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Background: Lennox-Gastaut syndrome (LGS) is a severe drug-resistant epileptic syndrome. Palliative treatments such as corpus callosotomy (CC) and vagus nerve stimulation (VNS) have emerged as treatments to reduce the number of seizures in patients. The aim of this study is to compare the effectiveness of CC and VNS in patients with LGS studied in the last 30 years., Materials and Methods: We conducted a systematic review with meta-analysis and collected papers from PubMed (MEDLINE), Ovidsp, Web of Science, and Cochrane Library data bases. The articles analyzed were published between January 1990 and December 2020. Keywords were chosen based on internal and external validation in the PubMed data base (the analysis is available in the Supplementary Data Supplementary Appendix). Prospective or retrospective case reports (n ≥ 2), case series, cohort studies, or case-control studies involving patients with LGS were included in the analysis. We selected studies that had no age or sex restriction and that provided data on seizures before and after treatments. Studies not written in English, published without peer review, or not indexed in the data bases were excluded. Other exclusion criteria were the absence of seizure data and the impossibility of extracting this information from the studies. To analyze the results, we used the random-effects model based on the assessment of heterogeneity (I 2 statistics) in two scenarios. In scenario 1, we assessed the incidence of patients with a seizure reduction ≥ 50%; in scenario 2, we assessed the incidence of patients with a seizure reduction > 0%., Results: Of the 7418 articles found using the keywords, 32 were considered eligible. Of these, 18 articles were on VNS (175 patients) and 14 on CC (107 patients). For scenario 1 (seizure reduction ≥ 50%), CC had an incidence of 65% (95% CI, 37%-94%), with an I 2 value of 82.7%; VNS had an incidence of 34% (95% CI, 11%-57%), with an I 2 value of 80.7%. For scenario 2 (seizure reduction > 0%), CC had an incidence of 80% (95% CI, 58%-100%), with an I 2 value of 84.7%; VNS had an incidence of 64% (95% CI, 38%-89%), with an I 2 value of 90.8%. There was an overlap of confidence intervals, with no statistical difference between the treatments in both scenarios., Discussion: Our analysis of LGS showed that the CC and VNS treatments are significantly beneficial to reducing seizures, without superiority between them., (Copyright © 2022 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Objective: Physiological parameters that predict electroconvulsive therapy (ECT) effectiveness may reflect propagation of the induced epileptic seizure. As an indication of seizure propagation to the diencephalon, we here examined the correlation between prolactin increase after ECT and clinical seizure evaluation parameters, focusing on peak heart rate. As a proxy for peripheral endocrine stress response, we examined the correlation to postictal cortisol increase., Methods: Participants were consecutively recruited from clinical ECT patients ( n  = 131, age 18-85 years). The first ECT session in a series was examined. For each participant, blood serum concentrations of prolactin and cortisol were measured immediately before and within 30 min after the seizure. Physiological parameters were extracted from clinical records: peak heart rate (HR) during seizure, electroencephalography (EEG) seizure duration, and motor seizure duration. Correlations were calculated using non-parametric tests., Results: Serum prolactin increased after ECT and correlated with peak HR, EEG seizure duration, and motor seizure duration. Peak HR during seizure also correlated positively with both EEG seizure duration and motor seizure duration. Correlations were unaffected by age, sex, baseline prolactin levels, antipsychotics, or beta-blocking agents. Serum cortisol increased after ECT but did not correlate with the seizure evaluation parameters, nor with prolactin concentrations., Conclusions: Our findings of a positive correlation between peak HR and prolactin that was independent from the peripheral endocrine stress response might be in line with the idea that tachycardia during ECT seizures reflects seizure propagation to the diencephalon. This supports the practice of monitoring cardiovascular response for ECT seizure evaluation.

Neuromodulation (neurostimulation) is a relatively new and rapidly growing treatment for refractory epilepsy. Three varieties are approved in the US: vagus nerve stimulation (VNS), deep brain stimulation (DBS) and responsive neurostimulation (RNS). This article reviews thalamic DBS for epilepsy. Among many thalamic sub-nuclei, DBS for epilepsy has been targeted to the anterior nucleus (ANT), centromedian nucleus (CM), dorsomedial nucleus (DM) and pulvinar (PULV). Only ANT is FDA-approved, based upon a controlled clinical trial. Bilateral stimulation of ANT reduced seizures by 40.5% at three months in the controlled phase (p = .038) and 75% by 5 years in the uncontrolled phase. Side effects related to paresthesias, acute hemorrhage, infection, occasional increased seizures, and usually transient effects on mood and memory. Efficacy was best documented for focal onset seizures in temporal or frontal lobe. CM stimulation may be useful for generalized or multifocal seizures and PULV for posterior limbic seizures. Mechanisms of DBS for epilepsy are largely unknown, but animal work points to changes in receptors, channels, neurotransmitters, synapses, network connectivity and neurogenesis. Personalization of therapies, in terms of connectivity of the seizure onset zone to the thalamic sub- nucleus and individual characteristics of the seizures, might lead to improved efficacy. Many questions remain about DBS, including the best candidates for different types of neuromodulation, the best targets, the best stimulation parameters, how to minimize side effects and how to deliver current noninvasively. Despite the questions, neuromodulation provides useful new opportunities to treat people with refractory seizures not responding to medicines and not amenable to resective surgery., Competing Interests: Declaration of Competing Interest Competing interests: Dr. Fisher has no specific competing interests. He was a former consultant to Medtronic and Cyberonics and currently holds stock or options in Avails Medical, Cerebral Therapeutics, Eysz, Irody, Smart Monitor and Zeto., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Intensive Short-Term Psychodynamic Therapy (ISTDP) has demonstrated promising evidence for the treatment of Functional Neurological Disorders (FND) including functional seizures. This paper aimed to further examine the therapeutic effects of a 3-session course of this treatment focusing on its potential to maintain reduced healthcare utility within a group of patients with complex difficulties, across an extended time period, post-therapy. The original study followed a mixed methods case series design and recruited 18 patients from secondary adult mental health care and specialist neurology services. Seventeen participants completed the intervention and attendance rates were very high (95%). In this follow-up study, which was solely focused on the utilization of healthcare resources, results showed decreases when comparing 12 months prior and 12 months post three sessions of ISTDP. The results provide further support for the use of ISTDP in this group of participants with complex clinical presentations, specifically, its capacity to reduce healthcare usage over 12 months post-therapy. Further evidence from controlled and randomized studies with larger sample sizes is warranted., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: There are three neurostimulation devices available to treat generalized epilepsy: vagus nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS). However, the choice between them is unclear due to lack of head-to-head comparisons. A systematic comparison of neurostimulation outcomes in generalized epilepsy has not been performed previously. The goal of this meta-analysis was to determine whether one of these devices is better than the others to treat generalized epilepsy., Methods: Following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic review of PubMed, Embase, and Web of Science was performed for studies reporting seizure outcomes following VNS, RNS, and DBS implantation in generalized drug-resistant epilepsy between the first pivotal trial study for each modality through August 2022. Specific search criteria were used for VNS ("vagus", "vagal", or "VNS" in the title and "epilepsy" or "seizure"), DBS ("deep brain stimulation", "DBS", "anterior thalamic nucleus", "centromedian nucleus", or "thalamic stimulation" in the title and "epilepsy" or "seizure"), and RNS ("responsive neurostimulation" or "RNS" in the title and "epilepsy" or "seizure"). From 4409 articles identified, 319 underwent full-text reviews, and 20 studies were included. Data were pooled using a random-effects model using the meta package in R., Results: Sufficient data for meta-analysis were available from seven studies for VNS (n = 510) and nine studies for DBS (n = 87). Data from RNS (five studies, n = 18) were insufficient for meta-analysis. The mean (SD) follow-up durations were as follows: VNS, 39.1 (23.4) months; DBS, 23.1 (19.6) months; and RNS, 22.3 (10.6) months. Meta-analysis showed seizure reductions of 48.3% (95% confidence interval [CI] = 38.7%-57.9%) for VNS and 64.8% (95% CI = 54.4%-75.2%) for DBS (p = .02)., Significance: Our meta-analysis indicates that the use of DBS may lead to greater seizure reduction than VNS in generalized epilepsy. Results from RNS use are promising, but further research is required., (© 2023 International League Against Epilepsy.)

