Treatment Of Drug-resistant Epilepsy Research Articles

Neuroprotective effects of chlorogenic acid against oxidative stress in rats subjected to lithium-pilocarpine-induced status epilepticus.

Epilepsy is a condition marked by sudden, self-sustained, and recurring brain events, showcasing unique electro-clinical and neuropathological phenomena that can alter the structure and functioning of the brain, resulting in diverse manifestations. Antiepileptic drugs (AEDs) can be very effective in 30% of patients in controlling seizures. Several factors contribute to this: drug resistance, individual variability, side effects, complexity of epilepsy, incomplete understanding, comorbidities, drug interactions, and no adherence to treatment. Therefore, research into new AEDs is important for several reasons such as improved efficacy, reduced side effects, expanded treatment options, treatment for drug-resistant epilepsy, improved safety profiles, targeted therapies, and innovation and progress. Animal models serve as crucial biological tools for comprehending neuronal damage and aiding in the discovery of more effective new AEDs. The utilization of antioxidant agents that act on the central nervous system may serve as a supplementary approach in the secondary prevention of epilepsy, both in laboratory animals and potentially in humans. Chlorogenic acid (CGA) is a significant compound, widely prevalent in numerous medicinal and food plants, exhibiting an extensive spectrum of biological activities such as neuroprotection, antioxidant, anti-inflammatory, and analgesic effects, among others. In this research, we assessed the neuroprotective effects of commercially available CGA in Wistar rats submitted to lithium-pilocarpine-induced status epilepticus (SE) model. After 72-h induction of SE, rats received thiopental and were treated for three consecutive days (1st, 2nd, and 3rd doses). Next, brains were collected and studied histologically for viable cells in the hippocampus with staining for cresyl-violet (Nissl staining) and for degenerating cells with Fluoro-Jade C (FJC) staining. Moreover, to evaluate oxidative stress, the presence of malondialdehyde (MDA) and superoxide dismutase (SOD) was quantified. Rats administered with CGA (30 mg/kg) demonstrated a significant decrease of 59% in the number of hippocampal cell loss in the CA3, and of 48% in the hilus layers after SE. A significant reduction of 75% in the cell loss in the CA3, shown by FJC+ staining, was also observed with the administration of CGA (30 mg/kg). Furthermore, significant decreases of 49% in MDA production and 72% in the activity of SOD were seen, when compared to animals subjected to SE that received vehicle. This study introduces a novel finding: the administration of CGA at a dosage of 30 mg/kg effectively reduced oxidative stress induced by lithium-pilocarpine, with its effects lasting until the peak of neural damage 72 h following the onset of SE. Overall, the research and development of new AEDs are essential for advancing epilepsy treatment, improving patient outcomes, and ultimately enhancing the quality of life for individuals living with epilepsy.

Thalamic stereoelectroencephalography for neuromodulation target selection: Proof of concept and review of literature of pulvinar direct electrical stimulation.

In patients with drug-resistant epilepsy (DRE) who are not candidates for resective surgery, various thalamic nuclei, including the anterior, centromedian, and pulvinar nuclei, have been extensively investigated as targets for neuromodulation. However, the therapeutic effects of different targets for thalamic neuromodulation on various types of epilepsy are not well understood. Here, we present a 32-year-old patient with multifocal bilateral temporoparieto-occipital epilepsy and bilateral malformations of cortical development (MCDs) who underwent bilateral stereoelectroencephalographic (SEEG) recordings of the aforementioned three thalamic nuclei bilaterally. The change in the rate of interictal epileptiform discharges (IEDs) from baseline were compared in temporal, central, parietal, and occipital regions after direct electrical stimulation (DES) of each thalamic nucleus. A significant decrease in the rate of IEDs (33% from baseline) in the posterior quadrant regions was noted in the ipsilateral as well as contralateral hemisphere following DES of the pulvinar. A scoping review was also performed to better understand the current standpoint of pulvinar thalamic stimulation in the treatment of DRE. The therapeutic effect of neuromodulation can differ among thalamic nuclei targets and epileptogenic zones (EZs). In patients with multifocal EZs with extensive MCDs, personalized thalamic targeting could be achieved through DES with thalamic SEEG electrodes.

