Epilepsia最新文献

Brain development and subsequent brain function are highly sensitive to genetic mutations, which can result in severe neurodevelopmental malformations. Alterations in PTEN signaling cause a spectrum of developmental malformations and neurological diseases including epilepsy. To date, a detailed understanding of the neuropathological underpinnings of PTEN-associated brain malformations, particularly in fetuses, is missing. We have thus investigated a fetal case of hemimegalencephaly (HME), which is a rare disorder characterized by hemispheric overgrowth, developmental delay, and epileptic seizures. Our assessment of the male fetus includes genetic, radiologic, and histologic features and provides a comprehensive characterization of the cellular alterations in HME together with a genotypic correlation. Genetic analyses uncovered that hemispheric overgrowth was caused by a somatic second hit resulting in biallelic PTEN alteration in the affected brain tissue, although the unaffected hemisphere carried the same PTEN variant as the heterozygous germline variant. Based on the latter, we interpret that the PTEN mutation is not a dominant-negative variant. Within the outer subventricular zone of the enlarged cortex, we found small nodular heterotopias, which can be origins of focal epileptic seizures. Cell type-specific marker stainings revealed that the heterotopias consisted exclusively of SATB2⁺ glutamatergic projection neurons. Altogether, our analyses and findings contribute to a deeper understanding of the pathomechanisms of a novel PTEN variant driving a severe brain malformation.

Recurrent seizures, the hallmark of epilepsy, are influenced by rhythms operating over multiple timescales. Chronobiology is the study of biological timing that aims to explain temporal patterns of events like seizures. Fueled by recent advances in genetics, computational modeling, and device engineering, the chronobiology of epilepsy is now a burgeoning field poised to shed new light on mechanisms governing seizure recurrence. Although seizures were long believed to occur at random, epilepsy is now understood as a cyclical disorder, and time-varying therapeutic interventions are increasingly possible. Yet, potential barriers to progress in this field exist, such as reconciling variable experimental methodology, deconvolving coexisting rhythms, and harnessing the power of new technologies and data sharing. In this report from the International League Against Epilepsy Task Force on Chronobiology, we review these knowledge gaps and offer recommendations to help close them. By unraveling mechanisms of seizure timing, chronobiology promises to usher in a new era of personalized epilepsy management in which seizures are viewed as predictable, potentially avoidable events.

Objective: Heterozygous loss-of-function mutations in the CHD2 gene, encoding chromodomain helicase DNA-binding protein 2, are associated with severe childhood onset epilepsy, global developmental delay, and autistic features. Animal models that accurately recapitulate human phenotypes are crucial for understanding rare neurodevelopmental disorders and developing novel treatments. However, such a model for CHD2-related disorders has been missing.

Methods: We performed behavioral, electrographic, epileptic, and transcriptomic analyses to characterize a mouse model harboring a frameshift truncating mutation in the Chd2 gene (Chd2^WT/m and Chd2^m/m mice) on the 129X1/SvJ background.

Results: The genetic background altered the severity of disease-related phenotypes, such that crossing the mice from the C57BL/6J onto the 129X1/SvJ background uncovered neurodevelopmental phenotypes. On the 129X1/SvJ background, Chd2^m/m mice exhibited growth retardation, and both Chd2^WT/m and Chd2^m/m mice showed motor deficits, including clasping behavior and impaired balance on a rotating rod. Autistic like features included reduced nest-building abilities in Chd2^m/m mice, whereas increased repetitive like behavior in the marble-burying test and altered social behavior were observed in Chd2^WT/m mice. Electrocorticographic analysis revealed a global reduction in the power of background oscillations in both Chd2^WT/m and Chd2^m/m mice, along with increased susceptibility to 4-aminopyridine-induced seizures. Transcriptomic analysis identified upregulation of Kcnj11 mRNA in Chd2^WT/m and Chd2^m/m mice on the 129X1/SvJ background.

Significance: This mouse model recapitulates key phenotypes observed in CHD2 patients, providing a valuable platform to study the molecular basis and potential treatment strategies for this intractable disorder.

Objective: Antiseizure medications are approved based on clinical trials that demonstrate their efficacy as measured by reductions in seizure frequency (SF). When designing these trials, trialists must select inclusion criteria where SF can be reliably measured to maintain statistical power. Statistical power is based on the magnitude and uncertainty of the difference between active treatment and placebo. To inform choices about how minimum, maximum, and individual participant SF impacts the statistical power of trials, we evaluated how the uncertainty in SF was associated with average SF within multiple clinical trials.

Methods: Using data from 11 double-blind placebo-controlled trials of antiseizure medications for either focal or generalized onset epilepsy, we used log-log multivariable regression to associate the SD of SF in maintenance with the average SF in baseline and maintenance. We also evaluated whether capturing more seizures in people with high average SF offset the increased uncertainty in SF and asked whether these associations persisted when time to event designs were used.

Results: The uncertainty (SD) of maintenance SF was proportional to baseline average SF (daily diaries: slope of log-log association = .575, 95% confidence interval [CI] = .556-.593; fortnightly diaries: .657, 95% CI = .0642-.0671). Increased uncertainty for high SF was offset by counting more seizures. These relationships were maintained with a time to event design.

Significance: This study validates the foundational L-relationship between average and SD of SF in which the uncertainty of seizure counts increased proportional to the number of seizures counted. When used for efficacy outcomes of trials, the statistical benefit of counting more seizures in participants with high SF was much greater than the increased challenge from higher uncertainty seizure counts. These results provide quantitative insights for SF-based inclusion criteria and statistical power calculations.

