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Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. In this open-label trial, patients (aged 1–30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2–5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death—a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30·0 (IQR 11·0–96·0) at baseline and 15·8 (5·6–57·6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36·5% (IQR 0–64·7). Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.

Background Intractable epilepsy in children poses significant clinical challenges due to limited efficacy of conventional anti-epileptic drugs (AEDs), leading to persistent neurodevelopmental impairments. This study investigated the therapeutic effects of ketogenic diet (KD), lacosamide (LCM), and their combination on refractory epilepsy, with comprehensive assessment of seizure control, EEG dynamics (including epileptiform patterns and spectral characteristics), cognitive function, lipid metabolism, and endothelial health. Methods Ninety children with refractory epilepsy were divided into three treatment groups: KD ( n  = 30), LCM ( n  = 30), and KD + LCM ( n  = 30). Assessments included detailed EEG characterization (seizure types, interictal discharges, spectral bands), cognitive testing (attention/memory), lipid profiles, and endothelial markers at baseline, 3-, and 6-months post-treatment. Results The KD + LCM group showed superior seizure reduction at 3/6 months (t = 2.171, P  = 0.035; t = 3.177, P  = 0.003), with 76.7% achieving ≥ 50% interictal discharge reduction ( P  = 0.008) and 63.3% seizure type simplification ( P  = 0.003) at 6 months. Cognitive performance significantly improved (attention: Δ=-10.8 ± 2.0; memory: Δ=-9.4 ± 1.8; both P  < 0.001), strongly correlating with frontal θ-band modulation (|r|>0.68). Combination therapy also enhanced α/β/δ/θ spectral power ( P  ≤ 0.019), improved lipid profiles, and restored endothelial function versus monotherapies (all P  < 0.05). Conclusions KD and LCM combination therapy provides comprehensive benefits—superior seizure control, EEG normalization, cognitive enhancement, metabolic optimization, and vascular protection—making it a promising multimodal approach for refractory epilepsy management.

Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus. This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894. Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus. National Institute for Health Research Health Technology Assessment programme.

Drug resistance is estimated to affect about a third of individuals with epilepsy, but its prevalence differs in relation to the epilepsy syndrome, the cause of epilepsy, and other factors such as age of seizure onset and presence of associated neurological deficits. Although drug-resistant epilepsy is not synonymous with unresponsiveness to any drug treatment, the probability of achieving seizure freedom on a newly tried medication decreases with increasing number of previously failed treatments. After two appropriately used antiseizure medications have failed to control seizures, individuals should be referred whenever possible to a comprehensive epilepsy centre for diagnostic re-evaluation and targeted management. The feasibility of epilepsy surgery and other treatments, including those targeting the cause of epilepsy, should be considered early after diagnosis. Substantial evidence indicates that a delay in identifying an effective treatment can adversely affect ultimate outcome and carry an increased risk of cognitive disability, other comorbidities, and premature mortality. Research on mechanisms of drug resistance and novel therapeutics is progressing rapidly, and potentially improved treatments, including those targeting disease modification, are on the horizon.

Many infancy-onset epilepsies have poor prognosis for seizure control and neurodevelopmental outcome. Ketogenic diets can improve seizures in children older than 2 years and adults who are unresponsive to antiseizure medicines. We aimed to establish the efficacy of a classic ketogenic diet at reducing seizure frequency compared with further antiseizure medicine in infants with drug-resistant epilepsy. In this phase 4, open-label, multicentre, randomised clinical trial, infants aged 1–24 months with drug-resistant epilepsy (defined as four or more seizures per week and two or more previous antiseizure medications) were recruited from 19 hospitals in the UK. Following a 1-week or 2-week observation period, participants were randomly assigned using a computer-generated schedule, without stratification, to either a classic ketogenic diet or a further antiseizure medication for 8 weeks. Treatment allocation was masked from research nurses involved in patient care, but not from participants. The primary outcome was the median number of seizures per day, recorded during weeks 6–8. All analyses were by modified intention to treat, which included all participants with available data. Participants were followed for up to 12 months. All serious adverse events were recorded. The trial is registered with the European Union Drug Regulating Authorities Clinical Trials Database (2013–002195–40). The trial was terminated early before all participants had reached 12 months of follow-up because of slow recruitment and end of funding. Between Jan 1, 2015, and Sept 30, 2021, 155 infants were assessed for eligibility, of whom 136 met inclusion criteria and were randomly assigned; 75 (55%) were male and 61 (45%) were female. 78 infants were assigned to a ketogenic diet and 58 to antiseizure medication, of whom 61 and 47, respectively, had available data and were included in the modifified intention-to-treat analysis at week 8. The median number of seizures per day during weeks 6–8, accounting for baseline rate and randomised group, was similar between the ketogenic diet group (5 [IQR 1–16]) and antiseizure medication group (3 [IQR 2–11]; IRR 1·33, 95% CI 0·84–2·11). A similar number of infants with at least one serious adverse event was reported in both groups (40 [51%] of 78 participants in the ketogenic diet group and 26 [45%] of 58 participants in the antiseizure medication group). The most common serious adverse events were seizures in both groups. Three infants died during the trial, all of whom were randomly assigned a ketogenic diet: one child (who also had dystonic cerebral palsy) was found not breathing at home; one child died suddenly and unexpectedly at home; and one child went into cardiac arrest during routine surgery under anaesthetic. The deaths were judged unrelated to treatment by local principal investigators and confirmed by the data safety monitoring committee. In this phase 4 trial, a ketogenic diet did not differ in efficacy and tolerability to a further antiseizure medication, and it appears to be safe to use in infants with drug-resistant epilepsy. A ketogenic diet could be a treatment option in infants whose seizures continue despite previously trying two antiseizure medications. National Institute for Health and Care Research.

