Association between Seizures and Outcomes among

Intracerebral Hemorrhage Patients: The China

National Stroke Registry
Zixiao Li, MD,* Xingquan Zhao, MD, PhD,* Yilong Wang, MD, PhD,*
Chunxue Wang, MD, PhD,* Liping Liu, MD, PhD,* Xiaoqiu Shao, MD, PhD,*
Wenjuan Wang, MD, PhD,*x Yuesong Pan, MD,* Chunjuan Wang, MD, PhD,*x
Ruijun Ji, MD, PhD,* Changqing Zhang, MD,* Jing Jing, MD, PhD,*
and Yongjun Wang, MD*

Background: To determine whether the presence of seizures in patients with spontaneous intracerebral hemorrhage (ICH) was associated with in-hospital complications and measured outcomes. Methods: This prospective cohort study from the
China National Stroke Registry included consecutive patients with ICH between
August 2007 and September 2008. In-hospital complications, functional outcomes,
and mortality at 3, 6, and 12 months were compared between patients with seizures
and those without seizures occurring at ICH onset and during hospitalization. Poor
functional outcome was defined as a modified Rankin Scale score between 3 and 6.
Poor functional outcome and mortality were stratified by stroke severity using Glasgow Coma Scale scores on admission. Results: The study included 3216 patients
with ICH and 139 of them (4.3%) experienced seizures. The presence of seizures
was associated with high in-hospital complications including atrial fibrillation
(P 5 .004), pneumonia (P 5 .001), as well as lower rehabilitation assessment rates
(P 5 .033) compared with patients without seizures. ICH patients with seizures
had poorer functional outcome at 3-month (P 5 .012), 6-month (P 5 .007), and
12-month (P 5 .001) follow-up. They also had higher mortality at 3 months
(P 5 .045), 6 months (P 5 .005), and 12 months (P 5 .002). Patients with mild strokes
had poorer functional outcome and higher mortality (P , .005) if seizures occurred.

From the *Department of Neurology, Beijing TianTan Hospital,

Capital Medical University, Beijing; China National Clinical
Research Center for Neurological Diseases, Beijing; Center of Stroke,
Beijing Institute for Brain Disorders, Beijing; and xBeijing Key Laboratory of Translational Medicine for Cerebrovascular Disease, Beijing,
China.
Received August 29, 2014; revision received September 4, 2014;
accepted September 16, 2014.
Z.L. and X.Z. were responsible for literature review, data collection,
data analysis, drafting the article, and review of submitted versions;
Y.W. was responsible for research design, study conception, and
data collection; C.W. and X.S. were responsible for draft revisions
and review of submitted versions; L.L. was responsible for study
conception; W.W., C.W., C.Z., and J.J. were responsible for data collection; Y.P. conducted statistical consultation and data analysis; R.J. was
responsible for literature review; Y.W. was responsible for research
design and concept development, critical revisions, and approval of
submitted versions.

Supported by grants from the Ministry of Science and Technology

and the Ministry of Health of the Peoples Republic of China (National S & T Major Project of China: 2006BA101A11 and
2011BAI08B02), the National Key Technology Research and Development Program of the Ministry of Science and Technology of China
(2013BAI09B03), and Beijing Institute for Brain Disorders (BIBDPXM2013_014226_07_000084).
All authors report no potential conflict of interest relevant to this
article.
Address correspondence to YongJun Wang, MD, Department of
Neurology, Beijing TianTan Hospital, Capital Medical University,
No. 6 Tiantan Xili, Dongcheng District, Beijing, China. E-mail:
yongjunwang1962@gmail.com.
1052-3057/$ - see front matter
2015 by National Stroke Association
http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.09.021

Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 2 (February), 2015: pp 455-464

455

Z. LI ET AL.

456

Conclusions: The presence of seizures in patients with ICH was associated with high
in-hospital complications and indicates poor outcomes at 3-, 6-, and 12-month
follow-up. Quality improvement strategies targeting ICH patients with seizures
especially mild stroke may help improve prognoses. Key Words: Intracerebral
hemorrhageall epilepsy/seizuresoutcome researchrisk factors.
2015 by National Stroke Association

Clinical seizures after spontaneous intracerebral hemorrhage (ICH) are encountered in clinical practice relatively frequently with incidence varying from 2.7% to
17%.1-6 However, the impact of seizures on stroke
outcome remains a matter of debate. In several
prospective and population-based studies, clinical seizures did not have a negative impact on neurologic outcomes or mortality.3,58 On the contrary, findings from 1
study showed that post-ICH seizures were associated
with worsening neurologic function and a trend toward
poorer outcomes.9 Interestingly, most of the available
data came from cohorts with stroke including ischemic
and hemorrhagic stroke, which are 2 very different diseases with different prognoses. Additionally, not many
previous studies took into account patients and health
care providers perspectives, particularly on resource utilization, performance measures,10 and influence of seizures on stroke outcome.11 So, we hypothesized the
following: (1) the presence of seizures in patients with
ICH might be associated with higher in-hospital complications and (2) the presence of seizures might have a
negative impact on short- and long-term stroke outcomes.
The primary aim of this study was to assess the association between seizure occurrence and outcomes after ICH
stroke, including in-hospital complications, short- and
long-term functional outcomes, and mortality.

