The latest advances in the pharmacological management of focal epilepsies in children: a narrative review.

INTRODUCTION: Focal epilepsy constitutes the most common epilepsy in children, and medical treatment represents the first-line therapy in this condition. The main goal of medical treatment for children and adolescents with epilepsy is the achievement of seizure freedom or, in drug-resistant epilepsies, a significant seizure reduction, both minimizing antiseizure medications (ASM)-related adverse events, thus improving the patient's quality of life. However, up to 20-40% of pediatric epilepsies are refractory to drug treatments. New ASMs came to light in the pediatric landscape, improving the drug profile compared to that of the preexisting ones. Clinicians should consider several factors during the drug choice process, including patient and medication-specific characteristics. AREAS COVERED: This narrative review aims to summarize the latest evidence on the effectiveness and tolerability of the newest ASMs administered as monotherapy or adjunctive therapy in pediatric epilepsies with focal onset seizures, providing a practical appraisal based on the existing evidence. EXPERT OPINION: The latest ASMs have the potential to be effective in the pharmacological management of focal onset seizures in children, and treatment choice should consider several drug- and epilepsy-related factors. Future treatments should be increasingly personalized and targeted on patient-specific pathways. Future research should focus on discovering new chemical compounds and repurposing medications used for other indications.

Outcomes and predictors of seizure recurrence in post-stroke epilepsy, a retrospective hospital-based study.

BACKGROUND: The occurrence of seizures following a stroke is a well-recognized complication associated with a significant increase in morbidity and mortality. Despite the numerous studies examining outcomes and risk factors related to post-stroke seizures (PSS), there remains a lack of clarity regarding the clinical characteristics, treatment, and PSS recurrence (PSSR) rates in patients experiencing their initial episode of PSS. PURPOSE: This study aimed to determine the risk factors for developing recurrent seizures after first PSS and their effects on functional outcomes and mortality. METHODS: All patients underwent an electroencephalography (EEG) and were monitored for a minimum of 24 months following the first PSS. The primary endpoint was the recurrence of seizures. Predictive factors for PSSR were determined by using the Cox-proportional hazards model, and the cumulative latency of recurrence at 90, 180, 360, and 720 days was estimated using Kaplan-Meier analysis. RESULTS: Seizure recurred in 36.8% (39/106). Significant association of PSSR was noted with female gender, use of older anti-seizure medications (ASMs) (p<0.001), EEG findings as focal slow wave activity (p<0.001), Ictal epileptiform abnormalities (p=0.015), status epilepticus (p=0.015), and with severe disability (p=0.008). However, multivariate cox-proportional hazards model showed significant association of female gender (HR=3.28; 95% CI: 1.42-7.58; p=0.006). Hazard ratio (HR) was increased with older ASMs use, focal aware seizure types, Ictal EAs, and periodic discharges on EEG; though, statistically significant. CONCLUSION: Factors such as the type of ASMs, EEG findings, and seizure type were significantly linked to PSSR. Female gender was the only independent predictor established. Additionally, significant functional decline was reported with recurrence.

[Experimental study of the influence of phenozanic acid and its combination with valproic acid on the development of the epileptic system]. / Izuchenie vliyaniya fenozanovoi kisloty i ee kombinatsii s val'proevoi kislotoi na razvitie epilepticheskoi sistemy v eksperimente.

OBJECTIVE: To study the effect of phenosanic acid (PA) and its combination with valproic acid (VA) on the development of the Epi system. MATERIAL AND METHODS: A model of focal chronic epilepsy in rats was created by applying metallic cobalt to the surface of the sensorimotor area of the cortex. Long-term electrodes were implanted in the sensorimotor cortex of the left and right hemispheres, the hippocampus, and the hypothalamus. The effect of PA (80 mg/kg) and its combination with VA (200 mg/kg) on discharge activity was carried out on the 2nd day and at the stage of generalization of the Epi system - on the 6th day. The stability of the Epi system on day 10 was assessed by provoking the development of epileptic status (Epi status) in response to the administration of thiolactone homocysteine (HMC) at a dose of 5.5 mmol/kg. RESULTS: In rats treated with PA, low discharge activity is observed, which is confirmed by the absence of EEG and motor manifestations of status epilepticus caused by HMC. PA does not suppress paroxysmal activity at the stages of development of the Epi system. VA significantly suppresses paroxysmal activity, but does not affect the formation of new foci of Epi activity in subcortical structures and the contralateral cortex. The epi system of rats treated with VA is characterized by high discharge activity by the 10th day of the experiment and lability to provocation of epi status. The combination of drugs is more pronounced than PA, but less than VA, reduces the numerical characteristics of paroxysmal activity in the brain structures of rats. CONCLUSION: PA when administered alone, in combination with VA, causes a slowdown in the generalization of convulsive foci of Epi activity and prevents the formation of a stable Epi system. VA, having a pronounced anticonvulsant effect, does not weaken the development of the Epi system in the model of focal cobalt-induced epilepsy.

