Journal of Clinical Neuroscience 20 (2013) 1079–1082

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Journal of Clinical Neuroscience

journal homepage: www.elsevier.com/locate/jocn

Clinical Study

A randomized open-label observational study to compare the efficacy and

tolerability between topiramate and valproate in juvenile myoclonic epilepsy q
Kang Min Park a, Sang Ho Kim b, Soon Ki Nho c, Kyong Jin Shin a, Jinse Park a, Sam Yeol Ha a, Sung Eun Kim a,⇑
a
Department of Neurology, Haeundae Paik Hospital, Inje University College of Medicine, 1435 Jwa Dong, Haewundae Gu, Busan, Republic of Korea
b
Department of Neurology, Dong A Medical Centre, Dong A University, Busan, Republic of Korea
c
Department of Neurology, Bong Sang Memorial Hospital, Busan, Republic of Korea

a r t i c l e i n f o a b s t r a c t

Article history: Juvenile myoclonic epilepsy (JME) is managed with valproate in most patients; however, valproate is an
Received 20 June 2012 antiepileptic drug that has relatively severe adverse effects, especially in women. We performed a pro-
Accepted 5 October 2012 spective, open-label, randomized observational study for comparison of efficacy and tolerability between
topiramate and valproate in patients with JME. The inclusion criteria were patients with newly diagnosed
JME or previously diagnosed JME with a history of a poor response or adverse effects to other antiepilep-
Keywords: tic drugs. The primary endpoint of this study was percentage of patients who were free of myoclonic sei-
Juvenile myoclonic epilepsy
zures for 24 weeks in the two groups. The frequency and severity of adverse effects were also assessed.
Open-label study
Randomization
Sixteen patients were randomized to topiramate and 17 to valproate. In the topiramate arm, 11 of 16
Topiramate patients (68.9%) completed 24-week maintenance therapy and seven of the 11 (64%) were seizure-free.
Valproate In the valproate arm, 16 of 17 patients (94.1%) completed 24-week follow-up and nine of 16 (56%) were
seizure-free. The difference (64% topiramate versus 56% valproate) did not reach statistical significance in
this study group (p = 0.08, Fisher’s exact test). However, the severity of adverse effects was significantly
different. Only 1 of 10 adverse effects from topiramate was ranked moderate-to-severe (10%), in compar-
ison with severe rankings for 10 of 17 adverse effects from valproate (59%) (p = 0.018, Fisher’s exact test).
In summary, the efficacy of topiramate and valproate was not different, but the severity of adverse effects
was favourable for topiramate. Our findings suggest that valproate may be replaced with topiramate,
especially for the patients with JME who do not tolerate valproate.
Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction Recently, a large, randomized controlled trial (the Standard and

Juvenile myoclonic epilepsy (JME) is a common idiopathic gen-
eralized epilepsy (IGE) syndrome characterized by myoclonic jerks,
generalized tonic clonic (GTC) seizures, and less frequent absence
seizures, with characteristic findings on electroencephalogram
(EEG).1 Although GTC seizures can be controlled by most antiepi-
leptic drugs (AED), myoclonic jerks and absence seizures can be
aggravated by narrow spectrum AED such as carbamazepine or
phenytoin.2 In clinical practice, especially when a medical physi-
cian fails to elicit a history of myoclonic seizures from patients
with JME, it is common to commence treatment with narrow spec-
trum AED in these patients, and AED-induced seizure aggravation
may result eventually.3,4 In contrast, broad spectrum AED such as
valproate can provide seizure control for at least 80–90% of
patients with JME.2
q blind randomized controlled trials have been conducted in IGE
This study was partially funded by Janssen Pharmaceuticals, Republic of Korea.
⇑ Corresponding author. Tel.: +82 51 7971405; fax: +82 51 7970489.
E-mail address: epidoc@inje.ac.kr (S.E. Kim).
New Antiepileptic Drugs [SANAD] trial) showed that valproate was
more effective than lamotrigine and better tolerated than topira-
mate in epilepsy patients with generalized seizures.5 However,
valproate is an AED that is associated with relatively high risk of
adverse effects, especially in women with JME; thus the need for
other options in patients with JME who cannot tolerate valproate,
or who do not become seizure-free, is emerging.6–8 New, broad
spectrum AED such as lamotrigine, topiramate, zonisamide, and
levetiracetam have been suggested as possible alternatives in pa-
tients with JME.9–20 However, the report from the International
League Against Epilepsy (ILAE) published in 2006 did not provide
definitive evidence for treating patients with JME with these new
AED.13
Evaluation of treatment in patients with IGE syndromes is chal-
lenging in randomized controlled trials (RCT): the syndrome is rel-
atively uncommon and is also more often controlled with a single
AED compared with partial epilepsies. Although only few double-
syndromes, the evidence from these trials has shown that topira-
mate may be effective in the patients with JME.9,21,22

