Nina M. Graves

Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy.

Purpose:  We report a multicenter, double‐blind, randomized trial of bilateral stimulation of the anterior nuclei of the thalamus for localization‐related epilepsy.

Electrical Stimulation of the Anterior Nucleus of the Thalamus for the Treatment of Intractable Epilepsy

Summary:  Purpose: Animal studies and sporadic case reports in human subjects have suggested that intermittent electrical stimulation of the anterior nucleus of the thalamus reduces seizure activity. We embarked on an open‐label pilot study to determine initial safety and tolerability of bilateral stimulation of the anterior nucleus of the thalamus (ANT), to determine a range of appropriate stimulation parameters, and to begin to gather pilot efficacy data.

Felbamate for partial seizures Results of a controlled clinical trial

Felbamate (2-phenyl-1,3-propanediol dicarbamate) has a favorable preclinical profile in animal models of epilepsy. We present the results of a double-blind, randomized, placebo-controlled clinical trial in patients with partial seizures. Criteria for entry included a requirement for four or more partial seizures per month despite concomitant therapeutic blood levels of phenytoin and carbamazepine. Fifty-six patients (mean age, 31.4 years; 32 men, 24 women) completed the trial. The mean seizure frequencies for the 8-week periods analyzed were felbamate = 34.9, placebo = 40.2. Felbamate was statistically superior to placebo in seizure reduction, percent seizure reduction, and truncated percent seizure reduction. The mean felbamate dosage was 2,300 mg/d. Plasma felbamate concentrations ranged from 18.4 to 51.9 mg/l, mean = 32.5 mg/l. Adverse experiences during felbamate therapy were minor and consisted primarily of nausea and CNS effects. This trial indicates that felbamate is safe and effective in the treatment of comedicated patients with severely refractory epilepsy.

Report of the American Epilepsy Society and the Epilepsy Foundation Joint Task Force on Sudden Unexplained Death in Epilepsy

The American Epilepsy Society and the Epilepsy Foundation jointly convened a task force to assess the state of knowledge about sudden unexplained death in epilepsy (SUDEP). The task force had five charges: (1) develop a position statement describing if, when, what, and how SUDEP should be discussed with patients and their families and caregivers; (2) design methods by which the medical and lay communities become aware of the risk of SUDEP; (3) recommend research directions in SUDEP; (4) explore steps that organizations can take to perform large‐scale, prospective studies of SUDEP to identify risk factors; and (5) identify possible preventive strategies for SUDEP. Some of the major task force recommendations include convening a multidisciplinary workshop to refine current lines of investigation and to identify additional areas of research for mechanisms underlying SUDEP; performing a survey of patients and their families and caregivers to identify effective means of education that will enhance participation in SUDEP research; conducting a campaign aimed at patients, families, caregivers, coroners, and medical examiners that emphasizes the need for complete autopsy examinations for patients with suspected SUDEP; and securing infrastructure grants to fund a consortium of centers that will conduct prospective clinical and basic research studies to identify preventable risk factors and mechanisms underlying SUDEP. For now, the principal effort in preventing SUDEP should be prompt and optimal control of seizures, especially generalized convulsive seizures.

Pharmacokinetics and safety of a phenytoin prodrug given IV or IM in patients

ACC-9653, a prodrug of phenytoin synthesized to be water soluble, is converted to phenytoin by phos-phatases. In this study, 43 patients received ACC-9653 IV or IM. Side effects were transient and minor. The conversion half-lives of ACC-9653 after intravenous and intramuscular administration averaged 8.4 and 32.7 minutes, respectively. Peak phenytoin concentrations occurred 42 minutes after IV and 151 minutes after IM administration.

Variability of total phenytoin serum concentrations within elderly nursing home residents.

Background: Approximately 6% of all elderly nursing home residents receive phenytoin. Phenytoin concentrations are often measured to guide therapy. Objective: To evaluate the intraresident variability among multiple measurements of total phenytoin serum concentrations in nursing home residents. Methods: This was an observational study of 56 elderly (≥65 years) nursing home residents from 32 nursing homes who had at least 3 phenytoin concentrations measured while on the same dose of phenytoin for at least 4 weeks and who were not taking any interfering concomitant medications. These were a subset of 387 elderly nursing home residents from 112 nursing homes across the United States who had total phenytoin concentration measurements between June 1998 and December 2000. Results: The mean age was 80.1 years (range, 65 to 100 years) and 58.9% were women. The mean daily dose of phenytoin per resident was 4.9 ± 1.5 mg/kg. Total phenytoin concentrations within an elderly nursing home resident varied as much as two- to threefold, even though there was no change in dose. The person with the smallest variability had a minimum concentration of 10.0 μg/mL and a maximum of 10.4 μg/mL. The person with the largest variability had a minimum concentration of 9.7 μg/mL and a maximum of 28.8 μg/mL. Conclusions: There is considerable variability in the total phenytoin concentrations in the elderly nursing home resident and measurement of a single total phenytoin concentration should not be used to guide treatment.

