This analysis aimed to evaluate patient-related outcomes for health-related quality of life (HRQoL) and cognitive performance in patients (≥ 16 years) with focal-onset seizures (FOS), with/without focal to bilateral tonic–clonic seizures, after initiating adjunctive brivaracetam (BRV) in routine clinical practice. A 12-month, prospective, real-world, noninterventional study in nine European countries (EP0077/NCT02687711) was performed. BRV was prescribed per clinical practice and the European Summary of Product Characteristics. The outcomes evaluated were the Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P), the Clinical and the Patient’s Global Impression of Change (CGIC and PGIC, respectively), and EpiTrack®. EpiTrack® scores were categorized into cognitive performance categories (excellent: ≥ 39 points; average: 32–38 points; mildly impaired: 29–31 points; significantly impaired: ≤ 28 points). The change in EpiTrack® score was evaluated [improvement: increase in score of ≥ 4 points; no change: change in score of − 2 to 3 points (inclusive); worsening: change in score of at least − 3 points]. Full Analysis Set: 541 patients. 46.6

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.

Efficacy/tolerability of adjunctive brivaracetam (BRV) for focal-onset seizures (FOS) in patients aged ≥ 16 years was established in randomized controlled trials. This study aimed to evaluate the effectiveness of adjunctive BRV in patients (≥ 16 years) with FOS with/without focal to bilateral tonic–clonic seizures in daily clinical practice. A 12-month, prospective, real-world, noninterventional study in nine European countries (EP0077/NCT02687711). BRV was prescribed per clinical practice and European Summary of Product Characteristics. Eligible patients had never received BRV before inclusion. Treating physicians made the decision to prescribe BRV, independently of study participation. Primary effectiveness outcome: BRV retention rate at 12 months; secondary effectiveness outcomes: 50

OBJECTIVE:Investigate real-world outcomes in drug-resistant epilepsy (DRE) patients treated with cenobamate as adjunctive treatment to other antiseizure medications (ASMs) within the Early Access Programs (EAP) in Germany, France, and the United Kingdom. METHODS:DRE adults with uncontrolled focal-onset seizures were included from 19 hospitals participating in the EAP in this retrospective study. Data were sourced from clinical records. Participants were evaluated at baseline, 1 months, and 3 months from cenobamate start, and 3, 6, and 12 months after maintenance. The primary effectiveness endpoint was the 50% responder rate, defined as the reduction in seizure frequency ≥50%. RESULTS:Data were collected from 298 patients who received at least one dose of cenobamate; efficacy was evaluated on 216 patients with seizure data available. At baseline, the median epilepsy duration was 22.2 years, and 41.9% of patients had previous epilepsy surgery, including vagus nerve stimulation, with a median of nine previously failed ASMs. The median number of seizures/month was 8.8. After 3 months of maintenance, the 50% responder rate (primary endpoint) was 49.3%; the median percentage seizure reduction from baseline was 49.1%. A total of 100%, ≥90%, and ≥75% seizures reduction were reported in 13.6%, 20.0%, and 33.6% of patients, respectively. Both the responder rate and the median percentage seizure reduction steadily increased during the observation period. At 6-month maintenance, the seizure-free rate was 24.2%. The retention rate assessed by Kaplan-Meier decreased from 96.6% at 1-month cenobamate start to 69.7% at 12-month maintenance. Adverse Drug Reactions (ADRs) to cenobamate occurred in 30.9% of patients, with asthenia, dizziness, and somnolence being the most frequent; the majority were mild-to-moderate and resolved during the observation period; three patients (1.0%) experienced a total of seven serious ADRs, all during titration. SIGNIFICANCE:In this study, cenobamate demonstrated to be an effective option for people with uncontrolled epilepsy even after multiple failed ASMs or failure of epilepsy surgery. PLAIN LANGUAGE SUMMARY:This study involved patients with drug-resistant epilepsy, who had continued seizures despite using at least two antiseizure medications (ASMs). Patients received cenobamate (Ontozry) as epilepsy treatment during the Early Access Program (EAP) in France, Germany, and the United Kingdom. An EAP allows patients to receive promising new drugs under clinical supervision before they are commercially available. After 6 months from cenobamate start, 49.3% of patients had their seizures cut by half or more, and 13.6% became seizure-free. A total of 30.9% of patients had an undesirable reaction to cenobamate, mostly mild-to-moderate and resolved; the most frequent were asthenia, dizziness, and somnolence.

