Epilepsy & Behavior 23 (2012) 3640

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Epilepsy & Behavior

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

Treatment of epilepsy in adults: Expert opinion in China

Pei-min Yu, Guo-xing Zhu, Ding Ding, Lan Xu, Ting Zhao, Xing-hua Tang, Yun-bo Shi, Zhen Hong
Institute of Neurology, Huashan Hospital, Fudan University, Shanghai, China

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

Article history: Objective: The goal of this study was to survey a group of epileptologists in China regarding the treatment of
Received 25 September 2011 adult epilepsy.
Revised 13 October 2011 Methods: A questionnaire on treatment of adult epilepsy was sent to a group of opinion leaders in the eld of
Accepted 18 October 2011 epilepsy.
Available online 25 November 2011
Results: For initial monotherapy for idiopathic generalized epilepsy (IGE), valproate was rated as the treat-
ment of choice. In symptomatic localization-related epilepsy (SLRE)/simple partial seizures and SLRE/
Keywords:
Epilepsy
complex partial seizures, carbamazepine and oxcarbazepine were the respective treatments of choice,
Treatment whereas in SLRE/secondarily generalized tonicclonic seizures, carbamazepine, lamotrigine, and oxcarbaze-
Idiopathic generalized epilepsy pine were treatments of choice. For women who were pregnant or trying to conceive, lamotrigine was the
Symptomatic localization-related epilepsy treatment of choice for both IGE and SLRE. In people with epilepsy who were HBsAg positive, whether
Expert consensus liver function was normal or not, topiramate and levetiracetam were treatments of choice for IGE. Valproate
and levetiracetam were treatments of choice for seizures in the emergency department.
Conclusion: A high level of consensus was reached on most treatments of choice and rst-line treatments for
patients with epilepsy, which were in accordance with published US expert opinion.
2011 Elsevier Inc. All rights reserved.

1. Introduction 2. Methods

Epilepsy is currently estimated to affect up to 9,000,000 people in 2.1. The experts

China, with an additional 660,000 developing the condition each
year. New treatments for epilepsy have proliferated over the past
20 years in China. However, the increasing number of choices
poses a challenge for physicians in identifying the best treatments
for a given individual [13]. Despite increasing amounts of data on
treatment of epilepsy, many clinical questions remain unanswered,
especially those regarding the use of a therapy in a particular clinical
situation. As a result physicians must often rely on individual clinical
judgment. In such situations, expert opinion can be especially
helpful.
We conducted a survey to collect the opinions of Chinese epilep-
tologists on the use of antiepileptic drugs (AEDs). Our methods
were based on those of a US study [4]. The questionnaire contained
questions about treatment choices and strategies for adult patients
with epilepsy. The aim of this investigation was to be able to describe
the medical treatment of epilepsy in China and to detect the presence
or absence of consensus on epilepsy treatment.
Corresponding author at: Institute of Neurology, Huashan Hospital, Fudan University,
No.12, Wulumuqi Road (M), Shanghai 200040, China. Fax: +86 21 62481930.
E-mail address: hongzhen@medmail.com.cn (Z. Hong).
Fifty experts were identied, all of whom are practicing physicians
in tertiary hospitals in China who specialize in epilepsy. Forty-nine
(98%) individuals completed the survey. These experts, selected on
the basis of recent publications, are considered leaders in the eld
of epilepsy and represent a geographic cross section of China.
2.2. The survey
The methods used in this survey were based on two previous
studies conducted in the United States that provided a template. We
modied our version to reect local circumstances. The questionnaire
contained questions on treatment choices concerning two main types
of epilepsy: idiopathic generalized epilepsy (IGE) and symptomatic
localization-related epilepsy (SLRE). For each syndrome, the ques-
tions focused rst on overall treatment strategies and then on choices
of specic medications. The questionnaire also contained questions
on treatment issues related to specic patient populations (e.g., com-
binations of medications, treatment of women who are pregnant or
breastfeeding, treatment of elderly patients).
Antiepileptic medications that are not available in China, such as
clobazam, methsuximide, felbamate, tiagabine, vigabatrin, pregaba-
lin, zonisamide, and ethosuximide, were not included in this survey.

