Therapy For Epilepsy Research Articles

Precision therapy with quinidine of KCNT1‐related epileptic disorders: A systematic review

Despite numerous studies on quinidine therapies for epilepsies associated with KCNT1 gene mutations, there is no consensus on its clinical utility. Thus, we reviewed studies evaluating the efficacy and safety of quinidine in KCNT1-related epileptic disorders. Electronic databases were queried for in vivo and in vitro studies on quinidine therapy in KCNT1-related epilepsies published on or before 1 May 2022. The evaluation of evidence was done as per the American Academy of Neurology's classification scheme. Identification of significant factors that possibly influenced therapeutic effects of quinidine were performed using χ2 tests. Twenty-seven studies containing 82 patient records were reviewed. Records of 80 patients with 33 KCNT1 mutations were analysed, of which 20 patients had gained ≥50% seizure reduction due to quinidine therapy. However, quinidine therapy often had different effects on patients with the same KCNT1 mutation. Age, genotypes of KCNT1 mutations, seizure types and brain MRI did not significantly influence the therapeutic effect of quinidine. Prolonged QTc was the most common among all adverse events with quinidine. Notably, results of in vitro quinidine tests did not correspond with in vivo tests. Therapeutic effects of quinidine on KCNT1-related epilepsies remained indefinite as contradictory results were detected in similar patients. Age, seizure types, genotypes of KCNT1 mutations and brain MRI did not influence the therapeutic effects of quinidine. Insensitivity to quinidine by a certain Kcnt1 genotype in molecular tests is predictive of its inefficacy in human populations of the respective mutation.

Deep brain stimulation of the anterior nuclei of the thalamus in focal epilepsy

ObjectiveTo 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. MethodsA 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. ResultsThe 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. ConclusionsWe 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. SignificanceA 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.

The first combined Russian experience of using perampanel in children and adolescents with epilepsy in everyday clinical practice

Background. Real world data help to provide more information on the effects and tolerability of therapy. However, data on the use of perampanel in Russian population of children remain limited.Aim. To conduct a retrospective analysis of perampanel efficacy and tolerability in children and adolescents with epilepsy in real clinical practice.Materials and methods. A total of 106 children aged 4–18 years receiving perampanel as part of combination therapy for epilepsy were observed at 18 centers. Seizure frequency at 1–3, after 6 and 12 months of treatment, presence and type of adverse events (AEs) were analyzed. The main assessed efficacy parameters were seizure control, significant (≥50 %) decrease in seizure frequency. All other outcomes (<50 % decrease, no change or increased seizure frequency) were considered to be no effect. The assessed safety parameters were the percentage of patients with or without AEs and the percentage of perampanel withdrawals due to AEs.Results. We defined 3 age groups for comparison: children 4–6, 7–11 and 12–17 years old. Perampanel efficacy was 69 % (seizure control – 23.6 %, ≥50 % decrease in seizure frequency – 45.3 %). The mean duration of the effect was 7.3 ± 4.1 months. No significant difference in efficacy between age groups was found. However, some greater efficacy of perampanel was noted in adolescents: absence of effect in the form of remission or significant decrease in seizures frequency was noted only in 25.5 %, with 40 % in children 4–11 years old. Among those with inefficacy, 3.8 % reported seizure aggravation. AEs occurred in only 23 % of patients, with the least frequent occurrence in adolescents (11.8 %) and the most frequent in children aged 7–11 years (40 %). The most frequent AEs was sluggishness and/or drowsiness. Discontinuation of perampanel due to AEs was required in 7.6 %.Conclusion. Perampanel has demonstrated high efficacy and good tolerability in real clinical practice among children from 4 years of age and adolescents with partial (focal) and secondary generalized seizures. The AEs that developed were not serious and very rarely led to withdrawal of the therapy. The results are comparable to those of phase III studies and previous real-world data. The usage of perampanel in children with primary generalized seizures should be further investigated.

Estimation of ANT-DBS Electrodes on Target Positioning Based on a New PerceptTM PC LFP Signal Analysis.

