seizure recurrence in children after stopping antiepileptic medication 5 year follow up

Accepted Manuscript Seizure Recurrence in Children after Stopping Antiepileptic Medication: 5-Year Follow-up Inn-Chi Lee, Shuan-Yow Li, PhD, Yung-Jung Chen, MD, PhD PII: S1875-9572(16)30371-0 DOI: 10.1016/j.pedneo.2016.08.005 Reference: PEDN 628 To appear in: Pediatrics & Neonatology Received Date: 15 April 2016 Revised Date: July 2016 Accepted Date: August 2016 Please cite this article as: Lee I-C, Li S-Y, Chen Y-J, Seizure Recurrence in Children after Stopping Antiepileptic Medication: 5-Year Follow-up, Pediatrics and Neonatology (2017), doi: 10.1016/ j.pedneo.2016.08.005 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain ACCEPTED MANUSCRIPT Seizure Recurrence in Children after Stopping Antiepileptic Medication: 5-Year Follow-up Inn-Chi Leea,b, Shuan-Yow Lib,c**, Yung-Jung Chend* Division of Pediatric Neurology, Department of Pediatrics, Chung Shan Medical RI PT a University Hospital, Taichung, Taiwan b Institute of Medicine, School of Medicine, Chung Shan Medical University, Genetics Laboratory and Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan d M AN U c SC Taichung, Taiwan Department of Pediatrics, College of Medicine, National Cheng Kung University Hospital, Tainan, Taiwan Running title: Seizure recurrence after stopping medications * TE D Correspondence to: Yung-Jung Chen, MD, PhD Department of Pediatrics, National Cheng Kung University Hospital AC C ** EP Tel: +886-6-235-3535; Fax: +886-6-275-3083 E-mail: pcyj@mail.ncku.edu.tw Shuan-Yow Li, PhD Genetics Laboratory and Department of Biomedical Sciences, Chung Shan Medical University, Taichung, Taiwan E-mail: i0000528@ms12.hient.net Tel: +886-4-2473-9535; Fax: +886-4-2471-0934 The authors declare no conflicts of interest ACCEPTED MANUSCRIPT Abstract Background: We wanted to identify in children with epilepsy the factors associated with seizure control and recurrence after a 2-year remission Methods: We did a 5-year follow-up of epileptic children whose antiepileptic medication had RI PT been stopped Bivariate and multivariate analyses were used to compare features of electroencephalograms (EEGs) and clinical findings Forty-three patients with and 64 without a seizure recurrence were enrolled SC Results: Clinical features strongly associated with seizure recurrence in the univariate analysis included a symptomatic etiology for seizures, a history of status epilepticus, of stopping antiepileptic drugs M AN U treatment duration before stopping antiepileptic drugs and abnormal EEG findings at the time Conclusions: We found that a history of status epilepticus, symptomatic partial epilepsy, treatment duration before stopping antiepileptic drugs and an abnormal EEG when the TE D medication was stopped are important predictors of seizure recurrence The risk factors of seizure recurrence after discontinuing antiepileptic drugs have been investigated in several AC C EP studies However, a history of status epilepticus as a predictive factor is rarely mentioned Keywords: children; antiepileptic drug; epilepsy; remission; recurrence; outcome ACCEPTED MANUSCRIPT Introduction Approximately 70% of epileptic children who are seizure-free for more than 2-4 years while on antiepileptic drugs will remain seizure-free after withdrawing from their antiepileptic drugs.1-3 Because epilepsy is a heterogeneous disorder (i.e., it can be lesional or RI PT genetic), rather than a single disease entity, some patients will require drugs for continued seizure control, but others might not There is no single, accepted duration for defining remission.4 Stopping antiepileptic drugs early is not recommended as a standard practice in SC children, even in those who rapidly respond to the medication However, many physicians believe that it is necessary to stop medication after years.1,5-7 Discontinuing antiepileptic M AN U drugs early might prevent unnecessarily prolonged treatment, or it might increase the risk of seizure recurrence Hence, it might be appropriate to consider in which patients medication can be safely stopped rather than just when it can be stopped.8 In addition, predictors of prognosis after discontinuation of treatment would be of considerable clinical value TE D Shorvon et al.9 reported that 13 (12%) of 108 