Efficacy and safety of modified medium-chain triglyceride ketogenic diet in patients with drug-resistant epilepsy

BackgroundMedium-chain triglyceride ketogenic diet (MCTKD) is previously less commonly used in China. This study was aimed to assess the efficacy and safety of the modified MCTKD in the treatment of drug-resistant epilepsy in Chinese patients.MethodsPatients with drug-resistant epilepsy were enrolled to receive treatment with modified MCTKD in Guangdong Sanjiu Brain Hospital during December 2020 and September 2022. The modified MCTKD contained fat that provided 50–70% of the total energy, as well as proteins and carbohydrates that provided 20–30% and 20% of energy, respectively. The fat component was composed of 20–30% medium-chain triglycerides (MCTs) and 30–40% long-chain triglycerides. The efficacy and safety of the diet were assessed at 1, 3 and 6 months.ResultsA total of 123 patients aged 2.5 to 65 years, were included in this study. The response rates at 1, 3 and 6 months were 49.6%, 43.1%, and 30.9%, respectively. The seizure freedom rates at 1, 3 and 6 months were 12.2%, 10.6%, and 6.5%, respectively. The retention rates at 1, 3 and 6 months were 98.4%, 65.0% and 33.3% respectively. Side effects occurred in 21.14% of patients, which were predominantly gastrointestinal symptoms such as abdominal pain, diarrhea, vomiting, and constipation, and most of them resolved after dietary adjustments. A total of 82 patients (66.7%) discontinued the treatment with the reason of refusing to eat (8.1%), poor efficacy (35.0%), poor compliance (4.9%), and inability to follow-up (9.8%). Only 4 patients (3.3%) withdrew the diet due to side effects.ConclusionsThe modified MCTKD with MCTs providing 20–30% of energy has a good safety in patients with drug-resistant epilepsy, but its effectiveness needs to be enhanced. Further modifications of MCTKD with an optimal energy ratio are required to achieve a better efficacy and safety.

Seizing the moment: communicating ethics, decisions, and neurotechnological approaches to pediatric drug-resistant epilepsy

It is a fundamental duty of neuroscientists to discuss the results of research and related ethical implications. Engagement with neuroscience is especially critical for families with children affected by disorders such as drug resistant epilepsy (DRE) as they navigate complex decisions about innovations in treatment that increasingly include invasive neurotechnologies. Through an evidence-based, iterative, and value-guided approach, we created the short-form documentary film, Seizing Hope: High Tech Journeys in Pediatric Epilepsy, to delve into the relationship between experts with first-hand, lived experience – youth with DRE and caregivers – and physician experts as they weigh medical and ethical trade-offs on this landscape. We describe the co-creation and evolution of this film, screenings, and feedback. Survey responses from 385 viewers highlight new developments in technologies for the treatment of DRE, how families navigate choices for treatment with brain technology, and a sense of hope for the future for children with epilepsy as key attributes of this science communication piece.

Hippocampal sclerosis is associated with celiac disease type immunity in patients with drug-resistant temporal lobe epilepsy

Abstract Background A prior small-scale single center study suggested an association between celiac disease (CD)-type immunity and refractory temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS). The present study addresses this putative association in a large, well-characterized group of drug-resistant epilepsy (DRE) patients. These patients were grouped based on the spectrum of CD and gluten sensitivity-associated antibodies. Methods In this cross-sectional study, 253 consecutive adult epilepsy patients (135 females, 118 males; age 16–76 years) were categorized into three groups: (i) CD-positive group with either prior diagnosis of CD or CD-specific TG2/EmA antibodies, (ii) AGA-positive group with antigliadin antibodies (AGA) but without CD, and (iii) CD/AGA-negative group without any gluten sensitivity-associated antibodies or CD. Clinical and immunological findings were then compared among the groups. Results TLE with HS was more common in the CD-positive group compared to CD/AGA-negative group (31.8% versus 11.9%, P = 0.019). Autoimmune disorders were more common in the AGA-positive group than in the CD/AGA-negative group (P = 0.025). Considering HS lateralization; left lateralization was more common in CD-positive group compared to CD/AGA-negative group (71.4% versus 25%, P = 0.030). TG6 seropositivity did not differ among the groups (P > 0.05). Conclusions This study provides further evidence linking TLE with HS and CD-type autoimmunity suggesting that CD-type immune response to gluten can be one potential mechanism as a disease modifier leading to DRE and HS. Understanding these immunological factors is imperative for developing immunomodulatory or dietary treatments for DRE potentially preventing HS progression.