Deep brain stimulation of the Anterior Nucleus of the Thalamus (ANT-DBS) is an effective therapy in epilepsy. Poorer surgical outcomes are related to deviations of the lead from the ANT-target. The target identification relies on the visualization of anatomical structures by medical imaging, which presents some disadvantages. This study aims to research whether ANT-LFPs recorded with the PerceptTM PC neurostimulator can be an asset in the identification of the DBS-target. For this purpose, 17 features were extracted from LFPs recorded from a single patient, who stayed at an Epilepsy Monitoring Unit for a 5-day period. Features were then integrated into two machine learning (ML)-based methodologies, according to different LFP bipolar montages: Pass1 (nonadjacent channels) and Pass2 (adjacent channels). We obtained an accuracy of 76.6% for the Pass1-classifier and 83.33% for the Pass2-classifier in distinguishing locations completely inserted in the target and completely outside. Then, both classifiers were used to predict the target percentage of all combinations, and we found that contacts 3 (left hemisphere) and 2 and 3 (right hemisphere) presented higher signatures of the ANT-target, which agreed with the medical images. This result opens a new window of opportunity for the use of LFPs in the guidance of DBS target identification.

The value of immunotherapy in children with initial short-term frequent seizures.

This study aimed to discuss clinical characteristics, therapy, and antibody prevalence in epilepsy (APE) score for short-term, frequent epileptic seizures in children who are autoimmune-antibody negative and respond well to immunotherapy. The clinical characteristics, imaging manifestations, electrophysiology, and effective treatment plan of 9 children who met the above criteria were retrospectively analyzed in the Pediatric Neurology Department of Qilu Hospital at Shandong University from June 2019 to December 2021. All 9 patients (6 boys, 3 girls; aged 13 months−11 years and 5 months, median 3.5 years) had acute-onset seizures within 3 months. All had previous normal growth/development with no family history of disease. Seizure types were focal motor seizures (6), generalized tonic-clonic seizures (2), and generalized secondary-to-focal (1); occurred >10 times/day; and lasted <1 min/episode. Formal treatment with ≥2 types of antiseizure medicine (ASM) achieved an unsatisfactory effect. Cranial magnetic resonance imaging showed an abnormal result in 1 case. The APE score was ≥4 in 3 cases and <4 in 6 cases. All patients experienced symptomatic relief with immunotherapy; subsequently, 8 patients were free of recurrence and 1 had significantly reduced seizure frequency. Autoimmune antibody screening is recommended for children who were previously well and have acute-onset epilepsy; high frequency, short-duration seizures; no good response to 2 types of ASM; and other etiologic factors excluded, even with APE score <4. Even with negative autoimmune antibody results, the possibility of autoimmune epilepsy should be considered for urgent initiation of immunotherapy, which can achieve good results.

Ketogenic Diet Alleviates Hippocampal Neurodegeneration Possibly via ASIC1a and the Mitochondria-Mediated Apoptotic Pathway in a Rat Model of Temporal Lobe Epilepsy.

BackgroundThe ketogenic diet (KD) is a proven therapy for refractory epilepsy. Although the anti-seizure properties of this diet are understood to a certain extent, the exploration of its neuroprotective effects and underlying mechanisms is still in its infancy. Tissue acidosis is a common feature of epileptogenic foci. Interestingly, the activation of acid-sensing ion channel 1a (ASIC1a), which mediates Ca2+-dependent neuronal injury during acidosis, has been found to be inhibited by ketone bodies in vitro. This prompted us to investigate whether the neuroprotective effects induced by the KD occur via ASIC1a and interconnected downstream mechanisms in a rat model of temporal lobe epilepsy.MethodsMale Sprague-Dawley rats were fed either the KD or a normal diet for four weeks after undergoing pilocarpine-induced status epilepticus (SE). The effects of KD on epileptogenesis, cognitive impairment and hippocampal neuron injury in the epileptic rats were subsequently evaluated by video electroencephalogram, Morris water maze test and Nissl staining, respectively. The expression of ASIC1a and cleaved caspase-3 in the hippocampus were determined using Western blot analysis during the chronic period following SE. Moreover, the intracellular Ca2+ concentration, mitochondrial membrane potential (MMP), mitochondrial reactive oxygen species (mROS) and cell apoptosis of hippocampal cells were detected by flow cytometry.ResultsWe found that the KD treatment strongly attenuated the spontaneous recurrent seizures, ameliorated learning and memory impairments and prevented hippocampal neuronal injury and apoptosis. The KD was also shown to inhibit the upregulation of ASIC1a and the ensuing intracellular Ca2+ overload in the hippocampus of the epileptic rats. Furthermore, the seizure-induced structure disruption of neuronal mitochondria, loss of MMP and accumulation of mROS were reversed by the KD treatment, suggesting that it has protective effects on mitochondria. Finally, the activation of caspase-3 was also inhibited by the KD.ConclusionThese findings indicate that the KD suppresses mitochondria-mediated apoptosis possibly by regulating ASIC1a to exert neuroprotective effects. This may provide a mechanistic explanation of the therapeutic effects of KD.