Methods
This study was conducted from the largest stroke registry in China, the China National Stroke Registry (CNSR),
which is a national hospital-based, multicenter, and prospective registry of consecutive patients with acute cerebrovascular events sponsored by the Ministry of Health
between August 2007 and September 2008. A total of
132 hospitals were selected as registry hospitals. The
study was approved by the central Institutional Review
Board at Beijing Tiantan Hospital, and all patients or their
designated relatives gave informed consents. Further details of CNSR have been published elsewhere.12
The current analysis included all patients in CNSR who
had been diagnosed with ICH according to World Health
Organization criteria.13 Patients were excluded if they
met any following criteria: history of seizures, primary
intraventricular hemorrhage or prestroke modified Rankin Scale (mRS) of more than 2, neoplastic cause of ICH,

unavailable data of ICH hematoma volume, disagreement to participate in the study, or loss to follow-up.14

Demographic Characteristics and Medical History

In the present study, we prospectively collected demographic information: age (stratification: ,60, 60-79, and
$80 years of age), gender, and vascular risk factors: history of stroke, hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, cardiovascular disease, current
smoking, moderate or heavy alcohol consumption (2
standard alcoholic beverages per day).14

Clinical Evaluation at Admission

We assessed the severity of neurologic impairment by
using the National Institutes of Health Stroke Scale
(NIHSS; 3 categories: mild [0-3], moderate [4-14], and severe [15-42]) and Glasgow Coma Scale (GCS) at admission (3 categories: mild [13-15], moderate [9-12], and
severe [3-8]).

Image Analysis
Initial noncontrast computed tomography (NCCT)
scans were employed with a slice thickness of 9 mm
supratentorially and 4.5 mm infratentorially. ICH hematoma volume was measured on the initial head NCCT
scan using the ABC/2 method.15 Additionally, the locations of ICH were considered as follows: (1) strictly
deep locations (putamen, caudate nucleus, internal
capsule, thalamus, brain stem, and cerebellar); (2) deep
and lobe locations; and (3) strictly lobe locations (frontal,
parietal, temporal, and occipital). The presence or absence
of intraventricular extension was also noted on the initial
head NCCT.
All images were prospectively viewed by a neuroradiologist blinded to clinical data at different study centers. The
neuroradiologists of the study centers received the same
training regarding the computed tomography protocol.

Definition of Seizures
The status of seizures was based on clinical diagnosis.
According to International League Against Epilepsy
criteria, seizures were defined as paroxysmal disorders
of the central nervous system, possible subsequent loss
of consciousness, and/or with or without motor involvement at any point since stroke onset or during the period

SEIZURES AND OUTCOMES IN HEMORRHAGE STROKE

457

Table 1. Definition of in-hospital medical complications after intracerebral hemorrhage

Complications
Hematoma expansion
Myocardial infarction
Atrial fibrillation/flutter
Pneumonia

Gastrointestinal bleeding
Urinary tract infection
Deep vein thrombosis
Decubitus ulcer

Definition
An increase in volume of 33%-50% or an absolute change in hematoma volume of 12$5-20 mL (on
repeat computed tomography).
Electrocardiography (ECG) or laboratory evidence of acute myocardial infarction.
Intermittent or new persistent atrial fibrillation/flutter on ECG or ECG monitoring not present on
admission.
Clinical and laboratory indices of respiratory tract infection (fever, cough, auscultatory respiratory
crackles, new purulent sputum, or positive sputum culture), and supported by typical chest X-ray
findings.
Clinical (any episode of fresh blood or coffee ground emesis, hematemesis, melena, or
hematochezia), laboratory or radiographic evidence of gastrointestinal bleeding.
Clinical symptoms of urinary tract infection combined with a positive urine examination or culture.
Clinical diagnosis of deep vein thrombosis and with radiographic evidence.
Any skin breaks or necrosis resulting from either pressure or trivial trauma.

of hospitalization.16,17 At admission, physicians actively

inquired about seizures occurring at onset of ICH and
observed all seizures that occurred during hospitalization.

