ORIGINAL ARTICLE

Efficacy of phenytoin, valproic acid, carbamazepine and new

antiepileptic drugs on control of late-onset post-stroke epilepsy in
Taiwan
Y.-H. Huanga,b, N.-F. Chia,b, Y.-C. Kuana,b,c, L. Chana,b, C.-J. Hua,b, H.-Y. Chioud and L.-N. Chiene

a
Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City; bDepartment of Neurology, School of
Medicine, College of Medicine, Taipei Medical University, Taipei; cDepartment of Neurology, School of Medicine, National Yang-Ming
University, Taipei; dSchool of Public Health, College of Public Health and Nutrition, Taipei Medical University, Taipei; and eSchool of
Health Care and Administration, College of Public Health and Nutrition, Taipei Medical University, Taipei, Taiwan

EUROPEAN JOURNAL OF NEUROLOGY

Keywords:
antiepileptic drugs,
cerebrovascular disease/
stroke, epilepsy/seizures,
treatment
Received 27 September 2014
Accepted 7 May 2015
European Journal of
Neurology 2015, 22: 1459–
1468
doi:10.1111/ene.12766
Background and purpose: To assess the efficacy of various antiepileptic drugs
(AEDs) for controlling post-stroke epilepsy.
Methods: This nationwide cohort study was conducted by using data from
2004 to 2008 on new occurrence of post-stroke epilepsy obtained from the
National Health Insurance Research Database of Taiwan. The examined AEDs
were phenytoin (PHT), valproic acid (VPA), carbamazepine (CBZ) and new
AEDs. Recurrent seizures requiring either emergency room (ER) visits or hospi-
talization were used to measure the efficacy of seizure control. The Kaplan Me-
ier failure curve and Cox proportional hazard regression analyses were used to
compare the risk of seizure recurrence in patients taking various AEDs.
Results: In all, 3622 late-onset post-stroke epilepsy patients were selected. Over-
all, 1.05 and 0.70 recurrent seizure incidences occurred per 100 person-months
based on ER visits [95% confidence interval (CI) 0.95–1.15] and hospitalizations
(95% CI 0.62–0.78), respectively. The incidences of ER visits for patients using
different AEDs were 1.26, 0.70, 0.43 and 0.38 per 100 person-months for PHT,
VPA, CBZ and new AEDs, respectively. Compared with patients using PHT, the
adjusted hazard ratios for ER visits were 0.56 (95% CI 0.42–0.74; P < 0.001), 0.37
(95% CI 0.18–0.75; P = 0.006) and 0.28 (95% CI 0.15–0.52; P < 0.001) for
patients using VPA, CBZ and new AEDs, respectively. The adjusted hazard ratios
of hospitalizations for seizure recurrence yielded similar results.
Conclusions: This large nationwide, population-based study demonstrated
that late-onset post-stroke epilepsy patients using VPA and new AEDs have
better seizure control than those using PHT as demonstrated by lower risks of
ER visits and hospitalization.

almost half of all cases of epilepsy with identifiable

Introduction
Stroke is commonly considered as one of the major
causes of epilepsy in elderly people, and accounts for
Correspondence: L.-N. Chien, School of Health Care
Administration, College of Public Health and Nutrition, Taipei
Medical University, No. 250 Wu-Hsing Street, Taipei 110, Taiwan
(tel.: +886-2376-1661-6610; fax: 886-2376-1661-6614; e-mail:
lnchien@tmu.edu.tw) or H.-Y. Chiou, School of Public Health,
College of Public Health and Nutrition, Taipei Medical University,
No. 250 Wu-Hsing Street, Taipei 110, Taiwan (tel.: +886-2376-
1661-6512; fax: +886-2376-1661-6614 and +886-2377-9188;
e-mail: hychiou@tmu.edu.tw).
etiologies [1,2]. The incidence of post-stroke epilepsy
ranges from 3% to 67% [3–8]. This heterogeneity
mainly results from differences in study designs, ter-
minology definitions and the selected study popula-
tions [9].
Currently, numerous antiepileptic drugs (AEDs) are
approved for controlling epilepsy with different etiolo-
gies, but studies on managing post-stroke epilepsy
have offered conflicting results. Although stroke is a
major cause of epilepsy, no published guidelines spe-
cifically address the treatment of post-stroke epilepsy

