Therapy For Epilepsy Research Articles

Pharmacological impact on the expression of microglial and astroglial proteins involved in the regulation of epileptogenesis as a possible new strategy for epilepsy therapy

Pharmacological impact on the expression of microglial and astroglial proteins involved in the regulation of epileptogenesis as a possible new strategy for epilepsy therapy

Ultrasonic therapies for seizures and drug-resistant epilepsy.

Ultrasonic therapy is an increasingly promising approach for the treatment of seizures and drug-resistant epilepsy (DRE). Therapeutic focused ultrasound (FUS) uses thermal or nonthermal energy to either ablate neural tissue or modulate neural activity through high- or low-intensity FUS (HIFU, LIFU), respectively. Both HIFU and LIFU approaches have been investigated for reducing seizure activity in DRE, and additional FUS applications include disrupting the blood-brain barrier in the presence of microbubbles for targeted-drug delivery to the seizure foci. Here, we review the preclinical and clinical studies that have used FUS to treat seizures. Additionally, we review effective FUS parameters and consider limitations and future directions of FUS with respect to the treatment of DRE. While detailed studies to optimize FUS applications are ongoing, FUS has established itself as a potential noninvasive alternative for the treatment of DRE and other neurological disorders.

Vagus nerve stimulation therapy for intractable epilepsy in a patient with Kleefstra syndrome

Vagus nerve stimulation therapy for intractable epilepsy in a patient with Kleefstra syndrome

Strategic therapy of refractory epilepsy in insular lobe epilepsy with limited resources centre

Strategic therapy of refractory epilepsy in insular lobe epilepsy with limited resources centre

Ketogenic diet therapy for pediatric epilepsy is associated with alterations in the human gut microbiome that confer seizure resistance in mice

The gut microbiome modulates seizure susceptibility and the anti-seizure effects of the ketogenic diet (KD) in animal models, but whether these relationships translate to KD therapies for human epilepsy is unclear. We find that the clinical KD alters gut microbial function in children with refractory epilepsy. Colonizing mice with KD-associated microbes promotes seizure resistance relative to matched pre-treatment controls. Select metagenomic and metabolomic features, including those related to anaplerosis, fatty acid β-oxidation, and amino acid metabolism, are seen with human KD therapy and preserved upon microbiome transfer to mice. Mice colonized with KD-associated gut microbes exhibit altered hippocampal transcriptomes, including pathways related to ATP synthesis, glutathione metabolism, and oxidative phosphorylation, and are linked to susceptibility genes identified in human epilepsy. Our findings reveal key microbial functions that are altered by KD therapies for pediatric epilepsy and linked to microbiome-induced alterations in brain gene expression and seizure protection in mice.

Schisandrin B, a dual positive allosteric modulator of GABAA and glycine receptors, alleviates seizures in multiple mouse models.

Epilepsy is a prevalent and severe neurological disorder and approximately 30% of patients are resistant to existing medications. It is of utmost importance to develop alternative therapies to treat epilepsy. Schisandrin B (SchB) isa major bioactive constituent of Schisandra chinensis (Turcz.) Bailland has multiple neuroprotective effects, sedative and hypnotic activities.In this study, we investigated the antiseizure effect of SchB in various mouse models of seizure and explored the underlying mechanisms. Pentylenetetrazole (PTZ), strychnine (STR), and pilocarpine-induced mouse seizure models were established.We showed that injection ofSchB (10, 30, 60 mg/kg, i.p.) dose-dependentlydelayed the onset of generalized tonic-clonic seizures (GTCS), reduced the incidence of GTCS and mortality in PTZ and STR models. Meanwhile, injection ofSchB (30 mg/kg, i.p.) exhibited therapeutic potential in pilocarpine-induced status epilepticus model, which was considered as a drug-resistant model. In whole-cell recording from CHO/HEK-239 cells stably expressing recombinant human GABAA receptors (GABAARs) and glycine receptors (GlyRs) and cultured hippocampal neurons, co-application of SchB dose-dependently enhanced GABA or glycine-induced current with EC50 values at around 5 μM, and application of SchB (10 μM) alone did not activate the channels in the absence of GABA or glycine.Furthermore, SchB (10 μM) eliminated both PTZ-induced inhibition on GABA-induced current (IGABA) and strychnine (STR)-induced inhibition on glycine-induced current (Iglycine).Moreover, SchB(10 μM) efficiently rescued the impaired GABAARs associated with genetic epilepsies. In addition,the homologous mutants in both GlyRs-α1(S267Q) and GABAARs-α1(S297Q)β2(N289S)γ2L receptors by site-directed mutagenesis testsabolishedSchB-induced potentiation of IGABA and Iglycine. In conclusion, we have identified SchB as a natural positive allosteric modulator of GABAARs and GlyRs, supporting its potential as alternative therapies for epilepsy.

