Original Articles
Efficacy of Felbamate in the Treatment of
Intractable Pediatric Epilepsy
Mary L. Zupanc, MD*†, Rhonda Roell Werner, RN, CNS*, Michael S. Schwabe, MD*,
Sunila E. O’Connor, MD*, Charles J. Marcuccilli, MD, PhD*, Kurt E. Hecox, MD, PhD*,
Maria S. Chico, RN, CPNP*, and Kathy A. Eggener, RN, CPNP*
The antiepileptic drug felbamate has demonstrated
efficacy against a variety of seizure types in the pediat-
ric population, particularly seizures associated with
Lennox-Gastaut syndrome. Postmarketing experience,
however, revealed serious idiosyncratic adverse effects
not observed during clinical trials, including aplastic
anemia and liver failure. As a result, many physicians
have been hesitant to prescribe felbamate. This retro-
spective study evaluated the efficacy of felbamate in
a pediatric population with intractable epilepsy. Of 38
patients, 22 had Lennox-Gastaut syndrome (58%); 6
had myoclonic-astatic epilepsy of Doose (16%); 5 had
symptomatic generalized epilepsy, not otherwise speci-
fied (13%); and 5 had symptomatic localization-related
epilepsy (13%). Most patients had multiple seizure
types and had been tried on a variety of antiepileptic
medications. With felbamate treatment, 6 patients
(16%) became seizure free, including 4 of the 6 patients
with myoclonic-astatic epilepsy of Doose; 24 patients
(63%) had a greater than 50% reduction in seizure fre-
quency. In this population felbamate appeared to be
safe, with minimal adverse effects. The study is limited
by the small number of patients and by its retrospective
nature, but nonetheless adds to the evidence that felba-
mate is an important antiepileptic drug for medically
refractory epilepsy in children and is well tolerated
with few adverse effects. Ó 2010 by Elsevier Inc. All
rights reserved.
Zupanc ML, Werner RR. Schwabe MS, O’Connor SE,
Marcuccilli CJ, Hecox KE, Chico M, Eggener K. Efficacy
of felbamate in the treatment of intractable pediatric epi-
lepsy. Pediatr Neurol 2010;42:396-403.
From the Departments of *Neurology and †Pediatrics, Medical
College of Wisconsin and Children’s Hospital of Wisconsin,
Milwaukee, Wisconsin.
396 PEDIATRIC NEUROLOGY Vol. 42 No. 6
Introduction
Epilepsy is a common neurologic disorder, occurring in
0.5-1% of the population. In newly diagnosed patients, sei-
zure control is achieved with use of an appropriately chosen
antiepileptic drug in approximately 60%. If the first antiep-
ileptic drug fails to provide seizure control, the chance of
a second antiepileptic drug producing complete seizure
control drops to 10% [1]. Therefore, 20-30% of all patients
diagnosed with epilepsy remain medically refractory [2].
Some of these patients are candidates for epilepsy surgery,
particularly those with lesional magnetic resonance imag-
ing scans. Many, however, have Lennox-Gastaut syn-
drome, one of the most medically refractory childhood
epilepsy syndromes. Patients with Lennox-Gastaut syn-
drome have a triad of symptoms, including (1) multiple sei-
zure types including tonic, atonic, myoclonic, or atypical
absence seizures; (2) an electroencephalogram (EEG) that
demonstrates generalized slow spike and wave discharges
at 1-2.5 Hz; and (3) cognitive impairments.
In patients with refractory epilepsy, there is significant
morbidity and mortality, including the risk of injury due
to seizures and sudden explained death with epilepsy.
Many patients with epilepsy require extended or lifelong
treatment with antiepileptic drugs. Until 1991, only six
major antiepileptic drugs were available for treatment,
and each was associated with significant pharmacologic,
cognitive, and behavioral disadvantages, including the po-
tential for teratogenic effects, interaction with other drugs,
sedation, and cognitive impairment. Since that time,
however, more than 10 antiepileptic drugs have been
approved by the U.S. Food and Drug Administration
(FDA) for the treatment of epilepsy, and one of these is
felbamate.
Communications should be addressed to:
Dr. Zupanc; Children’s Hospital of Wisconsin; 9000 W. Wisconsin Ave.;
CHW CCC Suite C540; Milwaukee, WI 53201.
E-mail: mzupanc@mcw.edu
Received July 20, 2009; accepted February 11, 2010.
Ó 2010 by Elsevier Inc. All rights reserved.
doi:10.1016/j.pediatrneurol.2010.02.013  0887-8994/$—see front matter
 Felbamate was approved by the FDA in 1993 as mono-
therapy and as adjunctive therapy in the treatment of partial