Drug-resistant epilepsy treated with a vagus nerve stimulator – case report and literature review

The average incidence of epilepsy worldwide is estimated at 7.60 cases per 1,000 inhabitants, with an average annual incidence of 67.77 cases per 100,000 inhabitants. Epilepsy is one of the most common neurological diseases. However, it is not a disease entity, but a set of symptoms that may occur against the background of various morphological and metabolic changes in the brain. Symptoms of epilepsy include epileptic seizures, i.e. temporary disturbances in the bioelectric activity of brain nerve cells. Epilepsy is a brain disorder characterized by a persistent predisposition to trigger seizures, and the condition has neurobiological, cognitive, psychological, and social consequences. Effective treatment of epilepsy may require the use of various methods. In this paper, we would like to present a case report on the treatment of drug-resistant epilepsy using a vagus nerve stimulator (VNS). The described case may prove the effectiveness of treatment of focal drug-resistant epilepsy using vagus nerve stimulation (VNS). Choosing an appropriate, effective method of treating children with drug-resistant epilepsy is crucial; it is especially worth thinking about innovative methods such as VNS.

The impact of ketogenic diet on drug-resistant epilepsy in children: A comprehensive review and meta-analysis.

The ketogenic diet (KD), characterized by high-fat and low-carbohydrate intake, is currently gaining widespread popularity as a treatment for drug-resistant epilepsy (DRE). In addition to the traditional ketogenic diet, several variants have been introduced to enhance compliance and flexibility, such as the modified Atkins diet (MAD) and the low glycemic index diet (LGID). These adaptations aim to provide patients with more manageable and sustainable options while harnessing the potential therapeutic benefits of DRE. The objective of this study is to evaluate the efficacy and safety of the KD in pediatric patients who exhibit DRE. In this study, we conducted a thorough review of existing literature by searching Cochrane, Embase, Medline, and PubMed. Our approach involved predefined criteria for data extraction and the assessment of study quality. Eleven RCTs with 788 participants were included in this study. The pooled effect estimates revealed a significant association between dietary interventions and seizure frequency reduction of > 50% (OR 6.68, 96% CI 3.52, 12.67) and > 90% (OR 4.37, 95% CI 2.04, 9.37). Dietary interventions also increased the odds of achieving seizure freedom (OR 4.13, 95% CI 1.61, 10.60). The common adverse effects included constipation (39.07%) and vomiting (10%). In conclusion, dietary interventions, notably the KD, hold promise for pediatric DRE, reducing seizures and achieving freedom. These non-pharmacological options improve the quality of life of non-responsive and non-surgical patients. The KD has emerged as a potential therapeutic approach. Further research is needed to address the limitations and investigate their long-term effects.

Treatment of drug-resistant epilepsy: diet or pill?

Treatment of drug-resistant epilepsy: diet or pill?

A nomogram to predict the treatment benefit of perampanel in drug-resistant epilepsy patients

ObjectiveThe objective of this study was to identify the factors that affect the efficacy of added perampanel for the treatment of drug-resistant epilepsy (DRE), and to develop a reliable nomogram to predict the benefit of this addition.MethodsA retrospective clinical analysis was conducted on DRE patients who received perampanel treatment and who were followed up for at least 6 months from January 2020 and September 2023 at the Epilepsy Center of Fujian Medical University Union Hospital. Data from January 2020 to December 2021 were used as development dataset to build model, while the data from January 2022 to September 2023 were used as validation dataset for internal validation. The predictive factors that affected the efficacy of perampanel as DRE treatment were included in the final multivariate logistic regression model, and a derived nomogram was established.ResultsA total of 119 DRE patients who received perampanel treatment were included in this study (development datasets: n = 76; validation data: n = 43). Among them, 72.3% (n = 86) showed a 50% or greater reduction in seizure frequency after perampanel treatment. Of all the parameters of interest, sex, age, history of generalized tonic-clonic seizures, and the number of antiseizure medications were identified as significant predictors for estimating the benefit of adding perampanel for the treatment of DRE. A model incorporating these four variables was developed, and a nomogram was constructed to calculate the probability of benefit of adding perampanel using the model coefficients. The C-index of the predictive model was 0.838, and the validation C-index was 0.756. The goodness-of-fit test showed good calibration of the model (p = 0.920, 0.752 respectively).ConclusionThe proposed nomogram has significant clinical potential for predicting the probability of benefit of perampanel as DRE treatment. This nomogram can be used to identify DRE patients who could benefit from the early addition of perampanel to their treatment regimen.

