A. James Rowan

A comparison of four treatments for generalized convulsive status epilepticus

BACKGROUND AND METHODS Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled. RESULTS Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. CONCLUSIONS As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.

Comparative Bioavailability of a Generic Phenytoin and Dilantin

Summary: Generic substitution of antiepileptic drugs(AEDs) has been controversial, with many alleged in‐stances of biologic and therapeutic inequivalence re‐ported. The recall of a generic phenytoin (PHT) formula‐tion used in the Veterans Administration (VA) medicalsystem allowed us to evaluate the question of biologicequivalence systematically in a relatively large number ofpatients at the Bronx VA Medical Center. Serum PHTlevels were 22–31% lower during the period of genericintake as compared with levels in the same patients re‐ceiving Dilantin. Review of the literature showed onlyone other adequately documented report of potential clin‐ically significant inequivalence between a brand nameand generic AED. Despite the apparent infrequency ofgeneric inequivalence, several areas in which proceduresfor certification of therapeutic equivalence should be im‐proved were identified.

Treatment of Refractory Complex-Partial Status Epilepticus with Propofol : Case Report

Summary: Purpose: We report a case of a 65‐year‐old woman who had a subarachnoid and intraventricular hemorrhage secondary to rupture of an anterior communicating artery aneu‐rysm and developed nonconvulsive status epilepticus of the complex‐partial type, refractory to phenytoin (PHT), phenobar‐bital (PB), valproate (VPA), and lorazepam (LZP).

Outcomes research: Clinical trials in the elderly

Very few clinical trials have been done in the elderly. This report reviews results of two completed studies and describes one in progress. The largest published study was a United States Veterans Affairs Administration study in newly diagnosed patients with epilepsy. It compared carbamazepine to gabapentin and lamotrigine, and found that, although equivalent in efficacy, the newer antiepileptic drugs (AEDs) were better tolerated. This study also highlighted many of the difficulties in recruiting and retaining elderly patients in studies, the large number of comorbidities, and the problems of distinguishing seizures in the elderly from other symptoms. Another study of new-onset epilepsy suggested that a large percentage of elderly patients respond to initial AED therapy, but side effect profiles differ. More studies are needed to better define the risk/benefit relationships in elderly patients.

Provocative testing for nonepileptic seizures: Attitudes and practices in the United States among American Epilepsy Society members

We sent a survey to American Epilepsy Society (AES) members about the use of provocative tests (PT) for the diagnosis of nonepileptic seizures (NES). The survey was limited to physicians practicing in the United States. Nearly 40% of the respondents routinely used PT to diagnose NES; the technique most often used was intravenous saline. The techniques most often used to stop NES were hyperventilation and suggestion alone. Respondents who routinely induced NES were more likely to consider these techniques useful than those who did not ( p p

Population pharmacokinetics of lamotrigine in elderly patients.

Lamotrigine is being used more frequently in elderly patients. Dosing of lamotrigine in elderly patients is based largely on studies from younger adults and not evidence‐based data from elderly patients. The goal of this study is to determine the pharmacokinetic parameters, such as clearance, and the factors that have a significant effect on these parameters to provide evidence‐based information that can be used to dose elderly patients taking lamotrigine. Lamotrigine plasma concentrations from 148 elderly patients (aged 59–92 years) were used to develop a population pharmacokinetic model. Data were analyzed using NONMEM. Model evaluation was performed using the bootstrap approach and predictive check. The results showed that the blood urea nitrogen/serum creatinine ratio, weight, and phenytoin use significantly affect apparent clearance of lamotrigine. These results show that clinicians may need to take into account these covariates when dosing lamotrigine in this population.

Unilateral Truncal Seizures: Frontal Origin

Summary: The locus of origin of seizures involving the muscles of the trunk is unresolved. The brainstem has been postulated by some investigators, whereas others have implicated the parietal cortex. We report a patient with epilepsia partialis continua involving the rectus ab‐dominus of one side in whom each contraction correlated with an epileptiform complex in the contralateral central‐vertex scalp region. This appears to be the first instance in which ictal EEG has localized truncal seizures to an area that probably corresponds to the precentral cortex.

Palinacousis—Auditory Perseveration: Two Cases and a Review of the Literature

Summary:  Palinacousis is an auditory illusion rarely reported in cases of temporal lobe dysfunction. Detailed observations where made by Jacobs et al. in 1973. Since that time, only a few other cases have been described in the literature. After reviewing the literature and comparing our clinical experience, we believe that palinacousis can occur as an aura, a simple partial seizure, a complex partial seizure, and/or a postictal event. Within one academic year, we observed two patients who experienced palinacousis. Palinacousis maybe more common than recognized in patients with receptive aphasias or diffuse cerebral dysfunction, whose language deficits preclude adequate description. It is important to differentiate palinacousis from auditory hallucinations seen in psychotic and psychiatric patients. Identification of palinacousis as an aura, simple partial seizure, complex partial seizure, and/or postictal phenomenon can help localize potential lesions and improve patient care.

Recruitment and retention in clinical trials of the elderly.

The recruitment and retention of elderly patients in clinical trials provide many challenges. Factors affecting recruitment, retention, and cost of recruitment are discussed in this chapter. Various methods are described that were used in recruiting and retaining elderly patients in a Veterans Affairs (VA) Administration clinical trial that compared two newer antiepileptic drugs (AEDs), gabapentin and lamotrigine, to the established standard AED, carbamazepine. Various strategies were utilized in the VA study to improve recruitment, and each strategys overall effectiveness was monitored. Modification of the patient inclusion criteria, by lowering the age of eligibility from 65 to 60 years, added approximately 100 patients to the study. Replacing five trial sites that had poor recruiting records, extending the patient recruitment period by 3 months, and conducting site visits also improved patient recruitment rates, such that 82.4% of target enrollment (720 patients) was achieved. The main reasons that screened patients were excluded from the study included: lack of seizures during the prior 3 months, unstable medical condition, adequate treatment with an AED, satisfaction with current treatment, and the inability to give informed consent. Retaining patients for 1 year was the primary outcome measure of this trial, with 46.8% of patients completing the year. The most common reasons for early termination were study drug-related adverse events (43.0%) and lack of seizure control (10.8%). Comorbidities and polypharmacy occurred more frequently in the elderly, and both had a negative influence on recruitment and retention.

Aspartame and Seizure Susceptibility: Results of a Clinical Study in Reportedly Sensitive Individuals

Summary: The high intensity sweetener aspartame has been implicated anecdotally in seizure provocation. This possibility was investigated with a randomized, double‐blind, placebo‐controlled, cross‐over study. After an extensive search, 18 individuals (16 adults and 2 children) who had seizures allegedly related to aspartame consumption were admitted to adult or pediatric epilepsy monitoring units where their EEG was monitored continuously for 5 days. Aspartame (50 mg/kg) or identically enpackaged placebo was administered in divided doses at 800, 1000, and 1200 h on study days 2 and 4. All meals were uniformly standardized on treatment days. No clin‐ical seizures or other adverse experiences were observed after aspartame ingestion. Mean plasma phenylalanine (Phe) concentrations increased significantly after aspar‐tame ingestion (83.6 pIM) as compared with placebo (52.3 μCM).Results suggest that aspartame, in acute dosage of ε50 mg/kg, is no more likely than placebo to cause seizures in individuals who reported that their seizures were provoked by aspartame consumption.