Seizure Cycles under Pharmacotherapy.

OBJECTIVE: This study was undertaken to determine the effects of antiseizure medications (ASMs) on multidien (multiday) cycles of interictal epileptiform activity (IEA) and seizures and evaluate their potential clinical significance. METHODS: We retrospectively analyzed up to 10 years of data from 88 of the 256 total adults with pharmacoresistant focal epilepsy who participated in the clinical trials of the RNS System, an intracranial device that keeps records of IEA counts. Following adjunctive ASM trials, we evaluated changes over months in (1) rates of self-reported disabling seizures and (2) multidien IEA cycle strength (spectral power for periodicity between 4 and 40 days). We used a survival analysis and the receiver operating characteristics to assess changes in IEA as a predictor of seizure control. RESULTS: Among 56 (33.3%) of the 168 adjunctive ASM trials suitable for analysis, ASM introduction was followed by an average 50 to 70% decrease in multidien IEA cycle strength and a concomitant 50 to 70% decrease in relative seizure rate for up to 12 months. Individuals with a ≥50% decrease in IEA cycle strength in the first 3 months of an ASM trial had a higher probability of remaining seizure responders (≥50% seizure rate reduction, p < 10-7) or super-responders (≥90%, p < 10-8) over the next 12 months. INTERPRETATION: In this large cohort, a decrease in multidien IEA cycle strength following initiation of an adjunctive ASM correlated with seizure control for up to 12 months, suggesting that fluctuations in IEA mirror "disease activity" in pharmacoresistant focal epilepsy and may have clinical utility as a biomarker to predict treatment response. ANN NEUROL 2024;95:743-753.

Pitfalls of using video-EEG for a trial endpoint in children aged <4 years with focal seizures.

OBJECTIVE: Double-blind, randomized, and placebo-controlled trial SP0967 (NCT02477839/2013-000717-20) did not demonstrate superior efficacy of lacosamide versus placebo in patients aged ≥1 month to <4 years with uncontrolled focal seizures, per ≤72 h video-electroencephalogram (video-EEG)-based primary endpoints (reduction in average daily frequency of focal seizures at end-of-maintenance [EOM] versus end-of-baseline [EOB], patients with ≥50% response). This was unexpected because randomized controlled trial SP0969 (NCT01921205) showed efficacy of lacosamide in patients aged ≥4 to <17 years with uncontrolled focal seizures. SP0969's primary endpoint was based on seizure diary instead of video-EEG, an issue with the latter being inter-reader variability. We evaluated inter-reader agreement in video-EEG interpretation in SP0967, which to our knowledge, are the first such data for very young children with focal seizures from a placebo-controlled trial. METHODS: Local investigator and central reader agreement in video-EEG interpretation was analyzed post hoc. RESULTS: Analysis included 105 EOB and 98 EOM video-EEGs. Local investigators and central reader showed poor agreement based on ≥2 focal seizures at EOB (Kappa = 0.01), and fair agreement based on ≥2 focal seizures at EOM (Kappa = 0.23). Local investigator and central reader seizure count interpretations varied substantially, particularly for focal seizures, but also primary generalized and unclassified epileptic seizures, at both timepoints. INTERPRETATION: High inter-reader variability and low inter-reader reliability of the interpretation of seizure types and counts prevent confident conclusion regarding the lack of efficacy of lacosamide in this population. We recommend studies in very young children do not employ video-EEGs exclusively for accurate study inclusion or as an efficacy measure.

Efficacy and tolerability of adjunctive lacosamide in patients aged <4 years with focal seizures.

