Perampanel for Treatment of People with a Range of Epilepsy Aetiologies in Clinical Practice: Evidence from the PERMIT Extension Study.

INTRODUCTION: It is important to assess the effectiveness of an antiseizure medication in treating different epilepsy aetiologies to optimise individualised therapeutic approaches. Data from the PERaMpanel pooled analysIs of effecTiveness and tolerability (PERMIT) Extension study were used to assess the effectiveness and safety/tolerability of perampanel (PER) when used to treat individuals with a range of epilepsy aetiologies in clinical practice. METHODS: A post hoc analysis was conducted of PERMIT Extension data from individuals with a known aetiology. Retention was assessed after 3, 6 and 12 months. Effectiveness was assessed after 3, 6 and 12 months and at the last visit (last observation carried forward). Effectiveness assessments included responder rate (≥ 50% seizure frequency reduction) and seizure freedom rate (no seizures since at least the prior visit). Safety/tolerability was assessed by evaluating adverse events (AEs) and AEs leading to discontinuation. RESULTS: PERMIT Extension included 1945 individuals with structural aetiology, 1012 with genetic aetiology, 93 with an infectious aetiology, and 26 with an immune aetiology. Retention rates at 12 months were 61.1% (structural), 65.9% (genetic), 56.8% (infectious) and 56.5% (immune). At the last visit, responder rates (total seizures) were 43.3% (structural), 68.3% (genetic), 37.0% (infectious) and 20.0% (immune), and corresponding seizure freedom rates were 15.8%, 46.5%, 11.1% and 5.0%, respectively. AE incidence rates were 58.0% (structural), 46.5% (genetic), 51.1% (infectious) and 65.0% (immune), and corresponding rates of discontinuation due to AEs over 12 months were 18.9%, 16.4%, 18.5% and 21.7%, respectively. The types of AEs reported were generally consistent across aetiology subgroups, with no idiosyncratic AEs emerging. CONCLUSION: Although PER was effective and generally well tolerated when used to treat individuals with a range of epilepsy aetiologies in clinical practice, variability in its effectiveness and tolerability across the subgroups indicates that PER may be particularly useful for individuals with specific epilepsy aetiologies.

Body transfer illusions in the schizophrenia spectrum: a systematic review.

Schizophrenia has been viewed as a disorder of the self. Accordingly, the question arises if and how senses of ownership and agency are impaired in schizophrenia. To address this question, several body transfer illusions (BTIs) have been investigated in schizophrenia patients and other schizophrenia spectrum (SCZ-S) populations. The objective of the study was to systematically review the current evidence from BTIs in the SCZ-S. A systematic literature search in PubMed and CENTRAL (search date: February 12, 2022) was conducted on BTI studies carried out in SCZ-S populations. Studies were included if they were published in English after peer review, reported original research data, related to the SCZ-S, and used a BTI as its study method. Conference papers, study protocols, and reviews were excluded. For each included BTI study, various study characteristics and outcomes were retrieved, and a risk-of-bias score was calculated based on six study quality criteria. K = 40 studies were identified, of which k = 20 studies met the eligibility criteria. For BTI paradigms using visuotactile stimulation, most studies found elevated sense of ownership ratings in SCZ-S populations compared to healthy controls (HC). Implicit illusion measures (e.g., proprioceptive drift), in turn, did not generally indicate elevated embodiment levels in SCZ-S populations. Likewise, no consistent group differences emerged between SCZ-S populations and HC with respect to BTI paradigms using visuomotor stimulation. Furthermore, BTI vividness was found to correlate significantly with core symptoms of schizophrenia and various subclinical characteristics related to the SCZ-S. In line with the self-disturbance hypothesis, SCZ-S populations appear to be affected by aberrations in bodily self-awareness. Review registration: PROSPERO (identifier: CRD42022287960).

Atrioventricular Conduction in Mesial Temporal Lobe Seizures.

Purpose: Asymmetric cerebral representation of autonomic function could help to stratify cardiac complications in people with epilepsy, as some seizures are associated with potentially deleterious arrhythmias including bradycardia and atrioventricular (AV) conduction block. We investigated seizure-related changes in AV conduction and ascertained whether these alterations depend on the hemisphere in mesial temporal lobe epilepsy (mTLE). Methods: EEG and ECG data of people with pharmacoresistant mTLE undergoing pre-surgical video-EEG telemetry with seizures independently arising from both hippocampi, as determined by intracranial depths electrodes were reviewed. RR and PR intervals were measured using one-lead ECG. Statistics were done with paired student's t-tests and linear regression analysis. Data are given as mean ± SD. Results: Fifty-six seizures of 14 patients (5 men, age 34.7 ± 9.8 years) were included (2 seizures per hemisphere and patient). There were no differences of absolute PR intervals and HR before and during unilateral ictal activity between left- and right-sided hippocampal seizures. Peri-ictal modulation of AV conduction, however, appeared greater with left-sided seizures, as the slope of the PR/HR correlations was significantly steeper with seizures originating in the left hippocampus. PR lengthening >200 ms or full block did not occur in any seizure. Conclusions: Our data show that on average, PR intervals shortens with mesial temporal lobe seizures with more prominent effects in seizures with left-sided onset, supporting the notion of lateralized cerebral control of cardiac function. The clinical relevance of this subtle finding is unclear but may indicate a lateralized susceptibility to seizure-related AV node dysfunction in mTLE.

Predictors of focal to bilateral tonic-clonic seizures during long-term video-EEG monitoring.

