Epilepsia最新文献

Objective: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature mortality in epilepsy. Genetic studies have identified that loss-of-function (LOF) KCNH2 variants are enriched in SUDEP patients, suggesting that they may act as a risk factor. KCNH2 encodes the K_V11.1 channel, with LOF pathogenic variants a cause of long-QT syndrome (LQTS), increasing the risk of arrhythmia and sudden cardiac death. Here, we engineered preclinical rodent models that combine epilepsy-causing pathogenic variants with heterozygous Kcnh2 knockout mice to explore the impact of reduced K_V11.1 channel function on mortality.

Methods: Both the Gabrg2^R43Q/+ and Hcn1^M294L/+ genetic mouse models of monogenic epilepsy were crossed with Kcnh2^+/- mice. All genotypes were video-recorded post-weaning and time to death was measured. Additional mice underwent surgery to enable simultaneous electrocorticography and electrocardiography recordings. Atenolol was delivered in drinking water to a subset of mice.

Results: Both single mutant Gabrg2^R43Q/+ and Hcn1^M294L/+ mice displayed spontaneous seizures recapitulating the human phenotypes. Single mutant Kcnh2^+/- mice exhibited an LQTS phenotype. Double mutant mice (Gabrg2^R43Q/+/Kcnh2^+/- and Hcn1^M294L/+/Kcnh2^+/-) had both seizure and prolonged QT interval phenotypes that were similar to their respective single mutant mice. Survival analysis revealed that Gabrg2^R43Q/+/Kcnh2^+/- and Hcn1^M294L/+/Kcnh2^+/- mice experienced a disproportionately higher rate of seizure-related death when compared to wild-type and their respective single mutant littermates. Oral administration of the cardiac-selective β-blocker atenolol significantly improved survival in Gabrg2^R43Q/+/Kcnh2^+/-, Hcn1^M294L/+, and Hcn1^M294L/+/Kcnh2^+/- mice. Atenolol attenuated the sympathetic cardiac response to non-terminal seizures.

Significance: The data support the premise that LOF KCNH2 variants can contribute to SUDEP risk in a subset of epilepsy patients. Our findings also highlight the potential use of β-blockers as a prevention strategy in SUDEP.

Juvenile myoclonic epilepsy (JME) is a common idiopathic generalized epilepsy often accompanied by executive dysfunction, affective symptoms, unfavorable behavior, and social outcomes, yet its impact on theory of mind (ToM) remains underexplored. We conducted an unmatched case-control study assessing 34 JME patients and 48 healthy controls, adjusted for age, sex, education, intelligence quotient, anxiety, and depression. Participants completed a brief version of the Faux Pas Recognition Test (FPRT) and the Reading the Mind in the Eyes Test, alongside measures of executive function, prospective memory, and mood. In raw analyses, JME patients showed significantly lower FPRT total scores (mean ± SD = 22.9 ± 9 vs. 27.5 ± 7, p = .01) and FPRT Understanding (.80 ± .11 vs. .87 ± .14, p = .02). After adjusting for cognitive and affective covariates via propensity scoring, group differences in ToM performance were no longer significant (p > .20). These results suggest that ToM deficits in JME are mediated by broader cognitive and affective disturbances rather than reflecting a social cognitive impairment. Future longitudinal studies with larger samples and tighter pharmacological control are warranted.

Objective: Conditions presenting with both epilepsy and movement disorders (EPIMDs) range from relatively benign cases to severe developmental encephalopathies. However, the full clinical and genetic spectrum still needs to be better defined. The aim of this study is to describe the presentation of EPIMDs in pediatric patients with known genetic etiologies, correlating these features with age at onset and underlying pathological mechanisms to identify patterns that could improve patient management.

Methods: We retrospectively analyzed the clinical records of pediatric patients who underwent genetic testing for EPIMDs at our institution between 2009 and 2022. Genetic testing included single-gene Sanger sequencing, multigene next-generation sequencing panels targeting epilepsy and/or MDs, and array comparative genome hybridization. Demographic, clinical, and electroencephalography (EEG) data were collected. Statistical analyses were conducted using multivariate and cluster analyses.