Purpose of ReviewFor millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy.Recent FindingsWhile the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD’s inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD.SummaryUnderstanding of CBD’s efficacy and safety in the treatment of TRE has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.

Background Clinical trials have shown that cenobamate (CNB) is an efficacious and safe anti-seizure medication (ASM) for drug-resistant focal epilepsy. Here, we analyzed one of the largest real-world cohorts, covering the entire spectrum of epilepsy syndromes, the efficacy and safety of CNB, and resulting changes in concomitant ASMs. Methods We conducted a retrospective observational study investigating CNB usage in two German tertiary referral centers between October 2020 and June 2023 with follow-up data up to 27 months of treatment. Our primary outcome was treatment response. Secondary outcomes comprised drug response after 12 and 18 months, seizure freedom rates, CNB dosage and retention, adverse drug reactions (ADRs), and changes in concomitant ASMs. Results 116 patients received CNB for at least two weeks. At 6 months, 98 patients were eligible for evaluation. Thereof 50% (49/98) were responders with no relevant change at 12 and 18 months. Seizure freedom was achieved in 18.4% (18/98) at 6 months, 16.7% (11/66), and 3.0% (1/33) at 12 and 18 months. The number of previous ASMs did not affect the seizure response rate. Overall, CNB was well-tolerated, however, in 7.7% (9/116), ADRs led to treatment discontinuation. The most frequent changes of concomitant ASMs included the discontinuation or reduction of sodium channel inhibitors, clobazam reduction, and perampanel discontinuation, while brivaracetam doses were usually left unchanged. Conclusions CNB proved to be a highly effective and generally well-tolerated ASM in patients with severe drug-resistant epilepsy, comprising a broad array of epilepsy syndromes beyond focal epilepsy.

Background Helicobacter pylori ( H. pylori ) causes chronic infection in more than half of the population worldwide. Accumulating body of evidence indicates the possible role of H. Pylori infection in extra-intestinal health problems, including epilepsy. This study aims to investigate the efficacy of treating H. pylori infection on seizure frequency among children with drug-resistant idiopathic generalized epilepsy (IGE). Methods A parallel, two-arm, open-label, randomized controlled trial was conducted on 126 children with drug-resistant IGE and positive H. pylori stool antigen test who were randomly assigned to study and comparison groups in 1.2:1 ratio. Only the study group received H. pylori eradication therapy (esomeprazole, amoxicillin, and clarithromycin) for two weeks. The primary outcome was seizure improvement (≥ 50% seizure frequency reduction compared with baseline) after 2.5 months. Secondary outcomes were occurrence of status epilepticus, escalation of antiseizure medication (ASMs), and adverse effects. Outcomes between the two groups were compared using Chi-square/Fisher exact tests on an intention-to-treat principle. Logistic regression analysis was performed to investigate possible effects of baseline variables on primary outcome. Results Seizure improvement occurred in 23 (33%) children in the study group compared with seven (12%) children in the comparison group (Risk ratio [RR] 2.7, 95% confidence interval [CI]: 1.3–5.9; p 0.006). The study group had lower occurrence of status epilepticus (2.9% vs. 14%; RR 0.21, 95%CI: 0.05–0.93; p 0.042) and lesser need for ASMs escalation (4.4% vs. 19.3%; RR 0.23, 95%CI: 0.07–0.77; p 0.010). Adverse effects were more frequent among subjects in the study group, including nausea (15.9% vs. 10.5%) vomiting (8.7% vs. 3.5%), diarrhea (11.6% vs. 5.3%), and skin rash (4.4% vs. 1.8%), but the differences were not statistically significant ( p  > 0.05). None of baseline participants’ variables was significantly associated with the primary outcome. Conclusion Treating H. pylori infection may improve seizure control in children with drug-resistant IGE, but further studies are warranted to confirm our findings and explore mechanisms behind seizure improvement following H. pylori eradication therapy. Trial registration Registered on www.clinicaltrials.gov (identifier: NCT05297695) on 17 March 2022. https://clinicaltrials.gov/study/NCT05297695 .

