Add-on treatment with cenobamate is already effective at low doses in refractory focal epilepsy: A prospective observational study.

OBJECTIVE: Cenobamate, a novel antiseizure medication with a dual mechanism of action, has been shown in pivotal trials to significantly improve seizure control in treatment-resistant focal epilepsy. We aimed to evaluate whether these promising results could be confirmed in a real-world setting with a follow-up period of up to 12 months. METHODS: Patients from a tertiary epilepsy center who received cenobamate add-on between June 2021 and October 2023 were followed up prospectively at 3, 6, and 12 months after treatment initiation for assessment of seizure outcomes and treatment-related adverse events. RESULTS: The clinical cohort included 112 adult patients with 30% nonlesional cases and a wide spectrum of epileptogenic lesions underlying refractory focal epilepsy. We observed a significant reduction in monthly seizure frequency of all seizure types already after 3 months of treatment at a median cenobamate dose of 100 mg/day. Forty-six percent of patients were responders with a ≥50% seizure reduction, 26% had a ≥75% seizure reduction, and 9% became seizure-free. Among the 74 patients with available follow-up of 12 months, the responder rates reached 55%, 35%, and 19% for ≥50%, ≥75%, and 100% seizure reduction, respectively. After 3 months of treatment, 38% of patients reported adverse effects, mainly (84%) mild to moderate in intensity. Adjustment of comedication allowed successful management of adverse effects in 32% of patients. At a group level, there was no correlation between the cenobamate daily dose and the incidence of adverse events. SIGNIFICANCE: We found a clinically relevant response to cenobamate already at a low daily dose of 100 mg also in a patient cohort with a higher degree of drug resistance than in pivotal trials. Our prospectively collected data provide real-world evidence for high efficacy and good tolerability of the drug, although no standardized treatment protocol or comparison with a control group was applied.

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.

Drug-resistant idiopathic generalized epilepsy: A meta-analysis of prevalence and risk factors.

BACKGROUND: Idiopathic generalized epilepsy (IGE) is a common epilepsy syndrome with early age onset and generally good seizure outcomes. This study aims to determine the incidence and predictive risk factors for drug-resistant IGE. METHODS: We systematically searched three databases (PubMed, Embase, and Cochrane Library) in November 2022 and included 12 eligible studies which reported long-term outcomes (mean = 14.05) after antiseizure medications (ASMs) from 2001 to 2020. We defined drug resistance as the persistence of any seizure despite ASMs treatment (whether as monotherapies or in combination) given the criteria of drug resistance varied in original studies. A random-effects model was used to evaluate the prevalence of refractory IGE. Studies reporting potential poor prognostic factors were included for subsequent subgroup meta-analysis. RESULTS: The pooled prevalence of drug resistance in IGE cohorts was 27% (95% CI: 0.19-0.36). Subgroup analysis of the risk factors revealed that the psychiatric comorbidities (odds ratio (OR): 4.87, 95% confidence interval (CI): 2.97-7.98), combined three seizure types (absences, myoclonic jerks, and generalized tonic-clonic seizures) (OR: 5.37, 95% CI: 3.16-9.13), the presence of absence seizure (OR: 4.38, 95% CI: 2.64-7.28), generalized polyspike trains (GPT) (OR: 4.83, 95% CI: 2.42-9.64), sex/catamenial epilepsy (OR: 3.25, 95% CI: 1.97-5.37), and status epilepticus (OR: 5.94, 95% CI: 2.23-15.85) increased the risk of poor prognosis. Other factors, including age onset, family history, and side effects of ASMs, were insignificantly associated with a higher incidence of refractory IGE. CONCLUSION: Drug resistance is a severe complication of IGE. Further standardized research about clinical and electroencephalography factors is warranted.

Gabapentin monotherapy for epilepsy: A review.