© 2015 EAN 1459

1460 Y.-H. HUANG ET AL.
[10]. Post-stroke epilepsy is typically categorized as
focal onset type epilepsy. Expert opinion regarding
the treatment of epilepsy in adults in the USA pub-
lished by Karceski et al. in 2005 rated lamotrigine
(LTG) as the treatment of choice in either medically
stable or ill elderly patients, with levetiracetam (LEV)
and gabapentin (GBP) as appropriate in these groups.
On the other hand, LEV and valproic acid (VPA)
were considered as first-line agents in the setting of an
emergency department [11]. According to a 2013
International League Against Epilepsy (ILAE) publi-
cation, only LTG and GBP provided level A evidence
regarding efficacy in elderly adults with focal onset
seizures [12]. Studies on AED use from nursing homes
(NHs) in the USA and Europe revealed that NH resi-
dents have a considerably higher rate of AED use
compared to the general population, ranging from
4.3% to 11% [13–17]. Older AEDs were still the most
frequently prescribed. In the USA, phenytoin (PHT)
is the most commonly used (32%) [15]. In northern
Italy, up to 80% of all AEDs prescribed to NH resi-
dents were phenobarbitone (PHB) [14], whereas in
Germany [16], Sweden [18] and Ireland [19] carbamaz-
epine (CBZ) dominated over other AEDs. Austrian
NH residents, in contrast to other European coun-
tries, received newer AEDs more frequently, with
GBP being the most frequent [13]. To date numerous
clinical trials have compared the efficacy and tolerabil-
ity of AEDs in treating post-stroke epilepsy [20–22].
However, these trials are limited by their small sample
sizes, and most of the trials compared only the effi-
cacy and tolerability of two kinds of AEDs. More-
over, although the three traditionally used AEDs
(PHT, VPA and CBZ) remain the most widely
prescribed [23–25], no studies have compared the effi-
cacy of these AEDs.
Various patho-physiological mechanisms underly-
ing post-stroke seizure have been proposed. An
acute derangement of metabolic function and bio-
chemical homeostasis resulting in a lowered thresh-
old for seizure activity may cause early-onset
seizures after an acute ischaemic injury [26,27]. Gli-
otic scarring may be responsible for the persistent
changes in neuronal excitability that cause late-onset
seizures [28,29]. Although no definite patho-physio-
logical basis exists, a 7–14 day cut-off point has
been established to distinguish between early- and
late-onset post-stroke seizures [4,6,27,28]. Our study
focused on a larger number of patients with late-
onset post-stroke epilepsy (>14 days) and aimed to
compare the efficacy of PHT, VPA, CBZ and new
AEDs for seizure control by assessing the risk of
emergency room (ER) visits and hospital admissions
for seizure attacks.
Methods and materials
Study design and data set
A nationwide cohort from the Taiwan National
Health Insurance Research Database (NHIRD) was
used. The NHIRD contains the medical claims data
for approximately 99% of 23 million Taiwanese citi-
zens. The data set used in this study is maintained by
the Collaboration Center of Health Information
Application (CCHIA), Ministry of Health and Wel-
fare. The Institutional Review Board of Taipei Medi-
cal University (no. 201311012) approved this study.
Study patients
The study cohort included all patients from the NHIRD
exhibiting new incidences of post-stroke epilepsy. New
incidences of stroke were defined as hospitalized patients
who had a primary diagnosis of stroke [International
Classification of Diseases, 9th Revision, Clinical Modifi-
cation (ICD-9-CM): 430–436] based on discharge
records between 2004 and 2008. The first date of hospi-
talization was considered as the index date of stroke. To
ensure that only new stroke cases were included, a ‘look-
back’ period of at least 3 years was used to ensure that
patients had no stroke diagnosis prior to the index date
of stroke. Of the patients who met these criteria, those
between 18 and 80 years old were selected.
These stroke patients were then screened for the
occurrence of post-stroke epilepsy. Patients with epi-
lepsy were included if they met all of the following
criteria. First, the patients had been diagnosed with
epilepsy (ICD-9-CM: 345) at one (or more) healthcare
visit, or had been diagnosed with non-febrile convul-
sions (ICD-9-CM: 780.3 or 780.39) at two (or more)
visits on different dates, regardless of whether the
diagnosis was coded at the outpatient department, ER
or hospitalization. The date of the first epilepsy diag-
nosis or the second non-febrile convulsion diagnosis
was used as the seizure index date. Patients who had
experienced an onset of seizures more than 14 days
after the stroke date were enrolled. This is referred to
as late-onset post-stroke epilepsy [4,29,30]. Patients
who presented with seizures that occurred within
7 days after stroke, which is typically during a
patient’s hospital stay, were excluded because the defi-
nite seizure onset date in hospitalized patients cannot
be retrieved from the NHIRD. Additionally, stroke
patients who were hospitalized for more than 14 days
and had a concurrent diagnosis of epilepsy were
excluded, because the NHIRD does not record the
date of seizure onset if it occurs during the same
admission.
© 2015 EAN

