Stopping seizures early and the surgical epilepsy trial that stopped even earlier.

EPILEPSY, A COMMON CHRONIC NEUROLOGICAL DISORder, literally means “recurrent seizures” and affects approximately 1% to 1.5% of the population. Approximately 30% of individuals with epilepsy continue to experience seizures despite using antiepileptic drugs (AEDs). Many patients have serious adverse effects from the use of AEDs. Those with refractory epilepsy are forced to endure the risk of sudden unexpected (unexplained) death from epilepsy or premature death from other causes. Most patients with epilepsy have focal onset seizures or “partial epilepsy. ” A subset has mesial temporal lobe epilepsy (MTLE), a disorder with well-recognized premonitory symptoms that include deja vu, rising epigastric distress, experiential and hallucinatory phenomena, altered awareness, and automatisms. These patients also have well-recognized radiographic imaging abnormalities, eg, hippocampal atrophy, sclerosis, or both, and a reasonably predictable long-term course. Many patients with refractory partial epilepsy may benefit from a neurosurgical removal of the seizure “focus. ” Although the diagnosis, methods for defining the focus, surgical techniques, and retrospective improvement in seizure control have been well-documented in the literature, little class 1 evidence exists for surgical intervention. The Early Randomized Surgical Epilepsy Trial (ERSET), reported in this issue of JAMA, was designed as a second prospective study evaluating the efficacy of surgical treatment for patients with refractory MTLE. Engel et al enrolled patients 12 years or older with no more than 2 years of disabling MTLE, despite adequate treatment with AEDs, and randomized them to receive either continued medical therapy alone or “classic” en bloc anteromesial temporal resection (AMTR) combined with medical therapy. The primary outcome was seizure freedom during the second year of follow-up. Secondary outcomes were quality of life (QOL) measures, cognitive functioning, employment and educational status, permission to drive, and hospitalizations. The trial intent was to enroll 200 patients but was terminated on recommendation of the data and safety monitoring board (DSMB) after 38 patients had been randomized. The DSMB based this recommendation on the slow pace of enrollment, although the DSMB apparently had access to unblinded primary outcome data for study participants who had completed the second year of follow-up. The difference in the primary outcome was striking. Based on the prespecified analysis, none of 23 patients in the medical therapy group were seizure free during the second year of follow-up, whereas 11 of 15 patients (73%) in the surgical resection group were seizure free. QOL was better in the surgical group as well. An adverse effect on memory that was statistically significant was observed in the surgical group: worse scores on immediate and delayed recall tests at 24 months and a higher percentage with decline (36% vs 0%) in delayed verbal recall at 12 months. There was no significant difference between treatment groups in terms of employment status. Even though the benefit of AMTR in reducing disabling seizures observed in ERSET appears substantial, results of trials that are terminated very early should be interpreted with caution, especially when termination is not based on prespecified rules, because of the risk of bias. During any clinical trial, random fluctuations in observed treatment effects are seen over time, although the relative magnitude of these variations decreases as cumulative data increase. The greatest risk of positive bias occurs if the decision to terminate the trial is influenced by knowledge of the apparent treatment effect and occurs very early in the trial, because the timing of the termination most likely coincides with a substantial and positive random fluctuation in the apparent treatment effect. In contrast, early termination of a trial without knowledge of the currently observed treatment effect should not lead to bias. Contemporary clinical trials often include prespecified stopping rules that define a limited number of planned interim analyses and allow the trial to be terminated early should the evidence of treatment difference be overwhelming. While such stopping rules are informed by the apparent treatment effect at the interim analysis, and thus could introduce bias, the magnitude of the bias is actually quite minimal for commonly used approaches. Controversy nonetheless exists and some authors have reported empiri-