OBJECTIVE: Primary objective was to evaluate efficacy of lacosamide administered concomitantly with 1-3 antiseizure medications in young children with uncontrolled focal (partial-onset) seizures. METHODS: Double-blind, parallel-group trial (SP0967: NCT02477839/2013-000717-20) conducted between June 2015 and May 2020 at hospitals and clinics in 25 countries. Patients (aged ≥1 month to <4 years) with uncontrolled focal seizures were randomized 1:1 to adjunctive lacosamide or placebo using an interactive voice/web response system and stratified by age. After a 20-day titration period, patients who reached target-dose range (8-12 mg/kg/day) entered a 7-day maintenance period. Region-specific primary efficacy variables were based on ≤72-h video-electroencephalograms: change in average daily frequency (ADF) of electrographic focal seizures as measured on end-of-maintenance video-electroencephalogram versus end-of-baseline video-electroencephalogram (United States); 50% responder rate (≥50% reduction in ADF of focal seizures) during maintenance (European Union). RESULTS: In total, 255 patients were randomized (lacosamide/placebo: 128/127) and received ≥1 trial medication dose. Percentage reduction in ADF of focal seizures for lacosamide (116 patients) versus placebo (120 patients) was 3.2% (95% confidence interval = -13.6 to 17.5, p = 0.69). 50% responder rate was 41.4% for lacosamide (116 patients), 37.5% for placebo (120 patients) (p = 0.58). Treatment-emergent adverse events were reported by 44.5% of lacosamide-treated patients (placebo 51.2%). INTERPRETATION: Adjunctive lacosamide did not show superior efficacy versus placebo in young children with focal seizures. However, efficacy variables were potentially affected by high variability and low reliability between readers in video-electroencephalogram interpretation. Lacosamide was generally well tolerated; safety profile was acceptable and consistent with that in adults and children aged ≥4 years.

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.

Management of patients with epilepsy and Intellectual disabilities in group homes vs. Family Homes: Insights into polypharmacy and seizure characteristics.

OBJECTIVES: This study aimed to investigate the differences in ASMs prescription, seizure characteristics and predictors of polypharmacy in patients with epilepsy and Intellectual disabilities (IDs) residing in group homes versus family homes. METHODS: This nine-year retrospective study analyzed patients with epilepsy and IDs who were admitted to the EMU, epilepsy clinics at LHSC and rehabilitation clinics for patients with IDs at Parkwood Institution. The study included individuals aged 16 years and older residing in either group homes or family homes. Data on demographics, epilepsy characteristics, and ASMs use were collected and analyzed using the Statistical Package for Social Sciences. The study utilized binary logistic regression to identify predictors of polypharmacy in patients with epilepsy and IDs. RESULTS: The study enrolled a total of 81 patients, of which 59.3 % resided in family homes. Group home residents were significantly older (41 vs. 24.5 years; p = 0.0001) and were prescribed more ASMs (3 vs. 2; p = 0.002). Specific ASMs were more common in group homes, including valproic acid (54.5 % vs. 25.0 %), lacosamide (54.5 % vs. 22.9 %), topiramate (33.3 % vs. 14.6 %), and phenytoin (30.3 % vs. 6.2 %). Admission to the EMU was more prevalent in group homes (93.9 % vs. 52.1 %; p = 0.0001). Living in a group home increased the risk of polypharmacy (OR = 10.293, p = 0.005), as did older epilepsy onset age (OR = 1.135, p = 0.031) and generalized or focal & generalized epilepsy (OR = 7.153, p = 0.032 and OR = 10.442, p = 0.025, respectively). SIGNIFICANCE: Our study identified notable differences in the demographic and clinical characteristics of patients with epilepsy and IDs living in group homes versus family homes. Age of epilepsy onset, EMU admissions, epilepsy types, and residency setting were significant predictors of polypharmacy. These findings highlight the need for personalized care strategies and increased awareness of the potential risks associated with polypharmacy.

Cognitive and psychiatric adverse events during adjunctive cenobamate treatment in phase 2 and phase 3 clinical studies.

