Drug treatment failures and effectivity in children with newly diagnosed epilepsy
Ebru Arhan*, Ayse Serdaroglu, Ayse Nese Cıtak Kurt, Memet Aslanyavrusu
Department of Pediatric Neurology, Gazi University School of Medicine, Turkey
Epilepsy is a group of neurologic conditions characterized by
recurrent, unprovoked seizures. A large proportion of epilepsy
beginsinchildhood.The prevalenceofepilepsy inchildrenhasbeen
estimated at 3.5–7.2 per 1000 children.1Many types of epilepsy
occur in children, with diagnosis depending on the type of seizure
(simple partial, complex partial, partial becoming generalized,
generalized) and etiology (symptomatic, idiopathic, cryptogenic).
frequency with as few side effects while minimising long-term
detrimental effects. Knowing the response to antiepileptic drug
treatment will undoubtedly influence the treatment strategy in
childhood epilepsy. Data on why children fail medications would
allow better counseling of patients and parents as well. There are
relatively fewer studies examining the tolerability and treatment
failure of antiepileptic drugs in children compared with adults. We
provide a comprehensive and current literature review of the AEDs,
focusing on treatment failure and tolerability data in children.
Previous studies have yielded data for adults suggesting that fewer
than one half of patients become seizure free with the first-line
antiepileptic drug tried,2–6whereas antiepileptic drug treatment
failure and reasons in children is virtually unknown and few data
or failure of the initial AED in the first year of treatment, as well as
long-term seizurecontrol and remission. They showed that, overall,
treatment failures of up to 24% were more common in those with
partial seizures (compared with generalized tonic/clonic seizures).7
Dudley et al. found that treatment with the first antiepileptic drug
failed in 31.6% of the children.9An audit of childhood antiepileptic
druguse overa 4-yearperiod inthe Netherlandsfounda 40%failure
rate with the first antiepileptic drug prescribed.8
In clinical practice, it would be desirable to better predict the
effectivity of the antiepileptic drug within a short period after
diagnosis. Because studies on the treatment failure and tolerability
of the first antiepileptic drug in children are very rare, the present
retrospective study was designed with the objective of determin-
ing the percentage of children whom first-line antiepileptic drug
treatment failed and the specific reasons for the treatment failure.
2.1. Patients and treatment
The study group was identified from the patient charts of
Pediatric Neurology Department of Gazi University Faculty of
Seizure 19 (2010) 553–557
A R T I C L EI N F O
Received 29 March 2010
Received in revised form 26 July 2010
Accepted 30 July 2010
A B S T R A C T
Purpose: Todeterminethepercentageofchildrenwhomfirst-lineantiepilepticdrug treatmentfailedand
the specific reasons for the treatment failure in newly diagnosed epilepsy.
Methods: Hospital records were reviewed for 225 children who were newly diagnosed with epilepsy,
started on the first antiepileptic drug, and then monitored for approximately 4.2 years.
Results: Of the 225 patients analyzed, the mean age was 7.9 ? 0.6 years at diagnosis. Most of the patients
suffered from primarily generalized tonic-clonic seizures (in 84 patients, 37.3%). 114 patients (50.6%) were
classified as having idiopathic epilepsy, 64 (28.4%) had symptomatic epilepsy and 47 (20.8%) has cryptogenic
epilepsy. Valproic acid (n: 120, 53.3%), carbamazepine (n: 45, 20%) and oxcarbazepine (n: 31, 13.7%) were the
most frequently prescribed antiepileptic drugs. Overall, 67.5% (n: 152) patients were treated successfully
with the first antiepileptic drug. Seventy-three patients failed with the first-line antiepileptic drug. Of these
patients, 28discontinuedmedicationbecauseofadverse effects(38.3%), 26because oflackofefficacy(35.6%)
and 19 (26.02%)because of a combination of inefficacy and adverse effects. Age at diagnosis, seizure, etiology
and antiepileptic drug selection are considered to be associated with drug treatment failure in childhood
antiepileptic drug. Adverse effects and lack of efficacy contributed equally to the treatment failures.
? 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
* Corresponding author at: Yunus Emre Cad. Yigitler Sok, No: 9/3, 06010 I˙ncirli-
Ankara, Turkey. Tel.: +90 312 3232 995.
E-mail address: firstname.lastname@example.org (E. Arhan).