Measurements
(1) Recorded in-hospital medical complications: hematoma expansion, atrial fibrillation (AF), urinary
tract infection (UTI), decubitus ulcer, myocardial
infarction (MI), deep venous thrombosis (DVT),
pneumonia, and gastrointestinal bleeding (GIB)
(specific definitions listed in Table 1)18,19;
(2) Medical resource utilization: admission department (neurological ward or others, stroke unit,
and intensive care unit [ICU]/neurologic ICU
[NICU]), length of stay in the hospital or ICU,
and supporting interventions (nasal feeding, central venous catheterization, tracheal intubation,
and mechanical ventilation). Management by
stroke unit, NICU, and ICU was defined as when
a patient was admitted to a stroke unit, NICU, or
ICU at any point during the hospitalization;
(3) Performance measures: antihypertensive therapy
for patients whose blood pressure was more than
140/90 mm Hg during hospitalization, dysphagia
screening before any oral intake, and rehabilitation
evaluation during hospitalization10;
(4) Mortality and functional outcomes: at 3, 6, and
12 months after ICH onset, patients or their authorized caregivers were contacted through telephone by trained research personnel who
followed standardized scripts for follow-up. Poor
functional outcome (dependency or death) was
defined as mRS of 3-6 scores.20 We compared mortality and functional outcomes for patients with
and without seizures and stratified according to
stroke severity based on GCS.

Statistical Analysis
Categorical variables were summarized as proportion;
continuous variables were summarized with median
and interquartile range. In univariate analysis, the c2 or
Fisher exact test was used to compare categorical variables, and the Student t test or MannWhitney test was
used to compare continuous variables.
Impact of Seizures on Mortality and Functional
Outcomes
The mortality and poor functional outcome at 3, 6, and
12 months after ICH onset in patients with and without
seizures and stratified according to stroke severity based
on GCS were compared using the c2 test or Fisher exact
test. A logistic model was employed to identify risk factors associated with mortality and poor functional
outcome at 3, 6, and 12 months after ICH onset. Variables
were selected using stepwise regression. These variables
included the presence of seizures, age at admission,
gender, NIHSS and GCS at admission, vascular factors
of stroke, diabetes, hypertension, dyslipidemia, AF, cardiovascular disease, current smoking; and moderate or
heavy alcohol consumption, the volume and locations of
ICH and intraventricular extension, in-hospital complications of hematoma expansion, AF, MI, UTI, decubitus ulcer, DVT, pneumonia, and GIB, performance measures of
antihypertensive therapy, dysphagia screening, and rehabilitation evaluation. All variables with a P less than .2
(equivalent to maximizing the information criteria) in
the univariate analysis were considered in the multivariable regression model.
Factors Associated with the Occurrence of Seizures
Multivariable logistic regression was performed to
evaluate relative factors of the occurrence of seizures. Variables in this model were as previously mentioned except
for performance measures.

458

All tests were 2 tailed, and statistical significance was

determined at a level of .05. Statistical analysis was performed using SAS version 9.2 (SAS Institute, Cary, NC).

Results
Study Population
From September 2007 to August 2008, 22,216 hospitalized patients with acute cerebrovascular events were
consecutively recruited in the CNSR. Among them, 5136
patients were finally diagnosed as acute ICH. The
following patients were excluded from this study: (1)
138 patients with primary intraventricular hemorrhage;
(2) 881 patients with lack of data of hematoma volume;
(3) 12 ICH patients with intracranial tumor; (4) 261 patients with a prestroke mRS more than 2; (5) 308 patients
who were not willing to participate in this study; (6) 39
patients who had a history of seizures; and (7) 281 patients lost to follow-up. Finally, our cohort consisted of
3216 patients without a history of seizures (1241 [38.6%]
female) with median age of 62 years (interquartile range
[IQR], 53-72 years). The median length between onset
symptoms and discharge was 19 days (IQR, 13-27 days),
the median NIHSS score was 9 (IQR, 4-16), the median
GCS score was 14 (IQR, 9-15), and the median volume
of ICH was 12.5 mL (IQR, 5.4-28.0).

Demographic and Clinical Characteristics of Patients

with or without Seizures
Among 3216 consecutive patients with ICH, 139 (4.3%)
had seizures. Their median age was 62 years (IQR, 52-73),
and 57 (41.0%) patients with seizures were female, which
had no difference from those without seizures. Patients
with seizures had higher NIHSS (16, [IQR, 7-30];
P , .001) and lower GCS (8, [IQR, 6-14]; P , .001). We
did not find difference in vascular risk factors (Table 2).

