Sudden Unexpected Death in Epilepsy (SUDEP) is a leading cause of death in patients with epilepsy and is thought to result from dysfunctional and/or failure of cardiorespiratory control systems. Post-mortem brainstem tissue analyses in human SUDEP cases point to reductions in markers of the brainstem serotonin (5-HT) system, which is known as a brainstem center that provides excitatory neuromodulation. We have previously shown in a knockout rat model (SS kcnj16-/- rats) that repeated seizures led to progressively greater ventilatory inhibition in the post-seizure period, seizure-associated mortality, and reduced brainstem 5-HT and tryptophan hydroxylase (Tph) particularly within the Raphe Magnus (RMg). Here, we account for the cellular constituency and local transcriptional responses to repeated seizures in male SS kcnj16-/- rats that experienced daily seizures for 3, 5, 7, or 10 consecutive days using single nuclear RNA sequencing (snRNA seq) from brainstem tissue biopsies including the RMg (-12.12 mm to -10.30 mm caudal to Bregma) two hours post-seizure. Unbiased cluster analysis identified 18 cell major clusters that were by identified by the expression of known gene markers, with most cells being oligodendrocytes. However, local RMg neurons showed the greatest numbers of differentially expressed genes with seizures compared to all other cell types. Further re-clustering of neuronal cell types yielded 14 distinct RMg neuron subpopulations, including 5 types of GABAergic neurons, 2 glutamatergic clusters, and 2 groups of 5-HT neurons which all had unique expression profiles. Nearly all DEGs across neuronal subtypes were increased following seizures, and a large fraction of which were common across seizure days and across neuron type suggesting uniformity in cellular response to seizures in this region. These studies provide foundational information regarding the cellular constituency of the RMg region in the rat, and altered neuronal function following repeated seizures in the absence of changes in other cell types in this key region of cardiorespiratory control.
Clozapine is associated with a high risk of central nervous system abnormalities. However, seizure risk related to interactions between clozapine and other antipsychotics remains poorly characterized, and the pharmacological mechanisms underlying these seizures are unclear. We aimed to evaluate safety signals for seizures associated with clozapine augmentation by other antipsychotics and analyze the relationship between these signals and neurotransmitter receptor occupancy profiles. A pharmacovigilance-pharmacodynamic analysis using a spontaneous reporting system. This pharmacovigilance study used VigiBase, an adverse drug reaction database maintained by the World Health Organization. Drug-drug interactions (DDIs) between clozapine and other antipsychotics were assessed using the Ω shrinkage measure model. The association between DDI signals and neurotransmitter receptor occupancy was evaluated using linear regression. Robustness was tested using four frequency statistical models: additive, multiplicative, combination risk ratio, and chi-square statistic models. Of 38,758,077 reports in VigiBase between 1990 and 2024, 230,371 involved clozapine. Among antipsychotics classified under ATC code N05A, DDIs with clozapine were detected for amisulpride, chlorpromazine, haloperidol, lurasidone, olanzapine, penfluridol, risperidone, sulpiride, zotepine, and zuclopenthixol. A significant association between dopamine D4 receptor occupancy and the point estimates of signal values was observed in the Ω shrinkage measure model (β = 0.295, 95% confidence interval: 0.119-0.471, p = 0.002) and replicated across all frequency statistical models. These findings suggest a potential role of dopamine D4 receptor occupancy in seizures associated with clozapine augmentation by other antipsychotics. Further large-scale epidemiological studies are needed to validate these findings. Seizures associated with clozapine augmentation by other antipsychotics Clozapine is associated with a high risk of central nervous system abnormalities. However, seizure risk related to interactions between clozapine and other antipsychotics remains poorly characterized, and the pharmacological mechanisms underlying these seizures are unclear. We aimed to evaluate safety signals for seizures associated with clozapine augmentation by other antipsychotics and analyze the relationship between these signals and neurotransmitter receptor occupancy profiles. This pharmacovigilance study used VigiBase, an adverse drug reaction database maintained by the World Health Organization. Of 38,758,077 reports in VigiBase between 1990 and 2024, 230,371 involved clozapine. Among antipsychotics in ATC code N05A, drug–drug interactions with clozapine were detected for amisulpride, chlorpromazine, haloperidol, lurasidone, olanzapine, penfluridol, risperidone, sulpiride, zotepine, and zuclopenthixol. In addition, antipsychotics associated with seizure signals when combined with clozapine tended to exhibit higher estimated dopamine D4 receptor occupancy. These observations suggest a possible association between dopamine D4 receptor occupancy and seizure signals observed during clozapine augmentation. Further large-scale epidemiological studies are needed to validate these findings.