Objective: We aim to provide a quantitative description of the relation between seizure duration and the postictal state using features extracted from the postictal electroencephalogram (EEG)., Methods: Thirty patients with major depressive disorder treated with electroconvulsive therapy (ECT) were studied with continuous EEG before, during, and after ECT-induced seizures. EEG recovery was quantified as the spectral difference between postictal and baseline EEG using the temporal brain symmetry index (BSI). The postictal temporal EEG evolution was modeled with a single exponential. The parameters of the model, including the time constant τ, describe the change and speed of postictal EEG recovery. The change from baseline EEG at t = 60 minutes post-seizure (ΔBSI) was calculated from the exponential fit. Postictal clinical reorientation time (ROT) was clinically established. A multivariate generalized multi-level Bayesian model was estimated with seizure duration and ROT as predictors of τ and ΔBSI., Results: EEG features of 290 seizures and postictal states were used for analyses. The model faithfully described the dynamics of the postictal EEG in nearly all patients. Seizure duration was associated with the recovery time constant, τ, and ΔBSI. ROT was associated with τ, but not with ΔBSI., Conclusions: Longer seizures are associated with slower postictal EEG recovery and more enduring EEG changes compared to baseline., Significance: Quantitative EEG allows objective assessment of the postictal state., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: The major advances in critical care EEG have been the development of rapid response EEG, major revision of the American Clinical Neurophysiology Society's (ACNS) standardized critical care EEG terminology, and the commencement of treatment trials on rhythmic and periodic patterns (RPPs) that do not qualify as seizures., Recent Findings: Rapid response EEG (rEEG) has proven an important supplement to full montage continuous EEG monitoring (cEEG). This EEG can be applied in a few minutes and provides excellent ability to exclude seizures, selecting those where conversion to cEEG would have the greatest diagnostic yield. Once cEEG has been commenced, the durations required to adequately exclude seizures have been refined. The ACNS provided major revision and expansion to the standardized critical care EEG terminology, which paved the way for determining with great accuracy the RPPs that are associated with seizures and that are capable of causing neurologic symptoms and/or secondary neuronal injury. The current limitations to multicenter treatment trials of these patterns have been highlighted., Summary: Novel methods of EEG in critical care have been expanding access to all patients where clinically indicated. Standardized EEG terminology has provided the framework to determine what patterns in which presenting causes warrant treatment vs. those that do not., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Neurostimulation is a quickly growing treatment approach for epilepsy patients. We summarize recent approaches to provide a perspective on the future of neurostimulation., Recent Findings: Invasive stimulation for treatment of focal epilepsy includes vagus nerve stimulation, responsive neurostimulation of the cortex and deep brain stimulation of the anterior nucleus of the thalamus. A wide range of other targets have been considered, including centromedian, central lateral and pulvinar thalamic nuclei; medial septum, nucleus accumbens, subthalamic nucleus, cerebellum, fornicodorsocommissure and piriform cortex. Stimulation for generalized onset seizures and mixed epilepsies as well as increased efforts focusing on paediatric populations have emerged. Hardware with more permanently implanted lead options and sensing capabilities is emerging. A wider variety of programming approaches than typically used may improve patient outcomes. Finally, noninvasive brain stimulation with its favourable risk profile offers the potential to treat increasingly diverse epilepsy patients., Summary: Neurostimulation for the treatment of epilepsy is surprisingly varied. Flexibility and reversibility of neurostimulation allows for rapid innovation. There remains a continued need for excitability biomarkers to guide treatment and innovation. Neurostimulation, a part of bioelectronic medicine, offers distinctive benefits as well as unique challenges., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: We examined seizure control during spontaneous responsive neurostimulation (RNS) battery failure to investigate the persistent benefits of RNS in the absence of neurostimulation. We hypothesized that the loss of direct RNS does not immediately result in seizure worsening., Methods: Patients with RNS battery failure between August 2019 and December 2020 at a single institution were studied. During periods of battery depletion, the RNS device does not store any electrocorticography records, so we used a telephone-based survey and chart review to assess seizure control during battery depletion., Results: Eight of 10 eligible participants responded to the survey, with a mean duration of battery failure of 36 days (range: 10-219 days). During battery depletion, one patient reported decreased seizures and five reported no changes in seizure frequency. Only two patients reported increased seizure frequency., Significance: The benefits of RNS treatment may outlast the immediate effects of direct neurostimulation, lending support to the notion of persistent neuroplasticity. Larger studies should confirm our preliminary findings., (© 2023 International League Against Epilepsy.)