Seizure outcomes and safety profiles of surgical options for epilepsy associated to hypothalamic hamartomas: a systematic review and meta-analysis

PurposeSeveral surgical options are available for treating hypothalamic hamartoma-related epilepsy but their respective efficacy and safety profiles are poorly defined. MethodsA literature search identified English-language articles reporting series of patients (minimum 3 patients with a follow-up ≥12 months) operated on by either microsurgery, endoscopic surgery, radiosurgery, radiofrequency thermocoagulation or laser interstitial thermal therapy for hypothalamic hamartoma-related epilepsy. The unit of analysis was each selected study. Pooled rates of seizure freedom and of neurological and endocrinological complications were analyzed using meta-analysis to calculate both fixed and random effects. The results of meta-analyses were compared. ResultsThirty-nine studies were included. There were 568 and 514 participants for seizure outcome and complication analyses, respectively. The pairwise comparison showed that: i) the proportion of seizure-free cases was significantly lower for radiosurgery as compared to microsurgery, radiofrequency thermocoagulation and laser ablation, and significantly lower for endoscopic surgery as compared to radiofrequency thermocoagulation; ii) the proportion of permanent hypothalamic dysfunction was significantly higher for microsurgery as compared to all other techniques, and significantly lower for endoscopic surgery as compared to radiofrequency thermocoagulation and laser ablation; iii) the incidence of permanent neurological disorders was significantly higher for microsurgery as compared to endoscopic surgery, radiosurgery and radiofrequency thermocoagulation, and significantly lower for radiosurgery as compared to laser ablation. ConclusionsMinimally invasive surgical techniques, including endoscopic surgery, radiofrequency thermocoagulation and laser ablation, represent an acceptable compromise between efficacy and safety in the treatment of hypothalamic hamartoma-related epilepsy. Microsurgery and radiosurgery should be considered in carefully selected cases.

Use of ketogenic dietary therapy for drug-resistant epilepsy in early infancy.

There is growing evidence that ketogenic dietary therapy (KDT) can be safely and efficiently used in young children, but little evidence exists on its use in newborns. Developmental and epileptic encephalopathies starting in the neonatal period or early infancy usually present a poor prognosis. The aim of this study was to evaluate effectiveness, safety, and survival of infants younger than 3 months of age with drug-resistant epilepsy in whom KDT was used. A retrospective study was conducted to evaluate neonates and infants younger than 3 months who started KDT for drug-resistant developmental and epileptic encephalopathies at three referral centers. Data were collected on demographic features, time of epilepsy onset, epilepsy syndrome, seizure type, seizure frequency at diet onset, etiology, details regarding diet initiation, type of ketogenic formula, breastfeeding, route of administration, blood ketones, growth, length of NICU stay, and survival. Nineteen infants younger than 12 weeks of life who received KDT with a minimum follow-up of 1 month were included; 13 had early-infantile developmental and epileptic encephalopathy, four epilepsy of infancy with migrating focal seizures, and two focal epilepsy. A >50% response was observed in 73.7% at 1 month on the diet; 37% achieved a > 75% seizure reduction, and 10.5% became seizure free. At 3 months, a >50% decrease in seizure frequency was observed in 72.2%; 15.8% had a >75% reduction; 21% became seizure free. Overall survival was 76% at 1 year on diet. Incidence of acute and late adverse effects was low and most adverse effects were asymptomatic and manageable. Our experience suggests that KDT is safe and effective in newborns and very young infants; however, further studies on the management of the diet in this vulnerable age group are necessary.

