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Objective: In recent years, the treatment of drug-resistant epilepsy (DRE) has made greater use of surgery and expanded options for neurostimulation or neuromodulation. Up to this point, responsive neurostimulation (RNS) has been very promising but has mainly used only the cortex as a target. In this individual patient data meta-analysis (IPDMA), the authors sought to establish if a novel RNS target, the thalamus, can be used to treat DRE., Methods: The literature regarding the management of DRE by targeting the thalamus with RNS was reviewed per IPDMA guidelines. Five databases were searched with keywords [((Responsive neurostimulation) OR (RNS)) AND ((thalamus) OR (thalamic) OR (Deep-seated) OR (Diencephalon) OR (limbic))] in March 2022., Results: The median (interquartile range) age at implantation was 17 (13.5-27.5) years (n = 42) with an epilepsy duration of 12.1 (5.8-15.3) years. In total, 52.4% of patients had previously undergone epilepsy surgery, 28.6% had prior vagus nerve stimulation, and 2.4% had prior RNS. The median preimplant seizure frequency was 12 per week. The median seizure reduction at last follow-up was 73%. No study in this IPDMA reported complications, although 7 cases (16.3%) did require reoperation. Behavioral improvements and reduced antiepileptic drug dose or quantity were reported for 80% and 28.6% of patients, respectively., Conclusions: This review indicates that thalamic RNS may be safe and effective for treating DRE. Long-term and controlled studies on thalamic RNS for DRE would further elucidate this technique's potential benefits and complications and help guide clinical judgment in the management of DRE.

Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9-mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

Fragile X syndrome is a neurodevelopmental disorder caused by the absence of the mRNA-binding protein fragile X messenger ribonucleoprotein (FMRP). Because FMRP is a highly pleiotropic protein controlling the expression of hundreds of genes, viral vector-mediated gene replacement therapy is viewed as a potential viable treatment to correct the fundamental underlying molecular pathology inherent in the disorder. Here, we studied the safety profile and therapeutic effects of a clinically relevant dose of a self-complementary adeno-associated viral (AAV) vector containing a major human brain isoform of FMRP after intrathecal injection into wild-type and fragile X-KO mice. Analysis of the cellular transduction in the brain indicated primarily neuronal transduction with relatively sparse glial expression, similar to endogenous FMRP expression in untreated wild-type mice. AAV vector-treated KO mice showed recovery from epileptic seizures, normalization of fear conditioning, reversal of slow-wave deficits as measured via electroencephalographic recordings, and restoration of abnormal circadian motor activity and sleep. Further assessment of vector efficacy by tracking and analyzing individual responses demonstrated correlations between the level and distribution of brain transduction and drug response. These preclinical findings further demonstrate the validity of AAV vector-mediated gene therapy for treating the most common genetic cause of cognitive impairment and autism in children.

Background: To evoke a therapeutically effective seizure, electrical stimulation in electroconvulsive therapy (ECT) has to overcome the combined resistivity of scalp, skull and other tissues. Static impedances are measured prior to stimulation using high-frequency electrical alternating pulses, dynamic impedances during passage of the stimulation current. Static impedance can partially be influenced by skin preparation techniques. Earlier studies showed a correlation between dynamic and static impedance in bitemporal and right unilateral ECT., Objective: This study aims at assessing the correlation of dynamic and static impedance with patient characteristics and seizure quality criteria in bifrontal ECT., Methods: We performed a cross-sectional single-centre retrospective analysis of ECT treatments at the Psychiatric University Hospital Zurich between May 2012 and March 2020 and used linear mixed-effects regression models in 78 patients with a total of 1757 ECT sessions., Results: Dynamic and static impedance were strongly correlated. Dynamic impedance was significantly correlated with age and higher in women. Energy set and factors positively (caffeine) and negatively (propofol) affecting seizure at the neuronal level were not associated with dynamic impedance. For secondary outcomes, dynamic impedance was significantly related to Maximum Sustained Power and Average Seizure Energy Index. Other seizure quality criteria showed no significant correlation with dynamic impedance., Conclusion: Aiming for low static impedance might reduce dynamic impedance, which is correlated with positive seizure quality parameters. Therefore, good skin preparation to achieve low static impedance is recommended.

