Fritz E. Dreifuss

Levetiracetam for partial seizures Results of a double-blind, randomized clinical trial

Objective: To evaluate the efficacy and safety of 500 mg bid and 1500 mg bid levetiracetam as adjunctive therapy for refractory partial seizures in a double-blind, randomized, placebo-controlled, parallel-group, multicenter trial. Methods: The authors studied patients with uncontrolled partial seizures (minimum 12 per 12 weeks), regardless of whether they became secondarily generalized, for 38 weeks. A 12-week baseline was followed by random assignment to adjunctive therapy with placebo (n = 95), levetiracetam 1000 mg/day (n = 98), or levetiracetam 3000 mg/day (n = 101). Upward titration over 4 weeks was followed by 14 weeks of fixed dose treatment, and concluded with an 8-week medication withdrawal period or entering a follow-up study. Results: Of 294 patients randomized, 268 completed the study. Partial seizure frequency during the entire evaluation period (primary efficacy variable) was lower with levetiracetam compared to placebo (p ≤ 0.001 for both groups). More patients responded (defined as minimum 50% reduction in partial seizure frequency) to levetiracetam than placebo, with rates of 33.0% in the 1000 mg/day and 39.8% in the 3000 mg/day group, compared to 10.8% in the placebo group (p < 0.001). Of 199 patients receiving levetiracetam, 11 became seizure free; no patient became seizure free in the placebo group. Treatment-emergent adverse events (≥10%), mostly mild to moderate in severity, with incidences higher than placebo were asthenia, dizziness, flu syndrome, headache, infection, rhinitis, and somnolence. Conclusion: Adjunctive therapy with levetiracetam was effective and well tolerated in controlling partial seizures.

Valproic acid hepatic fatalities A retrospective review

We reviewed all US cases of fatal hepatotoxicity coincident with valproate anticonvulsant therapy that were reported between 1978 and 1984. Thirty-seven hepatic fatalities were determined to have occurred coincident with the use of valproate. All but one patient had such other medical conditions as mental retardation, developmental delay, congenital abnormalities, and other neurologic diseases. The primary risk of fatal hepatic dysfunction (1/500) was found to be in children 0 to 2 years old receiving valproate as polytherapy. The risk declined with age and was low in patients receiving valproate as monotherapy (1/37,000). No hepatic fatalities occurred in patients above the age of 10 years receiving valproate as monotherapy.

Valproic acid hepatic fatalities. III. U.S. experience since 1986

We report the results of a third retrospective study of the U.S. experience with fatal hepatotoxicity associated with valproic acid (VPA). In the United States, over one million patients received new prescriptions for VPA during the years 1987 to 1993, and 29 patients developed fatal hepatotoxicity. Decreased alertness, jaundice, vomiting, hemorrhage, increased seizures, anorexia, and edema were the most common presenting signs. Risk factors included young age, polytherapy, developmental delay, and coincident metabolic disorders. Patients less than 2 years old receiving VPA as polytherapy were at the greatest risk (1:600) of developing this complication. NEUROLOGY 1996;46: 465-469

A Comparison of Rectal Diazepam Gel and Placebo for Acute Repetitive Seizures

BACKGROUND Acute repetitive seizures are readily recognizable episodes involving increased seizure frequency. Urgent treatment is often required. Rectal diazepam gel is a promising therapy. METHODS We conducted a randomized, double-blind, parallel-group, placebo-controlled study of home-based treatment for acute repetitive seizures. Patients were randomly assigned to receive either rectal diazepam gel, at a dosage varying from 0.2 to 0.5 mg per kilogram of body weight on the basis of age, or placebo. Children received one dose at the onset of acute repetitive seizures and a second dose four hours later. Adults received three doses -- one dose at onset, and two more doses 4 and 12 hours after onset. Treatment was administered by a care giver, such as a parent, who had received special training. The number of seizures after the first dose was counted for 12 hours in children and for 24 hours in adults. RESULTS Of 125 study patients (64 assigned to diazepam and 61 to placebo) with a history of acute repetitive seizures, 91 (47 children and 44 adults) were treated for an exacerbation of seizures during the study period. Diazepam treatment was superior to placebo with regard to the outcome variables related to efficacy: reduced seizure frequency (P<0.001) and improved global assessment of treatment outcome by the care giver (frequency and severity of seizures and drug toxicity) (P<0.001). Post hoc analysis showed diazepam to be superior to placebo in reducing seizure frequency in both children (P<0.001) and adults (P=0.02), but only in children was it superior with regard to improvement in global outcome (P<0.001). The time to the first recurrence of seizures after initial treatment was longer for the patients receiving diazepam (P<0.001). Thirty-five patients reported at least one adverse effect of treatment; somnolence was the most frequent. Respiratory depression was not reported. CONCLUSIONS Rectal diazepam gel, administered at home by trained care givers, is an effective and well-tolerated treatment for acute repetitive seizures.

