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Design considerations for a multicenter randomized controlled trial of early surgery for mesial temporal lobe epilepsy.

ABSTRACT: To describe the trial design for the multicenter Early Randomized Surgical Epilepsy Trial (ERSET). Patients with pharmacoresistant epilepsy are generally referred for surgical treatment an average of two decades after onset of seizures, often too late to avoid irreversible disability. ERSET was designed to assess the safety and efficacy of early surgical intervention compared to continued pharmacotherapy.ERSET is a randomized controlled, parallel group clinical trial with blinded outcome adjudication. Participants are patients with mesial temporal lobe epilepsy (MTLE) older than the age of 12 who have had pharmacoresistant seizures for not >2 years and are determined by detailed evaluation to be surgical candidates prior to randomization. The primary outcome measure is seizure freedom in the second year of a 2-year follow-up period. Health-related quality of life (HRQOL), neurocognitive function, ancillary outcomes, and adverse events were also measured.Significant methodologic problems addressed by the study design included the following: recruitment of participants early in the course of epilepsy; establishment of operational definitions for "pharmacoresistant" and "early"; and standardization of diagnostic testing, medical treatment, and surgical interventions across multiple centers.Rigorous trial designs to assess surgical interventions in epilepsy are necessary to provide evidence to guide treatment. This article is the first of a series; trial results will be reported in subsequent publications.

SUBMITTER: Engel J

PROVIDER: S-EPMC2941700 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Design considerations for a multicenter randomized controlled trial of early surgery for mesial temporal lobe epilepsy.

Engel Jerome J McDermott Michael P MP Wiebe Samuel S Langfitt John T JT Erba Giuseppe G Gardiner Irenita I Stern John J Dewar Sandra S Sperling Michael R MR Jacobs Margaret M Kieburtz Karl K

Epilepsia 20101001 10

<h4>Purpose</h4>To describe the trial design for the multicenter Early Randomized Surgical Epilepsy Trial (ERSET). Patients with pharmacoresistant epilepsy are generally referred for surgical treatment an average of two decades after onset of seizures, often too late to avoid irreversible disability. ERSET was designed to assess the safety and efficacy of early surgical intervention compared to continued pharmacotherapy.<h4>Methods</h4>ERSET is a randomized controlled, parallel group clinical tr ...[more]

PMID: 20550556

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Project description:BackgroundMRI-guided laser interstitial thermal therapy (MRgLITT) is a new minimally invasive treatment for temporal lobe epilepsy (TLE), with limited effectiveness data. It is unknown if the cost savings associated with shorter hospitalization could offset the high equipment cost of MRgLITT. We examined the cost-utility of MRgLITT versus surgery for TLE from healthcare payer perspective, and the value of additional research to inform policy decision on MRgLITT.MethodsWe developed a microsimulation model to evaluate quality adjusted life years (QALYs), costs, and incremental cost-effectiveness ratio (ICER) of MRgLITT versus surgery in TLE, assuming life-time horizon and 1.5% discount rate. Model inputs were derived from the literature. We conducted threshold and sensitivity analyses to examine parameter uncertainties, and expected value of partial perfect information analyses to evaluate the expected monetary benefit of eliminating uncertainty on probabilities associated with MRgLITT.ResultsMRgLITT yielded 0.08 more QALYs and cost $7,821 higher than surgery, with ICER of $94,350/QALY. Influential parameters that could change model outcomes include probabilities of becoming seizure-free from disabling seizures state and returning to disabling seizures from seizure-free state 5 years after surgery and MRgLITT, cost of MRgLITT disposable equipment, and utilities of disabling seizures and seizure-free states of surgery and MRgLITT. The cost-effectiveness acceptability curve showed surgery was preferred in more than 50% of iterations. The expected monetary benefit of eliminating uncertainty for probabilities associated with MRgLITT was higher than for utilities associated with MRgLITT.ConclusionsMRgLITT resulted in more QALYs gained and higher costs compared to surgery in the base-case. The model was sensitive to variations in the cost of MRgLITT disposable equipment. There is value in conducting more research to reduce uncertainty on the probabilities and utilities of MRgLITT, but priority should be given to research focusing on improving the precision of estimates on effectiveness of MRgLITT.

