Efficacy and safety of six new antiseizure medications for adjunctive treatment of focal epilepsy and epileptic syndrome: A systematic review and network meta-analysis.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of six new antiseizure medications (ASMs) for adjunctive treatment in adult patients with focal epilepsy and adolescents with Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), or tuberous sclerosis complex (TSC). METHODS: A comprehensive literature search was performed using PubMed, Medline, Embase, and Cochrane library databases from inception to October 13, 2023. We included published studies for a systematic review and a network meta-analysis (NMA). The efficacy and safety were reported in terms of a 50% response rate and dropout rate along with serious adverse events (SAEs). The outcomes were ranked with the surface under the cumulative ranking curve (SUCRA). RESULTS: Twenty eligible trials with 5516 patients and 21 interventions, including placebo, contributed to the analysis. Included ASMs were brivaracetam (BRV), cenobamate (CBM), cannabidiol (CBD), fenfluramine (FFM), everolimus (ELM), and soticlestat (SLT). The six new ASMs were compared in four different epilepsy subtypes. In focal epilepsy treatment, BRV seemed to be safe [vs placebo, risk ratio (RR) = 0.69, 95 % confidence interval (CI): 0.25-1.91] and effective (vs placebo, RR = 2.18, 95 % CI: 1.25-3.81). In treating focal epilepsy, CBM 300 mg was more effective at a 50 % response rate (SUCRA 91.8 %) compared with BRV and CBD. However, with the increase in dosage, more SAEs (SUCRA 85.6 %) appeared compared with other ASMs. CBD had good efficacy on LGS (SUCRA 88.4) and DS (SUCRA 66.2), but the effect on adult focal epilepsy was not better than that of placebo [vs placebo, RR = 0.83 (0.36-1.93)]. The NMA indicated that the likelihood of the most appropriate intervention (SUCRA 91.2 %) with minimum side effects（SUCRA 12.5 %）for the DS was FFM. Compared with CBD, high exposure to ELM demonstrated a more effective treatment of TSC (SUCRA 89.7 %). More high-quality SLT studies are needed to further evaluate the efficacy and safety. The comparison-adjusted funnel plots of annualized relapse rate and side effects in the included studies revealed no significant funnel plot asymmetry. CONCLUSIONS: This NMA indicated that the most effective treatment strategy for focal epilepsy, DS, Lennox-Gastaut syndrome, and TSC, respectively, included CBM 300 mg, FFM, CBD, and ELM. However, the aforementioned findings need further confirmation.

Anticonvulsive treatment in autoimmune encephalitis: a systematic literature review.

BACKGROUND: Epileptic seizures are a common manifestation of autoimmune encephalitis (AIE). Immunosuppression (IT) is an efficient therapeutic approach, particularly in AIE associated with antibodies against extracellular structures. The role of antiseizure medication (ASM) is less clear. However, it may be beneficial in disease refractory to IT or in chronic post-AIE epilepsy. METHODS: We conducted a systematic review assessing the PubMed and Cochrane databases to identify all reports on patients with epileptic seizures due to AIE in whom ASM was used and report it according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. We included case series (minimum 3 eligible patients), retrospective and prospective observational studies, and randomized controlled trials. The main outcome assessed was therapeutic efficacy of ASM. Secondary outcomes comprise number, type, and adverse effects of ASM. Descriptive statistics were used. The level of evidence was assessed according to the Centre for Evidence-Based Medicine. RESULTS: We screened a total of 3371 studies and included 30 (7 prospective, 23 retrospective). The reports cover a total of 708 patients, the majority (72.5%) suffering from AIE with antibodies against extracellular structures. Type of AIE, seizure frequency, and number and type of ASM used were heterogenous. While most patients profited from IT and/or ASM, the effect of ASM could rarely be isolated. Nine studies report on patients who received ASM monotherapy or were on ASM for a relevant length of time before IT initiation or after IT failure. One study reports a significant association between seizure freedom and use of sodium channel inhibitors. However, levels of evidence were generally low. CONCLUSION: Few robust data exist on the particular efficacy of ASM in autoimmune epileptic seizures. While these patients generally seem to respond less well to ASM or surgical interventions, sodium channel blockers may have an additional benefit compared to other substances. However, levels of evidence are low and early IT remains the mainstay of AIE therapy. Future trials should address optimal ASM selection and dosing in AIE.

Prospective study of cenobamate on cognition, affectivity, and quality of life in focal epilepsy.