seizures with and without generalization in adults, and also
as adjunctive therapy for partial and generalized seizures as-
sociated with Lennox-Gastaut syndrome [3]. Felbamate
was the first new major antiepileptic drug approved by
the FDA since the approval of valproic acid in 1978 [4].
Felbamate is a dicarbamate that is chemically similar to
meprobamate. It entered the U.S. National Institutes of
Health (NIH) antiepileptic drug development program in
the early 1980s and was found to be highly effective in ro-
dent seizure models [5]. Felbamate is effective against max-
imal electroshock seizures, which predicts activity against
partial onset and tonic-clonic seizures. It has also exhibits
protection against pentylenetetrazol-induced seizures,
which indicates possible efficacy against absence seizures
[5]. The exact mechanisms of action of felbamate remain
unknown. Probable mechanisms of action include (1)
blockade of voltage-gated sodium channels; (2) interfer-
ence with both N-methyl-D-aspartate and non-N-methyl-D-
aspartate subtypes of the glutamate receptor; (3) inhibition
of voltage-gated calcium currents; and (4) modulation of
g-aminobutyric acid receptors [6]. Blockage of voltage-
gated sodium channels decreases excessive excitation and
the inhibition of calcium currents probably interferes with
neurotransmitter release. The relatively minor degree of fel-
bamate effect on g-aminobutyric acid function may explain
the striking lack of sedative effects and absence of adverse
effects on cognition [7].
Premarketing clinical trials indicated that felbamate was
a highly effective antiepileptic drug with few adverse ef-
fects. Felbamate was the first antiepileptic drug to be eval-
uated in a double-blind study in patients undergoing
evaluation for epilepsy surgery and was one of the first an-
tiepileptic drugs to be included in monotherapy trials. All of
these studies demonstrated significant efficacy in the con-
trol of seizures [8-11]. In premarketing experience,
felbamate was also shown to be an effective treatment for
Lennox-Gastaut syndrome. Among 73 patients treated in
a double-blind controlled trial, felbamate and placebo
reduced atonic seizures by 34% and 9%, respectively
(P < 0.01) [12]. Additionally, felbamate resulted in a total
seizure frequency decrease of 19%, compared with a 4% in-
crease in seizure frequency among patients in the placebo
group (P = 0.002); of the 71 patients who completed the
double-blind phase of the study, 70 continued into an
open-label extension phase. An eventual 50% reduction
of atonic seizures frequency was observed in 33 of 50 pa-
tients (66%) [13]. Most participants in felbamate trials
were also receiving valproate.
When felbamate was initially released, there was wide-
spread optimism that it would be a highly effective and
safe antiepileptic drug therapy. The premarketing experi-
ence involved 1000 patients. After 12 months, approxi-
mately 110,000 patients were prescribed felbamate.
Unfortunately, serious adverse effects, including aplastic
anemia and liver failure, were reported within the first year.
The first cases of aplastic anemia were reported in Janu-
ary 1994, and the first case of liver failure was reported in
March 1994. There have now been 34 reported cases of
aplastic anemia in patients treated with felbamate in the
United States; 33 of these cases were reported during the
first year of marketing. During the same time frame, 18
cases of liver failure were reported.
Of the 34 reported cases of felbamate-related aplastic
anemia reported in the United States, the majority of pa-
tients (23, or 68%) were women. No patients younger
than 13 years of age have developed aplastic anemia.
Only 8 of the 34 patients were on felbamate monotherapy;
the remaining patients were on polytherapy. The mean time
to presentation of aplastic anemia symptoms was 145 days.
Only 23 of the 34 reported cases met the full diagnostic cri-
teria for aplastic anemia. Of these 23 cases, 3 were found to
be definitely related to felbamate, and felbamate was deter-
mined to be the most likely etiologic agent in 11 additional
cases, for a total of 14 patients. In the 9 remaining cases,
confounding factors existed and felbamate was only one
of several plausible etiologic agents. For the 34 reported
cases of aplastic anemia, 18 patients recovered, 14 patients
died, and 2 patients were lost to follow-up [14].