Second, the patients had attended at least one addi-
tional consultation related to epilepsy or non-febrile
convulsions 4 weeks or more after the seizure index
date. Third, the patients had made a minimum of two
pharmacy-dispensing AED [Anatomical Therapeutic
Chemical (ATC): N03A] claims at least 7 days apart
after the seizure index date. Finally, only epilepsy that
occurred after the stroke diagnosis was defined as
post-stroke epilepsy. Therefore, patients who received
an epilepsy diagnosis or AED prescriptions prior to
the index seizure date were excluded, resulting in a
total of 5906 post-stroke epilepsy patients.
Written informed consent
No written informed consent needed to be obtained
as all patient records/information were anonymized
and de-identified by the CCHIA prior to any further
analysis of the clinical data.
Antiepileptic drug prescription
The first 3 months of each patient’s AED pharmaceuti-
cal claims after the seizure index date were examined to
determine the primary AED medications used in the
cohort based on the ATC Classification System, includ-
ing PHT (ATC: N03AB02, N03AB52), VPA (ATC:
N03AG01), CBZ (ATC: N03AF01) and new-genera-
tion AEDs [oxcarbazepine (ATC: N03AF02), vigaba-
trin (ATC: N03AG04), tiagabine (ATC: N03AG06),
LTG (ATC: N03AX09), topiramate (ATC: N03AX11),
GBP (ATC: N03AX12), LEV (ATC: N03AX14) and
pregabalin (ATC: N03AX16)].
Patients were grouped based on four major types of
AED medication: PHT, VPA, CBZ and new AEDs.
To avoid the confounding effects of AED dosage
titration, shifts or a combination thereof on the out-
come measurements, patients in the PHT medication
group were included if they had received PHT but
had not received the other three types of AEDs con-
tinually for at least 3 months. The same approach
was used to set the criteria for patient inclusion in the
VPA, CBZ and new AED groups. Patients who had
been prescribed more than two major AEDs were
excluded, resulting in 3935 patients who had been pre-
scribed the same type of AED medication for a 3-
month period. The first date of AED prescription was
treated as the index date of AED.
Main outcome measure
The two main outcomes were an ER visit and hospital
admission for a seizure recurrence within a 12-month
period beginning 3 months after the seizure index
© 2015 EAN
ANTIEPILEPTICS IN POST-STROKE EPILEPSY 1461
date. Patients who visited the ER and were hospital-
ized for a seizure recurrence within 3 months after the
index date of AED were excluded, resulting in 3622
post-seizure stroke patients. These exclusion criteria
were made as our study aimed to examine a group of
patients exhibiting a relatively stable epilepsy condi-
tion. Therefore the follow-up period began 3 months
after the first AED medication was defined. The 3-
month period observation was considered necessary in
order to exclude patients who had been prescribed
AEDs for indications other than epilepsy [31]. Patients
who had visited the ER and were hospitalized on dif-
ferent occasions during the observational period were
included in the analyses. Figure 1 shows the detailed
process used to select the study patients.
Covariates
The covariates that were considered to increase the
risk of seizure recurrence included age, sex, stroke
type, previous or coexisting medical conditions, and
drug compliance. Twenty-one comorbidities [32] were
selected: hypertension, diabetes, hyperlipidemia, coro-
nary artery disease, heart failure, hypertensive heart
disease, atrial fibrillation, peripheral artery disease,
malignant neoplasm, renal disease, moderate or severe
liver disease, rheumatoid arthritis or collagen vascular
disease, aspiration pneumonia, dementia, traumatic
brain and head injuries, cerebral palsy, anoxic brain
injury, encephalopathy, alcohol abuse, drug abuse and
central nervous system infections. Appendix S1 shows
the disease diagnostic codes. To increase the disease
diagnosis validity, patients who had made at least two
visits (that were at least 4 weeks apart) and were
assigned the same disease code were considered to
have that disease. The regularity of consultation visits
was used to estimate drug compliance; good drug
compliance was defined as >0.75 consultation rate, at
regular 3-month intervals.
Statistical analysis
Log-rank tests were conducted and Kaplan Meier
failure curves were produced for the types of AEDs.
Cox proportional hazard regression analyses were
used to compare the risk of an ER visit and hospital-
ization for seizure recurrence, adjusted for potential
confounders. No model violated the proportional haz-
ard assumptions of the covariates. All analyses were
performed using SAS/STAT 9.3 software (SAS Insti-
tute Inc., Cary, NC, USA) and STATA 12 software
(Stata Corp LP, College Station, TX, USA). A P
value <0.05 was considered to be statistically signifi-
cant.
1462 Y.-H. HUANG ET AL.