OBJECTIVE: Cenobamate is a recently approved antiseizure medication that proved to be safe and effective in randomized controlled trials. However, little is known about its impact on some areas frequently affected by epilepsy. For this reason, we explored the effects of cenobamate on cognitive performance, as well as on negative affectivity and quality of life in a sample of patients with drug-resistant epilepsy. METHODS: Two prospective cohort studies were carried out. In Study 1, 32 patients (22 men and 10 women) underwent a baseline (T0) and a short-term (T1) neuropsychological assessment after 3 months of cenobamate administration. In Study 2, 22 patients (16 men and 6 women) from the T1 sample also underwent a baseline and a follow-up evaluation (T2) 6 months after T0. RESULTS: No significant differences were found in cognitive variables, negative affectivity, and quality of life either in Study 1 or Study 2. Similarly, based on the reliable change index, it was found that most patients showed no changes in these variables. SIGNIFICANCE: These results suggest that cenobamate is a safe antiseizure medication in terms of cognition, negative affectivity, or quality of life since no adverse events have been found after 3 and 6 months of treatment. PLAIN LANGUAGE SUMMARY: Cenobamate is a new antiseizure medication. In patients with epilepsy, cenobamate seems to not affect cognition, anxiety, depression, or quality of life.

Lamotrigine add-on therapy for drug-resistant focal epilepsy.

BACKGROUND: This is an updated version of a Cochrane Review last updated in 2020. Epilepsy is a common neurological disorder, affecting 0.5% to 1% of the population. In nearly 30% of cases, epilepsy is resistant to currently available drugs. Pharmacological treatment remains the first choice to control epilepsy. Lamotrigine is a second-generation antiseizure medication. When used as an add-on (in combination with other antiseizure medications), lamotrigine can reduce seizures, but with some adverse effects. OBJECTIVES: To evaluate the benefits and harms of add-on lamotrigine, compared with add-on placebo or no add-on treatment in people with drug-resistant focal epilepsy. SEARCH METHODS: For this update, we searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid) on 3 October 2022 with no language restrictions. CRS Web includes randomised and quasi-randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialised Registers of Cochrane Review Groups, including Epilepsy. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that investigated add-on lamotrigine versus add-on placebo or no add-on treatment in people of any age with drug-resistant focal epilepsy. We used data from the first period of eligible cross-over trials. DATA COLLECTION AND ANALYSIS: For this update, two review authors independently selected trials and extracted data. Our primary outcome was 50% or greater reduction in seizure frequency. Our secondary outcomes were treatment withdrawal, adverse effects, cognitive effects, and quality of life. Primary analyses were by intention-to-treat. We performed sensitivity best- and worse-case analyses to account for missing outcome data. We calculated pooled risk ratios (RRs) with 95% confidence intervals (95% Cls) for dichotomous outcomes. MAIN RESULTS: We identified no new studies for this update, so the results and conclusions of the review are unchanged. We included five parallel-group studies in adults or children, eight cross-over studies in adults or children, and one parallel study with a responder-enriched design in infants. In total, these 14 studies enroled 1806 eligible participants (38 infants, 199 children, 1569 adults). Baseline phases ranged from four to 12 weeks and treatment phases ranged from eight to 36 weeks. We rated 11 studies (1243 participants) at low overall risk of bias and three (697 participants) at unclear overall risk of bias due to lack of information on study design. Four studies (563 participants) reported effective blinding. Lamotrigine compared with placebo probably increases the likelihood of achieving 50% or greater reduction in seizure frequency (RR 1.80, 95% CI 1.45 to 2.23; 12 trials, 1322 participants (adults and children); moderate-certainty evidence). There is probably little or no difference in risk of treatment withdrawal for any reason among people treated with lamotrigine versus people treated with placebo (RR 1.11, 95% CI 0.91 to 1.37; 14 trials; 1806 participants; moderate-certainty evidence). Lamotrigine compared with placebo is probably associated with a greater risk of ataxia (RR 3.34, 99% Cl 2.01 to 5.55; 12 trials; 1525 participants; moderate-certainty evidence), dizziness (RR 1.76, 99% Cl 1.28 to 2.43; 13 trials; 1768 participants; moderate-certainty evidence), nausea (RR 1.81, 99% CI 1.22 to 2.68; 12 studies, 1486 participants; moderate-certainty evidence), and diplopia (RR 3.79, 99% Cl 2.15 to 6.68; 3 trials, 944 participants; moderate-certainty evidence). There is probably little or no difference in the risk of fatigue between lamotrigine and placebo (RR 0.82, 99% CI 0.55 to 1.22; 12 studies, 1552 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Lamotrigine as an add-on treatment for drug-resistant focal seizures is probably effective for reducing seizure frequency. Certain adverse effects (ataxia, dizziness, diplopia, and nausea) are probably more likely to occur with lamotrigine compared with placebo. There is probably little or no difference in the number of people who withdraw from treatment with lamotrigine versus placebo. The trials were of relatively short duration and provided no long-term evidence. In addition, some trials had few participants. Further trials are needed to assess the long-term effects of lamotrigine and to compare lamotrigine with other add-on drugs.

Efficacy and tolerability of oxcarbazepine in the treatment of focal epilepsy in neonates and infants under 3 months of age: A single-center retrospective analysis.

