Abstract-Objective:To assess the evidence demonstrating efficacy, tolerability, and safety of seven new antiepileptic drugs (AEDs) (gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, and zonisamide) in the treatment of children and adults with refractory partial and generalized epilepsies. Methods: A 23-member committee including general neurologists, pediatric neurologists, epileptologists, and doctors in pharmacy evaluated the available evidence based on a structured literature review including MEDLINE, Current Contents, and Cochrane library for relevant articles from 1987 until March 2003. Results: All of the new AEDs were found to be appropriate for adjunctive treatment of refractory partial seizures in adults. Gabapentin can be effective for the treatment of mixed seizure disorders, and gabapentin, lamotrigine, oxcarbazepine, and topiramate for the treatment of refractory partial seizures in children. Limited evidence suggests that lamotrigine and topiramate are also effective for adjunctive treatment of idiopathic generalized epilepsy in adults and children, as well as treatment of the Lennox Gastaut syndrome. Conclusions: The choice of AED depends upon seizure and/or syndrome type, patient age, concomitant medications, AED tolerability, safety, and efficacy. The results of this evidence-based assessment provide guidelines for the prescription of AEDs for patients with refractory epilepsy and identify those seizure types and syndromes where more evidence is necessary.
OXC adjunctive therapy administered in a dose range of 6 to 51 mg/kg/day (median 31.4 mg/kg/day) is safe, effective, and well tolerated in children with partial seizures.
Summary:Purpose: A double-blind, randomized, placebocontrolled clinical trial to examine the safety, tolerability, and antiepileptic activity of ganaxolone in patients after withdrawal from other antiepileptic drugs during presurgical evaluations was performed.Methods: Fifty-two eligible patients were withdrawn from antiepileptic drugs and randomized to receive ganaxolone (24 patients) or placebo (28 patients) for up to 8 days. Ganaxolone was administered at a dose of 1500 mg/d on day 1 and 1875 mg/d on days 2 to 8. Dosing occurred three times per day: immediately after breakfast, lunch, and dinner.Results: The primary measure of antiepileptic activity was duration of treatment before withdrawal from the trial. KaplanMeier curves depicted a clear separation between treatment groups, with 50% of the ganaxolone-treated patients completing the entire study, compared with 25% of patients treated with placebo. Intent-to-treat survival analyses revealed a trend toward efficacy with ganaxolone (p = 0.0795, log rank test). Covariate analyses revealed a significant treatment effect on survival time in men (p = 0.03). Post-hoc x' probe analyses focusing on patients who completed the entire study revealed a significant difference (p = 0.04) between treatment groups. The tolerability of ganaxolone was similar to that of placebo, with adverse events being reported by 79% of patients in the ganaxolone group and 68% of patients in the placebo group.Conclusions: Ganaxolone monotherapy was well tolerated for the duration of this clinical trial, and the results provide preliminary evidence that ganaxolone does have antiepileptic activity. Key Words: Ganaxolone-Epilepsy-Presurgical trial-Partial seizures-y-Aminobutyric acid A modulator.Ganaxolone is a member of a novel class of neuroactive steroids called epalons, which allosterically modulate the y-aminobutyric acid type A receptor complex via a unique recognition site (1). The compound was developed after it was observed that endogenously occurring metabolites of progesterone and deoxycorticosterone, such as 3a-hydroxy-501-pregnan-2O-one and 501-tetrahydrodeoxycorticosterone, had substantial anticonvulsant effects in animal models of epilepsy (24). Ganaxolone (3au-hydroxy-3~-methyl-5a-pregnan-20-one) is the 3P-methylated, synthetic analog of 301-hydroxy-501-pregnan-20-one and possesses no detectable hormonal acAccepted May 12, 2000. Dr. Morrell is now with The Neurological Institute, Columbia Presbyterian Medical Center, New York, NY.Address correspondence to Dr. Edward P. Monaghan at Serono, Inc., 700 Longwater Dr, Norwell, MA 02061. E-mail: edward.monaghan. us-bos0 1 @ serono.com tivity (5). In vivo pharmacology studies demonstrated that ganaxolone provides protection in a wide variety of animal models, including pentylenetetrazol-, bicuculline-, aminophylline-, t-butylbicyclophosphorothionate-, and corneal kindling-induced seizure models, suggesting that it may have utility in the treatment of a broad range of seizure types (6-8).Traditionally, early clinical trials in epilep...
This study evaluated gabapentin monotherapy in 275 patients with medically refractory complex partial or secondarily generalized seizures who were taking one or two antiepileptic drugs (AEDs). Following an 8-week baseline, patients received randomized dosages of gabapentin (600, 1,200, or 2,400 mg/d) during a 26-week double-blind phase comprising 2 weeks gabapentin add-on therapy, an 8-week AED taper, and a 16-week gabapentin monotherapy period. Patients exited the study if they experienced a protocol-defined exit event. Results of outcome measures, including time to exit, completion rate, and mean time on monotherapy, showed no significant differences among dosage groups. Possible reasons for this lack of a dose-response relationship include withdrawal seizures and the limited range of gabapentin dosages studied. Overall, 20% of patients completed the study. Completion rates were higher among patients who had discontinued one AED (23%) than two AEDs (14%), and higher among patients who were not withdrawn from carbamazepine (27%) than among those who were (16%).
We report identification of a genetic locus for familial mesial temporal lobe epilepsy. The identification of a disease-causing gene will contribute to our understanding of the pathogenesis of temporal lobe epilepsies.
Summary:Purpose: To evaluate the safety and efficacy of high dose gabapentin (GBP) monotherapy (3,0004,800 mg/ day) in patients with medically refractory partial epilepsy.Methods: GBP monotherapy at daily doses up to 4,800 mg was attempted in patients participating in the open-label phase of a double-blind, dose-controlled, GBP monotherapy trial. For those who achieved monotherapy, the types and severity of adverse events were assessed and the average seizure frequency per 28 days while maintained on the highest daily GBP dose was compared to the seizure frequency during the baseline phase of the double blind trial. Correlation analysis between GBP serum level, total daily dose, and percentage of seizure change from baseline was performed.Results: A total of 45 patients participated in the open-label phase of the trial and 23 (51%) were converted successfully to GBP monotherapy. In those patients, the average daily gabapentin dose was 3,900 mg and the mean length of follow-up was 252 days. Compared to baseline, there was a mean reduction of 54%, 43%, and 14% for simple partial, complex partial and secondarily generalized seizures respectively, while maintained on high-dose GBP monotherapy. A significant linear correlation between daily GBP dosage (2,4004,800 mg) and resultant mean serum levels was found (r = 0.51; p < 0.01). There was no significant correlation between seizure frequency and total daily GBP dose or with serum levels. High-dose GBP monotherapy was well tolerated; only one patient exited the trial because of adverse events. The most common adverse event was tiredness/sleepiness and was not dose-related.Conclusions: GBP monotherapy is well tolerated in daily doses of up to 4,800 mg and is effective in a subgroup of patients with medically refractory partial epilepsy.
The results of intra-operative cortical EEG recordings (ECoG) were assessed in 30 patients with medically refractory complex partial seizures submitted to temporal lobectomy. Interictal spiking was most frequently recorded from mesial temporal lobe structures (amygdaloid-hippocampal region) and from the temporal neocortex synchronously, as observed in 21/30 patients. In 7 patients, the interictal spiking involved the temporal neocortex exclusively. Electrical stimulation of mesial temporal lobe structures reproduced the patient's habitual warning in 10 patients. The results of this study confirms that ECoG provides reliable intra-operative mapping of the epileptogenic brain tissue to be excised.
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