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There are limited treatment options for individuals with drug-resistant idiopathic generalized epilepsy (IGE). Small, limited case series suggest that centromedian thalamus deep brain stimulation (CM-DBS) may be an effective treatment option. The optimal CM-DBS target for IGE is underexamined. Here, we present a retrospective analysis of CM-DBS targeting and efficacy for five patients with drug-resistant IGE. Volume of tissue activated (VTA) overlap with CM nucleus was performed using an open-source toolbox. Median follow-up time was 13 months. Median convulsive seizure frequency reduction was 66%. One patient had only absence seizures, with >99% reduction in absence seizure frequency. Four patients had electrode contacts positioned within the CM nucleus target, all of whom had >50% reduction in primary semiology seizure, with 85% median seizure reduction (p = .004, paired-sample t test). Volumetric "sweet-spot" mapping revealed that best outcomes were correlated with stimulation of the middle ventral CM nucleus. Connectivity strength between the sweet-spot region and central peri-Rolandic cortex was increased significantly relative to other cortical regions (p = 8.6 × 10 -4 , Mann-Whitney U test). Our findings indicate that CM-DBS can be an effective treatment for patients with IGE, highlight the importance of accurate targeting and targeting analysis, and within the context of prior work, suggest that ideal CM-DBS targets may be syndrome specific., (© 2024 International League Against Epilepsy.)

Purpose: Photosensitivity is a phenomenon that may be elicited by standardized intermittent photic stimulation during EEG recording and is detected more frequently in children and adolescents. Nevertheless, at our Epilepsy Center, we routinely assess photosensitivity in all newly referred adult patients. In this investigation, we sought to address the diagnostic yield under the prerequisites described., Methods: We reanalyzed all routine EEG recordings among referrals to the department of adults during the first six months of 2019, including a simultaneous video that is always coregistered in our center. The prevalence of abnormal findings during photic stimulation was assessed., Results: Intermittent photic stimulation was performed on 344 patients. Photoparoxysmal response were detected in five subjects (1.5%). All patients were female. Four patients were diagnosed with idiopathic generalized epilepsy, and one with Doose syndrome. Photomyogenic responses were recorded in 1.1% and only in patients with psychogenic nonepileptic seizures. In two subjects with psychogenic nonepileptic seizures, the typical seizure was provoked by intermittent photic stimulation (8.7% of all subjects with psychogenic nonepileptic seizures in this cohort). Photoparoxysmal response was not detected in any subject with focal epilepsy, syncope, or other nonepileptic paroxysmal events. In every case of photoparoxysmal responses, increased photosensitivity had already been reported before recording., Conclusions: In our study, photoparoxysmal responses was a rare phenomenon among adults with a preponderance of females and idiopathic generalized epilepsies. Intermittent photic stimulation may be helpful in provoking typical psychogenic nonepileptic seizures and thus abbreviate the diagnostic process. Provided a careful history, routine intermittent photic stimulation in adults with epilepsy does not appear to be mandatory., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2023 by the American Clinical Neurophysiology Society.)

Purpose: Despite availability of commercial EEG software for automated epileptiform detection, validation on real-world EEG datasets is lacking. Performance evaluation of two software packages on a large EEG dataset of patients with genetic generalized epilepsy was performed., Methods: Three epileptologists labelled IEDs manually of EEGs from three centres. All Interictal epileptiform discharge (IED) markings predicted by two commercial software (Encevis 1.11 and Persyst 14) were reviewed individually to assess for suspicious missed markings and were integrated into the reference standard if overlooked during manual annotation during a second phase. Sensitivity, precision, specificity, and F1-score were used to assess the performance of the software packages against the adjusted reference standard., Results: One hundred and twenty-five routine scalp EEG recordings from different subjects were included (total recording time, 310.7 hours). The total epileptiform discharge reference count was 5,907 (including spikes and fragments). Encevis demonstrated a mean sensitivity for detection of IEDs of 0.46 (SD 0.32), mean precision of 0.37 (SD 0.31), and mean F1-score of 0.43 (SD 0.23). Using the default medium setting, the sensitivity of Persyst was 0.67 (SD 0.31), with a precision of 0.49 (SD 0.33) and F1-score of 0.51 (SD 0.25). Mean specificity representing non-IED window identification and classification was 0.973 (SD 0.08) for Encevis and 0.968 (SD 0.07) for Persyst., Conclusions: Automated software shows a high degree of specificity for detection of nonepileptiform background. Sensitivity and precision for IED detection is lower, but may be acceptable for initial screening in the clinical and research setting. Clinical caution and continuous expert human oversight are recommended with all EEG recordings before a diagnostic interpretation is provided based on the output of the software., (Copyright © 2023 by the American Clinical Neurophysiology Society.)

Objectives: We hypothesized that the frequency (in Hertz) of generalized spike-waves (GSWs) in patients with idiopathic generalized epilepsy (IGE) has associations with the syndromic diagnosis as well as with the prognosis of patients (their response to medical treatment)., Methods: This was a retrospective study of a prospectively developed database. All patients with a diagnosis of IGE were studied at the epilepsy center at Shiraz University of Medical Sciences, Shiraz, Iran, from 2008 until 2022. Patients were classified into four IGE syndromes: childhood absence epilepsy; juvenile absence epilepsy; juvenile myoclonic epilepsy; and generalized tonic-clonic seizures alone., Results: Five hundred and eighty-three patients were studied. GSWs were commonly observed in all four syndromes of IGE. Frequency of GSW (in Hertz) did not have a significant association with the syndromic diagnosis of the patients (p = .179). The presence of GSW did not have a significant association with the seizure outcome (becoming seizure free or not) of the patients (p = .416). Frequency of GSW did not have a significant association with the seizure outcome of the patients either (p = .574)., Conclusion: GSWs are the hallmark electroencephalographic footprints of idiopathic generalized epilepsies; however, neither their presence nor their frequency has practical associations with the syndromic diagnosis of IGEs or their outcome (response to treatment)., (© 2024 The Author(s). Brain and Behavior published by Wiley Periodicals LLC.)

Background: Patients with genetic deficiency of the adaptor protein complex 4 (AP-4) exhibit earlyonset developmental delay, spastic diplegia, intellectual disability, speech impairment. The phenotype overlaps with other hereditary spastic paraplegias and cerebral palsies. Febrile seizures are common at onset. Epilepsy has been described in more than half of cases, arising in early infancy often with status epilepticus, but no typical seizure semiology or electroencephalographic features have been identified thus far., Purpose: We aimed to specifically investigate the epileptological characteristics of the syndrome to unveil possible biomarkers of seizure development and prognosis in AP-4 deficiency., Methods: Observational cohort study on patients with bi-allelic pathogenic variants in AP-4 subunits and epilepsy. We focused on the seizure semiology, electroencephalographic characteristics and response to antiseizure medications., Results: Patients harboured pathogenic variants in AP4S1 (n = 5) or AP4M1 (n = 1). The phenotype included spastic paraparesis, intellectual disability, speech/language impairment, microcephaly, and MRI evidence of hypoplasia of the corpus callosum. In 66 % of the patients, febrile seizures preceded the onset of epilepsy, which spanned from infancy to adolescence (range=14 months-13 years). Absences (66 %) and focal motor seizures (50 %) were common. No patient met the criteria for drug-resistance. Peculiar electroencephalographic features arose after the epilepsy onset and persisted at long-term follow-up: bilateral and asynchronous focal discharges combined with independent diffuse spike-wave-discharges (100 %) and reflex abnormalities (66 %)., Conclusion: In AP-4 complex disease, epilepsy could arise beyond early infancy, until adolescence, with variable combination of generalized and focal seizures. The prognosis was favourable. We observed a common electroencephalographic signature - combined focal/generalized and reflex abnormalities - which may constitute a biomarker of AP-4 deficiency with epilepsy, applicable to inform genetic testing and disentangle the differential diagnosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Generalized epilepsy (GE) encompasses a heterogeneous group of hyperexcitability disorders that clinically manifest as seizures. At the whole-brain level, distinct seizure patterns as well as interictal epileptic discharges (IEDs) reflect key signatures of hyperexcitability in magneto- and electroencephalographic (M/EEG) recordings. Moreover, it had been suggested that aperiodic activity, specifically the slope of the 1/ ƒ x decay function of the power spectrum, might index neural excitability. However, it remained unclear if hyperexcitability as encountered at the cellular level directly translates to putative large-scale excitability signatures, amenable to M/EEG. In order to test whether the power spectrum is altered in hyperexcitable states, we recorded resting-state MEG from male and female GE patients ( n  = 51; 29 females; 28.82 ± 12.18 years; mean ± SD) and age-matched healthy controls ( n  = 49; 22 females; 32.10 ± 12.09 years). We parametrized the power spectra using FOOOF ("fitting oscillations and one over f ") to separate oscillatory from aperiodic activity to directly test whether aperiodic activity is systematically altered in GE patients. We further identified IEDs to quantify the temporal dynamics of aperiodic activity around overt epileptic activity. The results demonstrate that aperiodic activity indexes hyperexcitability in GE at the whole-brain level, especially during epochs when no IEDs were present ( p  = 0.0130; d  = 0.52). Upon IEDs, large-scale circuits transiently shifted to a less excitable network state ( p  = 0.001; d  = 0.68). In sum, these results uncover that MEG background activity might index hyperexcitability based on the current brain state and does not rely on the presence of epileptic waveforms., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Kopf et al.)

