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Risks of subsequent epilepsy among patients with hypertensiveencephalopathy: A nationwide population-based study
Tzu-Tsao Chung a,1, Chi-Yu Lin b,1, Wen-Y en Huang c,d, Cheng-Li Lin e,f ,Fung-Chang Sung g,h,i, j, Chia-Hung Kao d,e,⁎a Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwanb Department of Neurology, Changhua Christian Hospital, Changhua, Taiwanc Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwand Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwane Management Of ce for Health Data, China Medical University Hospital, Taichung, Taiwanf Department of Public Health, China Medical University, Taichung, Taiwang
Graduate Institute of Clinical Medicine Science, College of Medicine, China Medical University, Taichung, Taiwanh School of Medicine, College of Medicine, China Medical University, Taichung, Taiwani Department of Nuclear Medicine, China Medical University Hospital, Taichung, Taiwan j PET Center, China Medical University Hospital, Taichung, Taiwan
a b s t r a c ta r t i c l e i n f o
Article history:
Received 15 May 2013
Revised 10 August 2013
Accepted 12 August 2013
Available online 30 September 2013
Keywords:
Hypertensive encephalopathy
Epilepsy
Seizure
Reversible posterior leukoencephalopathy
syndrome
Risk factors
Background: To determine whether the diagnosis of hypertensive encephalopathy (HE) is linked to an increased
risk of subsequent epilepsy by using a nationwide population-based retrospective study.
Methods: Our study featured a study cohort and a comparison cohort. The study cohort consisted of all patients
with newly diagnosed HE between 1997 and 2010, compiled from universal insurance claims data on patients
with hypertension taken from the National Health Insurance Research Database. The comparison cohort
comprised the remaining hypertensive patients without encephalopathy. The follow-up period was terminated
followingthe development of epilepsy,death, withdrawalfrom theNational HealthInsurance system, or theend
of 2010. We determined the cumulative incidences and hazard ratios (HRs) of epilepsy development.
Results: The incidence of subsequent epilepsy was 2.25-fold higher in the patients with HE than in comparisons(4.17 vs. 1.85 per 1000 person-years), with an adjusted HR of 2.06 (95% CI = 1.66–2.56) in the multivariable
Cox proportional-hazards regression analysis. The incidence of epilepsy was higher in men, younger patients
with HE, and those with brain disorders.
Conclusions: We found that, in Taiwan, patients with HE are at an increased risk of subsequent epilepsy. Physi-
cians should be aware of HE's link to epilepsy when assessing patients with HE.
© 2013 Elsevier Inc. All rights reserved.
1. Introduction
In 1928, Oppenheimer et al. rst introduced the term “hypertensive
encephalopathy” (HE) to describe acute episodes of several cerebral
phenomena correlated with hypertension [1]. It is now known as an
acute organic brain syndrome characterized by unspecic neurological
symptoms such as headache, visual disturbance, altered mental status,
and seizure [2]. The term “reversible posterior leukoencephalopathy
syndrome” has also been used because the most common abnormality
associated with the syndrome in computed tomography and magnetic
resonance images is edema involving white matter in the parieto-
occipital areas [2–4]. It is suggested that extreme elevation of systemic
blood pressure causes the breakdown of the autoregulatory capability
of the brain vasculature, resulting in associated neurological syndromes
[4]. Although HE is usually reversible, failure to promptly treat the
dramatic rise in blood pressure may lead to fatal consequences. It is an
emergent syndrome that requires correct identication and early man-
agement. Theexactincidenceof HE is unknown. However, hypertensive
crises represent more than one-fourth of all medical emergencies and
can result in acute end-organ injuries such as cerebral infarction, acute
myocardial infarction, heart failure, acute renal failure, and HE [5].
Epilepsy is commonly concomitant with acute episodes of HE, most
likely because of the irritation caused by transudate in the interstitium.
However, the probability and frequency of epilepsy in the durable
follow-up of patients with a history of acute episodes of HE remain
unclear. The understanding of this issue may provide information valu-
able to follow-up strategies for patients with HE.
Epilepsy & Behavior 29 (2013) 374–378
⁎ Corresponding author at: Graduate Institute of Clinical Medicine Science and School of
Medicine, China Medical University, 2 Yuh-Der Road Taichung 404, Taiwan. Fax: +886 4
2233 6174.
E-mail address: [email protected] (C.-H. Kao).1 Tzu-Tsao Chung and Chi-Yu Lin contributed equally to this work.
