Timing of antiepileptic drug withdrawal and long-term seizure outcome after paediatric epilepsy surgery (TimeToStop): a retrospective observational study Kim Boshuisen, Alexis Arzimanoglou, J Helen Cross, Cuno S P M Uiterwaal, Tilman Polster, Onno van Nieuwenhuizen, Kees P J Braun, for the TimeToStop study group*
Summary Lancet Neurol 2012; 11: 784–91 Published Online July 27, 2012 http://dx.doi.org/10.1016/ S1474-4422(12)70165-5 See Comment page 745 *Members listed at end of paper Department of Child Neurology, Rudolf Magnus Institute of Neuroscience (K Boshuisen MD, Prof O van Nieuwenhuizen MD, Prof K P J Braun MD) and Julius Center for Health Sciences and Primary Care (C S P M Uiterwaal MD), University Medical Center Utrecht, Utrecht, Netherlands; Department of Epilepsy, Sleep and Paediatric Neurophysiology, Hôpital Femme Mère Enfant, University Hospitals of Lyon, Lyon, France (A Arzimanoglou MD); TIGER Research Group, INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Center, Brain Dynamics and Cognition Team, Lyon, France (A Arzimanoglou); Neurosciences Unit, University College London, Institute of Child Health, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK (Prof J H Cross MD); Young Epilepsy, Lingﬁeld, UK (Prof J H Cross); and Department of Child Neurology, Bethel Epilepsy Center, Bielefeld, Germany (T Polster MD) Correspondence to: Prof Kees P J Braun, Department of Child Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, PO Box 85090, 3508 AB Utrecht, Netherlands [email protected]
Background Postoperative antiepileptic drug (AED) withdrawal practices remain debatable and little is known about the optimum timing. We hypothesised that early AED withdrawal does not aﬀect long-term seizure outcome but allows identiﬁcation of incomplete surgical success earlier than late withdrawal. We aimed to assess the relation between timing of AED withdrawal and subsequent seizure recurrence and long-term seizure outcome. Methods TimeToStop included patients aged under 18 years from 15 centres in Europe who underwent surgery between Jan 1, 2000, and Oct 1, 2008, had at least 1 year of postoperative follow-up, and who started AED reduction after having reached postoperative seizure freedom. Time intervals from surgery to start of AED reduction (TTR) and complete discontinuation (TTD) were studied in relation to seizure recurrence during or after AED withdrawal, seizure freedom for at least 1 year, and cure (deﬁned as being seizure free and oﬀ AEDs for at least 1 year) at latest follow-up. Cox proportional hazards regression models were adjusted for identiﬁed predictors of timing intervals. Findings TimeToStop included 766 children. Median TTR and TTD were 12·5 months (95% CI 11·9–13·2) and 28·8 months (27·4–30·2), respectively. 95 children had seizure recurrence during or after AED withdrawal. Shorter time intervals predicted seizure recurrence (hazard ratio [HR] 0·94, 95% CI 0·89–1·00, p=0·05 for TTR; and 0·90, 0·83–0·98, p=0·02 for TTD). After a mean postoperative follow-up of 61·6 months (SD 29·7), 728 patients were seizure free for at least 1 year. TTR and TTD were not related to regain of seizure freedom after restart of drug treatment (HR 0·98, 95% CI 0·92–1·05, p=0·62; and 0·93, 0·83–1·05, p=0·26, respectively), or to seizure freedom (0·97, 0·89–1·07, p=0·55; and 1·03, 0·93–1·14, p=0·55, respectively) or cure (0·97, 0·97–1·03, p=0·84; and 0·98, 0·94–1·02, p=0·31, respectively) at ﬁnal follow-up. Interpretation Early AED withdrawal does not aﬀect long-term seizure outcome or cure. It might unmask incomplete surgical success sooner, identifying children who need continuous drug treatment and preventing unnecessary continuation of AEDs in others. A prospective randomised trial is needed to study the possible cognitive eﬀects and conﬁrm the safety of early AED withdrawal after epilepsy surgery in children. Funding Dutch National Epilepsy Fund.