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.

36 Impact of Neuropsychological Performance and Anxiety on Meditation in Drug Resistant Epilepsy (DRE) Patients Implanted with a Responsive Neurostimulation (RNS) Device

Objective:Responsive neurostimulation (RNS) is a surgical intervention to reduce the frequency of seizures as an adjunctive therapy for patients with drug-resistant epilepsy (DRE). Presurgical neuropsychological evaluations capture symptoms of anxiety and depression, which occur in higher rates within the epilepsy population than in the general population; however, the effects of mood are commonly overlooked or underappreciated in the conceptualization of cognitive functioning and overall quality of life. Previous studies have shown the effects of attentional control and executive functioning on engagement in meditative states. The present study examines pre and post-meditation self-reported anxiety symptoms and the electrophysiological changes captured intracranially during meditation sessions in patients implanted with an RNS device. This study seeks to utilize presurgical neuropsychological evaluations to explore relationships between cognitive profiles and meditative state changes, and reductions in anxiety.Participants and Methods:This study presents a series of 10 patients who underwent RNS device implantation for the treatment of DRE at Mount Sinai Hospital. All patients had at least one contact in the basolateral amygdala. Prior to surgical implantation of the RNS device, all patients completed a comprehensive neuropsychological evaluation based on the NIH Common Data Elements Battery for Epilepsy Patients. Patients in this study completed a 17-and 22-minute meditation protocol based on loving-kindness and Focal Awareness (FA) meditation. Control points and mind-wandering phases were utilized to distinguish the meditative portion of the study during intracranial recordings. All patients completed a pre- and post-meditation questionnaire adapted from the PROMIS Anxiety Short Form as well as self-ratings on meditation depth and satisfaction.Results:Presurgical neuropsychological evaluation of patients showed elevated levels of anxiety on the BAI (M = 18.14, SD = 12.03) and depression on the BDI-II (M = 15.57, SD = 6.92). Neuropsychological findings localized to frontal or frontotemporal deficits in 80% of the patients were captured in this study. Regarding lateralization, 50% of patients presented with bilateral weakness on neuropsychological evaluation, with the rest showing unilateral profiles. A negative correlation was observed between patient responses on pre-meditation anxiety measures and self-reported depth of engagement in meditation, r = -0.65, p = .043. When all meditation sessions were evaluated, patients displayed a reduction in anxiety levels pre- and post- meditation, t = 2.3, p = .03.Conclusions:Present findings suggest a reduction in anxiety symptoms following completion of a meditation paradigm. Additionally, a relationship between anxiety and depth of engagement in meditation was identified. During each meditation session, electrocorticography data was collected and analyzed. Given the high comorbidities of anxiety and depression as well as cognitive symptoms common for individuals with epilepsy, a systems-based approach may enhance conceptualization of neuropsychological and neuropsychiatric evaluations, which may have a significant clinical impact. Evaluation of neuropsychological profiles, meditation effects, and anxiety in this population may support cross-discipline understanding of cognitive and psychiatric profiles to better inform treatment recommendations.