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/yseiz
1059-1311/$ – see front matter ? 2010 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
Medicine in Ankara. The target population consisted of all patients
who were followed by well-established diagnosis of epilepsy as
defined by the International Classification of Epilepsies and
Epileptic Syndromes10and treated with the antiepileptic drugs
for the first time. We retrospectively reviewed through the records
of a total of 225 patients aged 0–18 years who were newly
diagnosed with epilepsy and prescribed an antiepileptic drug
during the period from January 2000 to December 2004. Children
who were not treated nor followed for epilepsy, children who had
started treatment elsewhere but came to our center for follow-up
and those diagnosed with febrile seizures were not included in the
chart review. In the study hospital, when the children are
diagnosed with epilepsy, they are followed at our clinic until
they achieve seizure remission and are taken off treatment. To
determine if and why patients failed the first-line antiepileptic
drug prescribed, the hospital records of these children were
reviewed for an average of 4.2 years. Seizure freedom was defined
as having no more seizures for the 4.2-year duration of this study
or had no seizures for an adequate period of time (i.e., 2 years). The
first prescribed antiepileptic drug was considered as a treatment
failure if (1) it does not seem to control seizure to a significant
degree (lack of efficacy)2causes intolerable adverse effects. If the
antiepileptic drug decreased seizure frequency to some reasonable
degree butnot entirelywithoutcausing intolerableadverseeffects,
the drug was not considered a treatment failure. The Gazi
approved this study.
Detailed chart review of the patient’s included age, sex,
diagnosis, seizure type, etiology, medication dose and duration
of treatment, the reason for discontinuation of the drug and
adverse effects experienced. The results of any electroencephalog-
raphy or brain imaging were recorded. Etiology was defined
according to the quidelines of the International League Against
Epilepsy.10The percentage of patients who failed initial treatment
and the reason for each treatment failure was determined.
Association between the percentage of each failed drugs and age
at onset, seizure types, etiology was determined.
2.2. Statistical analysis
Statistical analysis was performed using Statistical Package for
Social Sciences software, version 11.5 (SPSS Inc., Chicago, IL, 2002).
Data were reported as means with standard error. The major
objective of the study was to study the interaction among drug
treatment failure rates, effectiveness of the first antiepileptic drug
prescribed in newly diagnosed pediatric epilepsy. Differences
between number of patients in various subgroups were compared
using chi-square test, and group means were compared using
unpaired two-tailed t-tests. Statistical significance was defined as
p < 0.05.
3.1. Clinical features
Between January 1, 1999, and December 30, 2005, a total of 502
children were admitted to the Gazi University Pediatric Neurology
Department for seizures. 183 were febrile seizures, 85 were seen at
another clinic for seizure before and drug was started. Upon being
seen in clinic, 234 patients were newly diagnosed with epilepsy
and started on an antiepileptic drug. The charts of these patients
were reviewed for 5.3 years. Nine patients were lost to follow-up.
Eventually, 225 patients remained for the analyses.
Characteristics of the patients treated with first-line antiepileptic drug.
CharacteristicsSeizure-free group Failure groupTotal
Patients enrolled, n (%)
Female, n (%)
<1, n (%)
1–6, n (%)
6–12, n (%)
>12, n (%)
CPS with sec. generalization
Primarily generalized tonic clonic
CPS without sec. generalization
Antiepileptic drug used
Antiepileptic drug dosage (mg/kg per day)
152 (67.5) 73 (32.4) 225
E. Arhan et al./Seizure 19 (2010) 553–557
Table 1 demonstrates the characteristics of the patients
included in the study. More than 86% of the patients attended
the clinic for 3.5 years, with follow-up periods ranging from 18 to
72 months. Of the 225 patients analyzed, there were 122 boys
(54.2%), and the mean age of the group was 7.9 ? 0.6 years at
diagnosis. Most of the patients suffered from primarily generalized
tonic-clonic seizures (in 84 patients, 37.3%). The other seizure types
encountered were complex partial seizures with secondary generali-
zation(in 49patients,%21.7),absence seizures (in32 patients, 14.2%),
complex partial seizures without secondary generalization (in 21
patients, 9.3%), infantile spasm (in 18 patients, 8%), myoclonic (in 15
patients, 6.6%), undetermined (in 6 patients, 2.6%). In addition, 114
patients (50.6%) were classified as having idiopathic epilepsy, 64
(28.4%) had symptomatic epilepsy and 47 (20.8%) has cryptogenic
Valproic acid (n: 120, 53.3%), carbamazepine (n: 45, 20%) and
oxcarbazepine (n: 31, 13.7%) were the most frequently prescribed
antiepileptic drugs. Other first-line medications used were
phenobarbital, clobazam, lamotrigine and vigabatrin. Concomitant
antiepileptic drugs used were topiramate, levatiracetam, ethosux-
imide and clobazam.