Absence seizures evolving to bilateral tonic-clonic seizures may have focal or asymmetric clinical features. Using quantitative electroencephalography (EEG) may evaluate this phenomenon and the involved neuronal network. We conducted a retrospective chart review of pediatric patients with generalized epilepsy and normal brain magnetic resonance imaging (MRI) admitted to an epilepsy monitoring unit. Our results show that seven of 66 patients with generalized epilepsy, all females, had generalized onset seizures with focal evolution (GOFE) to bilateral tonic-clonic seizures. Age at seizure onset was 7.5 years, at epilepsy syndrome diagnosis 8.14 years, and at GOFE diagnosis 13.04 years. Three had juvenile absence epilepsy, two had juvenile myoclonic epilepsy, and two had generalized genetic epilepsy. Eight seizures were recorded. Six patients had normal EEG background and one mild slowing. Quantitative EEG (QEEG) spectrogram with spike detection analysis showed 2.5-3.5-Hz generalized spike-wave activity followed by focal buildup over the lateral frontal, occipital, and frontal-central regions (right more than left) before bilateral tonic-clonic progression. In conclusion, in our cohort of patients with GOFE, QEEG analysis accurately showed that after absence seizure there is focal activation of the frontal (mainly right) and occipital cortices with evolution to bilateral tonic-clonic seizure. We hypothesize that GOFE could involve the activation of the thalamus and the cortex via the thalamocortical network, based on the QEEG analysis and the literature functional MRI evidence in absence seizures. Additional study of more patients to confirm findings is required.
Childhood absence epilepsy (CAE) is a common genetic epilepsy with a frequently complex polygenic etiology, for which a genetically tractable animal model is lacking. Current anti-seizure medications fail to address the significant neurocognitive and social comorbidities of CAE, highlighting a critical unmet need for comprehensive therapies and a better understanding of the underlying mechanisms. To address this, we developed a digenic mouse model (Cacng2stargazer/+;Cacna1a+/-, hereafter DiGstg+Ca1A) that mimics human polygenicity. The double mutant mice exhibit both absence seizures and altered social novelty preference. We found that ethosuximide, a first-line anti-CAE medication targeting thalamic low-threshold T-type calcium currents, suppressed seizures in DiGstg+Ca1A mice but failed to rescue their social deficit. Similarly, deletion of Cacna1g, which encodes the T-type Ca2+ channel CaV3.1, prevented seizure generation but did not ameliorate the social deficit. These findings reveal a dissociation between the T-type current that mediates seizures and the mechanism underlying the social deficits. We further demonstrate that in Cacng2stargazer/+ mice, selective deletion of one copy of Cacna1a in stargazin-enriched parvalbumin (PV) interneurons induced absence seizures and impaired social behavior. Remarkably, chemogenetic activation of cortical and thalamic PV interneurons using DREADDs not only suppressed seizures but also rescued the impaired social behavior. Together, our results suggest that selective modulation of PV interneuron activity in polygenic absence epilepsy could serve as a promising therapeutic strategy to address both absence seizures, and the often treatment-resistant neurocognitive comorbidities observed in CAE.
Everolimus is an established therapy for tumor manifestations and refractory focal seizures in tuberous sclerosis complex (TSC) in patients aged ≥2 years. Evidence regarding its use during the neonatal period, particularly for seizure control, remains extremely limited. We describe the clinical course, neuroimaging findings, treatment response, and developmental outcome of a neonate with genetically confirmed TSC who received early everolimus therapy for refractory seizures. A term female neonate developed multifocal drug-resistant seizures beginning on day 3 of life. Brain magnetic resonance imaging demonstrated multiple cortical and subcortical tubers, and electroencephalography revealed multifocal epileptiform discharges. Despite treatment with phenobarbital, midazolam, and vigabatrin, seizures remained uncontrolled. Everolimus was initiated on day 30 of life. Seizure activity resolved completely within one week and remained controlled for over one year. The treatment was well tolerated, with no serious adverse events. Early developmental assessment at 12 months showed cognitive, language, and motor scores within the lower range of normal. This case suggests that early initiation of everolimus may represent a feasible adjunctive treatment option for selected neonates with TSC-associated refractory seizures.
