogenic trigger zone in the rat brain in the 1980s. However, whether the primate piriform cortex can trigger seizures remains unknown. Here, in a nonhuman primate model, we aimed to localize a similar trigger zone in the piriform cortex and, subsequently, evaluated the ability of focal inhibition of the substantia nigra pars reticulata (SNpr) to suppress the evoked seizures. Methods Focal microinjection of the γ‐aminobutyric acid type A (GABAA) antagonist bicuculline methiodide into the piriform cortex was performed, in macaque monkeys, on a within‐subject basis to map the ictogenic regions within this area. Glutamate antagonists were used to characterize the local circuit pharmacology. Focal inhibition of the substantia nigra by infusion of the GABAA agonist muscimol suppressed seizures evoked from piriform cortex. Results We documented a well‐defined region highly susceptible to bicuculline‐induced seizures in the piriform cortex, just posterior to the junction of the frontal and temporal lobes, indicating that a functional homolog to the rodent area tempestas is present in the primate brain. Focal infusion of glutamate receptor antagonists into the area tempestas revealed that α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor‐mediated, but not N‐methyl‐D‐aspartate‐mediated, neurotransmission was necessary for the expression of seizures. Pharmacological inhibition of the SNpr robustly suppressed area tempestas‐evoked seizures. Significance Together, these data point to the area tempestas as a potent ictogenic zone in the primate brain and underscore the antiseizure effects of inhibition of the SNpr. Building on decades of studies in rodents, our present findings emphasize the relevance of these targets to the primate brain and provide further rationale for exploring these targets for clinical use.

Objective Epilepsy surgery in the operculoinsular cortex is challenging due to the difficult delineation of the epileptogenic zone and the high risk of postoperative deficits. Methods Pre‐ and postsurgical data from 30 pediatric patients who underwent operculoinsular cortex surgery at the Motol Epilepsy Center Prague from 2010 to 2022 were analyzed. Results Focal cortical dysplasia (FCD; n = 15, 50%) was the predominant cause of epilepsy, followed by epilepsy‐associated tumors (n = 5, 17%) and tuberous sclerosis complex (n = 2, 7%). In eight patients where FCD was the most likely etiology, the histology was negative. Seven patients (23%) displayed normal magnetic resonance imaging results. Seizures exhibited diverse semiology and propagation patterns (frontal, perisylvian, and temporal). The ictal and interictal electroencephalographic (EEG) findings were mostly extensive. Multimodal imaging and advanced postprocessing were frequently used. Stereo‐EEG was used for localizing the epileptogenic zone and eloquent cortex in 23 patients (77%). Oblique electrodes were used as guides for better neurosurgeon orientation. The epileptogenic zone was in the dominant hemisphere in 16 patients. At the 2‐year follow‐up, 22 patients (73%) were completely seizure‐free, and eight (27%) experienced a seizure frequency reduction of >50% (International League Against Epilepsy class 3 and 4). Fourteen patients (47%) underwent antiseizure medication tapering; treatment was completely withdrawn in two (7%). Nineteen patients (63%) remained seizure‐free following the definitive outcome assessment (median = 6 years 5 months, range = 2 years to 13 years 5 months postsurgery). Six patients (20%) experienced corona radiata or basal ganglia ischemia; four (13%) improved to mild and one (3%) to moderate hemiparesis. Two patients (7%) operated on in the anterior insula along with frontotemporal resection experienced major complications: pontine ischemia and postoperative brain edema. Significance Epilepsy surgery in the operculoinsular cortex can lead to excellent patient outcomes. A comprehensive diagnostic approach is crucial for surgical success. Rehabilitation brings a great chance for significant recovery of postoperative deficits.

Up to 80% of the world's population with epilepsy lives in low and middle‐income countries. Around one‐third of these patients will have drug‐resistant epilepsy, for which epilepsy surgery is an option. Unfortunately, many of these regions, as well as some more developed nations, lack sufficient epilepsy surgery units and trained neurosurgeons. With this in mind, the International League Against Epilepsy (ILAE) formed the Epilepsy Surgery Education Taskforce to address the shortage of further educational opportunities for surgeons and neurologists and to promote the creation of more epilepsy surgery units around the world. In this article, we publish our findings from a web‐based international survey, in which we investigated the global distribution and experience of neurosurgeons who perform epilepsy surgery, their educational paths, and opinions on the further need for epilepsy surgery education, as well as the resources available to them. We report a detailed analysis of the 202 survey replies received from 35 different countries across six continents. The lack of adequate numbers of epilepsy surgery units in the Southern Hemisphere is notable, and the aim of this task force with other ILAE committees, is to improve access to epilepsy surgery for patients and to enhance training for their health care providers.