3.3. Treatment failures
Overall, 67.5% (n: 152) patients were treated successfully with
the first antiepileptic drug. Sixteen (7.1%) patients were added on
adjunct antiepileptic drugs without stopping the first antiepileptic
drug to achieve a better seizure control during follow-up. In these
patients, the first prescribed antiepileptic drug did not totally stop
seizures but decrease seizure frequency, therefore these patients
were not considered treatment failures.
The successfully treated group was compared to the failed
group in terms of age at seizure onset, seizure type, antiepileptic
drug used and drug dose.
A higher proportion of patients with symptomatic and
cryptogenic epilepsy had to discontinue the first prescribed
antiepileptic drug because of either intolerable side effects or
lack of efficacy, compared with patients with idiopathic epilepsy
(symptomatic vs. idiopathic:14.1% vs. 4.3%; p: 0.004; cryptogenic
vs. idiopathic:8.5% vs. 4.3%; p: 0.04) (data not shown).
No statistically significant differences were seen between two
groups in terms of age at seizure onset, antiepileptic drug used and
3.4. Reasons for treatment failures
Certain age groups (children with seizure onset within the first
year), seizure types (infantile spasms, myoclonic, atonic), etiology
(idiopathic, symptomatic, cryptogenic) and antiepileptic drug
selection are considered to be associated with drug treatment
failure in childhood epilepsy.
Seventy-three patients failed with the first-line antiepileptic
drug. Of these patients, 28 discontinued medication because of
adverse effects (38.3%), 26 because of lack of efficacy (35.6%) and
19 (26.02%) because of a combination of inefficacy and adverse
effects. Most common adverse event was rashes, which developed
more often with carbamazepine and carbamazepine was discon-
tinued. For valproate, the most frequent side effects causing drug
discontinuation were weight gain and behavioral problems.
Tiredness and dizziness was the most often adverse effect for
oxcarbazepine (Table 2). The rate of discontinuation because of
adverse events was lower among patients on oxcarbazepine but it
was not statistically significant.
3.5. Age at diagnosis and treatment failures
We compared the treatment failure rates at different age
groups. For the group who failed the first-line drug, there was an
inclination toward aged less than 1 year at diagnosis. There were
fewer children aged more than 10 years at diagnosis. But there was
not a statistically significant difference between age groups (chi-
square analysis, p: 0.375) (Table 1).
3.6. Comparison of antiepileptic drugs
Valproic acid, carbamazepine and oxcarbazepine were com-
pared among the children with treatment failure. There was no
statistically significant group between the number of failures for
each medication (p: 0.856). Failure rate was 30%, 26.6%, 29% for
valproic acid, carbamazepine and oxcarbazepine, respectively.
Eleven treatment failures occurred in patients treated with other
antiepileptic drugs other than valproic acid, carbamazepine and
oxcarbazepine. All were attributed to lack of efficacy.
Doseoftheantiepilepticdrugusedcouldalso affectthe efficacy.
The majority of seizure-free patients used only a moderate daily
dose (valproic acid, 22.45 ? 5.67 mg/kg; carbamazepine, 14.78 ?
5.03 mg/kg; oxcarbazepine 31.56 ? 7.78 mg/kg). Dosages were also
of efficacy or a combination of both factors (Table 1). There was no
valproic acid, carbamazepine and oxcarbazepine and those who had
to change treatment because of intolerable adverse effects in all three
antiepileptic drugs. Although the difference did not reach signifi-
cance, patients who became seizure free took slightly lower doses
than those with the treatment failures because of adverse effects for
all three antiepileptic drugs. In contrast, the children with drug
treatment due to lack of efficacy, the drug doses were slightly higher.
3.7. Effects of specific seizure types and etiology
There was no significant difference (p: 0.664) in the drug
treatment failure rates between the idiopathic, symptomatic and
cryptogenic groups. There was also no statistical significance
between the etiology groups in the proportion of patients who
continued the first drug.
Likewise, no statistically significant difference were found by
analysis for seizure type (p: 0.745) (Table 1).
Adverse effects leading to antiepileptic drug failure for the three most commonly
Increased appetite/weight gain
Change in mood
Tiredness or drowsiness
Total adverse eventsa
Number of patients
aSome patients experienced more than one adverse effect.