Academic Achievement of Children with Epilepsy

Summary: The academic achievement scores of 122 children with epilepsy were examined in relation to demographic and clinical seizure variables. As a group, these children were making less academic progress than expected for their age and IQ level. Academic deficiencies were greatest in arithmetic, followed by spelling, reading, comprehension, and word recognition. Results of the multiple regression analyses indicated a modest combined predictive significance of the demographic and clinical seizure variables for academic performance. In addition, the magnitude of these relationships varied by academic area. Among the individual variables examined the strongest correlates of academic performance were age of the child, age of seizure onset, lifetime total seizure frequency, and presence of multiple seizures (absence and tonic‐clonic). These results are discussed in relation to developing an understanding of the factors which underlie academic vulnerability in children with epilepsy.

Valproic acid hepatic fatalities. II. US experience since 1984

We have analyzed the usage pattern of valproate and the associated hepatic fatalities that have been reported in the 2 years since our first study evaluating US experience during the period 1978-1984. In this follow-up study (1985-1986), we have observed a nearly fivefold decrease in the incidence of hepatic fatality during a time when the overall use of valproate has increased significantly. The dramatically decreased incidence, from 0.93 per 10,000 (1/10,000) in 1978–1984 to 0.20 per 10,000 (1/49,000) in 1985-1986 appears to be due to changes in the prescribing patterns of physicians, prompted by greater awareness of low-risk versus high-risk patients. More patients are receiving valproate as monotherapy, considerably more low-risk patients are being treated with valproate, and fewer high-risk patients (0 to 2 years old) are being treated with valproate. During 1985-1986, no hepatic fatalities were reported in any patients above the age of 10 years, regardless of whether valproate was administered as monotherapy or polytherapy. The altered exposure pattern, with an increased use of monotherapy, appears to have had a positive impact on the number of hepatic fatalities (four among 198,000 patients treated during 1985–1986) and contributed to a decreased rate of valproate-associated hepatic fatality.

Valproic acid versus ethosuximide in the treatment of absence seizures

Valproic acid (VPA) and ethosuximide (ESM) were compared in a double-blind, response- conditional crossover study of absence seizures in 16 naive (previously untreated for absence seizures) and 29 refractory patients (18 male and 27 female; 4 to 18 years of age). In the naive patients VPA was as effective as ESM in reducing generalized spike-wave discharges on the telemetered EEG. Adverse reactions to VPA or ESM were generally mild and responded to withdrawal or dosage reduction of the drug.

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.

l‐Carnitine Supplementation in Childhood Epilepsy: Current Perspectives

Summary: In November 1996, a panel of pediatric neurologists met to update the consensus statement issued in 1989 by a panel of neurologists and metabolic experts on L‐carnitine supplementation in childhood epilepsy. The panelists agreed that intravenous L‐carnitine supplementation is clearly indicated for valproate (VPA)‐induced hepatotoxicity, overdose, and other acute metabolic crises associated with carnitine deficiency. Oral supplementation is clearly indicated for the primary plasmalemmal carnitine transporter defect. The panelists concurred that oral L‐carnitine supplementation is strongly suggested for the following groups as well: patients with certain secondary carnitine‐deficiency syndromes, symptomatic VPA‐associated hyperammonemia, multiple risk factors for VPA hepatotoxicity, or renal‐associated syndromes; infants and young children taking VPA; patients with epilepsy using the ketogenic diet who have hypocarnitinemia; patients receiving dialysis; and premature infants who are receiving total parenteral nutrition. The panel recommended an oral L‐carnitine dosage of 100 mg/kg/day, up to a maximum of 2 g/day. Intravenous supplementation for medical emergency situations usually exceeds this recommended dosage.

Responsiveness before, during, and after spike‐wave paroxysms

In 26 patients 5 to 20 years of age with absence seizures, 413 auditory reaction times were determined by a paroxysm detection device during 310 spike-wave paroxysms. All reaction times during the 1 second before a paroxysm were within normal limits, but only 43 percent of reaction times at the onset of a paroxysm were normal and after a delay of 0.500 second into a paroxysm, only 20 percent were normal. After 4 seconds of spike-wave discharge, 52 percent of reaction times were normal. Responsiveness was recovered quickly after a paroxysm. The degree of impairment of response to auditory stimuli markedly decreased when spike-wave discharge was fully generalized. The degree of maximal impairment of auditory responsiveness was the same in paroxysms of both long and short duration. Thus, any spike-wave paroxysm, regardless of duration, can impair consciousness, and therapy for absence seizures should aim at controlling all spikewave paroxysms, not just the longer bursts.