Journal of the Neurological Sciences 359 (2015) 318–322

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Journal of the Neurological Sciences

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

Seizures after intracerebral hemorrhage; risk factor, recurrence, efficacy

of antiepileptic drug
Shuichiro Neshige a,⁎,1, Masaru Kuriyama a, Takeshi Yoshimoto a, Shinichi Takeshima a, Takahiro Himeno a,
Kazuhiro Takamatsu a, Michiyoshi Sato b, Shinzo Ota b
a
Department of Neurology, Brain Attack Center Ota, Memorial Hospital, 3-6-28 Okinogami, Fukuyama, Hiroshima 720-0825, Japan
b
Department of Neurosurgery, Brain Attack Center Ota, Memorial Hospital, 3-6-28 Okinogami, Fukuyama, Hiroshima 720-0825, Japan

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

Article history: Objective: This study aimed to determine the risk factors for recurrent post stroke seizure (PSS) and the efficacy
Received 18 May 2015 of anti-epileptic drugs (AED) in patients having intracerebral hemorrhage (ICH) with initial seizure.
Received in revised form 23 August 2015 Methods/subjects: A total of 1920 consecutive patients with ICH from 2004 to 2012 were investigated retrospec-
Accepted 21 September 2015
tively. The relationships among the baseline clinical and radiological data, administration of AED, and incidence of
Available online 25 September 2015
initial and recurrent PSS were evaluated using multiple logistic regression analysis.
Keywords:
Results: Seizures occurred in 127 (6.6%) of the 1920 patients, displaying statistically significant relationships with
Early seizure cortical involvement of a cerebral lesion (P b 0.001), non-hypertensive ICH (P b 0.001), younger age (P b 0.001),
Late seizure and severe neurological deficits (P b 0.001). Early (4.3%) and late seizure (2.3%) had no significant relationship
Post stroke epilepsy with the development of recurrent PSS. Larger volume of hematoma was the only independent factor associated
Volume of hematoma with recurrence of PSS (OR 1.03; 95% CI 1.00–1.05; P = 0.027). A Kaplan Meier survival analysis revealed that
Recurrent seizure AED treatment had a poor association with recurrence of PSS (P = 0.750).
Intracerebral Conclusions: Larger volume of hematoma was predictive of recurrence of PSS. AED therapy had poor association
Hemorrhage
with preventing the recurrence of PSS.
© 2015 Published by Elsevier B.V.

1. Introduction to be 2.0–26.1%, and the wider variance is attributed to the divergent

Post stroke seizures (PSS) are occasionally associated with intrace-
rebral hemorrhage (ICH), with some patients having recurrent PSS.
However, the risk factors of recurrent seizure for patients with an ini-
tial PSS after first ever ICH, and the effects of antiepileptic drugs (AED)
for preventing recurrence of PSS, remains limited.
Electrographic seizures occur in 28% of patients with ICH during the
initial 72 h after admission [1], and may be associated with expanding
hemorrhages and periodic electrical discharges during cortical ICH [2].
PSS are commonly classified as early and late seizure (ES and LS)
based on the differences of their timing after stroke. An arbitrary cut
point of 1 or 2 weeks after the presenting stroke has been recognized
to distinguish between them. Previous studies have reported that the
incidence rate of seizures after ICH is 2.7–18.7% [3–9], with ES occurring
in 2.7–17%, after ICH and the majority of seizures occurring at, or near,
the onset of ICH [1,3–5,8]. The incidence rate of LS after ICH is reported
⁎ Corresponding author.
E-mail address: neshige@shouwa.or.jp (S. Neshige).
1
Present address: Department of Clinical Neuroscience and Therapeutics, Hiroshima
University Graduate School of Biomedical Sciences, Hiroshima, Japan.
definitions of LS between studies [3,4,6,9–12]. Several studies report
that the factors provoking seizures following ICH are related to hemor-
rhage volume, hemorrhage location within the cerebrum, cortical in-
volvement, and the severity of neurological deficits [5,11–14].
There are also several previous reports on the effects of AED for sei-
zures associated with ICH. Prophylactic administration of AED for lobar
ICH reduces clinical seizures [5]. Short-term prophylactic AED therapy
during the acute stage of ICH is effective for patients, because the
seizures lead to additional damage such as herniation or re-bleeding
[15]. However, these reports did not show the correlation between
AED therapy in acute state and long-term outcome. Prospective and
population-based studies do not show clear evidence for the direct
influence of clinical seizures on neurological outcome or mortality
[6,9,13,16], which may suggest the benefit little from AED therapy.
Several reports have examined the preventative effects of AED therapy
on the development of recurrent PSS, which showed prophylactic AED
therapy was not significantly associated with outcome [17–19]. The
clinical decision about beginning and/or continuing AED therapy for
an initial PSS after ICH is an important issue. This study aimed to deter-
mine the risk factors for recurrence of PSS and the efficacy of AED to pre-
vent the recurrent PSS for patients having ICH with ES and LS.

