Cognitive consequences of early versus late antiepileptic drug withdrawal after pediatric epilepsy surgery, the TimeToStop (TTS) trial: study protocol for a randomized controlled trial.

Background: The goals of intentional curative pediatric epilepsy surgery are to achieve seizure-freedom and antiepileptic drug (AED) freedom. Retrospective cohort studies have indicated that early postoperative AED withdrawal unmasks incomplete surgical success and AED dependency sooner, but not at the cost of long-term seizure outcome. Moreover, AED withdrawal seemed to improve cognitive outcome. A randomized trial is needed to confirm these findings. We hypothesized that early AED withdrawal in children is not only safe, but also beneficial with respect to cognitive functioning.

Design: This is a multi-center pragmatic randomized clinical trial to investigate whether early AED withdrawal improves cognitive function, in terms of attention, executive function and intelligence, quality of life and behavior, and to confirm safety in terms of eventual seizure freedom, seizure recurrences and "seizure and AED freedom." Patients will be randomly allocated in parallel groups (1:1) to either early or late AED withdrawal. Randomization will be concealed and stratified for preoperative IQ and medical center. In the early withdrawal arm reduction of AEDs will start 4 months after surgery, while in the late withdrawal arm reduction starts 12 months after surgery, with intended complete cessation of drugs after 12 and 20 months respectively. Cognitive outcome measurements will be performed preoperatively, and at 1 and 2 years following surgery, and consist of assessment of attention and executive functioning using the EpiTrack Junior test and intelligence expressed as IQ (Wechsler Intelligence Scales). Seizure outcomes will be assessed at 24 months after surgery, and at 20 months following start of AED reduction. We aim to randomize 180 patients who underwent anticipated curative epilepsy surgery below 16 years of age, were able to perform the EpiTrack Junior test preoperatively, and have no predictors of poor postoperative seizure prognosis (multifocal magnetic resonance imaging (MRI) abnormalities, incomplete resection of the lesion, epileptic postoperative electroencephalogram (EEG) abnormalities, or more than three AEDs at the time of surgery).

Discussion: Growing experience with epilepsy surgery has changed the view towards postoperative medication policy. In a European collaboration, we designed a multi-center pragmatic randomized clinical trial comparing early with late AED withdrawal to investigate benefits and safety of early AED withdrawal. The TTS trial is supported by the Dutch Epilepsy Fund (NL 08-10) ISRCTN88423240/ 08/05/2013.