Objective Neuronal cell death and neuroinflammation are characteristic features of epilepsy, but it remains unclear whether neuronal cell death as such is causative for the development of epileptic seizures. To test this hypothesis, we established a novel mouse line permitting inducible ablation of pyramidal neurons by inserting simian diphtheria toxin (DT) receptor (DTR) cDNA into the Ccl17 locus. The chemokine CCL17 is expressed in pyramidal CA1 neurons in adult mice controlling microglial quiescence. Methods Seizure activity in CCL17‐DTR mice was analyzed by electroencephalographic recordings following treatment with DT for 3 consecutive days. Neuroinflammation and neuronal cell death were evaluated by (immuno)histochemistry. Pharmacological inhibition of TNFR1 signaling was achieved by treatment with XPro1595, a dominant‐negative inhibitor of soluble tumor necrosis factor. Results Neuronal cell death was detectable 7 days (d7) after the first DT injection in heterozygous CCL17‐DTR mice. Spontaneous epileptic seizures were observed in the vast majority of mice, often with an initial peak at d6–9, followed by a period of reduced activity and a gradual increase during the 1‐month observation period. Microglial reactivity was overt from d5 after DT administration not only in the CA1 region but also in the CA2/CA3 area, shortly followed by astrogliosis. Reactive microgliosis and astrogliosis persisted until d30 and, together with neuronal loss and stratum radiatum shrinkage, reflected important features of human hippocampal sclerosis. Granule cell dispersion was detectable only 3 months after DT treatment. Application of XPro1595 significantly reduced chronic seizure burden without affecting the development of hippocampal sclerosis. Significance In conclusion, our data demonstrate that sterile pyramidal neuronal death is sufficient to cause epilepsy in the absence of other pathological processes. The CCL17‐DTR mouse line may thus be a valuable model for further mechanistic studies on epilepsy and assessment of antiseizure medication.

The interaction between basic science epilepsy researchers and clinical epileptologists is a longstanding issue. Efforts to provide opportunities for a dialogue between preclinical and clinical epilepsy professionals are crucial to reduce the knowledge gap between them and improve the translational success of neurobiology‐based research. The International League Against Epilepsy (ILAE) Research and Innovation Task Force circulated a survey to investigate the need for an update on new clinical epilepsy concepts within the basic science community. The 336 respondents included basic scientists (BS), preclinical scientists (PCSs), and/or clinical scientists (CSs). The majority of the 237 BSs/PCSs were engaged in preclinical studies in translational epilepsy research and declared translational research as a priority research interest. Fewer respondents from low‐middle‐income countries than from upper‐middle or high‐income countries (40.7% vs 65%) considered translational research a critical aspect of their research. A broad understanding of both clinical and neurobiological aspects of epilepsy was declared by 48% of BSs/PCSs; 96% of CSs declared a superficial knowledge of neurobiology of epilepsy. Most BSs/PCSs were aware that epilepsy is a complex condition that should be investigated with the help of clinical epileptologists, even though concerns were expressed on the relationship with clinicians. A focused training program on emerging clinical epileptological aspects tailored for BSs/PCSs was recommended by 81% of the participants; the majority of respondents preferred either 1‐ or 2‐week in‐presence tutoring or continuous online training coordinated by ILAE at the regional/national level. The survey also underscored the value of educational programs on neurobiology of epilepsy targeting CSs and low‐middle‐income countries (LMIC) investigators.

Objective Benzodiazepine rescue medications are established as therapy for acute termination of seizure clusters. A post‐hoc analysis of a clinical trial of seizure cluster treatment with diazepam nasal spray found a potential longer‐term impact over a year of treatment. In this retrospective analysis, we tested the hypothesis that benzodiazepine‐treated seizure clusters are associated with prolonged time to the next seizure cluster compared with untreated seizure clusters in a patient‐reported real‐world database. Methods We analyzed data on self‐reported seizures and benzodiazepine rescue medication administration in the Seizure Tracker™ database between 2007 and 2022. Kaplan–Meier analysis was used to compare treated vs untreated seizure clusters with respect to time to start of the next seizure cluster or immediate‐use medication administration. Mixed‐effects analysis was used to compare the number of seizures per cluster for treated and untreated seizure clusters. Robustness of findings was evaluated across three operational seizure‐cluster definitions: ≥2 seizures in 4 hours as primary analysis and in 6 and 24 hours as sensitivity analyses. Results A total of 10 889 benzodiazepine immediate‐use medication administrations (n = 220 patients) met inclusion criteria. Benzodiazepine rescue administrations were followed by longer time to the next seizure cluster or rescue administration, compared with untreated seizure clusters, corresponding to a median of 4.9 days following treated seizure clusters and a median of 0.8 days following untreated seizure clusters. This prolongation was driven by a minority of patients (accounting for 45.9% of seizure clusters in the sample) and patients were more likely to be women. The number of seizures per cluster was lower when treatment was administered earlier in the seizure cluster. Significance These retrospective real‐world data suggest that the effect of benzodiazepines on termination of seizure clusters may be more pronounced when administration occurs earlier after onset, and support a hypothesis of a possible longer‐term effect of benzodiazepines beyond immediate‐use acute seizure termination.