0967-5868/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jocn.2012.10.020
1080 K.M. Park et al. / Journal of Clinical Neuroscience 20 (2013) 1079–1082

The aim of this study was assess whether topiramate could re-
place valproate in patients with JME. We compared efficacy and
tolerability during 32 weeks of treatment for JME with topiramate
or valproate, which is considered the gold standard, in an open-
label randomized comparison observational study.
statistical analysis was performed using MedCalc Ver 12.1 (Med-
Calc Software, Mariakerke, Belgium). For all calculations, the signif-
icance level was taken as p < 0.05.
3. Results

2. Methods There were 16 patients randomized to the topiramate group

We conducted a prospective, open-label randomized compari-
son for 32 weeks for patients with JME. Patients with JME were re-
cruited between July 2006 and August 2008 from three major
regional epilepsy centres in the Busan area of Korea, with a popu-
lation of approximately 3.0 million. All patients were informed of
the study procedure and at recruitment provided written consent
to participate. The Institutional Review Boards of each epilepsy
centre approved this study.
Patients who were: (i) newly diagnosed with JME and were
AED-naïve, or (ii) previously diagnosed with JME, with a history
of unacceptable adverse events or uncontrolled seizures with
AED, were eligible for inclusion in the study. A history of myoclonic
seizures was mandatory for the diagnosis of JME, and patients with
coexistent GTC or absence seizures were also included. EEG was
not an absolute criterion for a diagnosis of JME, but generalized
epileptiform abnormalities (polyspikes) on EEG were supportive
for the diagnosis. Patients had to have active epilepsy in the form
of myoclonus as a requisite for study entry.
Exclusion criteria were: (i) previous exposure to topiramate or
valproate, (ii) absence of myoclonic seizures, (iii) significantly
abnormal cranial CT scans or MRI, (iv) progressive neurological
dysfunction such as progressive myoclonic epilepsy or dementia,
(v) unstable medical conditions, (vi) history of nephrolithiasis,
(vii) liver function tests with abnormalities more than twice the
upper limit of the normal range, and (viii) pregnancy.
Patients underwent computerized randomization in a 1:1 ratio
to primary treatment with topiramate or valproate. Monotherapy
was initiated in newly diagnosed patients and other AED were re-
placed with topiramate or valproate monotherapy in those diag-
nosed earlier with JME. An 8-week titration phase was followed
by a 24-week maintenance phase. The assigned AED was titrated
up to 1200 mg/day for valproate or 100 mg/day for topiramate.
The dose of valproate was titrated up 300 mg/day for 2 weeks,
whereas topiramate was increased 25 mg/day for 2 weeks. In pa-
tients with a poor response to medication during the 24-week
maintenance phase, the dose of valproate was increased 300 mg/
day for 1 month to a maximum dose of 2400 mg/day, and the dose
of topiramate was increased 50 mg/day for 1 month to a maximum