OBJECTIVE: Cognitive and psychiatric adverse events in patients with epilepsy are important determinants of therapeutic outcomes and patient quality of life. We assessed the relationship between adjunctive cenobamate treatment and selected cognitive and psychiatric treatment-emergent adverse events (TEAEs) in adults with uncontrolled focal epilepsy. METHODS: This was a retrospective analysis of pooled populations of patients with focal epilepsy from two phase 2, randomized, double-blind clinical trials; two open-label extensions (OLEs) of those trials; and a long-term, open-label, phase 3 safety study. Occurrence of cognitive and psychiatric TEAEs in patients treated with adjunctive cenobamate or placebo during double-blind treatment were evaluated. Exposure-adjusted incidence rates of the cognitive and psychiatric TEAEs, defined as the number of TEAEs per patient-year of treatment, during up to 7 years of long-term adjunctive cenobamate treatment, were determined in the pooled OLE and phase 3 patient populations. RESULTS: The pooled randomized trials resulted in a population of 442 patients treated with cenobamate (100 mg/day: n = 108; 200 mg/day: n = 223; 400 mg/day: n = 111) and 216 placebo-treated patients. The combined open-label studies resulted in pooled populations of cenobamate-treated patients ranging from n = 1690 during Year 1 to n = 103 during Year 7. Among cenobamate-treated (all doses) and placebo-treated patients during double-blind treatment, cognitive TEAEs were reported by ≤ 1.9 % (range, 0 %-1.9 %) and ≤ 0.5 % (range, 0 %-0.5 %), respectively, and psychiatric TEAEs by ≤ 3.6 % (range, 0 %-3.6 %) and ≤ 3.2 % (range, 0 %-3.2 %), respectively. During up to 7 years of open-label adjunctive cenobamate treatment, exposure-adjusted incidence rates of cognitive and psychiatric TEAEs were < 0.018 and < 0.038 events per patient-year, respectively. Discontinuation of adjunctive cenobamate due to cognitive or psychiatric TEAEs assessed in this study during double-blind or open-label treatment occurred in ≤ 0.3 % and ≤ 1.7 % of patients, respectively. CONCLUSIONS: Cognitive and psychiatric TEAEs were reported by similar numbers of cenobamate- and placebo-treated patients during double-blind adjunctive cenobamate treatment (< 4 % of patients), and exposure-adjusted incidence rates of these TEAEs remained low during open-label cenobamate treatment for up to 7 years. Treatment discontinuations due to these TEAEs were rare. The results of this post-hoc analysis indicate that adjunctive cenobamate treatment exhibits a low incidence of cognitive or psychiatric TEAEs in patients with uncontrolled focal seizures.

Use of lacosamide for focal epilepsy in a child with kidney failure undergoing peritoneal dialysis.

BACKGROUND: Lacosamide (LCM) has become commonly used for focal onset seizures due to its high tolerability and low drug interactions. Unlike patients on hemodialysis (HD), pharmacokinetic data and dosing recommendations for patients undergoing peritoneal dialysis (PD) are scant. CASE REPORT: A 2-year-old girl with end-stage kidney disease undergoing PD suffered prolonged focal onset seizures. The patient had congenital anomalies of the kidney and urinary tract associated with branchio-oto-renal syndrome due to an EYA1 gene mutation. She also had neurological sequelae from post-resuscitation encephalopathy at the age of one month. Antiseizure medication with few drug interactions, less impact on the neurodevelopmental state and possibility of intravenous administration was preferred. LCM met those criteria and was carefully administered. Although the patient had recurrent prolonged seizures during the titration periods, LCM could be continued without any apparent side effects. The blood levels of LCM increased linearly to the optimal level. We confirmed excretion of LCM in the PD fluid. Kidney transplantation was done three months after and her seizures were well controlled. CONCLUSIONS: LCM might be a promising option for patients undergoing PD. Due to the lower removal efficacy in PD compared with in HD, close attention should be paid to possible drug excess.

Role of Perampanel in the Management of Pediatric Epilepsies in Asia: Expert Opinion.

Management of pediatric epilepsies poses unique challenges around diagnosis, treatment options, comorbidities, and the potential for these factors to interact with processes in the developing brain. In pediatric patients, broad-spectrum antiseizure medications (ASMs) with minimal potential for adverse events (AEs) and limited impact on cognition and behavior are preferred. Perampanel is a first-in-class ASM with broad-spectrum efficacy, a tolerable safety profile, minimal negative impact on cognitive function, and other features that make it a viable treatment option in this patient population. However, evidence and experience of its use in pediatric patients are less extensive than in adult patients. Experts in pediatric epilepsy across the region convened at a series of meetings to discuss the use of perampanel in pediatric patients, including dose optimization, AE prevention and management, and considerations in particular groups. This article summarizes key evidence for perampanel in the pediatric population and consolidates the experts' recommendations for using the ASM in managing pediatric epilepsies.

Managing delayed or missed pregabalin doses in patients with focal epilepsy: a Monte Carlo simulation study.

