Laboratory for Economic Management and Auctions Understanding Beta (A) “I don’t understand it! Yahoo has been such a winner, why has it collapsed so much?” bellowed Frank in the next cubicle. Sarah had endured Frank’s gloating over the success of his stock the year before last, but she suppressed a slight chuckle and decided to show him some pity. She felt she had to, since her
Timing of antiepileptic drug withdrawal and long-term seizure outcome after paediatric epilepsy surgery (timetostop): a retrospective observational studyArticles
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* Lancet Neurol 2012; 11: 784–91
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 aﬀ ect long-term seizure outcome but
allows identiﬁ cation 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.
See Comment page 745
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
Department of Child
after having reached postoperative seizure freedom. Time intervals from surgery to start of AED reduction (TTR) and
Neurology, Rudolf Magnus
Institute of Neuroscience
complete discontinuation (TTD) were studied in relation to seizure recurrence during or after AED withdrawal,
seizure freedom for at least 1 year, and cure (deﬁ ned as being seizure free and oﬀ AEDs for at least 1 year) at latest
follow-up. Cox proportional hazards regression models were adjusted for identiﬁ ed predictors of timing intervals.
Prof K P J Braun MD) and Julius
Center for Health Sciences and
Findings TimeToStop included 766 children. Median TTR and TTD were 12·5 months (95% CI 11·9–13·2) and
(C S P M Uiterwaal MD),
28·8 months (27·4–30·2), respectively. 95 children had seizure recurrence during or after AED withdrawal. Shorter
University Medical Center
time intervals predicted seizure recurrence (hazard ratio [HR] 0·94, 95% CI 0·89–1·00, p=0·05 for TTR; and 0·90,
Utrecht, Utrecht, Netherlands;
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
Department of Epilepsy, Sleep
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
Femme Mère Enfant,
(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,
University Hospitals of Lyon,
0·94–1·02, p=0·31, respectively) at ﬁ nal follow-up.
(A Arzimanoglou MD); TIGER
Research Group, INSERM
Interpretation Early AED withdrawal does not aﬀ ect long-term seizure outcome or cure. It might unmask incomplete
U1028, CNRS UMR5292, Lyon
surgical success sooner, identifying children who need continuous drug treatment and preventing unnecessary
Neuroscience Research Center,
continuation of AEDs in others. A prospective randomised trial is needed to study the possible cognitive eﬀ ects and
Brain Dynamics and Cognition
Team, Lyon, France
conﬁ rm the safety of early AED withdrawal after epilepsy surgery in children.
Neurosciences Unit, University
Funding Dutch National Epilepsy Fund.
College London, Institute of
Child Health, Great Ormond
Street Hospital for Children,
from some studies have suggested a worse seizure NHS Foundation Trust,
Epilepsy surgery is an eﬀ ective treatment for children outcome after early compared with late postoperative London, UK (Prof J H Cross MD);
with intractable epilepsy. Seizure freedom rates vary AED with drawal, results are conﬂ icting,5–9 and there is no Young Epilepsy, Lingﬁ eld, UK
from 50% to over 80%1 and are generally reported consensus among centres about the optimum timing of (Prof J H Cross); and
Department of Child
without reference to antiepileptic drug (AED) use. Since drug withdrawal. We hypothesised that timing of drug Neurology, Bethel Epilepsy
AEDs have cognitive side-eﬀ ects, drug withdrawal after withdrawal itself does not aﬀ ect seizure outcome in the Center, Bielefeld, Germany
successful surgery will optimise the child’s cognitive long term, but that early AED withdrawal merely abilities. Ultimately, surgery should be undertaken with identiﬁ es the need for continuation of postoperative the aim of curing the epilepsy, which can be deﬁ ned as AEDs sooner in patients who were not cured by surgery. reaching both seizure freedom and drug freedom.2 We undertook a collaborative European multicentre In our experience, many parents report improved study, the TimeToStop study, to assess AED withdrawal alertness, attention, and behaviour once AEDs are practices after epilepsy surgery in children and to study discontinued after surgery. Findings from withdrawal the relation between timing of AED withdrawal and email@example.com
studies show that AED withdrawal improves several seizure outcome.
