OBJECTIVE: This study was undertaken to assess the effectiveness/tolerability of adjunctive cenobamate, variations in the load of concomitant antiseizure medications (ASMs) and predictors of clinical response in people with focal epilepsy.
METHODS: This was a retrospective study at 21 centers participating in the Italian Expanded Access Program. Effectiveness outcomes included retention and responder rates (≥50% and 100% reduction in baseline seizure frequency). Tolerability/safety outcomes included the rate of treatment discontinuation due to adverse events (AEs) and their incidence. Total drug load was quantified as the number of concomitant ASMs and total defined daily dose (DDD). Concomitant ASMs were also classified according to their mechanism of action and pharmacokinetic interactions to perform explorative subgroup analyses.
RESULTS: A total of 236 subjects with a median age of 38 (Q1-Q3 = 27-49) years were included. At 12 months, cenobamate retention rate was 78.8% and responders were 57.5%. The seizure freedom rates during the preceding 3 months were 9.8%, 12.2%, 16.3%, and 14.0% at 3, 6, 9, and 12 months. A higher percentage of responders was observed among subjects treated with clobazam, although the difference was not statistically significant. A total of 223 AEs were recorded in 133 of 236 participants, leading to cenobamate discontinuation in 8.5% cases. At 12 months, a reduction of one or two concomitant ASMs occurred in 42.6% and 4.3% of the subjects. The median total DDD of all concomitant ASMs decreased from 3.34 (Q1-Q3 = 2.50-4.47) at baseline to 2.50 (Q1-Q3 = 1.67-3.50) at 12 months (p < .001, median percentage reduction = 22.2%). The highest rates of cotreatment withdrawal and reductions in the DDD were observed for sodium channel blockers and γ-aminobutyric acidergic modulators (above all for those linked to pharmacokinetic interactions), and perampanel.
CONCLUSIONS: Adjunctive cenobamate was associated with a reduction in seizure frequency and in the burden of concomitant ASMs in adults with difficult-to-treat focal epilepsy. The type of ASM associated did not influence effectiveness except for a favorable trend with clobazam.

UNASSIGNED: This study aimed to examine differences in factors influencing quality of life (QOL) in people with extratemporal lobe epilepsy (ETLE) and mesial temporal lobe epilepsy (MTLE).
UNASSIGNED: We obtained data from the medical records of 84 (47 ETLE and 37 MTLE) people with epilepsy. The data included age, sex, employment, seizure frequency, number of antiseizure medication (ASM), Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) score, and Quality of Life in Epilepsy Inventory-31 (QOLIE-31) score. Multiple regression analyses were performed using QOLIE-31 as the dependent variable and age, sex, employment, seizure frequency, number of ASM, and NDDI-E score as the independent variables in ETLE or MTLE.
UNASSIGNED: From the results of the multiple regression analyses, QOLIE-31 in ETLE was associated with NDDI-E (β = -0.757, p < 0.001) and employment (β = 0.388, p = 0.008). Meanwhile, QOLIE-31 in MTLE was associated with NDDI-E (β = -0.625, p < 0.001), employment (β = 0.396, p = 0.041), and number of ASMs (β = -0.399, p = 0.018).
UNASSIGNED: Overall, our findings indicate that the number of ASMs is potentially an influence on QOL of MTLE but similar effect is not observed in ETLE.

OBJECTIVE: Intravenous (IV) push (IVP) is an alternative administration method for levetiracetam, but evidence evaluating it compared to IV piggyback (IVPB) for loading doses in acutely seizing patients is limited, particularly in patients with status epilepticus (SE). This study aimed to compare the efficiency and safety of IVP versus IVPB levetiracetam loading doses.
METHODS: This was a single-center sequential retrospective study conducted in adult (≥18 years) patients who received an IV levetiracetam loading dose (>2000 mg or ≥20 mg/kg) for acute or suspected seizure. The primary outcome was time to administration, compared between doses given as IVP versus IVPB. Secondary outcomes included rates of adverse events (AEs), rescue benzodiazepine or antiseizure medication administration, intubation, and intensive care unit (ICU) admission between groups.
RESULTS: A total of 246 patients were included; 116 received IVP and 130 received IVPB loading doses. Median age was 56 years; most patients were male (62%) and White (60%) and had witnessed seizures (67%). Doses were administered for SE in 32 (27.5%) and 46 (35.4%) patients in the IVP and IVPB arms, respectively. Median time to administration was shorter in the IVP group (12 vs. 38 min, p < .001). Bradycardia (1.7% vs. 2.3%, p = .99), hypotension (7.8% vs. 12%, p = .30), sedation (6% vs. 12.3%, p = .09), intubation (10% vs. 8%, p = .37), ICU admission (32% vs. 39%, p = .31), and rescue medication administration (8.6% vs. 14.6% p = .10) were similar between groups. In SE patients, IVP was associated with shorter time to administration (12 vs. 44 min, p = .003) and lower odds of ICU admission after adjustment for age, dose, Status Epilepticus Severity Score, and seizure history (adjusted odds ratio = .23, 95% confidence interval = .06-.81).
CONCLUSIONS: IVP reduced time to levetiracetam administration versus IVPB and was not associated with more AEs. Rescue agent use, intubation, and ICU admission were similar between arms, but IVP may reduce ICU admissions in SE patients. Prospective studies should assess the effectiveness of IVP versus IVPB.