Donanemab is an immunoglobulin G1 (IgG1) monoclonal antibody that was recently approved by the United States Food and Drug Administration for the treatment of early symptomatic Alzheimer's disease (AD). The drug was approved with boxed warnings for amyloid-related imaging abnormalities (ARIA). While seizures are recognized adverse events, they are predominantly characterized in the context of ARIA and accompanied by edema (ARIA-E) or hemosiderin deposition (ARIA-H). The precise epileptogenic mechanisms of anti-amyloid immunotherapies independent of macroscopic ARIA remain poorly understood. We report the case of a 90-year-old man with mild cognitive impairment due to AD and a history of well-controlled focal epilepsy on levetiracetam, who experienced two generalized tonic-clonic seizures. Each paroxysmal event occurred within two hours of completing his fifth and sixth monthly donanemab (1,400 mg intravenous) infusions. Inter-ictal magnetic resonance imaging (MRI), including fluid-attenuated inversion recovery (FLAIR) and susceptibility-weighted imaging (SWI) sequences, demonstrated no evidence of ARIA-E or ARIA-H. Routine electroencephalography (EEG) revealed no interictal epileptiform discharges. Seizure recurrence necessitated an escalation of his levetiracetam dosage to 750 mg twice daily and the immediate discontinuation of donanemab therapy, after which he remained seizure-free. The temporal proximity of the seizures to the infusions, the positive rechallenge, and the absence of identifiable structural, metabolic, or infectious precipitants raise the possibility of an association with donanemab. However, causality cannot be established from a single case report. Several biologically plausible mechanisms may explain this temporal association, including rapid amyloid-beta (Aβ) clearance, microglial activation, neuroinflammatory responses, and transient blood-brain barrier dysfunction, which may lower the seizure threshold in a patient with pre-existing epileptogenic networks. However, these mechanisms remain hypothetical and were not directly demonstrated in this patient. Clinicians should maintain a high index of suspicion for acute post-infusion seizures in patients receiving donanemab, particularly those with a history of epilepsy, even in the absence of radiographically detectable ARIA. Clinicians should be aware of this potential safety signal in patients with pre-existing epilepsy. Additional studies are needed before specific monitoring or treatment recommendations can be established.
Epilepsy care is often guided by incomplete snapshots: patient-reported seizures, intermittent drug levels and medication histories that may not reflect current exposure. Between these snapshots, clinicians have little objective information about how the brain is responding to antiseizure medication. In this study, we tested whether intracranial EEG synchrony, a measure of coordinated neural activity across intracranial electrodes, tracks antiseizure medication load in patients with drug-resistant epilepsy. We retrospectively studied 80 consecutive patients with drug-resistant epilepsy who underwent presurgical intracranial EEG monitoring at the Hospital of the University of Pennsylvania. Antiseizure medication load was estimated continuously from medication administration records using a validated pharmacokinetic model. Synchrony was computed from intracranial EEG using the Kuramoto order parameter. We first compared synchrony within the same patient during high and low medication exposure. We then tested the continuous association between synchrony and medication load across the epilepsy monitoring unit admission, adjusting for time since admission, seizure timing, wakefulness, time of day and interictal spike rate. Analyses accounted for repeated measurements within patients and tested robustness to temporal structure in the recordings. We also assessed whether synchrony dynamics were preserved when fewer electrodes were sampled. Forty-five patients had sufficient high- and low-exposure data after peri-ictal exclusion. Synchrony was higher during low medication exposure in 32 of 45 patients, corresponding to a median 7.4% increase and a median paired difference of 0.0082 on the 0-1 synchrony scale (sign test P = 0.007; Wilcoxon P < 0.001). In the continuous analysis of 67 patients and 23,402 repeated 10-minute observations, higher synchrony was associated with lower medication load (β = -0.153, 95% confidence interval -0.293 to -0.012, P = 0.033); interictal spike rate was not independently associated with medication load. The inverse association remained evident in circular-shift, temporally binned and likelihood-based sensitivity analyses. Relative synchrony dynamics were preserved under electrode subsampling, with a median correlation of 0.85 with full-array synchrony at 40% sampling. These findings support synchrony as a candidate continuous physiological readout of antiseizure medication load in patients with drug-resistant epilepsy. By linking medication exposure to a measurable brain-network state, synchrony may help move epilepsy monitoring beyond seizure counting alone and toward continuous assessment of how the brain is responding to treatment.