State-dependent modulation of low-threshold-current-regulated dendritic Ca2+ response in thalamic reticular neurons with extracellular electric fields

Deep brain stimulation (DBS) in thalamic reticular nucleus (TRN) neuron provides a novel treatment for drug-resistant epilepsy via the induced electrical field (EFs). However, the mechanisms underlying EF effects remain unclear. This paper investigated how EFs regulate low-threshold dendritic Ca2+ (dCa) response and thus contribute to the input–output relationship of TRN cell. Our results showed that EFs modulate firing modes differently in a neuronal state-dependent manner. At the depolarized state, EFs only regulate the spike timing of a somatic stimulus-evoked single action potential (AP) with less contribution in the regulation of dCa response but could induce the transition between a dendritic stimulus-evoked single AP and a tonic burst of APs via the moderate regulation of dCa response. At the hyperpolarized state, EFs have significant effects on the dCa response, which modulate the large dCa response-dependent burst discharge and even cause a transition from this type of burst discharge to a single AP with less dCa response. Moreover, EF effects on stimulation threshold of somatic spiking prominently depend on EF-regulated dCa responses and the onset time differences between the stimulus and EF give rise to the distinct effect in the EF regulation of dCa responses. Finally, the larger neuronal axial resistance tends to result in the dendritic stimulus-evoked dCa response independent of somatic state. Interestingly, in this case, the EF application could reproduce the similar somatic state-dependent dCa response to dendritic stimulus which occurs in the case of lower axial resistance. These results suggest that the influence of EF on neuronal activities depends on neuronal intrinsic properties, which provides insight into understanding how DBS in TRN neuron modulates epilepsy from the point of view of biophysics.

Highly purified cannabidiol in the treatment of drug-resistant epilepsies: A real-life impact on seizure frequency, quality of life, behavior, and sleep patterns from a single Italian center

Seizure frequency in treatment-resistant epilepsies seems to be decreased by cannabidiol (CBD), but contrasting data are available on its effect on sleep, behavior, and quality of life (QoL), and no data is reported on its effect on parental stress in patients with epilepsy (PWE). Thus, we conducted a retrospective study on a cohort of children and adults with drug-resistant epilepsy (DRE) who had been treated with highly purified, pharmaceutical-grade CBD to evaluate its effects on seizure frequency, QoL, behavior, parental stress, and sleep. Eighteen patients (12 adults and 6 children) were included in the cohort and followed for a median of 9 months. At the last follow-up (Tn), nine patients (50%) were considered CBD responders with at least a 50% decrease in seizure frequency. No serious adverse effects were found. No statistically significant differences were found concerning sleep, including daytime sleepiness, and no statistically significant effect was found on parental stress at Tn. An improvement was found for social interaction in quality of life (p < 0.05) for all patients. Our results demonstrate that CBD is a safe and effective antiseizure medication (ASM). CBD doesn’t seem to affect sleep measures in adults and children or worsen daytime sleepiness. However, CBD improves specific QoL measures, which could indicate a possible use of CBD for other childhood disabilities. No impact of CBD was seen on parental stress, which could possibly be due to the limited follow-up or could mean that parental stress is not dependent on seizure frequency.

Does Ketogenic Diet Used in Pregnancy Affect the Nervous System Development in Offspring?─FTIR Microspectroscopy Study.

Anti-seizure medications used during pregnancy may have transient or long-lasting impact on the nervous system of the offspring. Therefore, there is a great need to search for alternative therapies for pregnant women suffering from seizures. One of the solutions may be the use of the ketogenic diet (KD), which has been successfully applied as a treatment of drug-resistant epilepsy in children and adults. However, the risks associated with the use of this dietary therapy during pregnancy are unknown and more investigation in this area is needed. To shed some light on this problem, we attempted to determine the potential abnormalities in brain biomolecular composition that may occur in the offspring after the prenatal exposure to KD. To achieve this, the female Wistar rats were, during pregnancy, fed with either ketogenic or standard laboratory diet, and for further studies, their male offspring at 2, 6, or 14 days of age were used. Fourier transform infrared microspectroscopy was applied for topographic and quantitative analysis of main biological macromolecules (proteins, lipids, compounds containing phosphate and carbonyl groups, and cholesterol) in brain samples. Performed chemical mapping and further semi-quantitative and statistical analysis showed that the use of the KD during pregnancy, in general, does not lead to the brain biochemical anomalies in 2 and 6 days old rats. The exception from this rule was increased relative (comparing to proteins) content of compounds containing phosphate groups in white matter and cortex of 2 days old rats exposed prenatally to KD. Greater number of abnormalities was found in brains of the 14 days old offspring of KD-fed mothers. They included the increase of the relative level of compounds containing carbonyl groups (in cortex as well as multiform and molecular cells of the hippocampal formation) as well as the decrease of the relative content of lipids and their structural changes (in white matter). What is more, the surface of the internal capsule (structure of the white matter) determined for this age group was smaller in animals subjected to prenatal KD exposure. The observed changes seem to arise from the elevated exposition to ketone bodies during a fetus life and the disturbance of lipid metabolism after prenatal exposure to the KD. These changes may be also associated with the processes of compensation of mother organism, which slowly began to make up for the deficiencies in carbohydrates postpartum.