Overexpression of KCNN4 channels in principal neurons produces an anti-seizure effect without reducing their coding ability.

Gene therapy offers a potential alternative to the surgical treatment of epilepsy, which affects millions of people and is pharmacoresistant in ~30% of cases. Aimed at reducing the excitability of principal neurons, the engineered expression of K+ channels has been proposed as a treatment due to the outstanding ability of K+ channels to hyperpolarize neurons. However, the effects of K+ channel overexpression on cell physiology remain to be investigated. Here we report an adeno-associated virus (AAV) vector designed to reduce epileptiform activity specifically in excitatory pyramidal neurons by expressing the human Ca2+-gated K+ channel KCNN4 (KCa3.1). Electrophysiological and pharmacological experiments in acute brain slices showed that KCNN4-transduced cells exhibited a Ca2+-dependent slow afterhyperpolarization that significantly decreased the ability of KCNN4-positive neurons to generate high-frequency spike trains without affecting their lower-frequency coding ability and action potential shapes. Antiepileptic activity tests showed potent suppression of pharmacologically induced seizures in vitro at both single cell and local field potential levels with decreased spiking during ictal discharges. Taken together, our findings strongly suggest that the AAV-based expression of the KCNN4 channel in excitatory neurons is a promising therapeutic intervention as gene therapy for epilepsy.

Black Phosphorus Flake-Enabled Wireless Neuromodulation for Epilepsy Treatment.

Epilepsy is a prevalent and severe neurological disorder and generally requires prolonged electrode implantation and tether brain stimulation in refractory cases. However, implants may cause potential chronic immune inflammation and permanent tissue damage due to material property mismatches with soft brain tissue. Here, we demonstrated a nanomaterial-enabled near-infrared (NIR) neuromodulation approach to provide nongenetic and nonimplantable therapeutic benefits in epilepsy mouse models. Our study showed that crystal-exfoliated photothermal black phosphorus (BP) flakes could enhance neural activity by altering the membrane capacitive currents in hippocampus neurons through NIR photothermal neuromodulation. Optical stimulation facilitated by BP flakes in hippocampal slices evoked action potentials with a high spatiotemporal resolution. Furthermore, BP flake-enabled NIR neuromodulation of hippocampus neural circuits can suppress epileptic signals in epilepsy model mice with minimal invasiveness and high biocompatibility. Consequently, nanomaterial-enabled NIR neuromodulation may open up opportunities for nonimplantable optical therapy of epilepsy in nontransgenic organisms.

Low glycemic index diet restrains epileptogenesis in a gender-specific fashion

Dietary restriction, such as low glycemic index diet (LGID), have been successfully used to treat drug-resistant epilepsy. However, if such diet could also counteract antiepileptogenesis is still unclear. Here, we investigated whether the administration of LGID during the latent pre-epileptic period, prevents or delays the appearance of the overt epileptic phenotype. To this aim, we used the Synapsin II knockout (SynIIKO) mouse, a model of temporal lobe epilepsy in which seizures manifest 2–3 months after birth, offering a temporal window in which LGID may affect epileptogenesis. Pregnant SynIIKO mice were fed with either LGID or standard diet during gestation and lactation. Both diets were maintained in weaned mice up to 5 months of age. LGID delayed the seizure onset and induced a reduction of seizures severity only in female SynIIKO mice. In parallel with the epileptic phenotype, high-density multielectrode array recordings revealed a reduction of frequency, amplitude, duration, velocity of propagation and spread of interictal events by LGID in the hippocampus of SynIIKO females, but not mutant males, confirming the gender-specific effect. ELISA-based analysis revealed that LGID increased cortico-hippocampal allopregnanolone (ALLO) levels only in females, while it was unable to affect ALLO plasma concentrations in either sex. The results indicate that the gender-specific interference of LGID with the epileptogenic process can be ascribed to a gender-specific increase in cortical ALLO, a neurosteroid known to strengthen GABAergic transmission. The study highlights the possibility of developing a personalized gender-based therapy for temporal lobe epilepsy.