270 262 patients admitted with a primary diagnosis of stroke

based on their discharge records, excluding those with a stroke
diagnosis 2 years before the stroke index.

263 390 patients excluded because:

250 954 without diagnosis of epilepsy
8923 only one diagnosis of epilepsy or no AED-use
3513 with a diagnosis of epilepsy before stroke or within
14 days after initial stroke

6872 patients with late-onset post-stroke epilepsy

966 patients excluded because:

sex, birth date, insurance type, or insurance amount data were missing
they were not between 18 and 80 years old

5906 patients with a diagnosis of post-stroke epilepsy and without

a prior diagnosis of epilepsy or AED-use history

1971 patients excluded because

170 had received other types of AEDs
1494 had changed their types of AED (296 due to seizure recurrence)
307 had received at least two combinations of AEDs

3935 post-stroke epilepsy patients who had continually received

the same type of AED prescriptions for at least 3 months

313 patients were excluded because they experienced seizure recurrence

within 3 months after the seizure index date

3622 post-stroke epilepsy patients were included in the study

cohort
Figure 1 Study patient selection process.

(CI) 0.95–1.15] and 0.70 (95% CI 0.62–0.78) per 100

Results
The baseline characteristics of the post-stroke seizure
patients are shown in Table 1. The most common fac-
tors associated with the risk of seizure recurrence were
dementia (15%), malignant neoplasm (14%) and trau-
matic brain injuries (9%). Most of the patients (69%)
had been prescribed PHT to manage post-stroke sei-
zures, followed by VPA (20%), new AEDs (7%) and
CBZ (4%). Within the follow-up period (1 year), 17%
of the patients had visited the ER at least once and
12% had been admitted to a hospital for seizure
recurrence. Drug compliance estimation using the reg-
ularity of consultation visits showed that patients tak-
ing PHT had the highest consultation rate in either
the group of ER visits or the group of hospitalization
(0.76, P = 0.1708, and 0.77, P = 0.1466, respectively).
However, these findings were not statistically signifi-
cant (Appendix S2).
The incidences of ER visits and hospitalizations for
seizure recurrence were 1.05 [95% confidence interval
person-months, respectively (Table 2). The risk of ER
visits for patients taking various AEDs was 1.26 (95%
CI 1.13–1.4) for PHT, 0.70 (95% CI 0.54–0.91) for
VPA, 0.43 (95% CI 0.22–0.86) for CBZ and 0.38
(95% CI 0.21–0.68) for new AEDs. The risk of hospi-
tal admission was similar to that in the ER visit
results PHT was associated with the highest risk of
hospitalization for seizure recurrence, compared with
that for the other three AEDs. The incidences of ER
visits and hospitalization for seizure recurrence
amongst patients with and without various comorbidi-
ties are shown in Appendices S3 and S4. The Kap-
lan Meier failure curve showed that patients taking
PHT had a higher risk of visiting the ER than
patients taking other AEDs (log-rank test, P < 0.001,
Fig. 2a). Similarly, the cumulative hospital admission
hazard rate was the highest for patients taking PHT
(log-rank test, P < 0.001, Fig. 2b).
Compared with patients taking PHT, patients
taking VPA had a lower risk of visiting the ER for