VALIDATION OF SCREENING MODELS OF EPILEPSY: A REVIEW

Epilepsy is a severe neurological illness characterized by abnormal, recurring, and synchronized brain discharges. Long-term recurring seizure attacks can cause substantial brain function loss, as seen in people with temporal lobe epilepsy. Controlling seizure events is critical for epilepsy therapy and prognosis. The disease is more common in developing countries than in developed countries. The causes of epilepsy include chemical imbalances such as low blood sugar or sodium, head injuries, drug abuse or withdrawal, alcohol withdrawal, stroke tumor affecting the blood vessels (vascular system) in the brain, hardening of the arteries (atherosclerosis) in the brain, brain tumours, and brain infections such as meningitis or encephalitis. Given the prevalence of epilepsy and the challenges associated with currently available antiepileptic medicines, such as side effects, resistance, safety concerns, and high cost, screening models are utilized in epilepsy analysis. Screening models for seizures and epilepsy have been critical in expanding our understanding of the fundamental mechanisms underlying ictogenesis and epileptogenesis, as well as in the discovery and preclinical development of novel antiepileptic medicines (AEDs). Diverse screening models of epilepsy have been developed in recent years to imitate various seizure forms, with no clear advantages or disadvantages. In this study, we will cover the numerous screening models for epilepsy, which will aid in gaining a better understanding of the disease.

Anti-epileptic effect of 2-deoxy-D-glucose by activation of miR-194/KATP signaling pathway.

Epilepsy is a syndrome of central nervous system dysfunction caused by many reasons, which is mainly characterized by abnormal discharge of neurons in the brain. Therefore, finding new targets for epilepsy therapy has always been the focus and hotspot in neurological research field. Studies have found that 2-deoxy-D-glucose (2-DG) exerts anti-epileptic effect by up-regulation of KATP channel subunit Kir6.1, Kir6.2 mRNA and protein. By using the database of TargetScan and miRBase to perform complementary pairing analysis on the sequences of miRNA and related target genes, it predicted that miR-194 might be the upstream signaling molecule of KATP channel. This study aims to explore the mechanism by which 2-DG exerts its anti-epileptic effect by regulating KATP channel subunits Kir6.1 and Kir6.2 via miR-194. A magnesium-free epilepsy model was established and randomly divided into a control group, an epilepsy group (EP group), an EP+2-DG group, and miR-194 groups (including EP+miR-194 mimic, EP+miR-194 mimic+2-DG, EP+miR-194 mimic control, EP+miR-194 inhibitor, EP+miR-194 inhibitor+2-DG, and EP+miR-194 inhibitor control groups). The 2-DG was used to intervene miR-194 mimics, patch-clamp method was used to detect the spontaneous recurrent epileptiform discharges, real-time PCR was used to detect neuronal miR-194, Kir6.1, and Kir6.2 expressions, and the protein levels of Kir6.1 and Kir6.2were detected by Western blotting. Compared with the control group, there was no significant difference in the amplitude of spontaneous discharge potential in the EP group (P>0.05), but the frequency of spontaneous discharge was increased (P<0.05). Compared with the EP group, the frequency of spontaneous discharge was decreased (P<0.05). Compared with the EP+miR-194 mimic control group, the mRNA and protein expressions of Kir6.1 and Kir6.2 in the EP+miR-194 mimic group were down-regulated (all P<0.05). Compared with the EP+miR-194 inhibitor control group, the mRNA and protein expressions of Kir6.1 and Kir6.2 in the EP+miR-194 inhibitor group were up-regulated (all P<0.05). After pretreatment with miR-194 mimics, the mRNA and protein expression levels of KATP channel subunits Kir6.1 and Kir6.2 were decreased (all P<0.05). Compared with the EP+2-DG group, the mRNA and protein expression levels of Kir6.1 and Kir6.2 in the EP+miR-194 mimic+2-DG group were down-regulated (all P<0.05) and the mRNA and protein expression levels of Kir6.1 and Kir6.2 in the EP+miR-194 inhibitor+2-DG group were up-regulated (all P<0.05). The 2-DG might play an anti-epilepsy effect by up-regulating KATP channel subunits Kir6.1 and Kir6.2via miR-194.