OBJECTIVE: The neonatal and infantile period is the age group with the highest incidence of epilepsy, in which gene variants in sodium and potassium channels are an important etiology, so the sodium channel blocker class of antiseizure medications may be effective in the treatment of early onset epilepsy. This study aimed to summarize the efficacy and tolerability of oxcarbazepine (OXC) in the treatment of focal epilepsy in neonates and infants under 3 months of age. METHODS: A retrospective analysis of children with focal epilepsy onset within 3 months of age and treated with OXC in a tertiary pediatric epilepsy center in China was conducted. The efficacy, tolerability and influencing factors of OXC were evaluated. RESULTS: A total of 50 patients were enrolled, with a median age of epilepsy onset of 11.5 (2, 42) days. There were 32 cases of early infantile developmental and epileptic encephalopathy, 10 cases of self-limited neonatal or neonatal-infantile epilepsy, and 8 cases of focal epilepsy that could not be classified as epileptic syndrome. The median age of application of OXC was 47 (31, 66) days. The median follow-up time was 16.5 (10, 25) months, with 7 deaths. Thirty-eight cases (76.0 %) were effective with OXC treatment, including 28 cases (56.0 %) achieved seizure freedom. Of the 34 cases whose pathogenesis involved genetic factors, 19 cases with sodium/ potassium channel gene variants had higher effective and seizure-free rates than those with other gene variants. The most common adverse event was transient hyponatremia. 2 cases had rash and 2 cases had abnormal electrocardiogram, 3 of which discontinued OXC. SIGNIFICANCE: This single-center retrospective study suggests that OXC is effective and tolerable for the treatment of focal epilepsy in neonates and infants under 3 months of age. The efficacy of OXC is better in patients with sodium/ potassium channel gene variants.

Immunomodulatory interventions for focal epilepsy.

BACKGROUND: This is an updated version of an original Cochrane Review published in 2013 (Walker 2013). Epilepsy is a common neurological disorder affecting 0.5% to 1% of the population. Pharmacological treatment remains the first choice to control epilepsy. However, up to 30% of people do not respond to drug treatment, and therefore do not achieve seizure remission. Experimental and clinical evidence supports a role for inflammatory pathway activation in the pathogenesis of epilepsy which, if effectively targeted by immunomodulatory interventions, highlights a potentially novel therapeutic strategy. OBJECTIVES: To assess the efficacy and tolerability of immunomodulatory interventions on seizures, adverse effect profile, cognition, and quality of life, compared to placebo controls, when used as additional therapy for focal epilepsy in children and adults. SEARCH METHODS: For the latest update, we searched the following databases on 11 November 2021: Cochrane Register of Studies (CRS Web) and Medline (Ovid) 1946 to 10 November 2021. CRS Web includes randomised or quasi-randomised, controlled trials from PubMed, EMBASE, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Specialized Registers of Cochrane Review Groups including Epilepsy. We placed no language restrictions. We reviewed the bibliographies of retrieved studies to search for additional reports of relevant studies. SELECTION CRITERIA: Randomised placebo-controlled trials of add-on immunomodulatory drug interventions, in which an adequate method of concealment of randomisation was used. The studies were double-, single- or unblinded. Eligible participants were children (aged over 2 years) and adults with focal epilepsy. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. We assessed the following outcomes. 1. 50% or greater reduction in seizure frequency. 2. Seizure freedom. 3. Treatment withdrawal for any reason. 4. Quality of life. 5. ADVERSE EFFECTS: We used an intention-to-treat (ITT) population for all primary analyses, and we presented results as risk ratios (RRs) with 95% confidence intervals (95% Cl). MAIN RESULTS: We included three randomised, double-blind, placebo-controlled trials on a total of 172 participants. All trials included children and adults over two years of age with focal epilepsy. Treatment phases lasted six weeks and follow-up from six weeks to six months. One of the three included trials described an adequate method of concealment of randomisation, whilst the other two trials were rated as having an unclear risk of bias due to lack of reported information around study design. Effective blinding of studies was reported in all three trials. All analyses were by ITT. One trial was sponsored by the manufacturer of an immunomodulatory agent and therefore was at high risk of funding bias. Immunomodulatory interventions were significantly more effective than placebo in reducing seizure frequency (risk ratio (RR) 2.30, 95% confidence interval (CI) 1.15 to 4.60; 3 studies, 172 participants; moderate-certainty evidence). For treatment withdrawal, there was insufficient evidence to conclude that people were more likely to discontinue immunomodulatory intervention than placebo (RR 1.04, 95% CI 0.28 to 3.80; 3 studies, 172 participants; low-certainty evidence). The RR for adverse effects was 1.16 (95% CI 0.84 to 1.59; 1 study, 66 participants; low-certainty evidence). Certain adverse effects such as dizziness, headache, fatigue, and gastrointestinal disorders were more often associated with immunomodulatory interventions. There were little to no data on cognitive effects and quality of life. No important heterogeneity between studies was found for any of the outcomes. We judged the overall certainty of evidence (using the GRADE approach) as low to moderate due to potential attrition bias resulting from missing outcome data and imprecise results with wide confidence intervals. AUTHORS' CONCLUSIONS: Immunomodulatory interventions as add-on treatment for children and adults with focal epilepsy appear to be effective in reducing seizure frequency. It is not possible to draw any conclusions about the tolerability of these agents in children and adults with epilepsy. Further randomised controlled trials are needed.