Results: A total of 97 subjects were included. The mean age ± SD at epilepsy onset was 3.6 ± 4.4 years, whereas the mean age at MD onset was 5.2 ± 4.9 years. Based on the mechanism of genetic dysfunction, we identified six groups: transportopathies (n = 18), synaptopathies (n = 11), channelopathies (n = 18), metabolic disorders (n = 15), intracellular trafficking defects (n = 8), and unknown/complex function disorders (n = 27). Cluster analysis identified three distinct groups: (1) early-onset epilepsy and paroxysmal MDs with normal intelligence quotient (IQ) and mild intellectual disability, associated with transportopathies (n = 38); (2) early-onset epilepsy with dystonia and myoclonus, low IQ, and developmental and epileptic encephalopathy, associated with channelopathies (n = 31); (3) epilepsy onset between 1 and 5 years of age with developmental delay, parkinsonism, and low IQ, associated with metabolic etiology (n = 26).

Significance: Our study demonstrates that, despite the phenotypic and genetic pleiotropy observed in EPIMDs, a precise characterization of semiological and cognitive features remains essential to support variant interpretation and to refine the diagnostic process and patient management in these rare conditions.

Objective: To characterize the clinical, electroencephalographic, and genetic features of epilepsies featuring absence seizures within monogenic etiology, highlighting the diagnostic, treatment and prognostic implications.

Methods: We conducted a retrospective, multicenter study including patients with monogenic epilepsies and electroencephalography (EEG)-documented absence seizures. We analyzed clinical data, electroclinical findings, neurodevelopmental outcomes, and treatment responses through standardized questionnaires and medical records. We classified genetic variants according to American College of Medical Genetics and Genomics (ACMG) guidelines and performed univariate and multivariate analyses to identify predictors of developmental outcomes.

Results: We included 160 patients (111 female; median age at last follow-up: 13 years) with absence seizures and confirmed pathogenic or likely pathogenic monogenic variants. The most frequently implicated genes were SLC2A1, SLC6A1, SYNGAP1, CHD2, and SCN1A. Four genes-HESX1, NCKAP1, SON, STARD9-had not been previously associated with absence seizures. In 35% of patients, absence seizures were the only seizure type and in 67% were the initial manifestation. Atypical features included irregular EEG discharges (56%) eyelid myoclonia (42%), and automatisms (33%). Early-onset (before age 3) seizures occurred in 58% and was significantly associated with atypical features (p < .03). Using existing International League Against Epilepsy (ILAE) epilepsy syndrome classification, 60% of patients could not be classified. Developmental delay occurred in 54%, intellectual disability in 65%, and other neurodevelopmental comorbidities in 49%. Predictors of poor developmental outcomes included early developmental delay, drug-resistant epilepsy, and early absence onset. We found no difference in the prevalence of drug resistance across the various genetic etiologies. The most effective medications for absence seizures included valproate, ethosuximide, benzodiazepines, and lamotrigine. Disease-specific therapies (e.g., ketogenic diet in SLC2A1, stiripentol/fenfluramine in SCN1A) were effective in select cases.

Significance: Absence seizures are a common manifestation of different monogenic epilepsies, often associated with early onset, atypical clinical and/or EEG features, developmental delay or drug resistance. Classification models should incorporate genetic data alongside electroclinical features, especially as next-generation sequencing is increasingly used.

Objective: Interictal epileptiform discharges (IEDs) in people with epilepsy (PWE) can impair cognitive functions and increase reaction time (RT) and the likelihood of missed reactions. These effects are not routinely assessed, because reliable methods for detecting IEDs of variable appearance in real time and suitable tests to measure IED effects do not yet exist. The objective was to assess different IED effects using new artificial intelligence and medical electronics.