BACKGROUND: Epilepsy is one of the most common chronic neurological disorders, affecting more than 50 million people globally. In this review we summarised the evidence from randomised controlled trials of gabapentin used as monotherapy for the treatment of focal epilepsy, both newly diagnosed and drug-resistant, with or without secondary generalisation. OBJECTIVE: To assess the effects of gabapentin monotherapy for people with epileptic focal seizures with and without secondary generalisation. METHODS: We searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 24 February 2020) on 25 February 2020. CRS Web includes randomised or quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, the Cochrane Central Register of Controlled Trials (CENTRA), and the specialised registers of Cochrane Review Groups including the Cochrane Epilepsy Group. We also searched several Russian databases, reference lists of relevant studies, ongoing trials registers, conference proceedings, and we contacted trial authors. RESULTS: We found five randomised controlled trials (3167 participants) comparing gabapentin to other antiepileptic drugs (AEDs) and differing doses of gabapentin as monotherapy for newly diagnosed focal epilepsy and drug- resistant focal epilepsy with or without secondary generalisation. Two review authors independently applied the inclusion criteria, assessed trial quality, risk of bias, and extracted data. We used the GRADE approach to assess the certainty of evidence and present seven patient-important outcomes in the "Summary of findings" tables. The quality of evidence was very low to moderate due to poor reporting quality, poor trial design, and other risks of bias, such as selective presentation of findings and potential heavy industry input. Better quality research may change our certainty in the effect estimates. None of the included trials reported on the number of people with 50% or greater reduction in seizures and time to withdrawal (retention time) in an extractable way. Gabapentin-treated participants were more likely to withdraw from treatment for any cause (285/539) than those treated with lamotrigine, oxcarbazepine, or topiramate pooled together (695/1317) (RR 1.13, 95% CI 1.02 to 1.25; 3 studies, 1856 participants; moderate-certainty evidence), but not carbamazepine. Fewer people treated with gabapentin withdrew from treatment owing to adverse events (190/525) than those treated with carbamazepine, oxcarbazepine, or topiramate (479/1238), (RR 0.79, 95% CI 0.69 to 0.91; 1763 participants, 3 studies; moderate-certainty evidence), but not lamotrigine. CONCLUSION: Gabapentin as monotherapy probably controlled seizures no better and no worse than comparator AEDs (lamotrigine, carbamazepine, oxcarbazepine, and topiramate). Compared to carbamazepine, gabapentin was probably better in retaining people in studies and preventing withdrawals due to adverse events. The most common side effects associated with gabapentin were ataxia (poor co-ordination and unsteady gait), dizziness, fatigue, and drowsiness.

Cannabidiol as an adjuvant treatment in adults with drug-resistant focal epilepsy.

Cannabidiol oil (CBD) has been approved as an anti-seizure medication for the treatment of uncommon types of epilepsy, occurring in children: Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. There are few publications in relation to use the CBD in adult patients with focal drug-resistant epilepsy. The objective of this study was to evaluate the efficacy, tolerability, safety, and quality of life, of adjuvant treatment with CBD, in adult patients with drug-resistant focal epilepsy for at least 6 months. An open, observational, prospective cohort study was conducted using a before-after design (time series) in adult patients undergoing outpatient follow-up in a public hospital in Buenos Aires, Argentina. From a total of 44 patients, 5% of patients were seizure-free, 32% of patients reduced more than 80% of their seizures and 87% of patients reduced 50% of their monthly seizures. Eleven percent presented a decrease of less than 50% in seizure frequency. The average final dose was 335 mg/d orally administered. Thirty-four percent of patients reported mild adverse events and no patient reported severe adverse effects. At the end of the study, we found in most patients a significant improvement in the quality of life, in all the items evaluated. Adjuvant treatment with CBD in adult patients with drug-resistant focal epilepsy was effective, safe, well tolerated, and associated with a significant improvement in their quality of life.

Real-world, long-term evaluation of the tolerability and therapy retention of Epidiolex® (cannabidiol) in patients with refractory epilepsy.

OBJECTIVE: Epidiolex® (CBD) is FDA-approved for seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC). Phase III studies suggest that certain adverse effects (AEs), possibly linked to pharmacokinetic/pharmacodynamic (PK/PD) interactions may be therapy-limiting. We sought to identify these factors that contribute to treatment success and retention of therapy. METHODS: A single-center, retrospective review of patients with refractory epilepsy taking Epidiolex® was performed. Kaplan-Meier analysis was performed to describe Epidiolex® retention, as a measure of overall effectiveness. RESULTS: One hundred and twelve patients were screened; 4 were excluded due to loss to follow-up or never starting Epidiolex®. Of 108 patients, mean age was 20.3 years (13.1, range 2 to 63), and 52.8% were female. Mean initial and maintenance doses were 5.3 mg/kg/day (1.3) and 15.3 mg/kg/day (5.8), respectively. At the final evaluation, 75% of patients remained on Epidiolex®. The 25th percentile for discontinuation was 19 months. 46.3% of patients experienced at least one treatment-emergent adverse effect (TEAE) with 14.5% d/c Epidiolex® due to treatment emerging adverse effects (TEAE). The most common reasons for discontinuation were lack of efficacy (37%), increased seizure activity (22%), worsened behavior (22%), and sedation (22%). One out of 27 discontinuations was due to liver function test (LFT) elevations (3.7%). At initiation, 47.2% were concurrently taking clobazam, and 39.2% of those patients had an initial clobazam dose decrease. 53% of patients were able to either discontinue or lower the dose of at least one other antiseizure medication. SIGNIFICANCE: Epidiolex® is generally well-tolerated and the majority continued long-term treatment. Patterns of adverse effects were similar to clinical trials, however gastrointestinal complaints, and significant LFT elevations were less common. Our data suggest most patients discontinue within the first several months of treatment and suggest that further studies designed to evaluate early identification and potential mitigation of adverse effects and including drug interactions are warranted.