The adaptation of the desirability of outcome ranking for interventional clinical trials in epilepsy: A novel consumer-led outcome measure.

Interventional clinical trials in epilepsy are typically designed and powered to detect a change in seizure frequency as the primary endpoint, with little consideration given to other benefits or harms of the therapy, or impacts on common epilepsy comorbidities. Desirability of outcome ranking (DOOR) is a novel methodology for evaluating benefits and harms associated with introduction of a new treatment. Multiple outcomes are combined and the resulting combinations are ranked according to their desirability. Herein we describe the adaptation of DOOR for use in therapy trials in epilepsy. Consumers with epilepsy were presented with a selection of measures typically included in epilepsy trials and asked to rank their importance in terms of a desirable outcome and to identify interactions between different seizure control levels and other measures. Seizure control, adverse events, and psychiatric comorbidities were identified as most important, and combinations of these outcomes were ranked to form epilepsy-DOOR. A separate consumer discussion group verified the appropriateness and accuracy of the ranking. The resultant epilepsy-DOOR includes 60 possible outcomes, representing high granularity for the assessment of future interventions. It demonstrates the importance of consumer involvement in trial design and presents an alternative to seizure frequency for evaluating new treatments for epilepsy.

Cenobamate in refractory epilepsy: Overview of treatment options and practical considerations.

Management of drug resistant epilepsy (DRE) represents a challenge to the treating clinician. This manuscript addresses DRE and provides an overview of treatment options, medical, surgical, and dietary. It addresses treatment strategies in polytherapy, then focuses on the role cenobamate (CNB) may play in reducing the burden of DRE while providing practical advice for its introduction. CNB is a recently approved, third generation, anti-seizure medication (ASM), a tetrazole-derived carbamate, thought to have a dual mechanism of action, through its effect on sodium channels as well as on GABAA receptors at a non-benzodiazepine site. CNB, having a long half-life, is an effective add-on ASM in refractory focal epilepsy with a higher response rate and a higher seizure-freedom rate than is usually seen in regulatory clinical trials. Experience post-licensing, though still limited, supports the findings of clinical trials and is encouraging. Its spectrum of action in relation to generalized epilepsies and seizures remains to be established, and there are no data on its efficacy in monotherapy. At the time of writing, CNB has been prescribed for some 50 000 individuals with DRE and focal epilepsy. A larger number is needed to fully establish its safety profile. It should at all times be introduced slowly to minimize the risk of serious allergic drug reactions. It has clinically meaningful interactions which must be anticipated and managed to maximize tolerability and likelihood of successful treatment. Despite the above, it may well prove to be of major benefit in the treatment of many patients with drug resistant epilepsy.

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.

Perampanel add-on for drug-resistant focal epilepsy.