1525-5050/$ – see front matter © 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.yebeh.2013.08.013
Contents lists available at ScienceDirect
Epilepsy & Behavior
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y e b e h
http://-/?-http://-/?-http://-/?-http://dx.doi.org/10.1016/j.yebeh.2013.08.013http://dx.doi.org/10.1016/j.yebeh.2013.08.013http://dx.doi.org/10.1016/j.yebeh.2013.08.013mailto:[email protected]://dx.doi.org/10.1016/j.yebeh.2013.08.013http://www.sciencedirect.com/science/journal/15255050http://crossmark.crossref.org/dialog/?doi=10.1016/j.yebeh.2013.08.013&domain=pdfhttp://www.sciencedirect.com/science/journal/15255050http://localhost/var/www/apps/conversion/tmp/scratch_5/Unlabelled%20imagehttp://dx.doi.org/10.1016/j.yebeh.2013.08.013http://localhost/var/www/apps/conversion/tmp/scratch_5/Unlabelled%20imagemailto:[email protected]://dx.doi.org/10.1016/j.yebeh.2013.08.013http://-/?-http://-/?-
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In this study, we investigated whether the diagnosis of HE is linked
to an increased risk of developing subsequent epilepsy by using the
Taiwanese National Health Insurance Research Database (NHIRD). The
database is available to researchers in Taiwan and has been extensively
used in epidemiologic studies [6]. The wide coverage of this large,
nationwide database allowed us to examine the relationship between
HE and the subsequent development of epilepsy.
2. Materials and methods
2.1. Data sources
This retrospective study used data retrieved from several claimsles
of the NHIRD, managed by Taiwan's National Health Insurance Research
Institute (NHRI) at the Department of Health. The universal National
Health Insurance (NHI) program was implemented in March 1995
in Taiwan and covered approximately 99% of the total 23.74-million
residents in 2009. This study analyzed the nationwide population-
based database released by the NHRI from 1996 to 2010 for academic
and administrative use. The NHI database includes information on the
basic patient demographic status, medical institutions, details of inpa-
tient orders, ambulatory care, expenditures for care, and physicians
providing services. To protect patient privacy, all patient-level informa-
tion can be retrieved and linked only through scrambled personal iden-
tication. This study was approved by theEthics Review Board of China
Medical University (CMU-REC-101-012).
2.2. Study patients
We identied patients with a diagnosis of hypertension (ICD-9-CM
codes 401–405) from claims data for inpatients for 1997–2010. Patients
aged 20 years and older with newly diagnosed HE (ICD-9-CM code
437.2) were selected for the study cohort. The inpatient diagnosis date
was denedas the index date. Thecomparison cohort wasrandomly se-
lectedfrom therest of the hypertensive patients without a history of HE.
For each patient in the study cohort, 4 comparisons were randomly se-
lected, frequency-matched by sex, age (every 5-year span),and theyear
of the index date. Patients with any record of epilepsy and/or stroke(ICD-9-CM codes 430–438) before the index date were excluded. In
order to exclude acute provoked seizure, we set a lag time of 1 week
to exclude those who had seizures in the rst week after the diagnosis
of HE. Thus, 5 patients were excluded: 3 in the study cohort and 2 in
the comparison cohort.
2.3. Outcome measures
Both cohorts were followed from the index date to the date the pa-
tients received the diagnosis of epilepsy (ICD-9-CM code 345) or until
the patients were censored because of lack of follow-up, death, with-
drawal from the NHI system, or the end of 2010. Because epilepsy was
an emergent and critical condition clinically, we believed that physi-
cians made the diagnosis with caution. We supposed that one codingof345 was enoughto dene the epilepsy. The comorbidities considered
in this study included head injury (ICD-9-CM codes 850–854, 959.01),
meningitis (ICD-9-CM codes 0130, 0360,0470, 0471, 0478, 0479, 0490,
0491, 0530, 0721, 0942, 1142, 320, 321, 322, 00321, 05472, 09042,
09181, 09882, 10081, 11283, 11501, 11591), encephalitis (ICD-9-CM
codes 0136, 0361, 0462, 0520, 0550, 0722, 1390, V050, 062, 063, 064,
323, 09041, 09481), multiple sclerosis (ICD-9-CM code 340), and alco-
holism (ICD-9-CM codes 303, 305.00, 305.01, 305.02, 305.03, V11.3).
