Epilepsia最新文献

Objective: Idiopathic generalized epilepsy (IGE) in adults comprise juvenile myoclonic epilepsy (JME), juvenile absence epilepsy (JAE), and epilepsy with generalized tonic-clonic seizures alone (EGTCS), which are defined by their seizure types but also cover a broad endophenotype of symptoms. Controversy exists on whether adult IGE is a group of distinct diseases or a clinical spectrum of one disease. Here, we used a deeply phenotyped cohort to test the hypothesis that IGE comprises three distinct clinical entities.

Methods: Patients (>18 years old) with IGE were recruited between 2016 and 2020 at Odense University Hospital and the Danish Epilepsy Center. Complete data were available for basic demographics, imaging, social status, and treatment response. Subjects were offered neuropsychological screening (including symptoms of psychiatric disease). Electroencephalograms (EEGs) were reanalyzed, and missing data were imputed. After selecting the features and normalizing the data, the dataset and an identical randomized dataset were subjected to k-means cluster analysis.

Results: The dataset comprised 502 patients and 22 distinct nonoverlapping clinical features. Elbow and gap analyses revealed an optimal number of clusters of 1; the features with the highest eigenvalues were age at diagnosis and self-reported executive dysfunction. Applying k-means clustering yielded three low-quality clusters as assessed by silhouette score (mean = .400 ± .01). The corresponding mean silhouette score for the randomized control dataset was .390 (±.002). Age at diagnosis was associated with the epileptic discharges on EEG and treatment response. Self-reported executive dysfunction showed associations with psychiatric symptoms and impulsivity. JME, JAE, and EGTCS were loosely associated with the clusters (k = .088, p = .002) but showed a specific distribution within a matrix defined by age at diagnosis and self-reported executive dysfunction.

Significance: IGE in adults is best described as a continuum of symptoms, where age at diagnosis and executive dysfunction are two main factors explaining most of its clinical variability. The seizure-defined syndromes cover different patient groups within the clinical spectrum.

Objective: Hypoxic-ischemic brain damage (HIBD) is a leading cause of neonatal mortality, resulting in brain injury and persistent seizures that can last into the late neonatal period and beyond. Effective treatments and interventions for infants affected by hypoxia-ischemia remain lacking. Clinical investigations have indicated an elevation of nuclear factor of activated T cells 5 (NFAT5) in whole blood from umbilical cords of severely affected HIBD infants with epilepsy. Experimental research has demonstrated that NFAT5 has ambivalent effects on neuroprotection and neurologic damage. However, the mechanistic role of NFAT5 in HIBD remains unclear. This investigation aims to further clarify the role of NFAT5 in epilepsy following HIBD insult.

Methods: We created a neonatal HIBD mouse model through left common carotid artery occlusion. By specifically knocking down astrocytic NFAT5 and its downstream molecule, Nedd4-2, using hippocampal delivery of adeno-associated virus 5-driven targeted shRNA, we investigated the role of astrocytic NFAT5 in epilepsy susceptibility in HIBD mice. This was assessed through electroencephalographic recordings, behavioral observations in vivo, and whole-cell recordings of hippocampal neuronal activity. In vitro, we evaluated the effects of astrocytic NFAT5 alteration on Kir4.1 expression and I_Kir4.1 in both brain slices from HIBD mice and cultured astrocytes treated with oxygen-glucose deprivation/reoxygenation.

Results: Hypoxia-ischemia-induced upregulation of hippocampal NFAT5 occurs in astrocytes rather than in neurons. This upregulation leads to increased expression of the ubiquitin ligase Nedd4-2, resulting in excessive degradation of Kir4.1 in astrocytes. Consequently, astrocytic function in buffering extracellular K⁺ is impaired, causing depolarization of the resting potential and enhanced neuronal discharge. This disruption ultimately affects local neural network balance and increases susceptibility to epilepsy. In contrast, inhibiting or knocking down astrocytic NFAT5 almost completely reverses these effects.

Significance: Our findings suggest that manipulating the NFAT5-Nedd4-2-Kir4.1 axis in astrocytes could provide a potential therapeutic strategy for the epileptic complications of HIBD.