Objective: Despite antiepileptic drugs, more than 30% of people with epilepsy continue to have seizures. Patients with such drug-resistant epilepsy (DRE) may undergo invasive treatment such as resection, laser ablation of the epileptogenic focus, or vagus nerve stimulation, but many are not candidates for epilepsy surgery or fail to respond to such interventions. Responsive neurostimulation (RNS) provides a neuromodulatory option. In this study, the authors present a single-center experience with the use of RNS over the last 5 years to provide long-term control of seizures in patients with DRE with at least 1 year of follow-up., Methods: The authors performed a retrospective analysis of a prospectively collected single-center database of consecutive DRE patients who underwent RNS system implantation from September 2015 to December 2020. Patients were followed-up postoperatively to evaluate seizure freedom and complications., Results: One hundred patients underwent RNS placement. Seven patients developed infections: 2 responded to intravenous antibiotic therapy, 3 required partial removal and salvaging of the system, and 2 required complete removal of the RNS device. No postoperative tract hemorrhages, strokes, device migrations, or malfunctions were documented in this cohort. The average follow-up period was 26.3 months (range 1-5.2 years). In terms of seizure reduction, 8 patients had 0%-24% improvement, 14 had 25%-49% improvement, 29 experienced 50%-74% improvement, 30 had 75%-99% improvement, and 19 achieved seizure freedom. RNS showed significantly better outcomes over time: patients with more than 3 years of RNS therapy had 1.8 higher odds of achieving 75% or more seizure reduction (95% CI 1.07-3.09, p = 0.02). Also, patients who had undergone resective or ablative surgery prior to RNS implantation had 8.25 higher odds of experiencing 50% or more seizure reduction (95% CI 1.05-65.1, p = 0.04)., Conclusions: Responsive neurostimulator implantation achieved 50% or more seizure reduction in approximately 80% of patients. Even in patients who did not achieve seizure freedom, significant improvement in seizure duration, severity, or postictal state was reported in more than 68% of cases. Infection (7%) was the most common complication. Patients with prior resective or ablative procedures and those who had been treated with RNS for more than 3 years achieved better outcomes.

Objective: The aim of this study was to assess the safety and efficacy of combined active responsive neurostimulation (RNS) and vagus nerve stimulation (VNS) therapies in pediatric patients with drug-resistant epilepsy., Methods: A single-center retrospective chart review was conducted on pediatric patients implanted with the RNS System with a concomitant active VNS System (VNS+RNS) between 2015 and 2021. Patients with at least 1 month of overlapping concomitant VNS and RNS treatment were included. Patients who had an RNS device implanted after 21 years of age, those who had responsive neurostimulators implanted after their VNS was inactivated, or those in whom the VNS battery died and was not replaced before RNS System implantation were excluded., Results: Seven pediatric VNS+RNS patients were identified, and their courses of treatment were evaluated. All patients tolerated concurrent VNS and RNS treatment well, no device-device interactions were identified, and no major treatment-related adverse effects were noted. The median follow-up after RNS System implantation was 1.2 years. By electroclinical criteria, all 7 patients achieved 75%-99% reductions in the frequency of disabling seizures after RNS System implantation. By patient and caregiver report, 2 patients (28.6%) had 75%-99% reductions in the frequency of their disabling seizures, 2 patients (28.6%) achieved 50%-74% reductions, 2 patients achieved 1%-24% reduction in frequency of disabling seizures, and 1 patient (14.3%) experienced a 1%-24% increase in seizure frequency. The available VNS magnet swipe data identified 2 patients with 75%-99% reductions in seizure frequency as measured by magnet swipes, one with 25%-49% reductions and the other with 1%-24% increases in seizure frequency as measured by magnet swipes., Conclusions: This study demonstrated that RNS and VNS therapies can safely be used simultaneously in pediatric patients. RNS may potentially augment the therapeutic effects of VNS treatment. Patients in whom a response to VNS has been suboptimal should still be considered for RNS therapy.