High-titer glutamic acid decarboxylase 65 (GAD65) antibodies (>20 nmol/L) are linked to chronic focal epilepsy, usually of temporal regional onset. Identification of these antibodies has treatment and prognostic implications. We compared patients with drug-resistant epilepsy and high-titer GAD65 antibodies to an age- and sex-matched control group with drug-resistant GAD65 antibody-negative temporal lobe epilepsy. From 1432 patients presented at a single-center surgical epilepsy conference (2007-2024), we identified 15 patients (1% from surgical epilepsy conference: 13 female, 86.7%) with high-titer serum GAD65 antibodies (median serum titer = 960 nmol/L; range 34-4678). The median age at epilepsy onset was 25 years (range 4-44). All had temporal regional-onset epilepsy; 53% had bitemporal seizures. Three patients had limbic encephalitis, and three developed mesial temporal sclerosis. Those with GAD65 antibody-associated epilepsy were more likely to have depression and/or anxiety and less likely to undergo resection after evaluation than those in the control group. Although seizure types, electroencephalography (EEG), imaging, and autoimmune history were not statistically significantly different from the control group, we found that musicogenic seizures, limbic encephalitis, and type 1 diabetes occurred only in GAD65-positive patients. These features, when present, may suggest an autoimmune etiology and warrant antibody testing. Identifying patients with GAD65 antibody-associated epilepsy is important due to its drug resistance, lower rate of satisfactory surgical outcomes, and potential responsiveness to immunotherapy. Further research is needed to define the optimal treatment and distinguish this subgroup from other causes of drug-resistant epilepsy.

There is debate on the predictive value of multiday seizure cycles versus simple statistical baselines. Multidien seizure cyclicity is a prevalent, patient-specific phenomenon with promise for epilepsy management. We challenge the assertion that cycle tracking is no better than a moving average, which is an inherently retrospective model that lags changes in seizure likelihood. This commentary compared a causal cyclic forecast to a prospectively applied moving average across a large seizure diary cohort (n = 768) and two gold-standard chronic EEG cohorts (n = 24). For the EEG and diary cohorts, cycle tracking demonstrated significantly superior accuracy to the moving average for both hourly and daily forecasts (p < 0.0001), using multiple performance metrics. These results confirm that event-based cyclical models offer more accurate, simulated real-world forecasts. Robust forecasting tools must prioritize the detection and modeling of seizure cycles to move beyond simple baseline performance and provide actionable clinical utility.

Objective: To estimate the incidence and determine the consequences of status epilepticus (SE) associated with idiopathic generalized epilepsy (IGE) in adults.

Methods: Based on International Classification of Diseases, Tenth Revision (ICD-10) codes we extracted patients with IGE in the period from January 1, 2005 to December 31, 2018, and divided them into two groups: patients with and without a hospitalization with SE before the end of the study. Each patient was matched with 10 normal population controls from the Danish National Patient Register based on age, sex, and geography. Survival, drug resistance, medical history, and surrogate markers for social status were compared.

Results: We identified 6295 IGE patients and 62 950 normal population controls with slight female preponderance (3338 female; 55.5%). At least one admission with SE was documented for 4.5% (n = 283 patients), of which 57.2% (n = 162) had two or more admissions with SE. The comparison of patients with and without SE before first-time admission for SE showed higher age, surrogate markers for lower social status (affiliation with the labour market, household income, marital status), indicators of more severe IGE (number of antiseizure medications tried, prescription patterns suggestive for drug resistance), and higher psychiatric comorbidity in patients with SE than without. It is important to note that an episode of SE only transiently and slightly affected markers for social status. All-cause mortality was increased in IGE patients with SE (17.7%) as compared to 6.2% in age-matched population controls.

Significance: SE in IGE has a high rate of occurrence and is associated with drug-resistant IGE, poor social status, and psychiatric comorbidity already before the first episode of SE. Although the social impact of SE in the short term remains limited, all-cause mortality after SE is increased.

Objective: This study aimed to identify risk factors and develop a predictive scoring system for autoimmune-associated epilepsy in subjects with autoimmune encephalitis presenting with new onset refractory status epilepticus (NORSE).

Methods: This retrospective, multicenter, cohort study included subjects who presented with NORSE at the onset of autoimmune encephalitis and had at least 24 months of follow-up after immunotherapy. The outcome was the development of autoimmune-associated epilepsy, defined as persistent seizures despite adequate immunotherapy and absence of active inflammation. Factors independently associated with the outcome were identified through a backward stepwise selection. Adjusted regression coefficients of each independent predictor were transformed to produce a points-based risk-scoring system.

Results: Seventy participants were included (median age = 24.2 years, 38.6% male). During a median follow-up of 53 months, 54.3% of subjects developed autoimmune-associated epilepsy. Status epilepticus duration ≥ 10 days (odds ratio [OR] = 31.14, 95% confidence interval [CI] = 2.12-456.87, p = .012), positivity for antibodies against surface antigens (OR = .12, 95% CI = .02-.85, p = .034), bitemporal magnetic resonance imaging (MRI) abnormalities suggestive of autoimmune encephalitis during acute stage (OR = 49.80, 95% CI = 2.95-841.77, p = .007), and interictal epileptiform discharges during electroencephalographic (EEG) follow-up (OR = 71.32, 95% CI = 6.48-785.32, p < .001) were independently associated with the study outcome. The duration-antibodies-MRI-EEG (DAME) score was developed as an integer-based scoring system predictive of autoimmune-associated epilepsy. With an optimal cutoff of ≥3 points, it yielded a sensitivity of 86.8%, a specificity of 87.5%, and an overall accuracy of 87.1%.

Significance: The DAME score could serve as a user-friendly score to predict the risk of autoimmune-associated epilepsy in patients with NORSE due to autoimmune encephalitis.