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.


METHODS
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).


CONCLUSIONS
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.
Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. K.Boshuisen-2@umcutrecht.nl.
Kim
K
Boshuisen
Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. H.J.Lamberink@umcutrecht.nl.
Herm J
HJ
Lamberink
Department of Child Neuropsychology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands. M.vanSchooneveld-2@umcutrecht.nl.
Monique Mj
MM
van Schooneveld
Neurosciences Unit, UCL-Institute of Child Health, Great Ormond Street Hospital for Children NHS Foundation Trust, London & Young Epilepsy Lingfield, UK. H.cross@ucl.ac.uk.
J Helen
JH
Cross
Epilepsy, Sleep and Pediatric Neurophysiology Department (ESEFNP), University Hospitals of Lyon (HCL), Lyon, France. aarzimanoglou@orange.fr.|Lyon Neuroscience Research Center, DYCOG team (CRNL, INSERM/CNRS), Lyon, France. aarzimanoglou@orange.fr.
Alexis
A
Arzimanoglou
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. I.vanderTweel@umcutrecht.nl.
Ingeborg
I
van der Tweel
Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. C.P.W.Geleijns-4@umcutrecht.nl.
Karin
K
Geleijns
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. C.S.P.M.Uiterwaal@umcutrecht.nl.
Cuno Spm
CS
Uiterwaal
Department of Child Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands. K.Braun@umcutrecht.nl.
Kees Pj
KP
Braun
D000293:Adolescent; D000294:Adolescent Behavior / Q000187:drug effects; D000927:Anticonvulsants / Q000008:administration & dosage*; D001288:Attention / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000503:physiopathology / Q000601:surgery*; D058256:Brain Waves / Q000187:drug effects; D002648:Child; D002652:Child Behavior / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D004334:Drug Administration Schedule; D004569:Electroencephalography; D004827:Epilepsy / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology / Q000601:surgery*; D056344:Executive Function / Q000187:drug effects; D005260:Female; D006801:Humans; D007360:Intelligence / Q000187:drug effects; D007361:Intelligence Tests; D008279:Magnetic Resonance Imaging; D008297:Male; D009426:Netherlands; D009483:Neuropsychological Tests; D019635:Neurosurgical Procedures; D011788:Quality of Life; D013997:Time Factors; D016896:Treatment Outcome
D000927:Anticonvulsants