Here, we present a protocol using optogenetics or chemogenetics to assess the neuronal circuits contributing to seizure initiation. Both approaches allow for targeted control of neuronal populations in vivo and can be combined with experimental manipulations to acutely induce seizures in rodent models. We describe how to (1) introduce and (2) activate optogenetic or chemogenetic actuators while (3) inducing seizures via hyperthermia in a mouse model of epilepsy. This protocol can be adapted for use in other induced seizure models. For complete details on the use and execution of this protocol, please refer to Mattis et al. (2022). 1 ., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Millions of people around the world are affected by different kinds of epileptic seizures. A deep brain stimulator is now claimed to be one of the most promising tools to control severe epileptic seizures. The present study proposes Hodgkin-Huxley (HH) model-based Active Fault Tolerant Deep Brain Stimulator (AFTDBS) for brain neurons to suppress epileptic seizures against ion channel conductance variations using a Deep Neural Network (DNN). The AFTDBS contains the following three modules: (i) Detection of epileptic seizures using black box classifiers such as Support Vector Machine (SVM) and K-Nearest Neighbor (KNN), (ii) Prediction of ion channels conductance variations using Long Short-Term Memory (LSTM), and (iii) Development of Reconfigurable Deep Brain Stimulator (RDBS) to control epileptic spikes using Proportional Integral (PI) Controller and Model Predictive Controller (MPC). Initially, the synthetic data were collected from the HH model by varying ion channel conductance. Then, the seizure was classified into four groups namely, normal and epileptic due to variations in sodium ion-channel conductance, potassium ion-channel conductance, and both sodium and potassium ion-channel conductance. In the present work, current controlled deep brain stimulators were designed for epileptic suppression. Finally, the closed-loop performances and stability of the proposed control schemes were analyzed. The simulation results demonstrated the efficacy of the proposed DNN-based AFTDBS., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Inhibitory interneuron progenitors capable of integrating into epileptic host circuitry hold great potential for correcting network hyperexcitability and reducing seizures in temporal lobe epilepsy. In this issue of Neuron, Zhu and colleagues 1 report robust seizure suppression by hPSC-derived interneurons up to 9 months post-transplantation, significantly extending the duration observed previously., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Previously, we demonstrated the efficacy of human pluripotent stem cell (hPSC)-derived GABAergic cortical interneuron (cIN) grafts in ameliorating seizures. However, a safe and reliable clinical translation requires a mechanistic understanding of graft function, as well as the assurance of long-term efficacy and safety. By employing hPSC-derived chemically matured migratory cINs in two models of epilepsy, we demonstrate lasting efficacy in treating seizures and comorbid deficits, as well as safety without uncontrolled growth. Host inhibition does not increase with increasing grafted cIN densities, assuring their safety without the risk of over-inhibition. Furthermore, their closed-loop optogenetic activation aborted seizure activity, revealing mechanisms of graft-mediated seizure control and allowing graft modulation for optimal translation. Monosynaptic tracing shows their extensive and specific synaptic connections with host neurons, resembling developmental connection specificity. These results offer confidence in stem cell-based therapy for epilepsy as a safe and reliable treatment for patients suffering from intractable epilepsy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Seizure emergencies and potential emergencies, ranging from seizure clusters to prolonged seizure and status epilepticus, may affect adults with epilepsy despite stable antiseizure therapy. Seizure action plans (SAPs) are designed for patients and their caregivers/care partners to provide guidance on the individualized treatment plan, including response to potential seizure emergencies and appropriate use of rescue therapy. The use of pediatric SAPs is common (typically required by schools), however, most adults with epilepsy do not have a plan. Patient-centered action plans are integral to care for other chronic conditions and may offer insights applicable to the care of adults with epilepsy. This review analyzes the potential benefits of action plans for medical conditions by exploring their utility in conditions such as asthma, diabetes, chronic obstructive pulmonary disease, heart disease, and opioid overdose. Evidence across these conditions substantiates the value of action plans for patients, and the benefits of adult SAPs in epilepsy are emerging. Because wide implementation of SAPs has faced barriers, other conditions may provide insights that are relevant to implementing SAPs in epilepsy. Based on these analyses, we propose concrete steps to improve the use of SAPs among adults. A recent consensus statement promoting the use of formal SAPs in epilepsy and advances in rescue therapy delivery methods provides support to engage patients around the value of SAPs. The precedent for use of SAPs for pediatric epilepsy patients serves as the foundation to support increased usage in adults. Seizure action plans in the context of improved clinical outcomes are expected to reduce healthcare utilization, improve patient quality of life, and optimize epilepsy management., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr Herman is a consultant for BioSerenity, and has received grant funding from Cerebral Therapeutics; CREmedical; Equilibre; Marinus Pharmaceuticals; Medtronic; Neuroelectrics, and the Epilepsy Foundation. She is President of the National Association of Epilepsy Centers and is a co-leader of the Epilepsy Learning Healthcare System. Dr Detyniecki is a consultant for Aquestive; Neurelis, Inc.; UCB; and Greenwich Biosciences. Ms O’Hara is on the Advisory Board of Greenwich Biosciences. Dr Penovich has served on speakers bureaus for GW Pharmaceuticals; Neurelis, Inc.; SK Life Science; and UCB, and is an advisor to Engage Therapeutics; LVIS Corporation; Neurelis, Inc.; and SK Life Science. Dr Rao has served as a consultant for NeuroPace, Inc., manufacturer of the RNS System. Dr Tatum receives a stipend from Elsevier as Editor-in-Chief of Epilepsy & Behavior Reports and is on the Editorial Board of Journal of Clinical Neurophysiology. He has received grant funding from Esai; Mayo Clinic; McElvey Fund; and Martin Family Foundation and industry research support from Cerevel; Engage; Liva Nova; and Xenon. He serves as a consultant for BioSerenity; Medtronic; Neurelis, Inc.; and Zimmer-Biomet. Royalties from Demos and Springer Publishers. He has patents/patents pending on intraoperative monitoring devices (#62527896; #62770362). Ms Long is a consultant for Neurelis, Inc.; SK Life Science; and Supernus Pharmaceuticals, and is a speaker for LivaNova. Dr Stern is a consultant for Eisai; Jazz; Neurelis, Inc.; SK Life Science; and UCB. Dr Carrazana is an employee of and has received stock and stock options from Neurelis, Inc. Dr Rabinowicz is an employee of and has received stock options from Neurelis, Inc., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Acute symptomatic seizures (ASyS) after stroke are not uncommon. However, the impact of ASyS and its management with anti-seizure medications (ASMs) on patient-reported outcome measures (PROMs) remains poorly investigated. The objective of our study is to evaluate the association between PROMs and ASyS and ASMs following stroke., Methods: We performed a retrospective cohort study of all stroke patients who underwent inpatient continuous EEG (cEEG) monitoring performed due to suspected ASyS, including the ones with observed convulsive ASyS, from 04/01/2012 to 03/31/2018, who completed PROMs within 6 months of hospital discharge. Patient-reported outcome measures, including one Neuro-QoL and six PROMIS v1.0 domain scales, were completed by patients as the standard of care in ambulatory stroke clinics. Since ASMs are sometimes used without clearly diagnosed ASyS, we performed group comparisons based on ASM status at discharge, irrespective of their ASyS status. T-tests or Wilcoxon rank sum tests compared continuous variables across groups and chi-square tests or Fisher's exact tests were used for categorical variables., Results: A total of 508 patients were included in the study [mean age 62.0 ± 14.1 years, 51.6% female; 244 (48.0%) ischemic stroke, 165 (32.5%) intracerebral hemorrhage, and 99 (19.5%) subarachnoid hemorrhage]. A total of 190 (37.4%) patients were discharged on ASMs. At the time of the first PROM, conducted a median of 47 (IQR = 33-78) days after the suspected ASyS, and 162 (31.9%) were on ASMs. ASM use was significantly higher in patients diagnosed with ASyS. Physical Function and Satisfaction with Social Roles and Activities were the most affected health domains. Patient-reported outcome measures were not significantly different between groups based on ASyS (electrographic and/or convulsive), ASM use at hospital discharge, or ASM status on the day of PROM completion., Significance: There were no differences in multiple domain-specific PROMs in patients with recent stroke according to ASyS status or ASM use suggesting the possible lack of the former's sensitivity to detect their impact. Additional research is necessary to determine if there is a need for developing ASyS-specific PROMs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Deep brain stimulation (DBS) and electromagnetic induction are new techniques that are increasingly used in modern epilepsy treatments; however, the mechanism of action remains unclear. In this study, we constructed a bidirectional-coupled cortico-thalamic model, based on which we proposed three regulation schemes: isolated regulation of DBS, isolated regulation of electromagnetic induction and combined regulation of the previous two. In particular, we introduced DBS with a lower amplitude and considered the influence of electromagnetic induction caused by the transmembrane current on the membrane potential. The most striking finding of this study is that the three therapeutic schemes could effectively control abnormal discharge, and combined regulation could reduce the occurrence of epileptic seizures more effectively. The present study bridges the gap between the bidirectional coupling model and combined control. In this way, the damage induced by electrical stimulation of the patient's brain tissue could be reduced, and the abnormal physiological discharge pattern of the cerebral cortex was simultaneously regulated by different techniques. This work opens new avenues for improving brain dysfunction in patients with epilepsy, expands ideas for promoting the development of neuroscience and is meaningful for improving the health of modern society and developing the field of science., (© 2023 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: The purpose of this review is to present the current literature and to highlight the most recent findings in brain arteriovenous malformations (bAVM)-related epilepsy research., Methods: We searched Medline, PubMed, Biblioinserm, Cochrane Central to study the latest research reports about the different factors that could be responsible for the genesis of bAVM-related epilepsy. We analyzed if epileptogenesis has any characteristics traits and its relation with the vascular malformation. The results of different treatments on epilepsy were considered. Typical errors that may lead towards incorrect or worse management of the seizures for these patients were also examined., Results: The development of bAVM results from multifactorial etiologies and bAVM-related epileptogenesis is likely specific for this pathology. Different types of evidence demonstrate a bidirectional relationship between bAVM and epilepsy. Currently, there is not enough published data to determine what may be the right management for these patients., Conclusions: A better understanding of epileptogenesis in conjunction with knowledge of the complex alterations of structures and functions following bAVM-related seizures is necessary. Identification of biomarkers that can identify subgroups most likely to benefit from a specific intervention are needed to help guide clinical management. A new concept for the treatment of epilepsy related to an unruptured bAVM that cannot be treated invasively is proposed as well as new therapeutic perspectives. The next necessary step will be to propose additional algorithms to improve the development of future trials., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