Cost-effectiveness of cenobamate for focal seizures in people with drug-resistant epilepsy.

OBJECTIVE: This study was undertaken to estimate the cost-effectiveness of add-on cenobamate in the UK when used to treat drug-resistant focal seizures in adults who are not adequately controlled with at least two prior antiseizure medications, including at least one used adjunctively. METHODS: We estimated the cost per quality-adjusted life-year (QALY) for cenobamate compared to brivaracetam, eslicarbazepine, lacosamide, and perampanel in the UK National Health Service over a lifetime time horizon. We used a Markov cohort structure to determine response to treatment, using pooled data from three long-term studies of cenobamate. A network meta-analysis informed the likelihood of response to therapy with brivaracetam, eslicarbazepine, lacosamide, and perampanel relative to cenobamate. Once individuals discontinued treatment, they transitioned to subsequent treatment health states, including other antiseizure medicines, surgery, and vagus nerve stimulation. Costs included treatment, administration, routine monitoring, event management, and adverse events. Published evidence and expert opinion informed the likelihood of response to subsequent treatments, associated adverse events, and costs. Utility data were based on Short-Form six-dimension form utility. Discounting was applied at 3.5% per annum as per National Institute for Health and Care Excellence guidance. Uncertainty was explored through deterministic and probabilistic sensitivity analyses. RESULTS: In the base case, cenobamate led to cost savings of £51 967 (compared to brivaracetam), £21 080 (compared to eslicarbazepine), £33 619 (compared to lacosamide), and £28 296 (compared to perampanel) and increased QALYs of 1.047 (compared to brivaracetam), 0.598 (compared to eslicarbazepine), 0.776 (compared to lacosamide), and 0.703 (compared to perampanel) per individual over a lifetime time horizon. Cenobamate also dominated the four drugs across most sensitivity analyses. Differences were due to reduced seizure frequency with cenobamate relative to comparators. SIGNIFICANCE: Cenobamate improved QALYs and was less costly than brivaracetam, eslicarbazepine, lacosamide, and perampanel. Therefore, cenobamate may be considered as a cost-effective adjunctive antiseizure medication for people with drug-resistant focal seizures.

Number needed to treat and associated cost analysis of cenobamate versus third-generation anti-seizure medications for the treatment of focal-onset seizures in patients with drug-resistant epilepsy in Spain.

INTRODUCTION: Epilepsy is a serious neurological disease, ranking high in the top causes of disability. The main goal of its treatment is to achieve seizure freedom without intolerable adverse effects. However, approximately 40% of patients suffer from Drug-Resistant Epilepsy (DRE) despite the availability of the latest options called third-generation Anti-Seizure Medications(ASMs). Cenobamate is the first ASM approved in Spain for the adjunctive treatment of Focal-Onset Seizures (FOS) in adult patients with DRE. The introduction of a new drug increases the number of therapeutic options available, making it important to compare it with existing alternatives in terms of clinical benefit and efficiency. PURPOSE: This study aimed to compare the clinical benefit, in terms of the Number Needed to Treat (NNT), and the efficiency, in terms of Cost per NNT (CNT), associated with cenobamate versus third-generation ASMs used in Spain for the adjunctive treatment of FOS in patients with DRE. METHODS: The Number Needed to Treat data was calculated based on the ≥50% responder rate and seizure freedom endpoints (defined as the percentage of patients achieving 50% and 100% reduction in seizure frequency, respectively), obtained from pivotal clinical trials performed with cenobamate, brivaracetam, perampanel, lacosamide, and eslicarbazepine acetate. The NNT was established as the inverse of the treatment responder rate minus the placebo responder rate and was calculated based on the minimum, mid-range Daily Defined Dose (DDD), and maximum doses studied in the pivotal clinical trials of each ASM. CNT was calculated by multiplying the annual treatment cost by NNT values for each treatment option. RESULTS: In terms of NNT, cenobamate was the ASM associated with the lowest values at all doses for both ≥50% responder rate and seizure freedom compared with the alternatives. In terms of CNT, for ≥50% responder rate, cenobamate was the ASM associated with the lowest CNT values at DDD and lacosamide and eslicarbazepine acetate at the minimum and maximum dose, respectively. For seizure freedom, cenobamate was associated with the lowest CNT value at DDD and the maximum dose and lacosamide at the minimum dose. CONCLUSIONS: Cenobamate could represent the most effective ASM in all doses studied compared to the third-generation ASMs and the most efficient option at DDD for both ≥50% responder rate and seizure freedom. This study could represent an important contribution towards informed decision-making regarding the selection of the most appropriate therapy for FOS in adult patients with DRE from a clinical and economical perspective in Spain.

