Bernhard J. Steinhoff

Objective: To evaluate the effectiveness and tolerability of cenobamate in patients with a significant reduction in concomitant antiseizure medication (ASM) in European cenobamate Early Access Programs (EAPs). Method: Anonymized patient data from real‐world studies/registries associated with European cenobamate EAPs were pooled. Patients were included if they had significantly reduced their concomitant drug load (i.e., converted to cenobamate monotherapy or reduced from multiple to one concomitant ASM) between baseline and the last visit. Effectiveness, tolerability, and dosage of cenobamate were evaluated. Responses according to therapeutic regimen at last visit were studied. Results: Of 694 patients within cenobamate EAPs, 75 (10.7%) met the inclusion criteria (mean age 39.5 years [range 19–65]). At baseline, the median number of prior ASMs was 10 (interquartile range [IQR] 6–13); 46 patients (61.3%) were taking two, 23 (30.7%) were taking three, and six (8%) were taking four concomitant ASMs at baseline. At the last visit, seven patients (9.3%) were converted to monotherapy and 68 (90.7%) were receiving one concomitant ASM. The median cenobamate dosage at last visit was 300 mg (IQR 200–350). Median cenobamate follow‐up was 22 months; 73 patients (97%) had at least 1 year of follow‐up and one discontinued cenobamate at 1 year. Twenty‐five patients (33.3%) were seizure‐free at last visit; 51 (68%) had a ≥50% reduction in seizure frequency. The seizure‐freedom rate was numerically, but not significantly, higher in patients converted to monotherapy (57.1%) versus those receiving one concomitant ASM (30.9%; p = 0.16). Cenobamate plus clobazam was the most effective combination. Adverse events (AEs) were reported in 55/75 patients (73.3%); the most common were somnolence (30.7%), dizziness/vertigo (28%), and fatigue (26.7%). No AEs led to treatment discontinuation. Significance: Cenobamate demonstrated good effectiveness and tolerability in a population of patients within European EAPs who achieved a significant reduction of concomitant ASM. Plain Language Summary: People with highly drug‐resistant epilepsy often need to take several antiseizure medications at the same time. Combined data from European Early Access Programs show that about 10% of people treated with cenobamate were able to stop all other antiseizure medications or reduce treatment to cenobamate plus one other medication. Despite this simplification of treatment, one‐third of these patients became seizure‐free and more than two‐thirds experienced at least a 50% reduction in seizure frequency. Within this group, no patients stopped cenobamate because of side effects.

Background and Purpose: Polytherapy in epilepsy is associated with a higher risk of adverse events, poorer adherence, and impaired quality of life. Thus, reducing concomitant antiseizure medications (ASMs) and/or using a newly added ASM such as cenobamate with only 1 other ASM (i.e., bitherapy) may improve tolerability. This post hoc analysis evaluated the impact of the number and type of concomitant ASMs on treatment‐emergent adverse events (TEAEs) that occurred in the cenobamate C021 open‐label clinical trial. Methods: Adjunctive cenobamate was initiated in adults (aged 18–70 years) with uncontrolled focal seizures who were taking 1 to 3 ASMs. The number and type of concomitant ASMs and the frequency, severity, and time to resolution of TEAEs were assessed. Results: The most frequently reported (≥ 10%) TEAEs in the overall population ( n = 1340) were somnolence, dizziness, fatigue, and headache. The percentage of patients with dizziness, somnolence, and fatigue increased with increasing numbers of concomitant ASMs, especially when combined with benzodiazepines, chiefly clobazam, and in patients taking ≥ 2 sodium channel blockers. Median time to resolution of frequently reported TEAEs was shorter in patients taking fewer concomitant ASMs, with the exception of fatigue. The proportion of patients experiencing more severe TEAEs (except for headache) also increased with increasing numbers of concomitant ASMs. Conclusions: Patients taking fewer concomitant ASMs reported better tolerability as evidenced by fewer and less severe AEs and faster time to resolution. These findings emphasize the importance of optimizing concomitant ASM regimens through dose adjustments, ASM substitution, and treatment simplification to improve tolerability.