Effect of Felbamate on Phenytoin and Carbamazepine Serum Concentrations

Summary: Felbamate (FBM) is a novel antiepileptic drug (AED) undergoing clinical trials in the United States. During a double‐blind, cross‐over clinical trial, patients received concomitant phenytoin (PHT) and carbamazepine (CBZ). Dosages of PHT and CBZ were adjusted to maintain serum concentrations ±20 and ±25% of baseline values. All patients required a PHT dosage decrease of 10–30% during active FBM treatment to maintain stable concentrations. CBZ serum concentrations decreased significantly in patients receiving active FBM. The mean decrease was 1.3 u.g/ml and occurred in 30 of 32 patients. Therefore, FBM apparently causes a bidirectional effect on the serum concentrations of PHT and CBZ when all three drugs are taken concomitantly.

Discontinuation of Phenytoin and Carbamazepine in Patients Receiving Felbamate

Summary: Five patients participated in a controlled discontinuation of phenytoin (PHT) and carbamazepine (CBZ) after a study in which all subjects had felbamate (FBM) added to both PHT and CBZ. Four subjects (three women and 1 man aged 23–36 years) completed the protocol. Mean total seizure frequency per day with PHT and CBZ was 1.33 ± 0.93 (mean ± SEM), decreasing to 0.87 ± 0.71 with addition of FBM, and 0.82 ± 0.78 after discontinuation of PHT. Only one subject tolerated discontinuation of CBZ; the other three had dosage reductions of 33, 54, and 63%. Toxicity attributable to FBM was not observed, and patients often described less severe seizures. Results from four refractory patients indicated that FBM was able to replace PHT and reduce the need for CBZ. In addition, as PHT dosages were reduced, FBM clearance decreased 21%. As the CBZ dosages were reduced, FBM clearance decreased an additional 16.5%.

Felbamate Increases Phenytoin but Decreases Carbamazepine Concentrations

Summary: Felbamate (FBM), a novel antiepileptic drug, was observed to have opposite effects on the serum concentrations of phenytoin (PHT) and carbamazepine (CBZ). Data from two male subjects who stabilized while they received both PHT and CBZ, with serum concentration fluctuations of <20 and 25%, respectively, form the basis of this report. Both patients required a ≫20% reduction in PHT dose while receiving 38–40 mg/kg/day of FBM. When FBM was tapered to <20 mg/kg/day, a sudden drop in PHT concentrations occurred in both patients. As PHT concentrations rose, CBZ concentrations fell in both patients. The CBZ epoxide to parent ratio increased to 0.46 and 0.39, respectively during FBM treatment. The ratios were 0.18 in both patients when not receiving FBM. CBZ concentrations returned to baseline values after FBM was discontinued. This unusual and unexpected effect of FBM on two standard antiepileptic drugs underscores the need for evaluating pharmacokinetic interactions before major drug trials.

A randomized double-blind study of carbamazepine in the treatment of cocaine abuse

A 12‐week, randomized, double‐blind, placebo‐controlled, fixed‐dose outpatient study of carbamazepine (400 mg and 800 mg) in the treatment of cocaine dependence was performed. Data were analyzed with respect to both treatment condition and carbamazepine serum levels. Outcome variables included subject retention, cocaine urinalysis, self‐reported cocaine use, cocaine craving, patient and clinical global impressions, the Drug Impairment Rating Scale for Cocaine, and side effects. Compared with placebo, the 400 mg treatment condition exhibited a greater decrease in the rate of positive cocaine urinalyses and a reduction in intensity and duration of craving over the course of the study. Higher serum carbamazepine levels were associated with a lower rate of positive cocaine urinalysis, fewer days of self‐reported cocaine use, briefer craving episodes, and greater subject interval retention. The clinical and methodologic implications of these findings and of the study design are discussed.