Epilepsia, 43(5):518524, 2002

Blackwell Publishing, Inc.

International League Against Epilepsy

Efficacy and Safety of Levetiracetam in Children with Partial

Seizures: An Open-label Trial
*Tracy A. Glauser, John M. Pellock, E. Martina Bebin, Nathan B. Fountain, Frank J. Ritter,
Christof M. Jensen, and **W. Donald Shields
*Childrens Hospital Medical Center, Cincinnati, Ohio; Medical College of Virginia of Virginia Commonwealth University,
Richmond, Virginia; University of Alabama at Birmingham, Huntsville, Alabama; University of Virginia, Charlottesville,
Virginia; The Minnesota Epilepsy Group, Saint Paul, Minnesota; UCB Pharma, Inc., Atlanta, Georgia; and **Mattel
Childrens Hospital at UCLA, Los Angeles, California, U.S.A.

Summary: Purpose: To assess the efficacy and safety of

levetiracetam (LEV) as adjunctive therapy in children with
treatment-resistant partial-onset seizures.
Methods: Children (aged 612 years) with treatmentresistant partial-onset seizures receiving one standard antiepileptic drug (AED) were eligible. After a 4-week baseline
period, children received LEV in a 6-week titration phase (target dose, 40 mg/kg/day) followed by an 8-week evaluation
phase. Seizure frequency during the evaluation period with
individualized LEV doses (2040 mg/kg/day) were compared
with the 4-week baseline seizure frequency. Plasma concentrations of LEV and other AEDs were determined to evaluate
potential drug interactions.
Results: Twenty-four subjects enrolled and received LEV;
23 entered the evaluation phase, and 22 completed the evaluation phase. Compared with their baseline seizure frequency,
12 (52%) of 23 subjects entering the evaluation phase had their

seizure frequency decrease by >50%. Two subjects remained

seizure free during the entire evaluation period. LEV did not
significantly affect plasma concentrations of any concomitant
AED during this study, and no alteration of mean clinical laboratory values was observed. The most commonly reported
adverse events were headache, infection, anorexia, and somnolence.
Conclusions: This open-label study of adjunctive LEV
therapy (at 2040 mg/kg/day) suggests that LEV is effective,
safe, and well tolerated in children ages 612 years with
treatment-resistant partial-onset seizures. A randomized,
placebo-controlled, double-blind trial of LEV adjunctive
therapy in children with treatment-resistant partial-onset
seizures is needed and ongoing to confirm these open-label
findings. Key Words: LevetiracetamKeppraChildren
Partial seizuresEpilepsy.

Every new antiepileptic (AED) medication approved

worldwide during the past decade has demonstrated efficacy as adjunctive therapy in adults with treatmentresistant partial-onset seizures (111). Some newer
AEDs have established efficacy as monotherapy in
adults with partial-onset seizures (1222). In contrast,
only four of these newer AEDs [gabapentin (GBP), lamotrigine (LTG), oxcarbazepine (OCBZ), and topiramate (TPM)] have successfully demonstrated efficacy as
adjunctive therapy in children with treatment-resistant
partial-onset seizures (2326). Outside of comparative
trials with older AEDs, there are no published active
control or placebo-controlled clinical trials establishing

the monotherapy efficacy of any of the newer AEDs in

children with partial-onset seizures.
Two main reasons underlie the need to examine formally the efficacy and safety of newer AEDs in children
with epilepsy. Direct application of the results from adult
clinical epilepsy trials to children is problematic, because
pediatric and adult epilepsy are different in many respects. These differences include age-related seizure
types, etiologic differences in partial seizures between
adults and children, a higher frequency of localizationrelated epilepsy syndromes in children, and a higher rate
of comorbidities in children (27). As a result, in children
with partial epilepsy, AED selection is often influenced
by differences in side-effect profiles resulting from concern about these comorbidities, such as mental retardation and behavioral problems (27).
Second, a need for new therapies for children with
epilepsy still exists despite the recent explosion in pharmacologic options. Approximately 25% of children with

Revision accepted February 9, 2002.