Objective: Detection of focal cortical dysplasia (FCD) remains a major challenge in presurgical epilepsy diagnostics. Magnetic resonance imaging (MRI) morphometry increasingly improves lesion detection and postsurgical outcomes. The volume‐based Morphometric Analysis Program, version 2018 (MAP18) with integrated artificial neural network and surface‐based Multi‐centre Epilepsy Lesion Detection (MELD; MELD Graph) MRI morphometry algorithms have demonstrated diagnostic utility, but their performance has not been directly compared within a single cohort of surgically treated patients with histopathologically confirmed FCD. Methods: We retrospectively analyzed 3‐T MRIs of 32 FCD patients who underwent epilepsy surgery. MAP18 was applied to MP2RAGE (magnetization‐prepared 2 rapid gradient echo) sequences and MELD to T1MPRAGE (magnetization‐prepared rapid gradient echo) and three‐dimensional FLAIR (fluid‐attenuated inversion recovery) sequences. Binary lesion masks served as ground truth for evaluating detection accuracy, precision, and recall at cluster and voxel levels. Clinical correlation analysis assessed spatial concordance with seizure onset zone (SOZ) and irritative zone (IZ) from video‐electroencephalography (EEG) and postoperative outcome. Results: The cohort included 34 histopathologically proven FCD lesions (91.2% FCD II, 5.8% mild malformation of cortical development, 2.9% unspecified). MELD identified 32 of 34 lesions (94.1%), and MAP18 identified 33 of 34 lesions (97.1%), with concordance in 32 of 34 lesions (94.1%). At the cluster level, MELD showed significantly higher precision ( p < .001) and fewer false positive clusters per patient (median 0 vs. 3, p < .001). Voxelwise analysis revealed that MELD demonstrated significantly higher precision than MAP18 (.42 vs. .13, p < .0001) and recall (.44 vs. .23, p < .01). Lobar concordance with SOZ reached 90.6% and with IZ reached 87.5%. Among invasive EEG patients, overlap with SOZ and IZ was 100%. Seizure freedom (Engel I) was achieved in 87.5% of patients. Significance: Under standardized high‐resolution 3‐T MRI, both algorithms achieved high detection rates with strong concordance. Combined application may enhance presurgical lesion detection, with results limited to surgically treated patients.

Despite the use of appropriately selected antiseizure medications (ASMs), seizure freedom remains elusive for some patients at each treatment line, and those failing two ASMs are then classified with drug-resistant epilepsy (DRE). Living with long-term uncontrolled epilepsy can lead to discouragement and disillusionment for both people with epilepsy and clinicians. In the context of potential treatment failure, maximizing seizure control while minimizing adverse events becomes even more critical, necessitating continual symptom surveillance and consideration of therapeutic trials of ASMs where appropriate. This requires truly individualized care, and in this pursuit, physicians will encounter the diametrically opposed challenges of overtreatment (or a burdensome drug load) and therapeutic nihilism (caused by missing consideration of treatment possibilities). This paper presents a detailed review of these issues and the influence of patient- and physician-related factors. Diagnostic and treatment strategies include ensuring accurate diagnosis and epilepsy classification for optimization of ASM treatment, considering the risk-to-benefit ratio when choosing treatment, encouraging treatment adherence, considering the initiation of alternative therapies, adjusting concomitant medications when needed, maintaining awareness of variations in patient characteristics, re-framing emotions effectively, and engaging in effective communication with patients and their families. All will have to be undertaken in conjunction with cognitive and psychological approaches. Seizure freedom is an important and worthwhile goal, and patients and families should be aware that increased therapeutic options available today can make seizure freedom possible even in the context of a challenging a priori prognosis or after previous ASM failures.

Objective: Focal cortical dysplasia (FCD) causes drug‐resistant epilepsy requiring presurgical evaluation. Invasive electroencephalographic (EEG) studies demonstrate that sleep modulates epileptic activity, including interictal epileptiform discharges (IEDs), fast oscillations (FOs) in the beta (14–40 Hz) and gamma (40–80 Hz) frequency bands, and seizures. This study aimed to quantify sleep‐associated changes in IEDs, FOs, and seizures in FCD patients using noninvasive magnetoencephalography (MEG). Methods: Nineteen patients with FCD were prospectively recruited and underwent simultaneous MEG/EEG recordings lasting 89 ± 19 min during daytime sleep. Sleep stages were classified from the EEG. Beamformer source signals were computed from the MEG signal to enhance sensitivity for visual detection of IEDs, FOs in the beta and gamma frequency bands, and seizures. Magnetic source imaging (MSI) was performed using the Maximum Entropy on the Mean (MEM) method, which is particularly sensitive to the spatial extent of sources, enabling accurate localization of epileptic activity. Results: N1 sleep was reached in 17 of 19 patients and N2 sleep in 14 of 19 patients. Compared to wakefulness, sleep recordings showed significantly higher rates of FOs and seizures (both p < .05), whereas IED rates showed nonsignificant trends. Ten patients demonstrated FOs or seizures, and 12 showed IEDs. MSI of IEDs demonstrated consistent accuracy across vigilance states, with median Euclidean distances of 12.74 mm (interquartile range [IQR] = 22.74) in wake and 8.34 mm (IQR = 27.58) in sleep, and no systematic amplitude or spatial extent changes. Wavelet‐MEM enabled frequency‐specific source imaging, with FOs and seizures localizing concordantly to FCD lesions in five of seven and seven of eight patients, respectively. Significance: Daytime sleep MEG recordings are clinically feasible and significantly enhance the detection of seizures (37% of patients) and FOs compared to wakefulness. Sleep protocols enable noninvasive capture of ictal patterns—the gold standard for epileptogenic zone localization—alongside increased FO rates. These findings support incorporating sleep into standard MEG protocols for presurgical epilepsy evaluation.