http://dx.doi.org/10.1016/j.jns.2015.09.358
0022-510X/© 2015 Published by Elsevier B.V.
 S. Neshige et al. / Journal of the Neurological Sciences 359 (2015) 318–322
2. Methods
2.1. Study population and design
This retrospective study analyzed hospitalized patients enrolled
in our stroke registry from January 2004 to April 2012. The study sam-
ple consisted of 1920 patients with ICH. Exclusion criteria for ICH
consisted of the following: (1) traumatic ICH, (2) subarachnoid hem-
orrhage, subdural hematoma, hemorrhagic infarct, or inflammatory
vascular diseases, and (3) ICH caused by a primary or metastatic
brain tumor. All records regarding subsequent hospitalization and
death were reviewed. For the resulting 1920 patients, we reviewed
the medical records to determine if they had a PSS or not, divided
into patients with and without PSS, during the period from admission
to last follow-up visits. The characteristics of patients with initial PSS
were compared to those of patients without PSS. In addition, for the
patients with PSS, we recorded the relevant events occurring during
follow-up visits, including recurrence of PSS, to compare the charac-
teristics of patients with recurrent PSS and patients free from recur-
rent PSS. Initiation of AED therapy during follow-up period was also
recorded.
2.2. Seizure
We defined PSS as seizure after ICH and thought to be related to
cerebral damage due to ICH regardless of time of onset following
the stroke. For this article, we mention stroke limited in ICH. PSS
was classified in 2 groups, ES and LS, according to timing. ES was
defined as PSS occurring within 1 week of ICH onset. LS was defined
as that occurring more than 1 week after onset of ICH up to last day
of following. On admission for their stroke detailed medical character-
istics included were as follows: sex, age, National Institute of Health
Stroke Scale (NIHSS) score on admission, lesion and etiology of ICH,
treatment, modified Rankin Scale (mRS) score at discharge, and pres-
ence of the first seizure. Additional characteristics, for the patient
with PSS, were considered: volume of hematoma, status epilepticus,
blood pressure level, ES or LS, period of days following ES/LS, and
accompanied diseases during their hospitalization. These characteris-
tics of the patients with PSS were compared to those of patients with-
out PSS.
2.3. Recurrent PSS
The definition of recurrent PSS was as follow: 1) Seizures those oc-
curring at least 1 month after onset of the initial PSS or 2) Two or
more epileptic seizures occurring at ≥1 week after ICH, and the duration
between initial and recurrent seizure is more than 1 week.
We excluded patients whose observation period from the initial sei-
zure was less than 2 month, those diagnosed with epilepsy before ICH,
or those who had taken AED before ICH.
2.4. Radiologic assessment
All patients underwent a brain CT (computed tomography) scan.
Lesions of hemorrhage were classified according to location into 7
groups: cortex, putamen, thalamus, cerebellum, brainstem, caudate
nucleus, and other. ICH in the cortex was defined as a hemorrhage in-
volving cortical areas without an origin in deep structures. Pathogenesis
was classified as hypertensive or non-hypertensive ICH; the later
including vascular abnormalities such as ICH due to arteriovenous
malformation, cerebral amyloid angiopathy, dural arteriovenous fistu-
lous malformations, cavernous angioma, venous angioma, moyamoya
disease, unknown origin. Hemorrhage volumes were measured on the
CT image by using a computerized technique of Volume calc software
(Activion16, Toshiba Medical Systems, Tokyo, Japan).
319
2.5. Antiepileptic drugs (AED)