In the general population, the risk of aplastic anemia is
2-6 cases per 1 million [14]. The risk of aplastic anemia
in patients who are taking felbamate is estimated to be be-
tween 27 and 209 cases per 1 million [15]. Probable risk
factors for aplastic anemia include (1) female sex, (2) post-
pubertal status, (3) history of cytopenia, (4) history of auto-
immune disease, such as systemic lupus erythematosus,
rheumatoid arthritis, Hashimoto’s thyroiditis, panhypo-
gammaglobulinemia, idiopathic thrombocytopenia pur-
pura, and (5) a positive antinuclear antibody titer. If two
risk factors are present, a patient’s relative risk of develop-
ing aplastic anemia quadruples [15]. There have been
approximately 40,000 new exposures to felbamate since
1994 and only 1 new reported case of aplastic anemia,
occurring in a 45-year-old woman in 2000.
Liver failure has been reported in 18 cases, 9 children
and 9 adults taking felbamate, with a definite female pre-
dominance (4 male, 22%; 14 female, 78%). Felbamate
monotherapy was only reported in 1 case (6%) [15]. The
mean time to symptom presentation was 217 days. Of these
18 reported cases of liver failure, 7 cases (39%) were deter-
mined likely due to felbamate and 9 cases (50%) were
determined unlikely due to felbamate; several of the cases
occurred in the context of status epilepticus. Nine deaths
due to liver failure were reported [15], five of them being
children: one death was deemed likely related to felbamate,
three deaths were deemed unlikely due to felbamate, and
for one death the relation to felbamate was undetermined
[15].
The risk of felbamate-related liver failure is estimated to
be between 1:6097 and 1:15,625 patients. The risk of death
due to liver failure related to felbamate use is 1 in 12,345
[15]. To place this risk factor in the context of antiepileptic
drugs, the risk of death due to liver failure from valproate in
Zupanc et al: Felbamate in Intractable Epilepsy 397
high-risk pediatric patients (age, <2 years; underlying neu-
rologic condition; polytherapy) is 1 in 500 [16].
Felbamate now carries a black box warning about the
risks of aplastic anemia and liver failure. The FDA prescrip-
tive guidelines have been changed. The current clinical in-
dications for the use of felbamate include (1) patients with
medically refractory epilepsy whose epilepsy has not been
controlled, despite the use of several other antiepileptic
medications, and (2) patients with medically refractory
Lennox-Gastaut syndrome over the age of 4 years. None-
theless, relatively few physicians have prescribed this med-
ication, because of their concern about potentially fatal
adverse effects.
The use of felbamate continues to be limited in the treat-
ment of pediatric epilepsy, with lingering doubts with re-
gard to the safety profile of felbamate as the chief
concern. Unfortunately, few published studies on pediatric
epilepsy have used recently developed patient selection
guidelines to choose patients in whom a trial of felbamate
is a reasonable decision. Presented here is experience based
on a group of well characterized pediatric patients with
intractable seizures, as part of an overall process of accu-
mulating sufficient published clinical experience to re-
establish the context in which this antiepileptic drug should
be considered.
Patients and Methods
This study is based on a retrospective chart review of 38 pediatric pa-
tients with medically refractory epilepsy who were placed on felbamate
as adjunctive therapy over a 4-year period.
The FDA-approved indications for felbamate were used in patient selec-
tion: only patients with medically refractory epilepsy were started on felba-
mate, including patients with Lennox-Gastaut syndrome. Lennox-Gastaut
syndrome was defined as patients with (1) multiple seizure types, including
tonic, tonic-clonic, atonic, atypical absence, or myoclonic seizures; (2)
EEG demonstration of generalized slow spike and slow wave discharges
at 1.5-2.5 Hz; and (3) cognitive impairments. The majority of patients ei-
ther had Lennox-Gastaut syndrome or other generalized epilepsy syn-
dromes. Four patients met the clinical criteria for myoclonic-astatic
epilepsy of Doose. Myoclonic-astatic epilepsy was defined using the fol-
lowing criteria: (1) seizure onset between 2-5 years of age; (2)
myoclonic-astatic-absence seizures, typically combined with occasional