Objective: Early response to anti‐seizure medication (ASM) is associated with a favorable prognosis in patients with epilepsy. Research is required to confirm existing data on the clinical use of perampanel as first adjunctive therapy in different patient groups and different regions. Here, we present a post hoc analysis of four post‐marketing studies to examine side by side the efficacy and safety of perampanel administered as the first adjunctive ASM across different geographic settings. Methods: Data from patients receiving first adjunctive perampanel were included in this post hoc analysis from Study 412 (NCT02726074, South Korea), Study 410 (NCT03288129, US), Study 509 (NCT04202159, Germany), and Study 501 (NCT04257604, Italy). Assessments included the median percent reduction from baseline/screening in seizure frequency, seizure‐freedom rate, retention rate, and safety. Results: A total of 170 patients who received first adjunctive perampanel were included in this study, including 102 patients from Study 412, 44 from Study 410, 13 from Study 509, and 11 from Study 501. At the latest time point in each study, 50% responder rates were ≥62.5% (range, 62.5%–100.0%) across seizure types, while seizure‐freedom rates ranged from 25.0% to 100.0% (median, 51.6%). Retention rates were ≥61.8% at Month 6 in all studies and ≥54.5% at Month 12 in Studies 410 and 501 where these data were available. Overall, 46.2%–90.9% of patients experienced ≥1 treatment‐emergent adverse event (TEAE) and 13.7%–27.3% discontinued perampanel due to TEAE(s). The most common TEAEs reported across each study were dizziness (≤50.0%), somnolence (≤36.4%), and fatigue (≤13.6%). Significance: The results from this post hoc analysis demonstrated that perampanel as first adjunctive therapy had a good treatment response with no new safety signals observed. Limitations included the post hoc nature of the analysis and the inability to pool data due to study design differences. Overall, these data support the use of perampanel as an early‐line treatment in patients with epilepsy. Plain Language Summary: This analysis looked at a medicine called perampanel and how well it works for people with epilepsy when it was one of the first medicines added to their regular seizure treatment. Data were collected from four separate studies that were done in South Korea, the United States, Germany, and Italy. Most patients had fewer seizures across all four studies after 6 months of treatment. The most common side effects reported in patients included dizziness and sleepiness. Perampanel worked well when used early during treatment, and most people were able to keep taking perampanel without significant difficulties.

Objective: The PERPRISE study (Study 509; NCT04202159) was a prospective, observational, non‐interventional study in a real‐world setting in Germany. This study was conducted to evaluate the effectiveness of perampanel as the only adjunctive treatment for 12 months in patients aged ≥18 years with focal to bilateral tonic–clonic seizures (FBTCS) or generalized tonic–clonic seizures (GTCS) in clinical practice. Methods: Adult patients with FBTCS or GTCS received perampanel as an adjunctive therapy to anti‐seizure medication (ASM) monotherapy (add‐on therapy) or as a substitute for one ASM in dual therapy (substitution therapy) per the approved indication. The primary endpoint was the 12‐month retention rate of perampanel; the secondary endpoints were the 6‐month retention rate, seizure freedom for FBTCS or GTCS at 12 months, and safety and tolerability. Exploratory endpoints included efficacy assessments by seizure type at 6 and 12 months and patient‐reported outcomes. Results: Of the 185 patients enrolled in the study, 183 patients were included in the full analysis set (add‐on, 86 patients; substitution, 96 patients; missing, 1 patient). The 12‐month retention rate was 66.7% (add‐on, 67.4%; substitution, 66.7%); the 6‐month retention rate was 80.3% (add‐on, 82.6%; substitution, 78.1%). At 12 months, the seizure‐freedom rate for FBTCS or GTCS was 42.3% (add‐on, 51.7%; substitution, 35.1%). Treatment‐emergent adverse events (TEAEs) occurred in 44.0% of patients; 6.0% of patients reported serious TEAEs, and 16.5% of patients withdrew from the study due to TEAEs. Treatment with perampanel did not adversely affect cognitive function in patients with FBTCS or GTCS, and improvements in quality of life were reported by patients at both 6 and 12 months following perampanel initiation. Significance: Findings from the PERPRISE study suggest that perampanel as an only adjunctive therapy is associated with favorable retention rates and good tolerability in patients with FBTCS or GTCS in a real‐world clinical setting in Germany. Plain Language Summary: Patients with epilepsy often take multiple treatments to control their seizures. It is important to look at how well they work in everyday life. This study looked at adult patients in Germany taking perampanel added to one other epilepsy treatment. After 1 year, 58 of 137 patients suffering from the most severe type of seizure were free of them. Side effects occurred in 80 patients (most commonly dizziness, fatigue, and nausea) and caused 30 of them to withdraw from treatment. Perampanel was effective and did not seem to negatively affect patients' thinking ability or quality of life.