There is increasing human and animal evidence that brain oscillations play a critical role in the development of spatial cognition. In rat pups, disruption of hippocampal rhythms via optogenetic stimulation during the critical period for memory development impairs spatial cognition. Early-life seizures are associated with long-term deficits in spatial cognition and aberrant hippocampal oscillatory activity. Here we asked whether modulation of hippocampal rhythms following early-life seizures can reverse or improve hippocampal connectivity and spatial cognition. We used optogenetic stimulation of the medial septum to induce physiological 7 Hz theta oscillations in the hippocampus during the critical period of spatial cognition following early-life seizures. Optogenetic stimulation of the medial septum in control and rats subjected to early-life seizures resulted in precisely regulated frequency-matched hippocampal oscillations. Rat pups receiving active blue light stimulation performed better than the rats receiving inert yellow light in a test of spatial cognition. The improvement in spatial cognition in these rats was associated with a faster theta frequency and higher theta power, coherence and phase locking value in the hippocampus than rats with early-life seizures receiving inert yellow light. These findings indicate that following early life seizures, modification of hippocampal rhythms may be a potential novel therapeutic modality., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Drug-resistant epilepsy can be difficult to cure and may pose emotional challenges for epilepsy providers. Neuropalliative care (NPC) can augment quality of life (QOL) in persons with neurological diseases and may add meaningful elements to the treatment repertoire of epilepsy specialists even if seizures continue. However, NPC has not been widely implemented in epilepsy. Our study aimed to determine whether physicians of persons with drug-resistant epilepsy (PWDRE) experience distress when faced with treatment failure (Engel class ≥ 2), either failure of medications-only (PWDREmo) or of both medications and surgery (procedures with curative intent (PWDREms)). Furthermore, we evaluated physician knowledge about and referrals to NPC following treatment failures to help improve patient QOL despite ongoing seizures., Methods: An anonymous online survey was distributed to US epilepsy physicians through the American Epilepsy Society website and personal email to assess levels of distress experienced when caring for PWDREmo and PWDREms (7-point Likert scale ["1" = "no distress", "7" = "most distress ever felt"]), and knowledge and use of NPC., Results: Eighty-two physicians completed the survey. Most experienced distress when epilepsy treatments failed: 59% felt moderate distress (≥4) with PWDREmo (median "4", mean 3.74, range 1-7), 90% suffered moderate to severe distress (5, 5.17, 1-7) with PWDREms. Distress over PWDREms was significantly greater than distress over PWDREmo (p < 0.0001). Forty-three percent reported confidence in their knowledge about NPC. Only 15% were likely to refer PWDREmo to NPC, while 44% would consider it for PWDREms., Conclusion: Among survey responders, physician distress was high when confronted with treatment failures, especially the failure of epilepsy surgery. Fewer than half of responders were likely to refer patients to NPC. Further research is necessary to determine extent, reasons, and effects of physician distress and whether improved understanding of and patient access to NPC would help alleviate physician distress when faced with treatment failures in PWDRE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purposeful induction of fever for healing, including the treatment of epilepsy, was used over 2000 years ago by Hippocrates. More recently, fever has been demonstrated to rescue behavioral abnormalities in children with autism. However, the mechanism of fever benefit has remained elusive due in large part to the lack of appropriate human disease models recapitulating the fever effect. Pathological mutations in the IQSEC2 gene are frequently seen in children presenting with intellectual disability, autism and epilepsy. We recently described a murine A350V IQSEC2 disease model, which recapitulates important aspects of the human A350V IQSEC2 disease phenotype and the favorable response to a prolonged and sustained rise in body core temperature in a child with the mutation. Our goal has been to use this system to understand the mechanism of fever benefit and then develop drugs that can mimic this effect and reduce IQSEC2-associated morbidity. In this study, we first demonstrate a reduction in seizures in the mouse model following brief periods of heat therapy, similar to what was observed in a child with the mutation. We then show that brief heat therapy is associated with the correction of synaptic dysfunction in neuronal cultures of A350V mice, likely mediated by Arf6-GTP.

Background: Arterial cerebral air embolism (CAE) is an uncommon but potentially catastrophic event. Patients can present with focal neurologic deficits, seizures, or coma. They may be treated with hyperbaric oxygen therapy. We review the causes, radiographic and clinical characteristics, and outcomes of patients with CAE., Methods: We performed a retrospective chart review via an existing institutional database at Mayo Clinic to identify patients with arterial CAE. Demographic data, clinical characteristics, and diagnostic studies were extracted and classified on predefined criteria of diagnostic confidence, and descriptive and univariate analysis was completed., Results: Fifteen patients met criteria for inclusion in our study. Most presented with focal deficits (80%) and/or coma (53%). Seven patients (47%) had seizures, including status epilepticus in one (7%). Five presented with increased muscle tone at the time of the event (33%). Computed tomography (CT) imaging was insensitive for the detection of CAE, only identifying free air in 4 of 13 who underwent this study. When obtained, magnetic resonance imaging typically showed multifocal areas of restricted diffusion. Six patients (40%) were treated with hyperbaric oxygen therapy. Age, Glasgow Coma Scale score at nadir, and use of hyperbaric oxygen therapy were not associated with functional outcome at 1 year in our cohort. Twenty-six percent of patients had a modified Rankin scale score of 0 one year after the event, and functional improvement over time was common after discharge., Conclusions: A high index of clinical suspicion is needed to identify patients with CAE because of low sensitivity of free air on CT imaging and nonspecific clinical presentation. Acute alteration of consciousness, seizures, and focal signs occur frequently. Because improvement over time is possible even among patients with severe presentation, early prognostication should be approached with caution., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.)