Imaging Features of Patients with or without Seizures

ICH patients experiencing seizures had a larger hemorrhage volume (16.9 [IQR, 9-36]; P 5 .005) and significant
difference of strictly deep locations, deep and lobe locations, and strictly lobe locations (P , .001), including
higher strictly lobar involvement rate (42.4% vs. 15.2%)
and lower strictly deep involvement rate (39.6% vs.
67.2%; Table 1).

In-hospital Complications with or without Seizures

Patients with seizures had more complications during
hospitalization including AF (6.5% vs. 2.1%, P 5 .004)
and pneumonia (29.5% vs. 17.4%, P 5 .001) than those
without seizures. We did not find a difference regarding
hematoma expansion, UTI, MI, DVT, or GIB (Table 3).

Z. LI ET AL.

Medical Resource Utilization and Performance

Measures with or without Seizures
There was no difference between patients with or
without seizures in terms of ICU/NICU admission and
length of hospital or ICU/NICU stay. Patients with seizures had higher rates of using supporting interventions,
such as nasal feeding (30.9% vs. 14.4%, P , .001) and
tracheal intubation (10.8% vs. 5.0%, P 5 .006) than those
without seizures. Regarding performance measures, patients with seizures underwent fewer rehabilitation assessments than those without seizures (30.2% vs. 39.3%,
P 5 .033). There was a relatively low adherence rate, but
no differences between patients with and without seizures in the number of patients who underwent antihypertensive therapy and screening for dysphagia (Table 3).

Univariate and Multivariable Analysis on 3-, 6-, and

12-Month Functional Outcomes and Mortality after
ICH Onset
In univariate analysis, patients with seizures had
higher rates of poor functional outcome at 3 months
(odds ratio [OR], 2.51; confidence interval [CI], 1.73-3.63;
P , .001), 6 months (OR, 2.63; CI, 1.83-3.8; P , .001) and
12 months (OR, 2.95; CI, 2.04-4.28; P , .001) after ICH
onset (Table 4) than those without seizures. Multivariable
logistic analysis adjusted for potential confounding variables in the entire cohort revealed that the presence of seizures was associated with the higher rate of poor
functional outcome at 3-month (adjusted OR, 1.9; CI,
1.15-3.14; P 5 .012), 6-month (adjusted OR, 1.94; CI,
1.19-3.15; P 5 .007), and 12-month (adjusted OR, 2.27;
CI, 1.41-3.65; P 5 .001) mortality after ICH onset (Table 3).
In univariate analysis, patients with seizures had
higher mortality at 3 months (OR, 2.64; CI, 1.85-3.76;
P , .001), 6 months (OR, 2.89; CI, 2.05-4.09; P , .001),
and 12 months (OR, 2.9; CI, 2.06-4.08; P , .001) after
ICH onset (Table 3) than those without seizures. Multivariable logistic analysis adjusted for potential confounding
variables in the entire cohort revealed that the presence
of seizures remained an independent predictor of 3month (adjusted OR, 1.6; CI, 1.01-2.53; P 5 .045), 6month (adjusted OR, 1.88; CI, 1.21-2.94; P 5 .005), and
12-month (adjusted OR, 1.97; CI, 1.27-3.05; P 5 .002) mortality after ICH onset (Table 4).

Comparisons of Functional Outcomes and Mortality by

ICH Severity
For patients with a GCS score of 13-15, those with seizures had poorer functional outcomes at 3 months
(53.6% vs. 30.8%, P 5 .001), 6 months (51.8% vs. 28.9%,
P , .001), and 12 months (55.4% vs. 29.0%, P , .001) after
ICH onset than those without seizures and had higher
mortality at 3 months (19.6% vs. 6.8%, P 5 .002), 6 months
(21.4% vs. 8.3%, P 5 .002), and 12 months (26.8% vs.

SEIZURES AND OUTCOMES IN HEMORRHAGE STROKE

459

Table 2. Baseline characteristics and imaging features of patients with spontaneous intracerebral hemorrhage with or without
seizures
Occurrence of seizures
Variable

Overall, N (%)

Yes, n (%)

No, n (%)

Patients, n
Demographic
Age, median (IQR), y
Age group, y
,60
60-79
$80
Female
Current smoking
Current heavy drinking
Medical history
Stroke
Diabetes mellitus
Hypertension
Dyslipidemia
Cardiovascular disease
Atrial fibrillation
NIHSS at hospital admission, median (IQR)
NIHSS at hospital admission
0-4
5-14
$15
GCS at hospital admission, median (IQR)
GCS at hospital admission
13-15
9-12
3-8
Hematoma location
Strictly deep locations
Deep and lobe locations
Strictly lobe locations
Hematoma volume, mL, median (IQR)
Intraventricular extension (extension into ventricles)