Responsive neurostimulation (RNS) has shown promising but limited efficacy in the treatment of drug-resistant epilepsy. The clinical utility of RNS is hindered by the incomplete understanding of the mechanism behind its therapeutic effects. Thus, assessing the acute effects of responsive stimulation (AERS) based on intracranial EEG recordings in the temporal lobe epilepsy rat model may provide a better understanding of the potential therapeutic mechanisms underlying the antiepileptic effect of RNS. Furthermore, clarifying the correlation between AERS and seizure severity may help guide the optimization of RNS parameter settings. In this study, RNS with high (130 Hz) and low frequencies (5 Hz) was applied to the subiculum (SUB) and CA1. To quantify the changes induced by RNS, we calculated the AERS during synchronization by Granger causality and analyzed the band power ratio in the classic power band after different stimulations were delivered in the interictal and seizure onset periods, respectively. This demonstrates that only targets combined with an appropriate stimulation frequency could be efficient for seizure control. High-frequency stimulation of CA1 significantly shortened the ongoing seizure duration, which may be causally related to increased synchronization after stimulation. Both high-frequency stimulation of the CA1 and low-frequency stimulation delivered to the SUB reduced seizure frequency, and the reduced seizure risk may correlate with the change in power ratio near the theta band. It indicated that different stimulations may control seizures in diverse manners, perhaps with disparate mechanisms. More focus should be placed on understanding the correlation between seizure severity and synchronization and rhythm around theta bands to simplify the process of parameter optimization., 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.)

Background: The ideal hypnotic agent for electroconvulsive therapy (ECT) is still under debate and previous studies comparing etomidate and methohexital have produced conflicting results. This retrospective study compares etomidate and methohexital as anesthetic agents in continuation and maintenance (m)ECT with regard to seizure quality and anesthetic outcomes., Methods: All subjects undergoing mECT at our department between October 1st, 2014 and February 28th, 2022 were included in this retrospective analysis. Data for each ECT session were obtained from the electronic health records. Anesthesia was performed with either methohexital/succinylcholine or etomidate/succinylcholine. Standard seizure quality parameters, anesthesiological monitoring data, pharmacological interventions and side-effects were recorded., Results: 573 mECT treatments in 88 patients were included (methohexital n = 458, etomidate n = 115). Seizures lasted significantly longer after using etomidate (electroencephalography: +12.80 s [95 %-CI:8.64-16.95]; electromyogram +6.59 s [95 %-CI:4.14-9.04]). Time to maximum coherence was significantly longer with etomidate (+7.34 s [95 %-CI:3.97-10.71]. Use of etomidate was associated with longer procedure duration (+6.51 min [95 %-CI:4.84-8.17]) and higher maximum postictal systolic blood pressure (+13.64 mmHg [95 %-CI:9.33-17.94]). Postictal systolic blood pressure > 180 mmHg, the use of antihypertensives, benzodiazepines and clonidine (for postictal agitation), as well as the occurrence of myoclonus was significantly more common under etomidate., Conclusions: Due to longer procedure duration and an unfavorable side effect profile, etomidate appears inferior to methohexital as an anesthetic agent in mECT despite longer seizure durations., Competing Interests: Conflict of interest Preliminary findings of this study were submitted as a poster to the 3. Gemeinsamer Kongress AGNP/DGBP in Berlin, Germany, September 2022. All authors have no conflict of interest related to this work to report., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Whereas high-level evidence exists on chronic neuromodulatory effects of different brain stimulation approaches in reducing seizure frequency, evidence for acute antiseizure effects of electrical brain stimulation during seizures is sparse. As part of an ongoing trial, we implanted a patient with a novel focal cortex stimulation (FCS) device with a Laplacian electrode placed over a precentral focal cortical dysplasia. The baseline seizure frequency was 125 per month, consisting of (i) focal aware sensory seizures that invariably progressed to uni- or bilateral tonic contraction and clonic jerking, and (ii) primary motor seizures. Besides an overall reduction in seizure frequency, on-demand stimulation had an immediate effect on seizures with a sensory phase, whereby 63%-86% of these seizures were terminated by ictal stimulation. These observations provide the first evidence that ictal self-triggered transcranial focal cortex stimulation can significantly interfere with the progression of seizure semiology., (© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Neuromodulation in epilepsy is a proven treatment for people with drug-resistant focal epilepsy. Dual device therapies are increasingly utilized in people with drug-resistant epilepsy. Vagus nerve stimulation (VNS) and deep brain stimulation (DBS) target the thalamus involving the primary neurobiological network in patients with genetic generalized epilepsy (GGE). We report a novel case of combined neuromodulation in a patient with drug-resistant GGE who achieved a partial response with seizure reduction after VNS implantation yet following VNS-DBS polyneurostimulation gradually achieved prolonged seizure freedom. We speculate that by combining the indirect activating effects of VNS with the direct inhibitory effects of DBS, this may provide synergy to thalamic modulated networks. We hypothesize a "rational polytherapy" may exist in some patients with GGE undergoing dual neuromodulation., (© 2023 International League Against Epilepsy.)