2.4. Statistical analysis
The sociodemographic distribution and prevalence of comorbidities
were compared between the study and comparison cohorts and exam-
ined using theχ 2
test.The sex-, age-, and comorbidity-specic incidence
densities of epilepsy were measured and compared for both cohorts.
Poisson regression was used to estimate an incidence rate ratio (IRR)
and a 95% condence interval between the study cohort and the
comparison cohort. Multivariate Cox proportional-hazards regression
analysis was used to estimate the risk of epilepsy in association
with HE, controlling for sociodemographic factors and comorbidities.
The follow-up years were partitioned into 4 segments (≤3 years,
3–6 years, 6–9 years, and N 9 years) to observe the change in epilepsy
hazard. The cumulative incidence of epilepsy for both the studyand the comparison cohorts was calculated using the Kaplan–Meier
method, and the difference was tested using the log-rank test. The
analyses were performed using the SAS statistical package (version
9.2; SAS Institute Inc., Cary, NC, USA), and the Kaplan–Meier survival
curve was plotted using R software (R Foundation for Statistical
Computing, Vienna, Austria). The statistical signicance was accepted
at an α-value of 0.05.
3. Results
Among patientswith hypertensionbut freefrom stroke,we identied
5766 patients with HE for the study cohort and selected 23,074 patients
for the comparison cohort. Patients in both cohorts were predominantly
female and over 65 years of age. Comorbidities were more prevalent
in the study cohort than in the comparison cohort, particularly for head
injury, meningitis, encephalitis, and alcoholism (Table 1).
The incidence of epilepsy in the study cohort was 2.26-fold greater
than that in the comparison cohort (4.17 vs. 1.85 per 1000 person-
years), with an adjusted HR of 2.06 (95% CI: 1.66–2.56) (Table 2). Men
were at higher risk than women to have epilepsy in both cohorts. The
HE to non-HE adjusted HR was also higher for males than for females
(2.27 vs. 1.84). Age-specic data showed that epilepsy incidence was
the highest in patients with HE 20–39 years of age, although there
were more cases of epilepsy in the older groups. The study cohort to
comparison cohort relative risk of epilepsy was the highest for those
aged 40–64 years old, with an adjusted HR of 2.59 (p b 0.001).
Table 2 also shows that epilepsy incidence increased for those with co-
morbidity, with the highest incidence for those with meningitis,
followed by those with encephalitis, alcoholism, and head injury.Theincidence of epilepsy wasconsistently higherin thestudy cohort
with HE than in the comparison cohort during the follow-up period
(Table 3). The incidence of epilepsy was the highest during the initial
3 years after HE diagnosis with an adjusted HR of 3.03 compared with
the corresponding comparisons. The cumulative incidence curve for
Table 1
Demographic characteristics and comorbidity in patients with and without hypertensive
encephalopathy.
Variable Hypertensive encephalopathy p-Valuea
No Yes
N = 23,074 N = 5766
n (%) n (%)
Sex
Female 13,210 (57.3) 3303 (57.3) 0.99
Male 9864 (42.8) 2463 (42.7)
Age, median (IQR) 69.5 (59.1–77.0) 69.5 (59.1–76.9) 0.84b
Stratied age
20–39 648 (2.81) 161 (2.79) 0.99
40–64 8024 (34.8) 2004 (34.8)
65+ 14,402 (62.4) 3601 (62.4)
Comorbidity
Head injury 2541 (11.0) 1190 (20.6) b0.0001
Meningitis 103 (0.45) 49 (0.85) 0.0002
Encephalitis 48 (0.21) 22 (0.38) 0.02
Multiple sclerosis 8 (0.03) 2 (0.03) 0.30
Alcoholism 232 (1.01) 84 (1.46) 0.003
a Chi-square test.b
Mann–
Whitney U test.
375T.-T. Chung et al. / Epilepsy & Behavior 29 (2013) 374– 378
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epilepsy showed that the study cohort had a signicantly higher risk of
epilepsy than the comparison cohort (log-rank test b 0.0001) (Fig. 1).
4. Discussion
To the best of ourknowledge, this study is the rst attempt to inves-
tigate the risk of epilepsy among patients with HE after adjusting for
patient comorbid medical disorders by using a nationwide population-
based data set. Our study shows that the likelihood of epilepsy develop-
ment is 2.06-fold greater among patients with HE than among hyper-
tensive patients without encephalopathy. Furthermore, we found that
patients with HE with comorbidities of head injury, meningitis, and
alcoholism were at an additionally higher risk of epilepsy than those
without the comorbidities.