Time-frequency analysis of focal seizure electroencephalographic signals performed with depth electrodes in human temporal lobe structures has revealed the occurrence at onset of oscillations at approximately 30-100 Hz that feature a monotonic rapid decay in frequency content. This seizure onset pattern, referred to as chirp, has been identified as a highly specific and sensitive marker of focal seizures that are characterized by low-voltage fast activity. We report that this chirp pattern is also observed in animal models of temporal lobe epilepsy in both in vivo and in vitro preparations. We propose here that chirps mirror the involvement of synchronous interneuron firing that is known to represent a specific cellular mechanism leading to the initiation of focal seizures, in particular those characterized by low-voltage fast activity.

Objective: Large language models (LLMs) have recently gained attention for clinical decision-making and diagnosis. This study evaluates the performance of the recently updated LLM (ChatGPT-4o) in predicting clinical outcomes in patients with status epilepticus and compares its prognostic performance to the Status Epilepticus Severity Score (STESS).

Methods: This retrospective single-center cohort study was performed at the University Hospital Basel (tertiary academic medical center) from January 2005 to December 2022. It included consecutive adult patients (≥18 years of age) with a diagnosis of status epilepticus. The primary outcome was survival at hospital discharge, and the secondary outcome was return to premorbid neurological function at hospital discharge. The performance characteristics of ChatGPT4-o (sensitivity, specificity, Youden Index) were evaluated and compared to those of the STESS.

Results: Of 760 patients, 689 patients (90.7%) survived to discharge, and 317 survivors (41.7%) regained their premorbid neurological function at discharge. ChatGPT-4o predicted survival in 567 of 760 patients (74.6%), of which 45 died. ChatGPT-4o predicted death in 193 of 760 patients (25.4%), of which 167 survived, resulting in a sensitivity of 75.8% and a specificity of 36.6% (Youden Index 0.12, 95% confidence interval [CI] 0-.28) for predicting survival. ChatGPT-4o predicted return to premorbid neurologic function in 249 of 760 patients (32.8%), of which 112 did not return to their premorbid neurological function. ChatGPT-4o predicted no return to premorbid function in 511 of 760 patients (67.2%), of which 180 returned to their premorbid function, resulting in a sensitivity of 43.2% and a specificity of 74.7% (Youden Index .12, 95% CI .08-.28) for predicting return to premorbid neurological function. There was no difference in the prognostic performance of ChatGPT-4o and the STESS. A second round of prompting did not increase the predictive performance of ChatGPT-4o.

Significance: ChatGPT-4o unreliably predicts outcomes in patients with status epilepticus. Clinicians should refrain from using ChatGPT-4o for prognostication in these patients.

Objectives: The pathophysiological mechanisms of status epilepticus (SE) underlying potential brain injury remain largely unclear. This study aims to employ functional near-infrared spectroscopy (fNIRS) combined with video-electroencephalography (vEEG) to monitor brain hemodynamics continuously and non-invasively in critically ill adult patients experiencing electrographic SE. Our primary focus is to investigate neurovascular coupling and cerebrovascular changes associated with seizures, particularly during recurring and/or prolonged episodes.

Methods: Eleven critically ill adult patients underwent simultaneous vEEG-fNIRS with large cortical coverage. Data from seven patients with identified electrographic SE were analyzed. The timing of recorded seizures was marked using standardized critical care EEG terminology. A general linear model was employed to extract the hemodynamic response to seizures from the fNIRS recordings. Linear mixed-effects models were utilized to correlate hemodynamic responses with seizure characteristics.

Results: A total of >200 h of monitoring and >1000 seizures were recorded. In most patients, an increase in oxyhemoglobin (HbO) and a decrease in deoxyhemoglobin (HbR) were observed during shorter-duration seizures. Although a similar response could also be seen initially for longer-duration seizures, this hemodynamic change was often followed by a progressive decline in HbO concentration and an increase in HbR. At the systemic level, no significant difference in peripheral oxygenation occurred during seizures, and only small changes in mean arterial blood pressure and heart rate occurred in four and two patients, respectively.