Objective: This study aimed to examine Chinese families' knowledge, attitudes, and practices regarding the management of acute seizures (AS) that occur outside the hospital in children with epilepsy (CWE) and factors that influence AS., Design: A mixed-methods sequential explanatory study was conducted, which was integrated at the design and methods levels. In phase 1, a questionnaire was developed for this study, and a family functioning assessment was administered from Nov 2021 to Apr 2022. Multivariate logistic regression was used to analyze the knowledge, attitudes, and practices (KAP) and factors that influence AS. In phase 2, family caregivers (FCGs) were recruited from Jul to Aug 2022 to participate in a qualitative exploration, using semi-structured interviews and a combination of inductive and deductive methods., Setting: The setting was five children's specialty hospitals in different regions of China., Participants: The participants were FCGs of CWE. A total of 645 participants were included in the quantitative phase, and 15 FCGs (eight parents, five grandparents, and two others) were recruited for the qualitative phase., Results: The FCGs' average total KAP score for AS management was 66.23 ± 15.12, with 45.42% of FCGs having a low level. Univariate and multivariate regression analyses showed that demographic factors, disease characteristics, and family function significantly predicted family management of AS. The three most salient themes and eight sub-themes from phase 2 were explored. The quantitative and qualitative databases were analyzed separately and combined through integration, and a conceptual model was constructed based on the individual and family self-management theory (IFSMT); the model consisted of context, knowledge, self-regulation, and promotion factors., Conclusion: Chinese families have a positive attitude toward the management of out-of-hospital AS in CWE, but lack practice and related knowledge. AS management for CWE families was associated with the demographic characteristics of FCGs, epilepsy, and family characteristics. The research findings expand the existing application requirements of an Acute Seizure Action Plan and patient safety. Our results also indicate a pressing need for localized development of AS emergency medicine in family medicine, the establishment of auxiliary information systems, the utilization of caregivers' positive psychological resources, and improvements in family function for intergenerational care., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cui, Li, Chen, Zhou and Zheng.)

Background: Hypoxic-ischemic encephalopathy (HIE) is one of the major complications that can lead to death or disability in neonates. We assessed the effect of citicoline as a neuroprotector in neonates with moderate and severe HIE., Methods: This clinical trial was carried on 80 neonates with moderate to severe HIE who were not candidates for therapeutic cooling. They were subdivided randomly into two groups; citicoline treatment group which included 40 neonates who received citicoline 10 mg / kg /12 h IV for 4 weeks plus other supportive measures and the control group which included 40 neonates who were managed with placebo and the same supportive measures. All patients were evaluated for duration of mechanical ventilation (MV), need for inotropes, seizures (type, frequency, and duration), and duration of NICU. Cranial ultrasounds and brain magnetic resonance image (MRI) were performed for all included neonates after 4 weeks of treatment. Follow- ups of all neonates for the neurodevelopmental outcomes were done at 3, 6, 9, and 12 months., Results: There was a significant reduction in the number of neonates having seizures after discharge in the citicoline-treated group (2 neonates) compared to the control group (11 neonates). Cranial ultrasound and MRI findings at 4 weeks were significantly better in the treatment group compared to the control group. Moreover, neurodevelopmental outcome showed significant improvement at 9 and 12 months in the citicoline treated neonates compared to the control group. There was statistically significant reduction in the duration of seizures, NICU stay, inotrope use, and MV in the treatment group compared to the control group. Citicoline was well tolerated with no remarkable side effects., Conclusion: Citicoline could be a promising neuroprotector drug in neonates with HIE., Trial Registration: The study was registered at ClinicalTrials.gov (NCT03949049). Registered at 14 May 2019, https://clinicaltrials.gov/ct2/show/NCT03949049., (© 2023. The Author(s).)