BACKGROUND: Epilepsy is one of the most common neurological disorders. Approximately 30% of people with epilepsy are considered to be drug-resistant, and usually need treatment with a combination of other antiepileptic drugs. Perampanel is a newer antiepileptic drug that has been investigated as add-on therapy for drug-resistant focal epilepsy. OBJECTIVES: To evaluate the benefits and harms of perampanel as add-on therapy for people with drug-resistant focal epilepsy. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 20 October 2022. SELECTION CRITERIA: We included randomised controlled trials comparing add-on perampanel with placebo. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was 1. 50% or greater reduction in seizure frequency. Our secondary outcomes were 2. seizure freedom, 3. treatment withdrawal due to any reason, 4. treatment withdrawal due to adverse effects, and 5. ADVERSE EFFECTS: We used an intention-to-treat population for all primary analyses. We presented the results as risk ratios (RR) with 95% confidence intervals (CIs), except for individual adverse effects, which we reported with 99% CIs to compensate for multiple testing. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We included seven trials involving 2524 participants, all aged over 12 years. The trials were double-blind, randomised, placebo-controlled trials with treatment duration of 12 to 19 weeks. We assessed four trials at overall low risk of bias, and three trials at overall unclear risk of bias, due to risk of detection, reporting, and other biases. Compared with placebo, participants receiving perampanel were more likely to achieve a 50% or greater reduction in seizure frequency (RR 1.67, 95% CI 1.43 to 1.95; 7 trials, 2524 participants; high-certainty evidence). Compared to placebo, perampanel increased seizure freedom (RR 2.50, 95% CI 1.38 to 4.54; 5 trials, 2323 participants; low-certainty evidence) and treatment withdrawal (RR 1.30, 95% CI 1.03 to 1.63; 7 trials, 2524 participants; low-certainty evidence). Participants treated with perampanel were more likely to withdraw from treatment due to adverse effects compared to those receiving placebo (RR 2.36, 95% CI 1.59 to 3.51; 7 trials, 2524 participants; low-certainty evidence). A higher proportion of participants receiving perampanel reported one or more adverse effects when compared to participants who received placebo (RR 1.17, 95% CI 1.10 to 1.24; 7 trials, 2524 participants; high-certainty evidence). Compared with placebo, participants receiving perampanel were more likely to experience ataxia (RR 14.32, 99% CI 1.09 to 188.31; 2 trials, 1098 participants; low-certainty evidence), dizziness (RR 2.87, 99% CI 1.45 to 5.70; 7 trials, 2524 participants; low-certainty evidence), and somnolence (RR 1.76, 99% CI 1.02 to 3.04; 7 trials, 2524 participants). Subgroup analysis indicated that a larger proportion of participants who received perampanel at a dose of 4 mg/day (RR 1.38, 95% CI 1.05 to 1.83; 2 trials, 710 participants), 8 mg/day (RR 1.83, 95% CI 1.51 to 2.22; 4 trials, 1227 participants), or 12 mg/day (RR 2.38, 95% CI 1.86 to 3.04; 3 trials, 869 participants) achieved a 50% or greater reduction in seizure frequency compared to placebo; however, treatment with perampanel 12 mg/day also increased treatment withdrawal (RR 1.77, 95% CI 1.31 to 2.40; 3 trials, 869 participants). AUTHORS' CONCLUSIONS: Add-on perampanel is effective at reducing seizure frequency and may be effective at maintaining seizure freedom for people with drug-resistant focal epilepsy. Although perampanel was well-tolerated, there was a higher proportion of treatment withdrawals with perampanel compared with placebo. Subgroup analysis suggested that 8 mg/day and 12 mg/day are the most efficacious perampanel doses; however, the use of 12 mg/day would likely increase the number of treatment withdrawals. Future research should focus on investigating the efficacy and tolerability of perampanel with longer-term follow-up, as well as exploring an optimal dose.

Use of sulthiame as add-on therapy in children with non-self-limited focal epilepsies of childhood.

PURPOSE: This retrospective study aimed to evaluate the efficacy and tolerability of sulthiame (STM) as an add-on treatment in 49 patients with non-self-limited focal epilepsies of childhood (non-SeLFE) resistant to other antiseizure medications (ASM) and/or non-pharmacological treatment. METHODS: Patients with non-SeLFE who had failed to respond to at least five previous ASM, alone or in combination, were included in the study. All patients underwent neurological examination, brain magnetic resonance imaging repeated prolonged electroencephalography (EEG) or video-EEG studies, and neurometabolic studies. School achievements and/or performance on neuropsychological tests were also assessed. Sulthiame was added in doses ranging from 10 to 40 mg/kg/day. Efficacy was measured by comparing seizure frequency before and after initiating STM therapy. RESULTS: Twenty-nine of 49 patients (59.1%) who received STM as add-on therapy had a greater than 50% decrease in seizures after a mean follow-up of 35 months. One patient (2%) became seizure-free. Fourteen patients (40%) had a 25-50% seizure reduction. The mean time of response was 5 months (range, 3.5 to 6 months). No differences were found either between patients with a response of more or less than 50% or between the response of the focal seizure types (motor or non-motor, with or without consciousness impairment). CONCLUSION: In our study, STM was found to be effective and well-tolerated in children and adolescents with non-SeLFE. In the patients who responded, improvement in the EEG was seen.

Cutaneous Hypersensitivity Reaction After Phenytoin Therapy in a Neonate: A Case Report and Review of Literature Elucidating the Potential Pharmacological Plausibility and Preventive Strategies.

BACKGROUND: Drug-induced hypersensitivity reaction is a potentially life-threatening condition reported among patients of different age groups. Phenytoin is a prototypic drug prescribed for the treatment of a variety of seizure disorders. Allergic reaction to phenytoin therapy in a newborn is relatively a rare clinical manifestation that is not frequently reported. OBJECTIVE: The objective of this study is to report a suspected case of hypersensitivity reaction in a newborn possibly due to phenytoin and the strategies to prevent these immune-mediated reactions. CASE REPORT: An early term newborn on the 4th day of life developed erythematous rashes over the abdominal region following phenytoin treatment for recurrent generalized tonic-clonic seizures. Prenatal history was uneventful except for the mother had preeclampsia during the third trimester of pregnancy. The suspected phenytoin was replaced with phenobarbitone to control seizure episodes. Subsequently, the rashes disappeared. The baby had also suffered from skin discolouration after phototherapy. Radiological investigations and cerebrospinal fluid culture were performed to detect the etiology of seizures. CONCLUSION: Hypersensitivity reaction to phenytoin in newborns is a rare clinical entity but may lead to serious lethal complications. Thus, stringent clinical monitoring of patients on phenytoin therapy is mandatory, especially in the pediatric population.