Introduction Epilepsy surgery is an eﬀective treatment for children with intractable epilepsy. Seizure freedom rates vary from 50% to over 80%1 and are generally reported without reference to antiepileptic drug (AED) use. Since AEDs have cognitive side-eﬀects, drug withdrawal after successful surgery will optimise the child’s cognitive abilities. Ultimately, surgery should be undertaken with the aim of curing the epilepsy, which can be deﬁned as reaching both seizure freedom and drug freedom.2 In our experience, many parents report improved alertness, attention, and behaviour once AEDs are discontinued after surgery. Findings from withdrawal studies show that AED withdrawal improves several neurocognitive outcome measures.3,4 Nevertheless, AEDs are usually continued for at least 2 years after epilepsy surgery,5 often because of fear of seizure recurrence after withdrawal and the anticipated risk of not regaining seizure freedom after restart of drugs. Although ﬁndings
from some studies have suggested a worse seizure outcome after early compared with late postoperative AED withdrawal, results are conﬂicting,5–9 and there is no consensus among centres about the optimum timing of drug withdrawal. We hypothesised that timing of drug withdrawal itself does not aﬀect seizure outcome in the long term, but that early AED withdrawal merely identiﬁes the need for continuation of postoperative AEDs sooner in patients who were not cured by surgery. We undertook a collaborative European multicentre study, the TimeToStop study, to assess AED withdrawal practices after epilepsy surgery in children and to study the relation between timing of AED withdrawal and seizure outcome.
Methods Patients The TimeToStop study is a retrospective European multicentre cohort study that was started within the www.thelancet.com/neurology Vol 11 September 2012
European Taskforce for Epilepsy Surgery in Children (appendix). 15 paediatric epilepsy surgery centres in Europe agreed to collaborate and shared their data on clinical characteristics, drug policy, and seizure outcome of children in whom AED withdrawal was started postoperatively. The decision to start withdrawal was generally made by the treating physician. The parents of some patients started withdrawing AEDs, but in these cases the date of drug withdrawal was known and noted in the medical ﬁles. Patients were included if they were operated on between Jan 1, 2000, and Oct 1, 2008, were younger than 18 years at surgery, had at least 1 year of postoperative follow-up, and if AED withdrawal was started postoperatively. Patients were excluded if their treating physician or parents decided to taper their drug treatment despite continuing postoperative seizures, including auras. The TimeToStop study was approved by the institutional ethical committee of the University Medical Center Utrecht, which concluded that the Dutch Medical Research Involving Human Subjects Act did not apply and written informed consent was not needed. The local ethical committees of all participating centres subsequently gave permission to undertake the study.
Procedures Between April 13, and Dec 19, 2009, one of the study investigators (KB) visited all centres and collected data in collaboration with local investigators and treating epileptologists. To ascertain accuracy of data extraction from the medical ﬁles, at least one collaborator per centre reviewed the data of his or her patients. Missing data were collected by means of telephone interviews with the patients or their parents, if possible. We collected data on general patient characteristics, MRI ﬁndings, pathological diagnosis, functional imaging ﬁndings, surgical strategies, ﬁrst postoperative electroencephalogram (EEG), AEDs that were ever tried during the course of the epilepsy, AEDs used at time of surgery, the ﬁrst AED to be withdrawn, and the timing of AED withdrawal. The data included all variables that were previously reported to be independently associated with seizure outcome after epilepsy surgery (appendix).1,6–21 Preoperative cognitive functioning was classiﬁed as developmental delay if intelligence or developmental quotients were below 70 or if mental retardation was noted but not further speciﬁed in the patient ﬁles. Invasive EEG recordings included grid or strip implantation, stereo-EEG, or other depth electrodes. Type of surgery was classiﬁed as lobar (including tailored) resection, multilobar resection, or hemispherectomy. Lobar resections were subclassiﬁed as frontal, temporal, parietal, and occipital. The resection of MRI-conﬁrmed lesions was classiﬁed as anatomically complete if the region of the structural abnormality was completely resected according to postoperative MRI scans or histology and incomplete if these examinations suggested www.thelancet.com/neurology Vol 11 September 2012
residual abnormal tissue. In all other patients, completeness of resection of the anatomical lesion was classiﬁed as not determined. Resection of the epileptogenic focus was classiﬁed as complete if post-resection intraoperative electrocorticography did not show persistent active spiking with consistent focality, rhythmic features such as trains of fast focal activity, or spiking associated with focal attenuation of background activity,13 and as incomplete if it showed persistent epileptic activity or if the resection did not include the whole epileptogenic zone, as assessed by preoperative intracranial recordings. In all other patients, completeness of resection of the epileptogenic focus was classiﬁed as not determined. Immediate seizure freedom was deﬁned as not having had any seizures since surgery. Delayed seizure freedom was deﬁned as either having had running down seizures (deﬁned as ongoing seizures in the immediate postoperative period that disappear within 2 weeks) or having had seizures over a period of more than 2 weeks after surgery and reaching seizure freedom at least 2 months before the start of AED w...