Background: Drug-resistant epilepsy is a challenging problem in pediatrics. Transcranial direct current stimulation (TDCS) is a non-invasive neurostimulation technique suggested as a promising method for treating epilepsy. This study aims to evaluate the efficacy of TDCS in focal epilepsy in children with drug-resistant epilepsy., Method: We conducted a randomized sham-controlled study with 18 subjects between 6 and 16 years of age, divided equally into two groups. TDCS was performed in 20-minute daily stimulation protocol for five days for both groups. The current intensity was one mA for the first three days, increasing to 1.5 mA on day four and 2 mA on the last day of stimulation. EEG was done before and after the intervention., Results: There was a significant reduction in seizure duration in the case group compared with the sham group., Conclusion: five consecutive days of performing TDCS significantly reduced seizure duration in children with focal Drug-resistant epilepsy. However,further studies in this field are necessary to test the effectiveness and set up a coherent and comprehensive protocol., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Electrical deep brain stimulation (DBS) is now a routine treatment option for patients suffering from medically refractory epilepsy. DBS of the anterior nucleus of the thalamus (ANT) has proven to be effective but, despite its success, few patients experience complete cessation of seizure activity. However, improving the therapy is challenging because the mechanism underlying its action remains largely unknown. One angle on improving the effectiveness of ANT stimulation is to better understand the various anatomic regions that send projections to and through this area. Here, the authors utilized a connectomic atlas of the mouse brain to better understand the regions projecting to the ANT and were particularly interested by the presence of robust cholinergic projections from the laterodorsal tegmentum (LDT). A subsequent review of the literature resulted in limited studies, which presented convincing evidence supporting this region's role in seizure control present in acute rodent models of epilepsy. It is thus the purpose of this paper to encourage further research into the role of the LDT on seizure mitigation, with mechanistic effects likely stemming from its cholinergic projections to the ANT. While previous studies have laid a firm foundation supporting the role of this region in modulation of seizure activity, modern scientific methodology has yet to be applied to further elucidate the mechanisms and potential benefits associated with LDT stimulation in the epileptic population., (© 2022 Wiley Periodicals LLC.)

Deep brain stimulation and responsive neurostimulation (RNS) use high-frequency stimulation (HFS) per the pivotal trials and manufacturer-recommended therapy protocols. However, not all patients respond to HFS. In this retrospective case series, 10 patients implanted with the RNS System were programmed with low-frequency stimulation (LFS) to treat their seizures; nine of these patients were previously treated with HFS (100 Hz or greater). LFS was defined as frequency < 10 Hz. Burst duration was increased to at least 1000 ms. With HFS, patients had a median seizure reduction (MSR) of 13% (interquartile range [IQR] = -67 to 54) after a median of 19 months (IQR = 8-49). In contrast, LFS was associated with a 67% MSR (IQR = 13-95) when compared to HFS and 76% MSR (IQR = 43-91) when compared to baseline prior to implantation. Charge delivered per hour and pulses per day were not significantly different between HFS and LFS, although time stimulated per day was longer for LFS (228 min) than for HFS (7 min). There were no LFS-specific adverse effects reported by any of the patients. LFS could represent an alternative, effective method for delivering stimulation in focal drug-resistant epilepsy patients treated with the RNS System., (© 2022 International League Against Epilepsy.)

Aims: Deep brain electrical stimulation (DBS), as a potential therapy for drug resistive epileptic patients, has inhibitory action on epileptogenesis. In the present investigation, the role of dopamine D 2 -like receptors in the antiepileptogenic action of DBS was studied., Methods: Seizures were induced in adult rats by stimulating the perforant path in a semi-rapid kindling method. Five minutes after the last kindling stimulation, daily DBS was applied to the perforant path at the pattern of low frequency stimulation (LFS; 1 Hz; pulse duration: 0.1 ms; intensity: 50-150 μA; 4 trains of 200 pulses at 5 min intervals). Sulpiride (10 μg/1 μl, i.c.v.), a selective dopamine D 2 -like receptor antagonist, was administered prior to the daily LFS application., Results: Kindling stimulations increased cumulative daily behavioral seizure stages, daily afterdischarge duration (dADD), and population spike amplitude (PS) in dentate gyrus following perforant path stimulation, while applying LFS decreased the kindled seizures' parameters. In addition, kindling potentiated the early (at 10-50 ms inter-pulse interval) and late (at 150-1000 ms inter-pulse interval) paired-pulse inhibition and decreased the paired-pulse facilitation (at 70-100 ms inter-pulse interval). These effects were also inhibited by applying LFS. All inhibitory effects of LFS on kindling procedure were prevented by sulpiride administration., Conclusion: These data may suggest that LFS exerts its preventive effect on kindling development, at least partly, through the receptors on which sulpiride acts which are mainly dopamine D 2 -like (including D 2 , D 3 , and D 4 ) receptors., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Objective: Decades of studies have indicated that activation of the deep and intermediate layers of the superior colliculus can suppress seizures in a wide range of experimental models of epilepsy. However, prior studies have not examined efficacy against spontaneous limbic seizures. The present study aimed to address this gap through chronic optogenetic activation of the superior colliculus in the pilocarpine model of temporal lobe epilepsy., Methods: Sprague Dawley rats underwent pilocarpine-induced status epilepticus and were maintained until the onset of spontaneous seizures. Virus coding for channelrhodopsin-2 was injected into the deep and intermediate layers of the superior colliculus, and animals were implanted with head-mounted light-emitting diodes at the same site. Rats were stimulated with either 5- or 100-Hz light delivery. Seizure number, seizure duration, 24-h seizure burden, and behavioral seizure severity were monitored., Results: Both 5- and 100-Hz optogenetic stimulation of the deep and intermediate layers of the superior colliculus reduced daily seizure number and total seizure burden in all animals in the active vector group. Stimulation did not affect either seizure duration or behavioral seizure severity. Stimulation was without effect in opsin-negative control animals., Significance: Activation of the deep and intermediate layers of the superior colliculus reduces both the number of seizures and total daily seizure burden in the pilocarpine model of temporal lobe epilepsy. These novel data demonstrating an effect against chronic experimental seizures complement a long history of studies documenting the antiseizure efficacy of superior colliculus activation in a range of acute seizure models., (© 2022 International League Against Epilepsy.)

Objective: Multifamily group (MFG) psychotherapy is widely used for mental and general medical conditions. MFG therapy engages family members in caring for a loved one experiencing illness and helps clarify the impact of illness on family. Use of MFG therapy for patients with nonepileptic seizures (NES) and their families to explore satisfaction with treatment and family functioning is described., Methods: MFG therapy for patients with NES and their participating family members was incorporated into an existing interdisciplinary group-based psychotherapy treatment program. The Family Assessment Device and a novel feedback questionnaire were used to understand the effect of MFG therapy on this population., Results: Patients with NES (N=29) and their corresponding family members (N=29) indicated on the feedback questionnaire their satisfaction with having MFG therapy as part of their treatment; satisfaction was also evidenced by a 79% (N=49 of 62) patient participation rate. Patients and family members reported enhanced understanding of the impact of illness on the family and believed MFG therapy would help them communicate about illness and reduce family conflict. Scores on the Family Assessment Device indicated that family members perceived better family functioning than did patients (average scores of 1.84 and 2.99, respectively)., Conclusions: The discrepancy in perceived family functioning supports the idea of integrating family members in treatment for patients experiencing NES. The group treatment modality was satisfactory to participants and may prove useful for other kinds of somatic symptom disorders, which are often external manifestations of internal distress. Family members can become treatment allies in psychotherapy when included in treatment., Competing Interests: The authors report no financial relationships with commercial interests.