neurocognitive outcome measures.3,4 Nevertheless, AEDs
are usually continued for at least 2 years after epilepsy Methods
surgery,5 often because of fear of seizure recurrence after
withdrawal and the anticipated risk of not regaining The TimeToStop study is a retrospective European seizure freedom after restart of drugs. Although ﬁ ndings multicentre cohort study that was started within the www.thelancet.com/neurology Vol 11 September 2012
European Taskforce for Epilepsy Surgery in Children residual abnormal tissue. In all other patients,
(appendix). 15 paediatric epilepsy surgery centres in completeness of resection of the anatomical lesion was See Online for appendix
Europe agreed to collaborate and shared their data on classiﬁ ed as not determined. Resection of the epilepto-
clinical characteristics, drug policy, and seizure outcome genic focus was classiﬁ ed as complete if post-resection
of children in whom AED withdrawal was started intraoperative electro
postoperatively. The decision to start withdrawal was sistent active spiking with consistent focality, rhythmic generally made by the treating physician. The parents of features such as trains of fast focal activity, or spiking some patients started with drawing AEDs, but in these associated with focal attenuation of background activity,13 cases the date of drug withdrawal was known and noted and as incomplete if it showed persistent epileptic activity in the medical ﬁ les.
or if the resection did not include the whole epileptogenic Patients were included if they were operated on between zone, as assessed by preoperative intracranial recordings. Jan 1, 2000, and Oct 1, 2008, were younger than 18 years at In all other patients, complete ness of resection of the surgery, had at least 1 year of postoperative follow-up, and epileptogenic focus was classiﬁ ed as not determined. if AED withdrawal was started postoperatively. Patients Immediate seizure freedom was deﬁ ned as not having were excluded if their treating physician or parents had any seizures since surgery. Delayed seizure freedom decided to taper their drug treatment despite continuing was deﬁ ned as either having had running down seizures postoperative seizures, including auras.
ned as ongoing seizures in the immediate The TimeToStop study was approved by the insti- postoperative period that disappear within 2 weeks) or tutional ethical committee of the University Medical having had seizures over a period of more than 2 weeks Center Utrecht, which concluded that the Dutch Medical after surgery and reaching seizure freedom at least Research Involving Human Subjects Act did not apply 2 months before the start of AED withdrawal. Subjective and written informed consent was not needed. The local determinants of withdrawal, such as AED side-eﬀ ects, ethical committees of all participating centres parents insisting on withdrawal, and the treating subsequently gave permission to undertake the study.
physician’s estimates of surgical success (the chance of reaching seizure freedom) were not consistently Procedures
documented and could therefore not be analysed.
Between April 13, and Dec 19, 2009, one of the study The course of AED withdrawal was divided into the investigators (KB) visited all centres and collected data in time interval between surgery and start of drug with- collaboration with local investigators and treating drawal (time to reduction [TTR]) and the time interval epileptologists. To ascertain accuracy of data extraction from surgery to complete discontinuation of AEDs (time from the medical ﬁ les, at least one collaborator per centre to discontinuation [TTD]). The study outcome measures reviewed the data of his or her patients. Missing data were (1) seizure recurrence during or after AED were collected by means of telephone interviews with the withdrawal, (2) seizure freedom at ﬁ nal follow-up, patients or their parents, if possible.
deﬁ ned as seizure freedom without auras for at least 1 year, We collected data on general patient characteristics, regardless of AED use (Engel class 1 or International MRI ﬁ ndings, pathological diagnosis, functional im aging League Against Epilepsy class 1),22,23 and (3) cure at ﬁ nal ﬁ ndings, surgical strategies, ﬁ rst postoperative electro- follow-up, deﬁ ned as being seizure free and oﬀ AEDs for encephalogram (EEG), AEDs that were ever tried during at least 1 year.