OBJECTIVE: To determine predictors of focal to bilateral tonic-clonic seizures (FBTCS) during video-electroencephalography (EEG) monitoring (VEM). METHODS: All adult patients undergoing presurgical VEM from 2014 to 2015 in the department of epileptology were eligible (N = 229). Those with refractory focal epilepsy and epileptic seizures recorded during VEM were analyzed (N = 188, Group 1). To assess the effects of antiepileptic drug (AED) taper, the total AED load was calculated as the sum of the ratios of prescribed daily dose and defined daily dose of all AEDs per VEM day and was correlated with the occurrence of focal seizures without bilateral tonic-clonic seizures (FwoBTCS) and FBTCS. To validate the findings, data of patients undergoing VEM in 2004 and 2005 (Group 2, eligible N = 243, analyzed N = 203) were also investigated. RESULTS: In Group 1, 53 patients had FBTCS and 135 patients had exclusively FwoBTCS during VEM. Reduced AED load at seizure onset was the most important modifiable risk factor for FBTCS (receiver-operating characteristic [ROC]: area under the curve [AUC] = 0.78). Furthermore, the risk of FBTCS varied with the history and frequency of FBTCS prior to VEM. For instance, patients had a 50% risk of FBTCS by reducing the AED load to ~20% when no information about history of FBTCS was taken into account, to ~30% when a positive history of FBTCS was taken into account, and to ~50% when a high frequency of FBTCS prior to VEM was taken into account. These findings were largely replicated in Group 2 (59 patients with FBTCS and 144 exclusively with FwoBTCS). SIGNIFICANCE: The risk of FTBCS during VEM depends on the history and frequency of FTBCS prior to VEM and is particularly associated with the extent of AED reduction. Our data underscore the need for appropriate tapering regimens in VEM units.

Perampanel in routine clinical use across Europe: Pooled, multicenter, observational data.

OBJECTIVE: To pool observational data on the routine use of perampanel to obtain information on real-world outcomes and data in populations typically underrepresented in clinical trials. METHODS: Individual-level data of people with epilepsy treated with perampanel at 45 European centers were merged into a single dataset. Prespecified outcomes were: 1-year retention rate, 1-year seizure freedom rate (duration ≥6 months), and incidence of treatment-emergent adverse events (TEAEs). In addition, relationships were explored with logistic regression analyses. RESULTS: The full analysis set comprised 2396 people: 95% had focal seizures; median epilepsy duration was 27 years; median number of concomitant antiepileptic drugs (AEDs) was 2; and median prior AEDs was 6. One-year retention rate was 48% (1117/2332; 95% confidence interval [CI] 46-50%), and 1-year seizure-free rate (≥6-month duration) was 9.2% (74/803; 95% CI 7-11%). Median treatment duration was 11.3 months (1832 patient-years); median dose was 8 mg. In 388 individuals with available data at 3, 6, and 12 months, responder rates were 42%, 46%, and 39%, respectively. During the first year, TEAEs were reported in 68% of participants (1317/1497; 95% CI 66-70%). Logistic regression found higher age at perampanel initiation was associated with higher seizure-free rate, and higher number of prior AEDs with lower seizure-free rate and lower rates of somatic TEAEs. In 135 individuals aged ≥65 years, 1-year retention rate was 48% and seizure-free rate was 28%. SIGNIFICANCE: Across a large, treatment-resistant population, add-on perampanel was retained for ≥1 year by 48% of individuals, and 9% were seizure-free for ≥6 months. TEAEs were in line with previous reports in routine clinical use, and less frequent than in the clinical trial setting. No new or unexpected TEAEs were seen. Despite the limitations of observational studies, our data indicate that some individuals may derive a marked benefit from the use of perampanel.

European trends in epilepsy surgery.

OBJECTIVE: Resective surgery is effective in treating drug-resistant focal epilepsy, but it remains unclear whether improved diagnostics influence postsurgical outcomes. Here, we compared practice and outcomes over 2 periods 15 years apart. METHODS: Sixteen European centers retrospectively identified 2 cohorts of children and adults who underwent epilepsy surgery in the period of 1997 to 1998 (n = 562) or 2012 to 2013 (n = 736). Data collected included patient (sex, age) and disease (duration, localization and diagnosis) characteristics, type of surgery, histopathology, Engel postsurgical outcome, and complications, as well as imaging and electrophysiologic tests performed for each case. Postsurgical outcome predictors were included in a multivariate logistic regression to assess the strength of date of surgery as an independent predictor. RESULTS: Over time, the number of operated cases per center increased from a median of 31 to 50 per 2-year period (p = 0.02). Mean disease duration at surgery decreased by 5.2 years (p < 0.001). Overall seizure freedom (Engel class 1) increased from 66.7% to 70.9% (adjusted p = 0.04), despite an increase in complex surgeries (extratemporal and/or MRI negative). Surgeries performed during the later period were 1.34 times (adjusted odds ratio; 95% confidence interval 1.02-1.77) more likely to yield a favorable outcome (Engel class I) than earlier surgeries, and improvement was more marked in extratemporal and MRI-negative temporal epilepsy. The rate of persistent neurologic complications remained stable (4.6%-5.3%, p = 0.7). CONCLUSION: Improvements in European epilepsy surgery over time are modest but significant, including higher surgical volume, shorter disease duration, and improved postsurgical seizure outcomes. Early referral for evaluation is required to continue on this encouraging trend.