The overall demographic-specic incidence of epilepsy after strati-
ed analyses of sex and age is signicantly higher in the cohort with
HE than in the comparison cohort. We found that the relative risk of
epilepsy was higher in men than in women (adjusted HR = 2.27 vs.
1.84), concurring with well-established databases of sex comparisons
in epilepsy [7].
Moreover, the relative incidence of epilepsy is still higher in the
long-term follow-up, further conrming that the risk of epilepsy in
patients with HE is “truly” increased. Furthermore, approximately half
of epilepsy diagnoses occurred within the initial 3 years after the rst
Table 2
Incidence of epilepsy by sex, age, and comorbidity and Cox model-measured hazards between patients with and without hypertensive encephalopathy.
Hypertensive encephalopathy
No Yes
Variables Event PY Ratea Event PY Ratea IRR b (95% CI) Adjusted HR (95% CI)
Allc 288 155,664 1.85 119 28,513 4.17 2.26 (2.08, 2.44)⁎⁎⁎ 2.06 (1.66, 2.56)⁎⁎⁎
Sexd
Female 145 89,951 1.61 53 16,939 3.13 1.94 (1.74, 2.17)⁎⁎⁎ 1.84 (1.34, 2.53)⁎⁎⁎
Male 143 65,713 2.18 66 11,574 5.70 2.61 (2.33, 2.94)⁎⁎⁎
2.27 (1.69, 3.07)⁎⁎⁎
Stratied agee
20–39 13 4526 2.87 5 920 5.43 1.89 (1.21, 2.96)⁎⁎ 1.58 (0.54, 4.61)
40–64 80 63,902 1.25 45 12,049 3.73 2.98 (2.62, 3.40)⁎⁎⁎ 2.59 (1.78, 3.76)⁎⁎⁎
65+ 195 87,236 2.24 69 15,545 4.44 1.99 (1.79, 2.20)⁎⁎⁎ 1.83 (1.38, 2.42)⁎⁎⁎
Comorbidity
Head injuryf
No 212 137,599 1.54 87 22,414 3.88 2.52 (2.31, 2.75)⁎⁎⁎ 2.55 (1.98, 3.27)⁎⁎⁎
Yes 76 18,065 4.21 32 6100 5.25 1.25 (1.02, 1.53)⁎ 1.23 (0.81, 1.87)
Meningitisg
No 281 155,051 1.81 113 28,285 4.00 2.20 (2.03, 2.39)⁎⁎⁎ 2.06 (1.65, 2.57)⁎⁎⁎
Yes 7 613 11.4 6 228 26.3 2.30 (1.07, 4.97)⁎ 2.00 (0.59, 6.80)
Encephalitish
No 286 155,309 1.84 118 28,437 4.15 2.25 (2.08, 2.44)⁎⁎⁎ 2.05 (1.64, 2.55)⁎⁎⁎
Yes 2 356 5.62 1 76 13.2 2.33 (0.57, 9.51) 2.21 (0.14, 34.7)
Multiple sclerosisi
No 288 155,597 1.85 119 28,511 4.17 2.26 (2.08, 2.44)⁎⁎⁎ 2.06 (1.66, 2.56)⁎⁎⁎
Yes 0 67 0.00 0 2.74 0.00 – –
Alcoholism j
No 279 154,099 1.81 116 28,039 4.14 2.29 (2.11, 2.48)⁎⁎⁎ 2.10 (1.68, 2.62)⁎⁎⁎
Yes 9 1566 5.75 3 474 6.33 1.10 (0.56, 2.18) 1.06 (0.28, 4.00)
a Incidence rate per 1000 person-years.b Incidence rate ratio.c Adjusted HR was calculated by Cox proportional hazard regression and adjusted for age, sex, head injury, meningitis, encephalitis, and alcoholism.d Adjusted HR was calculated by Cox proportional hazard regression stratied by sex and adjusted for age, head injury, meningitis, encephalitis, and alcoholism.e Adjusted HR was calculated by Cox proportional hazard regression stratied by age and adjusted for sex, head injury, meningitis, encephalitis, and alcoholism.f Adjusted HR was calculated by Cox proportional hazard regression stratied by head injury and adjusted for age, sex, meningitis, encephalitis, and alcoholism.g Adjusted HR was calculated by Cox proportional hazard regression stratied by meningitis and adjusted for age, sex, head injury, encephalitis, and alcoholism.h Adjusted HR was calculated by Cox proportional hazard regression stratied by encephalitis and adjusted for age, sex, head injury, meningitis, and alcoholism.i Adjusted HR was calculated by Cox proportional hazard regression stratied by multiple sclerosis and adjusted for age, sex, head injury, meningitis, encephalitis, and alcoholism. j Adjusted HR was calculated by Cox proportional hazard regression stratied by alcoholism and adjusted for age, sex, head injury, meningitis, and encephalitis.