patients with epilepsy had an intermittent pattern of seizure recurrence after certain periods of being seizure-free More than half of the recurrences occurred in children who were tapering or had completely tapered their EP medications or who had never taken medications.10 The risk of a recurrence after discontinuing antiepileptic drugs in unselected groups of seizure-free patients is on the order AC C of 25% in the first year and 29% after years.11 Many factors appear to affect the degree of risk for seizure recurrence after stopping medication: epileptic syndromes, age at onset of epilepsy, underlying etiology, an abnormal electroencephalogram (EEG), epilepsy severity, individual drug side effects, and a prediction of recurrence.11 However, there is no general agreement on the risk factors for seizure recurrence after stopping antiepileptic drugs This is most likely because studies often have different inclusion criteria, which affects the composition of the groups investigated ACCEPTED MANUSCRIPT Additionally, the duration of follow-ups and methodologies often differ In this study, we wanted to identify the risk factors of recurrence when discontinuing antiepileptic drugs after years of seizure remission; thus, we compared, in a 5-year AC C EP TE D M AN U SC RI PT follow-up, the clinical features between children with and without seizure recurrence ACCEPTED MANUSCRIPT Patients and Methods We retrospectively reviewed medical records in our epilepsy database from the Department of Pediatric Neurology at National Cheng Kung University Hospital and the Department of Pediatric Neurology at Chung Shan Medical University Hospital We RI PT identified 125 children with epilepsy who had been treated at our hospital and met the inclusion criteria: (a) onset of epilepsy at ≤ 15 years old; (b) seizure-free for years or more; (c) antiepileptic drugs (AEDs) discontinued; (d) information about seizure manifestation, SC medication, blood level of antiepileptic drugs, and EEG findings available Informed consent was obtained from all parents Relevant clinical information was obtained from the medical M AN U records, from a questionnaire completed by the parents, and from a structured telephone interview every three months The children were followed periodically after the medications had been discontinued If a seizure did occur, their antiepileptic drug was restarted at the previous dose Based on the outcome after stopping the medication, the patients were divided TE D into two groups: (i) Seizure Recurrence (SR) Group—seizure recurrence during the 5-year follow-up, and (ii) No Seizure Recurrence (NSR) Group—no seizure recurrence during the 5-year follow-up EP We recorded each patient’s sex, age at onset of epilepsy, types of seizures and epilepsy AC C syndromes, number of seizures before treatment, seizure frequency (low: one every 4-6 months; moderate: one to two every 1-3 months; and high: more than one per month), presence of status epilepticus, febrile seizures, family history of epilepsy, presence of abnormal neurological findings (e.g., delayed cognitive development), motor deficits, duration of treatment, number of antiepileptic drugs used, duration of the seizure-free period before stopping antiepileptic drugs, and interval between stopping antiepileptic drugs and seizure recurrence In addition, we looked at the serial EEG findings when epilepsy was diagnosed, when antiepileptic drugs were stopped, during the follow-up after antiepileptic ACCEPTED MANUSCRIPT drugs had been discontinued or when seizures recurred, and at the end of the 2-year follow-up An abnormal EEG was defined as a specific focal or generalized epileptiform or slow-wave abnormality The types of seizures and epileptic syndromes were classified according to the Commission on Classification and Terminology of the International League Against RI PT Epilepsy.12,13 For patients with seizure recurrence, outcomes were classified as good (seizures remitted for year after antiepileptic drug restart), fair (seizures remitted for less than year after SC antiepileptic drug restart), and deteriorated (seizures more frequent than before stopping antiepileptic drugs and not seizure-free even with polytherapy) M AN U Statistical analysis The risk of seizure recurrence was calculated using Kaplan-Meier