3216

139

3077

62 (53-72)

62 (52-73)

62 (53-72)

1391 (43.3)
1535 (47.7)
290 (9.0)
1241 (38.6)
1220 (37.9)
367 (11.4)

63 (45.3)
56 (40.3)
20 (14.4)
57 (41.0)
46 (33.1)
15 (10.8)

1328 (43.2)
1479 (48.1)
270 (8.8)
1184 (38.5)
1174 (38.2)
352 (11.4)

874 (27.2)
285 (8.9)
2190 (68.1)
228 (7.1)
267 (8.3)
52 (1.6)
9 (4-16)

46 (33.1)
18 (12.9)
84 (60.4)
8 (5.8)
11 (7.9)
3 (2.2)
16 (7-30)

828 (26.9)
267 (8.7)
2106 (68.4)
220 (7.1)
256 (8.3)
49 (1.6)
9 (4-16)

1072 (33.3)
1188 (36.9)
956 (29.7)
14 (9-15)

33 (23.7)
35 (25.2)
71 (51.1)
8 (6-14)

1039 (33.8)
1153 (37.5)
885 (28.8)
14 (9-15)

2002 (62.3)
474 (14.7)
740 (23.0)

56 (40.3)
16 (11.5)
67 (48.2)

1946 (63.2)
458 (14.9)
673 (21.9)

P value

.822
.039

.593
.246
.892
.119
.092
.051
.734
1.000
.491
,.001
,.001

,.001
,.001

,.001
2122 (66.0)
568 (17.7)
526 (16.3)
12.5 (5.4-28.0)
946 (29.4)

55 (39.6)
25 (18.0)
59 (42.4)
16.9 (9.0-36)
49 (35.3)

2067 (67.2)
543 (17.6)
467 (15.2)
12 (5.12-27)
897 (29.2)

.005
.128

Abbreviations: GCS, Glasgow Coma Scale; IQR, interquartile range; NIHSS, National Institute of Health Stroke Scale.

10.8%, P 5 .001) after ICH onset than those without seizures (Table 5). For patients with a GCS score of 9-12 or
3-8, the presence of seizures had not significant difference
on functional outcomes or mortality compared with the
absence of seizures (Table 5).

Multivariable Analysis of Variables Associated with

Seizures
Multivariable analysis demonstrated that the following
variables were associated with seizures: young age (,60
years as reference, 60-79 years, adjusted OR, .64; CI, .43.94), stroke severity at admission (NIHSS $15 [adjusted
OR, 2.24; CI, 1.25-4.01; P 5 .007] and GCS #8 [adjusted
OR, 2.57; CI, 1.51-4.38; P 5 .001]), lobar involvement
(adjusted OR, 6.45; CI, 4.26-9.77; P , .001), in-hospital
complications of AF (adjusted OR, 3.18; CI, 1.45-6.98;

P 5 .004) and pneumonia (adjusted OR, 1.63; CI, 1.082.45; P 5 .021; Fig 1).

Discussion
The impact of seizures after ICH on clinical outcomes is
controversial and is a challenge for clinicians. In this
largest cohort study of ICH in China, we found that presence of seizures in patients with ICH at onset or during
hospitalization was an independent risk factor of 3-, 6-,
and 12-month stroke mortality and poor functional outcomes after adjusting for other factors. Additionally, it
also was associated with higher in-hospital complications
and lower adherence to rehabilitation assessment.
These findings were somewhat different from those of
previous studies. A recent population-based observational study found that patients with seizures

Z. LI ET AL.

460

Table 3. Management and in-hospital complications of patients with spontaneous intracerebral hemorrhage with or without
seizures
Occurrence of seizures
P value

Variable

Overall, N (%)

Yes, n (%)

No, n (%)

Patients, n
Treated in
Stroke unit
NICU/ICU
Neurology ward/other ward
Length NICU/ICU of stay, median (IQR), d
Length hospital of stay, median (IQR), d
Supporting interventions
Nasal feeding
Central venous catheterization
Tracheal Intubation
Mechanical ventilation
Performance measures
Antihypertensive therapy
Swallow function evaluation
Rehabilitation assessment
In-hospital complications
Hematoma expansion
Myocardial infarction
AF
Pneumonia
UTI
Decubitus ulcer
DVT
GI hemorrhage

3216

139

3077

549 (17.1)
577 (17.9)
2090 (65.0)
0 (0-6)
18 (11-26)

23 (16.5)
34 (24.5)
82 (59.0)
2 (0-7)
16 (9-26)

526 (17.1)
543 (17.6)
2008 (65.3)
0 (0-5)
18 (12-26)

485 (15.1)
139 (4.3)
168 (5.2)
106 (3.3)