Address correspondence and reprint requests to Dr. T. A. Glauser at
Childrens Hospital Medical Center, Department of Neurology OSB5,
3333 Burnet Avenue, Cincinnati, OH 45229, U.S.A. E-mail: glauser@
chmcc.org

518

LEVETIRACETAM IN CHILDREN WITH SEIZURES

epilepsy experience treatment-resistant seizures, or
encounter significant side effects with existing AED
treatment (28). There is an imperative need for more
well-designed AED clinical trials aimed at assessing efficacy, safety, and pharmacokinetic considerations in
children (29).
Levetiracetam (LEV, Keppra, ()-(S)--ethyl-2-oxo1-pyrrolidine acetamide) is a novel AED with linear
pharmacokinetics, minimal metabolism (30), and proven
efficacy as adjunctive therapy in treatment-resistant
partial-onset seizures in adults (3133). In addition, LEV
is well tolerated; adverse events are usually mild to moderate, and symptoms of neurotoxicity (e.g., impaired
cognition) are rare (3133). Examining the efficacy and
safety of LEV in children is justified, given its efficacy
and safety profile in adults with epilepsy and the ongoing
need for additional AEDs for children with epilepsy. The
purpose of this open-label study was to provide preliminary information on the efficacy, safety, and dosing of
adjunctive LEV therapy in treatment-resistant partialonset seizures with or without secondary generalization
in pediatric patients.
METHODS
Patients
The study population consisted of 24 (15 male, 9 female) patients between the ages of 6 and 12 years,
inclusive. All subjects had a diagnosis of treatmentresistant partial-onset seizures, with or without secondary generalization, and were receiving a stable dose
regimen of one standard AED. Intermittent use of benzodiazepines (BZDs) for prolonged or iterative seizures
was allowed. During the 4-week baseline period, patients
had to have at least two seizures and not be seizure free
for >3 weeks. Participants could not be on the ketogenic
diet or have received an investigational AED for at least
30 days before study initiation. Patients with Lennox
Gastaut syndrome, clinically significant medical conditions, or abnormal laboratory values were excluded.
Criteria for removal from the study included an inability
to tolerate LEV, patient or parent noncompliance, loss to
follow-up, protocol violation, and parent or patient request. The study was conducted according to relevant
standard operating procedures of UCB Pharma, Inc.,
Good Clinical Practices, the United States Code of Federal Regulations, the Declaration of Helsinki (version
October 1996), and with local Institutional Review
Board approval. Written informed consent was obtained
before enrollment in the study from a parent or guardian
for each patient, and when applicable, assent was obtained from the patient.
Study design
This multicenter, open-label study consisted of four
phases (Fig. 1). During the baseline period, patients re-

519

FIG. 1. Schematic representation of the study timetable and

levetiracetam dosages. On the horizontal axis, each tic mark with
a week X label represents a scheduled patient visit.

ceived 4 weeks of monotherapy with one standard

AED at a stable dose, recorded use of any non-AED
medications, and maintained a daily record of seizures.
After successful completion of the baseline phase, patients entered the titration phase (6 weeks of increasing
doses of LEV), followed by the evaluation phase (8
weeks of LEV at a stable dose of 1040 mg/kg/day). At
the conclusion of the evaluation phase, patients could
either taper LEV over a 4-week period or continue in a
long-term follow-up study. The dosage of the patients
concomitant AED was changed only if clinically indicated during the course of this study.
Titration schedules and target doses of LEV were
based on prior LEV studies conducted in adults (3133).
At the start of the titration phase (study day 1), subjects
received a single 20-mg/kg dose of LEV as part of a
single-dose pharmacokinetic study. A full description of
the pharmacokinetic methods used and pharmacokinetic
results is presented in a separate report (34).
On the evening of study day 2, each subject was
started on a twice daily oral regimen of 10 mg/kg/day of
LEV. This dose was increased after 2 weeks to 20 mg/
kg/day, and then further increased to 40 mg/kg/day at
week 4 unless an excellent clinical response was seen at
the lower dose. After the visit at week 6, the patient
entered the 8-week evaluation phase. During this phase,
the LEV dose was held constant.
A medical history and ECG were obtained at baseline.
Interval history (including adverse events), physical and
neurologic examinations, clinical chemistry, hematology, and urinalysis assessments were performed, and vital signs were assessed, at screening and during titration,
evaluation, and (if applicable) withdrawal. At each visit
during the titration phase (weeks 2, 4, and 6), trough
plasma levels of LEV were obtained, as well as one
additional plasma level 1 to 7 h after dosing. Concomitant AED drug levels were obtained at screening and
throughout the study. Patients who withdrew from the
study were scheduled for a final visit 2 weeks after the
last LEV dose. This final visit included a full panel of
assessments (i.e., interval medical history, physical and
Epilepsia, Vol. 43, No. 5, 2002

