e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 6 5 8 e6 6 2

Official Journal of the European Paediatric Neurology Society

Original article

Efficacy and safety of felbamate in children with

refractory epilepsy

Eli Heyman a,c, Noa Levin a, Eli Lahat a,c, Orna Epstein a,
Revital Gandelman-Marton b,c,*
a
Department of Pediatric Neurology, Assaf Harofeh Medical Center, Zerifin, Israel
b
EEG and Epilepsy Unit, Department of Neurology, Assaf Harofeh Medical Center, Zerifin, Israel
c
Sackler School of Medicine, Tel Aviv University, Israel

article info abstract

Article history: Background: Despite the introduction of multiple new antiepileptic drugs in the past two
Received 27 October 2013 decades, many patients with epilepsy continue to experience uncontrolled seizures or
Received in revised form significant side effects.
3 April 2014 Aim: To present our experience with felbamate therapy in children with drug-resistant
Accepted 7 May 2014 epilepsy.
Methods: We retrospectively reviewed the medical charts and video-EEG recordings of all
patients receiving felbamate until May 2012. Efficacy was determined according to seizure
Keywords: frequency during the week prior to treatment initiation and the week after the maximal
Epilepsy dosage of felbamate was reached.
Felbamate Results: Fifty patients (34 boys) aged 4 months to 17 years (mean e 5.5 years) were identi-
Efficacy fied. Nearly third of the patients had LennoxeGastaut syndrome. Mean epilepsy duration
Safety was 3.4 years (range e 1 month to 13 years). The mean number of previous antiepileptic
Interictal EEG drugs was 7.5. The mean duration of follow-up was 1.1 years. Seizure frequency decreased
by at least 50% in 29 (58%) patients. Side effects were reported in 22 (44%) patients, none of
them included aplastic anemia or liver failure. In the responder group, the maximal dose of
felbamate was lower and the patients were older compared to non-responders.
Conclusions: Despite current recommendations, felbamate is initiated following multiple
AEDs. Based on its efficacy and safety data, earlier initiation of felbamate is recommended
in children with refractory epilepsy.
© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights
reserved.