43 (30.9)
10 (7.2)
15 (10.8)
8 (5.8)

442 (14.4)
129 (4.2)
153 (5.0)
98 (3.2)

,.001
.090
.006
.136

1892 (58.8)
837 (26.0)
1251 (38.9)

73 (52.5)
32 (23.0)
42 (30.2)

1819 (59.1)
805 (26.2)
1209 (39.3)

.134
.431
.033

90 (2.8)
25 (.8)
75 (2.3)
577 (17.9)
192 (6.0)
30 (.9)
22 (.7)
176 (5.5)

6 (4.3)
1 (.7)
9 (6.5)
41 (29.5)
11 (7.9)
3 (2.2)
1 (.7)
11 (7.9)

84 (2.7)
24 (.8)
66 (2.1)
536 (17.4)
181 (5.9)
27 (.9)
21 (.7)
165 (5.4)

.283
1.000
.004
.001
.356
.138
1.000
.183

.118

.506
.138

Abbreviations: AF, atrial fibrillation; DVT, deep venous thrombosis; GI, gastrointestinal bleeding; ICU, intensive care unit; IQR, interquartile
range; NICU, neurologic intensive care unit; UTI, urinary tract infection.

experienced higher mortality than patients without seizures but seizures were not an independent risk factor
of mortality at 30 days after stroke including ischemic
or hemorrhagic stroke.7 Another population-based study
showed that early seizures occurring within 2 weeks after
symptom onset were not independently associated with
poor early functional outcomes and mortality at 1 month
and 1 year after adjustment for confounding variables.6
The Prognosis of InTra-Cerebral Hemorrhage cohort, a
simple-center hospital-based prospective observational
study, showed that the occurrence of early seizures within
7 days from initial onset did not influence mortality at
7 days or at 6 months and functional outcomes at 6 months
for patients with ICH.5 Another recent study did not find
that seizures were related to functional outcomes in
young patients with ICH. However, there were a few
cases of epilepsy, which significantly limited statistical
power.21 A trend toward increased poor outcomes in patients with posthemorrhagic seizures was found, but a
relatively small sample size of patients with ICH limited
the result findings.9 Several previous studies included
both ischemic and hemorrhagic strokes, whose nature
and prognosis were different. Early seizures were twice

as frequent in hemorrhagic stroke as in ischemic stroke

patients.6 These heterogeneities of ischemic and hemorrhagic strokes may produce a mixed effect in evaluating
the impact of seizures on clinical outcomes. Meanwhile,
some previous studies involved a single center, small
sample size of patients with ICH, and short-term
follow-up, which also affected the measured impact of
seizures on clinical outcomes. In addition, in-hospital
complications and performance measures, which also
affected the clinical outcomes, were not taken into consideration sufficiently in several studies.
In our study from CNSR, a national hospital-based,
multicenter, and prospective registry of patients with acute
cerebrovascular events,12 3216 patients with ICH, excluding
a history of seizures, were included and analyzed regarding
the impact of seizures on 12-month stroke outcomes. Meanwhile, in-hospital complications and performance measures also were recorded and taken into account. Similar
to previous studies,17,22 seizure patients with ICH had
more severe stroke and in-hospital complications such as
pneumonia in our study, which may further worsen clinical
outcomes.18,19 This phenomenon could explain the higher
utilization of supporting interventions and mortality in

SEIZURES AND OUTCOMES IN HEMORRHAGE STROKE

461

Table 4. Poor functional outcome and mortality in patients with or without seizures after intracerebral hemorrhage
Univariate analysis
Clinical outcomes
At 3 mo
Poor outcomez
Death
At 6 mo
Poor outcome
Death
At 12 mo
Poor outcome
Death

Multivariable analysis*

Odds ratioy

95% CI

P value

Odds ratio

95% CI

P value

2.51
2.64

1.73-3.63
1.85-3.76

,.001
,.001

1.9
1.6

1.15-3.14
1.01-2.53

.012
.045

2.63
2.89

1.83-3.8
2.05-4.09

,.001
,.001

1.94
1.88

1.19-3.15
1.21-2.94

.008
.005

2.95
2.9

2.04-4.28
2.06-4.08

,.001
,.001

2.27
1.97

1.41-3.65
1.27-3.05

.001
.002

Abbreviation: CI, confidence interval.