Investigating the molecular mechanisms of Ashwagandha phytocompounds in epilepsy through differential gene expression and pathway analysis

Introduction and Aim: Withania somnifera (Ashwagandha) is a traditional Indian herb used in Ayurveda and Unani medicine, particularly in anti-inflammatory, anti-cancer, anti-stress, antioxidant, immune-boosting, and rejuvenating effects. Epilepsy is a severe neuropsychological condition that occurs sporadically and has a long-term effect on the electrical signals that travel between brain cells. The disorder is characterized by recurrent seizures that are brought on by a sudden increase in brain electrical activity. This is the outcome of abnormal neuronal discharges or coordinated neuronal hyperexcitability. The study’s main objective is to find out the therapeutic phytocompound in treating Epileptic disorder. Materials and Methods: This study investigated the potential use of phytochemicals from the Ashwagandha plant as epileptic seizure treatments that target key genes strongly associated with the disease. To forecast the binding affinity between the phytochemicals and the receptors, molecular docking simulations (PyRx) were used for the virtual screening. Results: The preliminary screening of the twenty-two phytocompounds from Withania somnifera was based on their affinity for epilepsy. The results showed that withasomnine exhibited great binding affinity to the receptors, indicating their potential as targeted epileptic seizure therapeutics. The ligands revealed stronger binding with the epilepsy targets, and the binding score less than -7 kcal/mol was taken into consideration for further exploration. This research lays the groundwork for upcoming in-vitro and in-vivo studies to confirm the effectiveness of these phytochemicals as cancer therapies. Conclusion: The results suggest that withasomnine derivatives from Withania somnifera could be a promising source of epilepsy therapies.

A simple, automated method of seizure detection in mouse models of temporal lobe epilepsy

The lack of preventive and disease modifying therapies for temporal lobe epilepsy (TLE) is a major unmet medical need. Search for such therapies utilize mouse models and require detection of seizures in electroencephalography (EEG) recordings. The labor-intensive nature of reviewing EEGs spanning many weeks underscores the need for a method of automated detection. Here we report a simple automated method of detecting seizures in long term EEG recordings from electrodes implanted in the hippocampus in animal models of TLE. We utilize a 2-pronged approach that relies on the increase in power within the gamma band range (20–50hz) during the seizure followed by suppression of activity following the seizure (post-ictal suppression [PIS]). We demonstrate the utility of this method for detecting seizures in hippocampal and amygdala EEG recordings from multiple models of TLE.

Real-world evidence on the use of cannabidiol for the treatment of drug resistant epilepsy not related to Lennox-Gastaut syndrome, Dravet syndrome or Tuberous Sclerosis Complex.

Highly purified cannabidiol (CBD) has a broad spectrum of action and could be useful for the treatment of drug resistant epilepsy regardless of etiology or syndrome. Multicenter retrospective study that evaluated the efficacy and safety of CBD for the treatment of drug resistant epilepsy of different etiologies in patients >2 years of age. Seventy-eight patients with a median age of 24 years and a wide spectrum of mainly structural and genetic etiologies were included. Patients were using a median of 3 antiseizure drugs (IQR=2-4) and had a median of 30 monthly seizures (IQR=12-100) before starting CBD. The median treatment time with CBD was 14 months (IQR=10-17). The efficacy analysis at the last available visit showed that mean percent reduction in seizures, ≥50% reduction in seizure frequency and seizure freedom was 67.8%, 68.8% and 11.5% respectively. We found no significant impact of concomitant clobazam use on the efficacy and safety of CBD. In the safety analysis, 28.2% (n=22) of patients presented adverse events related to CBD and drug-retention rate was 78.2%. In a real-world setting, highly purified CBD has been shown to be safe and effective for the treatment of drug resistant epilepsy not related to Lennox-Gastaut syndrome, Dravet syndrome or Tuberous Sclerosis Complex. Based on these findings, highly purified CBD should be considered as an adjuvant therapy for drug resistant epilepsy, regardless of its underlying cause or specific syndrome. Nevertheless, this assumption should be validated through further controlled trials.