Anfallssupprimierende Medikamente (ASM) werden bei erwachsenen Patientinnen und Patienten in der Regel über lange Zeit eingesetzt. Je nach pharmakokinetischem Profil sind dabei als Begleiterscheinung mannigfaltige Auswirkungen auf den Organismus und die Wirksamkeit und Verträglichkeit anderer Medikamente denkbar, die auch zu typischen Laborveränderungen führen können. Darauf bezogen ist es essenziell, vor Beginn mit einem ASM der Wahl durch geeignete Labordiagnostik Risikofaktoren zu identifizieren, die unter Therapie womöglich zu gesundheitsgefährdenden Änderungen führen können und unter Umständen auch die ASM-Auswahl vor Therapiebeginn beeinflussen. Die hier vorgelegte Übersicht soll dabei helfen, solche Konstellationen kennenzulernen und Ratschläge zu erteilen, welche Parameter wann bestimmt werden sollten. Eine zweite wichtige Säule der epileptologischen Labordiagnostik betrifft die Serumkonzentrationen von ASM. Deren generelle Wertigkeit einschließlich des sog. therapeutischen Bereichs wurde früher überschätzt. Heute wissen wir, dass Serumkonzentrationen von ASM nur bei geeigneten klinischen Fragestellungen und nicht routinemäßig bestimmt werden sollten. Wir bevorzugen heute die Definition eines individuellen und nicht pauschalen Referenzbereichs und schlagen sogar, gestützt auf die jüngsten Daten zu neu eingeführten ASM, vor, diesen Referenzbereich eher als typisch oder erwartbar zu bezeichnen, ohne dass unmittelbare klinische Schritte ohne klinisches Korrelat vorgenommen werden sollten.

AbstractObjectiveIn Europe, cenobamate has been approved for use as an adjunctive therapy in adult patients with epilepsy (PWE) with focal‐onset seizures (FOS) who have not responded satisfactorily to treatment with at least two antiseizure medications (ASMs). Pivotal trials and real‐world observational studies have demonstrated a high efficacy of cenobamate, even in very difficult‐to‐treat epilepsies. Our aim was to investigate the efficacy of add‐on cenobamate in adult PWE who were prospectively monitored. We compared these results with those previously obtained for add‐on lacosamide, perampanel, and brivaracetam therapy.MethodsPatients were enrolled from the CENKORK study, which is a prospective, non‐interventional, open‐label, monocenter cohort study of adult PWE experiencing FOS. The titration of cenobamate was performed according to the guidelines outlined in the summary of product characteristics. The primary outcome measure was the retention rate at 6 months and 1 year. In addition, we assessed seizure‐free rates, the proportion of patients achieving at least a 50% seizure reduction, adverse events, and the reasons for treatment discontinuation. These outcome measures were compared with historical controls treated with adjunctive lacosamide, perampanel, or brivaracetam at our center.ResultsBetween June 2021 and 2022, 172 PWE with ongoing FOS were included. 22 cases were lost to follow‐up, leaving 150 cases for the 1‐year assessment. The retention rates at 6 months and 1 year were 88.7% and 80%, respectively. Seizure freedom was achieved in 14% of patients at both the 6‐month and 1‐year marks, while the ≥50% responder rates were 50% and 61%, respectively. The 6‐month retention rate was significantly higher in cenobamate than in other ASMs (p < 0.001 for each comparator). Adverse events were significantly more common with perampanel (p < 0.001).SignificanceAdd‐on cenobamate proved to be particularly efficacious compared to our experience with other recently introduced ASMs.Plain Language SummaryThis observational study was carried out in 172 adult patients with difficult‐to‐treat epilepsy who were treated with adjunctive cenobamate. After 1 year, the data of 150 patients could be analyzed. Seizure freedom, in the preceding 3 months, was achieved in 14%. The rate of PWE continuing cenobamate was 80%. In our hands, cenobamate showed promising efficacy and tolerability even when compared to other recently introduced antiseizure medications.