General anesthesia (GA) earlier than recommended (as first‐ or second‐line treatment) was recently described to improve status epilepticus (SE) outcome. We aimed to assess the impact of early GA on outcome in matched groups. Data from a multicenter, prospective cohort of 1179 SE episodes in 1049 adults were retrospectively analyzed. Incident SE episodes were categorized as “early anesthesia” (eGA; GA as first‐ or second‐line treatment) or “non‐early anesthesia” (neGA; GA after second‐line treatment or not at all). Using propensity score matching, eGA episodes were paired 1:4 with neGA episodes. We assessed survival, functional outcomes at discharge (good: modified Rankin Scale = 0–2 or no worsening), SE cessation rate, SE duration, and hospital stay. Among 1049 SE episodes, 55 (5.2%) received eGA, and 994 constituted the neGA group; 220 represented the matched controls. Patients receiving eGA were younger (median = 63, interquartile range [IQR] = 56–76 vs. median = 70, IQR = 54–80 years, p = .004), had deeper consciousness impairment (80% vs. 40% stuporous/comatose, p < .001), and had more severe SE forms (89% vs. 54% generalized convulsive SE/nonconvulsive SE in coma, p < .001). Mortality, functional outcome, SE cessation rate, and duration of SE and hospital stay were similar between the eGA group and matched controls. We conclude that early anesthesia for SE treatment did not influence prognosis.

Objective The human brain undergoes an activity‐dependent organization during late gestation, making it very sensitive to all effects on the spontaneous neuronal activity. Pregnant mothers with epilepsy are treated with antiepileptic drugs (AEDs) that may reach the fetus and cause altered cortical network activity after birth. However, it is not known whether these functional effects of intrauterine AED exposure persist later in childhood. Methods We studied cortical activity networks computed from electroencephalographic recordings during sleep of 25, 6‐year‐old children with in utero exposure to AEDs and 21 without exposure. The frequency‐specific networks were determined for N1 and N2 sleep states, and the study groups were compared for sleep‐state–specific changes and dynamic differences between sleep states. Finally, we correlated these difference networks with the children's neurophysiological performance at 6 years. Results We found brain‐wide changes in the cortical activity networks and their sleep‐state dynamics in the children with intrauterine AED exposure. Moreover, the strength of cortical network connectivity was significantly associated with multiple domains of neurocognitive performance, in particular, verbal comprehension, processing speed, and IQ. Our findings together suggest that fetal AED exposure causes very long‐lasting changes in the cortical networks with significant links to early school‐age cognitive performance. Significance AED treatment of pregnant mothers is indicated for maternal health reasons; however, the long‐term neurodevelopmental effects on the offspring are poorly understood. Our present study shows that in utero exposure to AEDs causes persisting changes in the cortical activity networks, which can be measured with electroencephalography at 6 years of age. Moreover, these network changes correlate to the child's neurocognitive performance at the same age. These findings together suggest a pathway for how fetal drug exposures may cause persisting and neurocognitively meaningful changes in cortical connectivity patterns.