© 2015 EAN
 ANTIEPILEPTICS IN POST-STROKE EPILEPSY 1463

Table 1 Baseline characteristics of post-stroke epilepsy patients Table 2 Incidence of ER visits and hospital admissions for seizure
(N = 3622) recurrence amongst post-stroke epilepsy patients within the
follow-up period (1 year)
Characteristics N %
Failures,
Sex Outcomes AEDs Person-months n Rate (95% CI)
Male 2450 68
Female 1172 32 ER visits Overall 40 902 428 1.05 (0.95–1.15)
Age (years) PHT 27 897 351 1.26 (1.13–1.40)
Mean  SD 60.3  13.1 VPA 8241 58 0.70 (0.54–0.91)
18–44 464 13 New 2909 11 0.38 (0.21–0.68)
45–54 769 21 AEDs
55–64 764 21 CBZ 1854 8 0.43 (0.22–0.86)
65–74 1057 29 Hospital Overall 41 869 292 0.70 (0.62–0.78)
≥75 568 16 admissions PHT 28 750 232 0.81 (0.71–0.92)
Stroke type VPA 8348 42 0.50 (0.37–0.68)
SAH (ICD9: 430) 275 8 New 2922 9 0.31 (0.16–0.59)
ICH (ICD9: 431) 1505 42 AEDs
Other and unspecified 113 3 CBZ 1849 9 0.49 (0.25–0.94)
intracranial hemorrhages
(ICD9: 432) AED, antiepileptic drug; CBZ, carbamazepine; CI, confidence inter-
Ischaemic (ICD9: 433–436) 1729 47 val; ER, emergency room; PHT, phenytoin; VPA, valproic acid.
Previous or coexisting
medical conditions
Hypertension 2984 82
Diabetes 1219 34 P < 0.001, and HR 0.37, P = 0.006, respectively).
Hyperlipidemia 969 27 Additionally, patients taking new AEDs had a lower
Coronary artery disease 957 26 risk of visiting the ER for seizure recurrence than
Heart failure 470 13 those taking VPA. Similar results were obtained for
Hypertensive heart disease 1478 41
the risk of hospital admission. Patients taking VPA
Atrial fibrillation 371 10
Peripheral artery disease 109 3 had a lower risk of admission for seizures, with an
Malignant neoplasm 492 14 adjusted HR of 0.66 (95% CI 0.47–0.91, P = 0.013)
Renal disease 260 7 compared with patients taking PHT. It was also
Moderate or severe liver disease 48 1 observed that, compared to patients taking PHT,
Rheumatoid arthritis or 133 4
patients taking new AEDs had a lower risk of hospi-
collagen vascular disease
Aspiration pneumonia 151 4 tal admission (HR 0.38, 95% CI 0.19–0.74,
Dementia 546 15 P = 0.004) (Table 3).
Traumatic brain and head injuries 340 9 A subgroup analysis was performed of patients with
Cerebral palsy 31 1 post-stroke epilepsy after intracerebral hemorrhage
Anoxic brain injury 23 1
and subarachnoid hemorrhage. Patients taking VPA
Encephalopathy 23 1
Alcohol abuse 117 3 and new AEDs had a lower risk of visiting the ER for
Drug abuse 6 0 seizure recurrence (adjusted HR 0.55, 95% CI 0.37–
CNS infections 42 1 0.8, P = 0.002; adjusted HR 0.30, 95% CI 0.13–0.69,
AEDs P = 0.004; respectively) compared with patients taking
PHT 2507 69
PHT. However, the result for the risk of hospital
VPA 712 20
New AEDs 246 7 admission amongst patients taking different AEDs
CBZ 157 4 was not different (Table 4).
Epilepsy recurrence
ER visit 614 17
Hospital admission 441 12 Discussion
AED, antiepileptic drug; CBZ, carbamazepine; CNS, central nervous Post-stroke epilepsy, which is typically categorized as
system; ER, emergency room; ICH, intracerebral hemorrhage; PHT, partial seizures with or without secondary generaliza-
phenytoin; SAH, subarachnoid hemorrhage; VPA, valproic acid. tion, is effectively controlled by administering AED
monotherapy [8]. Up to 60% 80% of elderly patients
are free of seizures after beginning AED therapy
seizure recurrence [adjusted hazard ratio (HR) 0.56, [3,33,34]. Although using AEDs to control post-stroke
95% CI 0.42–0.74, P < 0.001]. The results of patients epilepsy has been recommended by both American and
taking new AEDs and CBZ were similarly lower com- European guidelines [35,36], numerous studies and
pared with those taking PHT (adjusted HR 0.28, publications on the topic, clinicians and neurologists

© 2015 EAN
1464 Y.-H. HUANG ET AL.