Children with epilepsy often experience deficits in both executive functioning (EF) and memory. However, how these two domains interact and relate to specific epilepsy types remains unclear. This study compared two groups of children: those with localization-related epilepsy (LRE) and those with genetic generalized epilepsy (GGE). We aimed to understand how performance-based and parent-reported EF differentially contribute to understanding memory function in each group. We examined neuropsychological measures assessing memory and EF in 75 children with LRE and 91 with GGE. Multiple linear regressions explored the impact of EF on memory performance. Performance-based EF scores accounted for greater variance in memory scores than parental EF reports. However, performance-based EF measures explained much more variance in visual memory for LRE than GGE and explained much more variance in verbal memory for the GGE group. Parental reports of EF contributed marginally to understanding variance. These findings suggest differential relationships between EF and memory based on epilepsy type. Performance-based EF measures appear more reliable at understanding memory variance than did parent reports. Our results have potential clinical implications for tailoring neuropsychological assessment and intervention for children with different epilepsy types., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Genetic generalized epilepsies (GGE) exhibit widespread morphometric alterations in the subcortical structures. Subcortical structures are essential for understanding GGE pathophysiology, but their fine-grained morphological diversity has yet to be comprehensively investigated. Furthermore, the relationships between macroscale morphological disturbances and microscale molecular chemoarchitectures are unclear. High-resolution structural images were acquired from patients with GGE (n = 97) and sex- and age-matched healthy controls (HCs, n = 184). Individual measurements of surface shape features (thickness and surface area) of seven bilateral subcortical structures were quantified. The patients and HCs were then compared vertex-wise, and shape anomalies were co-located with brain neurotransmitter profiles. We found widespread morphological alterations in GGE and prominent disruptions in the thalamus, putamen, and hippocampus. Shape area dilations were observed in the bilateral ventral, medial, and right dorsal thalamus, as well as the bilateral lateral putamen. We found that the shape area deviation pattern was spatially correlated with the norepinephrine transporter and nicotinic acetylcholine (Ach) receptor (α 4 β 2 ) profiles, but a distinct association was seen in the muscarinic Ach receptor (M 1 ). The findings provided a comprehensive picture of subcortical morphological disruptions in GGE, and further characterized the associated molecular mechanisms. This information may increase our understanding of the pathophysiology of GGE., (© 2024. The Author(s).)

Purpose: Coherence analysis in electroencephalography (EEG) allows measurement of the degree of consistency of amplitude between pairs of electrodes. Theoretically, disconnective epilepsy surgery should decrease coherence between corresponding areas. The study aimed to evaluate postoperative changes in interhemispheric coherence values after corpus callosotomy (CC)., Methods: Non-lesional, drug-resistant, generalized epilepsy patients who underwent total CC were retrospectively collected. To evaluate coherence, we divided the scalp interictal EEG into "baseline" and "discharge" states after excluding periods with artifacts. Interhemispheric coherence values were obtained between eight pairs of symmetrically opposite scalp electrodes in six different frequency bands. We analyzed both pre- and postoperative EEG sessions and calculated the percentage of difference (POD) in coherence values., Results: We collected 13 patients and analyzed 2496 interhemispheric coherence values. Preoperative coherence values differed significantly between baseline and discharge states (p = 0.0003), but postoperative values did not (p = 0.11). For baseline state, coherence values were decreased after CC and median POD was - 22.3% (p < 0.0001). Delta frequency showed the most decreased POD (-44.3%, p = 0.0009). Median POD was lowest in the Fp1-Fp2 pair of electrodes. For discharge state, coherence values were decreased after CC and median POD was - 24.7% (p < 0.0001). Delta frequency again showed the most decreased POD (-55.9%, p = 0.0016). Median POD was lowest in the F7-F8 pair., Conclusion: After total CC, interhemispheric coherence decreased significantly in both baseline and discharge states. The most decreased frequency band was the delta band, which may be used as a representative frequency band in future studies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: To test the hypothesis that myoclonic seizures can evolve to tonic seizures, we documented the electroclinical features of this under-recognized seizure type., Methods: We observed a distinct seizure pattern starting with myoclonus without returning to an interictal state, which subsequently evolved into generalized tonic seizures. The detailed symptomatic and electroencephalographic characteristics of this seizure were extracted, and the clinical manifestations, drug curative responses in patients with this seizure were reviewed and analyzed., Results: The onset of all seizures was characterized by a preceding period of myoclonus and bursts of generalized spike or poly-spike slow wave discharges with high amplitude. This was closely followed by the occurrence of tonic seizures, which were distinguished by bursts of generalized fast activity at 10 Hz or higher frequency. This under-recognized seizure type has been designated as myoclonic-to-tonic (MT) seizure. The number of patients identified with MT seizures in this study was 34. The prevalence rate of MT seizures was found to be higher in males. While MT seizures typically included a tonic component, it should be noted that some patients experiencing this seizure type never presented with isolated tonic seizures. Generalized Epilepsy not further defined (GE) accounted for approximately one-third of the diagnosed cases, followed by Lennox-Gastaut syndrome and Epilepsy with Myoclonic-Atonic seizures. In comparison to other types of epilepsy, GE with MT seizures demonstrated a more favorable prognosis., Conclusions: The classification of myoclonic-to-tonic seizure represents a novel approach in comprehending the ictogenesis of generalized seizures and can provide valuable assistance to clinicians in epilepsy diagnosis., (Copyright © 2024. Published by Elsevier B.V.)

Background and Objectives: Generalized convulsive seizures (GCSs) are the main risk factor of sudden unexpected death in epilepsy (SUDEP), which is likely due to peri-ictal cardiorespiratory dysfunction. The incidence of GCS-induced cardiac arrhythmias, their relationship to seizure severity markers, and their role in SUDEP physiopathology are unknown. The aim of this study was to analyze the incidence of seizure-induced cardiac arrhythmias, their association with electroclinical features and seizure severity biomarkers, as well as their specific occurrences in SUDEP cases., Methods: This is an observational, prospective, multicenter study of patients with epilepsy aged 18 years and older with recorded GCS during inpatient video-EEG monitoring for epilepsy evaluation. Exclusion criteria were status epilepticus and an obscured video recording. We analyzed semiologic and cardiorespiratory features through video-EEG (VEEG), electrocardiogram, thoracoabdominal bands, and pulse oximetry. We investigated the presence of bradycardia, asystole, supraventricular tachyarrhythmias (SVTs), premature atrial beats, premature ventricular beats, nonsustained ventricular tachycardia (NSVT), atrial fibrillation (Afib), ventricular fibrillation (VF), atrioventricular block (AVB), exaggerated sinus arrhythmia (ESA), and exaggerated sinus arrhythmia with bradycardia (ESAWB). A board-certified cardiac electrophysiologist diagnosed and classified the arrhythmia types. Bradycardia, asystole, SVT, NSVT, Afib, VF, AVB, and ESAWB were classified as arrhythmias of interest because these were of SUDEP pathophysiology value. The main outcome was the occurrence of seizure-induced arrhythmias of interest during inpatient VEEG monitoring. Moreover, yearly follow-up was conducted to identify SUDEP cases. Binary logistic generalized estimating equations were used to determine clinical-demographic and peri-ictal variables that were predictive of the presence of seizure-induced arrhythmias of interest. The z -score test for 2 population proportions was used to test whether the proportion of seizures and patients with postconvulsive ESAWB or bradycardia differed between SUDEP cases and survivors., Results: This study includes data from 249 patients (mean age 37.2 ± 23.5 years, 55% female) who had 455 seizures. The most common arrhythmia was ESA, with an incidence of 137 of 382 seizures (35.9%) (106/224 patients [47.3%]). There were 50 of 352 seizure-induced arrhythmias of interest (14.2%) in 41 of 204 patients (20.1%). ESAWB was the commonest in 22 of 394 seizures (5.6%) (18/225 patients [8%]), followed by SVT in 18 of 397 seizures (4.5%) (17/228 patients [7.5%]). During follow-up (48.36 ± 31.34 months), 8 SUDEPs occurred. Seizure-induced bradycardia (3.8% vs 12.5%, z = -16.66, p < 0.01) and ESAWB (6.6% vs 25%; z = -3.03, p < 0.01) were over-represented in patients who later died of SUDEP. There was no association between arrhythmias of interest and seizure severity biomarkers ( p > 0.05)., Discussion: Markers of seizure severity are not related to seizure-induced arrhythmias of interest, suggesting that other factors such as occult cardiac abnormalities may be relevant for their occurrence. Seizure-induced ESAWB and bradycardia were more frequent in SUDEP cases, although this observation was based on a very limited number of SUDEP patients. Further case-control studies are needed to evaluate the yield of arrhythmias of interest along with respiratory changes as potential SUDEP biomarkers.