the course of the epilepsy, AEDs used at time of surgery,
the ﬁ rst AED to be withdrawn, and the timing of AED Statistical analysis
withdrawal. The data included all variables that were Previously identiﬁ ed predictors of seizure outcome1,6–21
previously reported to be independently associated with were ﬁ rst tabulated against start and completion of
seizure outcome after epilepsy surgery (appen
drug withdrawal by Cox proportional hazard regression Preoperative cognitive functioning was classiﬁ ed as models to assess which factors were associated with the developmental delay if intelligence or developmental timing of AED withdrawal and could therefore be deemed quotients were below 70 or if mental retardation was potential confounders of the relation between timing and noted but not further speciﬁ ed in the patient ﬁ les. seizure outcome. Second, the crude asso ciations between Invasive EEG recordings included grid or strip TTR and TTD and the three outcome measures were implantation, stereo-EEG, or other depth electrodes. Type analysed by Cox proportional hazard regression models. of surgery was classiﬁ ed as lobar (including tailored) We then adjusted for the earlier identiﬁ ed potential resection, multilobar resection, or hemispherectomy. confounders. Continuous variables were introduced as Lobar resections were subclassiﬁ ed as frontal, temporal, such in the models; for categorical variables, we both parietal, and occipital. The resection of MRI-conﬁ rmed calculated a main eﬀ ect and created indicator variables. lesions was classiﬁ ed as anatomically complete if the Separate models were used for TTR and TTD because region of the structural abnormality was completely these were highly correlated. Data from patients who did resected according to postoperative MRI scans or not achieve 12 months of follow-up after the start of drug histology and incomplete if these examinations suggested withdrawal and who remained event-of-interest free were www.thelancet.com/neurology Vol 11 September 2012
444 completed AED withdrawal during follow-up 441 without recurrences during AED withdrawal 165 still in process of withdrawal at ﬁnal follow-up 3 after seizure recurrence, restart of AEDs, and 59 had seizure recurrence (55 AEDs restarted, 3 unknown, 1 re-operated and AEDs restarted) 55 for reasons unknown 34 had seizure recurrence after complete discontinuation* 344 cured (ie, seizure free and AED free) for >1 year at ﬁnal follow-up in patients with >1 year follow-up after start of withdrawal 2 AED free for >1 year but not seizure free 65 had not been seizure free or AED free for 1 year 734 seizure free at ﬁnal follow-up 629 Engel class 1† >1 year at ﬁnal follow-up in patients with >1 year follow-up after start of withdrawal 6 Engel class 1† <1 year at ﬁnal follow-up in patients with >1 year follow-up after start of withdrawal 99 Engel class 1† >1 year at ﬁnal follow-up but <1 year follow-up after start of withdrawal‡ 26 not seizure free at ﬁnal follow-up 6 seizure outcome unknown Figure: Study proﬁ le and postoperative AED withdrawal
AED=antiepileptic drug. *One of the patients had two recurrences, one during AED withdrawal and one after complete AED withdrawal. †Engel class 1 (patients could also have been classiﬁ ed as
International League Against Epilepsy class 1): seizure freedom without auras, regardless of AED use. ‡Censored for ﬁ nal outcome measures.
censored 1 year before ﬁ nal follow-up; ﬁ ndings from all time was 61·6 months (SD 29·7, range 12·0–117·4) after other patients were censored at ﬁ nal follow-up. In the surgery, 44·3 months (28·5, 0·3–114·9) after start of drug group of children with seizure recurrence, we analysed withdrawal, and 41·6 months (25·9, 0·0–104·9) after the crude association between time intervals and regain complete discontinuation of AEDs. The ﬁ gure shows the of seizure freedom. We used SPSS Statistics version 17.0. pattern of postoperative AED withdrawal and seizure Results are reported as hazard ratios (HRs) with 95% CIs. outcomes. 766 patients started AED reduction; median Additionally, we ran a random eﬀ ects Cox regression TTR was 12·5 months (95% CI 11·9–13·2). 62 patients analysis to exclude possible clustering eﬀ ects within had seizure recurrence during AED withdrawal. 444 (58%) centres that could bias our data, using Stata SE of 766 patients achieved complete discon version 11.1. p values were based on two-sided tests with drugs; median TTD was 28·8 months (95% CI 27·4–30·2). 0·05 as the cutoﬀ level for statistical signiﬁ cance.
seizure recurrence, one of whom also had a recurrence Role of the funding source
during AED withdrawal but discontinued the drug The sponsor of the study, the Dutch National Epilepsy afterwards, giving a total of 95 patients (12%) who had Fund (NEF 08-10), had no role in study design, data seizure recurrence overall. Of the 87 patients who restarted collection, data analysis, data interpretation, writing of the AEDs, 26 (30%) did not regain seizure freedom despite report, or the decision to submit for publication. KB and restart of drugs. At latest follow-up, 411 patients were AED KPJB had full access to all data in the study and had ﬁ nal free and 349 patients were still on AEDs.
responsibility for the decision to submit for publication.
