Epilepsia最新文献

Objective: Epilepsy is a common neurological disorder characterized by recurrent seizures, often resulting from an imbalance between neuronal excitation and inhibition. Loss of cerebellar Purkinje cells (PCs) has been observed in some patients with chronic epilepsy; however, whether PC loss can initiate seizures or exacerbate seizure severity remains unclear.

Methods: We established a mouse model of selective PC ablation in adulthood using the diphtheria toxin (DT)/DT receptor (DTR) system. Seizure susceptibility (epileptiform discharges, Racine score, and network activation) was assessed thoroughly in two distinct seizure models: the pentylenetetrazol (P-uced acute seizure model and the hippocampal kindling model. Furthermore, in vivo electrophysiology recordings in the deep cerebellar nuclei (DCN) were utilized to explore the single-unit firing characteristics following PC ablation.

Results: One month after intraperitoneal (i.p.) DT injection, PC ablation was successfully induced in adult Pcp2-DTR mice. No spontaneous seizures were observed in mice with PC ablation during 48-h wireless electroencephalography/electromyography (EEG/EMG) monitoring. However, PC ablation significantly increased seizure susceptibility in the PTZ-induced acute seizure model and accelerated the kindling process in the hippocampal kindling model. Although baseline DCN firing remained unchanged, these mice displayed a distinct post-ictal DCN electrophysiological signature: significantly enhanced delta/theta power compared to controls, and a decrease in neuronal firing frequency relative to their own baseline, with firing regularity preserved.

Significance: Together, these findings suggest that PC ablation contributes to heightened seizure susceptibility and seizure severity, highlighting a modulatory role of cerebellar circuits in epilepsy.

Objective: The mechanisms leading to the onset of a focal seizure are still not understood. Experimental data in animal models and patients suggest that both interneurons and principal cells contribute to focal seizure generation. We investigate here whether neurons are driven by non-synaptic γ-aminobutyric acid (GABA) release during seizures generated in models of focal ictogenesis.

Methods: We used the well-established 4-aminopyridine (4AP) seizure model to analyze epileptiform discharges in naïve mouse entorhinal cortex slices and in guinea pig brains maintained in vitro. Pharmacological dissection of epileptiform events was performed during simultaneous field potential and patch-clamp recordings.

Results: 4AP (100 μM) elicited periodic and large chloride currents in both principal neurons and GABAergic interneurons that steadily matched simultaneously recorded interictal population spikes. These population spike-associated chloride currents (PSACC) (i) survived glutamate receptor blockade, (ii) were abolished by GABA_A antagonists and by blocking the synaptic neurotransmitters release, (iii) were reduced by excitatory amino acid transporter antagonist, and (iv) were enhanced by GABA transporter 1 antagonist. Application of the antagonist of bestrophin-1 (BEST-1) channels inhibited both PSACCs and the associated spikes and prevented the occurrence of seizure-like events in entorhinal cortex mouse slices and in the isolated guinea pig brain.

Significance: We propose that GABA released via bestrophin-1 channels induces large and synchronous chloride currents in principal cells and interneurons, and establishes the conditions for the generation of seizure-like events. We propose that neuronal epileptiform discharges are generated by fast transmembrane ion changes imposed by non-vesicular GABA release, possibly sustained by astrocytes.

Objective: Focal epilepsy is increasingly conceptualized as a network disorder, yet the extent to which network dysfunction reflects a shared phenotype remains unknown. Spatially conserved patterns of network dysfunction may implicate a centralized mechanism underlying widespread impairment. Here, we investigate whether network connectivity disruptions are spatially similar across temporal lobe and extra-temporal lobe epilepsy cohorts and whether shared dysfunction aligns with thalamic connectivity profiles.

Methods: We retrospectively analyzed resting-state magnetoencephalographic imaging from 71 individuals with nonlesional, drug-resistant focal epilepsy (n = 45 temporal, n = 26 extratemporal), collected between 2014 and 2023, and healthy controls (n = 18). Source reconstructed time series were bandpass filtered, and long-range functional connectivity was quantified using imaginary coherence. Network disturbance maps were computed as T-score maps, comparing functional connectivity in epilepsy cohorts to controls, across topographical parcels and frequency bands. Spatial similarity of temporal and extratemporal network dysfunction maps were assessed using Pearson correlations. To infer thalamic involvement, shared network dysfunction maps were correlated with normative functional magnetic resonance imaging-derived thalamocortical connectivity profiles.