Objective Few studies have evaluated the efficacy of antiseizure medications (ASMs) according to the etiology of neonatal acute provoked seizures. We aimed to investigate the response to ASMs in term/near term neonates with acute arterial ischemic stroke (AIS), as well as the type of seizure at presentation and the monitoring approach. Methods We retrospectively evaluated neonates from 15 European level IV neonatal intensive care units who presented with seizures due to AIS and were monitored by continuous electroencephalography (cEEG) and/or amplitude‐integrated EEG (aEEG) in whom actual recordings, timing, doses, and response to ASMs were available for review. Results One hundred seven neonates were referred, and 88 were included. Of those, 56 met the criteria for evaluating the treatment response. The mean time to treatment was 7.9 h (SD = 16.4), and the most frequently administered first‐line ASM was phenobarbital (PB; 74/88, 84.1%). Seizures were controlled within 24 h from onset of symptoms in 64.3% (36/56) of neonates. Phenytoin (PHT) was effective in almost all neonates in whom it was trialed (24/25, 96.0%), whereas PB was effective in only 22.0% of patients (11/50). Infants treated with PB or PHT as first‐line treatment (53/56, 94.6%) showed a higher response rate with PHT (6/6, 100.0%) than with PB (11/47, 23.4%). Monitoring approach and seizure types were evaluated in 88 infants. Forty‐six of 88 (52.3%) were monitored with cEEG and 47.7% (42/88) with aEEG, with or without intermittent cEEG. The mean monitoring duration was 65.8 h (SD = 39.21). In 83 of 88 (94.3%) infants, the type of seizure suspected clinically prior to monitoring was confirmed afterward. Unilateral focal clonic seizures were seen in 71 of 88 infants (80.7%), whereas 11 of 88 (12.5%) presented with ictal apneas. Significance Our findings provide evidence in a large, homogenous cohort that PHT is more effective than PB in treating neonatal acute symptomatic seizures due to AIS.

Objectives The Phase 3 Study 338 (NCT02834793) assessed long‐term clinical outcomes of adjunctive perampanel in patients ≥2 years of age with uncontrolled seizures associated with Lennox–Gastaut syndrome (LGS). Methods Eligible patients were diagnosed with LGS and receiving one to four concomitant antiseizure medications with an average of two or more drop seizures/week during baseline. The study comprised an 18‐week double‐blind, randomized, placebo‐controlled Core Study and ≥52‐week open‐label Extension. The primary endpoint was median percent change in drop seizure frequency per 28 days during the Core Study. Key secondary endpoints included responder rates, seizure‐freedom rates, and safety outcomes. Post hoc analyses were performed encompassing a broader range of drop seizures or all countable motor seizures. Results Seventy patients were randomized into the Core Study (perampanel, n = 34; placebo, n = 36), and 58 entered the Extension. In the Core Study, numerically greater median percent reductions in drop seizure frequency were observed with perampanel (23.1%) vs placebo (4.5%) using prespecified assessments (p = .107), whereas significantly greater reductions were detected using the broader definition (48.6% vs −.7%, respectively, p = .001) or all countable motor seizures (44.0% vs −.6%, respectively, p = .017). The 50% responder rate for drop seizures was higher with perampanel vs placebo using modern definitions. Reductions in seizure frequency with perampanel were maintained over 52 weeks. Treatment‐emergent adverse events occurred in 85.3% of perampanel‐treated patients (somnolence [23.5%] was the most frequent) and 72.2% of placebo‐treated patients. Significance This study had a reduced sample size and was underpowered. Although the difference in reductions in drop seizure frequency between treatments was not statistically significant by prespecified assessments, adjunctive perampanel demonstrated sustained efficacy in reducing drop seizures associated with LGS for ≤71 weeks using modern definitions. No new safety signals emerged. These observations suggest the long‐term efficacy and safety of perampanel in the LGS population.

This case report shows the importance of multimodal evaluation to formulate a proper diagnosis of negative motor seizures (NMSs). Only few reports in literature document NMSs with video‐electroencephalographic (EEG) and electromyographic coregistration. A multimodal evaluation is crucial to exclude common mimics and propose correct therapy. We describe a case of a 62‐year‐old man with drug‐resistant focal epilepsy and NMSs, evaluated with video‐EEG recording with polygraphy, magnetoencephalography (MEG), and brain magnetic resonance imaging (MRI). Video‐EEG monitoring showed 182 focal NMSs, with preserved awareness and comprehension. The patient reported complex paresthesia of the left hand followed by left facial grimace, left arm flaccid paralysis, and bradycardia. EEG showed ictal discharges in the right frontocentral region associated with sudden electromyographical silence in left limb muscles consistent with loss of tonic contraction from distal to proximal muscles of the arm. MEG localized the epileptic zone in the right opercular region, consistent with MRI evidence of type II cortical dysplasia in the right inferior frontal gyrus. Multimodal evaluation is essential to document the temporal relationship between ictal discharges, clinical onset of limb paresis, and electrophysiologic evidence of loss of tonic muscular contraction. It allows definition of the specific cortical area involved in NMSs, offering new insight into physiological brain functioning.