300 mg/day. Patients were removed from the study if they contin-
ued to present with seizures even after reaching the maximal dose
or if they did not to tolerate the minimal dose (600 mg/day for val-
proate and 50 mg/day for topiramate) during the titration period.
Patients were requested to record the frequency of seizures in a
seizure diary, and the diary was reviewed at each visit.
The primary endpoint for this study was freedom from myo-
and 17 to the valproate group. Patient demographics for the two
groups are summarized in Table 1. Median age at time of study
and age of onset for all patients with JME was 18 years (range
13–42 years) and 17 years (range 11–29 years), respectively. Med-
ian duration from onset to randomization was 2 years (range
1 month to 23 years); 52% of patients (17/33) were male. Family
history of epilepsy was positive in 12% (4/33). All patients had a
history of myoclonic seizures, 39% (13/33) had absence seizures,
85% (28/33) had GTC seizures, and 27% (9/33) had both absence
and GTC seizures, whereas only 3% (1/33) had myoclonic seizures
alone. Although the EEG of one patient who had only myoclonic
seizures was normal, the myoclonus of this patient was so typical
for JME (including early morning occurrence, aggravated by fatigue
or sleep deprivation) that we included him in the study. Epilepti-
form discharges on EEG were founded in 64% (21/33). There was
newly diagnosed JME in 79% (26/33), whereas in 21% (7/33) JME
had been diagnosed earlier and patients had been treated with
AED but their seizures were not controlled. Three patients had
been treated with carbamazepine, three with lamotrigine, and
one with oxcarbazepine.
The median dose of topiramate was 100 mg/day (range
50–150 mg) and that of valproate was 1200 mg/day (range
1200–1500 mg). One patient who was randomized to topiramate
was removed from the study due to severe anorexia. Four patients
from the topiramate group and one patient from the valproate
group were lost to follow up. Finally, 11 of 16 patients randomized
to topiramate (69%) and 16 of 17 patients randomized to valproate
(94%) completed 24 weeks of maintenance treatment. There was
no significant difference between completion rates for the two
groups (p = 0.08 by Fisher’s exact test).
Among patients finishing the 24 weeks of maintenance therapy,
seven of 11 treated with topiramate (64%) and nine of 16 treated
with valproate (56%) were myoclonic seizure-free for 24 weeks.
There was no significant difference in control of myoclonic seizures
during the 24-week maintenance period between the groups
(p = 0.98, Fisher’s exact test). Patients in both groups whose myo-
clonic seizures were controlled also had control of GTC seizures
with their treatment regimen. In addition, there were five patients
who were lost to follow-up, but the retention rate for 24 weeks of
maintenance between groups was not different (92% Vs 100%,
p = 0.43 by Fisher’s exact test).
Table 1
Demographics of patients with juvenile myoclonic epilepsy (JME) treated with either
topirimate or valproate