Genetic Mutations That Lead to Ohtahara Syndrome and Childhood Absence Epilepsy

Since epilepsy has become one of the biggest problems worried by the world, especially affecting thousands of children every year, many scholars have developed some therapies to try to save those families. One of the reasons why some people suffer from such illness is the genetic factors, which changes the function of the corresponding protein and causes a seizure. Among them, two representative diseases are Ohtahara syndrome and Childhood Absence Epilepsy. In the last century, as the mutated genes and the mechanisms of these two syndromes were still largely unknown, general antiepileptic drugs for them weren’t performing well in some conditions. Therefore, the demands for the mechanisms for these two diseases were increasingly higher though the complexity of human genes and genetic mutation still remains a challenging problem to the current technology. Luckily, extensive preclinical studies have shown that new drugs have promising therapeutic effects on these two syndromes. This article introduces the therapies for Ohtahara syndrome and Childhood Absence Epilepsy. There are going to collect the factors resulting from Childhood Absence Epilepsy and Ohtahara syndrome. Concluding past treatments and comparing them with the new therapies to find the medical progress in these two illnesses and whether Allopregnanolone, antisense oligonucleotides (ASOs) can help to treat Ohtahara syndrome, Zonisamide (ZSN), Levetiracetam (LEV), Topiramate (TPM) can treat Therapy-Resistant CAE.

Elevated photic response is followed by a rapid decay and depressed state in ictogenic networks.

The switch between nonseizure and seizure states involves profound alterations in network excitability and synchrony. In this study, we aimed to identify and compare features of neural excitability and dynamics across multiple zebrafish seizure and epilepsy models. Inspired by video-electroencephalographic recordings in patients, we developed a framework to study spontaneous and photically evoked neural and locomotor activity in zebrafish larvae, by combining high-throughput behavioral tracking and whole-brain in vivo two-photon calcium imaging. Our setup allowed us to dissect behavioral and physiological features that are divergent or convergent across multiple models. We observed that spontaneous locomotor and neural activity exhibit great diversity across models. Nonetheless, during photic stimulation, hyperexcitability and rapid response dynamics were well conserved across multiple models, highlighting the reliability of photically evoked activity for high-throughput assays. Intriguingly, in several models, we observed that the initial elevated photic response is often followed by rapid decay of neural activity and a prominent depressed state. Elevated photic response and following depressed state in seizure-prone networks are significantly reduced by the antiseizure medication valproic acid. Finally, rapid decay and depression of neural activity following photic stimulation temporally overlap with slow recruitment of astroglial calcium signals that are enhanced in seizure-prone networks. We argue that fast decay of neural activity and depressed states following photic response are likely due to homeostatic mechanisms triggered by excessive neural activity. An improved understanding of the interplay between elevated and depressed excitability states might suggest tailored epilepsy therapies.