The epileptic seizure (ES) is one of the most prominent neurological conditions, whose detection and classification from the electroencephalogram (EEG) signals is crucial for effective diagnosis of seizures, thereby eliminating the detrimental effects associated with it. However, the development of an automated ES detection system is hindered by the non-stationary, non-linear, and high-dimensional nature of the EEG signals, compounded by noise contamination and inter-subject variability. To address these challenges, this paper proposes an automated ES detection framework based on the De-mixing Multivariate Variational Mode Decomposition (D-MVMD) integrated with the Bayesian Optimized Support Vector Machine (BO-SVM). The D-MVMD decomposes multichannel EEG signals into band-limited intrinsic mode functions (BIMFs) while alleviating the correlation between corresponding modes through an ensemble correlation coefficient, while preserving the seizure characteristics from contamination. Multi-domain features capturing temporal, spectral, and non-linear dynamics of seizure activity are then extracted from the de-mixed BIMFs. ReliefF-ranked random forest-based feature selection is employed to find discriminative features, which are subsequently classified using the optimally tuned BO-SVM classifier. Experimental evaluation on the CHB-MIT demonstrates superior performance, with an accuracy of 98.52%, precision of 98.67%, sensitivity of 98.54%, specificity of 98.54%, and F1 score of 0.98. The model is also evaluated on the Siena dataset to assess its robustness across recording sessions of the same patient. Further, it is analyzed with other state-of-the-art methods, confirming its superior mode separation and enhanced seizure detection. Hence, this developed model proves itself to be an effective and robust model for detecting seizures using the multichannel EEG analysis.
Every revision of the seizure classification-most recently the 2025 International League Against Epilepsy (ILAE) update-refines terminology, yet it is worth asking whether patients are treated better because their seizures were renamed. The focal versus generalized dichotomy has organized epilepsy classification since the 1960 s and is grounded in a pharmacologic rationale, but head-to-head data from the SANAD trials show that efficacy differences between individual antiseizure medications frequently equal or exceed differences across the focal/generalized boundary. Meanwhile, the distinction that is genuinely transformative-whether an epilepsy is surgically remediable-produces seizure-freedom differences of an entirely different order of magnitude, and yet epilepsy surgery remains among the most underutilized evidence-based treatments in medicine. We argue that classification should elevate therapeutic trajectory over electroclinical phenomenology, and we propose an Interventional Axis built around three pathways: focal resection, neuromodulation, and palliative surgery, operating in parallel with pharmacotherapy rather than after its serial failure. Refining terminology improves communication, but the ultimate metric of a classification is outcome, not taxonomic elegance.
Drug-resistant epilepsy (DRE) affects approximately one-third of patients with epilepsy and represents a major unmet clinical need. While traditional hypotheses of pharmacoresistance have focused on alterations in drug targets, efflux transporter overexpression, and intrinsic disease severity, the gut microbiome has recently emerged as a potentially modifiable factor that may function as a systems-level modifier of these established mechanisms rather than a standalone pathway. The gut microbiome harbors a vast repertoire of drug-metabolizing enzymes capable of directly biotransforming orally administered antiseizure medications (ASMs)-including valproic acid, lamotrigine, carbamazepine, and oxcarbazepine-thereby altering their pharmacokinetics, bioavailability, and therapeutic efficacy. Additionally, microbial metabolites modulate host cytochrome P450 enzymes, nuclear receptors, and efflux transporters such as P-glycoprotein, while bacterial β-glucuronidases influence the enterohepatic recirculation of glucuronidated ASMs. Conversely, chronic ASM exposure reshapes the gut microbial ecosystem, creating a self-perpetuating cycle of dysbiosis and pharmacoresistance. This narrative review synthesizes current evidence on microbiome-ASM interactions in DRE, proposes a concrete experimental pipeline for characterizing ASM-specific microbial biotransformation, and outlines a framework for integrating physiologically based pharmacokinetic modeling with microbiome data. We discuss clinical implications for epileptologists-including the role of therapeutic drug monitoring in detecting microbiome-mediated pharmacokinetic variability, the concept of microbiome-neutral ASM selection, and earlier deployment of the ketogenic diet as a microbiome-targeted intervention. We highlight the translational potential of pharmacomicrobiomics-the study of how microbiome variation influences drug disposition and response-and identify critical knowledge gaps that warrant future investigation. PLAIN LANGUAGE SUMMARY: About one in three people with epilepsy continue to have seizures despite treatment. This review summarizes growing evidence that the gut microbiome-the community of bacteria living in the intestines-can influence how seizure medications work by altering their absorption, metabolism, and clearance. The medications themselves can reshape the microbiome in return, creating a cycle that may sustain treatment failure. Understanding this gut-drug relationship may open new paths to personalized epilepsy care through diet, probiotics, and microbiome-guided prescribing.