520

T. A. GLAUSER ET AL.

neurologic examinations, and laboratory studies, including an ECG). Patients were allowed the option to continue LEV therapy in a long-term safety follow-up trial.
Data analysis
The primary efficacy outcome variable was the 50%
responder rate (i.e., the percentage of patients achieving
a 50% reduction in seizure frequency during the evaluation period as compared with baseline). Secondary efficacy variables included (a) the percentage of patients
achieving a 75% reduction in seizure frequency during
the evaluation period as compared with baseline, (b) the
number of seizure-free patients during the evaluation
phase, (c) the change from baseline in seizure frequency
per week observed with LEV treatment, and (d) the number of patients on each dose.
Safety assessments included evaluation of adverse
events, physical and neurologic examination findings,
and laboratory test results, including blood chemistry,
hematology, and urinalysis. The nature, pattern, and severity of all adverse events were recorded at each visit,
and the relation of each adverse event to LEV therapy
was evaluated by the investigator.
RESULTS
Twenty-five patients entered the baseline phase, but
one patient failed to continue to satisfy inclusion criteria
during baseline and withdrew before receiving LEV
(Fig. 2) The remaining 24 children composed the study
population. The group was predominantly male (62.5%,
15 of 24) and white (87.5%, 21 of 24), with a mean age
of 9.4 2.2 years. The etiologies of the groups epilepsy
were varied and included unknown etiology in 14 (58%)
patients, congenital brain malformation in six (25%)

children, tuberous sclerosis in two (8%) patients, a history of cerebral infection in two (8%) children, and individual cases of stroke and diphtheria/pertussis/tetanus
interaction (4%). Two patients had multiple etiologies
identified for their epilepsy. Additional demographic and
clinical characteristics of these patients are presented in
Table 1. The study populations concomitant AEDs during baseline are listed in Table 2.
One patient withdrew during the titration phase because of lack of efficacy. The 23 patients entering the
evaluation phase composed the evaluable efficacy data
set. One patient withdrew from the evaluation phase because of an increase in seizure frequency. Overall 22
(91.7%) of the 24 patients who entered the titration phase
completed the study and elected to continue LEV in a
follow-up safety trial.
Efficacy analysis
In the evaluable patient population (i.e., those patients
completing titration and entering the evaluation phase),
12 (52.2%) of 23 patients showed a 50% reduction in
seizure frequency per week during the evaluation phase
compared with the baseline phase. A 75% reduction
was seen in five (21.7%) of 23 patients. Two patients
remained seizure free throughout the evaluation period.
The mean and median percentage reduction in seizure
frequency per week for all partial-onset seizures and
specific partial-onset seizure subtypes is shown in Table 3.
Each patients change in seizure frequency during the
evaluation phase relative to baseline is shown in Table 4.
An increase in total seizure frequency from baseline was
observed in four patients. One patient experienced an
increase from 133.0 seizures per week during baseline to
149.2 seizures per week during evaluation; a second patient experienced an increase from 2.2 seizures per week
during baseline to 8.1 seizures per week during evaluation (268% increase); and a third patient experienced an
TABLE 1. Demographic and clinical characteristics
at baseline
Characteristic
Type of seizure
Simple partial
Complex partial
Partial secondarily generalized
Mean SD (median) and range of age at
study entry, in years

FIG. 2.

Flow diagram of patient disposition.

Epilepsia, Vol. 43, No. 5, 2002

Mean SD (median) and range of age at

onset of epilepsy, in years
Mean SD (median) and range of duration
of epilepsy, in years
Mean SD (median) and range of total
partial seizure frequency (simple partial,
complex partial, and partial secondarily
generalized), in seizures per week

N 24
7 (29.2%)
20 (83.3%)
8 (33.3%)
9.4 2.2 (median,
10) Range, 5.6 to
12.6
3.4 3.6 (median,
2.0) Range, 0 to 11
6.0 3.2 (median, 7)
Range, 1 to 12
19.2 28.0 (median,
9.9) Range, 0.5 to
133.0

