100 / Journal of Pediatric Neurosciences / Volume 9 / May-Aug / 2014

Original Article
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
Address for correspondence: Dr. Faruk Incecik, Toros M., Baris Manco Bul. 78178 Sk., Yesilpark Apt, A Bl, K: 7/13, Cukurova, Adana,
Turkey. E-mail: ncecik@yahoo.com
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.
Key words: Antiepileptic drug, epileptic children, recurrence risk factors, withdrawal
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.
[1-5]
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.
[2,4,6-9]
In literature, several studies have been done to determine
the risk of recurrence after AED withdrawal.
[2,10,11]
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.
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Incecik, et al.: Risk of recurrence after discontinuation of antiepileptic drug therapy
2014 / May-Aug / Volume 9 / Journal of Pediatric Neurosciences / 101
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:
1. Age at first seizure between 1-month and 15 years,
2. Follow-up period of at least 1 year after the withdrawal,
3. Seizures not due to neurometabolic or infectious diseases
of the central nervous system, and
4. No history of seizures in the newborn period. Seizures
were classified according to the 1989 classification of the
International League Against Epilepsy.
[12]
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
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Incecik, et al.: Risk of recurrence after discontinuation of antiepileptic drug therapy
102 / Journal of Pediatric Neurosciences / Volume 9 / May-Aug / 2014
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.
Discussion
In literature, there have been many studies for determining
the risk factors affecting seizure relapse after AEDs withdrawal
in epileptic children.
[1-5,10,11]
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.
[1-4,7,11]
Recurrences occurred mostly in
the first 2 years in our patients. In previous studies, 85-90%
of recurrences were also reported within 2 years.
[2,3,10]
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.
[10]
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.
[11]
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.
[1,2,4,9]
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.
[3,6,10]

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.
[2,10,13]

However, there are many authors like Emerson et al. who
reported that the age of onset of seizure is a significant risk
factor.
[14]
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.
[5,7]
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.
[3]
Contd...
Table 1: The general characteristics, clinical features
and possible risk factors of the patients
Parameters Subjects Recurrence
rate %
P values
Number Percentage
Sex
Boy 179 58.1 22.3 0.300
Girl 129 41.9 25.6
Age at onset (years)
<5 153 49.7 20.3 0.101
5 155 50.3 27.1
Perinatal/childhood history
Positive 41 13.4 29.3 0.241
Negative 266 86.6 22.9
Family history of epilepsy
Positive 91 29.5 20.9 0.274
Negative 217 70.5 24.9
History of febrile seizures
Positive 64 20.8 34.4 0.020
Negative 244 79.2 20.9
Neurological examination
Normal 284 92.2 23.6 0.522
Abnormal 24.0 7.8 25.0
Mental retardation
Yes 56 18.2 33.9 0.037
No 252 81.8 21.4
MRI
Normal 252 81.8 18.7 0.001
Abnormal 56 18.2 46.4
Type of seizure
Partial 98 31.8 26.5 0.457
Generalized 142 46.1 20.4
Mixed 68 22.1 26.5
Etiological epilepsy
classifcation
Idiopathic 235 76.3 17.9 0.001
Symptomatic-cryptogenic 73 23.7 42.5
Time between the onset of
frst seizure and the onset
of AED treatment (months)
0-2 174 56.5 23.6 0.459
2-12 124 40.3 22.6
>12 10 3.2 40.0
Treatment response time
(months)
<6 220 71.4 21.4 0.139
6 88 28.6 29.5
Total number of AED
before remission
Monotherapy 227 73.7 19.4 0.002
Polytherapy 81 26.3 37.0
Number of seizures
before starting AED
treatment
1-5 207 67.2 21.7 0.393
6-10 61 19.8 27.9
>10 40 13.0 30.0
Number of seizures after
AED treatment
No seizure 100 32.5 16.0 0.127
15 174 56.5 27.6
610 23 7.5 26.1
>10 11 3.6 36.4
Total time of AED
treatment (years)
<3 256 83.1 21.9 0.108
3 52 16.9 32.7
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Incecik, et al.: Risk of recurrence after discontinuation of antiepileptic drug therapy
2014 / May-Aug / Volume 9 / Journal of Pediatric Neurosciences / 103
Family history of epilepsy was reported as a risk factor in
idiopathic epileptic patients by Shinnar et al.
[7]
We also did
not find it as a risk factor for recurrence, which is consistent
with some of the studies.
[2,10]
There have been some reports
of history of febrile convulsions not to be a risk factor.
[3,10,15,16]

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.
[2]
Similarly,
Ramos-Lizana et al. detected that prior febrile seizures were
a predictor of a higher recurrence risk.
[17]
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,
[17,18]
whereas others
did not.
[2,7,10,14]
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.
[2]
Todt detected partial epilepsies and
mixed type of seizures as a risk factor.
[9]
Matricardi et al.
reported that infantile spasms and childhood absence epilepsy
carried a greater risk of relapse after AED withdrawal.
[19]
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.
[7,9,20]
In
our study, we found similar findings. However, no difference
was found in some studies.
[3,6,10]
In one of those studies, Olmez
et al. reported that etiology was not identified as a possible
risk factor.
[10]
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.
[9,13,14]
However, Altunbasak et al. and Olmez et al. reported
that none of these factors were found to be a significant
risk factor for recurrence.
[3,10]
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,
[21]
whereas other studies did not.
[2,10]
Verrotti et al.
reported polytherapy as a risk factor with partial epilepsy in
their study.
[22]
In another study, Camfield and Camfield found
seizure frequency and the time elapsed before starting AED
treatment as a risk factor for recurrence.
[23]
In recent years,
Verrotti et al. reported that polytherapy was a significant risk
factor in their new study in multivariate analysis.
[2]
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.
[4-6,14]
However, our results
showed that mental retardation and abnormality of MRI are
important factors influencing the recurrence, consistent with
some studies.
[14]
However, these factors were not reported
as significant risk factors for recurrence in some studies.
[2,18]
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
[5,24]

whereas others found it not to be a prognostic factor.
[3,5,20]

Verrotti et al. reported no effect on seizure recurrence on
the first EEG at the time of diagnosis or the EEG before the
withdrawal.
[2]
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.
[14]
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.
[10]
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.
[2]
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
Table 1: Contd...
Parameters Subjects Recurrence
rate %
P values
Number Percentage
First EEG
Normal 77 25.0 11.7 0.002
Abnormal 231 75.0 27.7
MRI: Magnetic resonance imaging, AED: Antiepileptic drug,
EEG: Electroencephalogram
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Incecik, et al.: Risk of recurrence after discontinuation of antiepileptic drug therapy
104 / Journal of Pediatric Neurosciences / Volume 9 / May-Aug / 2014
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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Cite this article as: 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.
Source of Support: Nil. Confict of Interest: None declared.
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