BACKGROUND: Delayed or missed doses are inevitable in epilepsy pharmacotherapy. The current remedial measures recommended by the United States Food and Drug Administration (FDA) for non-adherence are generic and lack clinical evidence. AIM: To assess remedial strategies for delayed or missed pregabalin doses in patients with epilepsy using Monte Carlo simulations. METHOD: Monte Carlo simulations were performed using a published population pharmacokinetic model for pregabalin. The applicability of five proposed remedial regimens as well as FDA recommendations was evaluated by simulating various poor adherence scenarios in eight populations, including those with renal dysfunction. RESULTS: All proposed remedial strategies were associated with delay duration and renal function. When delays are relatively short, an immediate regular dose is advised. The cut-off time points for taking the regular dose as a remedial regimen were 1, 2, 4, and 12 h for patients with mild renal impairment and normal renal function, moderate renal impairment, severe renal impairment, and end-stage renal disease, respectively. However, when delay aligns closely with a dosing interval, a regular dose combined with a partial dose proves effective. Generally, supplementing 1.3-fold the regular dose at the next scheduled time adequately compensates for the missed dose. CONCLUSION: Model-based simulations provided quantitative evidence for the effectiveness and feasibility of remedial strategies for missed or delayed pregabalin doses.

Epilepsy with generalized tonic-clonic seizures alone: Electroclinical features and prognostic patterns.

OBJECTIVE: Epilepsy with generalized tonic-clonic seizures alone (GTCA) is a common but poorly characterized idiopathic generalized epilepsy (IGE) syndrome. Hence, we investigated electroclinical features, seizure outcome, and antiseizure medication (ASM) withdrawal in a large cohort of GTCA patients. METHODS: In this multicenter retrospective study, GTCA patients defined according to the diagnostic criteria of the International League Against Epilepsy (2022) were included. We investigated prognostic patterns, drug resistance at the last visit, and ASM withdrawal, along with their prognostic factors. RESULTS: We included 247 patients with a median (interquartile range [IQR]) age at onset of 17 years (13-22) and a median follow-up duration of 10 years (IQR = 5-20). Drug resistance at the last visit was observed in 40 (16.3%) patients, whereas the median latency to achieve 2-year remission was 24 months (IQR = 24-46.5) with a median number of 1 (IQR = 1-2) ASM. During the long-term follow-up (i.e., 202 patients followed ≥5-years after the first ASM trial), 69 (34.3%) patients displayed an early remission pattern and 36 (17.9%) patients displayed a late remission pattern, whereas 16 (8%) and 73 (36.3%) individuals had no-remission and relapsing-remitting patterns, respectively. Catamenial seizures and morning predominance of generalized tonic-clonic seizures (GTCS) independently predicted drug resistance at the last visit according to multivariable logistic regression. Treatment withdrawal was attempted in 63 (25.5%) patients, with 59 (93.7%) of them having at least a 12-month follow-up after ASM discontinuation. At the last visit, 49 (83%) of those patients had experienced GTCS recurrence. A longer duration of seizure freedom was the only factor predicting a higher chance of successful ASM withdrawal according to multivariable Cox regression. SIGNIFICANCE: GTCA could be considered a relatively easily manageable IGE syndrome, with a low rate of drug resistance and a high prevalence of early response to treatment. Nevertheless, a considerable proportion of patients experience relapsing patterns of seizure control, highlighting the need for appropriate counseling and lifestyle recommendations.

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.

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.

A real-world comparison among third-generation antiseizure medications: Results from the COMPARE study.

OBJECTIVE: There are few comparative data on the third-generation antiseizure medications (ASMs). We aimed to assess and compare the effectiveness of brivaracetam (BRV), eslicarbazepine acetate (ESL), lacosamide (LCM), and perampanel (PER) in people with epilepsy (PWE). Efficacy and tolerability were compared as secondary objectives. METHODS: This multicenter, retrospective study collected data from 22 Italian neurology/epilepsy centers. All adult PWE who started add-on treatment with one of the studied ASMs between January 2018 and October 2021 were included. Retention rate was established as effectiveness measure and described using Kaplan-Meier curves and the best fitting survival model. The responder status and the occurrence of adverse events (AEs) were used to evaluate efficacy and safety, respectively. The odds of AEs and drug efficacy were estimated by two multilevel logistic models. RESULTS: A total of 960 patients (52.92% females, median age = 43 years) met the inclusion criteria. They mainly suffered from structural epilepsy (52.29%) with monthly (46.2%) focal seizures (69.58%). Compared with LCM, all the studied ASMs had a higher dropout risk, statistically significant in the BRV levetiracetam (LEV)-naïve (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.17-3.29) and PER groups (HR = 1.64, 95% CI = 1.06-2.55). Women were at higher risk of discontinuing ESL (HR = 5.33, 95% CI = 1.71-16.61), as well as PER-treated patients with unknown epilepsy etiology versus those with structural etiology (HR = 1.74, 95% CI = 1.05-2.88). BRV with prior LEV therapy showed lower odds of efficacy (odds ratio [OR] = .08, 95% CI = .01-.48) versus LCM, whereas a higher efficacy was observed in women treated with BRV and LEV-naïve (OR = 10.32, 95% CI = 1.55-68.78) versus men. PER (OR = 6.93, 95% CI = 3.32-14.44) and BRV in LEV-naïve patients (OR = 6.80, 95% CI = 2.64-17.52) had a higher chance of AEs than LCM. SIGNIFICANCE: Comparative evidence from real-world studies may help clinicians to tailor treatments according to patients' demographic and clinical characteristics.