Project description:The epilepsies represent one of the most common neurological disorders. Mesial temporal lobe epilepsies (MTLE) are the most frequent form of partial epilepsies and display frequent resistance to anti-epileptic drugs thus representing a major health care problem. In TLE, the origin of seizure activity typically involves the hippocampal formation, which displays major neuropathological features, described with the term hippocampal sclerosis (HS). HS is the most frequent pathological substrate of refractory mesial temporal lobe epilepsy. Complex partial seizures (CPS) are the predominant seizure type associated with medial temporal lobe epilepsy. MTLE is commonly due to mesial temporal sclerosis (MTS). The biology underlying the epilepstic seizures and the transcriptome associated to the seizure in intractable medial temporal lobe epilepsy is ill understood. The aim of the study was to identify potential biomarkers that could identify epileptic seizure. Thus we performed transcriptome profiling of ten medial temporal lobe epilepsy cases which are resistant to the drug and underwent temporal lobectomy. The cases constitutes of patients with intractable complex partial seizure, treated medically and have undergone detailed presurgical evaluation and subjected to surgery for standard temporal lobectomy and amygdalo-hippocampectomy. The spiking areas identified after the electrocorticography will form the test tissues, which compared with the nonspiking areas removed during the surgery, from the same patient. This could probably form one of the appropriate controls, as test and control are from same patient, which eliminates the genome variations that could incur due to the comparison with the tissues from the another patient. Also this could get rid of expression changes due to the treatments undergone by the patient. We performed two color microarray wherein we labled seizure focus (spiking area) with Cy5 and non-seizure region tissues (non-spiking) with Cy3. As a strategy to test the possibility of potential diagnostic biomarkers we are intended to test the differentially regulated molecules in an independent set of epilepsy samples. Two color experiment

Project description:OBJECTIVES:Brain functional topology was investigated in patients with mesial temporal lobe epilepsy (mTLE) by means of graph theory measures in two differentially defined graphs. Measures of segregation, integration, and centrality were compared between subjects with mTLE and healthy controls (HC). METHODS:Eleven subjects with mTLE (age 36.5±10.9years) and 15 age-matched HC (age 36.8±14.0years) participated in this study. Both anatomically and functionally defined adjacency matrices were used to investigate the measures. Binary undirected graphs were constructed to study network segregation by calculating global clustering and modularity, and network integration by calculating local and global efficiency. Node degree and participation coefficient were also computed in order to investigate network hubs and their classification into provincial or connector hubs. Measures were investigated in a range of low to medium graph density. RESULTS:The group of patients presented lower global segregation than HC while showing higher global but lower local integration. They also failed to engage regions that comprise the default-mode network (DMN) as hubs such as bilateral medial frontal regions, PCC/precuneus complex, and right inferior parietal lobule, which were present in controls. Furthermore, the cerebellum in subjects with mTLE seemed to be playing a major role in the integration of their functional networks, which was evident through the engagement of cerebellar regions as connector hubs. CONCLUSIONS:Functional networks in subjects with mTLE presented both global and local abnormalities compared to healthy subjects. Specifically, there was significant separation between groups, with lower global segregation and slightly higher global integration observed in patients. This could be indicative of a network that is working as a whole instead of in segregated or specialized communities, which could translate into a less robust network and more prone to disruption in the group with epilepsy. Furthermore, functional irregularities were also observed in the group of patients in terms of the engagement of cerebellar regions as hubs while failing to engage DMN-related areas as major hubs in the network. The use of two differentially defined graphs synergistically contributed to findings.

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Design considerations for a multicenter randomized controlled trial of early surgery for mesial temporal lobe epilepsy.

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Design considerations for a multicenter randomized controlled trial of early surgery for mesial temporal lobe epilepsy.

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