Cholesterol 24-hydroxylase is a novel pharmacological target for anti-ictogenic and disease modification effects in epilepsy

Therapies for epilepsy mainly provide symptomatic control of seizures since most of the available drugs do not target disease mechanisms. Moreover, about one-third of patients fail to achieve seizure control. To address the clinical need for disease-modifying therapies, research should focus on targets which permit interventions finely balanced between optimal efficacy and safety. One potential candidate is the brain-specific enzyme cholesterol 24-hydroxylase. This enzyme converts cholesterol to 24S-hydroxycholesterol, a metabolite which among its biological roles modulates neuronal functions relevant for hyperexcitability underlying seizures.To study the role of cholesterol 24-hydroxylase in epileptogenesis, we administered soticlestat (TAK-935/OV935), a potent and selective brain-penetrant inhibitor of the enzyme, during the early disease phase in a mouse model of acquired epilepsy using a clinically relevant dose. During soticlestat treatment, the onset of epilepsy was delayed and the number of ensuing seizures was decreased by about 3-fold compared to vehicle-treated mice, as assessed by EEG monitoring. Notably, the therapeutic effect was maintained 6.5 weeks after drug wash-out when seizure number was reduced by about 4-fold and their duration by 2-fold. Soticlestat-treated mice showed neuroprotection of hippocampal CA1 neurons and hilar mossy cells as assessed by post-mortem brain histology.High throughput RNA-sequencing of hippocampal neurons and glia in mice treated with soticlestat during epileptogenesis showed that inhibition of cholesterol 24-hydroxylase did not directly affect the epileptogenic transcriptional network, but rather modulated a non-overlapping set of genes that might oppose the pathogenic mechanisms of the disease.In human temporal lobe epileptic foci, we determined that cholesterol 24-hydroxylase expression trends higher in neurons, similarly to epileptic mice, while the enzyme is ectopically induced in astrocytes compared to control specimens. Soticlestat reduced significantly the number of spontaneous seizures in chronic epileptic mice when was administered during established epilepsy.Data show that cholesterol 24-hydroxylase contributes to spontaneous seizures and is involved in disease progression, thus it represents a novel target for chronic seizures inhibition and disease-modification therapy in epilepsy.

Association of intraoperative end-tidal carbon dioxide level with ablation volume during magnetic resonance-guided laser interstitial thermal therapy for mesial temporal lobe epilepsy.

Maximal safe ablation of target structures during magnetic resonance-guided laser interstitial thermal therapy (MRgLiTT) is critical to achieving good seizure outcome in patients with mesial temporal lobe epilepsy (mTLE). The authors sought to determine whether intraoperative physiological variables are associated with ablation volume during MRgLiTT. Patients with mTLE who underwent MRgLiTT at our institution from 2014 to 2019 were retrospectively analyzed. Ablation volume was determined with volumetric analysis of intraoperative postablation MR images. Physiological parameters (systolic blood pressure [SBP], diastolic blood pressure [DBP], mean arterial pressure [MAP], end-tidal carbon dioxide [ETCO2]) measured 40 minutes prior to ablation were analyzed. Univariate and multivariate regression analyses were performed to determine independent predictors of ablation volume. Forty-four patients met the inclusion criteria. The median (interquartile range) ablation volume was 4.27 (2.92-5.89) cm3, and median ablation energy was 7216 (6402-8784) J. The median MAP, SBP, DBP, and ETCO2 values measured during the 40-minute period leading up to ablation were 72.8 (66.2-81.5) mm Hg, 104.4 (96.4-114.4) mm Hg, 62.4 (54.1-69.8) mm Hg, and 34.1 (32.0-36.2) mm Hg, respectively. In univariate analysis, only total laser energy (r = 0.464, p = 0.003) and 40-minute average ETCO2 (r = -0.388, p = 0.012) were significantly associated with ablation volume. In multivariate analysis, only ETCO2 ≤ 33 mm Hg (p = 0.001) was significantly associated with ablation volume. Total ablation energy and ETCO2, but not blood pressure, may significantly affect ablation volume in mTLE patients undergoing MRgLiTT. Mild hypocapnia was associated with increased extent of ablation. Intraoperative monitoring and modulation of ETCO2 may help improve extent of ablation, prediction of ablation volume, and potentially seizure outcome.