clonic seizures during the 24-week maintenance period. Since Topiramate (n = 16) Valproate (n = 17) p-Value
counting the number of myoclonic seizures was very difficult, we Age (years) 19 (range 13–42) 17 (range 14–36) 0.55
counted the number of days without myoclonic seizures. The nat- Sex (male:female) 1:1 1:1.1 0.85
ure and the perceived degree of the effect, by both physician assess- Onset (years) 17.5 ± 4.3 16.7 ± 4.3 0.64
ment and patient report, of AED-related adverse effects (that is, Duration (years) 15 (range 1–17) 14 (range 1–23) 0.77
Family history (%) 19 9 0.54
severe, moderate, mild [the effect cannot be ignored], no distur- Absence seizure (%) 31 47 0.56
bance to daily activity [the effect can be ignored], no adverse effect) GTC (%) 88 82 0.94
before and after medication was evaluated at the final study visit. Absence seizure + GTC (%) 25 29 1.0
For comparison between groups, categorical variables were ED on EEG (%) 75 65 0.79
Newly diagnosed JME (%) 81 76 0.92
analysed with Pearson’s chi squared test or Fisher’s exact test,
and numerical variables were analysed with the student’s t-test ED = epileptiform discharges, GTC = generalized tonic clonic seizure, JME = juvenile
or Mann-Whitney test, depending to their distributions. The myoclonic epilepsy.
 K.M. Park et al. / Journal of Clinical Neuroscience 20 (2013) 1079–1082
The most frequent adverse effects, based on the number of pa-
tients who reported an adverse effect after taking each drug, from
topiramate were: paresthesia (four of 12), anorexia (three of 12),
fatigue (one of 12), somnolence (one of 12), and hallucination
(one of 12); whereas during valproate therapy adverse effects were
weight gain (six of 16), tremor (four of 16), hair loss (three of 16),
diarrhoea (two of 16), nausea (one of 16), and anorexia (one of 16).
The severity of adverse effects was significantly different between
groups. Only 1 out of 10 adverse effects associated with topiramate
was ranked as moderate-to-severe (10%), while 10 out of 17 (59%)
adverse effects linked to valproate were ranked as severe com-
plaints (p = 0.018, Fisher’s exact test) (Table 2).
4. Discussion
JME is a very unusual syndrome where three types of general-
ized seizures can be seen. In concordance with previous reports,
all of our patients had myoclonic seizures and 39% of patients with
JME in this study had absence seizures as well. Some researchers
believe that JME may be partial- rather than generalized epilepsy,
representing activation of the cortico-thalamo-cortical circuit
beginning in the from somato-sensory cortex.1 This has been a
matter of ongoing robust discussion, and the new classification of
epilepsy suggested by ILAE in 2010 may be useful for JME.23
Although the exact mechanism for JME has not been clarified, both
myoclonic seizures and absence seizures can be aggravated by
narrow spectrum AED such as carbamazepine or phenytoin.2–4,24
Indeed, seven of 33 patients with JME (21%) in the current study
had experienced adverse effects with AED including carbamazepine
and oxcarbazepine. Although there have not been definitive recom-
mendations for treatment of JME patients with new broad spectrum
AED such as lamotrigine, topiramate, zonisamide, and levetiracetam,
these medications have been suggested as alternative AED for
JME,9–20 although a number of reports suggest that lamotrigine
may be associated with AED-related aggravation of JME.25,26 Our
study supports this point of view, showing aggravation in three of se-
ven patients with JME who were treated with lamotrigine in this cur-
rent study. These characteristics of JME make selection of AED
therapy difficult.
This prospective observational study suggests that the efficacy
of topiramate may be similar to that of valproate in patients with
JME, and the severity of adverse effects from topiramate may be
lower in comparison with valproate. A pilot study comparing topi-
ramate and valproate also demonstrated that topiramate could be
an effective, well-tolerated alternative to valproate.17 In addition, a
small number of observational studies have supported our findings
that topiramate could be effective for JME.12
We chose to compare the percentage of patients who were
myoclonic seizure-free for 24 weeks in the topiramate group
Table 2
Severity of adverse effects
Topiramate Valproate
Tolerable Intolerable Tolerable Intolerable
Paresthesia 4 0 0 0
Anorexia 2 1 1 0
Fatigue 1 0 0 0
Somnolence 1 0 0 0
Hallucination 1 0 0 0
Weight gain 0 0 1 5
Tremor 0 0 1 3
Hair loss 0 0 1 2
Diarrhea 0 0 2 0
Nausea 0 0 1 0
Intolerable adverse effects were those scored as severe or moderate; tolerable
adverse effects were those scored as mild or no disturbance to daily activity.
1081
compared to the valproate group rather than the retention rate
for 24 weeks as the primary endpoint of this study. Even though
three types of generalized seizures are seen in JME, myoclonic sei-
zures are the prototype of seizures that can be aggravated by
AED.2–4,24 Given that the purpose of this study was to assess the
possibility that topiramate could be prescribed as a first-line AED