Social cognition is a set of mental skills necessary to create satisfactory interpersonal relationships and feel a sense of belonging to a social group. Its deficits significantly reduce the quality of life in people with epilepsy. Studies on social cognition and its impairments focus predominantly on people with focal epilepsies. Idiopathic generalised epilepsies are a group of diseases that share similar clinical, prognostic and electrographic characteristics. Despite their typically normal intelligence, people with Idiopathic generalised epilepsies can suffer from learning disabilities and executive dysfunctions. Current studies also suggest social cognition impairments, but their results are inconsistent. This review offers the latest knowledge of social cognition in adults with Idiopathic generalised epilepsies. In addition, we provide an overview of the most frequently used assessment methods. We explain possible reasons for different outcomes and discuss future research perspectives., Competing Interests: Declaration of Competing Interest We declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Rationale and Objectives: The white matter (WM) functional network changes offers insights into the potential pathological mechanisms of certain diseases, the alterations of WM functional network in idiopathic generalized epilepsy (IGE) remain unclear. We aimed to explore the topological characteristics changes of WM functional network in childhood IGE using resting-state functional Magnetic resonance imaging (MRI) and T 1 -weighted images., Methods: A total of 84 children (42 IGE and 42 matched healthy controls) were included in this study. Functional and structural MRI data were acquired to construct a WM functional network. Group differences in the global and regional topological characteristics were assessed by graph theory and the correlations with clinical and neuropsychological scores were analyzed. A support vector machine algorithm model was employed to classify individuals with IGE using WM functional connectivity as features, and the model's accuracy was evaluated using leave-one-out cross-validation., Results: In IGE group, at the network level, the WM functional network exhibited increased assortativity; at the nodal level, 17 nodes presented nodal disturbances in WM functional network, and nodal disturbances of 11 nodes were correlated with cognitive performance scores, disease duration and age of onset. The classification model achieved the 72.6% accuracy, 0.746 area under the curve, 69.1% sensitivity, 76.2% specificity., Conclusion: Our study demonstrated that the WM functional network topological properties changes in childhood IGE, which were associated with cognitive function, and WM functional network may help clinical classification for childhood IGE. These findings provide novel information for understanding the pathogenesis of IGE and suggest that the WM function network might be qualified as potential biomarkers., Competing Interests: Declaration of Competing Interest The authors declare that the study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Correctly diagnosing and classifying seizures and epilepsies is vital to ensure a tailored approach to patients with epilepsy. The ILAE seizure classification consists of two main groups: focal and generalized. Establishing if a seizure is focal or generalized is essential to classify the epilepsy type and the epilepsy syndrome, providing more personalized treatment and counseling about prognosis. EEG is one of the most essential tools for this classification process and further localization of the epileptogenic focus. However, some EEG findings are misleading and may postpone the correct diagnosis and proper treatment. Knowing the most common EEG pitfalls in focal and generalized epilepsies is valuable for clinical practice, avoiding misinterpretations. Some atypical features can be challenging in focal epilepsies, such as secondary bilateral synchrony, focal epileptiform activity induced by hyperventilation and photic stimulation, and non-focal slowing. On the other hand, more than 60 % of persons with idiopathic generalized epilepsies have at least one type of atypical abnormality. In this manuscript, we describe and illustrate some of the most common EEG findings that can make even experienced epileptologists question not only where the epileptogenic focus is but also if the patient has focal or generalized epilepsy. This review summarizes the perils and provide some pearls to assist EEG readers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to develop a machine learning algorithm using an off-the-shelf digital watch, the Samsung watch (SM-R800), and evaluate its effectiveness for the detection of generalized convulsive seizures (GCS) in persons with epilepsy., Methods: This multisite epilepsy monitoring unit (EMU) phase 2 study included 36 adult patients. Each patient wore a Samsung watch that contained accelerometer, gyroscope, and photoplethysmographic sensors. Sixty-eight time and frequency domain features were extracted from the sensor data and were used to train a random forest algorithm. A testing framework was developed that would better reflect the EMU setting, consisting of (1) leave-one-patient-out cross-validation (LOPO CV) on GCS patients, (2) false alarm rate (FAR) testing on nonseizure patients, and (3) "fixed-and-frozen" prospective testing on a prospective patient cohort. Balanced accuracy, precision, sensitivity, and FAR were used to quantify the performance of the algorithm. Seizure onsets and offsets were determined by using video-electroencephalographic (EEG) monitoring. Feature importance was calculated as the mean decrease in Gini impurity during the LOPO CV testing., Results: LOPO CV results showed balanced accuracy of .93 (95% confidence interval [CI] = .8-.98), precision of .68 (95% CI = .46-.85), sensitivity of .87 (95% CI = .62-.96), and FAR of .21/24 h (interquartile range [IQR] = 0-.90). Testing the algorithm on patients without seizure resulted in an FAR of .28/24 h (IQR = 0-.61). During the "fixed-and-frozen" prospective testing, two patients had three GCS, which were detected by the algorithm, while generating an FAR of .25/24 h (IQR = 0-.89). Feature importance showed that heart rate-based features outperformed accelerometer/gyroscope-based features., Significance: Commercially available wearable digital watches that reliably detect GCS, with minimum false alarm rates, may overcome usage adoption and other limitations of custom-built devices. Contingent on the outcomes of a prospective phase 3 study, such devices have the potential to provide non-EEG-based seizure surveillance and forecasting in the clinical setting., (© 2024 International League Against Epilepsy.)