Objective: Food and Drug Administration (FDA) approval for vagus nerve stimulator (VNS) implantation is limited to patients older than 4 years of age with medically refractory partial-onset seizures. In younger children with severe generalized epilepsy, however, VNS implantation remains off-label. In this study, the authors followed up on their previously reported cohort to review the longer-term safety and efficacy of VNS placement in children younger than 6 years with generalized medically refractory epilepsy (MRE), providing the largest cohort with > 2 years of follow-up to date in this age group., Methods: This was a retrospective observational cohort study of patients younger than 6 years of age with generalized MRE who underwent VNS implantation at a single institution between 2010 and 2020. Inclusion criteria encompassed failure of more than two antiepileptic drugs alone or in combination, neurologist referral for vagus nerve stimulation, informed consent with knowledge of the off-label status in young children, and > 1 year of follow-up. Outcome measures included seizure reduction rate ≥ 50% and postoperative morbidity defined nominally. Statistical analysis was conducted with Stata/SE., Results: Forty-five patients were included: 11 patients younger than 4 years of age and 34 between 4 and 6 years of age. There were no intraoperative complications. Perioperative complications within 1 year occurred in 11% (n = 5) of the patients and included two wound infections, a mild cough, hyperactivity, hoarseness, and 1 patient with persistent surgical site pain. A seizure reduction ≥ 50% was observed in 36.4% (n = 4) of the patients younger than 4 years of age at the 6-month and 1-, 2-, and 5-year follow-ups. In the 4- to 6-year-old cohort, this was observed in 32.4% (n = 11) of the patients at 6 months, 41.2% (n = 14) at 1 year, 38.2% (n = 13) at 2 years, and 41.2% (n = 14) at 5 years., Conclusions: VNS implantation for patients younger than 4 years of age with generalized onset MRE has not been approved by the FDA. This retrospective study establishes feasibility, illustrates an acceptable safety profile in children younger than 6 years, and demonstrates efficacy comparable to that reported in older patients.

Additional treatment options for temporal lobe epilepsy are needed, and potential interventions targeting the cerebellum are of interest. Previous animal work has shown strong inhibition of hippocampal seizures through on-demand optogenetic manipulation of the cerebellum. However, decades of work examining electrical stimulation-a more immediately translatable approach-targeting the cerebellum has produced very mixed results. We were therefore interested in exploring the impact that stimulation parameters may have on seizure outcomes. Using a mouse model of temporal lobe epilepsy, we conducted on-demand electrical stimulation of the cerebellar cortex, and varied stimulation charge, frequency and pulse width, resulting in over 1000 different potential combinations of settings. To explore this parameter space in an efficient, data-driven, manner, we utilized Bayesian optimization with Gaussian process regression, implemented in MATLAB with an Expected Improvement Plus acquisition function. We examined three different fitting conditions and two different electrode orientations. Following the optimization process, we conducted additional on-demand experiments to test the effectiveness of selected settings. Regardless of experimental setup, we found that Bayesian optimization allowed identification of effective intervention settings. Additionally, generally similar optimal settings were identified across animals, suggesting that personalized optimization may not always be necessary. While optimal settings were effective, stimulation with settings predicted from the Gaussian process regression to be ineffective failed to provide seizure control. Taken together, our results provide a blueprint for exploration of a large parameter space for seizure control and illustrate that robust inhibition of seizures can be achieved with electrical stimulation of the cerebellum, but only if the correct stimulation parameters are used., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dopamine may be involved in the anticonvulsant action of deep brain stimulation (DBS). Therefore, ventral tegmental area (VTA), as a brain dopaminergic nucleus, may be a suitable target for DBS anticonvulsant action. This study investigated the effect of tonic and phasic stimulations of the VTA on seizure parameters. Seizures were induced in adult mice by sequential injections of a sub-convulsive dose of 35 mg/kg pentylenetetrazole (PTZ) every 48 h to develop the chemical kindling until the mice reached full kindled state (showing three consecutive seizure stages 4 or 5). Fully kindled mice received DBS once a day as tonic (square waves at 1 Hz; pulse duration: 200 μs; intensity: 300 μA; 600 pulses in 10 min) or phasic (square waves at 100 Hz; pulse duration: 200 μs; intensity: 300 μA; 8 trains of 10 pulses at 1 min interval; 800 pulses in 10 min) stimulations applied into their VTA for 4 days. A single dose of PTZ was injected after each DBS. Simultaneously electrocorticography and video recordings were performed during the seizure for accuracy in seizure severity parameters detection. Tonic but not phasic stimulation significantly decreased the epileptiform discharge duration and the seizure behavioral parameters such as maximum seizure stage, stage 5 duration, seizure duration. In addition, focal to generalized seizure latency increased following VTA tonic stimulation. These data suggest that tonic (but not phasic) stimulation of VTA before PTZ injection on 4 test days had anticonvulsant effects on PTZ-kindled seizures., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The field of stem cell therapy is growing rapidly and hopes to offer an alternative solution to diseases that are historically treated medically or surgically. One such focus of research is the treatment of medically refractory epilepsy, which is traditionally approached from a surgical or interventional standpoint. Research shows that stem cell transplantation has potential to offer significant benefits to the epilepsy patient by reducing seizure frequency, intensity, and neurological deficits that often result from the condition. This review explores the basic science progress made on the topic of stem cells and epilepsy by focusing on experiments using animal models and highlighting the most recent developments from the last 4 years.

Earlier and more aggressive treatment of status epilepticus has long been established orthodoxy. In addition to increasing therapeutic options, it is of critical importance to understand whether or not this has translated into improved prognosis. In this review, we examine the evidence as to whether the mortality of convulsive status epilepticus changed over the past few decades. In particular, we discuss a recent systematic review and meta-analysis examining this question and its implications. We discuss potential reasons why there is no evidence of improved prognosis in terms of mortality and ways in which this may be addressed. Finally, we advocate the urgent need for accurate data on functional outcomes in non-fatal cases of status epilepticus. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AN has received a consultancy fee from SAGE Pharmaceuticals Ltd. SR has no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Direct electrical stimulation of the seizure focus can achieve the early termination of epileptic oscillations. However, direct intervention of the hippocampus, the most prevalent seizure focus in temporal lobe epilepsy is thought to be not practicable due to its large size and elongated shape. Here, in a rat model, we report a sequential narrow-field stimulation method for terminating seizures, while focusing stimulus energy at the spatially extensive hippocampal structure. The effects and regional specificity of this method were demonstrated via electrophysiological and biological responses. Our proposed modality demonstrates spatiotemporal preciseness and selectiveness for modulating the pathological target region which may have potential for further investigation as a therapeutic approach., (© 2022. The Author(s).)