In recent years, it has become somewhat fashionable to perform and publish so-called "real-world" studies. Usually, these are non-interventional observational and uncontrolled monocenter or multicenter studies dealing with the efficiency of recently introduced new generation antiseizure medications (ASMs) after labeling. But, is this real world really reflecting what we should call the real epilepsy world of 2024? An original article of Dedeken et al. published in this issue of the European Journal of Neurology [1] investigated a sociologically most important real-world question when 100 women with epilepsy (WWE) were interviewed in a cross-sectional study performed at one hospital in Umuhoza, Rwanda. Of 100 WWE (age range 18–67 years), 48 had been pregnant, most of them (n = 39) after the initial diagnosis of epilepsy. Due to the limited availability of ASM in Rwanda, first and second generation ASMs including valproic acid (VPA) were more widely used than would be the case for WWE of childbearing age in European countries. In fact, 46% of the WWE of reproductive age were on VPA. Interestingly, no congenital abnormalities were reported. Thirty-nine WWE with previous pregnancies reported 91 pregnancies with a rate of early abortions of 14%. Although only two WWE got advice prior to pregnancy and many pregnancies were carried out under the influence of VPA, no major malformations were reported. This certainly does not suggest that the teratogenic risk of valproate was negligible in the investigated group. In fact, the numbers of patients were too low to identify malformations with a reasonable probability. Another finding was the rather high frequency of seizure increases during pregnancy of 36% which supported the conclusion of unsatisfactory information since most of the seizure increases resulted from poor ASM adherence. The major limitation of this important work is the rather low number of patients and the monocenter study design. One has to suggest that a nationwide registry (which is probably a non-realistic goal) would reveal even more concerning outcome data than the pilot study published in this issue. Still, the most important studies in clinical medicine are those that finally confirm with the help of scientific methods what everybody was convinced about already. One famous example is the paper of Patrick Kwan and Martin Brodie back in 2000 [2] or the SANAD trials concerning the efficacy of VPA in generalized and unclassified epilepsies [3, 4]. Every experienced epileptologist knew that drug-resistant epilepsies are easy to identify early during ASM treatment and that VPA is extremely effective in generalized epilepsies but these studies finally confirmed that undoubtedly. The findings of the paper of Dedeken et al. [1] were predictable which in turn confirms its quality. Although the willingness to participate of both the investigated WWE and the participating hospital reflect a positive selection bias, still the results show the previously expected lack of education and knowledge that would help to improve the situation of WWE in subsaharan countries. Right now, we have to realize globally how dangerous a lack of education is. This lack of knowledge is certainly responsible for the extremely high rates of discrimination and stigma that are unveiled by the study of Dedeken et al. [1]. Finally, there are some economic facts that are difficult to change. The fancy new ASMs the so-called real-world studies deal with are not available in countries like Rwanda and will probably not be available in the next few years or even decades. Thus, so many people with epilepsy are not able to participate in the unquestionable progress epilepsy therapy has made recently. This is the ultimate tragedy this real real-world study confirms again. Bernhard Steinhoff: Conceptualization; writing – original draft. Advisory and consulting honoraria: Angelini, Jazz/GW Pharmaceuticals, Precisis, Roche Diagnostics, UCB. Speaker's honoraria: Al Jazeera, Angelini, Bial, Desitin, Eisai, Jazz/GW Pharmaceuticals, Medscape, Tabuk, Teva, UCB, Zogenix. Research support: Eisai, European Union, Jannsen-Cilag, Jazz/GW Pharmaceuticals, SK Life Sciences, UCB, Zogenix. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