OBJECTIVE: Given its key homeostatic role affecting mitochondria, ionotropic and metabotropic receptors, and voltage-gated ion channels, sigma-1 receptor (Sig1R) represents an interesting target for epilepsy management. Antiseizure effects of the positive allosteric modulator E1R have already been reported in acute seizure models. Although modulation of serotonergic neurotransmission is considered the main mechanism of action of fenfluramine, its interaction with Sig1R may be of additional relevance.
METHODS: To further explore the potential of Sig1R as a target, we assessed the efficacy and tolerability of E1R and fenfluramine in two chronic mouse models, including an amygdala kindling paradigm and the intrahippocampal kainate model. The relative contribution of the interaction with Sig1R was analyzed using combination experiments with the Sig1R antagonist NE-100.
RESULTS: Whereas E1R exerted pronounced dose-dependent antiseizure effects at well-tolerated doses in fully kindled mice, only limited effects were observed in response to fenfluramine, without a clear dose dependency. In the intrahippocampal kainate model, E1R failed to influence electrographic seizure activity. In contrast, fenfluramine significantly reduced the frequency of electrographic seizure events and their cumulative duration. Pretreatment with NE-100 reduced the effects of E1R and fenfluramine in the kindling model. Surprisingly, pre-exposure to NE-100 in the intrahippocampal kainate model rather enhanced and prolonged fenfluramine\'s antiseizure effects.
CONCLUSIONS: In conclusion, the kindling data further support Sig1R as an interesting target for novel antiseizure medications. However, it is necessary to further explore the preclinical profile of E1R in chronic epilepsy models with spontaneous seizures. Despite the rather limited effects in the kindling paradigm, the findings from the intrahippocampal kainate model suggest that it is of interest to further assess a possible broad-spectrum potential of fenfluramine.

OBJECTIVE: The cannabidiol (CBD) Expanded Access Program provided compassionate access to CBD for patients with treatment-resistant epilepsy, including tuberous sclerosis complex (TSC), at 35 US epilepsy centers. Here, we present the long-term efficacy and safety outcomes for add-on CBD treatment in patients with TSC.
METHODS: Patients received plant-derived, highly purified CBD (Epidiolex® 100 mg/mL, oral solution), increasing from 2 to 10 mg/kg/d to tolerance or maximum of 25-50 mg/kg/d. Efficacy endpoints were percentage change from baseline in median monthly convulsive, focal, and total seizure frequency and ≥ 50%, ≥75%, and 100% responder rates across 12-week visit windows through 144 weeks. Adverse events (AEs) are reported through 233 weeks.
RESULTS: Thirty-four patients with confirmed TSC were included. Mean age was 12.4 years (range, 1.8-31.2), and patients were receiving a median of 3 (range, 1-7) antiseizure medications (ASMs) at baseline. Median CBD dose was 25-28 mg/kg/d for 36 weeks and then 20-50 mg/kg/d through 228 weeks. Dose reduction from baseline occurred for most ASMs, except topiramate. Median reduction in the frequency of convulsive, focal, and total seizures was 44%-81%, 51%-87%, and 44%-87%, respectively, through 144 weeks. Responder rates (≥50%, ≥75%, and 100% reduction) were 43%-71%, 14%-58%, and 0%-25% for convulsive seizures; 52%-75%, 35%-60%, and 7%-32% for focal seizures; and 46%-79%, 26%-65%, and 0%-13% for total seizures. A total of 94% of patients experienced ≥1 AE; 47% had serious AEs, considered treatment unrelated by the investigator. Treatment-related AEs (TRAEs) occurred in 71% of patients. The most frequently reported TRAEs were somnolence, diarrhea, and ataxia. Two patients experienced AEs leading to discontinuation. There were no deaths.
CONCLUSIONS: Long-term add-on CBD use was associated with reduced seizure frequency through 144 weeks. The safety profile was consistent with previous reports.
CONCLUSIONS: In this study, we evaluated efficacy and safety of cannabidiol (CBD) treatment in patients with tuberous sclerosis complex receiving CBD in addition to other antiseizure treatments in an Expanded Access Program. After starting CBD, 46%-79% of patients had at least 50% reduction and 26%-65% had at least 75% reduction in the number of seizures per month; up to 13% had no seizures through 144 weeks. Safety results were similar to prior studies; sleepiness and diarrhea were common treatment-related side effects. These results show that long-term CBD treatment was associated with fewer seizures and mild/moderate side effects.