Purpose: This study investigated the characteristics of patients presenting with the first-time seizure (FTS) and whether neurology follow-up occurred in a medically underserved area., Methods: A retrospective study of adults with a FTS discharged from the Emergency Department (ED) at Loma Linda University between January 1, 2017 and December 31, 2018 was performed. The primary outcome was days from the ED visit to the first neurology visit. Secondary outcomes included repeat ED visits, percentage of patients who had specialty assessment in one year, type of neurologist seen, and percentage lost to follow-up., Results: Of the 1327 patients screened, 753 encounters met criteria for manual review, and after exclusion criteria were applied, 66 unique encounters were eligible. Only 30% of FTS patients followed up with a neurologist. The median duration for neurology follow-up was 92 days (range=5-1180). After initial ED visit, 20% of follow-up patients were diagnosed with epilepsy within 189 days, and 20% of patients re-presented to the ED with recurrent seizures while awaiting their initial neurology appointment. Reasons for lack of follow-up included: referral issues, missed appointments, and shortage of available neurologists., Conclusion: This study highlights the significant treatment gap that a first-time seizure clinic (FTSC) could fill in underserved communities. FTSC may reduce the morbidity and mortality associated with untreated recurrent seizures., Competing Interests: Declaration of Competing Interest D. Goldenholz – is a scientific advisor for Magic Leap, Epilepsy AI and Eysz. He has funding from NIH NINDS K23NS124656. A. Cabrera, C. Jenkins, N. Baker, T. Losey, M. Estes, C. Casassa – Declaration of interest: None., (Copyright © 2023. Published by Elsevier Ltd.)

Objectives: The on-scene time of Emergency Medical Services (EMS), including time for hospital selection, is critical for people in an emergency. However, the outbreak of the novel coronavirus disease 2019 (COVID-19) led to longer delays in providing immediate care for individuals with non-COVID-19-related emergencies, such as epileptic seizures. This study aimed to examine factors associated with on-scene time delays for people with epilepsy (PWE) with seizures needing immediate amelioration., Materials & Methods: We conducted a population-based retrospective cohort study for PWE transported by EMS between 2016 and 2021. We used data from the Hiroshima City Fire Service Bureau database, divided into three study periods: "Pre period", the period before the COVID pandemic (2016-2019); "Early period", the early period of the COVID pandemic (2020); and "Middle period", the middle period of the COVID pandemic (2021). We performed linear regression modeling to identify factors associated with changes in EMS on-scene time for PWE during each period. In addition, we estimated the rate of total EMS call volume required to maintain the same on-scene time for PWE transported by EMS during the pandemic expansion., Results: Among 2,205 PWE transported by EMS, significant differences in mean age and prevalence of impaired consciousness were found between pandemic periods. Total EMS call volume per month for all causes during the same month <5,000 (-0.55 min, 95% confidence interval [CI] -1.02 - -0.08, p = 0.022) and transport during the Early period (-1.88 min, 95%CI -2.75 - -1.00, p < 0.001) decreased on-scene time, whereas transport during the Middle period (1.58 min, 95%CI 0.70 - 2.46, p < 0.001) increased on-scene time for PWE transported by EMS. The rate of total EMS call volume was estimated as 0.81 (95%CI -0.04 - 1.07) during the expansion phase of the pandemic to maintain the same degree of on-scene time for PWE transported by EMS before the pandemic., Conclusions: On-scene time delays on PWE in critical care settings were observed during the Middle period. When the pandemic expanded, the EMS system required resource allocation to maintain EMS for time-sensitive illnesses such as epileptic seizures. Timely system changes are critical to meet dramatic social changes., 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.)