Objective Epilepsy is recognized increasingly as a network disease, with changes extending beyond the epileptogenic zone (EZ). However, more studies of structural connectivity are needed to better understand the behavior and nature of this condition. Methods In this study, we applied differential tractography, a novel technique that measures changes in anisotropic diffusion, to assess widespread structural connectivity alterations in a total of 42 patients diagnosed with medically refractory epilepsy (MRE), including 27 patients with focal epilepsy and 15 patients with multifocal epilepsy that were included to validate our hypothesis. All patients were compared individually to an averaged database constructed from 19 normal controls regressed by age and sex. Results Statistical analyses revealed specific distribution patterns of tracts with increased connectivity that were located in multiple subcortical structures across all patients including the arcuate fasciculus, inferior fronto‐occipital fasciculus, inferior longitudinal fasciculus, uncinate fasciculus, fornix, and short U fibers. Conversely, pathways with a significant decrease in connectivity (p < .05) exhibited a more central distribution near mesial structures across all patients (corpus callosum, cingulum, corticospinal tract, and sensory fibers). Significance Our findings add to the growing evidence that focal epilepsy is not solely anatomically confined, but is rather a network disorder that extends beyond the EZ, and differential tractography shows strong potential as a clinical biomarker for assessing structural connectivity alterations in patients with epilepsy.

Objective An accurate evaluation of behavioral responsiveness during and after seizures in people with epilepsy is critical for diagnosis and management. Current methods for assessing behavioral responsiveness are characterized by substantial variation, subjectivity, and limited reliability and reproducibility in ambulatory and epilepsy monitoring unit settings. In this study, we aimed to develop and implement a novel mobile platform for deployment of automated responsiveness testing in epilepsy—the ARTiE Watch—to facilitate standardized, objective assessments of behavioral responsiveness during and after seizures. Methods We prospectively recruited patients admitted to the epilepsy monitoring units for diagnostic evaluation and long‐term video‐electroencephalographic monitoring at Mayo Clinic and Yale New Haven Hospital. Participants wore the ARTiE Watch, a smartwatch paired with custom smartphone software integrated with cloud infrastructure allowing for remote activation of standardized assessment on the participants' smartwatches. The assessment consisted of 18 command prompts that test behavioral responsiveness across motor, language, and memory domains. Upon visually identifying an electrographic seizure during EMU monitoring, the BrainRISE platform was used to deploy the ARTiE Watch behavioral testing sequence. Responsiveness scoring was conducted on smartwatch files. Results Eighteen of 56 participants had a total of 39 electrographic seizures assessed with the ARTiE Watch. The 18 subjects with ARTiE Watch‐tested seizures had a total of 67 baseline (interictal) ARTiE Watch tests collected for analysis. The analysis showed distinct ARTiE Watch behavioral responsiveness phenotypes: (1) decreased responsiveness across all ARTiE Watch commands during seizure (ictal–postictal) periods compared (to baseline (p < .0001), (2) decreased responsiveness in bilateral tonic–clonic seizures compared to baseline (p < .0001) and compared to focal seizures (p < .0001), and (3) decreased responsiveness during focal impaired awareness seizures compared to baseline (p < .0001) and compared to focal aware seizures (p < .001). Significance ARTiE Watch behavioral testing deployed utilizing a mobile cloud‐based platform is feasible and can provide standardized, objective behavioral responsiveness assessments during seizures.

The early onset epilepsies encompass a heterogeneous group of disorders, some of which result in drug‐resistant seizures, developmental delay, psychiatric comorbidities, and sudden death. Advancement in the widespread use of targeted gene panels as well as genome and exome sequencing has facilitated the identification of different causative genes in a subset of these patients. The ability to recognize the genetic basis of early onset epilepsies continues to improve, with de novo coding variants accounting for most of the genetic etiologies identified. Although current disease‐specific and disease‐modifying therapies remain limited, novel precision medicine approaches, such as small molecules, cell therapy, and other forms of genetic therapies for early onset epilepsies, have created excitement among researchers, clinicians, and caregivers. Here, we summarize the main findings of presentations and discussions on novel therapeutic strategies for targeted treatment of early onset epilepsies that occurred during the Workshop on Neurobiology of Epilepsy (WONOEP XVI, Talloires, France, July 2022). The presentations discussed the use of chloride transporter inhibitors for neonatal seizures, targeting orexinergic signaling for childhood absence epilepsy, targeting energy metabolism in Dravet syndrome, and the role of cannabinoid receptor type 2, reversible acetylcholinesterase inhibitors, cell therapies, and RNA‐based therapies in early life epilepsies.