statistics and is shown in survival curves The Mann-Whitney test was used for univariate analyses of continuous variables; a χ2 or Fisher’s Exact test was used for bivariate analyses of dichotomous variables; TE D and a stepwise Cox hazard-function test was used for multivariate analyses to determine which factors were most strongly related to predicting seizure recurrence Significance was AC C EP set at p < 0.05 ACCEPTED MANUSCRIPT Results One hundred twenty-five eligible patients were identified Of these, declined to participate and 13 were unreachable The remaining 107 patients were recruited for the study Sixty-four (60%) remained seizure-free and 43 (40%) had recurrent seizures (Table 1) There RI PT was a significantly higher rate of status epilepticus and a longer follow-up period in patients with seizure recurrence than in those without After the initiation of antiepileptic drug therapy, remission occurred in 13.6 ± 18.2 SC months in the SR Group and in 12.5 ± 15.5 months in the NSR Group There were 26 (60%) seizure-free children in the SR Group and 40 (62%) in the NSR Group within 12 months of M AN U starting antiepileptic drug treatment (early remission) The remaining 41 children, 17 in the SR Group and 24 in the NSR Group, were seizure-free after more than year of treatment (late remission) On the initial EEG, when each of our patients was diagnosed with epilepsy, 102 of 107 TE D patients (95%) had an abnormal EEG: 39 (91%) in the SR Group and 63 (98%) in the NSR Group Sixty-one of 107 patients (57 %) had an abnormal EEG at the time of antiepileptic drug discontinuation: 30 (70%) of 43 in the SR Group and 31 (48%) of 64 in NSR Group In EP the last EEG—on each patient’s last visit to the outpatient clinic—48 of the 107 patients AC C (45%) had an abnormal EEG: 22 (51%) in the SR Group and 26 (41%) in the NSR Group Thus, the number of abnormal EEGs fell in both groups during the follow-up A significant number of children with an abnormal EEG when their antiepileptic drugs were discontinued had a recurrence of seizures, and the rate of abnormal EEGs was higher in the SR Group than in the NSR Group (p = 0.045, OR = 2.45, 95% CI: 1.08-5.55) There were significantly higher rates of status epilepticus and longer treatment duration before stopping antiepileptic drugs for patients with a seizure recurrence than without (Table 1and Table 2) ACCEPTED MANUSCRIPT The cumulative time dependent probability of remaining seizure free was significantly different in the two groups (Figure 1) The overall Kaplan-Meier estimate of seizure recurrence was 0.3 at months, 0.48 at 12 months, and 0.51 at 24 months The mean time to RI PT seizure recurrence was 10.8 ± 6.2 months, and the median was 12 months The risk of seizure recurrence was greatest in the first few months after the antiepileptic drugs had been discontinued: seizures recurred in 22 (51%) of the 43 patients in the SR Group within 12 SC months (mean: 5.7 ± 3.2 months; median: months), and in 21 (49%), within 24 months (mean: 16.1 ± 3.2 months; median 16 months; range: 13-24 months) Terminal remission M AN U after seizure recurrence occurred in 33 (76.8%) of the 43 patients The remaining 10 patients showed no remission, and of them had more seizures than before the recurrence More patients in the SR Group had symptomatic focal epilepsy than did patients in the NSR Group (p = 0.007) (Table and Table 4) TE D The most important predictors of seizure recurrence were a history of status epilepticus, symptomatic partial epilepsy, treatment duration before stopping antiepileptic drugs and an abnormal EEG when antiepileptic drugs were discontinued (Table and Table 4) EP Medication was used in the children without a seizure recurrence: 50 (78%) were treated AC C with a single antiepileptic drug, (14%) with two antiepileptic drugs, and (6%) with three antiepileptic drugs In the SR group, 30 children (69%) were treated with a single antiepileptic drug, (19%) with two antiepileptic drugs, with three antiepileptic drugs, with four antiepileptic drugs, and with five antiepileptic drugs ACCEPTED MANUSCRIPT Discussion We found significant risk factors related to seizure recurrence after discontinuing antiepileptic drugs: a history of status epilepticus, symptomatic partial epilepsy, treatment duration before stopping