LEVETIRACETAM IN CHILDREN WITH SEIZURES

TABLE 2. Concomitant antiepileptic medications
during baseline

521

TABLE 4. Changes in seizure frequency and final

levetiracetam (LEV) dose and plasma levels

Antiepileptic medication

N 24

Carbamazepine, immediate or
extended-release formulation
Lamotrigine
Valproic acid or Divalproex sodium
Topiramate
Felbamate
Gabapentin
Primidone

6 (25%)
6 (25%)
5 (20.8%)
4 (16.7%)
1 (4.2%)
1 (4.2%)
1 (4.2%)

increase from 1.0 seizure per week during baseline to 2.0

per week during evaluation. These three patients completed the evaluation phase of the trial and entered a
long-term follow-up study. The fourth patient withdrew
because of an increase in seizure frequency which, over
10 weeks, corresponded to an absolute increase from
baseline of 18%. The increase was primarily in complex
partial seizures, whereas the same patient experienced a
secondarily generalized seizure during the baseline phase
but none during LEV treatment.
One patient received 10 mg/kg/day of LEV, three received 20 mg/kg/day, and 20 received 40 mg/kg/day.
Pharmacokinetic results
Potential interactions of LEV with other AEDs were
assessed by comparison of serum AED levels before and
after LEV administration (Table 5). In nine (38%) patients, the dose of the concomitant AED was reduced
over the course of the study because of clinical indications (Table 6). There was no evidence that LEV, at
doses ranging from 10 mg/kg/day to 40 mg/kg/day, interacted with concomitantly administered carbamazepine
(CBZ; n 6), LTG (n 6), or valproic acid (VPA; n
5). The level of AED serum concentration was modified by <20% compared with baseline in 14 of these 17
patients. In the other three patients, the modifications
were +22.6%, 28.0%, and +29.3%. For the four patients
receiving TPM, a dose reduction of 27 to 75% of TPM
occurred >2 weeks after the addition of LEV because of
the development or worsening of adverse events such as
decreased appetite, weight loss, and nervousness. However, additional analysis of the data produced no evidence that LEV consistently increased TPM serum
TABLE 3. Mean and median percentage reduction in
seizure frequency for all partial seizures and partial-onset
seizure subtypes for evaluation phase compared with
baseline phase
Seizure type

Mean %
reduction

Median %
reduction

All partial onset

Simple partial only
Complex partial only
Partial secondarily generalized

29.8%
22.1%
13.5%
45.9%

53.0%
26.4%
46.9%
64.0%

23
7
19
8

Final LEV doseb

Seizure frequency/wk
Patient no.a
(mg/kg/day)/plasma
(n 23) Baseline Evaluation % Change
level (g/ml)c
14
21
20
17
11
8
2
1
6
13
12
9
10
5
18
22
4
16
23
7
15
3
19

24.5
0.5
10.3
0.9
16.3
1.6
29.8
9.7
29.4
4.2
39.8
26.4
56.8
4.2
3.2
9.5
10.2
7.7
8.4
133.0
16.9
1.0
2.2

0.0
0.0
0.4
0.1
1.9
0.4
8.8
3.6
11.2
1.8
18.7
12.4
31.0
2.6
2.2
6.8
8.4
6.4
8.2
149.2
20.0
2.0
8.1

100%
100%
96%
89%
88%
75%
70%
63%
62%
57%
53%
53%
45%
38%
31%
28%
18%
17%
2%
12%
18%
100%
268%

18.6/7.1
37.9/11.4
39.2/16.0
18.4/4.1
35.1/4.9
42.0/13.5
33.3/17.4
40.0/17.6
40.8/10.7
43.6/9.9
39.4/9.7
46.5/11.9
33.4/4.5
36.8/6.4
38.8/7.1
34.2/10.2
20.7/5.3
41.6/32.5
41.1/16.1
12.8/3.1
18.1/5.1
65.2/46.1
40.6/13.2

a
Patient 15 withdrew early (day 70) because of an adverse event.
Patient 24 withdrew before the evaluation phase and is not included in
this table.
b
Dose varied according to body weight at study entry.
c
Predose plasma concentrations on day 98, except for patient 15
(day 42).