Nutritional treatment with the ketogenic diet in children with refractory epilepsy: a narrative review

The two mainstays of therapy for refractory epilepsy are medication and surgery. Child behavioral and cognitive aspects of epilepsy can be improved by using a specialized dietary regimen such as the ketogenic diet (KD). The purpose of this review is to expand our understanding of KD as a nutritional therapy for children with refractory epilepsy and to provide insight into the physiological aspects of its efficacy as an alternative to anti-seizure medication. Either directly or indirectly, ketones, glucose restriction, and polyunsaturated fatty acids regulate epileptic seizures. For KD to be effective, all three of these components must be present, even though the exact mechanism is unknown. Increasing gamma-aminobutyric acid, mitochondrial biogenesis, and oxidative phosphorylation levels can also serve as a means of promoting stable synaptic function while also decreasing neural activity and excitability. Most side effects of KD are caused by mild metabolic abnormalities such as acidosis, hyperuricemia, hypercholesterolemia, hypocalcemia, and hypomagnesemia. Since medium-chain triglycerides (MCTs) produce more ketones per calorie than long-chain triglycerides, individuals who consume MCTs can consume more carbohydrates and protein. This review demonstrated that KD therapy led to positive outcomes for patients with refractory epilepsy. Further study is needed to evaluate whether less restrictive and easier-to-follow diets, such as the modified Atkins diet and MCT diets, have a similar effect on seizure treatment as the standard KD.

Antiepileptogenic Effects of Anakinra, Lamotrigine and Their Combination in a Lithium-Pilocarpine Model of Temporal Lobe Epilepsy in Rats.

Temporal lobe epilepsy is a common, chronic disorder with spontaneous seizures that is often refractory to drug therapy. A potential cause of temporal lobe epilepsy is primary brain injury, making prevention of epileptogenesis after the initial event an optimal method of treatment. Despite this, no preventive therapy for epilepsy is currently available. The purpose of this study was to evaluate the effects of anakinra, lamotrigine, and their combination on epileptogenesis using the rat lithium-pilocarpine model of temporal lobe epilepsy. The study showed that there was no significant difference in the number and duration of seizures between treated and untreated animals. However, the severity of seizures was significantly reduced after treatment. Anakinra and lamotrigine, alone or in combination, significantly reduced neuronal loss in the CA1 hippocampus compared to the control group. However, the drugs administered alone were found to be more effective in preventing neuron loss in the hippocampal CA3 field compared to combination treatment. The treatment alleviated the impairments in activity level, exploratory behavior, and anxiety but had a relatively weak effect on TLE-induced impairments in social behavior and memory. The efficacy of the combination treatment did not differ from that of anakinra and lamotrigine monotherapy. These findings suggest that anakinra and lamotrigine, either alone or in combination, may be clinically useful in preventing the development of histopathological and behavioral abnormalities associated with epilepsy.

