|Year : 2014 | Volume
| Issue : 2 | Page : 100-104
Risk of recurrence after discontinuation of antiepileptic drug therapy in children with epilepsy
Faruk Incecik, Ozlem M Herguner, Sakir Altunbasak, Gulen Mert, Nurcihan Kiris
Department of Pediatrics, Division of Pediatric Neurology, Faculty of Medicine, Cukurova University, Adana, Turkey
|Date of Web Publication||21-Aug-2014|
Toros M., Baris Manco Bul. 78178 Sk., Yesilpark Apt, A Bl, K: 7/13, Cukurova, Adana
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Objectives: The numerous antiepileptic drug (AED) withdrawal studies published in the last 40 years have relied mainly on heterogeneous study groups. There is still no general agreement on the criteria to predict safe discontinuation. The goal of this study was to assess the outcome of AED withdrawal in epileptic children. Materials and Methods: Three hundred and eight children with epilepsy were enrolled, and these patients followed at least 1 year after drug withdrawal. Time to seizure relapse and predictive factors were analyzed by survival methods. Results: Among the 308 patients, 179 (58.1%) were boys and 129 (41.9%) were girls and the mean age at the seizure onset was 60.41 ± 36.54 months (2-144 months). The recurrence occurred in 73 (23.7%) patients. Mental retardation, history of febrile seizure, etiological of epilepsy, abnormal first electroencephalogram (EEG), abnormal neuroimaging findings, and total number of AED before remission were significantly associated with relapse risk according to univariate analysis. In the multivariate analysis, abnormal first EEG and number of AED before remission (polytherapy) were the risk factors influencing seizure recurrence. Conclusions: In our study, recurrence rate was 23.7% in children and most occurred during the 1 st year. The potential risk factors of recurrence are history of febrile seizure, mental retardation, etiological of epilepsy, abnormal first EEG, abnormal neuroimaging findings, and total number of AED before remission. However, we found abnormal first EEG and polytherapy as risk factors of recurrence in multivariate analysis.
Keywords: Antiepileptic drug, epileptic children, recurrence risk factors, withdrawal
|How to cite this article:|
Incecik F, Herguner OM, Altunbasak S, Mert G, Kiris N. Risk of recurrence after discontinuation of antiepileptic drug therapy in children with epilepsy. J Pediatr Neurosci 2014;9:100-4
| Introduction|| |
More than 10 million children worldwide have some form of epilepsy. Long-term adverse effects of antiepileptic drugs (AEDs) are well-known, particularly in children. The issue of AED withdrawal in patients with clinical remission of seizures still draws the attention of physicians involved in the management of patients with epilepsy.
In previous studies, the risk of seizure relapse after withdrawal of AEDs in children has been reported from 16% to 56%, depending on method and design of the studies. ,,,, Young age of onset of seizures, absence of a neurological disease, young age at treatment withdrawal, negative family history of epilepsy, absence of interictal abnormalities on first electroencephalogram (EEG) and EEG before withdrawal are generally associated with a low risk of recurrence. ,,,,,
In literature, several studies have been done to determine the risk of recurrence after AED withdrawal. ,, However, there is still no consensus concerning the conditions for discontinuation of AED in children. Therefore, this study was designed to identify the risk factors associated with recurrence after AED withdrawal in children with epileptic seizures.
| Materials and Methods|| |
This study was conducted in patients with epilepsy in the Pediatric Neurology Department of our hospital between January 2004 and November 2011 whose AED therapies were withdrawn and were followed at least 1-year after withdrawal.
Inclusion criteria were as follows:
- Age at first seizure between 1-month and 15 years,
- Follow-up period of at least 1 year after the withdrawal,
- Seizures not due to neurometabolic or infectious diseases of the central nervous system, and
- No history of seizures in the newborn period. Seizures were classified according to the 1989 classification of the International League Against Epilepsy. 