Effectiveness and safety of perampanel as adjunctive therapy among Chinese patients with focal-onset epilepsy: A real-world prospective observational study.

OBJECTIVE: Perampanel (PER) has previously been shown to be effective and tolerable when used as an adjunctive therapy for patients with focal-onset seizures (FOS). This study aimed to evaluate the effect of PER as adjunctive therapy for patients with FOS in the Chinese population under real-world conditions for 1 year. METHODS: A prospective, single-center, 1-year observational study was conducted at Huashan Hospital, enrolling both under age (≥4 years old) and adult patients with FOS. Response to PER was assessed at 3-, 6-, and 12-month checkpoints by analyzing the 50 % responder rate, the seizure-free rate, and reduction in seizure frequency. RESULTS: One hundred and eight patients (mean age: 26.6 years, 56.5 % males) with FOS were included, with seventy-six patients finishing the 1-year follow-up (retention rate: 70.4 %, mean PER dose: 4.3 mg/day). The seizure frequency was reduced significantly at 3, 6, and 12 months relative to baseline (p < 0.001 for each seizure type). At 12 months, the responder rate was 65.8 %, and the seizure-free rate was 39.5 %. A significantly higher responder rate was found in patients with focal to bilateral tonic-clonic seizures (p = 0.024), among which the percentage of patients with sleep-related epilepsy was significantly high (p = 0.045). Responders had a lower number of concomitant anti-seizure medications (ASMs) than the non-responders (p = 0.009). Drug-related adverse events (AEs) were reported in 37 % of patients, mostly mild or moderate, and the patients who experienced AEs had a higher daily dose of PER than those who did not (p = 0.026). CONCLUSION: Perampanel, an add-on therapy for focal-onset seizures, was found to be effective and tolerable in Chinese patients at 12 months.

Efficacy and safety of adjunctive padsevonil in adults with drug-resistant focal epilepsy: Results from two double-blind, randomized, placebo-controlled trials.

OBJECTIVE: To characterize efficacy, safety/tolerability, and pharmacokinetics of padsevonil (PSL) administered concomitantly with ≤3 antiseizure medications (ASMs) for observable focal seizures in adults with drug-resistant epilepsy in two multicenter, randomized, double-blind, placebo-controlled, parallel-group trials. METHODS: The phase 2b dose-finding trial (EP0091/NCT03373383) randomized patients 1:1:1:1:1 to PSL 50/100/200/400 mg or placebo twice daily (b.i.d.). The phase 3 efficacy trial (EP0092/NCT03739840) randomized patients 1:1:1:1 to PSL 100/200/400 mg or placebo b.i.d. Patients with observable (focal aware with motor symptoms, focal impaired awareness, focal to bilateral tonic-clonic) focal seizures for ≥3 years, experiencing them ≥4 times per 28 days including during the 4-week baseline period despite treatment with ≥4 lifetime ASMs including current ASMs, were enrolled. RESULTS: In EP0091 and EP0092, 410 and 231 patients, respectively, were randomized and received at least one dose of trial medication. In patients in EP0091 on PSL 50/100/200/400 mg b.i.d. (n = 80/82/81/81, respectively) versus placebo (n = 81), outcomes included percentage reductions over placebo in observable focal seizure frequency during the 12-week maintenance period: 17.2%, 19.1% (p = 0.128), 19.2% (p = 0.128), 12.4% (p = 0.248); 75% responder rates (p-values for odds ratios): 13.8%, 12.2% (p = 0.192), 11.1% (p = 0.192), 16.0% (p = 0.124) versus 6.2%; 50% responder rates: 33.8% (p = 0.045), 31.7% (p = 0.079), 25.9% (p = 0.338), 32.1% (p = 0.087), versus 21.0%; TEAEs were reported by 82.7% (67/81), 78.3% (65/83), 74.4% (61/82), 90.1% (73/81) versus 78.3% (65/83). In patients in EP0092 on PSL 100/200/400 mg b.i.d. (n = 60/56/56, respectively) versus placebo (n = 54), outcomes included percentage reductions over placebo: -5.6% (p = 0.687), 6.5% (p = 0.687), 6.3% (p = 0.687); 75% responder rates: 15.3% (p = 0.989), 12.5% (p = 0.989), 14.3% (p = 0.989) versus 13.0%; 50% responder rates: 35.6% (p = 0.425), 33.9% (p = 0.625), and 42.9% (p = 0.125) versus 27.8%; TEAEs were reported by 80.0% (48/60), 78.9% (45/57), 83.1% (49/59) versus 67.3% (37/55). SIGNIFICANCE: In both trials, the primary outcomes did not reach statistical significance in any PSL dose group compared with placebo. PSL was generally well tolerated, and no new safety signals were identified.