tonic-clonic seizures, atypical absences seizures, and myoclonic seizures;
and (3) EEGs demonstrating irregular generalized polyspike and slow
wave complexes with normal background. All of the patients in this subset
had been tried on multiple antiepileptic drugs in the past, often combined
with the ketogenic diet, and were continuing to have 200 or more seizures
per day.
Seizure frequency was measured initially by 24- to 48-hour video EEG
monitoring, then by daily seizure calendars and chart reports. Most patients
had 24-48-hour video EEG monitoring repeated after the initiation of fel-
bamate. Other collected data included age of onset, types of seizures, epi-
lepsy syndrome (if identifiable), EEG reports, magnetic resonance imaging
scan findings, cognitive and developmental status, physical exam findings,
current and past antiepileptic medications, alternative therapies for epi-
lepsy (e.g., ketogenic diet), felbamate initial dosage, felbamate mainte-
nance dosage, adverse effects to felbamate, and (if applicable) reasons
for discontinuation.
Felbamate was initially used as an adjunctive antiepileptic drug, com-
bined with one or more other antiepileptic drugs. Felbamate was started
at 5-10 mg/kg per day divided either once or twice daily. The dosage
398 PEDIATRIC NEUROLOGY Vol. 42 No. 6
was subsequently titrated up over days or weeks to 30-100 mg/kg per
day divided two-three times daily. Rapid titration over days was used on
several occasions and was well tolerated.
Results
Of the 38 patients reviewed, the average age was 6
months to 18 years (mean, 8 years) (Table 1). Sex ratio
was evenly distributed. Average length of follow-up was
12 months, range 1 month to 6 years. All of these patients
had been on multiple antiepileptic medications before initi-
ation of felbamate. The most common antiepileptic drugs
included topiramate, valproate, lamotrigine, and clonaze-
pam. Some of the patients were on the ketogenic diet or
had tried it in the past.
Predominant seizure type was tonic and generalized
tonic-clonic seizures (25/38, or 66%). Other seizure types
included (1) atypical absence seizures (14/38, or 37%);
(2) myoclonic-astatic seizures (6/38, or 16%); (3) myo-
clonic seizures (5/38, or 13%); and (4) complex partial
with secondary generalization (5/38, or 13%). The majority
of patients had multiple seizure types.
Epilepsy syndromes, identified according to the Interna-
tional League Against Epilepsy criteria, were (1) Lennox-
Gastaut syndrome, 22/38 (58%); (2) myoclonic-astatic epi-
lepsy of Doose, 6/38 (16%); (3) symptomatic localization
related epilepsy, 5/38 (13%); and (4) symptomatic general-
ized epilepsy, 5/38 (13%).
The felbamate dosage range was 30-100 mg/kg per day.
The majority (>50%) had an initial positive response at the
initial maintenance dose of 30 mg/kg per day, but required
higher doses to achieve maximum efficacy. In several pa-
tients, it was possible to rapidly titrate the dosage, increas-
ing by 10 mg/kg per day each day to an initial maintenance
dose of 30 mg/kg per day in 3 days. This titration process
was performed in the hospital and was well tolerated by
the patients.
Seizure frequency was significantly reduced in the major-
ity of patients (Table 2). Of the 38 patients, 6 (16%)
achieved complete seizure freedom; 7 patients (18%) had
a greater than 75% reduction in seizure frequency; 16 pa-
tients (43%) had a greater than 50% reduction in seizure fre-
quency; 6 patients (16%) had a greater than 25% reduction
in seizure frequency; and 2 patients (5%) had no significant
change in seizure control.
Absence seizures were difficult to quantitate using sei-
zure diaries. The seizure diaries typically contained a log
of tonic, atonic, and generalized tonic-clonic seizures. The
frequency of tonic, atonic, and generalized tonic-clonic sei-
zures was used as the standard for calculation of seizure fre-
quency. Because of the retrospective nature of the data
collection, parental or care provider information about exact
seizure types could be obtained from the seizure diaries and
medical records. All 38 patients had initial long-term video
EEG monitoring, and their parents and other care providers
had been instructed on seizure types. The medical records
and seizure diaries were quite detailed in the description
Table 1. Clinicodemographic data and seizure reduction in 38 patients with intractable pediatric epilepsy treated with felbamate