Results: Extra-temporal lobe epilepsy demonstrated reduced global network connectivity relative to controls in the delta (p = .012), alpha (p = .034), and gamma (p < .001) frequency bands. Across all frequencies, the spatial patterns of network disturbances between temporal and extratemporal cohorts were significantly correlated (r = .287-.717, all p < .001), indicating a shared network dysfunction. Shared spatial maps of network dysfunction correlated with normative thalamocortical connectivity profiles, with significant correlations in the anterior, pulvinar, and dorsomedial thalamus.

Significance: Nonlesional focal epilepsy exhibits a common, frequency-dependent pattern of cortical network dysfunction that is spatially aligned with thalamic connectivity, supporting a thalamic hub contribution to widespread network impairment.

Objective: Dravet syndrome (DS) is a prototypical developmental and epileptic encephalopathy caused by mutations in the SCN1A gene, leading to loss of function of the voltage-gated sodium channel Naᵥ1.1. The latter causes early onset drug-resistant seizures and enduring cognitive and behavioral deficits. In this pathological context, the implication of astrocytes remains insufficiently explored.

Methods: Using a heterozygous Scn1a knockout (Scn1a⁺/^-) mouse model that recapitulates the DS-human phenotype, we examined astrocyte remodeling at landmark disease stages, as defined by video-electroencephalography and behavioral readouts.

Results: From initial disease aggravation (postnatal day [PN] 20-35) to long-term stabilization (up to PN90), Scn1a⁺/^- mice showed increased hippocampal and cortical glial fibrillary acidic protein (GFAP) transcript and protein levels compared to age-matched control littermates and to an earlier presymptomatic (+/^- mice, astrocyte branching, revealed by GFAP histological analysis and by intracellular delivery of Alexa Fluor 488 in hippocampal slices, was increased but not sustained long-term. Importantly, these disease-stage-dependent astrocyte modifications were not associated with macroscopic hippocampal sclerosis or cortical atrophy. To further study astrocyte remodeling, we used biocytin diffusion following single-astrocyte loading to reveal an expanded astrocyte-astrocyte network in Scn1a⁺/^- mice long-term, along with increased connexin (Cx30 and Cx43) protein levels. An ethidium bromide uptake assay indicated impaired astrocytic hemichannel function in Scn1a⁺/^- mice. Regionally, these long-term cellular and network astrocyte modifications coincided with augmented posttetanic synaptic potentiation.

Significance: In DS, astrocytes undergo long-term remodeling independent of tissue damage. We discuss the association between astrocyte network changes and seizures, as well as synaptic and cognitive deficits.

Objective: Epilepsy is a common neurological disorder with a strong genetic basis, most frequently arising from ion channel dysfunction. Although multiple inwardly rectifying potassium (Kir) channels have been implicated in epileptogenesis, the contribution of KCNJ4, which encodes the Kir2.3 channel, has not previously been established in human epilepsy. The present study aimed to identify pathogenic KCNJ4 variants and to elucidate their functional consequences in the context of epilepsy.

Methods: Trio whole exome sequencing was performed in four unrelated individuals with refractory epilepsy and neurodevelopmental abnormalities. Identified KCNJ4 variants were evaluated for rarity and inheritance patterns. Functional consequences were assessed using two-electrode voltage-clamp recordings in Xenopus laevis oocytes coexpressing wild-type or mutant Kir2.3 together with Kir2.1. Protein expression levels were examined by Western blot analysis to exclude effects attributable to altered channel expression or trafficking.

Results: We identified four rare heterozygous missense variants in KCNJ4 (Gly136Ser, Val206Met, Met293Lys, and Glu384Lys), all of which were absent from public population databases. Clinically, affected individuals exhibited a broad phenotypic spectrum ranging from isolated epilepsy to severe developmental and epileptic encephalopathy. Electrophysiological analyses revealed variant-specific functional alterations; the Gly136Ser and Glu384Lys variants significantly increased inwardly rectifying potassium currents, consistent with gain-of-function effects, whereas the Val206Met and Met293Lys variants markedly reduced current amplitudes, indicating loss of function. These functional changes were independent of channel protein expression levels.