From the medical records, we determined if patients were treated
with AED or not at the time of the initial PSS, recurrent PSS and the
last follow up visit. We defined the patients who had continued to re-
ceive AED therapy from the time of initial seizure to the last follow-up
day as “with AED group”. And those who had received AED therapy
only in acute stage temporarily or had never received AED therapy as
“without AED group”. We excluded patients with a pre-existing diagno-
sis of epilepsy or those who had taken AED before ICH, and patients
whose follow up period was less than 1 month. We then studied whether
AED treatment was related to prevention of recurrent seizure by using
Kaplan-Meier statistics. Whether each patient received prophylactic
AED treatment, or commenced AED treatment after the initial PSS, was
decided by their physician. The AEDs included valproate, carbamazepine,
zonisamide, and/or phenytoin.
2.6. Statistical analysis
Data are expressed as mean ± standard deviation (SD) or medians
(25th and 75th percentiles) for continuous variables and as frequencies
and percentages for discrete variables. The statistical significance of
intergroup differences was assessed by X2 tests. To identify the factors
associated with PSS occurrence in ICH, we performed multivariate
analyses, including age, sex, NIHSS score at admission, etiology of hem-
orrhage, lesion of hematoma, and treatment. Surgery was aimed only
the case which was done before initial seizure. Next, to identify the fac-
tors correlated with recurrent PSS, we performed multivariate analyses,
including stage of the first seizure (ES or LS), cortical involvement of the
ICH and hemorrhage volume. We performed survival analysis using life
tables, Kaplan-Meier statistics, and Cox models, starting at the date of
the first seizure presentation, and censoring on the date of the recurrent
PSS, date of death, or end of follow-up. Statistical significance was
established at P b 0.05. Statistical analysis was performed using SPSS
20 statistical software (IBM Institute Inc., USA).
3. Results
3.1. Total patient cohort
The total number of patients with spontaneous ICH was 1920, com-
prising 1103 men (mean age 65.7 ± 13.8 years) and 817 women (mean
age 71.9 ± 14.1 years). In this study, seizures occurred in 127 cases
(6.6%). The interval from the onset of ICH to initial PSS was 0–78.5
months (mean 6.1 ± 13.8 months). Sixty-five cases had PSS at onset,
and 72 had PSS within 24 h of onset. ES and LS were present in
83 (4.3%) and 44 cases (2.3%), respectively. Patients with PSS were sig-
nificantly younger (62.1 ± 18.1 vs. 68.8 ± 13.8; P b 0.001) and had
significantly higher NIHSS scores (18.6 vs. 14.8; P b 0.001) compared
to patients without PSS. Within the group with PSS, the number of pa-
tients with hypertensive ICH was smaller (63.0 vs. 87.6; P b 0.001)
with a larger number of patients undergoing surgery after admission
(30.7 vs. 14.7; P b 0.001) than in the group without PSS. The most com-
mon ICH sites were the cortex (58.3 vs. 17.0; P b 0.001) in the group
with PSS. Treatment strategies in this group consisted of craniotomy
and removal of the hematoma (30.8%), burr-hole evacuation or en-
doscopic hematoma evacuation (16.9%), or conservative treatment
(47.7%). There were no differences in mRS scores at discharge or hospi-
talization periods between the 2 groups (Table 1).
3.2. Multivariate analysis of initial seizure
Within the total ICH patient cohort, younger age (odds ratio (OR)
0.97; 95% CI 0.96–0.98; P b 0.001), non-hypertensive ICH (OR 1.04;
95% CI 1.02-1.05; P b 0.001), cortical involvement (OR 7.37; 95% CI
320 S. Neshige et al. / Journal of the Neurological Sciences 359 (2015) 318–322