Seizure Types
Case Age Epilepsy Syndrome Etiology (Baseline Seizure Frequency) Seizure Reduction

1. 7 yr Symptomatic generalized — Generalized tonic-clonic >50%

epilepsy, Lennox-Gastaut (1-2/d); clusters of atypical
syndrome absence seizures per day
2. 15 yr Symptomatic generalized Hypothalamic hamartoma Generalized tonic-clonic >25%
epilepsy, not otherwise (3-6/d) and tonic (5-6
specified gelastic seizures per day)
3. 7 yr Symptomatic generalized Idiopathic Generalized tonic-clonic >50%
epilepsy, tonic seizures, (1/wk) and astatic
myoclonic-astatic epilepsy myoclonic (10/d)
of Doose
4. 7 yr Symptomatic generalized Right frontal Generalized tonic-clonic, tonic, >50% (transient
epilepsy, Lennox-Gastaut and atypical absence close to 100%)
syndrome (in nonconvulsive status
epilepticus with atypical
absence seizures)
5. 3 yr Symptomatic generalized — Myoclonic epileptic spasms >50%
epilepsy, not otherwise (6-10 clusters per day)
specified
6. 18 yr Symptomatic generalized — Tonic, generalized tonic-clonic, >50%
epilepsy, Lennox-Gastaut and absence
syndrome
7. 4 yr Symptomatic generalized Left frontal Generalized tonic-clonic >25%
epilepsy, Lennox-Gastaut (2-3 GTCS/d) and atypical
syndrome absence (fluctuating
atypical absence)
8. 18 yr Symptomatic generalized — Tonic and generalized >50%
epilepsy, Lennox-Gastaut tonic-clonic (3-6 GTCS/d)
syndrome
9. 3 yr Symptomatic generalized Idiopathic Generalized tonic-clonic >50%
epilepsy, myoclonic-astatic (1-2/wk), astatic-myoclonic
epilepsy of Doose ($100/d)
10. 5 yr Symptomatic generalized ? Frontal dysplasia Tonic (10-20/d) and atonic (1-2/d) >50%
epilepsy, Lennox-Gastaut
syndrome
11. 7 yr Symptomatic generalized — Tonic (5-10/d), generalized 100%
epilepsy, Lennox-Gastaut tonic-clonic (1-2/wk), and
syndrome atypical absence (multiple
times per day)
12. 17 yr Symptomatic generalized ? Frontal dysplasia Tonic-nocturnal (3-4/d) and >75%
epilepsy, Lennox-Gastaut complex partial seizures (1-2/d)
syndrome
13. 10 yr Symptomatic generalized — Tonic or generalized >25%
epilepsy, Lennox-Gastaut tonic-clonic (2-3/d) and
syndrome atypical absence (multiple
times per day)
14. 3 yr Symptomatic generalized — Epileptic spasms (10-15/d) >50%
epilepsy, not otherwise
specified
15. 12 yr Symptomatic localization Left middle cerebral artery Atypical absence (multiple times >50% (after
related epilepsy infarction per day), tonic (rare), and epilepsy surgery)
GTCS (2/wk)
16. 6 mo Symptomatic generalized Midbrain Tonic spasms (multiple times >50%
epilepsy, not otherwise ? Cortical dysplasia per day)
specified
17. 6 yr Symptomatic generalized ? Cortical dysplasia Tonic (9-12/d), myoclonic >75%
epilepsy, Lennox-Gastaut ? Hypoxic ischemic (multiple times per day),
syndrome encephalopathy and atypical absence
(multiple times per day)

Zupanc et al: Felbamate in Intractable Epilepsy 399

 Table 1. Continued

Seizure Types
Case Age Epilepsy Syndrome Etiology (Baseline Seizure Frequency) Seizure Reduction

18. 4 yr Symptomatic localization ? Focal cortical dysplasia Tonic (3-4/d) and complex >50%
related epilepsy partial with 2 genl
(1-4/wk, often prolonged
requiring diazepam)
19. 7 yr Idiopathic generalized — Myoclonic, astatic, and absence 100%
epilepsy, myoclonic-astatic (in nonconvulsive status
epilepsy of Doose epilepticus for >2 yr)
20. 10 yr Symptomatic generalized — Tonic (1-2/wk), atypical absence >25%
epilepsy, Lennox-Gastaut (multiple times per day), and
syndrome myoclonic ($100/d)
21. 10 yr Symptomatic generalized — Tonic or generalized tonic-clonic >50%
epilepsy, Lennox-Gastaut (1-2/wk, often prolonged) and
syndrome atypical absence (multiple
times per day)
22. 8 yr Symptomatic generalized ? Metabolic disorder Tonic or atonic (2-12/night) and >25%
epilepsy, Lennox-Gastaut atypical absence (multiple
syndrome times per day)
23. 4 yr Idiopathic generalized — Myoclonic (multiple times per 100%
epilepsy, myoclonic-astatic day), astatic (multiple times
epilepsy of Doose per day), and absence (multiple
times per day) (presented in
nonconvulsive status
epilepticus)
24. 8 yr Symptomatic generalized — Myoclonic, astatic, and absence 100%
epilepsy, myoclonic-astatic (multiple times per day in
epilepsy of Doose clusters lasting 15-20 minutes)
25. 10 yr Symptomatic generalized — Myoclonic, astatic, and absence 100%
epilepsy, myoclonic-astatic (multiple times per day, too
epilepsy of Doose numerous to count)
26. 8 yr Symptomatic generalized Metabolic disorder Tonic (12-15/d; can occur in >50%
epilepsy, Lennox-Gastaut clusters) and atypical absence
syndrome (multiple times per day)
27. 1.5 yr Symptomatic localization — Complex partial with 2 genl >75%
related epilepsy (35 to >50/d, often in
clusters)
28. 5 yr Symptomatic generalized ? Focal cortical dysplasia Tonic (1-3/d), atypical absence No change
epilepsy, Lennox-Gastaut (multiple times per day, and
syndrome myoclonic (multiple times
per day)
29. 7 yr Symptomatic generalized Aicardi’s syndrome Tonic (4-10 times per day, >75%
epilepsy, Lennox-Gastaut often in clusters); atypical
syndrome absence seizures, occur
multiple times per day, also
in clusters
30. 11 yr Symptomatic generalized — Tonic (2-3/d), atypical absence >75% (tonic
epilepsy, Lennox-Gastaut (multiple times per day), and seizures: 100%)
syndrome myoclonic (multiple times
per day)
31. 8 yr Symptomatic generalized — Tonic (3-4 times per day, but can >75%
epilepsy, Lennox-Gastaut occur up to 10 times per day),
syndrome myoclonic (multiple times per
day), and atypical absence
(multiple times per day)
32. 12 yr Symptomatic generalized ? Frontal Tonic (clusters 1-2/day; every >50%
epilepsy, Lennox-Gastaut morning)
syndrome
33. 12 yr Symptomatic generalized ? Frontal Tonic (1-5/wk, nocturnal only) >50%
epilepsy, not otherwise
specified