Retention of brivaracetam in adults with drug-resistant epilepsy at a single tertiary care center.

INTRODUCTION: Brivaracetam (BRV) is licensed as an adjunctive treatment for focal epilepsy. We describe our clinical experience with BRV at a large UK tertiary center. METHODS: Adults initiated on BRV between July 2015 and July 2020 were followed up until they discontinued BRV or September 2021. Data on epilepsy syndrome, duration, seizure types, concomitant and previous antiseizure medication (ASM) use, BRV dosing, efficacy, and side effects were recorded. Efficacy was categorized as temporary (minimum three months) or ongoing (at last follow-up) seizure freedom, ≥50% seizure reduction, or other benefits (e.g., no convulsions or daytime seizures). Brivaracetam retention was estimated using Kaplan-Meier survival analysis. RESULTS: Two-hundred people were treated with BRV, of whom 81% had focal epilepsy. The mean (interquartile range [IQR]) follow-up time was 707 (688) days, and the dose range was 50-600 mg daily. The mean (IQR) of the previous number of used ASMs was 6.9 (6.0), and concomitant use was 2.2 (1.0). One-hundred and eighty-eight people (94%) had previously discontinued levetiracetam (LEV), mainly due to side effects. 13/200 (6.5%) were seizure free for a minimum of six months during treatment, and 46/200 (23%) had a ≥50% reduction in seizure frequency for six months or more. Retention rates were 83% at six months, 71% at 12 months, and 57% at 36 months. Brivaracetam was mostly discontinued due to side effects (38/75, 51%) or lack of efficacy (28/75, 37%). Concomitant use of carbamazepine significantly increased the hazard ratio of discontinuing BRV due to side effects (p = 0.006). The most commonly reported side effects were low mood (20.5%), fatigue (18%) and aggressive behavior (8.5%). These side effects were less prevalent than when the same individuals took LEV (low mood, 59%; aggressive behavior, 43%). Intellectual disability was a risk factor for behavioral side effects (p = 0.004), and a pre-existing mood disorder significantly increased the likelihood of further episodes of low mood (p = 0.019). CONCLUSIONS: Brivaracetam was effective at a broad range of doses in managing drug-resistant epilepsy across various phenotypes, but less effective than LEV in those who switched due to poor tolerability on LEV. There were no new tolerability issues, but 77% of the individuals experiencing side effects on BRV also experienced similar side effects on LEV.

Cannabidiol for the treatment of refractory epilepsy in children: a critical review of the literature.

OBJECTIVE: The aim of this current report was to present a critical review of the use of cannabidiol (CBD) in the treatment of refractory epilepsies in the pediatric population. DATA SOURCE: Literature review was carried out in the Medline (PubMed), Cochrane, and Scientific Electronic Library Online (SciELO) databases with the descriptors "Cannabidiol" and "Epilepsy." The search was not limited by the date of publication, language, or study design. A total of 69 articles were included in the review. DATA SYNTHESIS: The efficacy of CBD in treating epileptic seizures has been confirmed by randomized controlled trials for Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. The incidence of side effects reported in subjects of the studies is high. However, most studies indicate a good safety profile and tolerance to the drug, with most of the adverse effects being mild to moderate and transient. CONCLUSIONS: There is no consensus on the release of CBD as a therapeutic tool by the drug regulatory agencies worldwide. However, the use of CBD is promising since it has presented satisfactory results in crisis control in well-designed studies. In addition, this drug has a good safety and tolerance profile. However, further studies with a long follow-up period are needed to confirm its usefulness and the long-term safety in pediatric patients.

Adjunctive use of cenobamate for pediatric refractory focal-onset epilepsy: A single-center retrospective study.