With regard to the long-term outcome measures, at latest follow-up, 629 of 766 patients (82%) were seizure free for more than 1 year and had been followed up for at We included 766 patients in the study. The appendix lists least 1 year since start of drug withdrawal and 344 (45%) patient characteristics, surgical procedures, and other were cured. 32 children (4%) still had seizures (n=26) or preoperative and perioperative variables. Mean follow-up had not reached 1 year of seizure freedom (n=6). www.thelancet.com/neurology Vol 11 September 2012
Start of AED withdrawal (n=766)
Complete AED withdrawal (n=444)
Immediate postoperative seizure freedom† Proven complete resection of the anatomical lesion Proven incomplete resection of the anatomical lesion Data were analysed by multivariable Cox regression. For the categorical variables both the main eﬀ ect of the variable and the eﬀ ect per category using indicator variables are given. The indicator variable is always the ﬁ rst subcategory shown. Because the other subcategories are compared to this variable no HRs and p values are given. For type of surgery and time to reduction, no multivariable analysis was done because univariable analysis did not show a signiﬁ cant correlation. For categorical variables, numbers of patients are given as the total with data available for that category or by the number in each category; for non-categorical variables, numbers of patients are shown over the total number for whom information was available. AED=antiepileptic drug. HR=hazard ratio. EEG=electroencephalogram. *Malformations of cortical development: focal cortical dysplasia (n=213), hemimegalencephaly (n=20), tuberous sclerosis complex (n=26), other (n=11); tumour: dysembryoplastic neuroepithelial tumour (n=97), ganglioglioma (n=120), astrocytoma (n=32), meningioma (n=2), other (n=15); vascular lesions: ischaemic lesion (n=27), porencephalic cyst (n=31), cavernoma (n=5), Sturge-Weber syndrome (n=15), arteriovenous malformation (n=2), (old) haemorrhage (n=7). †Not having had any seizures since surgery. Table 1: Independent predictors of timing of withdrawal
99 children (13%) had been seizure free for at least 1 year Multifocal MRI lesions and epileptic EEG abnormal- at ﬁ nal follow-up, but data from these patients were ities decreased the chance of starting AED withdrawal, censored for analysis of the outcome measures because whereas a high number of AEDs used at time of surgery, they had less than 1 year of follow-up since the start of immediate postoperative seizure freedom, and no post-AED withdrawal.
operative EEG increased that chance (table 1; appendix). Between the onset of seizures and surgery, children Tumours, Rasmussen’s en cephalitis, hemispherectomy, had trialled a mean of 4·5 AEDs (SD 2·4, range 0–15). and complete ness of resection of the anatomical lesion Immediately before surgery, patients were taking a mean not having been determined increased the chance of of 1·8 AEDs (0·8, 0–5); two patients were using ﬁ ve achieving complete withdrawal of AEDs, whereas a high AEDs before surgery, 21 were using four, 112 were using number of AEDs used at surgery, previous surgery, and three, 305 were using two, 313 were using one, and seven epileptic abnormalities on post operative EEG decreased patients were already oﬀ AEDs. For six patients the latest the chance of achieving complete withdrawal of AEDs number of preoperative AEDs was unknown.
The ﬁ rst drug to be reduced was analysed in relation to In table 2, the relation between timing of withdrawal the patients who used this speciﬁ c AED preoperatively. and the three outcome measures—seizure recurrence, The appendix shows for every AED the percentage of seizure freedom, and cure—is given, with separate children who withdrew that drug ﬁ rst. The three drugs adjustment for confounders. In the unadjusted analysis, that were most frequently reduced ﬁ rst were primidone shorter TTR increased the risk of seizure recurrence (in 8 of 9 patients using this AED the time of surgery; during or after AED with drawal by 5% per 3 months. 89%), vigabatrin (in 34 of 47 patients; 72%), and TTR did not correlate with seizure freedom at ﬁ nal phenytoin (in 24 of 37 patients; 65%).
follow-up or cure. Shorter TTD increased the risk of www.thelancet.com/neurology Vol 11 September 2012
Seizure recurrences during or after AED withdrawal
Seizure freedom at end of study (Engel class 1 >1 year)
Cure at end of study (Engel class 1 and AED free >1 year)
Data were analysed by Cox regression analysis. AED=antiepileptic drug. HR=hazard ratio. TTR=time to start of AED reduction. TTD=time to complete discontinuation of AEDs. *Corrected for number of AEDs used at time of surgery, completeness of resection of the anatomical lesion, postoperative electroencephalogram ﬁ ndings, multifocal MRI lesions, immediate postoperative seizure freedom, previous surgery, cause of epilepsy, and type of surgery.
Table 2: Adjusted and unadjusted relation between timing of antiepileptic drug withdrawal and seizure outcome measures
Regain of seizure freedom
Long-term Engel class 1*
Time to start of AED reduction (per 3 months)
Incomplete resection of the anatomical lesion Incomplete resection of the epileptogenic zone Time to complete discontinuation of AEDs (per 3 months)
Incomplete resection of the anatomical lesion Incomplete resection of the epileptogenic zone Crude Cox regression analysis of the relation between timing and seizure outcome measures in the identiﬁ ed high-risk patients. EEG=electroencephalogram. HR=hazard ratio. AED=antiepileptic drug. ··=analyses that could not be undertaken because of small numbers. *Seizure freedom at end of study (Engel class 1 >1 year). †Cure at end of study (Engel class 1 and AED free >1 year).