Organophosphate poisoning is a major cause of acute cholinergic toxicity and can progress rapidly to respiratory failure and death. In the emergency setting, diagnosis is often clinical, and treatment should not be delayed while awaiting confirmation of the specific compound. We report a case of a 30-year-old male patient who presented after intentional ingestion of a large reported volume of diazinon-containing pesticide. Within approximately 30 minutes of ingestion, he developed acute cholinergic manifestations, including bradypnea, bradycardia, hypotension, hypersalivation, vomiting, diarrhea, and depressed level of consciousness, complicated by a generalized tonic-clonic seizure. The seizure was treated with diazepam, and atropine was initiated before transfer to the emergency department. On arrival, the patient was in severe respiratory distress with profuse secretions and required urgent endotracheal intubation and mechanical ventilation. Empiric treatment for suspected organophosphate poisoning was continued with atropine and pralidoxime, alongside supportive care. Collateral history later identified the ingested product as Diacidol 600 Emulsifiable Concentrate, containing diazinon 600 g/L, equivalent to 60% weight/volume. Plasma butyrylcholinesterase, red blood cell acetylcholinesterase, and toxicological confirmation testing were not available at our institution at the time of evaluation, which represents a limitation of this report. The patient was admitted to the intensive care unit and managed with atropine and pralidoxime infusions, ventilatory support, and close monitoring for delayed neuromuscular complications. His cholinergic features resolved, and he was successfully extubated within 24 hours. Antidotal therapy was discontinued after sustained clinical improvement, and he remained stable during subsequent ward observation. This case emphasizes that severe organophosphate poisoning remains a clinical diagnosis during initial resuscitation. Early airway protection, titrated atropinization, pralidoxime therapy, benzodiazepines for seizures, and observation for delayed complications are central to favorable outcomes.
A multi-electrode array (MEA) is a powerful extracellular recording technique for long-term monitoring of neuronal network activity. In recent years, MEA-based assays have been applied increasingly to evaluate drug efficacy and neurotoxicity, including the assessment of anti-seizure medications (ASMs). However, systematic comparisons of ASMs with different mechanisms of action under identical experimental conditions remain limited. In this study, we evaluated the effects of 18 ASMs on neuronal network activity using MEA recordings under standardized conditions. Network activity was characterized using four components-spike, burst, network burst, and synchrony-and a total of 44 MEA-derived parameters were analyzed. Dimensionality reduction by t-distributed stochastic neighbor embedding (t-SNE) followed by hierarchical clustering classified the 18 ASMs into four distinct clusters. Cluster 1, including S-licarbazepine, oxcarbazepine, and lamotrigine, exhibited pronounced effects across all four network components. Cluster 2, comprising carbamazepine, eslicarbazepine acetate, phenytoin, phenobarbital, and stiripentol, significantly affected spike and burst duration but showed only limited effects on burst frequency, network burst frequency, or synchrony. Cluster 3 was solely diazepam, for which minimal effects were detected. The remaining ASMs were assigned to Cluster 4 and produced only minimal measurable effects in network activity. Several limitations should be considered, including the use of primary neuron cultures, incomplete maturation of certain drug targets, evaluation of only acute drug effects, and the limited spatial resolution of low-density MEA systems. Nevertheless, our results demonstrate that this MEA-based platform enables systematic evaluation of ASM effects on neuronal networks under identical experimental conditions. Furthermore, multivariate and unsupervised clustering analysis of 44 MEA parameters facilitated classification independent of drug mechanism of action. These findings suggest that MEA, combined with multidimensional data analysis, may provide a useful platform for the direct comparison of ASMs and could contribute to future pharmacological screening and drug discovery efforts.