(a) (b)
0.15 0.15
PHT PHT
VPA VPA
NEW AEDs NEW AEDs
CBZ CBZ
0.10 0.10

0.05 0.05

Log-rank test, P < 0.001

Log-rank test, P < 0.001
0.00 0.00
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Month since observation Month since observation

Figure 2 Kaplan Meier failure curves for post-stroke epilepsy patients prescribed with different antiepileptic drug (AED) medications,
those who visited the emergency room (a) and those were admitted to a hospital (b) because of epilepsy within the follow-up year,
after accounting for information censored because of patient death. CBZ, carbamazepine; PHT, phenytoin; VPA, valproic acid.

Table 3 Unadjusted and adjusted HRs for

ER visit Hospital admission
ER visits and hospital admissions for sei-
Outcomes AEDs HR (95% CI) P HR (95% CI) P zure recurrence amongst post-stroke epi-
lepsy patients
Unadjusted PHT 1.00 (Ref.) 1.00 (Ref.)
VPA 0.56 (0.43–0.74) <0.001 0.63 (0.43–0.76) <0.001
New AEDs 0.30 (0.17–0.55) <0.001 0.29 (0.16–0.53) <0.001
CBZ 0.35 (0.17–0.70) 0.003 0.35 (0.17–0.71) 0.004
Adjusteda PHT 1.00 (Ref.) 1.00 (Ref.)
VPA 0.56 (0.42–0.74) <0.001 0.66 (0.47–0.91) 0.013
New AEDs 0.28 (0.15–0.52) <0.001 0.38 (0.19–0.74) 0.004
CBZ 0.37 (0.18–0.75) 0.006 0.67 (0.34–1.32) 0.245

AED, antiepileptic drug; CBZ, carbamazepine; CI, confidence interval; ER, emergency room;
HR, hazard ratio; PHT, phenytoin; VPA, valproic acid.
a
Adjusted for age, sex, stroke type, drug compliance, 21 previous or coexisting medical condi-
tions (hypertension, diabetes, hyperlipidemia, coronary artery disease, heart failure, hyperten-
sive heart disease, atrial fibrillation, peripheral artery disease, malignant neoplasm, renal
disease, moderate or severe liver disease, rheumatoid arthritis or collagen vascular disease,
aspiration pneumonia, dementia, traumatic brain and head injuries, cerebral palsy, anoxic
brain injury, encephalopathy, alcohol abuse, drug abuse and central nervous system infec-
tions), insurance eligibility and monthly income based on enrollment file.

are uncertain of which AED should be used first to
control post-stroke epilepsy [37]. Few randomized con-
trolled trials have compared the efficacy of older- and
newer-generation AEDs for primary or secondary pre-
vention of epileptic seizures in patients with a mixture
of diagnoses, including stroke [21,38,39]. The findings
suggest that LTG may be clinically more useful than
other AEDs such as CBZ; however, this result cannot
be applied to patients with post-stroke epilepsy as one
single population [40]. Recent expert recommendations
and the updated ILAE guidelines favor the use of
newer-generation AEDs for treating elderly patients
with partial-onset seizures because they interact with
fewer drugs than older-generation AEDs do
[12,33,37,41].
Our study showed most patients (93%) used older
AEDs (PHT, VPA, CBZ) for post-stroke epilepsy. It
is compatible with an NHIRD study for evaluating
AED usage in all Taiwanese patients with epilepsy
that 75%–85% patients used older AEDs with PHT
the most commonly prescribed between 2003 and
2007 [25]. The findings in Taiwan are in line with
population studies based on prescription databases
elsewhere, which revealed that older AEDs are still
the most widely used for the management of epilepsy.
In Denmark, Italy and Norway, CBZ and PHB were
the most commonly used AEDs for the management
of epilepsy [42–44], whereas in Australia VPA was
the most frequently prescribed AED, followed by
CBZ and PHT [24]. Most studies analyzing prescrip-
tion-based data showed an incremental trend of new
AED use. However, only a proportion of this growth
is attributed to their use in epilepsy, and they are
mainly used in pain control, migraine prevention or