400 PEDIATRIC NEUROLOGY Vol. 42 No. 6

 Table 1. Continued

Seizure Types
Case Age Epilepsy Syndrome Etiology (Baseline Seizure Frequency) Seizure Reduction

34. 1 yr Symptomatic localization Focal cortical dysplasia Complex partial with 2 genl and No change
related epilepsy generalized tonic-clonic (30-50
times per day)
35. 1.5 yr Symptomatic localization Mitochondrial disorder Tonic and complex partial with 2 100% (rare seizures)
related epilepsy genl (in convulsive status
epilepticus, with multiple
seizures per day until felbamate
started)
36. 6 yr Symptomatic generalized Aicardi’s syndrome Tonic (1-3/d, but can also have >75%
epilepsy, Lennox-Gastaut clusters of seizures) and
syndrome complex partial with 2 genl
(1-3/d)
37. 12 yr Symptomatic generalized ? Frontal Tonic (0-7 times per night) and >50%
epilepsy, Lennox-Gastaut atypical absence (multiple
syndrome times per day)
38. 17 yr Symptomatic generalized ? Frontal Tonic (1-5 times per day) and >25%
epilepsy, Lennox-Gastaut atypical absence ($30/d) and
syndrome myoclonic (3-4/d)

Abbreviations:
? = Possible etiology
2 genl = Secondary generalization
GTCS = Generalized tonic-clonic seizure

of seizure types and frequency, and the validity of the data is
considered good. In addition, the parent’s assessment of sei-
zure frequency was confirmed with follow-up video EEG
monitoring data on all of these patients.
The initial video EEG monitoring in the Lennox-Gastaut
syndrome patients typically evidenced multiple tonic and
atonic seizures, as well as prolonged trains of generalized
slow spike and wave discharges at 1.5-2 Hz, probably rep-
resenting atypical absence seizures. Many of these patients
also had frequent generalized and multifocal, independent
epileptiform discharges, with marked activation during
drowsiness and sleep. Some of these patients had electrical
status epilepticus of slow wave sleep. Unfortunately, in
a retrospective study it was not possible to confirm electri-
cal status epilepticus of slow wave sleep in the saved data
files. With felbamate treatment, not only did the tonic and
atonic seizures dramatically decrease, but the prolonged
trains of generalized slow spike and wave discharges also
significantly decreased, both in frequency and duration.
This occurred during all states (wakefulness, drowsiness,
and sleep).
Of the six patients with myoclonic-astatic epilepsy of
Doose, four became seizure free and two achieved greater
than 50% reduction. Their initial video EEG monitoring
evidenced multiple myoclonic-astatic seizures, in most
cases more than 200 per day, associated with generalized,
high-amplitude, irregular polyspike, spike and slow wave
discharges. In addition, their EEGs demonstrated robust
interictal epileptiform discharges with frequent trains of
generalized irregular polyspike, spike and slow wave dis-
charges, without overt clinical manifestations. Unfortu-
nately, no specific clinical response testing was performed
during these discharges. The EEGs also markedly activated
with drowsiness and sleep. With the initiation of felbamate,
not only did the myoclonic-astatic seizures disappear, but
the prolonged trains of generalized discharges were also
significantly reduced. Similar to the patients with Lennox-
Gastaut syndrome, but much more dramatically, the fre-
quency and duration of the epileptiform discharges de-
creased during all states (wakefulness, drowsiness, and
sleep). With two of these patients, there were only rare in-
terictal epileptiform discharges.
Adverse effects from felbamate were observed in 9 of the
38 patients (24%). The adverse effects included insomnia,
anorexia, irritability, and motor or vocal tics. In only one
patient were the adverse effects significant enough to war-
rant discontinuation of felbamate. This patient developed
significant vocal and motor tics, which were disruptive to
his family. There were no cases of aplastic anemia or liver
failure.
Discussion
In this retrospective study, felbamate proved to be
a highly effective antiepileptic medication for its primary
indication, the treatment of Lennox-Gastaut syndrome. In
addition, the six patients with myoclonic-astatic epilepsy
of Doose, another generalized, medically refractory syn-
drome, appeared to be exquisitely responsive to felbamate,
with four of the six becoming completely seizure free, on