Individual studies have highlighted elevated rates of post-traumatic stress disorder (PTSD) in cohorts of people with functional / dissociative seizures; however, prevalence estimates vary and the strength of the association between FDS and traumatic symptoms is contested. In the current review, we meta-analyse studies reporting the co-occurrence rate of PTSD and FDS before exploring sources of heterogeneity through moderator analysis. Systematic searches were performed in July 2025 in Scopus, MEDLINE and PsycInfo. We included studies reporting the proportion of adult FDS cohorts with clinically diagnosed or probable PTSD (e.g., passing thresholds on PTSD screening instruments). The Joanna Briggs Institute Quality Appraisal Tool was used to assess the quality of included studies. The random effects meta-analysis included 34 studies representing data from 31,711 individuals with FDS. The pooled effect size (PTSD and FDS co-occurrence) was 37.7% (95% CI = 30.0 - 45.6%). Between-study heterogeneity was partially explained by sample frame (clinical or non-clinical settings), risk of bias, and the method used for identifying PTSD. Studies of higher quality reported higher rates of comorbidity. Approximately one-third of those with FDS had been diagnosed with PTSD or were exhibiting symptoms likely to meet the diagnostic criteria for PTSD. Although this finding is clinically significant, most individuals with FDS do not meet this criterion, indicating PTSD is not a universal feature in the FDS population. Future meta-analyses would benefit from utilising individual patient data to enhance moderator interpretation.
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Children with generalized or multifocal drug-resistant epilepsy (DRE) without a clearly localizable and safely resectable seizure focus present a significant clinical challenge, as traditional resective interventions are often not viable. Emerging evidence supports the use of neuromodulation-particularly deep brain stimulation (DBS) and responsive neurostimulation (RNS)-for generalized and multifocal epilepsy in adults. However, safety and efficacy data for thalamic neuromodulation in pediatric populations remain limited. This single-institution case series describes, to our knowledge, the largest pediatric cohort treated with thalamic DBS or RNS for generalized or multifocal DRE, providing descriptive data on safety and seizure burden. The authors performed a retrospective chart review of pediatric patients with DRE who underwent thalamic neuromodulation using RNS or DBS at Seattle Children's Hospital between January 2020 and July 2025 with at least 6 months of follow-up. Clinical, surgical, and seizure outcome data were collected, including seizure frequency and complications. Seizure outcomes were stratified into categorical frequency bins, and a trend analysis was performed to evaluate postoperative shifts in seizure burden. Twenty-six patients (mean age 14.5, range 6-20 years) underwent thalamic neuromodulation with DBS (n = 12) or RNS (n = 14). The centromedian nucleus was the target in 24 cases; 1 patient each underwent targeting of the anterior nucleus and pulvinar nucleus. At the last follow-up (median 30.2 months), 65.4% of patients met the responder criteria (≥ 50% seizure reduction), with a higher response in the DBS group (83.3%) compared with the RNS group (50.0%). The median seizure reduction was 75.7% for DBS and 37.5% for RNS. A significant downward shift in seizure frequency was observed postoperatively across the entire cohort (p = 0.031), including among patients with the highest baseline seizure burden. No intraoperative complications occurred. Two patients (7.7%) required device explantation, 1 due to infection and 1 due to behavioral side effects, and 1 patient discontinued therapy without explantation. No instances of sudden unexpected death in epilepsy or hardware malfunction were observed. Thalamic neuromodulation using DBS and RNS was safe and well tolerated in pediatric patients with DRE, including multifocal and generalized seizure onsets. Meaningful seizure reduction was observed across a range of epilepsy phenotypes, with a trend toward greater benefit in the DBS group. These findings support thalamic neuromodulation as a promising treatment option in children with nonlesional DRE and highlight the need for prospective multicenter studies with extended follow-up.
SCN1A variants are the primary genetic cause of Dravet syndrome (DS), a severe developmental and epileptic encephalopathy characterized by early-onset prolonged seizures and progressive neurodevelopmental impairment. Early molecular diagnosis may influence treatment decisions and clinical outcomes. To characterize the molecular spectrum of SCN1A variants and describe the associated clinical and therapeutic features in children with suspected DS. This retrospective study included children evaluated between 2018 and 2020 with clinical suspicion of DS or febrile seizures with epilepsy who were referred for SCN1A genetic testing. Next-generation sequencing was used to detect sequence variants, complemented by multiplex ligation-dependent probe amplification for copy number analysis. A total of 60 patients were screened, and 18 patients carrying pathogenic or likely pathogenic SCN1A variants and fulfilling clinical criteria for DS were included. Eighteen patients were identified with heterozygous pathogenic or likely pathogenic SCN1A variants, including 6 novel variants. Segregation analysis demonstrated that all 15 tested patients had de novo variants. Seizure onset ranged from 2.5 to 8 months, predominantly before 6 months of age. Several patients were exposed to sodium channel-blocking agents prior to molecular confirmation, with seizure aggravation and subsequent treatment modification. All patients required multiple anti-seizure medications and showed varying degrees of neurodevelopmental impairment. SCN1A-confirmed DS is associated with substantial seizure burden and neurodevelopmental morbidity. Delayed molecular diagnosis may lead to inappropriate treatment exposure and seizure worsening. Early genetic testing in infants with early-onset seizures may improve treatment selection and clinical outcomes.