Gray matter heterotopia (GMH) is caused by abnormal neuronal migration during brain development. Subcortical band heterotopia (SBH), or double cortex, is a rare variant of GMH that mainly affects female patients with epilepsy (PWE) with different degrees of mental retardation. We present the case of a 25-year-old woman who was admitted to the neurology department of our tertiary hospital with generalized tonic-clonic seizures. Her mother had a normal antenatal period and a history of labor. There was a history of immediate crying and normal appearance, pulse, grimace, activity, and respiration (APGAR) scores. She had delayed milestones, which affected various categories of child development. Physical examination revealed a global developmental delay. Laboratory values, including complete blood count, serum calcium, and arterial blood gas tests, were all within normal limits. An EEG showed significant abnormalities suggestive of epilepsy. An MRI of the brain showed a continuous band of gray matter located deep and parallel to the cortex in both cerebral hemispheres, suggesting double cortex syndrome (DCS).

OBJECTIVE: This study aimed to develop a classifier using supervised machine learning to effectively assess the impact of clinical, demographical, and biochemical factors in accurately predicting the antiseizure medications (ASMs) treatment response in people with epilepsy (PWE).
METHODS: Data was collected from 786 PWE at the Outpatient Department of Neurology, Institute of Human Behavior and Allied Sciences (IHBAS), New Delhi, India from 2005 to 2015. Patients were followed up at the 2nd, 4th, 8th, and 12th month over the span of 1 year for the drugs being administered and their dosage, the serum drug levels, the frequency of seizure control, drug efficacy, the adverse drug reactions (ADRs), and their compliance to ASMs. Several features, including demographic details, medical history, and auxiliary examinations electroencephalogram (EEG) or Computed Tomography (CT) were chosen to discern between patients with distinct remission outcomes. Remission outcomes were categorized into \'good responder (GR)\' and \'poor responder (PR)\' based on the number of seizures experienced by the patients over the study duration. Our dataset was utilized to train seven classical machine learning algorithms i.e Extreme Gradient Boost (XGB), K-Nearest Neighbor (KNN), Support Vector Classifier (SVC), Decision Tree (DT), Random Forest (RF), Naïve Bayes (NB) and Logistic Regression (LR) to construct classification models.
RESULTS: Our research findings indicate that 1) among the seven algorithms examined, XGB and SVC demonstrated superior predictive performances of ASM treatment outcomes with an accuracy of 0.66 each and ROC-AUC scores of 0.67 (XGB) and 0.66 (SVC) in distinguishing between PR and GR patients. 2) The most influential factor in discerning PR to GR patients is a family history of seizures (no), education (literate) and multitherapy with Chi-square (χ2) values of 12.1539, 8.7232 and 13.620 respectively and odds ratio (OR) of 2.2671, 0.4467, and 1.9453 each. 3). Furthermore, our surrogate analysis revealed that the null hypothesis for both XGB and SVC was rejected at a 100 % confidence level, underscoring the significance of their predictive performance. These findings underscore the robustness and reliability of XGB and SVC in our predictive modelling framework.
CONCLUSIONS: Utilizing XG Boost and SVC-based machine learning classifier, we successfully forecasted the likelihood of a patient\'s response to ASM treatment, categorizing them as either PR or GR, post-completion of standard epilepsy examinations. The classifier\'s predictions were found to be statistically significant, suggesting their potential utility in improving treatment strategies, particularly in the personalized selection of ASM regimens for individual epilepsy patients.

OBJECTIVE: To identify the rate of successful antiseizure medication (ASM) withdrawal after resective surgery in patients with long-term epilepsy-associated tumors (LEATs).
METHODS: A retrospective analysis (from our prospectively archived data) on the post-operative ASM profile of 123 consecutive patients who completed a minimum of 2 years after resection of LEATs for ASM-resistant epilepsy. A comparison between recurred and non-recurred groups in terms of seizure recurrence was used to identify the potential predictors of seizure recurrence whose attributes were further analyzed using univariate and multiple logistic regression analysis. Kaplan-Meier survival curves were used to study the probability of ASM freedom following surgery.
RESULTS: We attempted ASM withdrawal in 102 (82.9 %) patients. Forty-eight (47.1 %) had seizure recurrence while reducing ASM, of which 22 (21.6 %) continued to have seizures even after ASM optimisation. On univariate analysis, presence of pre-operative secondary generalized seizure(s) was the only factor associated with seizure recurrence. At a mean follow-up of 6.1 years, 72 (58.5 %) patients were seizure-free and aura-free at terminal follow-up (53 patients were off any ASM). The cumulative probability of achieving complete ASM-free status was 29 % at fourth year, 42 % at sixth year, 55 % at eighth year, and 59 % at 10th year after surgery.
CONCLUSIONS: Following resective surgery for LEATs, ASM(s) could be successfully discontinued in half of the patients. About one-third of the patients may have recurrent seizures on follow-up. Presence of secondary generalized seizure(s) prior to surgery predicts seizure recurrence, whereas MRI defined completeness of resection will not. This information will help in rationalising decisions on ASM management post-resection.