In general, the prognosis of epilepsy in adults with a drug-resistant course for many years is poor if epilepsy surgery is not considered as a curative procedure. We tend to understand unusual positive courses to be a result of the therapeutic interventions, which may be the case but remains unproven. The aim of this article is to emphasize that the importance of therapeutic strategies should not be overemphasized by reporting three cases of patients who have been followed and advised by myself for decades, have almost never benefitted from my therapeutic interventions, have suffered from highly active and drug-resistant epilepsies, and, finally, who became and remained seizure free without any apparently beneficial supportive therapeutic action.

Zusammenfassung Psychogene nicht-epileptische Anfälle (PNEA) (synonym: funktionelle/dissoziative Anfälle) sind eine wichtige Differenzialdiagnose zu epileptischen Anfällen und keine seltene Erkrankung. Die Versorgung von Patientinnen und Patienten mit PNEA erfolgt in spezialisierten Epilepsiezentren, die jederzeit Anfälle der Betroffenen überwachen und einschätzen können. Diese Zentren verfügen über ein spezialisiertes Behandlungskonzept, das die Kommission „Psychosomatische Epileptologie“ der Deutschen Gesellschaft für Epileptologie erarbeitet hat und das ständig bearbeitet und evaluiert wird. Seit einiger Zeit wird diese Versorgungsform durch den Medizinischen Dienst infrage gestellt. Die Arbeitsgemeinschaft Diakonischer Epilepsiezentren fasst deshalb in einem Positionspapier die Argumente zusammen, die für eine Fortführung der etablierten und wissenschaftlich fundierten Versorgung mit entsprechender Kostenübernahme durch die Kostenträger sprechen.

Abstract Objective To report the interim results of the PERPRISE study (Study 509; NCT04202159), which is evaluating perampanel as the only adjunctive anti‐seizure medication (ASM) in adults with focal to bilateral tonic–clonic seizures (FBTCS) or primary generalized tonic–clonic seizures (GTCS). Methods PERPRISE is an ongoing 12‐month multicenter, prospective, observational, non‐interventional study of perampanel in a real‐world setting in Germany. Patients are aged ≥18 years with FBTCS or GTCS due to focal or idiopathic generalized epilepsy. Perampanel, as an adjunctive therapy to ASM monotherapy (‘add‐on therapy’) or as a substitute for one ASM in dual therapy (‘substitution therapy’), is prescribed in line with its SmPC. The Interim Analysis Set comprises the first 100 patients who received ≥1 dose of perampanel and attended or discontinued prior to the ~6‐month visit. Interim endpoints include retention rate, measures of effects on seizure frequency, and treatment‐emergent adverse events (TEAEs). Results One hundred patients were included in the Interim Analysis Set (add‐on, n = 43 [43.0%]; substitution, n = 55 [55.0%]; unknown, n = 2). The 6‐month retention rate was 78.0% (add‐on, 83.7%; substitution, 72.7%). For the overall population with GTCS and/or FBTCS, seizure‐freedom rate at 6 months was 58.8% (add‐on, 72.2%; substitution, 47.9%) and 50% responder rate at 6 months was 82.6% (add‐on, 89.2%; substitution, 76.6%). Retention rates and seizure outcomes were better with perampanel as an early‐line treatment than as a late‐line treatment. TEAEs were reported by 48 patients (48.0%), most commonly dizziness (n = 9), fatigue (n = 7), and irritability (n = 7). Sixteen patients (16.0%) withdrew from perampanel treatment due to TEAEs. Significance The interim analysis of PERPRISE offers insight into the real‐world use of perampanel in Germany, including for the first time, clinical practice data from patients with GTCS and switching ASMs within a dual therapy. Further data from PERPRISE will be of value to inform clinical decision‐making in this patient cohort. Plain Language Summary Patients with epilepsy often take more than one medication for seizure control. This 12month study looked at patients in Germany receiving perampanel as only add‐on medication. The interim analysis shows, that at 6 months, over 70% of the 100 patients continued to use perampanel; 59% experienced no seizures during treatment with perampanel, and in 83%, seizure frequency was reduced by half. Side effects occurred in 48% of patients (most commonly dizziness, fatigue, and irritability) and caused 16% to withdraw from the study. Overall, perampanel was a suitable as only add‐on medication for patients with epilepsy.