1525-5050/$ see front matter 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.yebeh.2011.10.018
 P. Yu et al. / Epilepsy & Behavior 23 (2012) 3640
Vagus nerve stimulation and the ketogenic diet are not widely used in
China, so they were not included in this study. To address the high
prevalence of hepatitis B in China, we added questions on therapy
for patients who were HBsAg positive with or without impaired he-
patic function. Additionally, we included questions on AED therapy
in patients with behavioral problems and in patients with poststroke
epilepsy. As HIV is rare in patients with epilepsy in China, we did not
include questions on this topic.
Two types of questions were used. The rst type was used to iden-
tify the overall approach used in the treatment of IGE or SLRE. The
second type asked the experts to use a modied 9-point scale to
rate specic treatment choices.
2.3. Statistics
For each option, we dened the presence or absence of consensus
as a distribution unlikely to occur by chance. This was done using a 2
test (P b 0.05) with the distribution of scores divided into three cate-
gories on the scale of appropriateness (13, 46, and 79). We calcu-
lated the mean, SD, and condence interval (CI) for each option. The
CI is calculated statistically, and indicates that if the survey were con-
ducted again, there is a 95% chance that the response would fall with-
in this range.
A categorical rating of rst, second, or third line was designated
for each option based on the lowest category into which its CI fell.
Thus, options with a CI that fell entirely at or above 6.5 were assigned
a rst-line rating, whereas those with a CI between 3.5 and 6.49 were
designated second line, and those with a CI below 3.5 were designat-
ed third line. First-, second-, and third-line options were determined
for each clinical situation. Items that were rated treatment of choice
within the rst-line category were options that at least 50% of the
experts thought were extremely appropriate, as indicated by a rating
of 9 on the appropriateness scale.
3. Results
All 49 respondents held an M.D. degree. Among the respondents,
11 (22.4%) were female and 38 (77.6%) male. Their mean age was
53.9 years, with a mean of 29.2 years in practice. Forty-six (93.9%)
worked in the epilepsy center of a tertiary referral hospital in China,
and 43 (87.8%) reported having participated in a research project in-
volving patients with epilepsy during the previous 5 years. The ex-
perts all reported that a median of 100 patients with epilepsy
visited their epilepsy clinic each month. The median time for comple-
tion of the survey was 2.75 hours.
Fig. 1. Overall treatment strategy for patients with idiopathic generalized epilepsy.
37
3.1. General treatment strategy
Initial monotherapy was unanimously the preferred treatment
strategy for IGE (100%) and SLRE (100%). In case of failure, a second
monotherapy was preferred by more than 90% of the experts for
both types of epilepsy. In the case of a third step, approximately
half of the experts used a combination of two AEDs. In any following
steps, approaches varied (Figs. 1 and 2).
3.2. Idiopathic generalized epilepsy
Valproate was the treatment of choice for all three seizure types
(tonicclonic, absence, and myoclonic) (Table 1). Topiramate and
lamotrigine were also regarded as rst-line treatment for generalized
tonicclonic seizures. If initial treatment for generalized tonicclonic
and absence seizures failed, the second choice for monotherapy was
lamotrigine; levetiracetam was the preferred rst-line treatment for
myoclonic epilepsy (see Table 1). For all three seizure types, valproate
was the treatment of choice in the case of failure of other AEDs.
3.3. Symptomatic localization-related epilepsy
Carbamazepine and oxcarbazepine were rated as the treatment of
choice for all three types of seizures. Lamotrigine was rated as the
treatment of choice for secondarily generalized seizures. Table 2
also lists preferred treatment approaches after failure of a rst-line
drug in cases of SLRE. Carbamazepine, oxcarbazepine, and lamotri-
gine were treatments of choice after unsuccessful trials of the other
AEDs. Lamotrigine was the treatment of choice after an unsuccessful
trial of carbamazepine or oxcarbazepine.
3.4. Combination therapy
Valproate was selected as the treatment of choice for IGE when
combined with other AEDs. For SLRE, carbamazepine or oxcarbaze-
pine in combination with topiramate, valproate, levetiracetam, lamo-
trigine, or gabapentin was considered the treatment of choice. In
combination with valproate, lamotrigine was considered the treat-
ment of choice. Lamotrigine, valproate, and phenytoin were consid-
ered treatments of choice in combination with topiramate.
3.5. Special patient populations
For women of reproductive age, whether planning to have a fam-
ily in the future or trying to conceive and planning to breastfeed,
lamotrigine was the treatment of choice for both IGE and SLRE. For
healthy elderly women and men, lamotrigine and oxcarbazepine
38 P. Yu et al. / Epilepsy & Behavior 23 (2012) 3640

