Alterations to brain structures and networks involved in central autonomic and respiratory control are possible biomarkers of SUDEP, but were mainly demonstrated in people at high risk. Postictal generalized EEG suppression (PGES) has been recorded in every case of near or confirmed SUDEP. The structural alterations underpinning PGES are not known.
This retrospective study included the brain MRIs of 100 patients with focal and generalized epilepsy who had experienced at least one generalized tonic-clonic seizure (GTCS) documented through long-term video-EEG monitoring, with PGES defined as postictal EEG activity below 10 microvolts lasting at least 20 s. Brain MRIs were parcellated into cortical and subcortical volumes, with further parcellation of thalamic subfields, and univariate and multivariate logistic regression models were applied to identify brain regions associated with PGES.
PGES was observed in 52 of 100 patients. Patients with PGES were older and had a slower heart rate before and after seizures compared to those without PGES. The tonic phase of GTCS was longer in patients with PGES. Univariate logistic regression analysis identified significant associations between PGES and six brain regions: the left and right lateral occipital cortices, left and right precuneus, and left and right thalamus. Multivariate analysis revealed that the right thalamus and both precuneus were independent predictors of PGES. Further analysis of thalamic subfields showed an increased volume of the ventral anterior nucleus of the right thalamus in patients with PGES.
Structural alterations in the right thalamus and precuneus are significantly associated with the presence of PGES in epilepsy patients.
Some people with epilepsy show a period of very low brain activity after a seizure, called PGES, which may be linked to a higher risk of sudden death. We analyzed brain scans from 100 people with epilepsy and found that two brain regions—the right thalamus and the precuneus—were different in those with PGES. These findings may help doctors understand which patients are more at risk after seizures and how to better protect them.
Status epilepticus (SE) consists of prolonged, self-sustaining seizures and is a common neurological emergency that causes respiratory compromise and neuronal injury. Without prompt treatment, the seizures can become resistant to benzodiazepines, leading to the progressive evolution of established, refractory, and super-refractory SE. Studies in experimental animals have found impaired GABAergic inhibition and potentiated glutamatergic neurotransmission in SE animals. These alterations increase the number of active neurons and expand the seizure network. Here, we first discuss the changes in GABA-A, NMDA, and AMPA receptor-mediated synaptic transmission during SE and elaborate on emerging studies showing the neuronal consumption of alternate energy sources to cope with increased energy demand. Then, we discuss the clinical studies that have tested the efficacy of various benzodiazepines and other anticonvulsant agents in treating SE in prehospital and in-hospital settings. Finally, we briefly summarize the ongoing clinical studies and the potential for other anticonvulsant agents to be tested for treating SE. PLAIN LANGUAGE SUMMARY: Most seizures are self-limiting, but some seizures change the brain such that a constant state of seizures, SE, is generated. These prolonged seizures can cause neuronal injury and increase the risk of death. We discuss the molecular mechanisms that sustain these seizures and the accompanying neuronal and network plasticity. We also review the current SE treatment and future directions.
Infantile epilepsy spasms syndrome (IESS), formerly known as infantile spasms or West Syndrome, is a severe epilepsy syndrome affecting about 3 in 10,000 newborns in the United States. Characterized by clusters of epileptic spasms, interictal hypsarrhythmia, and developmental delays, IESS has diverse causes, including structural-metabolic, genetic, infectious-immune, and unknown factors. FDA-approved therapies/medications, ACTH and vigabatrin, have limited efficacy and significant side effects, necessitating further research into better therapies. Our prenatal betamethasone-postnatal NMDA rat model provides valuable insights into IESS mechanisms and treatment responses. Mimicking human IESS in semiology, EEG patterns, and drug responsiveness, this model has been independently validated and adapted for infant mice. EEG recordings, crucial for validation and drug discovery, help assess treatment efficacy by tracking clinical spasms and the elimination of large amplitude irregular EEG waves occurring in clusters. Automated and manual EEG quantification enhance the model's precision. Proteomic analyses highlight significant differences in proteins like SNAP25 and creatine kinase between spasms and non-spasms groups. Imaging studies in the model reveal early activation of stress-responsive brain regions, consistent with epidemiological evidence linking prenatal stress to an increased risk of IESS in humans. ACTH and its analog, AQB-565, effectively suppress spasms, with AQB-565 potentially reducing corticosteroid-related side effects. The C5a receptor antagonist PMX53 shows efficacy in males, suggesting inflammation may be a therapeutic target. Neonatal β-estradiol increases GABAergic neurons but has limited impact on spasms and poses reproductive risks. These findings highlight the complexity of IESS and the need for targeted, sex-specific, and mechanism-based therapies to improve treatment outcomes for patients. PLAIN LANGUAGE SUMMARY: Infantile epilepsy spasms syndrome (IESS) is a severe epilepsy syndrome affecting 3 in 10 000 newborns in the United States, causing clusters of brief convulsions, abnormal brain activity, and developmental delays. It has various causes, including genetic and perinatal factors. Current medications, such as ACTH and vigabatrin, have limited effectiveness and side effects, highlighting the need for better options. We use a rodent model to study IESS and evaluate treatments. Some therapies, like AQB-565, show promise in reducing seizures with fewer side effects. Our findings suggest that personalized, targeted treatments based on individual causes and sex differences could improve outcomes.