The potential role of DNA methylation as preventive treatment target of epileptogenesis.

Pharmacological therapy of epilepsy has so far been limited to symptomatic treatment aimed at neuronal targets, with the result of an unchanged high proportion of patients lacking seizure control. The dissection of the intricate pathological mechanisms that transform normal brain matter to a focus for epileptic seizures—the process of epileptogenesis—could yield targets for novel treatment strategies preventing the development or progression of epilepsy. While many pathological features of epileptogenesis have been identified, obvious shortcomings in drug development are now believed to be based on the lack of knowledge of molecular upstream mechanisms, such as DNA methylation (DNAm), and as well as a failure to recognize glial cell involvement in epileptogenesis. This article highlights the potential role of DNAm and related gene expression (GE) as a treatment target in epileptogenesis.

Precision medicine for genetic epilepsy on the horizon: Recent advances, present challenges, and suggestions for continued progress.

The genetic basis of many epilepsies is increasingly understood, giving rise to the possibility of precision treatments tailored to specific genetic etiologies. Despite this, current medical therapy for most epilepsies remains imprecise, aimed primarily at empirical seizure reduction rather than targeting specific disease processes. Intellectual and technological leaps in diagnosis over the past 10 years have not yet translated to routine changes in clinical practice. However, the epilepsy community is poised to make impressive gains in precision therapy, with continued innovation in gene discovery, diagnostic ability, and bioinformatics; increased access to genetic testing and counseling; fuller understanding of natural histories; agility and rigor in preclinical research, including strategic use of emerging model systems; and engagement of an evolving group of stakeholders (including patient advocates, governmental resources, and clinicians and scientists in academia and industry). In each of these areas, we highlight notable examples of recent progress, new or persistent challenges, and future directions. The future of precision medicine for genetic epilepsy looks bright if key opportunities on the horizon can be pursued with strategic and coordinated effort.

Tiny CNN for Seizure Prediction in Wearable Biomedical Devices.

Epilepsy is a life-threatening disease affecting millions of people all over the world. Artificial intelligence epileptic predictors offer excellent potential to improve epilepsy therapy. Particularly, deep learning models such as convolutional neural networks (CNN) can be used to accurately detect ictogenesis through deep structured learning representations. In this work, a tiny one-dimensional stacked convolutional neural network (1DSCNN) is proposed based on short-time Fourier transform (STFT) to predict epileptic seizure. The results demonstrate that the proposed method obtains better performance compared to recent state-of-the-art methods, achieving an average sensitivity of 94.44%, average false prediction rate (FPR) of 0.011/h and average area under the curve (AUC) of 0.979 on the test set of the American Epilepsy Society Seizure Prediction Challenge dataset, while featuring a model size of only 21.32kB. Furthermore, after adapting the model to 4-bit quantization, its size is significantly decreased by 7.08x with only 0.51% AUC score precision loss, which shows excellent potential for hardware-friendly wearable implementation.

Carba Analogues of Flupirtine and Retigabine with Improved Oxidation Resistance and Reduced Risk of Quinoid Metabolite Formation.

The KV7 potassium channel openers flupirtine and retigabine have been valuable options in the therapy of pain and epilepsy. However, as a result of adverse reactions, both drugs are currently no longer in therapeutic use. The flupirtine‐induced liver injury and the retigabine linked tissue discolouration do not appear related at first glance; nevertheless, both events can be attributed to the triaminoaryl scaffold, which is affected by oxidation leading to elusive reactive quinone diimine or azaquinone diimine metabolites. Since the mechanism of action, i. e. KV7 channel opening, seems not to be involved in toxicity, this study aimed to further develop safer replacements for flupirtine and retigabine. In a ligand‐based design strategy, replacing amino substituents of the triaminoaryl core with alkyl substituents led to carba analogues with improved oxidation resistance and negligible risk of quinoid metabolite formation. In addition to these improved safety features, some of the novel analogues exhibited significantly improved KV7.2/3 channel opening activity, indicated by an up to 13‐fold increase in potency and an efficacy of up to 176 % compared to flupirtine, thus being attractive candidates for further development.