Effect of drug treatment changes and seizure outcomes on depression and suicidality in adults with drug-resistant focal epilepsy.

OBJECTIVE: To investigate changes in depressive and suicidality status and their relationship with seizure outcomes after the addition or substitution of another antiseizure medication (ASM) in adults with drug-resistant focal epilepsy. METHODS: Seven hundred seventy consecutively enrolled patients were assessed and followed prospectively for seizure outcome and depressive status over a 6-month period after starting treatment with a newly introduced ASM. The Neurological Disorders Depression Inventory for Epilepsy (NDDIE) was used to screen for depression and suicidality. Correlations of NDDIE results with clinical and treatment-related variables were assessed by using a stepwise logistic regression model. RESULTS: At baseline, 50% of patients had a positive screening test result for depression and 13% had a positive screening test result for suicidal ideation. A psychiatric comorbidity at baseline was associated with a 2.3 times increased risk of an initially negative NDDIE screening result becoming positive at re-assessment after 6 months. In addition, the number of ASMs taken at baseline correlated with an increased risk of a change in depression screening test results from negative to positive during follow-up, whereas no association was identified with sociodemographic and epilepsy-related variables, including seizure outcomes. Approximately 6% of patients who were initially negative at screening for suicidal ideation became positive at the 6-month re-assessment. The risk of switch from a negative to a positive screening test result for suicidal ideation was increased more than two-fold in individuals who screened positive for depression at baseline, and was unrelated to the type of ASM introduced, sociodemographic variables, or seizure outcomes. SIGNIFICANCE: Almost 1 in 5 adults with drug-resistant focal epilepsy who screen negative for depression become positive when re-assessed 6 months after a treatment change. At re-assessment 6 months later, 6.1% who screen initially negative for passive suicidal ideation become positive. These changes in screening status are independent of type of ASM introduced or seizure outcomes but correlate with psychiatric status at baseline.

Impact of antiseizure medication with a very long half-life on long term video-EEG monitoring in focal epilepsy.

PURPOSE: To assess the impact of antiseizure medications (ASMs) with a very long half-life on long term video-EEG monitoring (LTM) in people with focal epilepsy (FE). METHODS: In this retrospective cohort study, we searched our local database for people with FE who underwent ASM reduction during LTM at the University Hospital of 'La Fe', Valencia, from January 2013 to December 2019. Taking into account the half-life of the ASM, people with FE were divided into two groups: Group A contained individuals who were taking at least one ASM with a very long half-life at admission, and Group B consisted of those not taking very long half-life ASMs. Using multivariable analysis to control for important confounders, we compared the following outcomes between both groups: seizure rates per day, time to first seizure, and LTM duration. RESULTS: Three hundred seventy individuals were included in the study (154 in Group A and 216 in Group B). The median recorded seizure rates (1.3 seizures/day, range 0-15.3 vs.1.3 seizures/day, range 0-9.3, p-value=0.68), median time to the first seizure (24 h, range 2-119 vs. 24 h, range 2-100, p-value=0.92), and median LTM duration (4 days, range 2-5 vs. 4 days, range 2-5, p-value=0.94) were similar in both groups. Multivariable analysis did not reveal any significant differences in the three outcomes between the two groups (all p-values>0.05). CONCLUSION: ASMs with a very long half-life taken as co-medication do not significantly affect important LTM outcomes, including recorded seizure rates, time to the first seizure, or LTM duration. Therefore, in general, there is no need to discontinue ASMs with a very long half-life prior to LTM.

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.