Efficacy and safety of perampanel in patients with drug-resistant partial seizures after conversion from double-blind placebo to open-label perampanel

SummaryObjectiveTo evaluate the efficacy and safety of perampanel in patients with drug-resistant partial seizures after the conversion from double-blind placebo in three phase III studies to open-label perampanel, and to assess the impact of perampanel titration rates through a comparison of weekly vs biweekly dose increases.MethodsPatients who completed the three multinational, double-blind, placebo-controlled, phase III core studies (studies 304, 305, or 306) were eligible to enroll in the extension study (study 307). Patients completing the double-blind treatment (6-week titration, 13-week maintenance) with placebo (DB-PBO) or perampanel (DB-PER) began the extension study with a 16-week blinded conversion period, during which DB-PBO patients were switched to perampanel. Doses were titrated in 2-mg increments (biweekly) to an individualized maximum tolerated dose of perampanel (up to 12mg/day). Patients then entered a planned, open-label treatment period.ResultsPerampanel treatment during the extension study reduced total seizure frequency/28 days relative to the double-blind prerandomization baseline regardless of prior perampanel or placebo treatment in the core studies. In the DB-PBO patients, median percent reductions in seizure frequency at the end of the double-blind period, at the end of the conversion period, and at Weeks 40–52 in the open-label maintenance period were 18.6%, 44.3%, and 55.0%, respectively. Seizure control was also improved in the DB-PER patients during the extension period compared to the end of the double-blind period. Responder rates were similar between the 2 patient groups at the end of the conversion period. Perampanel was well tolerated, with the most common treatment-emergent adverse events being dizziness, somnolence, weight increase, irritability, fatigue, and headache. For those patients randomized to the 12mg group (DB-PER 12mg), 78.4% reached the daily dose of 10 or 12mg by the end of the 6-week titration period of the double-blind phase. By the end of the 16-week conversion period of the extension study, 64.0% of DB-PBO patients reached the daily dose of 10 or 12mg. Seizure frequency reduction was greater after the first 13-week maintenance period of the extension study in the DB-PBO group compared to patients assigned to DB-PER 12mg during the 13-week maintenance period of the double-blind study.ConclusionPatients who received placebo in the phase III core DB studies and transitioned to perampanel in the open-label extension study (DB-PBO) achieved seizure control at the end of the conversion period similar to that of patients who had been previously exposed to perampanel (DB-PER) as well as comparable safety outcomes. Patients who received perampanel during the core studies and continued with treatment during the extension study (DB-PER) also showed sustained improvements in seizure control with long-term exposure to perampanel

Effect of continuous positive airway pressure treatment on seizure control in patients with obstructive sleep apnea and epilepsy.

In patients with epilepsy, improvement in seizure control with treatment of coexisting obstructive sleep apnea (OSA) has been reported, but there is lack of data on the effect of continuous positive airway pressure (CPAP) compliance on seizure control in these patients. We examined the variability in seizure frequency in patients who were CPAP compliant and those who were not CPAP compliant. We undertook a retrospective review of clinical and polysomnographic data of adult patients with OSA and epilepsy seen at the Boston University Medical Center Epilepsy and Sleep Clinics between 2000 and 2010. Data were reviewed for CPAP compliance and seizure frequency after at least 6 months of CPAP use. Only patients with no changes in antiepileptic drug regimens during CPAP trial were included. Of the 660 patients identified, 41 fulfilled inclusion criteria, of whom 28 were CPAP compliant and 13 were not CPAP compliant. In the compliant group, CPAP use led to decreased seizure frequency from 1.8 per month to 1 per month (p = 0.01). In the noncompliant group, no significant difference in seizure frequency was noted between baseline (2.1 per month) and at follow-up (1.8 per month, p = 0.36). Sixteen of 28 CPAP-compliant subjects were seizure free, whereas only 3 of 13 non-CPAP compliant subjects were seizure free [relative risk (RR) 1.54, p = 0.05]. Patients with epilepsy and OSA not compliant with CPAP treatment are at higher risk of seizures than are CPAP-compliant patients. To validate this observation, further prospective studies are warranted

Caregiver burden in epilepsy: determinants and impact.

Aim. Caregiver burden (CB) in epilepsy constitutes an understudied area. Here we attempt to identify the magnitude of this burden, the factors associated with it, and its impact to caregiver quality of life (QOL). Methods. 48 persons with epilepsy (PWE) underwent video-EEG monitoring and their caregivers completed questionnaires providing demographic, disease-related, psychiatric, cognitive, sleep, QOL, and burden information. Results. On regression analysis, higher number of antiepileptic drugs, poorer patient neuropsychological performance, lower patient QOL score, and lower caregiver education level were associated with higher CB. Time allocated to patient care approximated but did not attain statistical significance. A moderate inverse correlation between CB and caregiver QOL physical component summary score and a stronger inverse correlation between CB and caregiver QOL mental component summary score were seen. Conclusion. In a selected cohort of PWE undergoing video-EEG monitoring, we identified modest degree of CB, comparable to that reported in the literature for other chronic neurological conditions. It is associated with specific patient and caregiver characteristics and has a negative effect on caregiver QOL