Real-world experience with cannabidiol as add-on treatment in drug-resistant epilepsy

PurposeTo evaluate the efficacy and safety of cannabidiol (CBD) for the treatment of epilepsy in a real-world setting. MethodsIn this retrospective observational study, we included PwE with epilepsy who received a prescription for CBD between 01.03.2019 and 30.11.2022 and had a follow-up period ≥ 3 months. Participants were evaluated at baseline and after 3, 6, and 12 months. "Responders" were defined as individuals experiencing a reduction in seizure frequency > 30% but < 80% compared to baseline, while "super responders" were those with a reduction ≥ 80%. Adverse events were recorded to assess safety. ResultsForty-two PwE were included (mean age 36.1 ± 10.9 years; 14 females). In 24 patients CBD was prescribed on-label (Lennox-Gastaut syndrome, n = 18; Dravet syndrome, n = 5; tuberous sclerosis, n = 1), while 18 patients were treated off-label (ring chromosome 20 syndrome, n = 1; ring chromosome 17 syndrome, n = 1; Lafora disease, n = 3; Unverricht-Lundborg disease, n = 1; polymicrogyria, n = 2; febrile infection-related epilepsy syndrome, n = 1; non-lesional focal epilepsy, n = 2; developmental and/or epileptic encephalopathy of unknown etiology n = 6). The mean number of concomitant antiseizure medications was 3.4 (≥2 for all patients). At 3 months, 10 subjects (23%) were “responders” and 12 (29%) were “super-responders”. Efficacy was sustained at 6 and 12 months of follow-up. Twenty-two patients (52.3%) developed AEs, with drowsiness (36.5%) and diarrhea (9.8%) being the most common. The retention rate was 85.7%, 78.6%, and 71.4% at 3, 6, and 12 months, respectively. ConclusionsIn this monocentric real-world study, CBD was a safe and effective therapeutic option for highly drug-resistant patients, leading to a dramatic reduction in seizure frequency in over one-fourth of them, including off-label indications.

Efficacy and Safety of Perampanel in Children with Drug-Resistant Focal-Onset Seizures: A Retrospective Review

Background: Epilepsy is one of the most common neurological disorders. Existing antiseizure medications (ASMs) are still unable to control seizures in one-third of these patients, making the discovery of antiseizure therapies with novel mechanisms of action a necessity. Aim of the Study: This study aimed to determine the safety and efficacy of perampanel (PER) as an adjuvant treatment for children with drug-resistant focal-onset seizures with or without focal to bilateral tonic-clonic seizures. Patients and methods: This is a single-center retrospective study of 38 epileptic pediatric patients, aged 2 to 14, at King Faisal Specialist Hospital and Research Center whose seizures were pharmaco-resistant to more than two antiseizure medications and followed for at least three months after PER adjuvant therapy initiation. Efficacy was assessed by the PER response rate at 3-, 6-, and 12-month follow-up evaluations, and side effects were also reported. Results: Multiple seizure types were reported. Myoclonic seizures were the predominant type of epilepsy in 17 children (44.7%). At 3 months, 6 months, and 12 months of follow-up, approximately 23.4%, 23.4%, and 18.4% of the patients were seizure-free at these time points, respectively. Adverse events were documented in 14 patients (35.7%) and led to the discontinuation of PER in 26.3%, 31.6%, and 36.8% of the studied group at the 3-, 6-, and 12-month follow-ups, respectively. The most common adverse events included dizziness or drowsiness, irritability, gait disturbance, and confusion; however, all were transient, and no serious adverse effects occurred. Conclusion: Our findings confirm the therapeutic efficacy of adjunctive PER in the treatment of drug-resistant epilepsy in children. As an adjunctive treatment for epilepsy, perampanel demonstrated sufficient effectiveness and tolerability.