Significance: Our findings establish KCNJ4 as a novel epilepsy-associated gene and demonstrate that both gain- and loss-of-function mechanisms of Kir2.3 can contribute to epileptogenesis. This study expands the genetic landscape of epilepsy and highlights the critical role of inward-rectifier potassium channel regulation in neuronal excitability, with potential implications for mechanism-based therapeutic strategies.

Objective: This study was undertaken to test whether arterial spin labeling (ASL) performs comparably to 2-[¹⁸F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET), the mainstay functional imaging technique, in pediatric lesional epilepsy, while avoiding radiotracer exposure and additional sedation.

Methods: We retrospectively included children with epilepsy due to focal cortical dysplasia, low-grade epilepsy-associated tumors, or hippocampal sclerosis who underwent standardized magnetic resonance imaging (MRI; including single-delay ASL) and FDG-PET during presurgical evaluation. Lesions, perilesional perfusion, and metabolic abnormalities were segmented and coregistered. Spatial overlap was quantified using DICE scores to compare functional modalities with each other (perfusion-to-metabolism: DICE_P-to-M), with the lesion (metabolism-to-lesion: DICE_M-to-L; perfusion-to-lesion: DICE_P-to-L), and, in seizure-free children, with the resection cavity (lesion-, metabolism-, perfusion-to-resection cavity: DICE_{L-/M-/P-to-Post}). We also assessed the temporal stability of perilesional ASL abnormalities and the presence of remote ipsilateral/contralateral abnormalities. Equivalence testing used the Wilcoxon signed-rank equivalence test with FDG-PET as reference; Cohen κ quantified agreement for remote abnormalities.

Results: Fifteen children were included; median ages at FDG-PET and ASL were 7.7 and 7.5 years; 53% required sedation. Median perilesional volumes were 11 339 mm³ (FDG-PET) and 10 791 mm³ (ASL); both were larger under sedation (p < .001). Perilesional volumes were equivalent (p = .037). Median DICE_M-to-L and DICE_P-to-L were .3 and .4; equivalence was confirmed (p < .001). Median DICE_P-to-M was .7, indicating strong ASL-FDG-PET concordance. In seizure-free children following surgery, DICE_M-to-Post and DICE_P-to-Post were both .6 and equivalent (p = .01). ASL findings were stable over time (DICE = .27-.75; n = 4 with repeat ASL). Remote ipsilateral abnormalities were common (ASL 73%, FDG-PET 67%; κ = .53), with poor contralateral agreement (κ = .12).

Significance: ASL yielded perilesional findings equivalent to FDG-PET and showed comparable overlap with the resection cavity in seizure-free children. As a radiation-free technique embedded into routine MRI, ASL reduces logistics and avoids an additional sedation session. These findings support ASL as a practical alternative to FDG-PET for presurgical workup, especially when FDG-PET access is limited.

Objective: Cognitive disorder is common after stroke at a young age, especially in patients with poststroke epilepsy (PSE). Whether the causative mechanism is direct (due to epilepsy-related network alterations) or indirect (due to effect-modifiers such as stroke severity) is not fully understood. We assessed the role of PSE in cognitive disorder in young stroke patients by investigating the association between vascular cognitive disorder (VCD) and PSE in young stroke patients, and by investigating the association between cognitive impairment per cognitive domain and PSE.

Methods: In this multicenter prospective cohort study, we investigated the occurrence of PSE in patients aged 18-49 years presenting with a first-ever transient ischemic attack, ischemic stroke, or primary intracerebral hemorrhage between 2013 and 2021 and assessed the cognitive function 1 year after the event. We calculated composite z-scores for seven cognitive domains. VCD was categorized as a composite z-score in any domain between -2.0 SD and -1.5 SD (mild) and <-2.0 SD (major). We performed multivariable regression analyses to examine the association between PSE and VCD and between PSE and cognitive impairment per domain.