Caregiver Burden in Epilepsy: Determinants and Impact

Aim. Caregiver burden (CB) in epilepsy constitutes an understudied area. Here we attempt to identify the magnitude of this burden, the factors associated with it, and its impact to caregiver quality of life (QOL). Methods. 48 persons with epilepsy (PWE) underwent video-EEG monitoring and their caregivers completed questionnaires providing demographic, disease-related, psychiatric, cognitive, sleep, QOL, and burden information. Results. On regression analysis, higher number of antiepileptic drugs, poorer patient neuropsychological performance, lower patient QOL score, and lower caregiver education level were associated with higher CB. Time allocated to patient care approximated but did not attain statistical significance. A moderate inverse correlation between CB and caregiver QOL physical component summary score and a stronger inverse correlation between CB and caregiver QOL mental component summary score were seen. Conclusion. In a selected cohort of PWE undergoing video-EEG monitoring, we identified modest degree of CB, comparable to that reported in the literature for other chronic neurological conditions. It is associated with specific patient and caregiver characteristics and has a negative effect on caregiver QOL

Challenges in identifying Lennox–Gastaut syndrome in adults: A case series illustrating its changing nature

The variable presentation and progression of Lennox–Gastaut syndrome (LGS) can make it difficult to recognize, particularly in adults. To improve diagnosis, a retrospective chart review was conducted on patients who were diagnosed as adults and/or were followed for several years after diagnosis. We present 5 cases that illustrate changes in LGS features over time. Cases 1 and 2 were diagnosed by age 8 with intractable seizures, developmental delay, and abnormal EEGs with 1.5–2 Hz SSW discharges. However, seizure type and frequency changed over time for both patients, and the incidence of SSW discharges decreased. Cases 3, 4, and 5 were diagnosed with LGS as adults based on current and past features and symptoms, including treatment-resistant seizures, cognitive and motor impairment, and abnormal EEG findings. While incomplete, their records indicate that an earlier LGS diagnosis may have been missed or lost to history. These cases demonstrate the need to thoroughly and continuously evaluate all aspects of a patient's encephalopathy, bearing in mind the potential for LGS features to change over time

Tiagabine in clinical practice: effects on seizure control and behavior

Preapproval randomized controlled trials of antiepileptic drugs provide data in limited patient groups. We assessed the side effect and seizure reduction profile of tiagabine (TGB) in typical clinical practice. Investigators recorded adverse effect (AE), seizure, and assessment-of-benefit data prospectively in sequential patients treated open label with TGB. Two hundred ninety-two patients (39 children) were enrolled to be treated long term with TGB. Seizure types were focal-onset (86%), generalized-onset (12%), both focal- and generalized-onset (0.3%), and multiple associated with Lennox–Gastaut Syndrome (2%). Two hundred thirty-one received at least one dose of TGB (median=28mg/day) and had follow-up seizure or AE data reported. Common AEs were fatigue, dizziness, psychomotor slowing, ataxia, gastrointestinal upset, weight change, insomnia, and “others” (mostly behavioral). Serious AEs occurred in 19 patients: behavioral effects (n=12), status epilepticus (n=3), others (n=3), and sudden unexplained death (n=1). No patients experienced suicidal ideation/behavior, rash, nephrolithiasis, or organ failure. Seizure outcomes were seizure freedom (5%), ≥75% reduction (12%), ≥50% reduction (23%), and increased number of seizures (17%), or new seizure type (1%). Behavioral AEs occurred in a larger proportion of patients compared to those reported in TGB preapproval randomized controlled trials. A moderate percentage of patients had a meaningful reduction in seizure frequency. In clinical practice, TGB remains a useful antiepileptic drug. •Tiagabine effects were assessed prospectively in typical clinical practice.•231 patients had a higher proportion of behavioral effects than those in preclinical trials.•Common AEs were fatigue, dizziness, psychomotor slowing, ataxia, and behavioral.•Serious AEs were behavioral, status epilepticus, and SUDEP.•No patients had suicidal ideation/behavior, rash, nephrolithiasis, or organ failure

A Quick and Reliable EEG Montage for the Detection of Seizures in the Critical Care Setting

Obtaining an emergent EEG for the diagnosis of nonconvulsive status epilepticus and conconvulsive seizures in the intensive care unit raises logistic problems in most hospitals. Previous studies have looked into the hairline EEG for a broader population than the critically ill, with controversial conclusions. The authors created a montage sufficiently simple to be performed and interpreted by residents and rapidly achievable to meet the time constraints of a busy on-call schedule. Seven electrodes (Fp1, Fp2, T3, T4, O1, O2, and Cz), easily applied without the need for tape measure by using only anatomic landmarks (pupils, ears, vertex, and inion), were used to configure three different montages: double diamond, circumferential, and Cz referential. EEG records obtained with the full 10-20 system in critically ill patients were reformatted into these montages and reviewed retrospectively independently by neurology attending physicians with expertise in EEG interpretation and senior neurology residents. A comparison was done with the previously studied hairline EEG. The average sensitivity of the study montage for seizure detection was 92.5%, whereas the average specificity was 93.5%. These results suggest that the seven-electrode montage could potentially be a quick and reliable EEG montage for the detection of seizures in the intensive care unit, when technical support is not available. Further prospective studies are required to validate these promising results in a larger population sample