in place of valproate, the exacerbation of myoclonic seizures by
topiramate was a critical issue. Myoclonic seizures generally occur
many times a day, making it impossible to assess their frequency.
We therefore counted the number of days without myoclonic sei-
zures and selected the percentage of patients who were myoclonic
seizure-free for 24 weeks as the primary endpoint.
The aim of this study was to test our hypothesis that topiramate
could be used as a replacement for valproate in patients with JME.
We sought to determine whether topiramate would be as effective
as valproate for symptom control. Because this study was a com-
parison with randomization, but not a cross-over design, we can-
not completely answer that question. If we had used a cross-over
study design, we would expect the same responsiveness to both
topiramate and valproate in study participants.
One long-term prospective observational study revealed that
responsiveness to AED might be associated with the biology of epi-
lepsy itself rather than the type of AED.27 JME is a heterogeneous
condition and may consist of several phenotypes.1,28,29 Given this
hypothesis, it is possible that patients with JME who are not
responsive to topiramate may also not be effectively managed with
valproate. The phenotype of JME that is unresponsive to AED may
be characterized by a specific biology of epilepsy. In daily clinical
practice, adverse effects from AED present a critical challenge in
selecting from alternative AED, especially when both AED have
similar efficacy. The SANAD trial also recognized the significant
role that adverse effects play in AED selection in daily clinical
practice.5,30
Although valproate is a drug of choice in IGE, including JME, it
can present serious problems, especially in women with epi-
lepsy.6,7 The frequent adverse effect of weight gain, and the risks
of teratogenicity or delayed cognitive development in children
after intrauterine exposure, have resulted in a search for alterna-
tive first-line therapies in women.6,7,31 In our study, we did not in-
clude pregnant women to avoid these adverse effects;
nevertheless, the severity of adverse effects from valproate was
significantly greater than effects from topiramate in the current
study. Only 10% of adverse effects from topiramate were reported
as moderate-to-severe, whereas 59% of adverse effects from val-
proate were described as severe. In concordance with our experi-
ence, greater systemic toxicity was also reported with valproate
compared to topiramate in another comparison study.17 In addi-
tion, a high adverse effects profile may limit patient compliance.
Serious adverse effects and poor compliance eventually lead to
uncontrolled seizures and decreased quality of life.
This study has limitations. First of all, this is a comparison
observational study in daily clinical practice. Even though we ran-
domized the patients with JME into topiramate and valproate
groups, this is not a RCT. Second, the 24-week follow-up period
was too short to draw conclusions for the longer term. Third, the
target dose of topiramate in this study was lower than that usually
recommended (200 mg/day). The dose of topiramate in one obser-
vational study comparing the effectiveness between topiramate
and valproate was 250 mg/day;17 however, this study was per-
formed in the USA, and most physicians in Korea usually agree that
the optimal AED dose for Korean epilepsy patients would be lower
than that recommended for Caucasians. In addition, in a study
enrolling patients with newly diagnosed epilepsy, an initial target
dose of topiramate 100 mg/day was at least as effective as
therapeutic doses of 1250 mg/day of valproate.21 Some may argue
that the severity of the adverse effects in this study could be
1082 K.M. Park et al. / Journal of Clinical Neuroscience 20 (2013) 1079–1082
related to dose, but the authors believe that the titration schedule
for this study was slower (8 weeks) than that in usual clinical prac-
tice, and the significantly different severity from topiramate and
valproate may be related to the AED itself rather than to therapeu-
tic doses for patients in this study.
In spite of the limitations of this study, our findings suggest that
the efficacy of topiramate and valproate may be similar in this pa-
tient population, while the profile of adverse effects associated with
the two medications was favourable for topiramate. Our experience
suggests that valproate may be replaced with topiramate, especially
for the patients with JME who do not tolerate valproate. Our findings
that topiramate may be an effective, well-tolerated alternative to
valproate warrant validation in a double-blind randomized con-
trolled trial.
Conflict of interest/disclosures
This study was partially supported by a grant from Janssen
Pharmaceuticals, Korea.
Acknowledgements
This research was supported by grants from the Korea Health
21 R&D Project, Ministry of Health & Welfare and Republic of Korea
(A040155) and Janssen Pharmaceuticals, Korea.
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