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.

Adjunctive Transdermal Cannabidiol for Adults With Focal Epilepsy: A Randomized Clinical Trial.

Importance: Cannabidiol has shown efficacy in randomized clinical trials for drug-resistant epilepsy in specific syndromes that predominantly affect children. However, high-level evidence for the efficacy and safety of cannabidiol in the most common form of drug-resistant epilepsy in adults, focal epilepsy, is lacking. Objective: To investigate the efficacy, safety, and tolerability of transdermally administered cannabidiol in adults with drug-resistant focal epilepsy. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled, multicenter clinical trial at 14 epilepsy trial centers in Australia and New Zealand. Participants were adults with drug-resistant focal epilepsy receiving a stable regimen of up to 3 antiseizure medications. Data were analyzed from July 2017 to November 2018. Interventions: Eligible participants were randomized (1:1:1) to 195-mg or 390-mg transdermal cannabidiol or placebo twice daily for 12 weeks, after which they could enroll in an open-label extension study for up to 2 years. Main Outcomes and Measures: Seizure frequency was self-reported using a daily diary. The primary efficacy end point was the least squares mean difference in the log-transformed total seizure frequency per 28-day period, adjusted to a common baseline log seizure rate, during the 12-week treatment period. Results: A total of 188 patients (45% male [85 patients] and 54.8% female [103 patients]) with a mean (SD) age of 39.2 (12.78) years were randomized, treated, and analyzed (195-mg cannabidiol, 63 participants; 390-mg cannabidiol, 62 participants; placebo, 63 participants). At week 12 of the double-blind period, there was no difference in seizure frequency between placebo (mean [SD] 2.49 [1.31] seizures per 28 days) and 195-mg cannabidiol (mean [SD] 2.51 [1.15] seizures per 28 days; least squares mean difference, 0.014; 95% CI, -0.175 to 0.203; P = .89) or 390-mg cannabidiol (mean [SD] 2.59 [1.12] seizures per 28 days; least squares mean difference, 0.096; 95% CI, -0.093 to 0.285; P = .32). By month 6 of the open-label extension, 115 patients (60.8%) achieved a seizure reduction of at least 50%. Treatment-emergent adverse events occurred in 50.4% (63 of 125 participants) of the cannabidiol group vs 41.3% (26 of 63 participants) in the placebo group, with a treatment difference of 9.1% (95% CI, -6.0% to 23.6%), and occurred at similar rates in the cannabidiol groups. Few participants discontinued (7% [14 of 188 participants]), and most (98% [171 of 174 participants]) continued into the open-label extension. Conclusions and Relevance: Both doses of transdermal cannabidiol were well tolerated and safe. No significant difference in efficacy was observed between cannabidiol and placebo during the double-blind treatment period. The open-label extension demonstrated the long-term safety, tolerability, and acceptability of transdermal cannabidiol delivery. Trial Registration: ACTRN12616000510448 (double-blind); ACTRN12616001455459 (open-label).

Comparative Efficacy and Safety of Lacosamide and Oxcarbazepine for Seizure Control in Children with Newly Diagnosed Solitary Neurocysticercosis.

BACKGROUND: In newly diagnosed neurocysticercosis (NCC) with seizures, the choice of anti-seizure medication (ASM) seems to be arbitrary due to a lack of comparative studies. Although oxcarbazepine (OXC) is often considered efficacious for focal seizures in NCC, due to adverse effects, newer ASMs like levetiracetam (LCM) and lacosamide are also being explored. METHODS: This study was performed by case record review of children with newly diagnosed solitary viable parenchymal NCC aged 4-18years who received lacosamide and OXC at least for 12 weeks between August 2019 and April 2021, from a prospective registry of a tertiary care teaching hospital in north India. Seizure control, electroencephalographic abnormalities, resolution of inflammatory granulomas and adverse effects were compared between two arms at 12 and 24 weeks. RESULTS: Total 31 (8.3 ± 4.7 years, 19 boys) and 72 (8.6 ± 4.2 years, 43 boys) completed at least 12 weeks follow-up in LCM and OXC groups, out of which 2 and 51 completed at least 24 weeks follow-up in LCM and OXC groups, respectively. The occurrence of breakthrough seizure was comparable in both arms at 12 and 24 weeks (1/31 and 2/22 in lacosamide group vs. 2/72 and 4/51 in OXC group, p = 0.66 and 0.59, respectively). Patients receiving OXC had more frequent treatment-emergent adverse events (p = 0.0001) and four patients required discontinuation due to severe adverse events (SAEs), while none in the lacosamide group had SAEs. CONCLUSIONS: Lacosamide appears to be efficacious and safe for achieving seizure freedom in patients with solitary viable parenchymal neurocysticercosis.