This study was undertaken to evaluate the safety, feasibility, and efficacy of low-intensity focused ultrasound (LIFU) as a noninvasive neuromodulation technique in patients with drug-resistant epilepsy (DRE). In this pilot, single-blind, randomized sham-controlled crossover trial, 12 patients with DRE underwent both LIFU and sham stimulation in a randomized sequence, targeting the seizure onset zone (SOZ), each followed by a 4-week observation period. Seizure frequency was analyzed as proportional change from baseline using linear mixed-effects models. An open-label extension phase evaluated longitudinal seizure outcomes following LIFU. Safety assessments included neurological examinations, magnetic resonance imaging (MRI), and neuropsychological and quality of life (QOL) measures. During the crossover phase, LIFU did not significantly reduce seizure frequency compared with sham (estimate = .49, 95% confidence interval [CI] = -.04 to 1.01, p = .068). No period or sequence effects were observed. Conversely, during the open-label extension phase, seizure frequency demonstrated a significant longitudinal reduction following LIFU (β = -14.0 percentage points per month, 95% CI = -22.2 to -5.8, p = .001). Post-LIFU MRI showed no structural lesions. No significant changes were observed in anxiety, depression, or QOL scores. There were only transient mild-to-moderate adverse events reported, without serious complications. LIFU neuromodulation targeting the SOZ is safe and well tolerated. Although the primary crossover analysis did not demonstrate a statistically significant antiseizure effect, delayed seizure reduction during the extended follow-up suggests potential sustained neuromodulatory effects. Larger parallel-group trials with longer observation periods are warranted.
Anterior nucleus of the thalamus (ANT) deep brain stimulation (DBS) is an effective therapy for frontotemporal and limbic drug-resistant focal epilepsies. The pulvinar nucleus (PUL) is an emerging neuromodulation target for seizure networks involving the posterior quadrant and temporal lobe. This study evaluates the safety and effectiveness of combined bilateral ANT plus PUL DBS for posterior quadrant and temporal lobe epilepsies. We conducted a single-center retrospective cohort study of patients receiving combined ANT/PUL DBS between 2021 and 2025. Outcomes included median seizure rate reduction (MSR), responder rate (RR; >50% seizure frequency reduction), and stimulation-related side effects, assessed across ANT, PUL, and concurrent ANT/PUL stimulation settings. Acute surgical complications were evaluated. Statistical significance was assessed using two-sided Wilcoxon signed-rank tests with Holm-Bonferroni correction. Nine patients with combined ANT/PUL DBS were identified, and eight patients had sufficient follow-up for inclusion (median follow-up = 20 months). Posterior predominant structural abnormalities were present in eight of nine patients. There were no acute surgical complications. Three instances of transient stimulation-related side effects resolved with parameter adjustments, whereas one patient required rescue antiseizure medication in addition to programming changes. Eight patients received periods of ANT stimulation, six PUL stimulation, and seven combined ANT/PUL stimulation. Regarding overall outcome, at last follow-up, there was a significant 80.8% MSR (p = .0078) and 87.5% RR, with two patients receiving ANT and six ANT/PUL stimulation. Regarding target-specific MSR, concurrent ANT/PUL DBS (68.8% MSR) showed a trend toward superior performance relative to ANT (43.3%) and PUL DBS (17.5%) alone, although subgroup analysis of target-specific performance did not reach statistical significance. Combined four-lead ANT/PUL DBS appears safe and effective for patients with drug-resistant posterior quadrant and temporal lobe epilepsies. Dual-network neuromodulation may provide greater flexibility to individually optimize neuromodulation for complex seizure networks.