Significance: We demonstrate the feasibility of using multichannel vEEG-fNIRS to measure the hemodynamic changes associated with electrographic seizures in critically ill adult patients. Our findings suggest that disrupted neurovascular coupling is more prevalent during prolonged seizures compared to recurrent short-duration seizures. This research provides valuable insights into the dynamic interplay between neuronal activity and hemodynamics during critical care seizures.

Objective: We comprehensively characterized a large pediatric cohort with focal cortical dysplasia (FCD) type 1 to expand the phenotypic spectrum and to identify predictors of postsurgical outcomes.

Methods: We included pediatric patients with histopathological diagnosis of isolated FCD type 1 and at least 1 year of postsurgical follow-up. We systematically reanalyzed clinical, electrophysiological, and radiological features. The results of this reanalysis served as independent variables for subsequent statistical analyses of outcome predictors.

Results: All children (N = 31) had drug-resistant epilepsy with varying impacts on neurodevelopment and cognition (presurgical intelligence quotient [IQ]/developmental quotient scores = 32-106). Low presurgical IQ was associated with abnormal slow background electroencephalographic (EEG) activity and disrupted sleep architecture. Scalp EEG showed predominantly multiregional and often bilateral epileptiform activity. Advanced epilepsy magnetic resonance imaging (MRI) protocols identified FCD-specific features in 74.2% of patients (23/31), 17 of whom were initially evaluated as MRI-negative. In six of eight MRI-negative cases, fluorodeoxyglucose-positron emission tomography (PET) and subtraction ictal single photon emission computed tomography coregistered to MRI helped localize the dysplastic cortex. Sixteen patients (51.6%) underwent invasive EEG. By the last follow-up (median = 5 years, interquartile range = 3.3-9 years), seizure freedom was achieved in 71% of patients (22/31), including seven of eight MRI-negative patients. Antiseizure medications were reduced in 21 patients, with complete withdrawal in six. Seizure outcome was predicted by a combination of the following descriptors: age at epilepsy onset, epilepsy duration, long-term invasive EEG, and specific MRI and PET findings.

Significance: This study highlights the broad phenotypic spectrum of FCD type 1, which spans far beyond the narrow descriptions of previous studies. The applied multilayered presurgical approach helped localize the epileptogenic zone in many previously nonlesional cases, resulting in improved postsurgical seizure outcomes, which are more favorable than previously reported for FCD type 1 patients.

Objective: This study was undertaken to characterize the clinical and genetic features of patients with 22q11.2 deletion syndrome (22q11.2DS) and generalized epilepsy compared with 22q11.2DS individuals without epilepsy.

Methods: This multicenter case-control study included 28 patients with 22q11.2DS-related generalized epilepsy and compared their data with 56 age-matched 22q11.2DS controls without epilepsy. Clinical and electroencephalographic features, neuropsychiatric and systemic comorbidities, family history of epilepsy, and genetic findings were collected.

Results: Generalized tonic-clonic seizures and myoclonic seizures were the most common electroclinical presentations, with a broader range of seizure type combinations also documented. Most patients achieved seizure remission with antiseizure medications, with only 4% exhibiting drug resistance. A higher prevalence of family history of epilepsy was observed among patients with 22q11.2DS-related generalized epilepsy compared to nonepilepsy controls, even when limiting the analysis to patients with known de novo deletions. No differences in deletion size or location were observed between the groups. Multivariable logistic regression analysis identified family history of epilepsy, intellectual disability, and lack of skeletal abnormalities as independent factors associated with generalized epilepsy, whereas a history of psychosis was significant only in univariable analysis.

Significance: This study provides a detailed characterization of generalized epilepsy in individuals with 22q11.2DS and highlights specific associated comorbidities. The higher prevalence of family history of epilepsy among cases suggests that genetic factors beyond the 22q11.2 deletion influence the development of the epilepsy phenotype, providing new insights into the genetic underpinnings of phenotypic variability in this syndrome.