Zupanc et al: Felbamate in Intractable Epilepsy 401

Table 2. Epilepsy syndromes and response to felbamate in 38 cases of intractable pediatric epilepsy.
Epilepsy syndrome Cases, no. Seizure free, no. (%)
Myoclonic-astatic epilepsy of Doose 6 4/6 (67)
Lennox-Gastaut syndrome 22 1/22 (5)
Symptomatic generalized epilepsy* 5 —
Localization related epilepsy 5 1/5 (20)
Total 38 6/38
* Not otherwise specified.
relatively small doses. Per the FDA indication, felbamate is
also approved for patients with medically intractable epi-
lepsy of sufficient severity to warrant the treatment. The pa-
tients with myoclonic-astatic epilepsy of Doose were all
having more than 200 seizures per day and were virtually
incapacitated by their epilepsy. This epilepsy syndrome
may represent a special subset that is exquisitely responsive
to felbamate, with patient dosages in this group typically
less than 50 mg/kg per day.
The majority of the patients had Lennox-Gastaut syn-
drome (22/38, or 58%). Most of these patients were having
multiple daily tonic seizures, both daytime and nocturnal,
that were unpredictable and extremely disruptive to quality
of life; many had had significant injury as a result of their
tonic seizures, including skull fractures, broken bones,
chipped teeth, and concussions. Seizures were greatly re-
duced with felbamate, 16 of the 22 patients with Lennox-
Gastaut syndrome having a greater than 50% reduction in
seizures, including 1 who achieved seizure freedom. Over-
all, 30 of the 38 patients (79%) had a greater than 50% re-
duction in seizure frequency, including 6 who achieved
seizure freedom (Table 2). In the majority of patients, felba-
mate was well tolerated without significant adverse effects.
There were no cases of aplastic anemia or liver failure in the
present cohort.
With respect to antiepileptic drug combinations, the
patients with myoclonic-astatic epilepsy of Doose were
on felbamate monotherapy. Patients with symptomatic
generalized epilepsy syndromes, including Lennox-
Gastaut syndrome, were typically on two antiepileptic
drugs. The most favorable combinations included felba-
mate and lamotrigine; felbamate and valproate; felbamate
and the ketogenic diet. The combination of felbamate and
topiramate was hard for the patients to tolerate and was
avoided, in large part because of appetite suppression and
weight loss.
With respect to adverse effects, there were no cases of
aplastic anemia or liver failure in the present patient popu-
lation. In the past, when aplastic anemia or liver failure has
occurred, it has almost always been reported within the first
6 months, with only one or two outliers [15]. At the authors’
center, the practice is to monitor hematologic parameters
(complete blood count with differential), reticulocyte count,
and liver function studies on a weekly basis for the first 2
402 PEDIATRIC NEUROLOGY Vol. 42 No. 6
>50% Reduction, no. (%) #50% Reduction, no. (%)
2/6 (33) —
15/22 (68) 6/22 (27)
4/5 (80) 1/5 (20)
3/5 (60) 1/5 (20)
24/38 8/38
months and then every other week for the next 2 months.
Subsequently, blood testing is done monthly for the next
4 months and then every 3-6 months thereafter. There has
been close and careful follow-up for this population of
patients on felbamate, and the blood testing is monitored
regularly.
Two patients presented unusual circumstances. The first
patient had symptomatic localization related epilepsy with
a history of frequent status epilepticus. She had bilateral
cortical dysplasia and had undergone a palliative left
temporal-parietal-occipital resection. After her epilepsy
surgery, her seizure burden, particularly the episodes of sta-
tus epilepticus, markedly reduced, but she continued to
have two complex partial seizures per week. She had
been tried on multiple antiepileptic drugs in the past and
had severe pancytopenia with phenytoin and thrombocyto-
penia with valproate. The hematologist, an expert in aplas-
tic anemia, suggested harvesting stem cells from the bone
marrow and preserving them for future use, should an aplas-
tic crisis develop. She did have this procedure performed.
Although felbamate did not completely eliminate her sei-
zures, she had a 25% reduction in seizure frequency.
The second patient had had acute lymphocytic leukemia
as a child and then subsequently went on to develop
Lennox-Gastaut syndrome with multiple tonic-atonic sei-