Fig. 2. Overall treatment strategy for patients with symptomatic localization-related epilepsy.

were the treatments of choice. Lamotrigine and levetiracetam were

Table 2
treatments of choice for medically ill elderly women and men Initial and second monotherapy for symptomatic localization-related epilepsy.
(Table 3).
Therapy Simple partial Complex partial Secondarily
seizures seizures generalized
3.6. Patients with comorbid conditions
seizures

Treatment First Treatment First Treatment First

For patients with depression or behavioral problems, valproate
of choice line of choice line of choice line
and lamotrigine were the treatments of choice for IGE. Lamotrigine,
oxcarbazepine, and carbamazepine were treatments of choice for Initial CBZ (89.8%) CBZ CBZ (93.9%) CBZ CBZ (87.8%) CBZ
OXC (67.3%) OXC OXC (72.9%) OXC OXC (64.6%) OXC
SLRE. LTG LTG LTG (50.0%) LTG
For patients with renal disease and hemodialysis, lamotrigine was TPM TPM TPM
the rst-line treatment for IGE; there was no consensus on treatment LEV LEV LEV
of choice. Lamotrigine was the treatment of choice and rst-line VPA
After LTG (64.6%) LTG LTG (63.8%) LTG LTG (63.0%) LTG
treatment for SLRE.
unsuccessful OXC (58.7%) OXC TPM TPM
For patients who were HBsAg positive and had normal hepatic trial of CBZ TPM OXC OXC
function, topiramate and levetiracetam were treatments of choice in LEV LEV LEV
IGE, and carbamazepine was the treatment of choice in SLRE. For pa- VPA VPA
tients who were HBsAg positive and had abnormal hepatic function, After OXC (83.3%) OXC OXC (81.3%) OXC OXC (79.2%) OXC
unsuccessful CBZ (66.7%) CBZ CBZ (76.6%) CBZ CBZ (70.8%) CBZ
topiramate and levetiracetam were treatments of choice for both trial of LTG TPM TPM TPM
IGE and SLRE. LEV LEV LEV
For patients with cognitive impairment, lamotrigine was the treat- VPA
ment of choice for IGE. Lamotrigine, oxcarbazepine, and levetiracetam After LTG (57.4%) LTG LTG (59.6%) LTG LTG (63.8%) LTG
unsuccessful TPM TPM TPM (51.0%) TPM
were treatments of choice for SLRE (Table 4).
trial of OXC LEV LEV LEV
VPA
3.7. Other treatment issues After CBZ (66.7%) CBZ CBZ (70.8%) CBZ CBZ (63.8%) CBZ
unsuccessful OXC (72.3%) OXC OXC (76.6%) OXC LTG (58.7%) LTG
Valproate (73.5%) and levetiracetam (50%) were considered treat- trial of PHT LTG (61.7%) LTG LTG (57.4%) LTG OXC (62.5%) OXC
TPM TPM TPM
ments of choice for cases of seizures in the emergency department LEV LEV VPA
VPA LEV
Table 1 After CBZ (68.8%) CBZ CBZ (76.6%) CBZ CBZ (75.0%) CBZ
Initial and second monotherapy for idiopathic generalized epilepsy. unsuccessful OXC (68.1%) OXC OXC (74.5%) OXC LTG (59.6%) LTG
trial of TPM LTG (59.6%) LTG LTG (55.3%) LTG OXC (68.1%) OXC
Therapy Generalized tonic Absence seizures Myoclonic seizures LEV LEV LEV
clonic seizures VPA
After CBZ (72.9%) CBZ CBZ (83.0%) CBZ CBZ (77.1%) CBZ
Treatment First Treatment First Treatment First
unsuccessful OXC (71.7%) OXC OXC (80.4%) OXC OXC (71.7%) OXC
of choice line of choice line of choice line
trial of VPA LTG (57.4%) LTG LTG (55.3%) LTG LTG (56.5%) LTG
Initial VPA VPA VPA VPA VPA VPA TPM TPM TPM
(93.9%) TPM (93.9%) (83.7%) LEV LEV LEV
LTG After OXC (76.1%) OXC CBZ (78.7%) CBZ CBZ (74.5%) CBZ
After unsuccessful LTG LTG LTG LTG LEV unsuccessful CBZ (74.5%) CBZ OXC (82.2%) OXC LTG (69.6%) LTG
trial of VPA (85.1%) TPM (60.4%) trial of GBP LTG (65.2%) LTG LTG (63.1% LTG OXC (68.9%) OXC
LEV TPM LEV TPM
After unsuccessful VPA VPA VPA VPA VPA VPA LEV TPM LEV
trial of LTG (89.6%) TPM (93.8%) (85.4%) LEV VPA
LEV After CBZ (70.8%) CBZ CBZ (79.2%) CBZ OXC (74.5%) OXC
After unsuccessful VPA VPA VPA VPA VPA VPA unsuccessful OXC (67.1%) OXC OXC (74.5%) OXC CBZ (70.8%) CBZ
trial of TPM (89.6%) LTG (93.9%) LTG (87.8%) LEV trial of LEV LTG (61.7%) LTG LTG (61.7%) LTG LTG (66.0%) LTG
LEV TPM TPM TPM
 P. Yu et al. / Epilepsy & Behavior 23 (2012) 3640 39