Objective: Focal seizure symptoms (FSS) and focal interictal epileptiform discharges (IEDs) are common in patients with idiopathic generalized epilepsies (IGEs), but dedicated studies systematically quantifying them both are lacking. We used automatic IED detection and localization algorithms and correlated these EEG findings with clinical FSS for the first time in IGE patients., Methods: 32 patients with IGEs undergoing long-term video EEG monitoring were systematically analyzed regarding focal vs. generalized IEDs using automatic IED detection and localization algorithms. Quantitative EEG findings were correlated with FSS., Results: We observed FSS in 75% of patients, without significant differences between IGE subgroups. Mostly varying/shifting lateralizations of FSS across successive recorded seizures were seen. We detected a total of 81,949 IEDs, whereof 19,513 IEDs were focal (23.8%). Focal IEDs occurred in all patients (median 13% focal IEDs per patient, range 1.1 - 51.1%). Focal IED lateralization and localization predominance had no significant effect on FSS., Conclusions: All included patients with IGE showed focal IEDs and three-quarter had focal seizure symptoms irrespective of the specific IGE subgroup. Focal IED localization had no significant effect on lateralization and localization of FSS., Significance: Our findings may facilitate diagnostic and treatment decisions in patients with suspected IGE and focal signs., (Copyright © 2024 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Epilepsy affects over 50 million people globally. Electroencephalography is critical for epilepsy diagnosis, but manual seizure classification is time-consuming and requires extensive expertise. This paper presents an automated multi-class seizure classification model using EEG signals from the Temple University Hospital Seizure Corpus ver. 1.5.2. 11 features including time-based correlation, time-based eigenvalues, power spectral density, frequency-based correlation, frequency-based eigenvalues, sample entropy, spectral entropy, logarithmic sum, standard deviation, absolute mean, and ratio of Daubechies D4 wavelet transformed coefficients were extracted from 10-second sliding windows across channels. The model combines multi-head self-attention mechanism with a deep convolutional neural network (CNN) to classify seven subtypes of generalized and focal epileptic seizures. The model achieved 0.921 weighted accuracy and 0.902 weighted F1 score in classifying focal onset non-motor, generalized onset non-motor, simple partial, complex partial, absence, tonic, and tonic-clonic seizures. In comparison, a CNN model without multi-head attention achieved 0.767 weighted accuracy. Ablation studies were conducted to validate the importance of transformer encoders and attention. The promising classification results demonstrate the potential of deep learning for handling EEG complexity and improving epilepsy diagnosis. This seizure classification model could enable timely interventions when translated into clinical practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Déjà vu (DV), a French term meaning "already seen," refers to inappropriate sensation of familiarity in the present moment, as if it had been experienced before without a specific recollection of when or where. Traditionally, DV has been closely associated with focal seizures originating from the medial temporal lobe. However, there are occasional reports of DV occurring in idiopathic generalized epilepsies (IGEs). The objective of our study was to assess the presence and frequency of DV in individuals with IGE., Methods: We used the Preferred Reporting Items for Systematic Review and Meta-Analysis for protocols (PRISMA-P) and searched PubMed and Embase from January 2000 to July 2022., Results: 5 studies were included with a total of 1177 IGE and 1026 with temporal lobe epilepsy (TLE) patients. The frequency of DV in IGE ranged from 0 to 11 %, and the average was 3 %, compared to 19.6 % in TLE. Broadly, 40 % of patients with IGE reported some type of aura. EEG correlation of DV in IGE was not appropriately evaluated in the studies., Conclusion: Clinicians should be aware that individuals with IGE may experience DV and other types of auras. Recognizing these auras is crucial in order to avoid misdiagnosing IGE as focal epilepsy. This is important to prevent unnecessary investigations and incorrect treatment decisions., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Epilepsy with eyelid myoclonia (EM) or Jeavons syndrome (JS) is an epileptic syndrome related to the spectrum of genetic generalized epilepsies (GGE). We report two untreated children on which EEGs were performed several hours after a generalized tonic-clonic seizure (GTCS). These showed a unilateral, nearly continuous posterior slowing. This slow-wave activity was associated with contralateral epileptiform activity in one case, while in the second case, it was associated with an ipsilateral activity. However, in the latter child, a few months later an independent focus on the contralateral side was observed. A diagnosis of focal occipital lobe epilepsy was proposed in both cases, and one child underwent a left occipital lobectomy at 3.5 years of age. Despite surgery, absences with EM persisted in this child, and a marked photosensitivity to photic stimulation was observed two years later. The focal slow wave activity of one occipital lobe several hours after a GTCS in these two subjects was in favor of a focal onset preceding the generalization. The EEG evidence for independent left and right posterior focus in these two cases, the persistence of EM, and the development of a marked photosensitivity to photic stimulation in the child who underwent an occipital lobectomy, allow us to suggest that JS is associated with a network of bi-occipital hyperexcitability that rapidly engages bilaterally to produce generalized seizures., Competing Interests: Declaration of competing interest Dr. Gelisse received support for teaching programs from Sanofi, UCB, EISAI and Psicofarma. He received a research grant from Janssen-Cilag. He worked as a consultant for Eisai-France in 2011. Dr. Crespel received support for teaching programs from Sanofi, UCB, GSK, Shire and is an advisory board member for Eisai-France. Dr. Genton received speaker invitations and honoraria from Sanofi-Aventis, Novartis, GSK, Pfizer, Janssen-Cilag, UCB, Eisai, and Actelion. He received support for teaching programs from Sanofi-Aventis and UCB. Dr Nilo received support as a consultant from Eisai-Italy. Dr. Gallegos, Dr Macorig report no conflicts of interest. All co-authors have been substantially involved in the study and preparation of the manuscript. No undisclosed persons have had a primary role in the study or manuscript preparation. All co-authors have approved the submitted version of the paper and accept responsibility for its content., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Objective: Epilepsy with generalized tonic-clonic seizures alone (GTCA) is the least studied syndrome within the idiopathic generalized epilepsy (IGE) spectrum. We characterize a large cohort of adult patients with GTCA to understand natural history and drug responsiveness., Methods: In this retrospective single-center study using our epilepsy electronic record, we evaluated clinical characteristics, seizure outcomes, anti-seizure medication (ASM) response including seizure recurrence after ASM withdrawal, and sex differences in a cohort of GTCA patients aged ≥17 years., Results: Within a cohort of 434 IGE patients, 87 patients (20 %) with GTCA were included. The mean age was 34.9 years (range 17-73 years). Forty-six patients (52.8 %) were females. Seventy-two patients (82.8 %) were seizure-free and 15 (17.2 %) had active epilepsy over the previous 12 months. Thirty-four patients (39.1 %) had ≤5 lifetime seizures, aligning with a prior definition of 'oligoepilepsy'. Sixty-five patients (74.7 %) were treated with monotherapy, 19 (21.8 %) were treated with polytherapy, and three were not taking any ASM. Levetiracetam (37.9 %) was the most commonly prescribed ASM, followed by lamotrigine (32.1 %) and valproate (31 %). Seventeen patients (19.5 %) attempted to withdraw their ASM. The rate of seizure recurrence after ASM withdrawal was 88.2 % (15/17), including two patients who relapsed more than 20 years after ASM discontinuation. Females had more seizures in their lifetime and had trialed more ASM compared to males., Significance: GTCA has a relatively good prognosis, with most patients becoming seizure-free on monotherapy. The high rate of seizure recurrence after ASM withdrawal supports lifetime seizure susceptibility. We found potential sex differences in seizure outcomes and ASM response, although further research is needed to validate this finding., Competing Interests: Conflict of Interest JPC served as a speaker and received travel expenses from Angelini Pharma. PBM served on an advisory board for Angelini Pharma and received travel expenses from UCB Pharma. RDK and HEN reported no conflicts of interest. Over the last three years, PWW has served as a speaker for Angelini Pharma and Jazz Pharmaceuticals, and ND has served as a paid advisor and/or speaker for Angelini Pharma, Eisai, Radius Pharma, and UNEEG Medical., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The 2017 International League Against Epilepsy (ILAE) classification suggested that the term "genetic generalized epilepsies" (GGEs) should be used for the broad group of epilepsies with so-called "generalized" seizure types and "generalized" spike-wave activity on EEG, based on a presumed genetic etiology. Within this framework, idiopathic generalized epilepsies (IGEs) are described as a subset of GGEs and include only four epileptic syndromes: childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and epilepsy