OBJECTIVE: We explored the efficacy and safety profile of cenobamate as an adjunctive therapy in patients with refractory focal-onset epilepsy in the pediatric population. METHODS: This was a retrospective, single-center study of cenobamate used as an adjunctive medication in pediatric patients with refractory focal-onset epilepsy . We measured seizure reduction, median reduction in seizure frequency, median dose, responder rate, and treatment-emergent adverse events. RESULTS: We studied the efficacy and safety profile of cenobamate in 21 pediatric patients (mean age 15.9). Cenobamate was up titrated using the prescribed starter pack with final doses ranging from 100 mg to 400 mg daily. The mean and median dose of cenobamate was 209.8 mg (±98.87 mg) and 200 mg (175-275), respectively. For patients weighing less than 50 kg, mean and median dose was 4.0 mg/kg/day (3.20-4.63) and 4.32 mg/kg/day, respectively. Mean and median baseline seizure frequency per month in this cohort was 15.38 and 16, respectively, prior to the introduction of cenobamate. After the adjunctive use of cenobamate, mean and median seizure frequency per month reduced to 7.29 and 1, respectively; median reduction in seizure frequency was 93.7%. Seizure reduction of at least 50% (responder rate) was noted in 13 (62.5%) patients and a seizure reduction of at least 75% noted in 11 (52.4%) patients, similar to that seen in adults. Four patients (19%) achieved seizure freedom. Of the 21 pediatric patients, 9 (42.8%) patients had treatment-emergent adverse events (TEAE) with the most commonly reported symptom being ataxia (5, 23.8%) and sedation (2, 9.5%). Three (14.3%) patients discontinued early due to these side effects. No children developed drug rash with eosinophilia and systemic symptoms (DRESS). CONCLUSION: Cenobamate demonstrates similar efficacy rates and safety profile within the pediatric population when compared to the published adult data, making it an effective, safe, and tolerable adjunctive medication for children with refractory focal-onset epilepsy, even at the maximum daily dose.

Lacosamide effectiveness and tolerability in patients with drug-resistant epilepsy and severe disability under polytherapy: Therapy optimization as emerging from an observational study.

OBJECTIVE: We explored the efficacy and safety of lacosamide combined with inhibitors of fast-inactivated sodium channels or with other antiepileptic drugs, in patients with drug refractory focal epilepsy associated with intellectual or psychiatric disability. METHODS: Observational study of lacosamide including the monitoring of lacosamide trough plasma levels and of electroencephalograms. RESULTS: We followed up 44 patients from the start of lacosamide therapy for up to 3 years, with a clinical, electroencephalogram (EEG), and pharmacological follow-up. Median patients' age was 32.7 years, median age at epilepsy onset was 3.5 years. Intellectual disability was severe in 55.4% of the cohort and drug refractoriness was diagnosed in 88.6% of patients, who had predominantly focal seizures (80%). The severity of their epilepsy was suggested by the use of combined therapies with non-sodium blockers and sodium blockers in 75% of patients. Lacosamide was added to previous therapies and up-titrated to a median of 300 mg/d. Lacosamide add-on led to simplification of the previous drug regimen with a dose reduction in 87.9% of users of sodium blockers and in 66.7% of users of non-sodium blockers, and to withdrawal of previously administered sodium blockers in 48.5% users and non-sodium blockers in 47.6% users. Lacosamide was prescribed at lower doses in the presence of oxcarbazepine (p = 0.029), lamotrigine (p = 0.015), and topiramate (p < 0.001). Mean lacosamide plasma levels were 6.0 ±â€¯2.4 mg/L; they were in linear correlation with the administered dose (R2 = 0.38, p < 0.001) and were influenced by the association with lamotrigine (p = 0.008), zonisamide (p = 0.012), and clobazam (p = 0.028). Lacosamide combination regimens led to an average reduction of 42% in baseline seizure frequency, with 50% patients reporting ≥50% seizure frequency reduction. Efficacy was directly correlated with lacosamide dose (R2 = 0.47, p < 0.001, B = 0.53) and trough plasma levels (R2 = 0.31, p < 0.001, B = 0.16). Electroencephalogram profiles were improved in 40.9% of patients and EEG improvement was not significantly correlated with seizure frequency reduction. Lacosamide safety was good, with 37 adverse reactions in 30 patients, of which 50% were attributed to lacosamide and led to lacosamide withdrawal in 18% of cases. The retention rate of lacosamide was of 88.6% at 1 year, 86.4% at 2 years, and 72.7% after three years. The severity of intellectual disability was directly correlated with increased possibility of lacosamide retention (OR = 0.46 per severity tier, p = 0.016). CONCLUSION: Lacosamide add-on allowed dose reduction of previous therapies and reduced the frequency of seizures, showing good tolerability even at high doses, without exceeding reference plasma levels.

Spontaneous recurrent seizures in an intra-amygdala kainate microinjection model of temporal lobe epilepsy are differentially sensitive to antiseizure drugs.