Psychogenic non-epileptic seizures resemble epileptic seizures but their pathophysiological mechanisms differ. Despite being quite frequent, they are often misunderstood, regularly leading to a misdiagnosis and therapeutic errors. The objective of this article is to provide a short review of the current knowledge about this pathology. We will detail the main epidemiological data of psychogenic non-epileptic seizures. We will then discuss the diagnostic approach, emphasizing the semiological differences that exist between psychogenic non-epileptic seizures and epileptic seizures. Then, we will detail the main therapeutic actions and discuss the importance of communication between clinicians, the patient and his/her family. Finally, we will discuss the long-term prognosis of this pathology, which remains quite poor.

Background: Differences in sense of control, cognitive inhibition, and selective attention in pediatric functional seizures (FS) versus matched controls implicate these as potential novel treatment targets. Retraining and Control Therapy (ReACT), which targets these factors, has been shown in a randomized controlled trial to be effective in improving pediatric FS with 82% of patients having complete symptom remission at 60 days following treatment. However, post-intervention data on sense of control, cognitive inhibition, and selective attention are not yet available. In this study, we assess changes in these and other psychosocial factors after ReACT., Methods: Children with FS (N = 14, M age  = 15.00, 64.3% female, 64.3% White) completed 8 weeks of ReACT and reported FS frequency at pre and post-1 (7 days before and after ReACT). At pre, post-1, and post-2 (60 days after ReACT), all 14 children completed the Pediatric Quality of Life Inventory Generic Core Scales, Behavior Assessment System (BASC2), and Children's Somatic Symptoms Inventory-24 (CSSI-24), and 8 children completed a modified Stroop task with seizure symptoms condition in which participants are presented with a word and respond to the ink color (e.g., "unconscious" in red) to assess selective attention and cognitive inhibition. At pre and post-1, ten children completed the magic and turbulence task (MAT) which assesses sense of control via 3 conditions (magic, lag, turbulence). In this computer-based task, participants attempt to catch falling X's while avoiding falling O's while their control over the task is manipulated in different ways. ANCOVAs controlling for change in FS from pre- to post-1 compared Stroop reaction time (RT) across all time points and MAT conditions between pre and post-1. Correlations assessed the relationships between changes in Stroop and MAT performance and change in FS from pre- to post-1. Paired samples t-tests assessed changes in quality of life (QOL), somatic symptoms, and mood pre to post-2., Results: Awareness that control was manipulated in the turbulence condition of the MAT increased at post-1 vs. pre- (p = 0.02, η 2  = 0.57). This change correlated with a reduction in FS frequency after ReACT (r = 0.84, p < 0.01). Reaction time significantly improved for the seizure symptoms Stroop condition at post-2 compared to pre- (p = 0.02, η 2  = 0.50), while the congruent and incongruent conditions were not different across time points. Quality of life was significantly improved at post-2, but the improvement was not significant when controlling for change in FS. Somatic symptom measures were significantly lower at post-2 vs. pre (BASC2: t(12) = 2.25, p = 0.04; CSSI-24: t(11) = 4.17, p < 0.01). No differences were observed regarding mood., Conclusion: Sense of control improved after ReACT, and this improvement was proportional to a decrease in FS, suggesting this as a possible mechanism by which ReACT treats pediatric FS. Selective attention and cognitive inhibition were significantly increased 60 days after ReACT. The lack of improvement in QOL after controlling for change in FS suggests QOL changes may be mediated by decreases in FS. ReACT also improved general somatic symptoms independent of FS changes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Aaron Fobian: Funding: NIMH grant R61MH127155. Jerzy Szaflarski: Funding: NIH, NSF, DoD, State of Alabama, Shor Foundation for Epilepsy Research, UCB Pharma Inc., NeuroPace Inc., Greenwich Biosciences Inc., Biogen Inc., Xenon Pharmaceuticals, Serina Therapeutics Inc., and Eisai, Inc.; Consulting/Advisory Boards: Greenwich Biosciences Inc., NeuroPace, Inc., Serina Therapeutics Inc., AdCel Biopharma Inc, iFovea Inc, LivaNova Inc., UCB Pharma Inc., SK Lifesciences Inc., and provided medico-legal services; Editorial Work: Editorial board member for Epilepsy & Behavior, Journal of Epileptology (associate editor), Epilepsy & Behavior Reports (associate editor), Journal of Medical Science, Epilepsy Currents (contributing editor), and Folia Medica Copernicana; Specifically related to this opinion article – DoD W81XWH-17-0169 and NIMH R61MH127155., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Management of postpartum stroke has been the focus of several quality improvement efforts in the past decade. However, there is little recent national trends data for postpartum stroke readmissions., Objective: This study aimed to determine trends, risk factors, and complications associated with postpartum stroke readmission., Study Design: The 2013 to 2019 Nationwide Readmissions Database was used to perform a retrospective cohort study that evaluated the risk for readmission for stroke within 60 days of delivery hospitalization discharge. Temporal trends in readmissions were analyzed using the National Cancer Institute's Joinpoint Regression Program to estimate the average annual percent change with 95% confidence intervals. Stratified trends were analyzed for hemorrhage stroke, ischemic stroke, and stroke readmissions at 1 to 10, 11 to 30, and 31 to 60 days after delivery discharge. Risk factors for stroke were analyzed using unadjusted and adjusted logistic regression models with odds ratios and 95% confidence intervals as measures of association. The risk for stroke complications, including mechanical ventilation, seizures, death, and a prolonged stay ≥14 days, was analyzed., Results: Of an estimated 21,754,603 delivery hospitalizations, 5006 were complicated by a 60-day postpartum readmission with a diagnosis of stroke. The average annual percent change for all stroke readmissions over the study period was not significant (average annual percent change, 0.1%; 95% confidence interval, -2.2% to 2.4%). When the trends in readmission for ischemic and hemorrhagic stroke were analyzed, the results were similar, as were the stratified analyses by readmission timing. Risk factors associated with increased odds included superimposed preeclampsia (odds ratio, 4.8; 95% confidence interval, 3.9-5.9), preeclampsia with severe features (odds ratio, 3.7; 95% confidence interval, 3.0-4.4), maternal cardiac disease (odds ratio, 3.0; 95% confidence interval, 2.5-3.7), chronic kidney disease (odds ratio, 5.0; 95% confidence interval, 3.4-7.5), and lupus (odds ratio, 7.0; 95% confidence interval, 4.9-10.2). Risk was retained in adjusted analyses. Common stroke-related complications included a prolonged hospital stay ≥14 days (12.1 per 1000 stroke-related readmissions), seizures (9.9 per 1000 stroke-related readmissions), and mechanical ventilation (6.6 per 1000 stroke-related readmissions)., Conclusion: This analysis of nationally representative data demonstrated no change in the rate of 60-day postpartum hospitalizations for stroke from 2013 to 2019. Further clinical research is indicated to optimize risk reduction for stroke after delivery hospitalization discharge., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: Different neurostimulation modalities are available to treat drug-resistant focal epilepsy when surgery is not an option including vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS). Head-to-head comparisons of efficacy do not exist between them nor are likely to be available in the future. We performed a meta-analysis on VNS, RNS, and DBS outcomes to compare seizure reduction efficacy for focal epilepsy., Methods: We systematically reviewed the literature for reported seizure outcomes following implantation with VNS, RNS, and DBS in focal-onset seizures and performed a meta-analysis. Prospective or retrospective clinical studies were included., Results: Sufficient data were available at years one (n = 642, two (n = 480), and three (n = 385) for comparing the three modalities with each other. Seizure reduction for the devices at years one, two, and three respectively were: RNS: 66.3%, 56.0%, 68.4%; DBS- 58.4%, 57.5%, 63.8%; VNS 32.9%, 44.4%, 53.5%. Seizure reduction at year one was greater for RNS (p < 0.01) and DBS (p < 0.01) compared to VNS., Conclusions: Our findings indicate the seizure reduction efficacy of RNS is similar to DBS, and both had greater seizure reductions compared to VNS in the first-year post-implantation, with the differences diminishing with longer-term follow-up., Significance: The results help guide neuromodulation treatment in eligible patients with drug-resistant focal epilepsy., 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., (Published by Elsevier Inc.)