*Adjusted for age, sex, smoking, heavy drinking, history of stroke, hypertension, diabetes mellitus, dyslipidemia, cardiovascular disease,
atrial fibrillation, National Institutes of Health Stroke Scale score and Glasgow Coma Scale score on admission, hematoma volume, hematoma
location, intraventricular hemorrhagic extension, in-hospital complications including hematoma expansion, atrial fibrillation, urinary tract infection, decubitus ulcer, myocardial infarction, deep venous thrombosis, pneumonia, and gastrointestinal bleeding and performance measures of
antihypertensive therapy, dysphagia screening, and rehabilitation evaluation.
yOdds ratio using the group without seizures as the reference.
zPoor outcome defined as modified Rankin Scale 3-6.

patients with seizures. Additionally, our findings

indicated that several performance measures including
antihypertensive therapy, screening for dysphagia, and
rehabilitation assessment played a positive role in
improving clinical outcomes.14,23 However, compared
with patients without seizures, those with seizures had
relatively low adherence of these performance measures
in our study. This may be because seizure patients had
more severe strokes and disturbance of consciousness,
making it difficult to give oral antihypertensive therapy
and unsuitable for dysphagia screening or rehabilitation
assessment.
Interestingly, for patients with moderate or severe
strokes (GCS of 9-12 or 3-8), we found no difference for
seizure patients in mortality and functional outcomes
compared with those without seizures, as these patients
demonstrated ceiling effects in mortality and poor functional outcome, which was also found in seizure patients
with ischemic severe stroke.17 However, among patients
with mild strokes (GCS of 13-15), patients with seizures
had higher rates of short- or long-term mortality and
worsened functional outcomes compared with those
without seizures. This indicated that seizures played a vital role in poor functional outcome and mortality, especially in patients with mild strokes.
The potential mechanisms by which seizures might
worsen the clinical outcomes of patients with ICH might
be as follows. First, the combination of sudden development of a space-occupying lesion with mass effect, perihematoma edema, and blood breakdown products has
been postulated to account for seizures especially in early
ICH.3 Within minutes to hours from the onset of bleeding,
damage begins and is primarily the result of mechanical

damage associated with the mass effect.24 Second, secondary damage after ICH is triggered by the presence
of intraparenchymal blood and components, which subsequently activates cytotoxic, oxidative and inflammatory
pathways, and causing death of surrounding cells.25,26
Third, secondary brain injury after seizures may have a
similar molecular pathophysiology with ICH. Seizures
can cause neuronal cell death through dynamic
processes that might cause excitotoxicity to induce
mitochondrial dysfunction, alter cytokine levels and
oxidative stress, and change plasticity or activation in
some late cell death pathways.27,28 Early epileptiform
activity has a deleterious impact on perihematoma
areas, possibly by increasing the cerebral blood flow
and glucose metabolic demand in a hypoxic tissue and
the previously mentioned molecular pathophysiology.2931
Additionally, early seizures occurring in patients with
ICH increased the risk of later seizures.32 Symptomatic
seizures due to stroke or other disease had a higher early
mortality.33 Therefore, it may be reasonably inferred that
epileptic seizures in patients with ICH occurring either
at onset or whilst in the hospital further worsen clinical
outcomes because ICH is coupling with early or later seizures, and they form overlying effects together.
Our study looked at a similar frequency of seizures in
ICH patients to that of previous studies ranging from
2.7% to 17%.16,34,35 Similarly, previous studies have
indicated a direct relationship between stroke severity,
lobar or cortical involvement, and seizures.5,32,35
Additionally, in our study, other associated factors with
occurrence of seizures also included the in-hospital complications of pneumonia.17,19 Interestingly, we also
observed that the presence of seizures was associated

Z. LI ET AL.

462

Table 5. Mortality and functional outcomes comparison stratified by GCS at admission

Occurrence of seizures
Variable

Overall, N (%)

Yes, n (%)

No, n (%)

All patients
Poor outcome* within 3 mo
Poor outcome within 6 mo
Poor outcome within 12 mo
Death within 3 mo
Death within 6 mo
Death within 12 mo
GCS 13-15
Poor outcome within 3 mo
Poor outcome within 6 mo
Poor outcome within 12 mo
Death within 3 mo
Death within 6 mo
Death within 12 mo
GCS 9-12
Poor outcome within 3 mo
Poor outcome within 6 mo
Poor outcome within 12 mo
Death within 3 mo
Death within 6 mo
Death within 12 mo
GCS 3-8
Poor outcome within 3 mo
Poor outcome within 6 mo
Poor outcome within 12 mo
Death within 3 mo
Death within 6 mo
Death within 12 mo

3216
1572 (48.9)
1507 (46.9)
1474 (45.8)
635 (19.7)
716 (22.3)
832 (25.9)
2002
629 (31.4)
592 (29.6)
595 (29.7)
144 (7.2)
173 (8.6)
225 (11.2)
474
324 (68.4)
308 (65.0)
291 (61.4)
103 (21.7)
125 (26.4)
150 (31.6)
740
619 (83.6)
607 (82.0)
588 (79.5)
388 (52.4)
418 (56.5)
457 (61.8)