The discovery and development of novel antiseizure drugs (ASDs) that are effective in controlling pharmacoresistant spontaneous recurrent seizures (SRSs) continues to represent a significant unmet clinical need. The Epilepsy Therapy Screening Program (ETSP) has undertaken efforts to address this need by adopting animal models that represent the salient features of human pharmacoresistant epilepsy and employing these models for preclinical testing of investigational ASDs. One such model that has garnered increased interest in recent years is the mouse variant of the Intra-Amygdala Kainate (IAK) microinjection model of mesial temporal lobe epilepsy (MTLE). In establishing a version of this model, several methodological variables were evaluated for their effect(s) on pertinent quantitative endpoints. Although administration of a benzodiazepine 40 min after kainate (KA) induced status epilepticus (SE) is commonly used to improve survival, data presented here demonstrates similar outcomes (mortality, hippocampal damage, latency periods, and 90-day SRS natural history) between mice given midazolam and those that were not. Using a version of this model that did not interrupt SE with a benzodiazepine, a 90-day natural history study was performed and survival, latency periods, SRS frequencies and durations, and SRS clustering data were quantified. Finally, an important step towards model adoption is to assess the sensitivities or resistances of SRSs to a panel of approved and clinically used ASDs. Accordingly, the following ASDs were evaluated for their effects on SRSs in these mice: phenytoin (20 mg/kg, b.i.d.), carbamazepine (30 mg/kg, t.i.d.), valproate (240 mg/kg, t.i.d.), diazepam (4 mg/kg, b.i.d.), and phenobarbital (25 and 50 mg/kg, b.i.d.). Valproate, diazepam, and phenobarbital significantly attenuated SRS frequency relative to vehicle controls at doses devoid of observable adverse behavioral effects. Only diazepam significantly increased seizure freedom. Neither phenytoin nor carbamazepine significantly altered SRS frequency or freedom under these experimental conditions. These data demonstrate that SRSs in this IAK model of MTLE are pharmacoresistant to two representative sodium channel-inhibiting ASDs (phenytoin and carbamazepine) and partially sensitive to GABA receptor modulating ASDs (diazepam and phenobarbital) or a mixed-mechanism ASD (valproate). Accordingly, this model is being incorporated into the NINDS-funded ETSP testing platform for treatment resistant epilepsy.

Paroxysmal sympathetic hyperactivity and the later development of epilepsy in a chemotherapy-associated brain damage.

BACKGROUND: Chemotherapy in childhood leukemia potentially induces brain lesions and neurological sequelae. Paroxysmal sympathetic hyperactivity (PSH) is known as a treatment-associated complication; however, the full clinical spectra of PSH remain to be elusive. CASE REPORT: A 5-year-old girl was diagnosed of acute myeloid leukemia (AML) M5. After the intensification therapy, she developed recurrent symptoms of episodic tachycardia, hypertension and perspiration lasting for several hours per day. The low-frequency-high-frequency ratio on Holter electrocardiography was rapidly increased from 0.84 to 2.24 at the onset of the paroxysmal event, whereas the video-monitoring electroencephalography (EEG) never identified ictal patterns of epileptiform discharges during the episodes. Thus, the diagnosis of PSH was given at 7 years of age. Myoclonic and generalized tonic-clonic seizures frequently appeared from 10 years of age, which poorly responded to anticonvulsants. EEG showed diffuse slow-wave bursts with multifocal spikes. Serial head magnetic resonance imaging (MRI) revealed diffuse cerebral and hippocampal atrophy, but not inflammatory lesions in the limbic system. CONCLUSION: We first demonstrate a pediatric case with PSH who developed drug-resistant epilepsy 3 years after the onset of PSH. Our data suggest the pathophysiological link of persistent PSH with chemotherapy-associated brain damage.

New-onset refractory status epilepticus following the ChAdOx1 nCoV-19 vaccine.

Coronavirus is a novel human pathogen causing fulminant respiratory syndrome (COVID-19). Developing an effective and reliable vaccine was emergently pursued to control the dramatic spread of the global pandemic. The standard stages for vaccine development were unprecedentedly accelerated over a few months. We report a case of new-onset refractory status epilepticus (NORSE) after receiving the first dose of the ChAdOx1 nCoV-19 vaccine. We attribute the occurrence of NORSE to the vaccine due to the temporal relationship and the lack of risk factors for epilepsy in the patient. This report adds to the literature a possible rare side effect of a COVID-19 vaccine and contributes to the extremely limited literature on potential neurological side effects of viral vector vaccines. Healthcare providers should be aware of the possibility of post-vaccination epilepsy. The patient had recurrent seizures that were refractory to conventional antiepileptic drug therapy with a dramatic response to immunotherapy with pulse steroids and plasmapheresis. This likely reflects an underlying autoimmune mechanism in the genesis of post-vaccination generalized seizures without fever. Further research is needed to probe and study the exact mechanism at a more molecular level.

Functional characterization of novel bumetanide derivatives for epilepsy treatment.