Efficacy, tolerability and safety of perampanel in population with pharmacoresistant focal seizures: A systematic review and meta-analysis.

BACKGROUND: Focal seizures are associated with various co-morbidities. Seizure disorders also affect the quality of life of the patients. A huge proportion of patients continue to have uncontrolled seizures despite the availability of numerous antiepileptic drugs. Novel therapeutic targets too, have failed to overcome this problem. Therefore, drugs acting on conventional targets are being explored. Perampanel is one such drug. The present study aimed to assess its efficacy, safety, and effect on quality of life and cognition in patients aged 12 years and above. METHODS: Database search was conducted using keywords perampanel, partial seizures and randomized controlled trials (RCTs). Single and double blinded RCTs were included in the analysis. The primary outcomes assessed were 50% responder rate and seizure freedom rates. Secondary outcomes assessed were Improvement in Clinical Global Improvement for Change (CGI-C), number of patients who experienced adverse events, number of patients who withdrew from trials, adverse drug reaction (ADR) profile from Vigibase, long term safety, quality of Life (QoL) assessment and cognitive assessment, especially in adolescents. The Risk ratios (RR) were calculated for these parameters. RESULTS: 24 full text articles were obtained out of a total 421 studies. From these seven double blind randomized controlled trials were included in the meta-analysis. Perampanel treated patients showed higher 50% responder rates than those treated with placebo. The Risk Ratios (RRs) were 1.39 [95% confidence interval (CI) 1.08-1.79], 1.83 [95% CI 1.51 - 2.22] and 1.81 [95% CI 1.45-2.27] for the 4 mg per day, 8 mg once daily and 12 mg once daily subgroups of perampanel respectively. The RRs for the seizure freedom rates were 4.52 [95% CI 1.30-15.73], 3.65 [95% CI 1.40-9.52] and 2.14 [95% CI 1.11-4.11] for 4 mg per day, 8 mg once daily and 12 mg once daily subgroups of perampanel respectively. There was a significantly higher risk of TEAEs with the 8 mg and 12 mg doses of perampanel as compared to that with placebo. Number of patients who withdrew from the trials due to adverse events was statistically significant in only the 12 mg subgroup of perampanel in comparison to that with placebo group. CONCLUSION: Perampanel was observed to be an effective add on drug for treating pharmacoresistant focal seizures. The patients achieved higher 50% response rates and freedom from seizures with its use. Tolerability of perampanel was more at lower doses.

Pregabalin as adjunctive therapy in adult and pediatric patients with generalized tonic-clonic seizures: A randomized, placebo-controlled trial.

OBJECTIVE: Generalized tonic-clonic (GTC) seizures are the most common type of generalized seizure and more common in children than adults. This phase 3 study evaluated the efficacy and safety of pregabalin for GTC seizures in adults and children with epilepsy. METHODS: This randomized, double-blind, multicenter study evaluated pregabalin (5 mg/kg/day or 10 mg/kg/day) vs placebo as adjunctive therapy for 10 weeks (following a 2-week dose escalation), in pediatric and adult patients (aged 5-65 years) with GTC seizures. Primary endpoint was change in log-transformed 28-day seizure rate during active treatment. Secondary endpoints included responder rates, defined as proportion of patients with ≥50% reduction in 28-day GTC seizure rate from baseline. Safety was monitored throughout. RESULTS: Of 219 patients, 75, 72, and 72 were randomized to adjunctive pregabalin 5 mg/kg/day, 10 mg/kg/day, and placebo, respectively. Fifteen, 11, and 6 patients discontinued from the 5 mg/kg/day, 10 mg/kg/day, and placebo arms, respectively, most commonly due to adverse events (AEs; 10.7%, 6.9%, and 5.6%, respectively). A nonsignificant change in log-transformed mean 28-day seizure rate was seen with pregabalin 10 mg/kg/day vs placebo (least-squares [LS] mean difference -0.01 [95% confidence interval (CI) -0.19 to 0.16]; P = .8889) and with pregabalin 5 mg/kg/day vs placebo (LS mean difference 0.02 [CI -0.15 to 0.19]; P = .8121). Similar observations were noted for adults and children. No significant differences were seen for secondary endpoints with pregabalin vs placebo, including responder rate. The most common AEs (≥10%) were dizziness, headache, and somnolence. Most were of mild/moderate intensity. Seven patients had serious AEs, with one death in the placebo arm (sudden unexpected death in epilepsy). SIGNIFICANCE: Adjunctive pregabalin treatment did not change GTC seizure rate in adults or children. The safety profile of pregabalin was similar to that known; treatment was well tolerated with few discontinuations due to AEs.