139
97 (69.8)
96 (69.1)
98 (70.5)
53 (38.1)
61 (43.9)
68 (48.9)
56
30 (53.6)
29 (51.8)
31 (55.4)
11 (19.6)
12 (21.4)
15 (26.8)
16
10 (62.5)
10 (62.5)
10 (62.5)
4 (25.0)
6 (37.5)
7 (43.8)
67
57 (85.1)
57 (85.1)
57 (85.1)
38 (56.7)
43 (64.2)
46 (68.7)

3077
1475 (48.0)
1411 (45.9)
1376 (44.7)
582 (18.9)
655 (21.3)
764 (24.8)
1946
599 (30.8)
563 (28.9)
564 (29.0)
133 (6.8)
161 (8.3)
210 (10.8)
458
314 (68.6)
298 (65.1)
281 (61.4)
99 (21.6)
119 (26.0)
143 (31.2)
673
562 (83.5)
550 (81.7)
531 (78.9)
350 (52.0)
375 (55.7)
411 (61.1)

P value
,.001
,.001
,.001
,.001
,.001
,.001
.001
,.001
,.001
.002
.002
.001
.594
.796
1.0
.759
.385
.287
.863
.617
.269
.522
.198
.238

Abbreviation: GCS, Glasgow Coma Scale.

*Poor outcome defined as modified Rankin Scale 3-6.

with the atrial fibrillation. However, the potential

mechanisms are not currently clear. Epileptic seizures
are often companied by the changes in cardiac
autonomic function.36 Atrial fibrillation or atrial flutter after epileptic seizures has been reported and the possible
underlying cause is augmentation in vagal tone and presence of a concealed cardiac dysfunction.37 Among patients with ischemic stroke, the involvement of insular
cortex damage can cause cardiac autonomic dysregulation.38,39 Hemorrhagic stroke involving the cortical lobe
is prone to seizures.32,35 So, we speculate that the
involvement of the insular cortex among ICH patients
might take a potential aspect on the relationship
between seizures and atrial fibrillation.
Our study has some limitations. First, we did not have
information on the results of electroencephalogram; some
seizures could have been missed or some paroxysmal
nonepileptic events could have been called seizures.
The true incidence of seizures might have been underestimated because subclinical seizures can be detected by
using continuous electroencephalogram monitoring

only.9,40,41 Second, we had no available information

about the specific time, types and frequency of seizures,
status epilepticus, and the use of antiepileptic drugs
during hospitalization and after discharge. Additionally,
the sequence of in-hospital seizures and complications
was unclear. It indicated that seizures were related factors
of some complications but not precipitating factors.
Despite some limitations, our study was the large ICH
cohort to assess the influence of seizures on outcomes
from CNSR including comprehensive clinical administrative data, which may provide some practical implications
for clinical management of ICH patients. Our findings
suggest that seizures should be considered as a neurologic complication in patients with ICH that have an
important impact on short- and long-term poor prognosis
and a relationship with complications, as well as medical
resource utilization. These results provide a supportive
evidence for the guideline recommendation that patients
with clinical seizures should be treated with antiepileptic
drugs.23 Currently, there is insufficient evidence to support the routine use of antiepileptic drugs for the primary

SEIZURES AND OUTCOMES IN HEMORRHAGE STROKE

Figure 1. Multivariate analysis: variables associated with the occurrence

of seizures in patients with ICH. Abbreviations: CI, confidence interval;
GCS, Glasgow Coma Scale; NIHSS, National Institutes of Health Stroke
Scale; OR, odds ratios.

or secondary prevention of seizures after stroke.42 However, in many hospitals worldwide, the use of antiepileptic drugs as a prophylactic intervention in ICH
patients is a common practice. According to the new definition of epilepsy, in the presence of a cortical lesion, 1
seizure is adequate for diagnosis of epilepsy.16 Thus, we
should be attentive to seizures, especially in patients
with mild hemorrhagic strokes in lobar or cortical regions,
and prophylactic or therapeutic antiepileptic drug for
these targeted patients may be evaluated more thoroughly in a randomized study. Strategies of targeting patients with seizures in ICH patients may be performed to
initiate specialized care, improve the outcomes, and quality of care in these individuals.
In conclusions, the presence of seizures in patients with
ICH was associated with increased in-hospital complications, poor functional outcome, and mortality at 3, 6, and
12 months and low adherent rate of performance measures. Quality improvement strategies targeting ICH patients with seizures especially mild stroke may help
improve outcomes.

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