Table 3: Relation between timing of AED withdrawal and seizure outcome in subgroups of patients at high risk of recurrence
seizure recurrence during or after AED withdrawal by hemispherectomy, epileptic abnormalities on post-9% per 3 months. TTD did not aﬀ ect the chance of operative EEG, incomplete resection of the anatomical seizure freedom or cure at ﬁ nal follow-up. Adjustment lesion, and previous surgery. The chance of reaching for potential confounders did not change the risk seizure freedom at follow-up was decreased in patients estimates or signiﬁ cance levels for seizure recurrence who used more AEDs at time of surgery and in patients during or after AED withdrawal, long-term seizure with incomplete resection of the anatomical lesion. freedom, or cure. Additional analyses accounting for The chance of cure at ﬁ nal follow-up was decreased in possible clus tering eﬀ ects within centres did not reveal children who used more AEDs at time of surgery, with substantial changes (data not shown). TTR and TTD incomplete resection of the anatomical lesion, and with were not related to the chance of regaining seizure previous surgery and was increased in hemispherectomy freedom after restart of drug treatment in children who patients. For patients who achieved complete withdrawal had seizure recurrence during or after withdrawal (crude of drugs, incomplete resection of the anatomical lesion analysis, n=87; HR 0·98, 95% CI 0·92–1·05, p=0·62; and increased the risk for seizure recurrence and decreased 0·93, 0·83–1·05, p=0·26 per 3 months, respectively). the chance of reaching seizure freedom or cure at follow- The appendix shows how each of the predictors of up, and Rasmussen’s encephalitis decreased the chance of timing of start and completion of AED withdrawal was reaching cure (appendix). associated with the three outcome measures in a For each of the identiﬁ ed high-risk groups of patients, multivariable analysis. The risk of seizure recurrence was we studied the association between timing of AED increased in patients with multifocal MRI lesions, withdrawal and seizure outcome measures. The only www.thelancet.com/neurology Vol 11 September 2012
signiﬁ cant inﬂ uence of time intervals on seizure out- In children, the risk of recurrence was increased in those come was noted in children who underwent hemispher- who discontinued AEDs within 6 months compared with ectomy. Their chance of reaching Engel class 1 at those who remained on drug treatment.7 Less and slower follow-up was decreased with later start of withdrawal AED withdrawal were the main predictors of seizure (HR 0·87, 95% CI 0·77–0·99, p=0·04; table 3). In all freedom 2 years after sur gery.5 Schmidt and colleagues6 other groups of patients with risk factors for unfavourable reviewed the published work in adults and showed that outcome (multifocal MRI abnormalities, previous delaying discontinuation more than 2 years after surgery surgery, post operative epileptic EEG abnormalities, and did not improve safety. Nowadays, starting withdrawal of incomplete resection), early withdrawal was not AEDs at least 1 year after surgery is regarded safe.6,7,25 The associated with long-term seizure outcome, although safety of earlier AED withdrawal is an important point of later complete discontinuation showed weak evidence of discussion. We and others have suggested that timing of increasing the chance of cure in children with previous withdrawal itself does not predict seizure recurrence but surgery (HR 1·70, 95% CI 0·98–2·93, p=0·06).
that other factors, such as delayed remission after sur gery, continuing auras, and com pleteness of resection, increase Discussion
the risk for seizure recurrence in patients who withdraw This study conﬁ rms that several, but not all, of the AEDs.20,26 In this study, we show not only that the risk of known predictors of seizure outcome also determine seizure recurrence seems to increase with earlier AED timing of AED withdrawal. Immediate postoperative withdrawal, but also, and more importantly, that there was seizure freedom had previously been associated with no association between timing variables and seizure AED reduction.20 Higher number of AEDs at the time of freedom or cure at ﬁ nal follow-up. These ﬁ nd ings support surgery increased the probability of early withdrawal, our hypothesis that early AED withdrawal identiﬁ es the possibly suggesting that clinicians were less concerned need for postoperative AEDs earlier in patients who are about the risk of recurrence because of the protective not completely cured by surgery, without aﬀ ecting their eﬀ ect of the remaining AEDs or were keen to reduce the high drug load, which is supported by the ﬁ nding that Regain of seizure freedom after restarting drug treat- AEDs with severe side-eﬀ ects were most often withdrawn ment in children with recurrence was not aﬀ ected by ﬁ rst. If surgical success is anticipated, postoperative timing of withdrawal. In adults who withdrew AEDs, EEG recordings might not be done, which explains the seizure freedom rates were higher than in those who higher chance of early AED reduction in children in continued drug treatment, and seizures that recurred in whom no EEG was done. Similarly, for children in patients who withdrew were more responsive to AEDs whom post operative EEGs were done, those with (63%) than those in patients who continued on AEDs epileptic abnormalities started and completed AED (10%), suggesting that seizure reccurence during or after withdrawal later.
