Epilepsia最新文献

Objective: Seizures are among the most common symptoms of cerebral arteriovenous malformations (AVMs). Although the main goal of AVM treatment remains complete obliteration, seizure control has become an important treatment aspect in recent years. Thus, we analyzed seizure control following Gamma Knife Radiosurgery (GKRS) treatment at our department in patients with AVMs.

Methods: We analyzed 130 patients with AVMs who had at least one seizure before treatment with GKRS at our tertiary referral center between 1992 and 2022. We analyzed predictors for treatment success, including AVM size, Virginia Radiosurgery AVM Scale, Radiosurgery-Based AVM Score, Spetzler-Ponce class, Spetzler-Martin grade, localization, and identified independent predictors of seizure persistence.

Results: Median follow-up was 9.7 years. Improved seizure control was documented for 89% of patients. Seizure-free status after radiosurgery was achieved for 78% of patients. Spetzler-Ponce class C (odds ratio [OR] = 4.6) and having multiple seizures before the first GKRS treatment (OR = 3.5) were independent predictors for seizure persistence. Still, 72% of patients with multiple seizures prior to AVM treatment were seizure-free at last follow-up. Among patients with multiple seizures, having a high-grade AVM was identified as an independent predictor of seizure persistence (OR = 12.1).

Significance: GKRS, as a stand-alone management option or in combination with endovascular therapy, is an effective treatment option in AVM management, not only to achieve AVM obliteration but also to control AVM-related seizures. The Spetzler-Ponce class is a powerful predictor of seizure persistence at last follow-up, especially in patients with multiple seizures prior to treatment.

Objective: This study aimed to evaluate the real-world performance of a wrist-worn seizure detection device for timely clinical interventions within an epilepsy monitoring unit (EMU).

Methods: We conducted a prospective observational study involving patients admitted to the EMU at a tertiary care center. Participants wore the Embrace2 device, which has US Food and Drug Administration approval for purchase and continuously monitored for convulsive seizures. The device was connected to the hospital's public Wi-Fi and was paired with a smartphone programmed to alert nursing staff through automated messages and phone calls upon seizure detection. Nursing staff were trained on the device's use, and implementation outcomes were documented, including technical performance, alert responses, and staff feedback.

Results: A total of 72 patients (57% female, mean age = 39 years, range = 19-81) were prospectively recruited between April 2024 and June 2025 at the Centre hospitalier de l'Université de Montréal EMU. The analysis included 373 monitoring days (mean = 5.1 days/patient). Eighteen focal to bilateral tonic-clonic seizures (FBTCSs), one generalized tonic-clonic seizure (GTCS), and 510 focal seizures (FSs) occurred. The Embrace2 wrist-worn device detected all 16 FBTCSs/GTCSs that occurred while the device was functioning and worn, but none of 510 FSs. Alerts successfully reached caregivers in 15 of 16 cases, with one failure due to a Wi-Fi disconnection. Seven of the successful alerts occurred during overnight shifts when electroencephalographically trained technicians are typically not on duty. Twenty-nine false alarms occurred (.077/24 h), mostly triggered by routine movements (e.g., toothbrushing). Practical challenges included the potential for missed alerts when nurses were not carrying their phones; however, no seizure events were missed for this reason during the study period.

Significance: Wearable devices show considerable value for seizure detection and triggering timely interventions in EMU settings, particularly during off-hours. However, successful integration requires robust coordination, reliable infrastructure, and staff engagement to maximize clinical benefit and maintain trust in the system.

Objective: GRIN-related disorders due to pathogenic variants in GRIN1, GRIN2A, GRIN2B, or GRIN2D genes are associated with altered N-methyl-D-aspartate receptor (NMDAR) function. Functional changes include gain (GoF) and loss of receptor function (LoF). Clinical reports describing the use of the NMDAR blocker memantine in GRIN-related disorders show a diverse and inconsistent spectrum of treatment responses.

Methods: To evaluate clinical responses to memantine, we collected retrospective data on 34 individuals with GRIN variants, including 20 unpublished and 14 published cases. Variants were reclassified following American College of Medical Genetics and Genomics guidelines, and six in vitro functional assays were used to assess receptor function. We compared individuals with pathogenic GoF versus LoF in terms of associated clinical improvements, memantine sensitivity, and variant localization within the gene.

Results: In 19 of the 34 variants, a pathogenic likely or possible GoF of the receptor was detected. Fourteen of 19 individuals (74%) benefited from memantine, comprising improvements in behavior (71%), development (50%), and seizure frequency (39%). Individuals with either LoF or a functionally indeterminate or no effect GRIN variant (15/34 individuals) showed significantly less benefit from memantine treatment but nevertheless rare adverse events (3/15). An increased distance of the variant from the memantine binding site was associated with a clinical benefit.

Significance: Our retrospective observational study outlines the importance of correct classification of GRIN variants with regard to pathogenicity and functional consequence prior to applying memantine or other precision medicine approaches in clinical trials. Furthermore, the distance from a GoF variant to the memantine binding site correlated with a positive treatment response and may, at least in part, explain different degrees of therapeutic benefit.

Objective: Epilepsy is a chronic neurological disorder characterized by recurrent seizures and frequent cognitive and psychiatric comorbidities. Although current antiseizure medications provide symptomatic relief, they fail to prevent or modify epileptogenesis. Heat shock protein 90 (Hsp90) is increasingly recognized as a regulator of neuroinflammatory and oxidative stress pathways implicated in seizure generation and disease progression. Here, we investigated the therapeutic potential of cemdomespib, a novel and selective Hsp90 inhibitor, across complementary preclinical models of epilepsy.

