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Valproate is widely accepted as a drug of first choice for patients with generalised onset seizures, and its broad spectrum of efficacy means it is recommended for patients with seizures that are difficult to classify. Lamotrigine and topiramate are also thought to possess broad spectrum activity. The SANAD study aimed to compare the longer-term effects of these drugs in patients with generalised onset seizures or seizures that are difficult to classify. SANAD was an unblinded randomised controlled trial in hospital-based outpatient clinics in the UK. Arm B of the study recruited 716 patients for whom valproate was considered to be standard treatment. Patients were randomly assigned to valproate, lamotrigine, or topiramate between Jan 12, 1999, and Aug 31, 2004, and follow-up data were obtained up to Jan 13, 2006. Primary outcomes were time to treatment failure, and time to 1-year remission, and analysis was by both intention to treat and per protocol. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN38354748. For time to treatment failure, valproate was significantly better than topiramate (hazard ratio 1·57 [95% CI 1·19–2·08]), but there was no significant difference between valproate and lamotrigine (1·25 [0·94–1·68]). For patients with an idiopathic generalised epilepsy, valproate was significantly better than both lamotrigine (1·55 [1·07–2·24] and topiramate (1·89 [1·32–2·70]). For time to 12-month remission valproate was significantly better than lamotrigine overall (0·76 [0·62–0·94]), and for the subgroup with an idiopathic generalised epilepsy 0·68 (0·53–0·89). But there was no significant difference between valproate and topiramate in either the analysis overall or for the subgroup with an idiopathic generalised epilepsy. Valproate is better tolerated than topiramate and more efficacious than lamotrigine, and should remain the drug of first choice for many patients with generalised and unclassified epilepsies. However, because of known potential adverse effects of valproate during pregnancy, the benefits for seizure control in women of childbearing years should be considered.

We used simultaneous EEG and functional MRI (EEG–fMRI) to study generalized spike wave activity (GSW) in idiopathic and secondary generalized epilepsy (SGE). Recent studies have demonstrated thalamic and cortical fMRI signal changes in association with GSW in idiopathic generalized epilepsy (IGE). We report on a large cohort of patients that included both IGE and SGE, and give a functional interpretation of our findings. Forty-six patients with GSW were studied with EEG–fMRI; 30 with IGE and 16 with SGE. GSW-related BOLD signal changes were seen in 25 of 36 individual patients who had GSW during EEG–fMRI. This was seen in thalamus (60%) and symmetrically in frontal cortex (92%), parietal cortex (76%), and posterior cingulate cortex/precuneus (80%). Thalamic BOLD changes were predominantly positive and cortical changes predominantly negative. Group analysis showed a negative BOLD response in the cortex in the IGE group and to a lesser extent a positive response in thalamus. Thalamic activation was consistent with its known role in GSW, and its detection in individual cases with EEG–fMRI may in part be related to the number and duration of GSW epochs recorded. The spatial distribution of the cortical fMRI response to GSW in both IGE and SGE involved areas of association cortex that are most active during conscious rest. Reduction of activity in these regions during GSW is consistent with the clinical manifestation of absence seizures.

Idiopathic generalized epilepsy (IGE) is a brain network disease, but the location of this network and its relevance for treatment remain unclear. We combine the locations of brain abnormalities in IGE (131 coordinates from 21 studies) with the human connectome to identify an IGE network. We validate this network by showing alignment with structural brain abnormalities previously identified in IGE and brain areas activated by generalized epileptiform discharges in simultaneous electroencephalogram-functional magnetic resonance imaging. The topography of the IGE network aligns with brain networks involved in motor control and loss of consciousness consistent with generalized seizure semiology. To investigate therapeutic relevance, we analyze data from 21 patients with IGE treated with deep brain stimulation (DBS) for generalized seizures. Seizure frequency reduced a median 90% after DBS and stimulation sites intersect an IGE network peak in the centromedian nucleus of the thalamus. Together, this study helps unify prior findings in IGE and identify a brain network target that can be tested in clinical trials of brain stimulation to control generalized seizures. Ji et al. identify an idiopathic generalised epilepsy network that links heterogeneously distributed brain abnormalities to a common brain network and deep brain stimulation sites which reduce generalised seizures.