Background and Objectives: Interfacility transfer protocols are important for seizure-related emergencies, the cause of approximately 1% of all emergency department (ED) visits in the United States, but data on current practices are lacking. We assessed the prevalence, temporal trends, and patterns of interfacility transfers following seizure-related ED visits., Methods: We performed a retrospective longitudinal cross-sectional analysis of ED dispositions for seizure-related emergencies among adult and pediatric populations using the Nationwide Emergency Department Sample (NEDS). We used joinpoint regression to analyze annual trends in ED visits and transfer rates from 2007 to 2018. Logistic regression models using data from 2016 to 2018 explored the patient- and hospital-level factors associated with transfer vs admission. Sampling weights were applied to account for the complex survey design of the NEDS., Results: Using nationally representative data from 2007 to 2018, there were 7,372,065 weighted ED visits for seizure-related emergencies, including 419,368 (5.6%) visits for a primary diagnosis of status epilepticus. We found that 2.3%-5.6% of all these seizure-related ED visits resulted in an interfacility transfer and that the rate of transfer increased significantly over time. Among ED visits specifically for status epilepticus, interfacility transfers resulted from 19.8% to 23.24% of visits, which also increased over time. Multivariable logistic regression of adult and pediatric visits for status epilepticus revealed that transferring hospitals were more likely to be nonmetropolitan (adjusted odds ratio [aOR] 2.2, 95% CI 1.6-2.9) and less likely to have continuous electroencephalography (cEEG) capabilities (aOR 0.3, 98% CI 0.3-0.4). Transferred patients were more likely to be children (aOR 1.5, 95% CI 1.3-1.6 for those 1-4 years old; aOR 1.5 (95% CI 1.3-1.7) for ages 5-14 years), have acute cerebrovascular disease (aOR 1.4, 95% CI 1.1-1.8), and have received mechanical ventilation (aOR 1.5, 95% CI 1.4-1.7)., Discussion: By 2018, approximately 1 in 19 seizure-related and 1 in 5 status epilepticus ED visits resulted in interfacility transfers. In order of strength of association, illness severity, ED seizure volume, comorbid meningitis and traumatic brain injury, nonrural location, cEEG capabilities, and pediatric age favored admission. Rural location, lack of cEEG capabilities, and comorbid stroke favored transfer. Thoughtful deployment of novel EEG technologies and teleneurology tools may help optimize triage and prevent unnecessary ED transfers., (© 2022 American Academy of Neurology.)

Developmental and epileptic encephalopathies (DEEs) are characterized by pharmaco-resistant seizures with concomitant intellectual disability. Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe of these syndromes. De novo variants in ion channels, including gain-of-function variants in KCNT1, which encodes for sodium activated potassium channel protein KNa1.1, have been found to play a major role in the etiology of EIMFS. Here, we test a potential precision therapeutic approach in KCNT1-associated DEE using a gene-silencing antisense oligonucleotide (ASO) approach. We generated a mouse model carrying the KCNT1 p.P924L pathogenic variant; only the homozygous animals presented with the frequent, debilitating seizures and developmental compromise that are seen in patients. After a single intracerebroventricular bolus injection of a Kcnt1 gapmer ASO in symptomatic mice at postnatal day 40, seizure frequency was significantly reduced, behavioral abnormalities improved, and overall survival was extended compared with mice treated with a control ASO (nonhybridizing sequence). ASO administration at neonatal age was also well tolerated and effective in controlling seizures and extending the life span of treated animals. The data presented here provide proof of concept for ASO-based gene silencing as a promising therapeutic approach in KCNT1-associated epilepsies.

Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) has been widely used as an effective treatment for refractory temporal lobe epilepsy. Despite its promising clinical outcome, the exact mechanism of how ANT-DBS alleviates seizure severity has not been fully understood, especially at the cellular level. To assess effects of DBS, the present study examined electroencephalography (EEG) signals and locomotor behavior changes and conducted immunohistochemical analyses to examine changes in neuronal activity, number of neurons, and neurogenesis of inhibitory neurons in different hippocampal subregions. ANT-DBS alleviated seizure activity, abnormal locomotor behaviors, reduced theta-band, increased gamma-band EEG power in the interictal state, and increased the number of neurons in the dentate gyrus (DG). The number of parvalbumin- and somatostatin-expressing inhibitory neurons was recovered to the level in DG and CA1 of naïve mice. Notably, BrdU-positive inhibitory neurons were increased. In conclusion, ANT-DBS not only could reduce the number of seizures, but also could induce neuronal changes in the hippocampus, which is a key region involved in chronic epileptogenesis. Importantly, our results suggest that ANT-DBS may lead to hippocampal subregion-specific cellular recovery of GABAergic inhibitory neurons., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Hyperphosphorylated microtubule-associated protein tau has been implicated in dementia, epilepsy, and other neurological disorders. In contrast, site-specific phosphorylation of tau at threonine 205 (T205) by the kinase p38γ was shown to disengage tau from toxic pathways, serving a neuroprotective function in Alzheimer's disease. Using a viral-mediated gene delivery approach in different mouse models of epilepsy, we show that p38γ activity-enhancing treatment reduces seizure susceptibility, restores neuronal firing patterns, reduces behavioral deficits, and ameliorates epilepsy-induced deaths. Furthermore, we show that p38γ-mediated phosphorylation of tau at T205 is essential for this protection in epilepsy, as a lack of this critical interaction reinstates pathological features and accelerates epilepsy in vivo. Hence, our work provides a scope to harness p38γ as a future therapy applicable to acute neurological conditions.

Objective: To review the therapeutic effects of deep brain stimulation of the anterior nuclei of the thalamus (ANT-DBS) and the predictors of its effectiveness, safety, and adverse effects., Methods: A comprehensive search of the medical literature (PubMed) was conducted to identify relevant articles investigating ANT-DBS therapy for epilepsy. Out of 332 references, 77 focused on focal epilepsies were reviewed., Results: The DBS effect is probably due to decreased synchronization of epileptic activity in the cortex. The potential mechanisms from cellular to brain network levels are presented. The ANT might participate actively in the network elaborating focal seizures. The effects of ANT-DBS differed in various studies; ANT-DBS was linked with a 41% seizure frequency reduction at 1 year, 69% at 5 years, and 75% at 7 years. The most frequently reported adverse effects, depression and memory impairment, were considered non-serious in the long-term follow-up view. ANT-DBS also has been used in a few cases to treat status epilepticus., Conclusions: We reviewed the clinical literature and identified several factors that may predict seizure outcome following DBS therapy. More large-scale trials are required since there is a need to explore stimulation settings, apply patient-tailored therapy, and identify the presurgical predictors of patient response., Significance: A critical review of the published literature on ANT-DBS in focal epilepsy is presented. ANT-DBS mechanisms are not fully understood; possible explanations are provided. Biomarkers of ANT-DBS effectiveness may lead to patient-tailored therapy., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)