with generalized tonic-clonic seizures alone. The recent 2022 ILAE definition of IGEs is based on the current state of knowledge and reflects a community consensus and is designed to evolve as knowledge advances. The term "frontiers of IGEs" refers to the actual limits of our understanding of these four syndromes. Indeed, among patients presenting with a syndrome compatible with the 2022 definition of IGEs, we still observe a significant proportion of patients presenting with specific clinical features, refractory seizures, or drug-resistant epilepsies. This leads to the discussion of the boundaries of IGEs and GGEs, or what is accepted within a clinical spectrum of a definite IGE. Here, we discuss several entities that have been described in the literature for many years and that may either constitute rare features of IGEs or a distinct differential diagnosis. Their recognition by clinicians may allow a more individualized approach and improve the management of patients presenting with such entities., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Objective: The long-term prognosis of photosensitive idiopathic generalized epilepsy (p-IGE) is generally considered favorable; however, its specific characteristics remain unclear. Our objective was to investigate the extended prognosis of p-IGE., Methods: We analyzed the demographics, clinical, and electroencephalographic (EEG) data of consecutive patients who were diagnosed as having p-IGE, who were under follow-up for a minimum of 10 years and exhibited a photoparoxysmal response (PPR) in their EEGs. Prognostic data, epilepsy course types, and electroclinical variables were compared using appropriate statistical methods., Results: The mean follow-up duration for 108 consecutive patients with p-IGE (74.1 % female) was 16.8 ± 6.5 years. The main syndromes within this cohort included juvenile myoclonic epilepsy (37 %), juvenile absence epilepsy (15.7 %), and epilepsy with eyelid myoclonia (EEM) (14.8 %). In terms of epilepsy course types, 27.8 % were in the relapse-remission group, and 13.9 % had never experienced remission. A low early remission rate (5.6 %) was evident, with the remaining half of the cohort categorized as the late remission group. Several significant poor prognostic factors were identified including self-induction, clinical symptoms accompanying PPR, asynchrony and focal findings in EEG discharges, a wide frequency range of PPR, the coexistence of three seizure types, the presence of accompanying focal seizure features, and a history of convulsive status epilepticus., Conclusions: Our long-term follow-up study, conducted within a substantial p-IGE group, unveiled newly proposed course types within this epilepsy category and highlighted significant poor prognostic factors related to photosensitivity. These findings furnish valuable insights for precise prognosis counselling and effective management strategies for patients with p-IGE., Competing Interests: Declaration of competing interest None of the other authors have any conflict of interest to disclose., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Objective: To prospectively investigate the course of epilepsy and assess seizure control during pregnancy in women with focal epilepsy (FE) compared with generalized epilepsy (GE), to ascertain the effects of epilepsy and its types on delivery and neonatal outcomes, and to compare adverse outcomes between pregnancies complicated by epilepsy and normal pregnancies., Methods: 124 pregnant women with epilepsy (WWE) were enrolled in a prospective study. Obstetric and neonatal outcomes were compared with those of 277 healthy women in the control group., Results: Occurrence of seizures during pregnancy was more often in FE (77.1 %) compared with GE (50.0 %) (Odds ratio [OR] 2.08; 95 % confidence interval [CI] 0.97-4.46, p = 0.06); the overall seizure freedom was significantly higher in women with GE compared with women with FE (p = 0.0038). Poor seizure control one year prior to the pregnancy and nonadherence to treatment were significantly associated with presence of seizures during pregnancy (p < 0.0001). Compared with pregnancies of women without epilepsy, WWE were at increased risk of cesarean section (CS) (p < 0.0001) and preterm birth (p = 0.03). Offspring of mothers with epilepsy were at higher risks of Apgar scores at 5 min ≤7 (p < 0.0001) and perinatal hypoxia (p = 0.03) compared with infants of unaffected women. Seizures during pregnancy were significantly correlated with the higher rate of CS, Apgar scores at 5 min ≤7, and perinatal hypoxia (p = 0.0069; p = 0.0098; and p = 0.0045, respectively). The risks of adverse outcomes were not significantly increased in women with FE compared to women with GE., Conclusion: Epileptic seizures in pregnancy are associated with increased risks of adverse delivery and neonatal outcomes. Hence, early assessment of seizure disorder, adequate seizure control prior to and during pregnancy, and effective treatment are required to prevent potential seizure-related complications and improve maternal and fetal outcomes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have seemed to influence the work reported in this paper., (Copyright © 2024 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Vagus nerve stimulation (VNS) at low frequencies (≤30 Hz) has been an established treatment for drug-resistant epilepsy (DRE) for over 25 years., Objective: To examine the initial safety and efficacy performance of an investigational, high-frequency (≥250 Hz) VNS paradigm herein called "Microburst VNS" (μVNS). μVNS consists of short, high-frequency bursts of electrical pulses believed to preferentially modulate certain brain regions., Methods: Thirty-three (33) participants were enrolled into an exploratory feasibility study, 21 with focal-onset seizures and 12 with generalized-onset seizures. Participants were titrated to a personalized target dose of μVNS using an investigational fMRI protocol. Participants were then followed for up to 12 months, with visits every 3 months, and monitored for side-effects at all time points. This study was registered as NCT03446664 on February 27th, 2018., Results: The device was well-tolerated. Reported adverse events were consistent with typical low frequency VNS outcomes and tended to diminish in severity over time, including dysphonia, cough, dyspnea, and implant site pain. After 12 months of μVNS, the mean seizure frequency reduction for all seizures was 61.3% (median reduction: 70.4%; 90% CI of median: 48.9%-83.3%). The 12-month responder rate (≥50% reduction) was 63.3% (90% CI: 46.7%-77.9%) and the super-responder rate (≥80% reduction) was 40% (90% CI: 25.0%-56.6%). Participants with focal-onset seizures appeared to benefit similarly to participants with generalized-onset seizures (mean reduction in seizures at 12 months: 62.6% focal [n = 19], versus 59.0% generalized [n = 11])., Conclusion: Overall, μVNS appears to be safe and potentially a promising therapeutic alternative to traditional VNS. It merits further investigation in randomized controlled trials which will help determine the impact of investigational variables and which patients are most suitable for this novel therapy., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CD, PA, LK, and The Microburst Study Group were investigators for the Microburst Feasibility Study, and they or their institutions received funding from LivaNova PLC or its subsidiaries to conduct the research. JS received compensation from LivaNova USA Inc to design the fMRI titration protocol for the study. RV, AK, MJ, and KN are employees of LivaNova USA Inc and hold stock or stock options with the company. No authors were compensated for time spent writing this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The postictal state after bilateral tonic-clonic seizures is often prolonged and can have significant impact on a patient's quality of life. Considerable variability exists in the magnitude of postictal agitation and in the speed of recovery, the determinants of which are not well understood. We studied postictal behavior after tonic-clonic seizures in various epilepsy localizations, focusing on postictal agitation and time to responsiveness., Methods: We retrospectively identified 15 adult patients each with idiopathic generalized, left temporal lobe, right temporal lobe and frontal lobe epilepsy. Localization in focal epilepsy was validated by good outcome after resective surgery at one-year of follow-up. The first tonic-clonic seizure with reliable video and EEG for each patient was analyzed by two reviewers, one of whom was blinded to clinical data. Clinical, ictal and postictal variables were collected for each patient and analyzed. Postictal agitation was classified as mild and marked., Results: We reviewed 60 tonic-clonic seizures, 15 in each of four patient groups. Postictal agitation was observed in 14 patients (23.3%; marked in one and mild in 13). Postictal agitation was most common in patients with left temporal (seven patients) and least common in idiopathic generalized epilepsy (one patient) groups (p=0.035). Based on subgroup analysis (n=28), time to responsiveness was 6.6 minutes for frontal, 7.2 minutes for generalized, 10 minutes for right temporal and 15.7 minutes for the left temporal groups (p<0.05 for frontal vs. left temporal, generalized vs. left temporal). Time to responsiveness was longer in patients with agitation than without (13.9 minutes vs. 7.7 minutes; p=0.048). Patient ictal and postictal characteristics demonstrated no relationship to agitation or latency to postictal recovery., Significance: To mitigate harm, patients must be monitored carefully after tonic-clonic seizures, especially patients with left temporal lobe epilepsy. Studies evaluating medical and behavioral interventions to promote postictal recovery are needed.