antiepileptic drugs, and an abnormal EEG at the time the RI PT antiepileptic drugs were stopped The longer duration of treatment in the SR group is probably because of the severity of the disease, which will normally influence a physician to not discontinue antiepileptic drug treatment Once antiepileptic drugs are started, many SC children with epilepsy will become seizure free, and after a period the antiepileptic drugs can be withdrawn with good results Although the risk of recurrent seizures after discontinuing M AN U the antiepileptic drugs is relatively low, there is no guarantee that their seizure freedom will be long lasting After antiepileptic drugs are stopped, as many as 21-37% of patients with childhood-onset epilepsy will undergo recurrent seizures.5,10,11,14-16 The risk factors of seizure recurrence after discontinuing antiepileptic drugs have been investigated in several mentioned TE D studies.5,11,14-17 However, a history of status epilepticus as a predictive factor is rarely Most studies have found that epilepsy with an onset in childhood has a more favorable EP prognosis than does epilepsy with an onset in adolescence (older than 10-12 years old).11 An AC C adolescent onset is consistently associated with a high risk of seizure recurrence after stopping antiepileptic drugs because the risk of recurrence is more a function of the age at epilepsy onset rather than the age at which antiepileptic drugs are discontinued.11,18 A younger age at onset is also associated with a higher risk of seizure recurrence after stopping antiepileptic drugs,18,19 but this appears to be limited to patients with a remote symptomatic etiology.18 Hence, a younger age at onset is frequently a marker for more severe neurological impairment In our study, the age at onset was correlated with a risk of seizure recurrence after stopping antiepileptic drugs Recurrence occurred before years in of children who ACCEPTED MANUSCRIPT were younger than years old at seizure onset, which was more often than in children who were older than years old at seizure onset Patients with remote symptomatic epilepsy are less likely to enter remission than are those with idiopathic or cryptogenic epilepsy Once in remission, they are about 50% more RI PT likely to have recurrent seizures if their antiepileptic drugs are stopped In one study18, 12 of 22 (55%) patients with IQs less than 70, and presumably with remote symptomatic epilepsy, had recurrent seizures, compared with of 45 (13%) patients with IQs (greater than 70) (p < SC 0.001) In our study, after antiepileptic drugs were discontinued, 11 of 43 (26%) children who had recurrent seizures also had cognitive developmental delays, but only of 64 (13%) M AN U children without recurrent seizures had cognitive developmental delays Focal slowing in EEG could suggest a structural basis for brain.20 Berg et al.7 reported that after discontinuing anti-epileptic drugs, the risk factors of seizure recurrence included status epilepticus, symptomatic etiology, and focal slow EEGs In our study, the ratio of focal slow EEGs was TE D greater in the SR group than in the NSR group, but not significant, probably because of the small number of cases number in our study Verrotti et al.21 evaluated the predictive value of interictal EEG findings after the EP antiepileptic drugs had been discontinued Two-thirds of the children in SR Group had EEG abnormalities at the time they stopped taking their antiepileptic drugs, but only 10% of the AC C children NSR Group did Verrotti et al.21 concluded that the reappearance of EEG abnormalities after discontinuing antiepileptic drugs is a risk factor for seizure recurrence Shinnar et al.18 reported that focal slowing on an EEG is a risk factor for a recurrence of seizures after withdrawing from antiepileptic drugs In the present study, we found that an abnormal EEG when discontinuing antiepileptic drugs was associated with an increased risk of seizure recurrence, which is consistent with Shinnar et al.18 and Verrotti et al.21 Focal slowing on EEGs was more common in the SR group than in the NSR group, which is ACCEPTED MANUSCRIPT compatible with Shinnar et al.18, despite the smaller number of cases and the absence of a significant difference Most seizure recurrence happens early: almost half occurs within months, and 