Levetiracetam (LEV) has been widely used as an antiseizure medication (ASM), but is associated with psychiatric and behavioral adverse effects (PBAEs). Brivaracetam (BRV) has demonstrated better psychiatric tolerability, albeit at a higher cost. This study aimed to evaluate the cost-effectiveness of initiating BRV versus LEV therapy with a subsequent switch to BRV in the event of PBAEs across the US, Australia, and Japan.
We developed a decision tree model with a 10-year time horizon comparing two strategies across the US, Australia, and Japan: initial BRV therapy versus initial LEV therapy with a switch to BRV upon the occurrence of PBAEs. We utilized clinical trial data and regional cost estimates to conduct base-case and probabilistic sensitivity analyses.
The results of the base-case analyses indicated that initial BRV therapy was cost-effective only in Australia. The results of the sensitivity analyses revealed that the probability of initial BRV being cost-effective was 0% in the US, 49.6% in Japan, and 99.99% in Australia. In Japan, when the risk of LEV-induced PBAEs was assumed to be 24%, the probability that initial BRV therapy would be cost-effective rose to 70%, supporting the potential utility of an initial BRV strategy in high-risk populations. By contrast, in the US, the risk of PBAEs needed to exceed 76% to achieve a comparable cost-effectiveness probability.
While the initial BRV strategy consistently demonstrated cost-effectiveness in Australia, it failed to do so in Japan and the US. However, Japan presents a unique opportunity where BRV can be used cost-effectively when combined with pre-assessments of LEV-induced risk for PBAEs.
BRV causes fewer PBAEs than LEV, but costs more, creating a clinical dilemma. A cost-effectiveness analysis comparing BRV versus LEV as initial monotherapy with a focus on PBAEs was conducted across the US, Australia, and Japan. The results indicated that compared with LEV, BRV is cost-effective in Australia, but not in the US. In Japan, BRV is cost-effective as initial treatment only for patients at high risk for LEV-induced PBAEs.
This prospective study aims to characterize the spectrum of epilepsy syndromes among adult patients newly diagnosed with genetic generalized epilepsy (GGE). Additionally, it aims to examine their clinical characteristics, evaluate their response to treatment, and assess the feasibility of treatment discontinuation across each syndrome.
Patients identified for this study were recruited from a prospective multicenter study evaluating patients with new-onset unprovoked seizures enrolled between March 2010 and March 2020. Participants underwent a comprehensive evaluation including a 3-h sleep-deprived video-EEG recording and an epilepsy protocol brain MRI with repeat EEG at each follow-up. Included were patients 18 years and older and meeting criteria for GGE. Treatment responses, antiseizure medication (ASM) withdrawal success rates, and achievement of a two-year terminal seizure remission were assessed.
A total of 67 patients with a mean age at seizure onset of 21.9 years were included, constituting 16% of the entire GGE cohort. The most frequently diagnosed electroclinical syndrome was GTCA in 34 patients (50.7%), followed by JME in 21 patients (31.3%) and GGE not otherwise specified (GGE-NOS) in 12 patients (17.9%). Most patients responded well to monotherapy with valproate and levetiracetam as the most frequently prescribed ASMs. ASM tapering was attempted in 28 patients and was more frequently successful in patients with GTCA and GGE-NOS (60%) compared with JME (12.5%). A two-year terminal seizure freedom for all seizure types was achieved in 85.3% of patients with GTCA, 83.3% of those with GGE-NOS, and 23.8% of those with JME.
This study provides comprehensive insights into the epidemiology, clinical features, and treatment outcomes of adult-onset GGE. It emphasizes the necessity of considering GGE in adults with new-onset seizures, highlighting the efficacy of ASM therapies and suggesting that certain electroclinical syndromes may not mandate lifelong treatment, underscoring the pivotal role of accurate diagnosis.
This study evaluated adults experiencing their first seizures who were diagnosed with a type of epilepsy called genetic generalized epilepsy (GGE). We found that this condition can begin in adult
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