Results: Eight (median age = 38.6 years, median NIHSS score = 2, 30% male) of 20 patients with PSE (40.0%) had major VCD, compared to 93 (median age = 44.2 years, median NIHSS = 2, 50% male) of 426 patients (20.1%) without PSE (adjusted odds ratio [OR] = 3.96, 95% confidence interval [CI] = 1.24-12.65). Additionally, PSE was independently associated with cognitive impairment in the domain attention and working memory (adjusted OR = 5.09, 95% CI = 1.15-22.59).

Significance: We found independent associations between PSE and major VCD, and between PSE and cognitive impairment in the attention and working memory domain. This could support the "second-hit hypothesis," in which epilepsy following a primary injury relates directly to increased cognitive impairment with a subcortical neuropsychological profile.

Objective: Malformations of cortical development (MCDs) are a frequent cause of drug-resistant epilepsy and a common indication for resective epilepsy surgery. As magnetic resonance imaging (MRI) lacks sensitivity for subtle MCDs, supplemental diagnostic tools are needed. This study aimed to characterize scalp electroencephalographic (EEG) patterns in MCDs and investigate their association with surgical outcomes.

Methods: This was a retrospective case-control study including patients who underwent inpatient video-EEG monitoring at two Australian hospitals. Cases were individuals with MCDs confirmed on MRI or histopathology; controls included patients with other focal epilepsies. Two epileptologists independently reviewed interictal and seizure-onset EEG patterns using a standardized classification framework. Patterns were compared between cases and controls and assessed with respect to postoperative seizure outcomes, adjusting for antiseizure medication reduction.

Results: We included 38 cases with MCDs (52.6% females, median age = 34 years) and 114 controls (45.6% females, median age = 41 years). Among interictal patterns, repetitive epileptiform discharges type 1 and type 2 were more prevalent in patients with MCDs than controls (p = .002 and .005, respectively). Focal fast epileptiform discharges were also more frequent in MCD patients, after excluding nonlesional focal epilepsy controls (p = .038). Among seizure-onset patterns, paroxysmal fast activity was more prevalent in MCDs (p < .001). Among 38 patients who underwent surgery, 70.0% of MCDs and 75.0% of controls had favorable outcomes. No EEG pattern predicted postoperative seizure outcomes.

Significance: Distinct scalp EEG patterns may support differentiation of MCDs from other focal epilepsies. Larger prospective studies are needed to clarify their role in detecting MRI-negative MCD or guiding targeted imaging.

Objective: Inclusion and exclusion criteria of clinical trials for seizures aim to select representative participants with a high enough seizure frequency to evaluate the efficacy of treatment in a relatively short double-blind period. To inform the selection of seizure frequency-based inclusion criteria, we evaluated the association between baseline seizure frequency and reduction of seizure frequency in the double-blind period.

Methods: Using data from 11 double-blind placebo-controlled trials of antiseizure medications for either focal or generalized onset epilepsy, we evaluated the association of baseline seizure frequency with 50% responder rate and percent reduction of seizure frequency in maintenance. We identified four patterns based on the presence or absence of significant association (p < .05) in placebo, active treatment, both, and neither. We also evaluated whether the time to prerandomization monthly seizure count (T-PSC) design impacted these associations.

Results: In 55% of trials (6/11), there was no significant association of maintenance seizure frequency change with baseline seizure frequency. In 19% of trials (2/11), there were parallel elevations in placebo and active treatment responses for lower baseline seizure frequency. In one trial (1/11), that shift was observed in placebo only, whereas there was a ceiling effect of high response in levetiracetam. In the remaining 19% of trials (2/11), there were more seizure frequency reductions in lower baseline seizure frequencies in active treatment but not placebo. These associations were not modified when the T-PSC design was used.

Significance: The association of the magnitude of change in seizure frequency with baseline seizure frequency was inconsistent across trials. In eight of 11 trials, these patterns did not reduce the magnitude of difference between active treatment and placebo and thereby may not reduce statistical power. In only one trial did elevated placebo response reduce the difference between active treatment and placebo. In two trials, active treatment appeared more efficacious in lower seizure frequencies.