60-80% occurs within year after discontinuing antiepileptic drugs Although late recurrence RI PT does happen, it is rare The British Medical Research Council study22,23 of antiepileptic drug withdrawal found that the increased risk of seizure recurrence attributable to withdrawal was limited to the first years after discontinuing antiepileptic drugs The risk of seizure SC recurrence was approximately twice as high in patients who had discontinued their antiepileptic drugs than in those who had not, but that difference was seen only for the first M AN U years after stopping antiepileptic drugs, after which the risk of subsequent recurrence was the same for both groups.24 Shinnar et al.18 reported that if seizures recur after discontinuing antiepileptic drugs, the prognosis is generally favorable and that the majority of patients become seizure-free again TE D after restarting antiepileptic drugs The prognosis for long-term remission appears to be primarily a function of the underlying epilepsy syndrome In our study, we found that although 33 of 43 (77%) patients with seizure recurrence reentered remission during the EP 5-year follow-up, 10 patients did not Six of these 10 patients had more seizures than before discontinuing antiepileptic drugs, even on antiepileptic drug polytherapy Camfield and AC C Camfield16 reported that 1% of children who became seizure-free and then discontinued antiepileptic drugs had recurrent seizures that could not be pharmacologically controlled again In the current study, of 43 patients (14%) in the SR Group had an increase in seizure frequency, and even status epilepticus, after they had discontinued their antiepileptic drugs This study has some limitations First, only patients whose seizures had been in remission for years were enrolled Thus, our series might include cases that are less severe than those in other studies However, the purpose of this study was to assess the risk factors of recurrence ACCEPTED MANUSCRIPT in patients after they had discontinued their antiepileptic drugs Second, this was not a population-based study Our patients probably presented more severe varieties of epilepsy than the typical pediatric patient with epilepsy in the general population; thus, our findings are most likely inapplicable in any context other than a referral center Remission rates after RI PT discontinuing antiepileptic drugs would presumably have been even higher in a more representative sample population In the present study, we excluded cases with status epilepticus caused by poor patient compliance The etiologies of status epilepticus are SC multiple and have traditionally been classified as acute or remote symptomatic, and idiopathic 25,26 We, however, did not classify status epilepticus as idiopathic or secondary; M AN U rather, classified the etiology as epilepsy syndrome itself In conclusion, our results indicate that the following might lead to seizure recurrence: a history of status epilepticus, symptomatic partial epilepsy, treatment duration before stopping antiepileptic drugs, and an abnormal EEG at the time of antiepileptic drug discontinuation TE D Acknowledgment This work was supported by Chung Shan Medical University Hospital grant (CS13036) EP CSH-2016-C-010 Ethical approval of the study was provided by the hospital’s IRB AC C Declaration of Conflicting Interests The authors declare that they have no conflicts of interest with respect to the authorship or publication of this article and confirm that they have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines ACCEPTED MANUSCRIPT References Shinnar S, Vining EP, Mellits ED, et al Discontinuing antiepileptic medication in children with epilepsy after two years without seizures: A prospective study New Engl J Med 1985;313:976-980 RI PT Arts WF, Visser LH, Loonen MC, et al Follow-up of 146 children with epilepsy after withdrawal of antiepileptic therapy Epilepsia 1988;29:244-250 Camfield PR, Camfield CS Antiepileptic drug therapy: When is epilepsy truly SC intractable? Epilepsia 1996;37(Suppl 1):S60-5 Commission on Epidemiology and Prognosis, International League Against Epilepsy M AN U Guideline for epidemiologic studies on epilepsy Epilepsia 1993;34:592-596 Verrotti A, Morresi S, Basciani F, et al Discontinuation of anticonvulsant therapy in children