* Corresponding author. Electroencephalography Laboratory, Assaf Harofeh Medical Center, Zerifin 70300, Israel. Tel.: þ972 8 9778134;
fax: þ972 8 9779758.
E-mail address: revitalgm@hotmail.com (R. Gandelman-Marton).
http://dx.doi.org/10.1016/j.ejpn.2014.05.005
1090-3798/© 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 6 5 8 e6 6 2
1. Introduction
It is estimated that 20%e30% of the patients with epilepsy are
refractory to medical treatment.1 Since the morbidity and
mortality in children with refractory epilepsy are significant,
candidacy for epilepsy surgery and vagal nerve stimulation
are routinely evaluated in these patients.2 However, most of
them will continue to need long-term treatment with anti-
epileptic drugs (AEDs).
Felbamate was reported to be effective both as adjunctive
and mono-therapy in the treatment of partial-onset seizures,
and as adjunctive therapy in children with LennoxeGastaut
syndrome.3 However, its association with aplastic anemia and
fatal hepatotoxicity significantly decreased its use, and it is
presently indicated in children with LennoxeGastaut syn-
drome, who failed to respond to other AEDs, and as a fourth or
fifth AED in patients with refractory epilepsy.4
Since we had the impression that felbamate was initiated
following failure of more than three or four AEDs in patients
referred to our tertiary pediatric epilepsy center, this study
was aimed to verify this impression, and to identity the pa-
tients that will respond favorably to felbamate.
2. Materials and methods
We retrospectively reviewed the medical charts, EEG records
and video-EEG monitoring sessions of all patients receiving
felbamate until May 2012. The data collected included age,
sex, epilepsy syndrome, duration of epilepsy prior to treat-
ment with felbamate, previous and concomitant AEDs, high-
est dosage of felbamate, reasons for felbamate
discontinuation, side effects, and seizure frequency and
amplitude of interictal epileptiform discharges (IEDs) on
routine EEG or video-EEG monitoring before treatment initia-
tion and at maximal felbamate dosage. Seizure types and
epilepsy syndromes were classified based on criteria of the
International League Against Epilepsy.5
Seizure frequency was determined during the week prior
to treatment initiation and the week after the maximal dosage
of felbamate was reached according to seizure diaries. Re-
sponders were defined as patients with decreased seizure
frequency at maximal felbamate dosage, whereas patients
with no change or increased seizure frequency were consid-
ered jointly as non-responders. Patients were regularly eval-
uated for seizure response and adverse events every month by
phone and every 6 months during a visit at the pediatric epi-
lepsy clinic.
Thirty-minute routine EEGs or the first day of video-EEG
monitoring obtained prior to felbamate initiation and
following at least one week of treatment with maximal fel-
bamate dosage were used for visual analysis. IED was defined
as a single spike, sharp wave, and spike/sharp waveeslow
wave complex. IED amplitude was measured in the EEG
channel with the highest IED amplitude in referential EEG,
which contained the highest IED voltage, and was adjusted for
awake and sleep states.
Statistical analysis was done by SPSS version 15, Chicago,
IL. Categorical variables were tested by Pearson ChieSquare
659
test, and continuous variables were analyzed by t-test. Sta-
tistical significance was determined at P < 0.05.
The study was approved by the Ethics Committee at Assaf
Harofeh Medical Center.
3. Results
Fifty patients (34 boys) aged 4 months to 17 years (mean e 5.5
years) were identified. Demographic and clinical data are
presented in Table 1. Mean epilepsy duration was 3.4 years
(range e 1 month to 13 years). The mean number of previous
AEDs was 7.5 (range e 4e19), 14 patients were previously
treated with ketogenic diet, and seven patients with intrave-
nous immunoglobulins. Felbamate was added to a stable
dosage of baseline AEDs in 43 (86%) patients, and seven (14%)
patients were treated with felbamate monotherapy. Starting
dosage was 10 mg/kg/day given twice a day in two equal
doses, and was increased every week by 10 mg/kg/day up to
40e100 mg/kg/day (mean e 55.6 ± 14.7 mg/kg/day), depending
on clinical response and tolerability. The mean duration of
follow-up was 1.1 years (range e two weeks to 4.3 years).
Seizure outcome is presented in Table 2. Felbamate was
discontinued in 20 (40%) patients, in 13 (65%) of them because
of inefficacy, in five (25%) because of side effects, and in two
(10%) patients because of both inefficacy and side effects. Side
effects were reported in 22 (44%) patients (Table 2). None of the
patients had aplastic anemia or liver failure.
Pre- and post-treatment routine EEG or video-EEG moni-
toring were available for 41 patients. The IED amplitude
decreased on the EEG at maximal felbamate dosage compared
to pre-treatment recordings in 21 (51%) patients, increased in
6 (15%) patients, and no IED amplitude change was apparent
in 14 (34%) patients.
There was no significant difference between responders
and non-responders regarding epilepsy syndrome, number of
current AEDs, age at epilepsy onset, epilepsy duration or
seizure frequency prior to felbamate initiation, follow-up
duration, and IED amplitude change (Table 1). However, the
maximal dose of felbamate was lower and the patients were
older in the responder group compared to non-responders
(p ¼ 0.072 and p ¼ 0.098, respectively).
4. Discussion
Children with epilepsy have increased mortality rate
compared to the general population,3 especially if neurologic
comorbidity is present. In these patients, the significant
morbidity associated with felbamate is acceptable with
respect to the morbidity related to refractory epilepsy. How-
ever, despite the more favorable risk to benefit ratio of felba-
mate in this group, felbamate was used in patients referred to
our tertiary pediatric epilepsy center as the eight or ninth AED,
following therapeutic failure of previous seven to eight AEDs.
Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a
broad spectrum AED. It has several mechanisms of action,
including inhibition of voltage-sensitive sodium and calcium
channels, reduction of glutamatergic transmission through
modulation of NMDA receptors, and potentiation of GABA
660 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 6 5 8 e6 6 2

Table 1 e Demographic and clinical data according to seizure outcome.

Responders (n ¼ 29) Non-responders (n ¼ 21) P
Boys/girls 18/11 16/5 0.365
Age at FBM initiation (years) 6.4 ± 4.8 4.3 ± 3.4 0.098
Age at epilepsy onset (years) 2.5 ± 2.4 1.6 ± 2.2 0.167
Epilepsy duration (years) 3.8 ± 3.6 2.8 ± 2.9 0.301
Epilepsy syndrome Generalized 13 10 0.767
Localization-related 10 9
Undetermined whether focal or generalized 6 2
Specific epilepsy syndromes LennoxeGastaut syndrome 9 6
Myoclonic-astatic epilepsy of Doose 1
Dravet syndrome 3 2
Epilepsy attributed to structural cause 7 6
CSWS 3
Metabolic etiology 1 1
West syndrome 1
Benign epilepsy with centrotemporal spikes 1
Childhood absence epilepsy 1
Unknown cause 6 2
Daily seizure frequency before FBM 9 ± 11.2 11.4 ± 22 0.611
Number of concomitant AEDs 0 4 3 0.462
1 11 4
2 10 12
3 3 2
4 1 0
Follow-up duration (years) 1 ± 1.1 0.8 ± 1.2 0.582
Maximal FBM daily dose (mg/kg/day) 52.4 ± 10.8 60 ± 18.1 0.072
IED amplitude decreased/increased or unchanged 15/11 6/9 0.514

Mean ± SD.
AEDs e antiepileptic drugs, EEG ¼ electroencephalography, FBM e felbamate, IED e interictal epileptiform discharges.