Temporal lobe epilepsy (TLE) is the most common type of focal epilepsies, affecting approximately 35 million people worldwide. Despite the introduction of numerous novel antiepileptic drugs during the last decades, the proportion of patients with therapy-resistant TLE is still high. As an impaired cellular chloride homeostasis appears involved in disease pathophysiology, bumetanide, an antagonist to Na-K-Cl cotransporters, gained interest as potential therapeutic option. However, bumetanide induces a strong diuretic effect and displays poor penetration across the blood-brain barrier (BBB). To reduce these unwanted effects, we modified the already described BUM690 by exchanging the allyl-into a trifluoro-ethyl group to yield BUM532. Furthermore, we exchanged the nitrogen for oxygen in the trifluoro-ethyl group to yield BUM97. In the intrahippocampal kainic acid mouse model of TLE BUM532 ±â€¯phenobarbital (PB), bumetanide ±â€¯PB and PB alone significantly reduced hippocampal paroxysmal discharges (HPDs) but not spike trains. By contrast, treatment with BUM97 suppressed HPDs as well as spike trains dose-dependently, more pronounced compared to the other tested compounds and exerted a synergistic anticonvulsant effect with PB. Moreover, at higher doses BUM97 achieved long-lasting reduction of spike trains. In pentylenetetrazole-induced acute seizures only BUM532 combined with a sub-effective dose of PB increased the seizure threshold. No diuretic effects were observed at any dose of the three derivatives. Our data demonstrate the successful optimization of the pharmacological profile of bumetanide and the potential of the improved derivative BUM97 for the treatment of therapy-resistant TLE, in particular in combinatorial drug regimens with a GABA mimetic.

Activation of adenosine receptors modulates the efflux transporters in brain capillaries and restores the anticonvulsant effect of carbamazepine in carbamazepine resistant rats developed by window-pentylenetetrazole kindling.

Up-regulation of efflux transporters in brain capillaries may lead to the decreased therapeutic efficacy of antiepileptic drugs in patients with Drug Resistant Epilepsy. Adenosine receptor activation in brain capillaries can modulate blood-brain barrier permeability by decreasing the protein levels and function of efflux transporters. Therefore, we aimed to investigate whether the activation of adenosine receptors improves convulsions outcome in carbamazepine (CBZ) resistant animals and modulates the protein levels of efflux transporters (P-GP, MRP1, MRP2) in brain capillaries. We employed the window-pentylenetetrazol (PTZ) kindling model to develop CBZ resistant rats by CBZ administration during the post-kindling phase, and tested if these animals displayed subsequent resistance to other antiepileptic drugs. Crucially, we investigated if the administration of a broad-spectrum adenosine agonist (NECA) improves convulsions control in CBZ resistant rats. Of potential therapeutic relevance, in CBZ resistant rats NECA restored the anticonvulsant effect of CBZ. We also evaluated how the resistance to CBZ and the activation of adenosine receptors with NECA affect protein levels of efflux transporters in brain capillaries, as quantified by western blot. While CBZ resistance was associated with the up-regulation of both P-GP/MRP2 in brain capillaries, with the administration of NECA in CBZ resistant rats, we observed a decrease of P-GP and an increase of MRP2 levels, in brain capillaries. Since the activation of adenosine receptors improves the outcome of convulsions probably through the modulation of the efflux transporters protein levels in brain capillaries, adenosine agonists could be useful as an adjunct therapy for the control of Drug Resistant Epilepsy.

Early polytherapy for benzodiazepine-refractory status epilepticus.