Ketogenic diet (KD) is an excess fat, enough protein, and minimal carbohydrate diet. The high fat content in KD lowers the oesophageal sphincter tone, slows gastric emptying, and decreases intestinal transit time. The primary aim of the current clinical trial was to study the effect of L -carnitine supplementation on gastric emptying in children with drug resistant epilepsy (DRE) on KD. Assessment of the protective effect of L -carnitine on bowel function and habits in those patients was a secondary aim. The current study recruited 30 patients aged 12 months to 18 years newly diagnosed with DRE assigned to start KD who were following up at the Pediatric Clinical Nutrition and Neurology Outpatient Clinics or were admitted due to DRE at the Pediatric Neurology Inpatient Department, Children’s Hospital, Ain Shams University (Egypt). Participants were assigned randomly into 2 arms; arm I: received KD with L -carnitine supplementation, arm II: received KD only. Patients were assessed at baseline and after 3 months of starting KD, the assessments of children included: 24-hour dietary recall, Chalfont Seizures Severity Scale, gastrointestinal symptoms score and Bristol stool chart, frequency of defecation per week, anthropometric measurements assessment, fasting serum lipid profile and measurement of the antral length by ultrasound. There was significant increase in antral length in the patients who received KD with L -carnitine supplementation compared to the non-supplemented group. The antral length showed a significant negative correlation with GI symptoms score in all cases and the L -carnitine supplemented group. It also showed a significant positive correlation with Bristol stool score in all patients and a significant positive correlation with stool frequency in the L -carnitine supplemented group only. L -carnitine supplementation to children with DRE on KD has a significant role in improving gastric motility and it increases the frequency of defecation. Further studies are recommended to explore additional benefits, meanwhile it is prudent to advise L -carnitine supplementation for such patients.

Background In randomized controlled trials, add-on brivaracetam (BRV) reduced seizure frequency in patients with drug-resistant focal epilepsy. Studies performed in a naturalistic setting are a useful complement to characterize the drug profile. Objective This multicentre study assessed the effectiveness and tolerability of adjunctive BRV in a large population of patients with focal epilepsy in the context of real-world clinical practice. Methods The BRIVAFIRST (BRIVAracetam add-on First Italian netwoRk STudy) was a retrospective, multicentre study including adult patients prescribed adjunctive BRV. Patients with focal epilepsy and 12-month follow-up were considered. Main outcomes included the rates of seizure‐freedom, seizure response (≥ 50% reduction in baseline seizure frequency), and treatment discontinuation. The incidence of adverse events (AEs) was also considered. Analyses by levetiracetam (LEV) status and concomitant use of strong enzyme-inducing antiseizure medications (EiASMs) and sodium channel blockers (SCBs) were performed. Results A total of 1029 patients with a median age of 45 years (33–56) was included. At 12 months, 169 (16.4%) patients were seizure-free and 383 (37.2%) were seizure responders. The rate of seizure freedom was 22.3% in LEV-naive patients, 7.1% in patients with prior LEV use and discontinuation due to insufficient efficacy, and 31.2% in patients with prior LEV use and discontinuation due to AEs ( p  < 0.001); the corresponding values for ≥ 50% seizure frequency reduction were 47.9%, 29.7%, and 42.8% ( p  < 0.001). There were no statistically significant differences in seizure freedom and seizure response rates by use of strong EiASMs. The rates of seizure freedom (20.0% vs. 16.6%;   p  = 0.341) and seizure response (39.7% vs. 26.9%; p  = 0.006) were higher in patients receiving SCBs than those not receiving SCBs; 265 (25.8%) patients discontinued BRV. AEs were reported by 30.1% of patients, and were less common in patients treated with BRV and concomitant SCBs than those not treated with SCBs (28.9% vs. 39.8%; p  = 0.017). Conclusion The BRIVAFIRST provided real-world evidence on the effectiveness of BRV in patients with focal epilepsy irrespective of LEV history and concomitant ASMs, and suggested favourable therapeutic combinations.