TABLE 5. Serum levels of concomitant antiepileptic drugs

(AEDs) before and after levetiracetam (LEV) administration

AED
Carbamazepine (n 6)

Felbamate (n 1)
Gabapentin (n 1)
Lamotrigine (n 6)

Primidone (n 1)
Topiramate (n 4)

Valproic acid (n 5)
or Divalproex sodium

Serum level (g/ml)

Patient
no.

Before LEV

Last AED dose

7
14
15
16
19
22
5a
17
8a
10a
12
18
20
21
11a
3a
6a
9a
13a

8.5
8.8
11.4
12.2
11.9
10.5
110
4.6
4.1
9.4
5.9
8.4
17.0
13.0
9.8
31.1
29.9
26.8
12.8

9.9
10.8
11.1
10.5
8.9
12.4
110
8.6
2.0
1.7
4.9
7.0
13.0
11.0
<2.0
19.6
12.7
12.2
9.4

1
2a
4
24
23

124.6
149.0
132.6
97.6
108.0

126.3
111.5
99.4
87.5
95.1

a
Patients with adverse events leading to dosage reductions (see
Table 6).

Epilepsia, Vol. 43, No. 5, 2002

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T. A. GLAUSER ET AL.

TABLE 6. Adverse events leading to dosage reductions of

concomitant antiepileptic drugs (AEDs)
AEDs

Topiramate

Lamotrigine

Divalproex sodium
Felbamate
Primidone

1
1
1

Reason for dose reduction

Malaise, anorexia/weight loss,
depersonalization, ataxia
Anorexia, nervousness, somnolence,
hostility, status epilepticus, NOS
Thrombocytopenia
Somnolence
Hostility, nervousness, emotional lability

NOS, not otherwise specified.

levels. Only one patient each received felbamate (FBM),

primidone (PRM), or GBP. Therefore no conclusions can
be reached concerning serum level changes for these
AEDs.
Safety evaluation
The safety of LEV was assessed for all 24 patients by
using adverse event reporting, clinical laboratory values,
physical and neurological examinations, and vital signs.
Adverse events occurring with a 10% frequency are
summarized in Table 7 by using COSTART terms. The
most commonly reported adverse events were headache
(33%), infection (33%), anorexia (25%), and somnolence
(25%). Three patients experienced nervousness; all three
were receiving concomitant TPM, which has been reported to cause nervousness in 28% of pediatric patients
(35). Overall, the adverse event profile of LEV in these
24 pediatric patients was very similar to that seen in
adults (3133).
One serious adverse event occurred. Due to a dispensing error, one patient received an accidental overdose of
71.4 mg/kg/day of LEV, as opposed to 40 mg/kg/day,
during the last 4 weeks of the evaluable phase of the
study. No ill effects were reported by the patient or observed on examination or laboratory testing on this
higher dose, and the patient completed the trial. Data for
this patient (patient 3) are given in Tables 4 and 5.
TABLE 7. Treatment-emergent adverse events occurring in
10% of levetiracetam-treated patients (N = 24)
Adverse event
(COSTART preferred term)
Headache
Infection
Anorexia
Somnolence
Injury, accidental
Nervousness
Pharyngitis
Convulsion
Gastroenteritis
Asthenia
Diarrhea
Emotional lability
Fever
Insomnia
Otitis media

Epilepsia, Vol. 43, No. 5, 2002

Incidence
[n (%)]
8
8
6
6
5
5
5
4
4
3
3
3
3
3
3

(33.3)
(33.3)
(25.0)
(25.0)
(20.8)
(20.8)
(20.8)
(16.7)
(16.7)
(12.5)
(12.5)
(12.5)
(12.5)
(12.5)
(12.5)