with partial epilepsy Neurology 2000;55:1393-1395 Verrotti A, D'Egidio C, Agostinelli S, et al Antiepileptic drug withdrawal in childhood 2012;16:599-604 TE D epilepsy: what are the risk factors associated withseizure relapse? Eur J Paediatr Neurol Li W, Si Y, Zou XM, An DM, Yang H, Zhou D Prospective study on the withdrawal and EP reinstitution of antiepileptic drugs among seizure-free patients in westChina J Clin AC C Neurosci 2014;21:997-1001 Geerts AT, Niermeijer JM, Peters AC, et al Four-year outcome after early withdrawal of antiepileptic drugs in childhood epilepsy Neurology 2005;64:2136-2138 Shorvon SD, Sander JW Temporal patterns of remission and relapse of seizures in patients In: Schmidt D, Morselli PL, eds Intractable Epilepsy New York: Raven Press, 1986;13-23 10 Berg AT, Shinnar S, Levy SR, et al Two-year remission and subsequent relapse in children with newly diagnosed epilepsy Epilepsia 2001;42:1553-1562 ACCEPTED MANUSCRIPT 11 Berg AT, Shinnar S Relapse following discontinuation of antiepileptic drugs: A meta-analysis Neurology 1994;44:601-608 12 Commission on Classification and Terminology of the International League Against Epilepsy Proposal for revised clinical and electroencephalographic classification of RI PT epileptic seizures Epilepsia 1981;22:489-501 13 Commission on Classification and Terminology of the International League Against Epilepsy Proposal for revised classification of epilepsies and epileptic syndromes SC Epilepsia 1989;30:389-399 14 Sillanpaa M, Schmidt D Prognosis of seizure recurrence after stopping antiepileptic M AN U drugs in seizure-free patients: A long-term population-based study of childhood-onset epilepsy Epilepsy Behav 2006;8:713-719 15 Bouma PA, Peters AC, Brouwer OF Long term course of childhood epilepsy following relapse after antiepileptic drug withdrawal J Neurol Neurosurg Psychiatry 2002; 72: TE D 507-510 16 Camfield P, Camfield C The frequency of intractable seizures after stopping AEDs in seizure-free children with epilepsy Neurology 2005;64:973-975 EP 17 Gherpelli JL, Kok F, dal Fomo S, et al Discontinuing medication in epileptic children: A AC C study of risk factors related to recurrence Epilepsia 1992;33:681-686 18 Shinnar S, Berg AT, Moshe SL, et al Discontinuing antiepileptic drugs in children with epilepsy: A prospective study Ann Neurol 1994;35:534-545 19 Emerson R, D’Souza BJ, Vining EP, et al Stopping medication in children with epilepsy: Predictors of outcome N Engl J Med 1981;304:1125-1129 20 Smith SJ EEG in neurological conditions other than epilepsy: when does it help, what does it add? J Neurol Neurosurg Psychiatry 2005;76 Suppl 2:ii8-12 ACCEPTED MANUSCRIPT 21 Dooley J, Gordon K, Camfield P, et al Discontinuation of anticonvulsant therapy in children free of seizures for year: A prospective study Neurology 1996;46:969-974 22 Bonnett LJ, Shukralla A, Tudur-Smith C, et al Seizure recurrence after antiepileptic drug withdrawal and the implications for driving: further results from the MRC RI PT Antiepileptic Drug Withdrawal Study and a systematic review 2011;82:1328-1333 23 Strozzi I, Nolan SJ, Sperling MR, et al Early versus late antiepileptic drug withdrawal for people with epilepsy in remission Cochrane Database Syst Rev 2015;2:CD001902 SC 24 Arts WF, Brouwer OF, Peters AC, et al Course and prognosis of childhood epilepsy: 5-year follow-up of the Dutch study of epilepsy in childhood Brain 2004; 127:1774- M AN U 1784 25 Gaspard N, Foreman BP, Alvarez V, et al New-onset refractory status epilepticus: Etiology, clinical features, and outcome Neurology 2015;85:1604-13 26 Spatola M, Novy J, Du Pasquier R, Dalmau J, Rossetti AO Status epilepticus of AC C EP TE D inflammatory etiology: a cohort study Neurology 2015;85:464-70 ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT Table Comparison of Seizure Recurrence Group (SR) and No Seizure Recurrence Group (NSR) children at the end of the 5-year follow-up SR Group† NSR Group† p Characteristics (n = 43) (n = 64) N.S Sex (male/female) 21/22 35/29 N.S (11.6) (9.3) Family history of epilepsy Age at onset of epilepsy (14) (5) N.S < years old N.S 2-12 years old 32 (74) 57 (89) N.S > 12 years old (12) (6) N.S Type of seizures Partial 24 (56) 26 (40) Generalized 19 (44) 38 (60) N.S History of febrile seizures (11.6) (12.5) 0.016 History of