The ERSET Trial of Early Surgery for Mesial Temporal Lobe Epilepsy

Pharmacoresistant epilepsy develops in approximately 25% to 30% of all epilepsy patients.1 Mesial temporal lobe epilepsy (MTLE) patients tend to be most refractory to treatment with antiepileptic drugs (AEDs), accounting for the highest percentage of epilepsy patients without seizure freedom.1 However, despite Wiebe et al demonstrating in a Canadian randomized controlled trial that temporal lobe resection (TLR) led to significantly higher rates of seizure freedom than medical management in patients with MTLE,2 temporal lobe epilepsy surgery remains underutilized. To investigate the potential benefits of early surgical intervention in medically refractory MTLE, the National Institutes of Health (NIH) funded the Early Randomized Surgical Epilepsy Trial (ERSET), the results of which were recently published in JAMA.3 ERSET was a multicenter randomized, controlled, parallel group trial led by Engel and colleagues at UCLA, comparing "early" TLR to best medical management in patients with pharmacoresistant MTLE. Strict criteria for entry into the study were designed to obtain as pure a population of “early” MTLE patients as possible. Patients were eligible for enrollment if they were >12 years old, diagnosed with MTLE, and had disabling seizures that persisted for no more than 2 years following adequate trials of 2 AEDs. Patients had to undergo a lengthy protocol-driven enrollment process including neuropsychological assessment, magnetic resonance imaging/positron emission tomography imaging and inpatient video-EEG telemetry, all of which had to be consistent with a diagnosis of MTLE. Unfortunately this, along with other factors such as patients who had decided on surgery not wanting to be randomized, led to slow patient accrual. The study was terminated early, after enrolling only 38 patients out of a target goal of 200. Nevertheless, the ERSET trial contains important data that can be used by neurosurgeons and inform us for future trials. Of the 38 patients, 23 were randomized to the medical group, and 15 to the surgical group. Although the medical group was, on average, younger and more likely to be male, the groups were remarkably comparable with similar durations of epilepsy, number of AEDs used, IQ scores, and pre-op quality of life (QOL) scores. The primary outcome measure was seizure freedom in the second year of follow-up. Strikingly, 0/23 patients in the medical group and 11/15 patients in the surgery group were seizure-free in the second year. QOL scores were significantly higher in the surgery group at 6, 12, and 18 months post-randomization (Figure). There were no significant differences in cognitive outcomes with respect to the primary memory and non-memory measures used. Surgery patients tended to perform worse on memory measures, however, and specifically performed statistically worse on delayed recall and naming tasks. The small sample size precludes any definitive conclusions to be made about the cognitive effects of surgery.Figure: Adjusted mean QOLIE-89 overall T-score over time by treatment group.The ERSET trial reflects both the possibility of TLR to positively impact MTLE patients' lives and the difficulties involved in recruiting them. While clinicians should be cautious about interpreting trials that have been stopped early because of a possible positive bias effect, it should be noted that this study was stopped early solely because of slow patient accrual. Combined with similar previous results,2 the clinical benefit of surgery for seizure freedom in this study was so large as to make its benefit seem unquestionable. If early surgery for MTLE has such positive benefits for patients in terms of seizure freedom, why is it still so difficult for these patients to reach a neurosurgeon's office? There is little data on barriers to referral,4 but patient attitudes towards surgery as a “last resort” and clinicians' concerns about surgical risks and cognitive deficits likely both contribute. Regardless, this study supports the use of TLR for MTLE patients soon after pharmacoresistance has been established. There is additional importance in ERSET's inability to recruit surgical candidates. Accurate estimates for recruitment for surgical randomized trials is critical to avoid trials being shut down for lack of enrollment. MTLE is now again being studied with randomization to either TLR or gamma knife radiosurgery (ROSE trial). While surgeons may believe in clinical equipoise between these 2 treatment arms, patients often view them very differently in terms of their potential risks and benefits. Hopefully the ERSET trial's limited but very positive results will provide momentum to the population of untreated MTLE patients to seek surgical treatment. It remains to be seen whether ERSET will help the ROSE trial to adequately randomize its treatment arms, rather than serve as a harbinger of the difficulty of trying to enroll a randomized MTLE surgical trial.

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