Objectives This study aimed to describe the clinical characteristics, investigational results, and management strategies in patients with drug-resistant epilepsy (DRE). Methods This retrospective cohort study included all adult and adolescent patients (aged 14 years or older) diagnosed with DRE who visited the adult neurology clinic at King Abdulaziz Medical City, Jeddah, Saudi Arabia from January 2019 to December 2021. DRE was defined as failure to achieve seizure freedom despite undergoing adequate trials of two well-tolerated and appropriately selected antiseizure medications. Results This study included 299 patients with DRE. Most patients were in their second to fourth decade, with a mean age of 37 ± 17 years. Focal onset epilepsy was diagnosed in 52.5% of the patients, and an etiology for epilepsy was determined in 44.1% of the patients. Findings in brain magnetic resonance imaging were abnormal in 49% of the patients, whereas abnormal findings in electroencephalograms were found in 27.5%. The most common antiseizure medication was levetiracetam (67.6% of cases). Conclusion The findings of this study confirm the challenges in diagnosing and managing patients with DRE and emphasize the necessity for careful and comprehensive patient evaluation. Further research is needed to investigate the effectiveness, safety, and accessibility of diagnostic and therapeutic resources for patients with DRE.

This analysis assessed the effectiveness and tolerability of brivaracetam (BRV) in older (≥65 years of age) and younger (≥16 to <65 years of age) adults with epilepsy. This was a subgroup analysis from EXPERIENCE/EPD332, a pooled analysis of individual patient records from multiple independent, non-interventional studies of patients with epilepsy starting BRV in Australia, Europe, and the United States. Included patients had ≥6 months of follow-up data. Outcomes included responders (≥50 % reduction from baseline in seizure frequency), seizure freedom (no seizures within 3 months before the time point), and continuous seizure freedom (no seizures from baseline) at 12 months; BRV discontinuation during the whole study follow-up; and treatment-emergent adverse events (TEAEs) at 3, 6, and 12 months. Patients with missing data after BRV discontinuation were deemed non-responders/not seizure-free. Analysis populations included the Full Analysis Set (FAS; patients who received ≥1 BRV dose and had seizure type and age documented at baseline) and the modified FAS (FAS patients who had ≥1 seizure recorded during baseline). The FAS was used for all outcomes except seizure reduction. The FAS included 147 (8.9 %) patients aged ≥65 years and 1497 (91.1 %) aged ≥16 to <65 years. Compared with the younger subgroup, patients aged ≥65 years had a longer median epilepsy duration (33.0 years [n = 144] vs 17.0 years [n = 1460]) and lower median seizure frequency at index (2.0 seizures/28 days [n = 129] vs 4.0 seizures/28 days [n = 1256]), and less commonly had >1 prior antiseizure medication (106/141 [75.2 %] vs 1265/1479 [85.5 %]). At 12 months, a numerically higher percentage of patients aged ≥65 years versus the younger subgroup achieved ≥50 % seizure reduction (46.5 % [n = 71] vs 36.0 % [n = 751]), seizure freedom (26.0 % [n = 100] vs 13.9 % [n = 1011]), and continuous seizure freedom (22.0 % [n = 100] vs 10.7 % [n = 1011]). During the whole study follow-up, 43/147 (29.3 %) patients aged ≥65 years and 508/1492 (34.0 %) aged ≥16 to <65 years discontinued BRV. The incidence of TEAEs since the prior visit was similar in both subgroups at 3 months (≥65 years vs ≥16 to <65 years: 38/138 [27.5 %] vs 356/1404 [25.4 %]), 6 months (19/119 [16.0 %] vs 176/1257 [14.0 %]), and 12 months (8/104 [7.7 %] vs 107/1128 [9.5 %]). This real-world analysis suggests BRV was effective in patients aged ≥65 years and ≥16 to <65 years, with numerically higher effectiveness in the older subgroup. BRV was well tolerated in both subgroups.