Objective: Focal cortical seizures travel long distances from the onset zone, but the long-distance propagation pathways are uncertain. In vitro and in vivo imaging techniques have investigated the local spread of seizures but did not elucidate long-distance spread. Furthermore, classical studies in slices suggested seizure spread locally along deep cortical layers, whereas more recent in vivo imaging studies posit a role for superficial cortical layers in local spread.

Methods: We imaged seizure-activated neurons using activity reporter mice and measured local field potentials (LFPs) using microelectrode arrays to map cortical seizure propagation in awake mice.

Results: Frontal lobe onset seizures activate more neurons in superficial layers 2-3 than deep layers 5-6 throughout the cortex. LFP recordings demonstrate that seizures spread faster through the superficial than deep layers over long cortical distances of 3.5 mm. We also show that monosynaptically connected long-distance neurons are in the seizure circuit.

Significance: We propose that long-distance cortical seizure spread occurs preferentially via synaptically connected superficial cortical neurons.

Objective: We aimed to quantify and predict lacosamide exposure during pregnancy by developing a pregnancy physiologically-based pharmacokinetic model, allowing the prediction of potential dose increases to support maintaining a patient's preconception lacosamide concentrations.

Methods: Models for nonpregnant adults and pregnant female patients were constructed using physiochemical and pharmacological parameters identified from literature review. Evaluation of plasma concentration data from human males was digitized from the literature. Concentration data in nonpregnant and pregnant human females were available from the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) study, a longitudinal observational study which followed 11 nonpregnant and 16 pregnant women receiving lacosamide. Evaluation was conducted qualitatively with visual overlay (>80% of observed concentrations within 90% confidence interval) and quantitatively with average fold error and absolute average fold error (0.8-1.25 ratio acceptance criteria). Simulations of intensively-sampled dosing regimens at steady-state dosing across multiple gestational ages were conducted in Simcyp to evaluate the potential changes in lacosamide pharmacokinetics during pregnancy. Additional simulations were performed to explore the effects of cytochrome polymorphisms and glomerular filtration rate variability.

Results: The model adequately described the evaluation data in nonpregnant adults and pregnant adults between 10 and 40 weeks of gestation. Estimates in patients at 40- weeks of gestation indicated that lacosamide clearance increased by 48.2% compared to nonpregnant patients. Maximum lacosamide concentration (Cmax) during a simulated dosing interval also fell by 30% from preconception to 40 weeks. A simulated dose increase of 50 mg once daily at 10 weeks of gestation supported maintenance of preconception concentration for a typical patient taking the most common dosing regimen of 200 mg, twice daily (BID), preconception.

Significance: Simulated changes in lacosamide concentration align with the limited data available in observational studies. Our simulations support the use of therapeutic drug monitoring and dose adjustments to maintain the efficacy of lacosamide pharmacotherapy.

Objective: SCN2A encodes the voltage-gated sodium (Na+) channel α subunit Na_V1.2, which is important for the generation and forward and back propagation of action potentials in neurons. Genetic variants in SCN2A are associated with a spectrum of neurodevelopmental disorders. However, the mechanisms whereby variation in SCN2A leads to disease remains incompletely understood, and the full spectrum of SCN2A-related disorders may not be fully delineated.

Methods: Here, we identified seven de novo heterozygous variants in SCN2A in eight individuals with developmental and epileptic encephalopathy (DEE) accompanied by prominent malformation of cortical development (MCD). We characterized the electrophysiological properties of Na + currents in human embryonic kidney (HEK) cells transfected with the adult (A) or neonatal (N) isoform of wild-type (WT) and variant Na_V1.2 using manual and automated whole-cell voltage clamp recording.

Results: The neonatal isoforms of all SCN2A variants studied exhibit gain of function (GoF) with a large depolarized shift in steady-state inactivation, creating a markedly enhanced window current common across all four variants tested. Computational modeling demonstrated that expression of the Na_V1.2-p.Met1770Leu-N variant in a developing neocortical pyramidal neuron results in hyperexcitability.

Significance: These results support expansion of the clinical spectrum of SCN2A-related disorders and the association of genetic variation in SCN2A with MCD, which suggests previously undescribed roles for SCN2A in fetal brain development.