The majority of clinical laboratory values in this study

were within normal limits, as defined by the control laboratory. Two patients experienced changes in laboratory
values that were considered clinically significant by the
investigator. During the evaluation, one patient exhibited
a decrease in red blood cell count from 4.1 to 3.7
106/l while receiving 40 mg/kg/day of LEV. Hemoglobin values for this patient were within normal limits for
the duration of the study (12.8 g/dl at baseline versus
12.3 g/dl at the final visit). A second patient exhibited an
elevation in mean corpuscular volume (103 fl during
baseline) from 109 fl to 113 fl during titration, then back
to 108 fl at the end of the evaluation period. This patient
showed no signs of anemia, but did exhibit thrombocytopenia during this time, which was considered by the
investigator to be related to a high level of VPA. Overall,
no trends in shifting chemistry, hematology, or urinalysis
values were evident during the course of LEV duotherapy during this study.
Physical examination and neurologic and ECG values
were stable over the course of LEV treatment. Five
(21%) patients experienced clinically significant changes
in body weight (7% from baseline). Three patients experienced weight gain, and two patients experienced
weight loss; thus no trends in body weight change can be
unambiguously assigned to LEV.
DISCUSSION
This open-label trial demonstrated that adjunctive
therapy with LEV, 2040 mg/kg/day, is effective and
well tolerated in children with treatment-resistant partialonset seizures. The overall responder rate was 12
(52.2%) of 23, with two patients remaining seizure free
during the 8-week evaluation phase. The groups median
percentage reduction for all partial-onset seizure types
was 53%, compared with a mean percentage reduction of
29.8%. Efficacy was noted across all subtypes of partialonset seizures. These efficacy results are consistent with
those from controlled clinical trials of LEV adjunctive
therapy in adults with partial-onset seizures (3133).
The difference between the median and mean percentage reductions is a reflection of the statistical influence
of the patient who experienced an increase from 2.2 seizures per week during baseline to 8.1 seizures per week
during evaluation (268% increase). There is no evidence
to date that LEV exacerbates partial-onset seizures (36).
LEV was most effective in reducing secondarily generalized seizure frequency but worked well in all seizure
subtypes. These findings are similar to those reported in
adults (32). However, results from this study are limited
by the small number of patients evaluated.
Adverse events were related to the central nervous
system, with somnolence the most frequent. The observed adverse-event profile of LEV among pediatric

LEVETIRACETAM IN CHILDREN WITH SEIZURES

patients in this trial was consistent with previous results
from adult patients (3133). The COSTART preferred
term infection referred to mild or moderate upper respiratory infections, with one common cold. Their incidence is consistent with that observed with other AEDs
in pediatric patients (37).
The full results from the single-dose LEV pharmacokinetic study conducted on the first dosing day of this
study are being published separately (34). In brief, the
half-life of LEV in patients aged 6 to 12 years after a
single 20-mg/kg oral dose was 6 h, with an apparent
body clearance 3040% higher than that reported for
adult patients. Interactions between LEV and other
AEDs have not been observed in adults, and there is no
reason to suspect that such interactions will occur in
children. In this study, pharmacokinetic analysis indicated a low potential for interaction of LEV with CBZ,
LTG, or VPA. However, dosing was individualized for
each patient; some serum levels were obtained as trough
levels, whereas others were obtained at variable intervals
after the patients morning AED dose; and the concomitant AED dose was changed in nine patients. Because of
these variations, caution should be used in interpreting
the serum AED levels and generalizing the results to
larger pediatric populations.
It should be noted that all dosage reductions were for
concomitant AEDs and not for LEV, which was titrated
as per protocol. Weight loss is a frequently observed
adverse event with TPM, and in this short-term study, a
weight loss of 7% over a 3-month period would be clinically significant. [The 7% weight change was taken
from Food and Drug Administration (FDA) guidelines
on clinically significant events for adults, but we used the
same for children]. After dosages of TPM were reduced,
the adverse events necessitating this step resolved and
did not reappear when patients were rechallenged.
The results of this open-label study suggest that LEV
at a target dose of 40 mg/kg/day is effective, safe, and
well tolerated in children aged 612 years with
treatment-resistant partial-onset seizures. A randomized,
placebo-controlled, double-blind trial of LEV adjunctive
therapy in children with treatment-resistant partial-onset
seizures to confirm these open-label findings is currently
ongoing.
Acknowledgment: This investigation was supported by a
grant from UCB Pharma Inc. and in part by PHS grant 5M01
RR00865-25. Investigators and Study Centers: E. Martin Bebin, University of Alabama, Birmingham; Nathan B. Fountain,
University of Virginia, Charlottesville; Tracy A. Glauser, Childrens Hospital Medical Center, Cincinnati, Ohio; John M. Pellock, Medical College of Virginia of Virginia Commonwealth
Institute, Richmond; Frank J. Ritter, The Minnesota Epilepsy
Group, St. Paul; W. Donald Shields, Mattel Childrens Hospital
at UCLA, Los Angeles, California.

523

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