We reviewed the medical records of these patients, retrospectively. The information on each patient recorded sex, the family history of epilepsy, febrile convulsion history, age at seizure onset, seizure types, seizure frequency, intelligence quotient level, events in perinatal or childhood history, neurological examination, etiology of epilepsy, time period between the onset of first seizure and start of AED treatment, time period between the first seizure and the last seizure, time period between starting AED and last seizure (treatment response time), total time of AED treatment, number of seizures prior to starting the AED treatment, number of seizures in the time period between the start of AED treatment and the last seizure, total number of AED before remission, first EEG and neuroimaging findings.
Patients with underlying signs and symptoms of brain injury, delayed psychomotor development, neurological abnormalities and abnormal neuroimaging studies were defined as having symptomatic epilepsy; those with normal physical and neurological examination and normal neuroimaging studies were regarded as having idiopathic epilepsy; and those not belonging to either idiopathic or symptomatic epilepsy groups were regarded as having cryptogenic epilepsy.
Psychomotor development was assessed by neurological and neurocognitive examination such as Bayley scales test, Stanford-Binet, or Wechsler Intelligence Scale for Children. Psychomotor retardation was found in 56 (18.2%) patients. Magnetic resonance imaging (MRI) and/or computerized tomography studies were performed in all patients and 56 (18.2%) of which were abnormal. Abnormal MRI consisted of asymmetrical ventricular dilatation, periventricular leukomalacia, cortical dysplasias, mesial temporal lobe sclerosis, hamartoma, and atrophies due to traumatic injury or cerebrovascular events.
Interictal EEG was recorded with 18 electrodes (10-20 system) during wakefulness and/or during sleep induced by chloral hydrate. Intermittent photic stimulation and hyperventilation tests were performed routinely in awakening EEG. For each EEG recording the following aspects were considered: The presence of clear-cut epileptiform abnormalities (spikes, spike and wave complexes, sharp waves), localization of any abnormalities, and their frequency. We reviewed in particular EEG recordings before, and during AED withdrawal. According to common practice, normalization of EEG was in favor of starting withdrawal process.
Antiepileptic treatment was initiated in all patients with single drug, such as carbamazepine, valproic acid, oxcarbazepine, or levetiracetam. The AED dose was increased until seizures were controlled. Two hundred and forty patients were receiving monotherapy, 141 valproic acid, 43 carbamazepine, 33 oxcarbazepine, 13 levetiracetam, and 10 phenobarbital, while 68 patients (22%) had received combined AED therapy (two or three AEDs). The withdrawal of AED was performed gradually in variable periods, with durations ranging from 6 to 12 months. When patients were taking two or more AEDs, withdrawal started by reducing one of the AEDs first. Withdrawal of the next AED began when the previous drug had been completely discontinued. The AED withdrawal was cancelled if the seizures recurred during the withdrawal course. Timing of the decision to attempt withdrawal was completely up to the physician.
SPSS statistical analysis software package version 19.5 (SPSS Inc., Chicago, IL) was used in the statistical analysis. Statistical significance was accepted at P < 0.05. The Chi-square tests were used to determine the associations between categorical data. We carried out univariate and multivariable analyses of potential predictors of recurrence risk using Cox regression analysis. The level of statistical significance was established at P < 0.05. Initially we performed a univariate analysis, in order to determine which variables to use in multivariate analysis.
| Results|| |
Three hundred and eight children, mean age 105.53 ± 38.15 months (10-208 months), were included in this study. Among the 308 patients, 179 (58.1%) were boys and 129 (41.9%) were girls, and the mean age at the seizure onset was 60.41 ± 36.54 months (2-144 months).
Of the 308 patients in whom treatment was withdrawn, 235 patients (76.3%) remained seizure-free until the end of the study period; in 73 patients (23.7%) seizures were relapsed. Fifty-six patients (61.7%) had their recurrence in the first 6 months after the withdrawal and 17 (38.3%) had after 6 months.