zures, occurring on a daily basis. He had sustained multiple
head injuries and chipped teeth because of the seizures. His
magnetic resonance imaging scan revealed significant white
matter changes, thought to be compatible with his history of
methotrexate chemotherapy. He was tried on valproate, top-
iramate, lamotrigine, and levetiracetam. He was not consid-
ered to be a candidate for the ketogenic diet, because of his
oppositional behaviors. Given his history, the medical team
was reluctant to start him on felbamate. After consultation
with the hematologist, however, stem cells were harvested
from the bone marrow. The patient was excluded from
this retrospective study, because his case was added to the
database only later. Notably, however, he achieved seizure
freedom on felbamate monotherapy, and he has not had any
hematologic abnormalities.
Although these two cases are rare, they do represent
important examples of high-risk patients who were success-
fully started on felbamate. Bone marrow harvest is not
thereby advocated for all patients who are started on
felbamate, even those at higher risk; however, these two
cases do illustrate that high-risk patients can be safely
started on felbamate.
When discussing the use of felbamate with parents, the
risks of felbamate, especially the risk of aplastic anemia
and liver failure, were all clearly outlined and documented
in the medical record. Upon the recommendation of the risk
management team, no consent form was used for this retro-
spective study. The risk-benefit ratio for using felbamate
was described in great detail. The statistical risks of aplastic
anemia and liver failure were specifically provided. Also
discussed were the risks of continued seizures, including
the risk of sudden unexplained death from epilepsy in ado-
lescent patients with uncontrolled seizures. The risk of sud-
den unexplained death from epilepsy is estimated to be
1:250-500 every year, without diminution year after year
[17]. There is also a risk of injury, particularly for those
patients with tonic and atonic seizures.
The most common adverse effects of felbamate in the
present series were insomnia and anorexia. The anorexia
was often tolerable, given that many of these patients had
been on valproate and had gained a considerable amount
of weight. If, however, the anorexia produced significant
weight loss or dehydration, cyproheptadine was used effec-
tively to increase appetite. The dosage varied from 2-8 mg
per day. Because the appetite stimulant effect declines over
several weeks, cyproheptadine should be intermittently
stopped and restarted intermittently (at the authors’ institu-
tion, it is typically 2-3 weeks on and then 2 weeks off).
Insomnia can also be a major disruptive adverse effect.
The insomnia was effectively treated by a variety of tech-
niques, in particular by (1) front-loading the dosage, so
that the biggest dosage was given in the morning, with
smaller dosages given at noon and bedtime; (2) giving the
last dosage at 5:00 to 6:00 PM, rather than before bedtime;
and (3) using melatonin for induction of sleep. For those pa-
tients who had difficulty with maintenance of sleep, cypro-
heptadine (2-4 mg) or diphenhydramine (12.5-50 mg) were
also used. Using one or more of these techniques, sleep was
induced quickly and effectively. Only one patient had to be
withdrawn from felbamate because of unacceptable adverse
effects. In this patient, the agitation and movement disorder
(vocal and motor tics) were significant enough to warrant
discontinuation of felbamate.
Conclusion
Findings from this retrospective study on the use of fel-
bamate in pediatric patients with medically intractable epi-
lepsy demonstrate that felbamate is a highly effective, well
tolerated, and safe antiepileptic drug in children with med-
ically refractory epilepsy. Myoclonic-astatic epilepsy of
Doose may constitute a subset of children with exceptional
responsiveness to felbamate therapy. With one non-life-
threatening exception, no serious adverse effects were
noted, despite therapy duration of 12 months or longer.
Limitations of the present study include the small number
of patients and its retrospective analysis, and further studies
will be necessary to confirm the results. A prospective con-
firmatory study has been initiated.
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