Introduction: Nonconvulsive status epilepticus (NCSE) is a condition involving seizures without convulsions; it is usually characterized by altered consciousness and behavioral and vegetative abnormalities. Owing to the nonspecific symptoms, NCSE is often overlooked, especially in neurological intensive care unit (NICU) patients. Therefore, we investigated the etiology, clinical features, electroencephalographic (EEG) changes, treatment options, and outcomes of NCSE in NICU patients with altered consciousness., Methods: This study retrospectively collected the data of 20 patients with altered consciousness in the NICU. NCSE diagnoses were established by the treating neurologist who had been trained to recognize nonspecific clinical signs and recognize complex EEG changes., Results: We identified 20 patients (43.95±20.70 years) with clinical signs and EEG findings consistent with NCSE; 9 were female. All the patients suffered from altered consciousness. Five patients had established epilepsy. NCSE was attributed to acute pathological conditions. The underlying cause of NCSE was intracranial infection in 6 patients (30%), cerebrovascular disease in 5 patients (25%), irregular use of epilepsy drugs in 2 patients (10%), immune-related inflammation in 1 patient (5%), other infections in 4 patients (20%), and unknown cause in 2 patients (10%). Fifteen patients had diffused, and five patients had temporal focal EEG abnormalities. Six of 20 NCSE cases (30%) resulted in death. All the patients, except for the patients who died, received anticonvulsant therapy and their altered conscious state was promptly altered., Conclusion: The clinical symptoms of NCSE without convulsions are often obscure and difficult to detect. NCSE can cause serious consequences and even death. Therefore, for patients with a high clinical suspicion of NCSE, continuous EEG monitoring is needed to quickly identify this condition and promptly start treat them.

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: 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.)

Background: Epileptic seizures are common symptoms in brain arteriovenous malformation patients and seizure control was an important issue in the treatments. This retrospective study attempted to define the risk factors of seizure presentation and to evaluate the effects of treatment modalities on seizure outcomes., Methods: Patients receiving single treatment modality during 2013-2016 years, followed up more than 2 years were recruited. Logistic regression analysis was used to detect independent predictors. The factors associated with seizure control were analyzed in patients with pre-treatment seizures, and the factors associated with de novo seizures were analyzed in patents without pre-treatment seizures., Results: Multivariate analysis identified that the independent predictors of seizure presentation were unruptured (ruptured vs. unruptured, OR = 0.314), and in the frontal (frontal vs. parietal, OR = 3.982) or temporal lobe (temporal vs parietal, OR = 3.313). In 47 patients with seizure presentation, good seizure outcomes were achieved in 26 cases. Partial obliteration of nidus (partial vs complete, OR = 32.301) and headache presentation were independent predictors of poor outcome. In 169 patients without seizure presentation, de novo seizures occurred in 22 cases. Treatments of microsurgery or radiosurgery led to a higher incidence of de novo seizures than intravascular embolization., Conclusions: Patients with unruptured and frontal/temporal lobe located nidus were more likely to manifest seizure presentation. Incomplete nidus obliteration was an independent risk factor of poor outcomes in patients with pre-existing seizures. However, compared to microsurgery or radiosurgery, endovascular embolization was less likely to cause de novo seizures in patients without pre-existing seizures.

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.)

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: 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: 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.

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: 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.)

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.

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.)

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.

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.)

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.)

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.)

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.)

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.)

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.

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.)

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.)

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.)

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.)

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.)