The transition from single seizures to status epilepticus (SE) is associated with malaptive trafficking of synaptic gamma-aminobutyric acid (GABAA) and glutamate receptors. The receptor trafficking hypothesis proposes that these changes are key events in the development of pharmacoresistance to antiepileptic drugs (AEDs) during SE, and that blocking their expression will help control drug-refractory SE (RSE). We tested this hypothesis in a model of SE induced by very high-dose lithium and pilocarpine (RSE), and in a model of SE induced by sc soman. Both models are refractory to benzodiazepines when treated 40 min after seizure onset. Our treatments aimed to correct the loss of inhibition because of SE-associated internalization of synaptic GABAA receptors (GABAAR), using an allosteric GABAAR modulator, sometimes supplemented by an AED acting at a nonbenzodiazepine site. At the same time, we reduced excitation because of increased synaptic localization of NMDA and AMPA (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and N-methyl-D-aspartate) receptors (NMDAR, AMPAR (?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, N-methyl-D-aspartate receptors)) with an NMDAR channel blocker, since AMPAR changes are NMDAR-dependent. Treatment of RSE with combinations of the GABAAR allosteric modulators midazolam or diazepam and the NMDAR antagonists dizocilpine or ketamine terminated RSE unresponsive to high-dose monotherapy. It also reduced RSE-associated neuronal injury, spatial memory deficits, and the occurrence of spontaneous recurrent seizures (SRS), tested several weeks after SE. Treatment of soman-induced SE also reduced seizures, behavioral deficits, and epileptogenesis. Addition of an AED further improved seizure outcome in both models. Three-dimensional isobolograms demonstrated positive cooperativity between midazolam, ketamine, and valproate, without any interaction between the toxicity of these drugs, so that the therapeutic index was increased by combination therapy. The midazolam-ketamine-valproate combination based on the receptor trafficking hypothesis was far more effective in stopping RSE than the midazolam-fosphenytoin-valproate combination inspired from clinical guidelines for the treatment of SE. Furthermore, sequential administration of midazolam, ketamine, and valproate was far less effective than simultaneous treatment with the same drugs at the same dose. These data suggest that treatment of RSE should be based at least in part on its pathophysiology. The search for a better treatment should focus on the cause of pharmacoresistance, which is loss of synaptic GABAAR and gain of synaptic glutamate receptors. Both need to be treated. Monotherapy addresses only half the problem. Improved pharmacokinetics will not help pharmacoresistance because of loss of receptors. Waiting for one drug to fail before giving the second drugs gives pharmacoresistance time to develop. Future clinical trials should consider treating both the failure of inhibition and the runaway excitation which characterize RSE, and should include an early polytherapy arm. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Transplanting GABAergic Neurons Differentiated from Neural Stem Cells into Hippocampus Inhibits Seizures and Epileptiform Discharges in Pilocarpine-Induced Temporal Lobe Epilepsy Model.

OBJECTIVE: This study aimed to explore whether intrahippocampal transplantation of GABAergic neurons generated in vitro ameliorated seizures and epileptiform discharges via increasing γ-aminobutyric acid (GABA)-associated inhibition mediated by the addition of new GABAergic neurons. METHODS: Neural stem cells (NSCs) isolated from newborn rats were induced and differentiated into GABAergic neurons. A total of 36 Pilocarpine-induced pharmacoresistant epileptic rats were divided into 3 groups: PBS (phosphate-buffered saline) group, NSCs group, and GABAergic neurons group (GABA group), with an additional 10 normal rats used (normal rat control group). The effects of grafting on spontaneous recurrent seizures (SRS) were examined and hippocampal GABA content was measured after grafting. RESULTS: In the GABA group, the frequency of electroencephalography decreased significantly compared with the PBS group (P < 0.001), but there was no significant difference between the GABA group and NSCs group. Compared with the PBS group, the overall frequency and duration of SRS significantly decreased in the transplantation group, especially in the GABA group (P < 0.01). The number of GABAergic neurons was highest in the GABA group compared with the other groups (P < 0.001). Furthermore, hippocampal GABA concentrations significantly increased in the GABA group. CONCLUSIONS: We show that GABAergic neurons generated in vitro from NSCs and grafted into the hippocampi of chronically epileptic rats can significantly reduce the frequency of electroencephalography and frequency and duration of SRS via increasing GABA-associated inhibition mediated by the addition of new GABAergic neurons.

Intravenously Administered Ganaxolone Blocks Diazepam-Resistant Lithium-Pilocarpine-Induced Status Epilepticus in Rats: Comparison with Allopregnanolone.

Ganaxolone (GNX) is the 3ß-methylated synthetic analog of the naturally occurring neurosteroid, allopregnanolone (ALLO). GNX is effective in a broad range of epilepsy and behavioral animal models and is currently in clinical trials designed to assess its anticonvulsant and antidepressant activities. The current studies were designed to broaden the anticonvulsant profile of GNX by evaluating its potential anticonvulsant activities following i.v. administration in treatment-resistant models of status epilepticus (SE), to establish a pharmacokinetic (PK)/pharmacodynamic (PD) relationship, and to compare its PK and anticonvulsant activities to ALLO. In PK studies, GNX had higher exposure levels, a longer half-life, slower clearance, and higher brain penetrance than ALLO. Both GNX and ALLO produced a sedating response as characterized by loss of righting reflex, but neither compound produced a full anesthetic response as animals still responded to painful stimuli. Consistent with their respective PK properties, the sedative effect of GNX was longer than that of ALLO. Unlike other nonanesthetizing anticonvulsant agents indicated for SE, both GNX and ALLO produced anticonvulsant activity in models of pharmacoresistant SE with administration delay times of up to 1 hour after seizure onset. Again, consistent with their respective PK properties, GNX produced a significantly longer anticonvulsant response. These studies show that GNX exhibited improved pharmacological characteristics versus other agents used as treatments for SE and position GNX as a uniquely acting treatment of this indication.