Table 1 Table 3
Demographic and clinical characteristics of the patients with ICH. Clinical characteristics of patients with an initial seizure.

With Without P value With Without P value

seizure seizure recurrence recurrence
(N = 127) (N = 1793) (N = 20) (N = 58)

Age, y, mean (SD) 62.1 (18.1) 68.8 (13.8) b0.001 Age, y, mean (SD) 58.3 (16.7) 60.0 (18.0) 0.710
Male sex, n (%) 80 (63.0) 1023 (57.1) 0.191 Male sex, n (%) 11 (55.0) 36 (62.1) 0.579
NIHSS score on admission — median (IQR) 18.6 (7–31) 14.8 (4–23) 0.001 Lesion (cortex), n (%) 16 (80.0) 43 (74.1) 0.593
Lesion, n (%) Cortex 74 (58.3) 305 (17.0) b0.001a Treatment (surgery), n (%) 11 (55.0) 21 (34.5) 0.028
Putamen 20 (15.7) 592 (33.0) Volume of hematoma, ml, mean (SD) 29.80 (25.2) 18.10 (19.7) 0.037
Thalamus 11 (8.7) 486 (27.1) Status epilepticus, n (%) 7 (35.0) 20 (34.5) 0.967
Cerebellum 4 (3.1) 164 (9.1) NIHSS score on admission, median (IQR) 17.5 (3–22) 10.5 (4–22) 0.456
Brainstem 12 (9.4) 150 (8.4) Etiology (non-hypertensive), n (%) 9 (45.0) 23 (39.7) 0.676
Caudate nucleus 1 (0.8) 25 (1.4) mRS at discharge, median (IQR) 2.5 (1.5–4) 2 (1–4) 0.9675
Others 5 (3.9) 71 (4.0) Blood pressure level Systolic, mm Hg, 153.4 (28.4) 163.7 (39.1) 0.283
Etiology of hypertensive, n (%) 47 (37.0) 222 (12.4) b0.001 on admission mean (SD)
Surgery, n (%) 39 (30.7) 263 (14.7) b0.001 Diastolic, mm Hg, 86.4 (23.3) 88.3 (20.0) 0.721
Days of hospitalization, d, (SD) 28.1 (2.1) 28.5 (13.7) 0.857 mean (SD)
The interval from the onset of ICH to last 32.3 (35.7) 19.9 (28.8) b0.001 Medicine AED, n (%) 14 (70.0) 36 (62.1) 0.520
follow up, M, (SD) APD, n (%) 1 (5.0) 5 (8.6) 0.585
mRS at discharge — median (IQR) 4 (2–5) 4 (2–5) 0.530 Period of following days, M, mean (SD) 60.8 (28.4) 60.5 (30.2) 0.976
Status epilepticus, n (%) 43 (33.9) Period from ICH to initial seizure, M, (SD) 6.7 (7.8) 10.8 (18.7) 0.351
The interval from the onset of ICH to 6.1 (13.8) Category of an initial ES (within 7 days) 8 (40.0) 29 (50.0) 0.439a
seizure, M, (SD) seizure, n (%) LS (following 7 days) 12 (60.0) 29 (50.0)
Category of initial ES (within 7 days) 83 (65.4) Accompanied Hypertension 12 (60.0) 38 (65.5) 0.659
seizure, n (%) LS (following 7 days) 44 (34.6) diseases, n (%) Atrial fibrillation 1 (5.0) 0 (0) 0.097
Cerebral infarction 1 (5.0) 6 (10.3) 0.446
The data are presented as the means ± SD for age, medians (interquartile ranges) for base-
Coronary disease 1 (5.0) 5 (8.6) 0.585
line NIHSS scores and mRS. Percentages may not total 100 because of rounding.
a Diabetes mellitus 2 (10.0) 12 (20.7) 0.259
Analysis was performed using the χ2 test comparing cortex and except cortex.
Chronic kidney 0 (0) 1 (1.7) 0.440
disease
Dyslipidemia 7 (35.0) 30 (51.7) 0.193
4.77–11.45; P b 0.001), and high NIHSS (OR 1.04; 95% CI 1.02–1.05; Alcohol, n (%) 7 (35.0) 21 (36.2) 0.923
Smoking, n (%) 8 (40.0) 22 (37.9) 0.870
P b 0.001) were independent risk factors for initial PSS (Table 2). Complication, n (%) 3 (15.0) 7 (12.1) 0.739
a
Analysis was performed using the χ2 test comparing ES and LS between the groups.
3.3. Factors associated with recurrent seizure