withdrawal might be regarded relatively benign.27 The rate Complete discontinuation of drug treatment was more of regaining seizure freedom (70%) in our study was likely in patients who underwent hemispherectomy, comparable to previously published data.7,20,25–27which is in accordance with the high rate of seizure The eﬀ ect of early withdrawal on recurrence risk is freedom in this population,24 showing the complete partly inherent to the present withdrawal policy in removal or dis connection of the epileptogenic lesion. clinical practice; withdrawal of AEDs is generally con- Although we expected that in children with complete sidered only in patients who are seizure free after surgery. resection, in whom successful surgery could be antici- Most recurrences after paediatric epilepsy sur gery occur pated, drug treatment would be withdrawn earlier, during the ﬁ rst postoperative year.5,26 The later the incomplete resection of the anatomical lesion was not decision to start withdrawing AEDs is made, the longer independently related to timing of withdrawal. One the child has potentially been seizure free and, thus, the explanation is that completeness of resection is diﬃ cult longer surgery has been able to prove its success. to judge in daily practice and might therefore not have Therefore, the group of children who withdrew late inﬂ native inevitably consists of fewer patients with incomplete explanation is that awareness of this important outcome surgical success and has a better prognosis than those predictor is relatively recent,11,13 and many of the patients who withdrew early after surgery.
in our cohort started withdrawal before publication of In our study cohort, several factors aﬀ ected seizure outcome. Incomplete resection of the anatomical lesion Although shorter TTR and TTD increased the risk of has previously been identiﬁ ed as one of the most seizure recurrence during the study, timing of with drawal important predictors for unfavourable seizure outcome did not aﬀ ect the chance of regaining seizure freedom after sur gery.1,11,13,28 The association between incomplete after restart of drugs or of reaching seizure freedom or resection and all outcome measures suggests that AEDs cure for at least 1 year at ﬁ nal follow-up (panel). Findings are needed in patients with incomplete surgery to protect from studies in adults have suggested that early them from the epileptogenicity of the remaining lesion. discontinuation increases the risk of seizure recurrence.8,21 The same notion might be applicable to patients with www.thelancet.com/neurology Vol 11 September 2012
83). At 5 years after surgery, seizure freedom rates were Panel: Research in context
still signiﬁ cantly higher in the post-1997 group, but cure rates (36%; 27 of 75) were similar to those in the pre-1997 Systematic review
cohort (44%; 27 of 61). Hemb and colleagues’ ﬁ ndings5 References for this study were identiﬁ ed through searches of PubMed for articles support the hypothesis that AED withdrawal does not published between Jan 1, 1980, and June 1, 2012, and were restricted to publications in English. Search terms were “epilepsy surgery”, “pediatric” or “paediatric”, “outcome”, Our study has several limitations. First, as agreed by the “seizure freedom”, “AED”, “antiepileptic drugs”, “anticonvulsants”, “withdrawal”, or study group, only patients who withdrew AEDs after “discontinuation”. A secondary search for missed references was done by reviewing the having reached postoperative seizure freedom were reference lists of the original articles and published reviews.
included in the study. In this selected subgroup of children, Interpretation
surgical success was anticipated and unfavourable Previous publications on postoperative drug withdrawal in children drew conﬂ icting predictors of postoperative seizure outcome were expected conclusions. Most agreed that tapering oﬀ drug treatment after 1 year of postoperative to be less common than in the total group of children who seizure freedom is safe,7,9,25,26 although others claimed that slow withdrawal of antiepileptic undergo epilepsy surgery. Therefore, the results of this drugs (AEDs) is the most important factor associated with better surgical outcome rates.5 study cannot be extrapolated to all children who undergo Drug withdrawal within 1 year of postoperative seizure freedom has been investigated in epilepsy surgery. Although early withdrawal of AEDs did only small groups and success rates diﬀ ered between studies.5,7,9,26 With this study, we provide not signiﬁ cantly aﬀ ect long-term seizure outcome in the more insight into the postoperative drug policy in children and its relation to seizure total cohort of children, or in subgroups of high-risk outcome. This study has three clinical messages. First, most of the identiﬁ ed predictors for patients (table 3), further prospective studies are warranted timing intervals have previously been reported to aﬀ ect postoperative seizure outcome; to establish to what extent early withdrawal inﬂ uences anticipation of surgical success thus determines postoperative drug policy. Second, although long-term seizure status in children who are particularly at in this seizure-free postoperative paediatric cohort earlier AED withdrawal increased the risk for seizure recurrence, this increase was not at the cost of seizure freedom or cure in the Second, timing of withdrawal probably largely depends longer term. Third, the strongest predictor for seizure outcome and cure was incomplete on subjective factors, such as the individual preference of resection of the anatomical lesion; early AED withdrawal seems safe in the group of patients treating physicians, side-eﬀ ects of the drug, and the with presumed complete resection of the anatomical lesion.