Epilepsy affects 65 million people worldwide, with 30% suffering from drug-resistant epilepsy. While surgical resection is the primary treatment, its application is limited in generalized epilepsy. Centromedian nucleus neurostimulation offers a promising alternative, yet its mechanisms remain unclear, limiting target optimization. We present a multimodal approach integrating intraoperative thalamic and sub-scalp electroencephalogram recordings with post-implant reconstructions to define neural targets affected by centromedian nucleus stimulation. We find that stimulating low-activity regions near the centromedian nucleus, particularly the white matter of internal medullary lamina, induces significant cortical delta power increases greater than stimulation within high-activity areas inside the nucleus. Implantation in these low-activity targets results in greater than 50% seizure reduction in all three subjects. These findings suggest that seizure control primarily involves stimulating white matter regions such as the internal medullary lamina rather than the centromedian nucleus itself. A personalized, electrophysiology-guided implantation approach may enhance neurostimulation efficacy in drug-resistant epilepsy. Centromedian nucleus neurostimulation targeting low-activity white matter of the internal medullary lamina shows immediate increase in cortical delta power associated with EEG slowing and decrease in epileptic activity.

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. 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.

Photoplethysmography (PPG) detects hemodynamic changes during epileptic seizures. This study aim to investigate PPG signals changes during generalized tonic‒clonic seizures (GTCSs) and focal impaired awareness seizures (FIASs). 17 GTCS and 19 FIAS episodes were recorded from 18 patients. The 30 min preictal period was divided into three 10-minute intervals. PPG features analyzed were pulse upslope (PUS), maximal compliance (Kmax), and skewness. Features across 3 preictal intervals showed significant reductions compared to the baseline: PUS ( F (3,64)   = 11.870 , p < 0.001 ), Kmax ( F (3,64)   = 7.419 , p < 0.001 ) and skewness ( F (3,64)   = 2.852 , p = 0.044 ) in the GTCS group. PUS ( Kruskal–Wallis [K-W] = 22.600 , p < 0.001) and Kmax ( K-W = 28.110 , p < 0.001 ) in the FIAS group. In the GTCS group, the largest difference was observed 30 min before seizure onset (PUS: p  < 0.001, Cohen’s d = 1.843; Kmas: p  < 0.001, Cohen’s d = 1.419; skewness: p  = 0.043, Cohen’s d = 0.808), whereas this was not the case in the FIAS group. PPG signals showed earlier changes in the GTCS group than in the FIAS group, highlighting their differences and the potential of PPG-based monitoring for early seizure detection.

This study investigated dynamic brain network changes and their genetic correlations in children with idiopathic generalized epilepsy (IGE). We included 26 children with IGE and 35 healthy controls, all participants underwent resting-state functional magnetic resonance imaging and cognitive assessments. Modular variability (MV) in time-varying networks was compared, and correlations with cognition and clinical variables were analyzed, we also explored classification problems using machine learning. Gene sets associated with IGE-related network remodeling were identified using the Allen Human Brain Atlas and gene enrichment analysis tools. The results showed that children with IGE exhibited reduced MV in sensorimotor and frontoparietal networks and increased MV in the default mode network (DMN). MV changes in the left prefrontal and right orbitofrontal cortices correlated with verbal and full-scale IQ scores, respectively. MV changes in the left precuneus/posterior cingulate cortex correlated with performance IQ scores. Transcriptomic analysis revealed 985 genes (FDR < 0.05) whose spatial expression patterns covaried with network alterations, prominently enriched for synaptic signaling and neuroactive ligand-receptor interactions, including GABA receptor subunits ( GABRE ) and neurodevelopmental regulators ( BCL11A ). Machine learning confirmed MV as a significant predictor of verbal IQ (permutation P  = 0.041), with DMN and frontoparietal regions contributing most to prediction. Dynamic brain network abnormalities in children with IGE were significantly associated with cognitive function and gene expression, providing new insights into the neural mechanisms underlying network dysfunction and cognitive impairment in epilepsy.