Of the 127 patients with initial PSS, 20 (15.7%) dropped out of
the follow-up survey, 18 (14.2%) died and 11 (8.7%) had a previous di-
agnosis of epilepsy or had taken AED before ICH. Among the 78 patients
studied, 20 (R group) had recurrent PSS and 58 (F group) were free from
recurrent PSSs over a 1-year period; i.e., 15.7% of the total ICH patients
with an initial PSS developed recurrent PSS. The follow-up intervals
were 60.8 ± 28.4 and 60.5 ± 30.2 months in the R and F groups, respec-
tively. On comparing these groups, the volume of hemorrhage in the R
group was significantly (P = 0.037) larger than that in the F group
(Table 3). Multivariate analysis showed that the hemorrhage volume
(OR 1.02; 95% CI 1.00–1.02; P = 0.044) was the only independent factor
associated with the recurrence of PSS (Table 4).
3.4. Effects of AED after initial PSS
Of the 127 patients with initial PSS, 63 (49.6%) had newly started
AED therapy after the initial PSS. Excluding patients with a previous
diagnosis of epilepsy, those who had taken AED before ICH, or those
observed for less than a month from initial seizure, the Kaplan–Meier
survival analysis for patients with or without AED treatment indicated
Table 2
Odds ratio for seizure in 1920 patients with intracerebral hemorrhage: Multiple logistic
regression analysis of factors associated with first seizures.
Odds ratio 95% CI
Age 0.97 0.96–0.98
Etiology (non-hypertensive) 1.63 1.02–2.56
Lesion (cortex) 7.37 4.77–11.45
NIHSS score (admission) 1.04 1.02–1.05
To identify the predictors of initial seizure, we performed multivariate analyses, including
age, sex, NIHSS score at admission, etiology of hemorrhage, lesion of hematoma, treatment
(surgery).
that AED treatment had a poor association (P = 0.750) with recurrence
of PSS (Fig. 1).
4. Discussion
The present study demonstrates that the incidence of PSS in 1920
patients with ICH is 6.6%, and that seizures occur frequently following
a cortical hemorrhage, non-hypertensive hemorrhage, severe neurolog-
ical deficits, or in young patients. ES and LS occurred in 4.3% and 2.3%
of the total ICH patient cohort, respectively, and 15.7% of the patients
with an initial seizure developed recurrent PSS. In the present study,
ES occurred in 4.3% of patients, which is consistent with past reports
[4–6,9,13]. On the other hand, LS occurred in only 2.3% of patients,
which is low compared to previous findings [3.4.6.9–12]. Previous stud-
ies have reported that the incidence rate of LS after ICH varies from 2.0%
to 26.1%; with the variation attributed to different definitions of LS in
each report. Some reports define LS as seizure occurring 24 h after ICH
[3,4,6,9]; however, in our study LS was defined as seizure occurring
7 days after ICH. The incidence of recurrent PSS in our study was also
low in comparison to recent reports that suggest the incidence rate of
developing recurrent PSS to be between 2% and 39% [3,5,6,12,22–27].
Some studies also included patients with ischemic stroke [12,24,25] or
Table 4
Odds ratio for recurrence of seizure (multivariable analysis of factors associated with
P value recurrence of seizures).
b0.001
Odds ratio 95% CI P value
0.039
b0.001 Volume of hemotoma 1.02 1.001–1.023 0.044
b0.001
We performed multivariate analyses, including age, sex, NIHSS score at admission, treat-
ment (surgery), status epilepticus, etiology, blood pressure level (admission), medicine,
basic disease, stage of first seizure (ES or LS), cortical involvement of the ICH and ICH
volume.
 S. Neshige et al. / Journal of the Neurological Sciences 359 (2015) 318–322
Fig. 1. Kaplan–Meire survival curves for patients with and without anticonvulsant drugs
showing the probability of remaining free of recurrent PSS. There were no significant dif-
ferences (log-lank test) between the recurrent seizure event curves (p 0.750).
pediatric cases [26]. Thus, these subjects were different from those in-
cluded in our study. The rate of PSS occurrence may sometimes be
underestimated in relation to the actual rate, because epileptic seizures
in elderly patients can be unclear due to discrete and attenuated clinical
signs [28]. Moreover, the major reason for a low incident rate of recur-
rent PSS in our study might be due to the low incident rate of LS.
The present study shows that the following clinical findings might
be predictive factors for seizure after ICH: cortical hemorrhage, non-