Prospects for Gene Therapy of Epilepsy Using Calcium-Acivated Potassium Channel Vectors

Prospects for Gene Therapy of Epilepsy Using Calcium-Acivated Potassium Channel Vectors

Role of HMGB1/TLR4 and IL-1β/IL-1R1 Signaling Pathways in Epilepsy.

Epilepsy is a chronic disorder of the nervous system characterized by recurrent seizures. Inflammation is one of the six major causes of epilepsy, and its role in the pathogenesis of epilepsy is gaining increasing attention. Two signaling pathways, the high mobility group box-1 (HMGB1)/toll-like receptor 4 (TLR4) and interleukin-1β (IL-1β)/interleukin-1 receptor 1 (IL-1R1) pathways, have become the focus of research in recent years. These two signaling pathways have potential as biomarkers in the prediction, prognosis, and targeted therapy of epilepsy. This review focuses on the association between epilepsy and the neuroinflammatory responses mediated by these two signaling pathways. We hope to contribute further in-depth studies on the role of HMGB1/TLR4 and IL-1β/IL-1R1 signaling in epileptogenesis and provide insights into the development of specific agents targeting these two pathways.

Perampanel as adjunctive therapy in drug resistant epilepsy in adolescents and children waiting for epilepsy surgery: A multicenter observational study in Thailand

PurposeTo evaluate the effectiveness and tolerability of perampanel (PER) in real-world settings in patients between 1 month and 18 years of age with drug resistant epilepsy (DRE) waiting for epilepsy surgery. MethodsIn this multicenter study, patients between 1 month and 18 years of age with DRE treated with PER between January 2020 and June 2021 were selected. The study outcome was effectiveness of PER treatment reported as reduction in seizure frequency and seizure freedom rate. Effectiveness was assessed at 30, 60, 90, 120, 150 and 180 days after initiation of PER. Tolerability profiles were reported as adverse events according to the observations of the patients’ family members and physician. ResultsEighty-five patients treated with PER were included in the study. The mean initial dose and mean maximum dose of adjunctive PER was 2 mg/day and 5.8 mg/day, respectively. The mean seizure frequency (rate/week) was 41.3, 25.4, 18.9, 14.3, 11.2, 11.1 and 8.9 seizures at baseline, 30, 60, 90, 120, 150 and 180 days, respectively; the reduction in the mean seizure frequency at all timepoints was significant compared at the baseline (p<0.001). At 180 days, ≥75% seizure reduction was seen in 64.9% (37/57) of the patients and seizure freedom was achieved in 36.8% (21/57). Drowsiness, ataxia, and behavioral changes were the common adverse events observed, and these improved after the dose of PER was reduced. No discontinuation of PER was required due to side effects or intolerance. ConclusionIn real-world settings, PER is well tolerated and effective in seizure control in pediatric and adolescent patients with DRE.

Stem Cell Therapy in Treating Epilepsy.

Epilepsy is a common disabling chronic neurological disorder characterized by an enduring propensity for the generation of seizures that result from abnormal hypersynchronous firing of neurons in the brain. Over 20–30% of epilepsy patients fail to achieve seizure control or soon become resistant to currently available therapies. Prolonged seizures or uncontrolled chronic seizures would give rise to neuronal damage or death, astrocyte activation, reactive oxygen species production, and mitochondrial dysfunction. Stem cell therapy is potentially a promising novel therapeutic strategy for epilepsy. The regenerative properties of stem cell-based treatment provide an attractive approach for long-term seizure control, particularly in drug-resistant epilepsy. Embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and adipose-derived regenerative cells (ADRCs) are capable of differentiating into specialized cell types has been applied for epilepsy treatment in preclinical animal research and clinical trials. In this review, we focused on the advances in stem cell therapy for epilepsies. The goals of stem cell transplantation, its mechanisms underlying graft effects, the types of grafts, and their therapeutic effects were discussed. The cell and animal models used for investigating stem cell technology in epilepsy treatment were summarized.