Objective: In epilepsy patients, Transcranial Magnetic Stimulation (TMS) may result in the induction and modulation of epileptiform discharges (EDs). We hereby investigate the modulatory effects of TMS on brain connectivity in Genetic Generalized Epilepsy (GGE) and explore their potential as a diagnostic biomarker in GGE., Methods: Patients with GGE (n=18) and healthy controls (n=11) were investigated with a paired-pulse TMS-EEG protocol. The brain network was studied at local and at global levels using Coherence as an EEG connectivity measure. Comparison of patients vs controls was performed in a time-resolved manner by analyzing comparatively pre- vs post-TMS brain networks., Results: There was statistically significant TMS-induced modulation of connectivity at specific frequency bands within groups and difference in TMS-induced modulation between the two groups. The most significant difference between patients and controls related to connectivity modulation in the γ band at 1-3 sec post-TMS (p=0.004)., Conclusions: TMS modulates the healthy and epileptic brain connectivity in different ways. Our results indicate that TMS-EEG connectivity analysis can be a basis for a diagnostic biomarker of GGE., Significance: The analysis identifies specific time periods and frequency bands of interest of TMS-induced connectivity modulation and elucidates the effect of TMS on the healthy and epileptic brain connectivity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

It is well established that abnormal thalamocortical systems play an important role in the generation and maintenance of primary generalised seizures. However, it is currently unknown which thalamic nuclei and how nuclear-specific thalamocortical functional connectivity are differentially impacted in patients with medically refractory and non-refractory idiopathic generalised epilepsy (IGE). In the present study, we performed structural and resting-state functional magnetic resonance imaging (MRI) in patients with refractory and non-refractory IGE, segmented the thalamus into constituent nuclear regions using a probabilistic MRI segmentation method and determined thalamocortical functional connectivity using seed-to-voxel connectivity analyses. We report significant volume reduction of the left and right anterior thalamic nuclei only in patients with refractory IGE. Compared to healthy controls, patients with refractory and non-refractory IGE had significant alterations of functional connectivity between the centromedian nucleus and cortex, but only patients with refractory IGE had altered cortical connectivity with the ventral lateral nuclear group. Patients with refractory IGE had significantly increased functional connectivity between the left and right ventral lateral posterior nuclei and cortical regions compared to patients with non-refractory IGE. Cortical effects were predominantly located in the frontal lobe. Atrophy of the anterior thalamic nuclei and resting-state functional hyperconnectivity between ventral lateral nuclei and cerebral cortex may be imaging markers of pharmacoresistance in patients with IGE. These structural and functional abnormalities fit well with the known importance of thalamocortical systems in the generation and maintenance of primary generalised seizures, and the increasing recognition of the importance of limbic pathways in IGE., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Introduction : typical absences (TAs), are brief, generalized epileptic seizures of abrupt onset and termination clinically manifesting with impairment of awareness and associated with 3 Hz spike-wave discharges on EEG. TAs may occur in different idiopathic generalized epilepsies (IGE). Despite treatment with adequate anti-seizure medications (ASMs), TAs may persist in ~25% of subjects. This narrative review focuses on the therapeutic approach to difficult-to-treat TAs occurring in the setting of IGE. Areas covered : a literature search was conducted on the topic of treatment of TAs. Expert opinion : ethosuximide (ESX), valproic acid (VPA) and lamotrigine (LTG), alone or in combination, are considered the first-choice drugs. In women of childbearing potential, VPA should be avoided. Alternative therapies (benzodiazepines, levetiracetam, topiramate, or zonisamide) should be considered in subjects unresponsive to monotherapy after the exclusion of pseudo-drug resistance. Newer ASMs such as brivaracetam and perampanel seem to be promising options. Well-conducted clinical trials aimed to evaluate the efficacy of alternative monotherapy (beyond ESX, VPA or LTG) or combination of ASMs on difficult-to-treat TAs, are warranted.

The purpose of this review is to provide a comprehensive update and highlight the distinct electroclinical features and discuss recent advances in the etiology, pathophysiology, and management strategies of epilepsy with eyelid myoclonia. Recent studies indicate that variations of certain genes including CHD2 (chromodomain helicase DNA-binding protein 2), KCNB1, KIAA2022, and NAA10 may occur in these patients. It has been postulated that the occipital cortex may play a role in the pathophysiology. Recent studies of functional imaging and connectivity of neuronal electrical activity have provided additional evidence to support this hypothesis. The frontal cortex has additionally been implicated, and it has been suggested that the epileptic cortex may extend beyond the occipital cortex to involve the posterior temporal cortex. We update the management strategies and describe tools that may predict seizure persistence. Epilepsy with eyelid myoclonias, or Jeavons syndrome, is an idiopathic generalized epilepsy characterized by the triad of eyelid myoclonia with or without absence seizures, eyelid closure-elicited electroencephalographic (EEG) paroxysms (epileptiform discharges and/or seizures), and photosensitivity. This condition may account for up to 13% of generalized epilepsies. However, it is frequently under-reported and under-recognized. Many of the patients develop medically refractory epilepsy, and seizures tend to persist throughout life., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The aberrant thalamocortical pathways of epilepsy have been detected recently, while its underlying effects on epilepsy are still not well understood. Exploring pathoglytic changes in two important thalamocortical pathways, that is, the basal ganglia (BG)-thalamocortical and the cerebellum-thalamocortical pathways, in people with idiopathic generalized epilepsy (IGE), could deepen our understanding on the pathological mechanism of this disease. These two pathways were reconstructed and investigated in this study by combining diffusion and functional MRI. Both pathways showed connectivity changes with the perception and cognition systems in patients. Consistent functional connectivity (FC) changes were observed mainly in perception regions, revealing the aberrant integration of sensorimotor and visual information in IGE. The pathway-specific FC alterations in high-order regions give neuroimaging evidence of the neural mechanisms of cognitive impairment and epileptic activities in IGE. Abnormal functional and structural integration of cerebellum, basal ganglia and thalamus could result in an imbalance of inhibition and excitability in brain systems of IGE. This study located the regulated cortical regions of BG and cerebellum which been affected in IGE, established possible links between the neuroimaging findings and epileptic symptoms, and enriched the understanding of the regulatory effects of BG and cerebellum on epilepsy., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: To assess whether neuronal signals in patients with genetic generalized epilepsy (GGE) are heritable, we examined magnetoencephalography resting-state recordings in patients and their healthy siblings., Methods: In a prospective, cross-sectional design, we investigated source-reconstructed power and functional connectivity in patients, siblings, and controls. We analyzed 5 minutes of cleaned and awake data without epileptiform discharges in 6 frequency bands (1-40 Hz). We further calculated intraclass correlations to estimate heritability for the imaging patterns within families., Results: Compared with controls (n = 45), patients with GGE (n = 25) showed widespread increased functional connectivity (θ to γ frequency bands) and power (δ to γ frequency bands) across the spectrum. Siblings (n = 18) fell between the levels of patients and controls. Heritability of the imaging metrics was observed in regions where patients strongly differed from controls, mainly in β frequencies, but also for δ and θ power. Network connectivity in GGE was heritable in frontal, central, and inferior parietal brain areas and power in central, temporo-parietal, and subcortical structures. Presence of generalized spike-wave activity during recordings and medication were associated with the network patterns, whereas other clinical factors such as age at onset, disease duration, or seizure control were not., Conclusion: Metrics of brain oscillations are well suited to characterize GGE and likely relate to genetic factors rather than the active disease or treatment. High power and connectivity levels co-segregated in patients with GGE and healthy siblings, predominantly in the β band, representing an endophenotype of GGE., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: Paroxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations., Methods: Confounding factors, including the heterogeneous etiology of epilepsies and medication effects, hamper studies on background brain activity in people with epilepsy. To overcome this limitation, we compared genetic data from a genome-wide association study (GWAS) on epilepsy (n = 12 803 people with epilepsy and 24 218 controls) with that from a GWAS on background EEG (n = 8425 subjects without epilepsy), in which background EEG oscillation power was quantified in four different frequency bands: alpha, beta, delta, and theta. We replicated our findings in an independent epilepsy replication dataset (n = 4851 people with epilepsy and 20 428 controls). To assess the genetic overlap between these phenotypes, we performed genetic correlation analyses using linkage disequilibrium score regression, polygenic risk scores, and Mendelian randomization analyses., Results: Our analyses show strong genetic correlations of genetic generalized epilepsy (GGE) with background EEG oscillations, primarily in the beta frequency band. Furthermore, we show that subjects with higher beta and theta polygenic risk scores have a significantly higher risk of having generalized epilepsy. Mendelian randomization analyses suggest a causal effect of GGE genetic liability on beta oscillations., Significance: Our results point to shared biological mechanisms underlying background EEG oscillations and the susceptibility for GGE, opening avenues to investigate the clinical utility of background EEG oscillations in the diagnostic workup of epilepsy., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: Increased Motor Evoked Potential (MEP) polyphasia was recently described in idiopathic/genetic generalized epilepsy (IGE). Here, we studied the association of MEP polyphasia with treatment response and other clinical characteristics in patients with IGE., Methods: MEPs were recorded from the biceps brachii, flexor carpi radialis and interosseus dorsalis muscles bilaterally during tonic contraction in IGE patients (n = 72) and historical controls (n = 54) after single pulse transcranial magnetic stimulation. Detailed clinical data was available for all IGE patients; predefined endpoint was the association of MEP polyphasia with treatment response., Results: The mean number of phases was higher in the interosseus dorsalis muscle (2.33 vs. 2.13, p = 0.002) in IGE patients as compared to normal controls, as was the proportion of MEPs with more than two phases in at least one test (59.4% vs. 30%, p < 0.002). MEP polyphasia did not differ between IGE patients and controls in the biceps brachii or the flexor carpi radialis muscles and was not associated with treatment response. Extensive exploratory analyses unveiled fewer phases under valproic acid treatment (p = 0.04) but no additional associations of MEP polyphasia in the interosseous muscle with other clinical characteristics., Conclusion: MEP polyphasia is a subclinical symptom of IGE patients but is not associated with treatment response or other routinely assessed clinical characteristics., Significance: MEP polyphasia is a fixed feature of IGE not modified by clinical variables., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: The clinical features of epilepsy determine how it is defined, which in turn guides management. Therefore, consideration of the fundamental clinical entities that comprise an epilepsy is essential in the study of causes, trajectories, and treatment responses. The Human Phenotype Ontology (HPO) is used widely in clinical and research genetics for concise communication and modeling of clinical features, allowing extracted data to be harmonized using logical inference. We sought to redesign the HPO seizure subontology to improve its consistency with current epileptological concepts, supporting the use of large clinical data sets in high-throughput clinical and research genomics., Methods: We created a new HPO seizure subontology based on the 2017 International League Against Epilepsy (ILAE) Operational Classification of Seizure Types, and integrated concepts of status epilepticus, febrile, reflex, and neonatal seizures at different levels of detail. We compared the HPO seizure subontology prior to, and following, our revision, according to the information that could be inferred about the seizures of 791 individuals from three independent cohorts: 2 previously published and 150 newly recruited individuals. Each cohort's data were provided in a different format and harmonized using the two versions of the HPO., Results: The new seizure subontology increased the number of descriptive concepts for seizures 5-fold. The number of seizure descriptors that could be annotated to the cohort increased by 40% and the total amount of information about individuals' seizures increased by 38%. The most important qualitative difference was the relationship of focal to bilateral tonic-clonic seizure to generalized-onset and focal-onset seizures., Significance: We have generated a detailed contemporary conceptual map for harmonization of clinical seizure data, implemented in the official 2020-12-07 HPO release and freely available at hpo.jax.org. This will help to overcome the phenotypic bottleneck in genomics, facilitate reuse of valuable data, and ultimately improve diagnostics and precision treatment of the epilepsies., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Introduction: A considerable proportion of patients with genetic/idiopathic generalized epilepsy (IGE) suffer from persistent seizures. In this study, it was questioned if generalized polyspike trains (GPT) or prolonged epileptiform EEG runs allow identification of difficult-to-treat patients in a first seizure clinic setting or after recurrent seizures., Methods: The first routine outpatient EEGs from untreated patients (later diagnosed with IGE) and routine EEGs from IGE patients with persistent seizures despite medical treatment were analyzed. Seizure outcome and clinical characteristics were retrospectively assessed based on the patients' records., Results: In routine EEGs recorded after first seizure in untreated patients (n = 79), the prevalence of GPT (n = 1; 1.3%) and prolonged epileptiform EEG runs (n = 13; 16.5%) was low. At follow-up, 24 patients (30.4%) were not seizure free, and 3 (3.8%) of them developed drug-resistant IGE. None of the interictal discharges studied was associated with long-term seizure outcome. Treated IGE patients with recurrent seizures (n = 69) had a similar prevalence of GPT (n = 3; 4.3%) and prolonged epileptiform EEG runs (n = 7; 10.1%). At follow-up, 42 patients (60.8%) suffered persistent seizures, and 18 (26%) were drug resistant. Generalized polyspike train and prolonged epileptiform EEG runs had a higher prevalence in patients with drug-resistant epilepsy (GPT: 11.1% vs. 2%; P = 0.1; prolonged epileptiform EEG runs: 27.8% vs. 3.9%; P = 0.004) and persistent seizures (GPT: 7.1% vs. 0%; P = 0.16; prolonged epileptiform EEG runs: 16.7% vs. 0%; P = 0.03) as compared with nonresistant patients., Conclusions: Generalized polyspike train and prolonged epileptiform EEG runs were associated with persistent seizures and drug-resistant IGE, but the overall prevalence was low. In a first seizure clinic setting, the diagnostic value of these biomarkers was limited., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2019 by the American Clinical Neurophysiology Society.)