Table 3 rely on their medical judgment: it is in this gray area in which

Therapy for special patient populations. expert opinions can be most helpful.
IGE SLRE Epilepsy is a chronic disease affecting approximately 50 million
individuals worldwide. Several epidemiological surveys of epilepsy
Treatment First Treatment First
of choice line of choice line have been carried out in the past 20 years in the People's Republic
of China, revealing that the lifetime prevalence of epilepsy is between
Healthy woman planning to have LTG (73.3%) LTG LTG (64.4%) LTG
a family in the future LEV (50.0%) LEV LEV 3 and 5 for every 1000 people. Approximately 40 to 50% of these peo-
TPM OXC ple, particularly those in rural areas, do not receive appropriate med-
TPM ical treatment [5]. One reason for this treatment gap is the lack of a
Healthy woman trying to conceive LTG (74.5%) LTG LTG (70.2%) LTG consensus regarding medical treatment in China, and physicians
and planning to breastfeed LEV LEV
Healthy elderly man/woman LTG (68.8) LTG
may not know how to select an appropriate treatment option for an
OXC (51.1%) OXC individual patient.
LEV To identify current preferences for treatment of adult patients
TPM with epilepsy, we surveyed experts in epileptology throughout
CBZ
China. Our results reveal that initial monotherapy was the preferred
VPA
Medically ill elderly man/woman LTG (59.6%) LTG treatment strategy. Valproate was the rst choice for patients with
LEV (56.8%) LEV IGE. Carbamazepine and oxcarbazepine were the rst choices in treat-
OXC ment of focal epilepsy with partial seizures. Newer AEDs were recom-
TPM mended in second-line treatment regimens. However, in special
populations, these were considered rst-line treatment, for example,
lamotrigine for women of reproductive age.
Table 4 Our results indicate that most ratings for preferred treatment of
Therapy for patients with comorbid conditions. choice and rst-line treatment for patients with epilepsy in China
IGE SLRE are in accordance with US expert opinion published in 2005, despite
the inclusion of a number of unmarketed AEDs in China.
Treatment of First Treatment of First
choice line choice line For patients with IGE, valproate was selected as the treatment of
choice when combined with other AEDs in this survey. However, in
Depression VPA (78.3%) VPA LTG (68.9%) LTG
LTG (64.4%) LTG OXC (62.8%) OXC US expert opinion, lamotrigine was the treatment of choice in combi-
CBZ (57.8%) CBZ nation with topiramate for patients with IGE. This revealed that epi-
VPA leptologists in China are more likely to use old drugs as rst-line
Behavioral problems VPA (86.0%) VPA CBZ (62.8%) CBZ treatment or to combine an old drug with a new drug, instead of com-
LTG (57.8%) LTG OXC (56.8%) OXC
LTG (59.5%) LTG
bining two new drugs. This may be due to concern for the economic
VPA burden of an individual patient. However, we still recommend the
Renal disease VPA (54.3%) LTG LTG (50.0%) LTG use of new general AEDs in combined therapy to avoid adverse
VPA LEV drugdrug interactions [6].
LEV
We also found that the experts employed levetiracetam signi-
HBsAg+ TPM (56.3%) TPM OXC (52.2%) TPM
Hepatic function normal LEV (50.0%) LEV LEV cantly more often as the treatment of choice or rst-line treatment
LTG LTG in the United States than in China. Levetiracetam has been on the
OXC market in China since 2007, and is used as an add-on medication in
HBsAg+ TPM (57.4%) TPM TPM (57.4%) TPM treatment of refractory partial seizures [7]. In this situation, epileptol-
Hepatic function abnormal LEV (52.3%) LEV LEV (56.8%) LEV
LTG LTG
ogists in China were not familiar with this newly marketed drug. That
Patients with cognitive LTG (64.6%) LTG LTG (70.8%) LTG could also indicate that it takes a longer period for a new drug to be
impairments LEV OXC (52.2%) OXC used condently by epileptologists in China.
VPA LEV (50.0%) LEV In China today, patients with epilepsy are not permitted to drive.
With China becoming the world's largest car market, more and more
people drive a car as part of their daily commute. Driving restrictions