Thalamic responsive neurostimulation for the treatment of refractory epilepsy: an individual patient data meta-analysis.

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. 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. 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. 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.

1019 New onset OSA after long term Vagus Nerve Stimulator implantation in a patient with Lennox-Gastaut syndrome: A case report

Abstract Introduction Implantable vagus nerve stimulation (VNS) is an established treatment for drug resistant epilepsy. New onset obstructive sleep apnea (OSA) is a rare side effect of VNS. There are few studies describing VNS induced sleep apnea in adults. [1-2] A study of 16 patients with drug-refractory epilepsy found 5 patients with normal AHI develop mild OSA after VNS treatment for 3 months. [2] However, no literature exists regarding OSA after long term VNS implantation. Untreated OSA in patients with epilepsy can impact epilepsy outcomes. We report a case of new onset OSA after long term VNS implantation, refractory to PAP therapy. Report of case(s) A 36 year-old man with Lennox-Gastaut syndrome presented with gasping during sleep and daytime hypersomnolence. He underwent VNS implantation at the age of 12. A prior PSG in 2018 showed no sleep apnea. Repeat PSG showed VNS-induced OSA (AHI 10.1/hour). After failed CPAP titration, BPAP-S at 25/16 cm H2O improved OSA. Review of therapy data on follow up showed AHI of 13.7/hour and CAI of 10.9/hour, which is concerning for treatment induced central sleep apnea on BPAP. Diagnostic study with VNS turned off revealed mild OSA (AHI 5.8/hour). A multidisciplinary approach involving ENT for drug-induced sleep endoscopy to optimize VNS stimulation parameters along with neurology and sleep involvement is planned. The optimized VNS setting could be used during planned sleep times using a VNS device with dual-programming capability. Conclusion To our knowledge, there is no literature on development of sleep apnea after long term VNS implantation. Although the exact mechanism is unknown, VNS can cause sleep apnea or worsen sleep apnea in patients with a preexisting diagnosis. [1] This case demonstrates need for continuous monitoring and screening for sleep apnea in patients who have been implanted with VNS, even if baseline and follow up PGSs are normal. Current literature suggests discontinuation of VNS to resolve VNS-induced OSA, but we describe a case here where VNS is needed for ongoing management of epilepsy. Further studies are needed to identify treatment options for patients that cannot discontinue VNS therapy who also cannot be successfully treated with PAP if they develop VNS-induced OSA. Support (if any)

Responsive Neurostimulation for the Treatment of Children With Drug-Resistant Epilepsy in Tuberous Sclerosis Complex

BackgroundTo review seizure outcomes in children with tuberous sclerosis complex (TSC) and drug-resistant epilepsy (DRE) treated with the responsive neurostimulation (RNS) System. MethodsWe retrospectively reviewed children (<21 years old) with TSC implanted with the RNS System at Texas Children's Hospital between July 2016 and May 2022. ResultsFive patients meeting the search criteria were identified (all female). The median age of the RNS implantation was 13 years (range: 5 to 20 years). The median epilepsy duration before the RNS implantation was 13 years (range: 5 to 20 years). Surgeries before RNS implantation included vagus nerve stimulator placement (n = 2), left parietal resection (n = 1), and corpus callosotomy (n = 1). The median number of antiseizure medications tried before RNS was 8 (range: 5 to 12). The rationale for the RNS System implantation included seizure onset in eloquent cortex (n = 3) and multifocal seizures (n = 2). The maximum current density for each patient ranged between 1.8 and 3.5 μC/cm2, with an average daily stimulation of 2240 (range: 400 to 4200). There was an 86% median seizure reduction (range 0% to 99%) at a median follow-up duration of 25 months (range: 17 to 25 months). No patient experienced implantation or stimulation-related complications. ConclusionsWe observed a favorable improvement in seizure frequency in pediatric patients with DRE secondary to TSC treated with the RNS System. The RNS System may be a safe and effective treatment for DRE in children with TSC.

Efficacy of different strategies of responsive neurostimulation on seizure control and their association with acute neurophysiological effects in rats

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.