hypertensive hemorrhage, younger age of onset, and severe neurologi-
cal deficits. In addition, a larger hemorrhage volume might be a predic-
tive factor for developing recurrent PSS. There have been several
previous reports regarding the predictive factors for recurrence of sei-
zure in patients with ischemic stroke [3,10,12,22–25]; however, there
is limited evidence in patients with ICH [3,4,6,27]. Using multivariate
analysis, we demonstrate here that the ICH volume is the only indepen-
dent predictive factor associated with the development of recurrent
PSS. Browne et al. [29] previously reported that patients with epilepsy
that have structural brain lesions, EEG abnormalities, or partial seizures
had a higher recurrence rate. Several authors reported that LS might be
the predictive factor for recurrent seizure after stroke [4,19,23,25]. In
our study, the number of the patients having LS in the recurrent seizure
group was larger than that in the non-recurrent group, but LS had
no statistically significant relationship with the occurrence of recurrent
PSS. Few reports have studied the relationship between the occurrence
of recurrent seizure and the hemorrhage volume in patients with ICH;
however, these studies are not supported by our data [4,6]. In the early
stage after ICH, the mechanisms resulting in ES have been implicated
in a combination of the sudden development of a space-occupying le-
sion with mass effect, focal ischemia, and blood products [3]. During
the late stage after ICH, the mechanisms contributing to seizure include
abnormal electrical discharge due to gliosis or irritability after brain in-
jury [30]. However, the exact mechanism producing seizure in ICH re-
mains unclear. The efficacy of prophylactic administration of AED for
seizure after ICH is controversial [31]. Passero et al. [5] reported that
AED significantly reduced clinical seizures after lobar ICH. In contrast,
several studies have reported a lack of effect of AED, especially in the
acute phase [17–19,31,32]. Our study showed that AED had no signifi-
cant relationship with recurrence of PSS after the initial PSS in patients
with ICH. However, the long-term benefit of prophylactic use of AED re-
mains unknown.
We analyzed Kaplan–Meier survival curves for patients with or
without AED, and found no significant differences between the 2 groups
with regard to developing recurrent PSS. Even when we limited the
subjects to those with only LS or a larger ICH volume (N10 mL), there
were no differences between the patients with or without LS or a
321
large hematoma volume using Kaplan–Meier survival curves. These
results suggest that the prophylactic administration of AED should be
considered with care, even if the patient with ICH has LS or a large
hematoma volume. Our study has several limitations, however. First,
this was a retrospective analysis and therefore subject to bias of un-
measured factors. Second, the selection bias for patients received AED
treatment after initial PSS. Due to non-approval of novel AED, there
were limited varieties of AED. Third, because the follow-up period was
short, there may be differences in the incidence rate of late seizures,
the sample size of the compared groups are small. We need to further
investigate the risks for seizure after ICH and the benefits of prophylac-
tic administration of AED for the patients with ICH.
5. Conclusion
Seizures are an important neurological complication of spontaneous
ICH. The incident rates of ES and LS were 4.3% and 2.3%. Initial seizures in
patients with ICH significantly correlated with cortical involvement of
the cerebral lesion, non-hypertensive ICH, younger age, and severe neu-
rological deficits. Of the patients with an initial seizure, 15.7% had recur-
rent PSS. Larger hematoma volume was the only predictive factor for
recurrence of PSS. AED therapy when administered after the initial sei-
zure showed no association with recurrence of PSS. More prospective,
randomized, double-blind trials are required to evaluate the efficacy of
prophylactic AED therapy in patients with spontaneous ICH and clarify
the optimal treatment strategies.
Conflicts of interest/disclosures
On behalf of all authors, the corresponding author states that there is
no conflict of interest.
Acknowledgments
We are grateful to Mrs. Tomoko Fukushima for providing statistical
analysis and help for this study.
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