Nicholas Barbaro, M.D. - US grants

DESCRIPTION (Applicant's Abstract): The purpose of this study is to determine whether gamma knife radiosurgery is effective in reducing or eliminating seizures in patients with temporal lobe epilepsy. The primary hypothesis is that radiosurgical treatment of mesial temporal lobe structures, including the amygdala and hippocampus, will result in a significant reduction in seizures in patients with medically refractory medial temporal lobe epilepsy with minimal morbidity to patients. Patients who are refractory to medical management (20% of epilepsy patients) may be referred for surgical management. Approximately half of them are found to be candidates for surgical resection of their seizure focus, most commonly by temporal lobectomy. Open surgical procedures have inherent risks including damage to the brain, bleeding, and infection. Radiosurgery is a technique whereby gamma radiation is focused (201 sources) using stereotaxic guidance into precisely controlled regions of the brain. The main risks of this procedure are radiation injury to important nearby structures, and radiation necrosis. There is preliminary evidence that high-dose radiation reduces seizures, but long-term outcome is available in very few cases. The optimal radiation dose, the minimum effective treatment volume, and the true morbidity of this approach have not been established. This protocol defines a homogeneous group of patients with mesial temporal lobe epilepsy in whom the outcome from open surgery is well established. It will compare two radiosurgical doses directed at the medial temporal lobe to standard medical therapy. Radiosurgical treatment will be standardized over all Treatment Centers using inter-center data transfer unique to the Gamma Knife instrument. Follow-up data on seizure frequency (including seizure-free outcome), neuropsychological testing, MRI (including Perfusion and Diffusion weighted studies), MRS findings and EEG changes will be collected for three years following radiosurgical treatment. The pilot data obtained from this protocol will result in a better definition of the safe and effective radiation dose for use in future protocols including a comparison of radiosurgery to temporal lobectomy. If radiosurgery can be shown to reduce or eliminate seizures in patients with medically refractory temporal lobe epilepsy, patients could be offered this minimally invasive technique, avoiding the morbidity of open cranial surgery.

DESCRIPTION (provided by applicant): It is estimated that 0.5%-1.0% of the U.S. population has epilepsy, and that 20% of patients with epilepsy have medically refractory seizures. Patients with unilateral temporal lobe seizure onsets have an excellent chance of becoming seizure-free following temporal lobectomy. Based on the successful completion of a Pilot Clinical Trial showing that seizure-free rates were in excess of 80% and with acceptable toxicity, there is equipoise for treating well-selected patients with either radiosurgery or temporal resection. The purpose of this study is to compare the effectiveness of radiosurgery with temporal lobectomy in the treatment of patients with pharmaco-resistant temporal lobe epilepsy including freedom from seizures, seizure reduction, neuropsychological outcomes, quality of life and cost-effectiveness. Aim 1: To compare the seizure-free outcomes and morbidity of Gamma Knife radiosurgery (GKS) for patients with pharmaco-resistant temporal lobe epilepsy with those of open temporal lobectomy. Our primary hypothesis is that radiosurgery and lobectomy will have equivalent seizure-free rates at 25-36 months following therapy (one-year of seizure freedom beginning 2 years after treatment). The two arms will be considered equivalent if a one-sided 95% confidence interval precludes a decrease in seizure-free rate of 15%. Our secondary hypothesis is that radiosurgery will result in significant reductions in seizures compared to baseline and that by 2 years following treatment the percentage reduction in seizures will be identical for these two treatments. Aim 2: To compare the neuropsychological outcomes in patients undergoing radiosurgery and temporal lobe surgery, in particular with respect to verbal memory function for language-dominant hemisphere treated patients. Our hypothesis is that patients treated for speech-dominant temporal lobe seizures with temporal lobectomy will show significant reductions in verbal memory and those patients treated with radiosurgery will not have significant reduction in measures of verbal memory. Aim 3: To determine what changes occur in the quality of life of patients with temporal lobe epilepsy following radiosurgical treatment as compared with open surgery. Our primary hypothesis is that there will be improvements (comparing baseline with 3 years post- treatment) in quality of life measures in both groups. Our secondary hypothesis is that both open surgery and radiosurgery subjects will undergo transient reductions in quality of life measures caused by treatment effects during the first year following treatment, but that quality of life will improve for subjects who become seizure-free, independent of treatment group. Aim 4: To compare the cost-effectiveness of radiosurgery compared with open surgery. We hypothesize that radiosurgery will be cost-effective compared to temporal lobectomy over the lifetime of the patient. The purpose of this study is to compare two methods of treatment of surgically-amenable epilepsy: standard anterior temporal lobectomy versus noninvasive Gamma Knife radiosurgery. Beyond the main outcome of the number of patients rendered seizure-free, we will compare preservation of language functions, quality of life measures, and the cost of treatment. PUBLIC HEALTH RELEVANCE: Pharmaco-resistant epilepsy is a significant health problem for which new therapies are needed. This study is designed to compare traditional surgery (temporal lobectomy) with the novel technique of Gamma Knife radiosurgery in the treatment of patients with temporal lobe epilepsy. This therapy would offer a non-invasive approach to this problem with potential reduction in morbidity (surgical complications, reduced language function). The study is designed to show that this therapy will improve quality of life for patients with epilepsy with reduced complications and cost-savings.