**Carbamazepine versus valproic acid, p: 0.073; versus oxcarbazepine, p: 0.051.
E. Arhan et al./Seizure 19 (2010) 553–557
Childhood epilepsy in our clinical practice had a generally
favorable outcome, with two-thirds of children achieving remis-
sion withthe first antiepilepticdrugprescribed.Althoughthereare
many studies dealing with the treatment failure of the first
antiepileptic drug in adults, few studies have assessed the drug
treatment failure rates and effectiveness of the first antiepileptic
drug in children. Previous studies have reported that the first-line
antiepileptic drug will eventually be effective in seizure control in
67–80% of the children.7,9
The present study has two main findings. The first is that in
approximately 30% of the patients first-line antiepileptic drug
treatmentfailed. Thesecondfindingisthat adverseevents andlack
of efficacy contributed equally to the drug failure.
4.1. Treatment failure rate
Nearly two-thirds of the patients became seizure free and 32%
failure rate was found with the first prescribed antiepileptic drug.
Previous studies have largely agreed with this finding.2,7,9,11
Carpay et al. found 40% of children not responding successfully for
the first antiepileptic drug.8Kwan and Brodie reported a failure
rate less than 50% for patients of all ages, including the 9.8% of their
patient population who were between 9 and 15 years.2Camfield
et al. obtained more hopeful results for children for whom their
first AED failed. They reported a 20% drug treatment failure rate
over the first year.7It should be underlined that Camfield included
only children with generalized tonic clonic, partial and partial with
secondary generalized seizures and did not include treatment
failures due to adverse effects. Therefore, we cannot compare our
results with Camfield directly. Similar findings, however, have
et al. studied a group of 520 children aged <18 years and
investigated the interaction among efficacy, tolerability and
overall effectiveness of the first antiepileptic drug in children
with newly diagnosed epilepsy. Overall, 66.2% of the children
became seizure free with the first prescribed antiepileptic drug.11
Dudley et al. assessed the percentage of children for whom
antiepileptic drug treatment fails and specific reasons for
treatment failures. They found that treatment with the first
antiepileptic drug failed in 30/95(31.6%) children.9Moreover,
further clinical studies are needed to validate our observations.
4.2. Antiepileptic drugs
In the present study, valproate, carbamazepine and oxcarba-
have similar effectiveness and failure rates. The percentages of
patients who changed the first-line antiepileptic drugs both using
valproate, carbamazepine and oxcarbazepine are not significantly
different. Although the difference is not statistically significant,
drug treatment failures because of adverse effects. This represents
the common clinical observation. AED doses are usually progres-
sively increased in patients experiencing ongoing seizures.
Therefore, it is not surprising that they received a higher dose
compared with the seizure-free patients. Those who had adverse
events due to the antiepileptic drugs took a lower dose than the
responding patients, as the majority of withdrawals due to adverse
events occurred at relatively low dosage for all three AEDs. The
reasons for such marked differences are not completely under-
stood. This may be due to the diversity of underlying neuro-
pathologies12,13and possible genetic variability influencing drug
two distinct populations of patients with newly diagnosed
epilepsy [i.e., those responding to monotherapy and those
requiring treatment with more than one AED15].
To the best of our knowledge, the present study is the first one
which provided data on treatment failures with a newer
antiepileptic drug, oxcarbazepine. Although statistically not
significant, our data may indicate that oxcarbazepine may be
better tolerated than the standard antiepileptic drugs with
equivalent efficacy. Comparative trials should be performed on
the failure rates and reasons for failures of newer antiepileptic
drugs in childhood epilepsy.
4.3. Reasons for drug treatment failure
In the present study, we observed no difference in the
proportion of treatment failure due to adverse effects, lack of
efficacy, or the combination of these. The data we found are
compatible with those reported in previous studies.2,9Kwan et al.
studied both children and adults. Dudley et al. also found that
adverse effects and lack of efficacy contributed equally to first-line
antiepileptic treatment failures in newly diagnosed epilepsy in
children.9The population we reported on here constituted only
pediatric patients. The proportions that we observed were more
similar to those reported by Dudley et al. The most frequent
adverse effect of carbamazepine treatment necessitating drug
discontinuation was rash. Increased weight gain and behavioral
problems were the most frequent adverse effects among patients
using valproate. No deaths or life threatening adverse events
occurred during the course of this study. Our data indicate that
adverse events were frequent but not severe, and were one of the
main reasons for withdrawal from AED monotherapy.