Methods: The Digital Response Test in Epilepsy (DigRTEpi) consisted of a laptop and electronic circuits in a closed loop. Our model with Markov Transition Fields and a deep neural network (ResNet34) visualized the electroencephalogram (EEG) and classified the resulting images. IED detection triggered stimuli in a driving game or in a new cognitive assessment, the interictal Automated Responsiveness Test (iART). DigRTEpi was validated in a prospective case series with 20 people with focal and generalized epilepsies. During offline analysis, sensitivity, specificity, false-positive IED detection rate, latency of EEG classification, IED-induced RT prolongation, virtual crashes, and impaired responses to neuropsychological tasks were determined.

Results: The model detected IEDs with 84% sensitivity and 96% specificity in our training dataset. In the prospective study with 20 PWE, median sensitivity was 90% (95% confidence interval [CI] = .81-.95), and false-positive IED detection rate was 2.8 (95% CI 2.1-5.9). The ongoing EEG was classified window-by-window in a median 98.7 ms (95% CI = 98.0-99.4). Median RT prolongation and crash probability due to IEDs were 43.8 ms (95% CI = 20.3-64.7) and .9% (95% CI = 0-6.0) per person, respectively. Two patients (10%) had delays of >100 ms, found to be clinically relevant in our prior publication. IEDs caused four patients (20%) each to respond incorrectly or miss answers to neuropsychological tasks. The median false-positive IED detection rates were 2.8/min (95% CI = 2.1-5.9; driving game) and 2.1/min (95% CI = 1.5-3.2; iART).

Significance: By effectively detecting IEDs of variable morphology in real time, DigRTEpi assessed the severity of IED-associated transitory impairment of virtual driving and cognition to improve personalized care.

Objective: Genetic testing can be necessary in the early diagnosis or confirmation of Dravet syndrome (DS). Despite major advances in availability of genetic testing, several barriers to timely testing persist. These include clinician recognition of the disease in its early stages and health disparities. Early diagnosis of DS has a growing list of management implications, including antiseizure medication selection, appropriate counseling regarding prognosis, access to resources, and clinical trial access.

Methods: To understand the barriers to early genetic testing in DS, we performed a retrospective chart review of patients with DS due to SCN1A variants and analyzed factors hypothesized to affect time to testing. Factors including the initial clinical presentation and health disparities were correlated with length of time to testing from the first documented seizure.

Results: Factors significantly correlated with time to testing included absence of early status epilepticus and the need for an English-language interpreter. Interestingly, neither race/ethnicity nor a composite social deprivation index were significantly correlated with delays in genetic testing in our population.

Significance: We identified significant factors associated with delay to genetic testing in DS. Purposefully addressing these factors through education and resources will likely be important for continued improvement in early and equitable diagnosis for patients with DS.

This study was undertaken to systematically evaluate the efficacy of cell therapy in reducing seizures in animal models of chronic epilepsy. Three databases, Ovid MEDLINE, Ovid Embase, and Web of Science, were searched using predetermined eligibility criteria. The relevant preclinical controlled studies were included for review and meta-analysis using a random-effects model to calculate summary estimates of the effect size (percentage reduction in seizures). The degree of heterogeneity among the included studies was assessed using the I² statistic. Subgroup meta-analysis and meta-regression were performed to further elucidate the sources of heterogeneity. Thirty published studies met the eligibility criteria, including a total of 1306 animals. The majority of studies used kainic acid and pilocarpine status epilepticus models of mesial temporal lobe epilepsy (MTLE). The random effects model revealed an overall reduction in seizure frequency of 54.8% (95% confidence interval = 48.0558-61.5455) compared to the control, and the heterogeneity was 87.1% among the included studies. The meta-regression revealed that seven study characteristics significantly accounted for the between-study heterogeneity. They can be grouped into three broad categories: epilepsy-specific, animal-specific, and cell transplantation-specific. The greatest seizure reduction was observed in the post-kainic acid status epilepticus model of chronic MTLE, when the cells were delivered intravenously and when the seizure reduction was measured as seizure frequency. Embryonic stem cell transplantation showed the greatest efficacy in reducing seizures. Cell transplantation shows favorable efficacy as a treatment that can reduce seizure recurrence in chronic animal models of epilepsy. High heterogeneity between studies reflects the diverse methodologies employed in preclinical research on cell therapy for epilepsy. Despite these encouraging findings, the high risk of publication bias and variability in study design emphasize the need for further robust preclinical studies to confirm these reported outcomes.