Background The effectiveness of adjunctive perampanel has not been systematically assessed in seizure types other than its approved indications of focal seizures and primary generalised tonic–clonic seizures (PGTCS) in idiopathic generalised epilepsies (IGEs). Objective We aimed to identify and review available evidence on outcomes with perampanel in generalised seizures and epilepsies to examine its potential as a broad-spectrum anti-seizure medication. Methods Bibliographic databases of publications, clinical trials, and conference abstracts were searched up to August 2020 to identify studies reporting seizure or safety outcomes in patients of any age, with any type of epilepsy-associated generalised seizures treated with perampanel. Data extracted from selected records were tabulated by seizure type and syndrome, and analysed qualitatively (PROSPERO protocol CRD42020201564). Results Ninety-one reports met inclusion criteria and were selected: 15 reports of 1 randomised controlled trial (RCT), 8 reports of 4 non-randomised interventional studies, 37 reports of observational studies, 21 case reports and 10 systematic reviews and meta-analyses. Extracted data included 359 patients with PGTCS of any aetiology, 251 with myoclonic seizures, 112 with absence seizures, 50 with tonic seizures and 32 children with epileptic spasms. The most commonly reported epilepsy type was IGE ( N  = 378) and the most common syndromes were juvenile myoclonic epilepsy ( N  = 92), progressive myoclonic epilepsies ( N  = 59) and absence epilepsies ( N  = 43). The RCT provided Class I evidence of the efficacy and tolerability of adjunctive perampanel for PGTCS in patients aged ≥ 12 years with IGE. Data from other studies provides weaker (observational) evidence of its effectiveness in multiple generalised seizure types, including myoclonic, absence and tonic seizures. There were no patterns suggesting seizure worsening or aggravation in any seizure or epilepsy type. Conclusions The identified studies suggest the potential of perampanel as a broad-spectrum antiseizure medication. Much of the available data, however, come from non-randomised, non-controlled studies and are open to high risk of bias. Further studies are warranted to provide more robust evidence.

Background Idiopathic generalized epilepsy (IGE) affects young individuals and is typically successfully managed with anti-seizure medications (ASMs). Discontinuing therapy in IGE patients is a critical decision due to the risk of seizure recurrence. This study aims to identify factors influencing seizure freedom (SF) or relapse after ASM discontinuation. Methods We retrospectively reviewed the medical records of patients seen at our clinic between 2002 and 2024. Collected data included demographics, disease history, seizure types, ASMs used, EEG findings, outcomes related to SF and ASM withdrawal. Results We identified 322 records, with a mean age of 30 ± 12.4 years and an age at onset of 16 ± 5.9 years. On average, patients tried 1.9 ASMs, 23% on polytherapy. The main seizure types were generalized tonic–clonic seizures (GTCS) in 53.1%, myoclonic seizures in 31.7%, absences in 15.2%. SF was achieved by 76.6%. Patients with GTCS as main seizure type or presenting with GTCS in the first year of disease experienced a delayed achievement of SF. ASM discontinuation was attempted in 64 patients. Predictors of relapse after discontinuation were myoclonic and generalized seizures as principal seizure type and higher seizure frequency. Early SF and lower seizure frequency were associated with successful discontinuation. EEG predictors of discontinuation failure included worsening during treatment tapering and specific abnormalities, such as spike waves, photosensitivity, and hyperpnoea sensitivity. Conclusions This study provides long-term follow-up data on IGE patients, highlighting key predictors of seizure control, including GTCS or myoclonic seizures and a rapid initial ASM response. EEG emerges as a valuable tool for the longitudinal monitoring of patients undergoing ASM discontinuation.

Background Genetic generalized epilepsy is characterized by transient episodes of spontaneous abnormal neural activity in anatomically distributed brain regions that ultimately propagate to wider areas. However, the connectome-based mechanisms shaping these abnormalities remain largely unknown. We aimed to investigate how the normative structural connectome constrains abnormal brain activity spread in genetic generalized epilepsy with generalized tonic–clonic seizure (GGE-GTCS). Methods Abnormal transient activity patterns between individuals with GGE-GTCS ( n  = 97) and healthy controls ( n  = 141) were estimated from the amplitude of low-frequency fluctuations measured by resting-state functional MRI. The normative structural connectome was derived from diffusion-weighted images acquired in an independent cohort of healthy adults ( n  = 326). Structural neighborhood analysis was applied to assess the degree of constraints between activity vulnerability and structural connectome. Dominance analysis was used to determine the potential molecular underpinnings of these constraints. Furthermore, a network-based diffusion model was utilized to simulate the spread of pathology and identify potential disease epicenters. Results Brain activity abnormalities among patients with GGE-GTCS were primarily located in the temporal, cingulate, prefrontal, and parietal cortices. The collective abnormality of structurally connected neighbors significantly predicted regional activity abnormality, indicating that white matter network architecture constrains aberrant activity patterns. Molecular fingerprints, particularly laminar differentiation and neurotransmitter receptor profiles, constituted key predictors of these connectome-constrained activity abnormalities. Network-based diffusion modeling effectively replicated transient pathological activity spreading patterns, identifying the limbic-temporal, dorsolateral prefrontal, and occipital cortices as putative disease epicenters. These results were robust across different clinical factors and individual patients. Conclusions Our findings suggest that the structural connectome shapes the spatial patterning of brain activity abnormalities, advancing our understanding of the network-level mechanisms underlying vulnerability to abnormal brain activity onset and propagation in GGE-GTCS.