Seizures revisited. Antiepileptic drugs help manage acute and chronic seizures, but what else works?

Explore pertinent drug therapy, emergency interventions, and financial considerations related to seizure management.     

Efficacy and Tolerability Exposure–Response Relationship of Retigabine (Ezogabine) Immediate-Release Tablets in Patients With Partial-Onset Seizures

Background

Retigabine (international nonproprietary name)/ezogabine (United States adopted name) is an antiepileptic drug (AED) that enhances KCNQ (K_v7) potassium channel activity.

Objectives

The aim of this study was to explore the relationship between retigabine/ezogabine systemic exposure and efficacy and adverse events (AEs) of retigabine/ezogabine from Phase III clinical trials.

Methods

Data were combined from Studies 301 and 302, which were both randomized, double-blind, placebo-controlled, multicenter, parallel-group studies with similar inclusion and exclusion criteria. All patients had partial-onset seizures and were receiving 1 to 3 concomitant AEDs. Systemic exposure was predicted for each patient as the average steady-state AUC_0–τ during the 12-week maintenance phase, based on a population pharmacokinetic model developed for retigabine/ezogabine. Efficacy end points included reduction in total partial-seizure frequency from baseline and probability of ≥50% reduction from baseline in seizure frequency. The probabilities of occurrence of 6 AEs were also evaluated.

Results

AUC_0–τ values increased linearly over the 600- to 1200-mg/d dose range. Over the entire AUC_0–τ range, the probability of efficacy was greater than that for any AE. The slopes of the exposure–response relationship for probability of dizziness and abnormal coordination were similar to that for efficacy, whereas the slopes for dysarthria, somnolence, tremor, and blurred vision were shallower, indicating that the probability of these events occurring was less affected than the probability of efficacy by increases in retigabine/ezogabine AUC_0–τ.

Conclusions

Based on the summary statistics of pharmacokinetic parameters, systemic exposure to retigabine/ezogabine increased linearly with dose (600–1200 mg/d). Population pharmacokinetics and pharmacodynamics showed that the probability of efficacy and AEs increased with increasing systemic retigabine/ezogabine exposure, and the probability of efficacy was higher than the probability of any of the AEs. The 35%–50% between-patient variability and overlap between retigabine/ezogabine dose levels in AUC_0-τ values indicate that, as with other AEDs, doses should be individually titrated based on a balance between efficacy and tolerability.     

Two Bankrobbers With “Antisocial” and “Schizoid/Avoidant” Personality Disorders, Comorbid With Partial Seizures: Temporal Lobe Epilepsy and Limbic Psychotic Trigger Reaction, Respectively

Diagnostic overshadowing is illustrated by two cases of unplanned, motiveless bank robbery, initially merely attributed to antisocoial or schizoid/avoidant (loner) personality disorder, respectively. Both disorders, however, were comorbid with their potentially unobservable counterparts, with brief partial seizures, supported by both men's abnormal scalp-EEG's, their symptomatology with psychosis, and their histories of closed head injury in childhood. Such injuries are known to render particularly the temporo-limbic brain system susceptible to later partial seizure: Mr. A. had temporal lobe epilepsy (TLE) with stereotypic auditory command hallucinations and clouding of consciousness. (His past antisocial aggressive behavior might also have reflected TLE-related inter-ictal events.) Mr. B. had the symptomatology proposed as limbic psychotic trigger reaction (LPTR). Mr. B., a social loner, typically ruminated on past intermittent moderate stresses, a specific precondition of seizure kindling, ultimately elicited by a specific stimulus, resembling his past hurts. As is typical for LPTR, Mr. B. had no clouding of consciousness and no amnesia for his atavistically regressive acts, committed with flat affect, nausea, and fleeting delusions of grandeur (being gifted, like Rembrandt).