request of parents to discontinue AEDs. Unfortunately, these factors were not documented systematically in the multifocal MRI lesions, in whom the risk for seizure patient ﬁ les and therefore their eﬀ ect on withdrawal recurrence was increased. Multifocal MRI lesions have decisions could not be investigated.
previously been associated with unfavourable outcome.1,11 Third, since we included only patients who achieved In a recent study of patients who had undergone hemi- postoperative seizure freedom and withdrew AEDs, spherectomy, signiﬁ cant MRI abnormalities in the the predictors of seizure outcome identiﬁ ed here are remaining hemisphere were associated with unfavour- applicable only to children in whom AEDs are tapered able outcome.29 Remaining MRI abnormalities seem to postoperatively. Nevertheless, our ﬁ ndings on outcome harbour epileptic potential, and reduction of AEDs predictors are similar to those in studies that investigated should be done with more caution in these patients. determinants of outcome in general surgical cohorts.
Epileptic abnormalities on postoperative EEG predict In this large collaborative study we found that early seizure recurrence.12 In clinical practice, EEG has often withdrawal of drug treatment unmasked incomplete been used to estimate the risk of recurrence before surgical success and AED dependency sooner, but not at starting AED reduction in non-surgical cohorts.30 We the cost of long-term seizure outcome. Unnecessary now show that epileptic abnormalities on EEG also long-term continuation of drugs can be prevented in a predict seizure recurrence after epilepsy surgery but not large number of children when starting withdrawal of long-term seizure outcome or cure. The total number of drugs early after surgery. Those who need continued AEDs used at time of surgery predicted both seizure medical treatment will be identiﬁ ed earlier, with the freedom and cure. This ﬁ nding suggests that the more same chance of regaining seizure freedom as they would drugs trialled, the more refractory the epilepsy and the have had when AEDs were withdrawn late. The less the chance of surgical success. implications of our study cannot be extrapolated to The rate of cure at ﬁ nal follow-up was 45% (344 of 766), adults, in whom the possibly increased relapse rate which is higher than that reported 5 years after surgery associated with early AED withdrawal has a greater eﬀ ect in the cohort of Hemb and colleagues (36%; 27 of 75).5 In than in children, because it can lead to temporary their study, seizure freedom at 2 years after surgery was suspension of the patient’s driving licence, stigmatisation, more frequent in patients who underwent surgery after and detrimental eﬀ ects on professional careers. However, 1997 compared with those who underwent surgery before for children, the slightly increased risk of recurrences 1997. However, the number of seizure-free chil dren who and their consequences does not, in our opinion, were oﬀ AEDs after 2 years was signiﬁ cantly lower in the outweigh the well known neurocognitive side-eﬀ ects of more recently operated patients, leading to a lower cure AEDs,3,4,31 and early AED withdrawal might have cognitive rate (24%; 27 of 113) than the pre-1997 cohort (53%; 44 of beneﬁ ts. The ﬁ ndings of this study justify the undertaking www.thelancet.com/neurology Vol 11 September 2012
of a future randomised controlled trial to study the 9 Park KI, Lee SK, Chu K, et al. Withdrawal of antiepileptic drugs
after neocortical epilepsy surgery. Ann Neurol 2010; 67: 230–38.
possible beneﬁ ts and conﬁ rm the safety of early AED 10 Cross JH, Jayakar P, Nordli D, et al. Proposed criteria for referral withdrawal after epilepsy surgery in children.
and evaluation of children for epilepsy surgery: recommendations of the Subcommission for Pediatric Epilepsy Surgery. Epilepsia Contributors
2006; 47: 952–59.
KB collected the data, wrote the manuscript, and did the statistical 11 Cossu M, Lo RG, Francione S, et al. Epilepsy surgery in children: analysis. AA, JHC, TP, and OvN contributed data and commented on results and predictors of outcome on seizures. Epilepsia 2008; and amended the content of the manuscript. CSPMU commented on 49: 65–72.
the manuscript and supervised the statistical analysis. KPJB contributed 12 Jeha LE, Najm IM, Bingaman WE, et al. Predictors of outcome after data, commented on and amended the content of the manuscript, temporal lobectomy for the treatment of intractable epilepsy. assisted with the statistical analysis, and supervised the study.
Neurology 2006; 66: 1938–40.