transmission.6 Felbamate is minimally bound to serum pro-
teins, and it is eliminated by renal excretion, oxidative
metabolism and hydrolysis.7 The elimination half-life of fel-
bamate in adult volunteers not taking other medications
range from 16 to 22 h, but its clearance is 40%e50% higher in
children.8 Enzyme-inducing AEDs increase the clearance of
felbamate, and it is decreased by valproic acid and
gabapentin.9 Felbamate increases the serum concentrations
of phenytoin, phenobarbital, valproic acid, carbamazepine-
10-11-epoxide, and N-desmethyl-clobazam, and it decreases
the serum concentration of carbamazepine.9
Seizure frequency in our patients was determined ac-
cording to seizure diaries. Parents' reports have limited value
for young children and for children with absence seizures, but

Table 2 e Seizure outcome and side effects in patients treated with felbamate.
Responders (n ¼ 29) Non-responders (n ¼ 21)
Seizure frequency >50% decrease 20 (40%)
Seizure freedom 9 (18%)
Increase 7 (14%)
No change 14 (28%)
Side effects Decreased appetite 4 1
Insomnia 1 2
Fatigue 3
Irritability 2
Leukopenia 2
Abnormal liver function tests 1 1
Rash 1
Hyperactivity 1
Weakness 1
Vomiting 1
Diarrhea 1
Unstable gait 1
Cognitive deterioration 1
Behavioral change 1

CSWS e epileptic encephalopathy with continuous spike-and-wave during sleep.

 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 6 5 8 e6 6 2
they are accurate for children with developmental delay.10
However, this limitation is expected to be equally present in
diaries filled out before and after treatment initiation.
Considering the very high frequency of seizures in our pa-
tients, a therapeutic effect can be adequately established
using a one week observation period.11
Seizure frequency reduction of at least 50% occurred in 58%
of our patients. Similarly, seizure reduction of at least 50% in
patients with partial-onset seizures was reported in 53%e79%
of children treated with adjunctive felbamate, and in 56% of
the adults treated with felbamate monotherapy.12e14 Felba-
mate is considered a highly effective AED in Lennox Gastaut
syndrome, with at least 50% seizure frequency reduction in
60% of our patients. According to previous studies, it was re-
ported to reduce total seizure frequency by 19% and atonic
seizures by 34%, with a 50% reduction of atonic seizures in 66%
of the patients with Lennox Gastaut syndrome.15,16 Felbamate
also proved to be highly effective in myoclonic eastatic epi-
lepsy of Doose, with seizure freedom in 66% of these
patients.12
Side effects occurred in 44% of our patients, while a lower
rate of 24%e30% was reported by others.12,17 This difference
may result from a more aggressive dose titration in our group
compared to that used by others. A rapid titration schedule
can sometimes lead to neurotoxicity, and that can be avoided
by a slightly slower titration schedule.3 Similar to previous
reports, the most common side effects that occurred in our
patients included decreased appetite, insomnia and fatigue.3,4
Aplastic anemia and liver failure, two idiosyncratic side ef-
fects, were estimated to occur in 27e209 and 29e38 cases per
million felbamate exposures respectively.3 None of these
occurred in our study group.
In our patients, responders did not differ significantly from
non-responders regarding different demographic and clinical
variables, including age at epilepsy onset, epilepsy syndrome,
number of current AEDs, epilepsy duration or seizure fre-
quency prior to felbamate initiation and follow-up duration.
However, two findings showed a trend toward significance:
the maximal dose of felbamate was lower and the patients
were older in the responder group. Several factors can explain
the trend to higher efficacy of felbamate in older children. The
clinical manifestations of epilepsy in younger children are
different compared to those in older age, and seizure fre-
quency is reported more accurately in older patients.18
Distinctive pharmacokinetic and pharmacodynamic features
are present in the younger age group,19 and it is also possible
that earlier onset of epilepsy in childhood is related to a more
significant severity of the illness and to refractoriness to
medical treatment.
The reported effects of felbamate on the EEG include
improvement of abnormally slow activity and background
EEG activity,20 a better organization of sleep structure,21
disappearance of periodic lateralized epileptiform dis-
charges,22 resolution of hypsarrhythmia pattern,23 and
decrease in frequency and duration of prolonged generalized
slow spike and wave discharges on the EEG.12,20,24 Several of
the EEG effects, such as decrease in frequency and duration of
prolonged generalized ictal slow spike and wave complexes,
resolution of hypsarrhythmia pattern and disappearance of
periodic lateralized epileptiform discharges, were correlated
661
with clinical improvement. The effect of felbamate on IED
amplitude was not studied before, although it is a quantitative
parameter that is influenced by sufficient source area and the
degree of synchrony, two of the factors that are mandatory for
generation of recordable ictal EEG patterns as well.25 We found
that the IED amplitude decreased at maximal felbamate
dosage in 51% of the patients. However, this finding did not
correlate with clinical response to felbamate.
In conclusion, despite current recommendations, felba-
mate is initiated following multiple AEDs. Based on its efficacy
and safety data, earlier initiation of felbamate is recom-
mended in children with refractory epilepsy.
Acknowledgement
We thank Ilana Gelernter, M.A., from the statistical laboratory
in the School of Mathematics, Tel-Aviv University, for the
statistical analysis.
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