Lightweight convolution transformer for cross-patient seizure detection in multi-channel EEG signals

BackgroundEpilepsy is a neurological illness affecting the brain that makes people more likely to experience frequent, spontaneous seizures. There has to be an accurate automated method for measuring seizures frequency and severity to assess the efficacy of pharmacological therapy for epilepsy. The drug quantities are often derived from patient reports which may cause significant issues owing to inadequate or inaccurate descriptions of seizures and their frequencies. Methods and materialsThis study proposes a novel deep learning architecture-based Lightweight Convolution Transformer (LCT). The Transformer model is able to learn spatial and temporal correlated information simultaneously from the multi-channel electroencephalogram (EEG) signal to detect seizures at smaller segment lengths. In the proposed work, the lack of translation equivariance and localization of ViT is reduced using convolution tokenization, and rich information from the Transformer encoder is extracted by sequence pooling instead of the learnable class token. ResultsExtensive experimental results demonstrate that the proposed model on cross-patient learning can effectively detect seizures from the raw EEG signals. The accuracy and F1-score of seizure detection in the cross-patient case on the CHB-MIT dataset are 96.31% and 96.32%, respectively, at 0.5 sec segment length. In addition, the performance metrics show that the inclusion of inductive biases and attention-based pooling in the model enhances the performance and reduces the number of Transformer encoder layers, which significantly reduces the computational complexity. In this research, we provide a novel approach to enhance efficiency and simplify the architecture for multi-channel automated seizure detection.

Seizing hope: Advancing cell therapy for pharmaco-resistant epilepsy toward the clinic.

In this issue of Cell Stem Cell, Bershteyn etal.1 developed a human interneuron cell therapy that reduced spontaneous seizure activity in a mouse model of mesial temporal lobe epilepsy (MTLE). The data presented here support an ongoing phase 1/2 clinical trial for the treatment of pharmaco-resistant epilepsy in patients.

Aesthetic transaxillary subpectoral placement of vagus nerve stimulator in children and young adults: A technical note

IntroductionVagus nerve stimulation (VNS) is a neuromodulation therapy for drug-resistant epilepsy (DRE), refractory status epilepticus, and treatment-resistant depression. The lead is tunneled into the subcutaneous space and connected to the generator, which is usually implanted in a subcutaneous pocket below the clavicle. Surgical complications in the chest region include skin breakdown or infection. An alternative approach is to perform a subclavear subpectoral implantation. In our surgical series, we report a new aesthetic implantation method for VNS generators in children and young patients: the transaxillary subpectoral placement. Materials and methodsFrom May 2021 to May 2023, 10 vagus nerve stimulation generators were placed subpectorally with a transaxillary approach by the authors. We considered operative time, surgical complications such as blood loss, infections, device migration, pain, and adverse events at follow-up. ResultsIn this surgical series, we reviewed all cases of subpectoral implantation of VNS generators in children and young adults at our institution in the last 2 years. All patients were treated with subpectoral Sentiva 1000 (Livanova PLC) insertion with axillary access by a neurosurgeon and a pediatric surgeon. The operative time was slightly longer compared to the traditional subcutaneous implant. All generators reported impedances within the optimal range. Blood loss was not significant and no other perioperative complications were reported. Patients and families were highly satisfied with the outcomes in terms of comfort and aesthetic results after surgery and at the last follow-up. No cases of infection occurred, and no malfunctions or displacements of the generator were registered at clinical follow-up. ConclusionThe transaxillary subpectoral placement of theVNS generator is an aesthetic and anatomic approach, which provides several benefits to children and young adults.

Nano Emulsion: The Targeted Drug Delivery in the Therapy of Epilepsy

Around the world, 50 million people suffer with epilepsy; it significantly burdens society in terms of finances, society, and health. Our comprehension of the pathophysiological processes causing the illness and the factors affecting its prognosis has significantly advanced during the last ten years. Around a third of patients are still resistive to medical intervention, despite the fact that the number of antiepileptic drugs has expanded dramatically over the past 20 years. The ability of nanotech-based anti-epileptic drug (AED) administration methods to cross the blood brain barrier, increase specificity, and have the capacity for extended brain administration of drugs have lately attracted interest. Nanotechnology appears to be a promising and innovative development in this area. Nano emulsions have a mean droplet size of 20 to 200 nm and remain kinetically stable dispersions of two incompatible liquids with the assistance of an emulsifier or emulsifiers. The effectiveness of NEs as a delivery system for Central Nervous System-active medications used in effective regimens against difficult-to-treat CNS conditions.