Objective: The effectiveness of surgery in drug-resistant epilepsies is often focused exclusively on seizure control. The Epilepsy Surgery Satisfaction Questionnaire-19 (ESSQ_19), developed in 2020, is a reliable tool for assessing the level of satisfaction of patients undergoing surgery. We aimed to perform a Spanish translation, adaptation, and validation of the ESSQ_19 questionnaire.

Methods: This was a prospective multicenter study (five Spanish-speaking countries) including an international cohort of adult patients who underwent epilepsy surgery at least 1 year prior to participation. We followed a translation and back-translation methodology to obtain the Spanish version of the questionnaire (ESP-ESSQ_19). For validation, internal consistency (Cronbach alpha) and test-retest reliability at 6 months were assessed, and psychometric properties were measured by correlating them with parallel aspects using validated questionnaires.

Results: One hundred fifty patients were included (59.3% women; mean age = 39.3 ± 13 years, interquartile range [IQR] = 28-49 years), of whom 94 completed the baseline and follow-up questionnaires, with a median time since surgery of 3 (IQR = 1-7) years. Temporal lobe epilepsy was the most common (n = 112, 77.8%), as was structural etiology (n = 139, 95.2%). At inclusion, 101 patients (68.7%) had been seizure-free for ≥1 year. The ESP-ESSQ_19 questionnaire showed an internal consistency index of .88-.95 for all domains and a test-retest reliability of .91 (95% confidence interval = .87-.94). Significant correlation coefficients were observed between the ESP-ESSQ_19 questionnaire and all validated questionnaires used.

Significance: The ESP-ESSQ_19 questionnaire is a Spanish-language instrument useful for assessing patient satisfaction after epilepsy surgery, with adequate psychometric properties that allow its use in clinical practice and in research.

Objective: Pathogenic variants in the KCNQ2 gene cause a spectrum of neonatal onset epilepsy, from self-limited familial neonatal epilepsy (SeLNE; mild end) to developmental and epileptic encephalopathy (DEE; severe end). The associations and differences in the molecular mechanisms between the developmental outcomes of different KCNQ2 variants (SeLNE vs. DEE) remain unclear.

Methods: Using brain slice patch-clamp and single-nucleus RNA sequencing, we revealed developmental dysregulation in two different phenotypic Kcnq2 mice (DEE vs. SeLNE) during postnatal days 14-28 (P14-P28).

Results: Compared to wild-type mice, both Kcnq2-SeLNE and Kcnq2-DEE mice exhibited neuronal hyperexcitability characterized by high-frequency firing of action potentials. Notably, whereas SeLNE mice showed timely recovery of excitability, DEE mice displayed delayed restoration of abnormal excitability in CA1 excitatory neurons. During P14-P28, particularly at P21, DEE mice demonstrated significant downregulation of synaptic plasticity- and cognitive development-related pathways in CA1 excitatory neuron subclusters (CA1.2/CA1.4 neurons). Conversely, SeLNE mice exhibited pronounced activation of neurodevelopmental signaling pathways. Transcriptomic analysis of differentially expressed genes between SeLNE and DEE mouse models revealed recurrent gene signatures, with persistent neuronal upregulation of Apoe in Kcnq2-DEE mice.

Significance: This study identifies that the age-related spontaneous remission of seizures is due to time-limited changes in neuronal excitability, and treatment interventions for KCNQ2-DEE patients need to consider critical developmental time windows. In the future, better therapeutic outcomes may be achieved through spatiotemporal transcriptional coordination with neurodevelopmental gene networks.