status epilepticus (13.9) (1.6) EEG when epilepsy was diagnosed N.S Epileptiform electroencephalogram (EEG) 38 (88.4) 61 (95.3) N.S Slowing EEG 12 (28) (14) 0.045 Abnormal EEG when AEDs stopped 30 (70) 31 (48) N.S Abnormal EEG at the end of follow-up 22 (51) 26 (41) Initial seizure frequency N.S High (> every month) 10 (23.2) 13 (20.3) N.S Moderate (1-2 every 1-3 months) (21) (12.5) N.S Low (1 every 4-6 months) 24 (55.8) 43 (67.2) Total no of seizures before control < 0.05 (7) 17 (26.5) N.S 3-10 30 (70) 33 (51.5) N.S > 10 10 (23) 14 (22) No of antiepileptic drugs N.S 30 (69.8) 51 (80) N.S (18.6) (14) N.S Withdrawal duration ≤ months 18 (42) 28 (44) > months 25 (58) 36 (56) Cognitive developmental delay N.S 11 (25.6) (12.5) (Intelligence quotient IQ < 70) Neurological abnormality N.S 12 (25.6) (12.5) Neuroimaging abnormality N.S 3/16 (19) 6/17 (35) Cognitive developmental delay N.S 11 (25.6) (12.5) (Intelligence quotient IQ < 70) † Unless otherwise indicated, data are n (%); N.S., not significant ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT Table Severity of epilepsy in SR Group and NSR Group children after stopping antiepileptic drugs SR Group† NSR Group† p Variables (n = 43) (n = 64) Time between seizure onset and treatment, months 10.2 ± 22.8 6.5 ± 13.3 N.S Time to seizure control, months 13.6 ± 18.2 12.5 ± 15.5 N.S Treatment duration before stopping antiepileptic 71.3 ± 37.5 55.0 ± 21.8 0.005 drugs, months Age at last seizure before stopping antiepileptic 7.4 ± 3.9 7.8 ± 3.2 N.S drugs, years Seizure-free duration before stopping antiepileptic 4.9 ± 1.9 5.0 ± 2.1 N.S drugs, years Age when antiepileptic drugs were stopped, years 11.3 ± 4.3 11.1 ± 3.3 N.S Age at end of follow-up, years 16.1 ± 5.9 15.7 ± 3.3 N.S † Data are mean ± standard deviation; N.S., not significant ACCEPTED MANUSCRIPT p N.S 0.007 AC C EP TE D M AN U SC RI PT Table Epilepsy syndrome distribution in patients with childhood-onset epilepsy Epilepsy Syndrome SR Group NSR Group (n = 43) (%) (n = 64) (%) Localization Related 39 48 Idiopathic 10 (23.2) 27 (42.2) Rolandic 22 Occipital Lesional (Symptomatic) 11 (25.6) (7.8) Temporal lobe Frontal lobe Occipital lobe 1 Cryptogenic (probable lesional) 18 (41.8) 16 (25) Generalized 14 Idiopathic (6.9) 14 (21.8) Childhood absence Juvenile myoclonic Generalized tonic-clonic seizures on awakening Other idiopathic generalized epilepsy / Unclassified idiopathic generalized epilepsy Undetermined whether focal or generalized (2.3) (3) Total 43 64 N.S., not significant N.S N.S ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT Table Risk factors for seizure recurrence in children after stopping antiepileptic drugs Risk Factors Hazard ratio 95% p confidence interval Early onset of epilepsy (< years) 1.85 1.08-3.17 N.S History of status epilepticus 2.32 1.55-3.44 < 0.02 Initial seizure frequency High (> every month) 1.10 0.64-1.89 N.S Seizure frequency Moderate (1-2 every 1-3 mo)-high (> every 1.32 0.83-2.09 N.S month) Seizure type (partial vs general) 1.44 0.90-2.29 N.S Symptomatic partial epilepsy 1.95 1.26-3.01 < 0.05 Abnormal EEG when antiepileptic drugs were 1.74 1.02-2.94 < 0.05 stopped Slowing EEG 1.58 0.99-2.52 N.S 1.59 0.99-2.55 N.S Cognitive developmental delay (Intelligence quotient < 70) EEG, electroencephalogram; N.S., not significant ACCEPTED MANUSCRIPT Figure Legend Figure Kaplan-Meier curve showing the probability of remaining seizure-free after discontinuing antiepileptic drugs in children with seizures after years of being seizure-free: AC C EP TE D M AN U SC RI PT overall recurrence risk Time “0” (lower left) refers to when antiepileptic drugs were stopped AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT ... D into two groups: (i) Seizure Recurrence (SR) Group? ?seizure recurrence during the 5- year follow- up, and (ii) No Seizure Recurrence (NSR) Group—no seizure recurrence during the 5- year follow- up. .. showing the probability of remaining seizure- free after discontinuing antiepileptic drugs in children with seizures after years of being seizure- free: AC C EP TE D M AN U SC RI PT overall recurrence. .. Time to seizure control, months 13.6 ± 18.2 12 .5 ± 15. 5 N.S Treatment duration before stopping antiepileptic 71.3 ± 37 .5 55. 0 ± 21.8 0.0 05 drugs, months Age at last seizure before stopping antiepileptic