Genetic generalized epilepsy is a network disorder typically involving distributed areas identified by classical neuroanatomy. However, the finer topological relationships in terms of continuous spatial arrangement between these systems are still ambiguous. Connectome gradients provide the topological representations of human macroscale hierarchy in an abstract low-dimensional space by embedding the functional connectome into a set of axes. Leveraging connectome gradients, we systematically scrutinized abnormalities of functional connectome gradient in patients with genetic generalized epilepsy with tonic-clonic seizure (GGE-GTCS, n = 78) compared to healthy controls (HC, n = 85), and further examined the reproducibility across multiple processing configurations and in an independent validation sample (patients with GGE-GTCS, n = 28; HC, n = 31). Our findings demonstrated an extended principal gradient at different spatial scales, network-level and vertex-level, in patients with GGE-GTCS. We found consistent results across processing parameters and in validation sample. The extended principal gradient revealed the excessive functional segregation between unimodal and transmodal systems associated with duration of epilepsy and age at seizure onset in patients. Furthermore, the connectivity profile of regions with abnormal principal gradients verified the disrupted functional hierarchy revealed by gradients. Together, our findings provided a novel view of functional system hierarchy alterations, which facilitated a continuous spatial arrangement of macroscale networks, to increase our understanding of the functional connectome hierarchy in generalized epilepsy., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021. Published by Elsevier Inc.)

Objective: The study aim was to compare interictal encephalographic (EEG) functional network topology between people with well-controlled idiopathic generalized epilepsy (WC-IGE) and drug-resistant IGE (DR-IGE)., Methods: Nineteen participants with WC-IGE, 18 with DR-IGE, and 20 controls underwent a resting state, 64-channel EEG. An artifact-free epoch was bandpass filtered into the frequency range of high and low extended alpha. Weighted functional connectivity matrices were calculated. Mean degree, degree distribution variance, characteristic path length (L), clustering coefficient, small world index (SWI), and betweenness centrality were measured. A Kruskal-Wallis H-test assessed effects across groups. Where significant differences were found, Bonferroni-corrected Mann-Whitney pairwise comparisons were calculated., Results: In the low alpha band (6-9 Hz), there was a significant difference in L at the three-group level (p < .0001). This was lower in controls than both WC-IGE and DR-IGE (p < .0001 for both), with no difference in L between WC-IGE and DR-IGE. Mean degree (p = .031), degree distribution variance (p = .032), and SWI (p = .023) differed across the three groups in the high alpha band (10-12 Hz). Mean degree and degree distribution variance were lower in WC-IGE than controls (p = .029 for both), and SWI was higher in WC-IGE compared with controls (p = .038), with no differences in other pairwise comparisons., Significance: IGE network topology is more regular in the low alpha frequency band, potentially reflecting a more vulnerable structure. WC-IGE network topology is different from controls in the high alpha band. This may reflect drug-induced network changes that have stabilized the WC-IGE network by rendering it less likely to synchronize. These results are of potential importance in advancing the understanding of mechanisms of epilepsy drug resistance and as a possible basis for a biomarker of DR-IGE., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

This study aimed to analyse the effect of neuropsychological activation methods on interictal epileptiform discharges, compared to standard activation methods, for both focal and generalized epilepsies. This was a multicentre, prospective study including 429 consecutive EEG recordings of individuals with confirmed or suspected diagnosis of epilepsy. Neuropsychological activation included reading aloud in foreign and native language, praxis and a letter cancelation task (each with a duration of three minutes). After counting interictal discharges in three-minute time windows, activation and inhibition were assessed for each procedure, accounting for spontaneous fluctuations (95% CI) and compared to the baseline condition with eyes closed. Differences between generalized and focal epilepsies were explored. Interictal epileptiform discharges were present in 59.4% of the recordings. Activation was seen during hyperventilation in 31%, in at least one neuropsychological activation method in 15.4%), during intermittent photic simulation in 13.1% and in the resting condition with eyes open in 9.9%. The most frequent single cognitive task eliciting activation was praxis (10.3%). Lasting activation responses were found in 18-25%. Significant inhibition was found in 88/98 patients with baseline interictal epileptiform discharges, and was not task-specific. Adding a brief neuropsychological activation protocol to the standard EEG slightly increased its sensitivity in patients with either focal or generalized epilepsy. However, in unselected epilepsy patients, this effect seems only exceptionally to result in ultimate diagnostic gain, compared to standard procedures. From a diagnostic perspective, cognitive tasks should be reserved for patients with a suspicion of cognitive reflex epilepsy/seizures and probably require longer exposure times. Further research is needed to explore potential therapeutic applications of the observed inhibition of interictal epileptiform discharges by cognitive tasks in some patients.