© 2015 EAN
 ANTIEPILEPTICS IN POST-STROKE EPILEPSY 1465

Table 4 Unadjusted and adjusted HRs for

ER visit Hospital admission
ER visits and hospital admissions for sei-
zure recurrence amongst post-stroke epi- Outcomes AEDs HR (95% CI) P HR (95% CI) P
lepsy patients after ICH and SAH
Unadjusted PHT 1.00 (Ref.) 1.00 (Ref.)
VPA 0.57 (0.39–0.82) 0.003 0.76 (0.49–1.19) 0.233
New AEDs 0.35 (0.15–0.79) 0.011 0.42 (0.15–1.14) 0.088
CBZ 0.70 (0.31–1.59) 0.396 1.47 (0.69–3.17) 0.320
Adjusteda PHT 1.00 (Ref.) 1.00 (Ref.)
VPA 0.55 (0.37–0.8) 0.002 0.78 (0.50–1.23) 0.294
New AEDs 0.30 (0.13–0.69) 0.004 0.37 (0.13–1.02) 0.055
CBZ 0.72 (0.32–1.63) 0.427 1.56 (0.72–3.37) 0.264

AED, antiepileptic drug; CBZ, carbamazepine; CI, confidence interval; ER, emergency room;
HR, hazard ratio; ICH, intracerebral hemorrhage; PHT, phenytoin; SAH, subarachnoid hem-
orrhage; VPA, valproic acid.
a
Adjusted for age, sex, stroke type, drug compliance, 21 previous or coexisting medical condi-
tions (including hypertension, diabetes, hyperlipidemia, coronary artery disease, heart failure,
hypertensive heart disease, atrial fibrillation, peripheral artery disease, malignant neoplasm,
renal disease, moderate or severe liver disease, rheumatoid arthritis or collagen vascular dis-
ease, aspiration pneumonia, dementia, traumatic brain and head injuries, cerebral palsy,
anoxic brain injury, encephalopathy, alcohol abuse, drug abuse, central nervous system infec-
tions), insurance eligibility and monthly income based on enrollment file.

mood stabilization [24,25,42–44]. It is speculated that
neurologists continue to prefer prescribing older
AEDs as treatments for epilepsy because these medi-
cations have been marketed for a long time and their
tolerability and safety profiles are well known [43].
Cost and peer-review concerns may also explain why
the older AEDs occupied the majority of the total
volume of AEDs used to manage epilepsy. In the
USA, PHT is also commonly prescribed for elderly
patients with epilepsy, in whom stroke is the leading
cause [23]. Although PHT is popularly used, our
study demonstrated that patients treated with PHT
had a higher risk of recurrent seizures requiring either
an ER visit or hospitalization compared to those trea-
ted with VPA, CBZ and new-generation AEDs. This
outcome may reflect the less favorable efficacy of
PHT. The extensive hepatic enzymatic system induc-
tion characteristics of PHT are also known to induce
interactions with other medications such as other
older-generation AEDs and anticoagulants, as well as
antiplatelets that are used for the secondary preven-
tion of ischaemic stroke [33,41]. Drug interaction
problems must be considered because poly-pharmacy
is prescribed for treating most elderly patients [45].
These situations may lead to either increased toxicity
or decreased efficacy of PHT or other concomitantly
used medications. Possible aging-process-related phar-
macokinetic changes including decreased plasma
protein binding, augmented volume of distribution
for lipophilic drugs caused by changes in adipose tis-
sue, decreased drug elimination related to reduced
liver or renal function [46,47] and age-related changes
in the number and affinity of receptors might cause
drug sensitivity and homeostasis to vary [48]. Poor
drug compliance might be associated with increased
risk of seizure recurrence. However, in our study,
patients taking PHT had in fact the highest drug
compliance rate.
Our study disclosed that post-stroke epilepsy
patients treated with VPA and newer-generation
AEDs are less likely to experience seizure recurrence
than patients treated with PHT. Despite its high
protein-binding properties and mild inhibitory effect
on the hepatic enzymatic system, VPA poses fewer
drug drug interaction risks and therefore may have
fewer adverse effects [49]. This may result in less
drug tolerability and better compliance. On the other
hand, a growing body of evidence has indicated that
new AEDs are as effective as older-generation AEDs
and are preferable in elderly patients, mainly because
of their enhanced safety profiles. Some prospective
studies have reported that several new AEDs such
as LTG [12,21,38,39], LEV [22] and GBP [39,50] are
efficacious and well tolerated by elderly patients with
post-stroke epilepsy. CBZ has been considered the
drug of choice for controlling partial-onset seizures
[47,49] and is favored by some experts for managing
post-stroke epilepsy [10]. The analysis of our data
does not disclose significantly better seizure control
in patients treated with CBZ. However, this result
may be biased by the small number of patients
(4%) treated with CBZ. The proportion of CBZ use
has decreased over time in Taiwan [25], because of
the risk of inducing Stevens Johnson syndrome a