(type of seizure and/or epilepsy syndrome was unclear). Lamotrigine for people with seizure disorders are intended to ensure public safety,
(66.7%) and oxcarbazepine (59.2%) were treatments of choice for pa- but driving is of such great importance that the imposed restrictions
tients with poststroke epilepsy. For patients with other systemic dis- also may unduly harm the welfare of these individuals [8]. In this
eases, levetiracetam (50.0%) was considered the treatment of choice. study, we investigated the length of time that experts in China recom-
In cases in which treatment was discontinued because seizures mend patients refrain from driving after the discontinuation of or
had been well controlled for an extended period, experts asked indi- change in treatment. Although this period was much longer than
viduals with IGE to refrain from driving for an average of 16.59 that recommended by US experts, it is still meaningful as these health
12.26 months, and people with SLRE, an average of 20.91 12.60. professionals may serve as consultants to regulatory authorities re-
When changing treatments, patients with IGE were asked to refrain garding the standards for licensing drivers with seizures in China.
from driving for an average of 17.17 13.58 months, and people To our knowledge, this is the rst survey of expert opinions on ep-
with SLRE, an average of 18.71 14.34 months. ilepsy treatment in a developing country. The study described here
provides an overall picture of clinical practices in the treatment of ep-
4. Discussion ilepsy in China in 2010, revealing that experts have reached a high
level of consensus on many key treatment options. Our ndings also
The increasing number of new treatments promises a better qual- reect the need for continued development of novel AEDs with better
ity of life for individuals with epilepsy. However, the ever-growing efcacy and improved tolerability. The application and improvement
list of options also makes it much more difcult to select the optimal of other treatment methods, such as vagus nerve stimulation and the
treatment or combination of treatments. The medical literature may ketogenic diet, are also urgently needed in China.
not offer sufcient information regarding the use of a therapy in a The results of this survey can aid clinicians in making clinical de-
particular clinical situation, and so clinicians may at times need to cisions for individual patients, especially in situations in which the
40 P. Yu et al. / Epilepsy & Behavior 23 (2012) 3640
medical literature is scant or lacking. Using the survey data, clinicians
can compare their own practices with those of a panel of experts. In
addition to aiding physician self-assessment, the recommendations
reinforce the importance of studies comparing epilepsy therapies.
As new data become available in China, the opinions of experts will
continue to change, reecting these advances as well as their personal
experience in the optimal use of these therapies. The recommenda-
tions in this publication reect the opinions of the experts and should
be evaluated in conjunction with evidence-based ndings.
Ethical approval
We conrm that we have read the ethical publication guidelines
for this Journal and afrm that this report is consistent with those
guidelines.
Conict of interest statement
None of the authors have any conicts of interest to disclose.
Acknowledgments
We thank these investigators for their contributions to this study:
Xiaohong Chen, Yangmei Chen, Zhaofu Chi, Benqiang Deng, Yanchun
Deng, Chengyun Ding, Meiping Ding, Xuguang Gao, Zhen Hong,
Xishun Huang, Yuangui Huang, Liri Jin, Sengyang Lang, Guoliang Li,
Weiping Liao, Weihong Lin, Xiaorong Liu, Xingzhou Liu, Xiuqin Liu,
Yuxi Liu, Zhenguo Liu, Qinchi Lu, Renfei Ma, Hui Reng, Xuzhong
Luan, Dinglie Shen, Hongbin Sun, Lan Tan, Xin Wang, Weiwei Wang,
Xuefeng Wang, Yuping Wang, Guohua Wei, Liwen Wu, Xun Wu,
Guofeng Wu, Shijing Wu, Bo Xiao, Yong Yan, Liyun Yu, Liming
Zhang, Yindong Zhang, Qinjie Zhao, Zhongxin Zhao, Rongyuan Zhen,
Dong Zhou, Lieming Zhou, Guoxing Zhu, Suiqiang Zhu.
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