ERSET was designed to compare medical and surgical therapy early in the course of pharmacoresistance, at which time the superiority of surgery is not proven and equipoise exists. The equipoise required was established by choosing a definition of “early” for which the demonstrated beneficial effects of surgical treatment are balanced by: 1) the possibility that seizures will be controlled by pharmacotherapy within one or two years and 2) the risks of adverse effects of surgery, including disturbances in memory and learning in individuals whose seizures have not persisted long enough to produce such cognitive deficits. The definition of “early” for this study was based on duration of pharmacoresistance; consequently pharmacoresistance first had to be defined.
Although an influential study reported that only 11% of patients became seizure free following failure of the first AED due to inefficacy and not intolerance, and only 3% became seizure free after failing two AEDs (Kwan and Brodie, 2000
),subsequent studies have suggested that there are
populations of patients who have a much higher likelihood of becoming seizure free after failing two or three AED trials (Bauer et al., 2008
; Callaghan et al., 2007
; Llimatainen et al., 2008
; Luciano and Shorvon, 2007
). ERSET defined pharmacoresistance as failure of two adequate AED trials due to inefficacy and not intolerance, and the International League against Epilepsy (ILAE) recently issued a report defining pharmacoresistance similarly (Kwan et al., 2009
ERSET investigators arbitrarily defined “early” as within two years of a diagnosis of pharmacoresistance; however, this proved to be difficult to operationally apply, given that patients with MTLE commonly experience a stuttering course with long periods of remission (Berg et al., 2003
). Consequently, this criterion was qualified by inserting the word “consecutive,” which was defined as no inter-seizure intervals of six months or greater during the two year period. This allowed inclusion of patients who met criteria for pharmacoresistance, but then entered a long period of remission within two years. Such patients would be eligible for ERSET if seizures later recurred at the required rate of one seizure day or more per two month period.
It was the intention of ERSET investigators to include as pure a population of MTLE patients as possible. MTLE, however, is not a single, homogeneous condition (Engel et al., 2008
; Wieser et al., 2004
). Although it was anticipated that most participants would have unilateral hippocampal sclerosis, patients with MRI evidence of mesial temporal lesions other than hippocampal sclerosis were also included. The important criterion was that all participants included in ERSET would be considered candidates for anteromesial temporal resection at most epilepsy surgery centers prior to randomization. Candidacy had to be established by noninvasive presurgical evaluation because it would be unethical to perform intracranial monitoring in patients randomized to pharmacotherapy. The standardized presurgical evaluation protocol included some studies that are not routinely performed at many epilepsy surgery centers. FDG-PET studies were required in all patients, in part because PET is capable of identifying mesial temporal abnormalities in patients with normal MRIs (Hogan et al., 2008
), but it is also important to know whether FDG-PET might contribute additional information of value even when MRIs are positive. Also, bilateral IAPs were performed in all patients, not only to ensure that the contralateral hemisphere could support memory, but to determine whether this procedure might be useful in predicting postoperative memory deficits in patients early in the course of MTLE who might not be experiencing memory disturbances.
ERSET excluded patients under the age of 12 years. Although MTLE typically begins in late childhood and takes several years to become pharmacoresistant, it is conceivable that early surgical intervention in some patients ought to occur in children younger than 12 years old. However, this lower age limit was necessitated by the fact that HRQOL was the most important secondary outcome domain, and none of the available quantitative instruments are valid below the age of 12.
An important feature of the ERSET experimental design was the standardized progressive pharmacotherapy protocol overseen by an independent pharmacotherapy committee made up of specialists in clinical pharmacology of AEDs who are not involved in epilepsy surgery. This was intended to ensure that although study sites were epilepsy surgery centers, investigators were committed to making every effort to eliminate disabling seizures as quickly as possible in participants randomized to the medical arm.
Standardization of surgical therapy required considerable effort to enlist the cooperation of surgeons, who had to agree, on occasion, to change their surgical approaches. To clarify situations in which surgical results can be generally applied, it was also necessary to establish specific minimal experience criteria not only for epilepsy surgery centers, but for the surgeons participating in the study. It is anticipated that results similar to those to be reported for the ERSET study might not be obtained at centers, and by surgeons, who do not meet these experience criteria.