Epilepsy is a common pediatric neurologic disorder, and its surgical management has increased over time. To characterize longitudinal changes in patient selection, surgical approach and outcomes, we report a 30-year retrospective review at a high-volume level 4 epilepsy center. Consecutive epilepsy surgeries from 1989 to 2018 were analyzed and grouped into early (1989-2003) and late (2004-2018) 15-year eras. Demographic, clinical, radiographic, surgical, and 2-year Engel outcome data were collected and analyzed. Multivariable logistic regression assessed independent associations between era, patient characteristics, imaging findings, surgical procedures, and seizure outcomes. Of 1241 surgical records, 1128 pediatric cases were included (415 early, 713 late; 55.50% male). Patients in the late era were older at surgery (10.27 vs. 8.53 years, p < .001), and repeat surgery was more common (p < .001). Focal (OR 1.72, p = .005) and cerebral insult related (OR 2.74, p < .001) MRI abnormalities were more frequently treated in the late era. Hemispherectomies, lobectomies and corpus callosotomies were performed less often (all p ≤ .001), while focal and multilobar resections remained stable (p > .05). Use of invasive monitoring and electrical stimulation mapping declined over time (p < .001). Seizure freedom rates were stable, however, ≥ 90% seizure reduction was more common in the late era (OR 1.60, p = .038). Over three decades, pediatric epilepsy surgical volume increased, surgery shifted towards older patients, with reduced extensive resection and reduced reliance on invasive monitoring. Despite these changes, seizure freedom rates remained stable, with improved near-complete seizure control in the later era.
Adults with developmental and epileptic encephalopathies (DEEs) often enter adult neurology care without etiologic clarification because of incomplete transition from pediatric services, outdated investigations, and attenuation of childhood electro-clinical features over time. We aimed to assess the clinical utility and diagnostic yield of a structured, phenotype-guided etiologic workup in adults meeting study criteria for DEE and to explore associations between electro-clinical phenotype and etiologic category. We prospectively enrolled consecutive adults (≥18 years) with drug-resistant epilepsy and neurodevelopmental impairment temporally related to epileptic activity, consistent with the ILAE operational definition of DEE, referred to a tertiary epilepsy center between May 2022 and December 2025. Patients underwent a 4-phase reassessment pathway including critical review of prior documentation, detailed clinical and semiologic phenotyping, prolonged video-EEG monitoring, phenotype-guided genetic testing (targeted resequencing, chromosomal microarray), high-resolution neuroimaging, and multidisciplinary case review to support etiologic clarification and treatment planning. Among 144 patients (mean age 28.4 years; 57.6% male), a confirmed etiology was identified in 91 (63.2%). Genetic causes predominated (65 patients, 45.1%), including monogenic (53, 36.8%) and chromosomal (12, 8.3%) disorders, primarily resolved via targeted resequencing gene panels and via chromosomal microarray analysis respectively, while structural-metabolic etiologies accounted for 26 cases (18.1%). Lennox-Gastaut syndrome was significantly associated with structural-metabolic and chromosomal etiologies (69.2% and 58.3% vs. 9.4% in monogenic; p < 0.0001), whereas, excluding patients with a broader Lennox-Gastaut syndrome phenotype, absence seizures occurred exclusively in monogenic cases (p = 0.024). Etiologic clarification changed clinical management in 27.1% of the cohort, including antiseizure medication optimization/precision therapies (25%) and pre-surgical referral (2.1%). In adults with suspected DEE, the practical value of this approach lies not only in diagnostic yield, but in showing that structured adult reassessment remains clinically worthwhile. Electro-clinical phenotype can help prioritize etiologic testing, and etiologic clarification can support more informed treatment planning and counseling even long after transition from pediatric care. Adults with developmental and epileptic encephalopathy (DEE) often reach adult epilepsy services without a clear diagnosis. In this study, we used a structured approach combining clinical review, video-EEG, MRI, genetic testing, and multidisciplinary discussion in 144 adults with suspected DEE. We identified a confirmed cause in 63.2% of patients. Genetic causes were the most common, but structural and metabolic causes were also important. Some seizure patterns helped guide diagnosis: Lennox-Gastaut syndrome was more common in structural-metabolic and chromosomal cases, while absence seizures occurred only in monogenic cases. Identifying the cause also helped guide treatment decisions, including medication changes, targeted therapies, surgery referral, and genetic counseling. This study shows that adults with suspected DEE can still benefit from careful diagnostic reassessment, even years after childhood.