© 2015 EAN
1466 Y.-H. HUANG ET AL.
life-threatening skin reaction that is strongly
associated with human leukocyte antigen HLA-
B*1502, which is highly prevalent in the Han Chi-
nese population [51]. Another reason for the limited
number of patients treated with CBZ may be the
lack of intravenous preparation in order to provide
a prompt seizure control when patients with post-
stroke epilepsy present to the ER service.
Limitations
The NHIRD was used for conducting this study
owing to several advantages including a large sample
that is representative of the general population, less
time consuming and reduced cost compared to com-
munity surveys, better availability of longitudinal data
for the detection of seizure recurrence, as well as recall
bias avoidance [52]. However, several limitations have
to be considered. First, the accuracy of using diagnos-
tic codes and drug prescriptions to identify patients
with a specific disease cannot be taken for granted,
despite the fact that a very strict approach for patient
selection was used. Secondly, the regularity of consul-
tations made by the patients was analyzed and was
used to estimate the possible medication compliance.
However, these data cannot fully reflect the actual
medication compliance by the patients, which is one
of the most important causes of seizure recurrence.
Thirdly, although underlying comorbidities were used
to adjust the confounders on the risk of seizure recur-
rence, concomitantly used medications other than
AEDs were not included in the analysis. Fourthly,
patients who had experienced seizure recurrence
within the first 3-month period were excluded a priori
in order to avoid inconsistencies in medication pre-
scription. Although this selection was arbitrary, it is
believed that the AED prescriptions, the patients’
medication dosage and compliance as well as the med-
ical condition post-cerebrovascular event have reached
a more stable condition after 3 months. To increase
the robustness of the findings, a separate analysis was
performed including patients who had an event within
the first 3 months which still yielded similar results
(Appendices S5 and S6). Finally, although an individ-
ual comparison of the efficacy of new AEDs is of
interest, it was not possible to conduct this analysis
because of few case patients under each type of new
AED, resulting in insufficient statistical power. The
result of our study might be interestingly different if
the follow-up period were extended to include most
recent years.
In conclusion, this large nationwide, population-
based study revealed that post-stroke epilepsy
patients taking VPA and new AEDs had a lower
risk of visiting the ER and being hospitalized for
seizure recurrence compared with patients taking
PHT. Thus, PHT is probably not the best choice
for the prevention of recurrent seizures in post-
stroke epilepsy. Further studies are warranted to
verify the present findings and investigate important
issues such as the underlying mechanisms of our
current result.
Acknowledgements
We would like to extend our gratitude to Ms Siran
M. Koroukia, associate professor of the Department
of Epidemiology and Biostatistics, Case Western
Reserve University, for manuscript revision and valu-
able inputs. We are indebted to the Health and Clini-
cal Research Data Center at Taipei Medical
University, Academia Sinica, Taiwan, ROC
(BM103010096), and the Ministry of Science and
Technology, Taiwan, ROC (NSC 102-2314-B-038-
046), as well as Dr Chi-Chin Huang Stroke Research
Center for their support in data acquisition and valu-
able advice on statistical analysis.
The Health and Clinical Research Data Center at
Taipei Medical University funded this study.
Disclosure of conflicts of interest
The authors declare no financial or other conflicts of
interest.
Supporting Information
Additional Supporting Information may be found in
the online version of this article:
Appendix S1. Disease diagnostic codes for previous
and coexisting medical conditions.
Appendix S2. Drug compliance analysis of the patients
in each AED group.
Appendix S3. Incidence of epilepsy ER visits amongst
post-stroke seizure patients within the follow-up per-
iod (1 year).
Appendix S4. Incidence of epilepsy hospitalization
amongst post-stroke seizure patients within the fol-
low-up period (1 year).
Appendix S5. Incidence of ER visits and hospital
admissions for seizure recurrence amongst post-stroke
epilepsy patients within the follow-up period (without
exclusion of 3-month period post index event).
Appendix S6. Unadjusted and adjusted HRs for ER
visits and hospital admissions for seizure recurrence
amongst post-stroke epilepsy patients (without exclu-
sion of 3-month period post index event).
© 2015 EAN

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