Among the 308 patients, 142 (46.1%) had generalized, 98 (31.8%) had partial, and 68 (22.1%) had mixed type of seizures.
There was no correlation between seizures recurrence and sex, events in perinatal or childhood history, the family history of epilepsy, neurological examination, age at seizures onset, type of seizure, time period between the onset of first seizure and start of AED treatment, number of seizures prior to starting the AED treatment, number of seizures after AED treatment, treatment response time, and total time of AED treatment. However, there was statistically significant correlation between seizure recurrence and febrile convulsion history, mental retardation, etiological of epilepsy, abnormal first EEG, abnormal neuroimaging findings, and total number of AED before remission.
The general characteristics, clinical features and possible risk factors of the patients are shown in [Table 1].
|Table 1: The general characteristics, clinical features and possible risk factors of the patients|
Click here to view
| Discussion|| |
In literature, there have been many studies for determining the risk factors affecting seizure relapse after AEDs withdrawal in epileptic children. ,,,,,, There is no general agreement on criteria for discontinuation of AED published so far.
The recurrence rate after discontinuation of AED therapy was 23.7% in our study. Reported rates have varied from 16% to 56% in other studies. ,,,,, Recurrences occurred mostly in the first 2 years in our patients. In previous studies, 85-90% of recurrences were also reported within 2 years. ,, We found the relapse rate is highest in the 1 st year, with a lower incremental rate after the 2 nd year. In the first 6 months, the recurrence rate was 61.7% after the withdrawal, 26.0% was after 6-12 months and 8.3% in the 12-24 months, and 4.0%) was after 2 years period. In a similar study, Olmez et al. have reported recurrence rate as 27%. They found that 12 patients (6%) had recurrence in the first 3 months after the withdrawal, 16 (8%) had in the 3-9 months period, 10 (5%) had in the 9-15 months period, 2 (1%) had in the 15-24 months period, and 14 (7%) had recurrence after 2 years.  In another study, Hindley and Staniforth reported recurrence rate as 32.4% and that cumulative relapse rates were 53.3% of children within 6 months, 66.7% during the 1 st year and 90% within 3 years in their study. 
Sex has usually been reported to have no influence on the recurrence risk as in our study. This finding is in agreement with most other studies. ,,, However, in some studies, Altunbasak et al., Dooley et al., and Olmez et al. reported that female sex was a significant risk factor for recurrence. ,, However, no single reason has been suggested for this sex difference in their studies.
We did not find age at onset of seizure as a significant risk factor for recurrence. Some authors reported similar results. ,, However, there are many authors like Emerson et al. who reported that the age of onset of seizure is a significant risk factor.  Bouma et al. reported the onset of seizures after 5 years and Shinnar et al. reported age at onset after 12 years as a risk factor for recurrence. , Altunbasak et al. found that seizure onset before 2 years to be a good prognostic factor but, their study did not include some types of epilepsy with a poor prognosis, such as West syndrome or severe myoclonic epilepsies of infancy. 
Family history of epilepsy was reported as a risk factor in idiopathic epileptic patients by Shinnar et al.  We also did not find it as a risk factor for recurrence, which is consistent with some of the studies. , There have been some reports of history of febrile convulsions not to be a risk factor. ,,, But, we detected that prior febrile seizures were a predictor of a higher recurrence risk in our study. This finding supports the results of others study, Verrotti et al. reported history of febrile convulsions as a risk factor for recurrence.  Similarly, Ramos-Lizana et al. detected that prior febrile seizures were a predictor of a higher recurrence risk. 
We did not find any significant difference according to seizure types on recurrence. Some previous studies have reported that seizure type is a significant risk factor, , whereas others did not. ,,, Verrotti et al. have reported multiple seizure types significantly increased recurrence risk in multivariable analyses. Most patients with multiple seizure types had simple or complex partial seizures plus secondarily generalized partial seizures in their study.  Todt detected partial epilepsies and mixed type of seizures as a risk factor.  Matricardi et al. reported that infantile spasms and childhood absence epilepsy carried a greater risk of relapse after AED withdrawal. 