Variables predictive of the drug treatment failure in childhood
epilepsy were etiology, seizure type and age at onset. Our findings
were similar to the previous studies.2,9Dudley et al. found age at
onset below 1 year is associated with treatment failure. Our group
of patients younger than 1 year also showed an inclination toward
treatment failure. Although the results were not statistically
significant, only the influence of age seemed to be correlated with
drug treatment failure.
4.4. Limitations of the study
The main limitation of the study is its retrospective design. In
our center, we increase drug dosage to the maximal recommended
dose or to the point at which the patient showed signs of toxicity
before consider it ineffective. After the drug is accepted as
ineffective, the pediatric neurologist stops the drug because of lack
of efficacy. Antiepileptic drug levels were not routinely measured,
and specific maximal dose guidelines were not used for this study.
However,it maybe possible that somepatients may havetolerated
a further increase in dose. If antiepileptic drugs were discontinued
prematurely in a small number of subjects, the success rate for the
first prescribed antiepileptic drug may be higher than we found.
To the best of our knowledge, this is the first study that assesses
the efficacy and treatment failure rate of older antiepileptic drugs;
valproate and carbamazepine and a newer antiepileptic drug;
oxcarbazepine in a large group of pediatrics patients with newly
diagnosed epilepsy. The rate of drug discontinuation because of
adverse events was lower among patients on oxcarbazepine but it
was not statistically significant. 32.5% of the children with newly
diagnosed epilepsy fail the first prescribed antiepileptic drug.
Adverse effects and lack of efficacy contributed equally to the
treatmentfailures. Althoughourunderstandingofthe treatmentof
childhood epilepsy has improved over the last two decades, much
E. Arhan et al./Seizure 19 (2010) 553–557
work lies ahead in this field. Future longitudinal prospective Download full-text
multicenter studies are needed to assess the outcome of
antiepileptic drug treatment. A better understanding of the natural
history of treated epilepsy would allow more accurate assessment
of the factors influencing drug treatment failure in pediatric
epilepsy and help formulate a strategic approach to management
in patients in whom monotherapy with the first-choice AED fails.
1. Kozyrskyj AL, Prasad AN. The burden of seizures in Manitoba children: a
population-based study. Can J Neurol Sci 2004;31:48–52.
2. Kwan P, Brodie MJ. Effectiveness of first antiepileptic drug. Epilepsia
3. Mattson RH, Cramer JA, Collins JF. The Department of Veterans Affairs Epilepsy
Cooperative Study No. 264 Group. A comparison of valproate with carbamaze-
pine for the treatment of complex partial seizures and secondarily generalized
tonic-clonic seizures in adults. N Engl J Med 1992;327:765–71.
4. Richens A, Davidson DL, Cartlidge NE, Easter DJ, Adult EPITEG Collaborative
Group. A multicentre comparative trial of sodium valproate and carbamazepine
in adult onset epilepsy. J Neurol Neurosurg Psychiatry 1994;57:682–7.
5. Brodie MJ, Richens A, Yuen AW, UK Lamotrigine/Carbamazepine Monotherapy
Trial Group. Double-blind comparison of lamotrigine and carbamazepine in
newly diagnosed epilepsy. Lancet 1995;345:476–9.
7. Camfield PR, Camfield CS, Gordon K, Dooley JM. If a first antiepileptic drug fails
J Pediatr 1997;131:821–4.
8. Carpay HA, Arts WF, Geerts AT, Stroink H, Brouwer OF, Boudewyn Peters AC,
et al. Epilepsy in childhood: An audit of clinical practice. Arch Neurol
9. Dudley RW, Penney SJ, Buckley DJ. First-drug treatment failures in children
newly diagnosed with epilepsy. Pediatr Neurol 2009;40:71–7.
10. Commission on Classification and Terminology of the International League
syndromes Epilepsia 1989;30:389–99.
11. Ma MS, Ding YX, Ying W, Fang F, Ding CH, Zou LP. Effectiveness of the first
antiepileptic drug in the treatment of pediatric epilepsy. Pediatr Neurol
12. Semah F, Picot MC, Adam C, Broglin D, Arzımanoglou A, Bazin B, et al. Is the
underlying cause of epilepsy a major prognostic factor for recurrence? Neurol-
13. Stephen LJ, Kwan P, Brodie MJ. Does the cause of localisation related epilepsy
influence the response to antiepileptic drug treatment? Epilepsia 2001;42:
14. Roses AD. Pharmacogenetics and future drug development and delivery. Lancet
15. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med
A. Monotherapytrialsof newantiepilepticdrugs.
E. Arhan et al./Seizure 19 (2010) 553–557