Objective: In 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.Methods: Patients 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.Results: Between 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).Significance: Add‐on cenobamate proved to be particularly efficacious compared to our experience with other recently introduced ASMs.Plain Language Summary: This 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.

After mild traumatic brain injury (mTBI), patients have increased long-term mortality rates, persisting even beyond 13 years. Pathophysiology is unclear. Yet, central autonomic network dysfunction may contribute to cardiovascular dysregulation and increased mortality. Purely parasympathetic cardiovascular challenge by eyeball pressure stimulation (EP), might unveil subtle autonomic dysfunction in post-mTBI patients. We investigated whether mild EP shows autonomic cardiovascular dysregulation in post-mTBI patients. In 24 patients (34 ± 12 years; 5–86 months post-injury) and 27 controls (30 ± 11 years), we monitored respiration, electrocardiographic RR intervals (RRI), systolic and diastolic blood pressure (BPsys, BPdia) before and during 2 min of 30 mm Hg EP, applied by an ophthalmologic ocular pressure device (Okulopressor ^® ). We calculated spectral powers of RRI in the mainly sympathetic low frequency (LF; 0.04–0.15 Hz) and parasympathetic high frequency (HF; 0.15–0.5 Hz) ranges, and of BP in the sympathetic LF range, the RRI-LF/HF ratio as index of the sympathetic–parasympathetic balance, normalized (nu) RRI-LF- and HF-powers, and LF- and HF-powers after natural logarithmic transformation (ln). Parameters before and during EP in post-mTBI patients and controls were compared by repeated measurement analysis of variance with post hoc analysis ( p < 0.05). During EP, BPsys and BPdia increased in post-mTBI patients. Only in controls but not in post-mTBI patients, EP increased RRI-HFnu-powers and decreased RRI-LF-powers, RRI-LFnu-powers, BPsys-LF-powers, BPsys-lnLF-powers and BPdia-lnLF-powers. RRI-LF/HF ratios slightly increased in post-mTBI patients but slightly decreased in controls upon EP. Even with only mild EP, our controls showed normal EP responses and shifted sympathetic–parasympathetic balance towards parasympathetic predominance. In contrast, our post-mTBI patients could not increase parasympathetic heart rate modulation but increased BP upon EP, indicating a paradox sympathetic activation. The findings support the hypothesis that central autonomic dysfunction might contribute to an increased cardiovascular risk, even years after mTBI.

In multiple sclerosis (MS) patients, Fingolimod may induce prolonged heart-rate slowing which might be caused by MS-related central autonomic lesions. To evaluate whether MS-patients with prolonged heart-rate slowing (> six hours) upon Fingolimod show cardiovascular-autonomic dysfunction before Fingolimod-initiation. Before Fingolimod-initiation, we recorded electrocardiographic RR-intervals (RRIs) and blood-pressure (BP) at rest, upon standing-up, during metronomic deep-breathing, Valsalva-maneuver, and “sustained-handgrip-exercise” in 21 patients with relapsing-remitting MS, and 20 healthy persons. We calculated sympathetic and parasympathetic cardiovascular parameters, including low- (LF) and high-frequency (HF) powers of RRI- and BP-oscillations, RRI-RMSSDs, RRI- and BP-changes during handgrip-exercise, parasympathetic heart-rate-slowing in relation to BP-overshoot after Valsalva-strain-release. We compared values of healthy persons and patients with and without prolonged heart-rate slowing after Fingolimod-initiation (ANOVA; significance: p<0.05). Upon Fingolimod-initiation, 7/21 patients had prolonged HR-slowing. Before Fingolimod, these patients had higher resting BP and higher BP increase during handgrip-exercise than had the other participants (p<0.05). They did not reduce parasympathetic HR-parameters upon standing-up. After Valsalva-strain-release, their parasympathetic HR-slowing in response to BP-overshoot was four times higher than in the other participants (p<0.05). The autonomic cardiovascular dysfunction in MS-patients with delayed HR-re-acceleration upon Fingolimod-initiation suggests that MS-related central autonomic lesions compromise HR-re-acceleration upon Fingolimod. German Clinical Trial Register DRKS00004548 http://drks-neu.uniklinik-freiburg.de/drks_web/setLocale_EN.do