PurposeBrivaracetam is often used as an alternative to levetiracetam in patients with epilepsy (PWE) encountering efficacy issues or adverse events with levetiracetam. This study evaluated the psychological status of PWE who were switched from levetiracetam to brivaracetam due to psychiatric tolerability concerns in comparison to those who remained on levetiracetam.MethodsWe used various psychological assessments including the Symptom Checklist SCL-90-R, the Beck Depression Inventory-II, and the adverse event profile. Eligible participants completed the questionnaires at baseline and again 8 days later. Psychological changes were assessed using standard statistical methods to show differences between a group that immediately switched from levetiracetam to brivaracetam and another group with unchanged levetiracetam.ResultsBetween May 2020 and May 2021, 63 patients participated in the study, of whom 34 switched from levetiracetam to brivaracetam. At baseline, participants who switched to brivaracetam had fewer antiseizure medications but experienced more monthly seizures. Baseline scores for anxiety (p=0.020) and psychoticism (p=0.046) on SCL-90-R in PWE switched to brivaracetam were higher than in the remaining group. In the subsequent assessment, all psychological scores were reduced and were no longer significantly different between both groups. Using multiple regression, initial treatment with a single antiseizure medication and male gender emerged as predictors of psychological improvement.ConclusionOur study found no increased risk of adverse events or psychiatric symptoms after switching from levetiracetam to brivaracetam. Though statistically non-significant, a trend towards improved psychiatric outcomes in the switch group warrants further investigation in future trials with stronger designs for enhanced statistical power.

Erfreulicherweise wurden im vergangenen Jahr nach langer Wartezeit die Leitlinien der Deutschen Gesellschaften für Neurologie und Epileptologie „Erster epileptischer Anfall und Epilepsien im Erwachsenenalter“ publiziert. Diese sorgfältig im Konsensverfahren erarbeiteten Ratschläge decken überwiegend die aktuelle Literatur und Praxisevidenz ab. Konsensbasierte Leitlinien haben den methodischen Nachteil, dass sie sich zwar nach der Evidenz richten, letztlich die Empfehlungen aber im Konsens gegeben werden, der in Würdigung der Sachlage und der Erfahrung der Experten richtig sein kann. Ein weiteres Problem von Leitlinien besteht darin, dass sie bei mäßiger Evidenzlage in der Literatur auch nur vage Empfehlungen ableiten kann, die in der Praxis wenig hilfreich sind. Die anfallssuppressive Pharmakotherapie stellt trotz aller Neuerungen auf den Gebieten der Epilepsiechirurgie, Neurostimulation und Diätbehandlung nach wie vor den Goldstandard der Epilepsietherapie dar. Neue Anfallssuppressiva und v. a. hochrangige Studien zur Sicherheit und Verträglichkeit bereits vorhandener Medikamente haben die Möglichkeiten zu einer verbesserten Pharmakotherapie deutlich verbessert. Die hier vorgelegte Übersichtsarbeit fasst den aktuellen Stand der anfallssuppressiven Pharmakotherapie zusammen und kommentiert die sich hieraus ergebenden Praxisempfehlungen zum „state of the art“ in Ergänzung und im Lichte der Leitlinien.