Etiology of seizures has also been related to increased risk of recurrence after AED withdrawal. The remote symptomatic epilepsy group has been most significantly related to higher relapse rates when compared to the idiopathic group. ,, In our study, we found similar findings. However, no difference was found in some studies. ,, In one of those studies, Olmez et al. reported that etiology was not identified as a possible risk factor. 
Number of seizures before AED therapy, the time between the onset of first seizure and the onset of AED therapy, number of seizures after starting AED therapy, total number of AED before remission, and treatment response time were all considered as measures of epilepsy severity. Gherpelli et al., Todt, and Emerson et al. identified the number of seizures before seizure control important for seizure recurrence. ,, However, Altunbasak et al. and Olmez et al. reported that none of these factors were found to be a significant risk factor for recurrence. , We did not find the number of seizures before AED therapy, number of seizures after starting AED therapy, treatment response time as a risk factors of recurrence. Evidence about the predictive value of the number of AEDs before remission is conflicting; a previous study has reported that polytherapy is a significant risk factor,  whereas other studies did not. , Verrotti et al. reported polytherapy as a risk factor with partial epilepsy in their study.  In another study, Camfield and Camfield found seizure frequency and the time elapsed before starting AED treatment as a risk factor for recurrence.  In recent years, Verrotti et al. reported that polytherapy was a significant risk factor in their new study in multivariate analysis.  In our study, we found that polytherapy significantly increased the recurrence risk in both univariate and multivariate analysis.
There have been some studies that reported significant risk factors for recurrence as mental retardation, neurological deficit, and abnormality of MRI. ,,, However, our results showed that mental retardation and abnormality of MRI are important factors influencing the recurrence, consistent with some studies.  However, these factors were not reported as significant risk factors for recurrence in some studies. ,
Studies have reported conflicting results about the role of abnormalities on EEG in predicting the recurrence. Some previous studies have found it to be a prognostic factor , whereas others found it not to be a prognostic factor. ,, Verrotti et al. reported no effect on seizure recurrence on the first EEG at the time of diagnosis or the EEG before the withdrawal.  We detected abnormal first interictal EEG findings at diagnosis as a significant risk factor. Ninety percent of our patients at withdrawal had a normal EEG. There were minor abnormalities (such as episodic slow wave activity) in 10% patients. We did not perform EEG after the withdrawal period. Therefore, we did not consider EEG pre-withdrawal and after the withdrawal period.
| Conclusion|| |
There seems to be no consensus as to the significance of the above factors on the risk of recurrence in the previous studies. Emerson et al. reported factors of mental retardation, age at onset seizure, frequency of seizures and EEG pattern to be significant for relapse rate in univariate analysis, but only EEG pattern at withdrawal and frequency of seizures were significant in multivariate analysis.  Olmez et al. showed EEG recordings after withdrawal (postwithdrawal EEG) in the follow-up were significantly different in the patients with recurrence with respect to presence of an abnormality. In the multivariate regression analysis, female gender and abnormal postwithdrawal EEG were the risk factors influencing seizure recurrence, with female gender identified as the main risk factor.  In another study, Verrotti et al. reported that multiple seizure types, previous polytherapy, history of febrile seizures and abnormalities in postwithdrawal EEG were associated with a higher risk of seizure recurrence.  We found factors of history of febrile seizures, mental retardation, etiology, polytherapy, and EEG abnormality at diagnosis significant for recurrence rate in univariate analysis, but polytherapy and abnormal first EEG findings were significant risk factors for recurrence in multivariate analysis.
There is still no general agreement on the criteria to predict safe discontinuation. We think the differences reported regarding the effect of risk factors can be attributed to differences in the study designs and characteristics of the studied populations.
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