Objective: To analyze the association between peri-ictal brainstem posturing semiologies with postictal generalized electroencephalographic suppression (PGES) and breathing dysfunction in generalized convulsive seizures (GCS)., Methods: In this prospective, multicenter analysis of GCS, ictal brainstem semiology was classified as (1) decerebration (bilateral symmetric tonic arm extension), (2) decortication (bilateral symmetric tonic arm flexion only), (3) hemi-decerebration (unilateral tonic arm extension with contralateral flexion) and (4) absence of ictal tonic phase. Postictal posturing was also assessed. Respiration was monitored with thoracoabdominal belts, video, and pulse oximetry., Results: Two hundred ninety-five seizures (180 patients) were analyzed. Ictal decerebration was observed in 122 of 295 (41.4%), decortication in 47 of 295 (15.9%), and hemi-decerebration in 28 of 295 (9.5%) seizures. Tonic phase was absent in 98 of 295 (33.2%) seizures. Postictal posturing occurred in 18 of 295 (6.1%) seizures. PGES risk increased with ictal decerebration (odds ratio [OR] 14.79, 95% confidence interval [CI] 6.18-35.39, p < 0.001), decortication (OR 11.26, 95% CI 2.96-42.93, p < 0.001), or hemi-decerebration (OR 48.56, 95% CI 6.07-388.78, p < 0.001). Ictal decerebration was associated with longer PGES ( p = 0.011). Postictal posturing was associated with postconvulsive central apnea (PCCA) ( p = 0.004), longer hypoxemia ( p < 0.001), and Spo 2 recovery ( p = 0.035)., Conclusions: Ictal brainstem semiology is associated with increased PGES risk. Ictal decerebration is associated with longer PGES. Postictal posturing is associated with a 6-fold increased risk of PCCA, longer hypoxemia, and Spo 2 recovery. Peri-ictal brainstem posturing may be a surrogate biomarker for GCS severity identifiable without in-hospital monitoring., Classification of Evidence: This study provides Class III evidence that peri-ictal brainstem posturing is associated with the GCS with more prolonged PGES and more severe breathing dysfunction., (© 2020 American Academy of Neurology.)

Epileptic encephalopathies (EE) are severe epilepsy syndromes characterized by multiple seizure types, developmental delay and even regression. This class of disorders are increasingly being identified as resulting from de novo genetic mutations including many identified mutations in the family of chromodomain helicase DNA binding (CHD) proteins. In particular, several de novo pathogenic mutations have been identified in the gene encoding chromodomain helicase DNA binding protein 2 (CHD2), a member of the sucrose nonfermenting (SNF-2) protein family of epigenetic regulators. These mutations in the CHD2 gene are causative of early onset epileptic encephalopathy, abnormal brain function, and intellectual disability. Our understanding of the mechanisms by which modification or loss of CHD2 cause this condition remains poorly understood. Here, we review what is known and still to be elucidated as regards the structure and function of CHD2 and how its dysregulation leads to a highly variable range of phenotypic presentations.

Epileptic activity in genetic generalized epilepsy (GGE) patients preferentially appears during sleep and its mechanism remains unknown. Here, we found that sleep-like slow-wave oscillations (0.5 Hz SWOs) potentiated excitatory and inhibitory synaptic currents in layer V cortical pyramidal neurons from wild-type (wt) mouse brain slices. In contrast, SWOs potentiated excitatory, but not inhibitory, currents in cortical neurons from a heterozygous (het) knock-in (KI) Gabrg2+Q/390X model of Dravet epilepsy syndrome. This created an imbalance between evoked excitatory and inhibitory currents to effectively prompt neuronal action potential firings. Similarly, physiologically similar up-/down-state induction (present during slow-wave sleep) in cortical neurons also potentiated excitatory synaptic currents within brain slices from wt and het KI mice. Moreover, this state-dependent potentiation of excitatory synaptic currents entailed some signaling pathways of homeostatic synaptic plasticity. Consequently, in het KI mice, in vivo SWO induction (using optogenetic methods) triggered generalized epileptic spike-wave discharges (SWDs), being accompanied by sudden immobility, facial myoclonus, and vibrissa twitching. In contrast, in wt littermates, SWO induction did not cause epileptic SWDs and motor behaviors. To our knowledge, this is the first mechanism to explain why epileptic SWDs preferentially happen during non rapid eye-movement sleep and quiet-wakefulness in human GGE patients., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The propagation of epileptic seizure activity in the brain is a widespread pathophysiology that, in principle, should yield to intervention techniques guided by mathematical models of neuronal ensemble dynamics. During a seizure, neural activity will deviate from its current dynamical regime to one in which there are significant signal fluctuations. In silico treatments of neural activity are an important tool for the understanding of how the healthy brain can maintain stability, as well as of how pathology can lead to seizures. The hope is that, contained within the mathematical foundations of such treatments, there lie potential strategies for mitigating instabilities, e.g. via external stimulation. Here, we demonstrate that the dynamic causal modelling neuronal state equation generalises to a Fokker-Planck formalism if one extends the framework to model the ways in which activity propagates along the structural connections of neural systems. Using the Jacobian of this generalised state equation, we show that an initially unstable system can be rendered stable via a reduction in diffusivity-i.e., by lowering the rate at which neuronal fluctuations disperse to neighbouring regions. We show, for neural systems prone to epileptic seizures, that such a reduction in diffusivity can be achieved via external stimulation. Specifically, we show that this stimulation should be applied in such a way as to temporarily mirror the activity profile of a pathological region in its functionally connected areas. This counter-intuitive method is intended to be used pre-emptively-i.e., in order to mitigate the effects of the seizure, or ideally even prevent it from occurring in the first place. We offer proof of principle using simulations based on functional neuroimaging data collected from patients with idiopathic generalised epilepsy, in which we successfully suppress pathological activity in a distinct sub-network prior to seizure onset. Our hope is that this technique can form the basis for future real-time monitoring and intervention devices that are capable of treating epilepsy in a non-invasive manner., Competing Interests: The authors have declared that no competing interests exist.

Objective: Autism spectrum disorder (ASD) is a neurodevelopmental disorder frequently associated with epilepsy and epilepsy is a leading cause of death in ASD patients. Despite growing interest in genetic, neurophysiological and clinical overlaps, data on ictal electroencephalographic (EEG) recordings in ASD are lacking since behavioral disorders often make it difficult to obtain EEG recordings. We examined ictal EEG features in a consecutive series of patients with ASD and epilepsy., Methods: We retrospectively identified 400 consecutive patients with ASD and epilepsy at our Level 4 Epilepsy center between 2015 and 2019; 45 had at least one EEG-recorded seizure captured. Demographics, age of nonfebrile seizure onset, age of ASD diagnosis, language, magnetic resonance imagining findings, genetic testing and EEG studies were reviewed. Seizures were classified by semiologic and electrographic features. Ictal findings were analyzed., Results: A total of 497 seizures were captured in 45 patients: 20 patients with focal onset epilepsy had 126 seizures (median: 1, range: 1-30), 17 patients with generalized onset epilepsy had 88 seizures (median: 2, range: 1-15), 7 patients with Lennox-Gastaut syndrome had 270 seizures (median: 12, range: 1-74) and one patient had both right hemisphere focal and generalized onsets (12 focal, 1 generalized)., Significance: Our study is the first to analyze a large set of ictal data in patients with autism spectrum disorder, a population traditionally difficult to obtain ictal recordings. Our results confirm the diverse spectrum of seizure types and provide clinical-EEG correlates of seizures in ASD patients. Both focal-onset and generalized-onset seizures were recorded, confirming that ASD patients have higher rates of both focal and generalized epilepsy syndromes. Among patients with focal epilepsy, temporal and frontal onsets were frequent, suggesting the possibility of epilepsy surgery or brain stimulation. EEG to classify seizures and epilepsies is critical to determine therapeutic options and effort should be made to obtain EEGs in this heterogenous population., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We present a rare patient clinically suspected to have mixed idiopathic generalized and focal epilepsy, which was supported by BOLD pattern based on EEG-fMRI. A 37-year-old female with three types of refractory seizures starting at age six - tonic with breathing difficulties and confusion, generalized tonic-clonic, and focal with brief impairment of awareness and versive head movement, initially thought to represent atypical absences - was evaluated by EEG-fMRI. She was also shown to have three types of interictal epileptic discharges: generalized spike or polyspikes and slow waves, and left fronto-temporal and right fronto-temporal discharges. We assessed BOLD activation and deactivation for each type. For generalized patterns, the BOLD activation and deactivation were typical of that seen in primary generalized epilepsy. Whereas maximum activation for left fronto-temporal EEG patterns was observed in the left superior frontal gyrus and posterior superior temporal gyrus, maximum activation for right fronto-temporal patterns was bilateral in the right posterior middle temporal gyrus and left posterior middle temporal gyrus. The EEG-fMRI results suggested that the patient had both refractory idiopathic generalized and focal epilepsy, and not a generalized epilepsy originating from a focus.