TimeToStop study group
13 Krsek P, Maton B, Jayakar P, et al. Incomplete resection of focal Austria M Feucht, G Gröppel (Medical University Vienna, Vienna). cortical dysplasia is the main predictor of poor postsurgical France P Kahane, L Minotti (University Hospital Grenoble, Grenoble); outcome. Neurology 2009; 72: 217–23.
A Arzimanoglou, P Ryvlin, E Panagiotakaki, J de Bellescize, 14 Cohen-Gadol AA, Wilhelmi BG, Collignon F, et al. Long-term K Ostrowsky-Coste (University Hospitals of Lyon, Lyon); E Hirsch, outcome of epilepsy surgery among 399 patients with nonlesional M Valenti (University Hospital Strasbourg, Strasbourg). Germany seizure foci including mesial temporal lobe sclerosis. J Neurosurg
2006; 104: 513–24.
T Polster (Bethel Epilepsy Center, Bielefeld); R Sassen, C Hoppe, S Kuczaty, C Elger (University Hospital, Bonn, Bonn); S Schubert 15 McIntosh AM, Kalnins RM, Mitchell LA, Fabinyi GC, Briellmann RS, Berkovic SF. Temporal lobectomy: long-term (University Hospital Heidelberg, Heidelberg); K Strobl, T Bast (Epilepsy seizure outcome, late recurrence and risks for seizure recurrence. Center Kork, Kehl-Kork). Italy C Barba, R Guerrini, F Giordano (Meyer Brain 2004; 127: 2018–30.
Children’s Hospital, University Hospital, Florence); S Francione, 16 Yun CH, Lee SK, Lee SY, Kim KK, Jeong SW, Chung CK. Prognostic D Caputo (Claudio Munari Epilepsy Surgery Center Ospedale Niguarda, factors in neocortical epilepsy surgery: multivariate analysis. Milan). Netherlands K Boshuisen, K P J Braun, C S P M Uiterwaal, Epilepsia 2006; 47: 574–79.
O van Nieuwenhuizen, F S S Leijten, P C van Rijen (University Medical 17 Knowlton RC, Elgavish RA, Bartolucci A, et al. Functional imaging: Center Utrecht, Utrecht). Switzerland M Seeck (Neurology Clinic, II. Prediction of epilepsy surgery outcome. Ann Neurol 2008; University Hospital Geneva, Geneva). Turkey D Yalnizoglu, G Turanli, 64: 35–41.
M Topcu (Haceteppe University Ankara, Ankara); C Özkara, M Uzan 18 Park CK, Kim SK, Wang KC, et al. Surgical outcome and prognostic (Istanbul Unversity, Cerrahpasa Medical Faculty, Istanbul). UK factors of pediatric epilepsy caused by cortical dysplasia. J H Cross, L D’Argenzio, W Harkness (University College London Childs Nerv Syst 2006; 22: 586–92.
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Conﬂ icts of interest
20 Berg AT, Vickrey BG, Langﬁ tt JT, et al. Reduction of AEDs in In the past 36 months, AA has received speaker’s or consultancy fees or postsurgical patients who attain remission. Epilepsia 2006; research grants, or both, from Cyberonics, Eisai, GlaxoSmithKline, 47: 64–71.
Pﬁ zer, Sanoﬁ -Aventis, Schwartz Pharma, UCB Pharma, and Valeant. In 21 Ziemba KS, Wellik KE, Hoﬀ man-Snyder C, Noe KH, the past 5 years, JHC has received speaker’s or consultancy fees or Demaerschalk BM, Wingerchuk DM. Timing of antiepileptic drug research grants, or both, from Eisai, GlaxoSmithKline, Sanoﬁ , and UCB. withdrawal in adult epilepsy patients after neocortical surgical In the past 36 months, TP has received speaker’s or consultancy fees resection: a critically appraised topic. Neurologist 2011; 17: 176–78.
from Eisai, Desitin, and UCB. KB, CSPMU, OvN, and KPJB declare that 22 Engel J Jr, van Nes PC, Rasmussen TB, Ojemann LM. Outcome they have no conﬂ icts of interest.
with respect to epileptic seizures. In: Engel J Jr, ed. Surgical Acknowledgments
treatment of the epilepsies. New York: Raven Press, 1993: 609–21.
This study was funded by the Dutch National Epilepsy Fund (NEF 08-10). 23 Engel J Jr. A proposed diagnostic scheme for people with epileptic Travel expenses were funded by the Epoch Foundation.
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Classiﬁ cation and Terminology. Epilepsia 2001; 42: 796–803.
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www.thelancet.com/neurology Vol 11 September 2012
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