Methods: In vitro, cemdomespib was evaluated in the low-magnesium model of epileptiform activity for its effects on neuronal calcium dynamics, mitochondrial membrane stability, and reactive oxygen species (ROS) generation. In vivo, acute seizure protection was assessed in the pentylenetetrazol (PTZ) model, and antiepileptogenic efficacy was tested in the kainic acid-induced status epilepticus (KA-SE) model using chronic video-electrocorticographic recordings. Behavioral outcomes relevant to epilepsy-associated comorbidities, including anxiety-like behavior and exploratory activity, were also examined.

Results: Cemdomespib reduced epileptiform calcium oscillations, stabilized mitochondrial membrane potential, and suppressed ROS generation in vitro. In the PTZ model, 45% of pretreated animals were protected from seizures, and those that seized exhibited reduced severity, shorter duration, and delayed onset. In the KA-SE model, cemdomespib significantly mitigated the severity of SE and reduced the emergence of spontaneous recurrent seizures during the chronic phase, as evidenced by lower seizure frequency, decreased cumulative seizure burden, and prolonged latency to seizure onset. Furthermore, treated animals demonstrated improved anxiety-like behavior and enhanced exploratory activity.

Significance: Cemdomespib confers both acute seizure protection and long-term suppression of epileptogenesis, likely through Hsp90-dependent regulation of mitochondrial integrity and redox signaling. These findings highlight Hsp90 inhibition as a promising therapeutic strategy for seizure control while also mitigating the progression of epileptogenesis and its associated neurobehavioral impairments.

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: Epilepsy treatment aims not only to control seizures but also to enhance quality of life. However, reliable blood-based biomarkers for epilepsy-related cognitive impairment are lacking. This study investigated the association between plasma neurofilament light chain (NfL) levels and cognitive function in epilepsy by integrating evidence from observational and Mendelian randomization (MR) analyses across different populations.

Methods: We conducted a cross-sectional observational study at the First Hospital of Jilin University, enrolling 152 adults with epilepsy. Demographic and clinical information was collected, and cognitive status and psychological status were assessed using the Montreal Cognitive Assessment (MoCA), Mini-Mental State Examination (MMSE), Memory and Executive Screening (MES) scale, Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD). Plasma NfL levels were measured using enzyme-linked immunosorbent assay (ELISA). Statistical analyses included logistic regression, linear regression, and receiver-operating characteristic (ROC) curve analysis. In parallel, two-sample MR was performed using genome-wide association study (GWAS) summary statistics from European cohorts. Shared genetic variants between epilepsy and cognitive impairment were identified using multi-trait analysis of GWAS (MTAG) and cross-phenotype association (CPASSOC), and served as instrumental variables to estimate the causal effect on plasma NfL levels.

Results: Plasma NfL levels were significantly higher in the cognitively impaired group. After adjusting for confounders, elevated NfL levels remained independently associated with increased risk of cognitive impairment and inversely correlated with cognitive scores. ROC curve analysis showed high diagnostic accuracy of plasma NfL. MR analysis confirmed a positive causal relationship between epilepsy-related cognitive impairment and plasma NfL levels.

Significance: Plasma NfL is associated with cognitive impairment in epilepsy and may serve as an early blood-based biomarker for identifying cognitive dysfunction in this population.

Objectives: γ-Aminobutyric acid B receptor (GABA_BR)-IgG (immunoglobulin G) is an intermediate-risk paraneoplastic autoantibody often associated with seizures. We aimed to assess the clinical and oncological features of GABA_BR-IgG autoimmune encephalitis (AE) and evaluate the performance of antibody testing.

Methods: Patients testing positive for GABA_BR-IgG in serum/cerebrospinal fluid (CSF) at Mayo Clinic Neuroimmunology Laboratory were identified. Archived sera were retested by cell-based assay (CBA) at 1:100 and 1:200 dilutions. A live-cell flow cytometry-based assay (LCFBA) was developed and validated using archived sera and CSF. True positivity included patients with classic presentations of GABA_BR-IgG AE or oncological explanations for antibody presence.

Results: Eighty-six patients (median age 63 years; 43 female) presented with classic presentations of GABA_BR-IgG AE: encephalopathy with prominent seizures (n = 55), status epilepticus (n = 23), and rapidly progressive dementia (n = 8). In addition, 44 patients (33%) had a false-positive result for GABA_BR-IgG characterized by non-specific symptoms/alternate diagnoses. Malignancy was identified in 78% of true-positive patients, predominantly small cell lung carcinoma (SCLC). Testing serum at 1:100 dilution on CBA and using tissue immunofluorescence assay (IFA) in serum and CSF improved the identification of true-positive patients (p < 0.001). CBA at 1:100 dilution performed better than conventional CBA (at 1:10 dilution, p < 0.001) and tissue IFA (p = 0.031). An in-house LCFBA showed 100% sensitivity and specificity in CSF, performing similarly to conventional CBA (p = 0.125) in CSF, but better than tissue IFA (p = 0.031). Furthermore, serum LCFBA performed better than conventional CBA (p = 0.022) and tissue IFA (p = 0.006). LCFBA had the highest diagnostic accuracy and was closely followed by CBA at 1:100 dilution.

Significance: GABA_BR-IgG AE often presents as encephalopathy with seizures or status epilepticus in the context of an underlying SCLC. Multimodal evaluation using tissue IFA and fixed CBA at higher dilutions improves detection of true cases. LCFBA performs very well as a diagnostic test with very high sensitivity and specificity.