⁎ p b 0.05.⁎⁎ p b 0.01.
⁎⁎⁎ p b 0.001.
Table 3
Hazard ratio for epilepsy compared between patients with and without hypertensive encephalopathy by follow-up duration.
Hypertensive encephalopathy
Follow-up timea No Yes IRR c (95% CI) Adjusted HR (95% CI)
Event PY Rateb Event PY Rateb
≤3 years 88 61,247 1.44 59 12,699 4.65 3.23 (2.98, 3.51)⁎⁎⁎ 3.03 (2.17, 4.23)⁎⁎⁎
3–6 years 89 46,898 1.90 29 8414 3.45 1.82 (1.63, 2.02)⁎⁎⁎ 1.65 (1.08, 2.52)⁎
6–9 years 72 30,892 2.33 20 4990 4.01 1.72 (1.51, 1.96)⁎⁎⁎ 1.48 (0.90, 2.45)
N9 years 39 16,625 2.35 11 2410 4.56 1.95 (1.63, 2.32)⁎⁎⁎ 1.57 (0.78, 3.17)
a Adjusted HR was calculated by Cox proportional hazard regression stratied by follow-up duration and adjusted for age, sex, head injury, meningitis, encephalitis, and alcoholism.b Incidence rate per 1000 person-years.c Incidence rate ratio.⁎ p b 0.05.
⁎⁎ p b 0.01.⁎⁎⁎
p b
0.001.
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episode of HE, with a decreased relative incidence of epilepsy in the
prolonged follow-up. In a recent meta-analysis, the estimated median
incidence of epilepsy was 0.504 per 1000 person-years [8]. However,
the overall incidence of epilepsy in our study was high, with a rate
of 4.17 per 1000 person-years in the cohort with HE and 1.85 per
1000 person-years in the comparison cohort. This is probably because
the participants were relatively older; 62.4% of both cohorts were age
65 or older. However, the age-specic incidence of epilepsy was the
lowest for those aged 40–64, indicating a U-shape association with
age. With the highest incidence of epilepsy, younger patients with HE
deserve greater attention after the diagnosis of HE.
Changes in the degree of hypertension can generate the auto-
regulatory dysfunction of cerebral blood ow [9]. Recent reports assertthat HE occurs in 15%–20% of patients in whom malignanthypertension
was present [10,11]. It is an acute organic brain syndrome resulting
from disrupted autoregulation of cerebral blood ow. An acute pro-
voked seizure is a frequently concomitant with HE [2,12]. There may
be generalized, focal, or focal with secondarily generalized tonic–clonic
convulsions. The pathogenesis of acute provoked seizure following HE
is incompletely understood. It seems to be the irritative effects of the
uid in the brain interstitium related to cytotoxic edema or vasogenic
edema [1,3,13–15]. The cytotoxic edema results from the infarction
caused by thrombosis of arterioles and brinoid necrosis [13–15].
Conversely, vasogenic edema is related to hypertensive cerebrovascular
endothelial dysfunction or disruption of the blood–brain barrier with
increased permeability [3,9,15]. However, the disruption is the most
widely accepted basis for HE [16]. Therefore, to reduce acute provokedseizure, neuroprotection following diagnosis of HE deserves further re-
search. The pathogenesis of later spontaneous unprovoked seizures, the
endpoint of thepresent study, is even less studied and discussed. It may
reect more permanent structural and physiologic changes within the
brain. We found an increased risk of later epilepsy in patients with HE.
This may provide the basis of ongoing research on the pathogenesis
and prevention strategy of later spontaneous unprovoked seizures in
patients with HE.
The timing of the most development of spontaneous unprovoked
seizures after HE is important. We found that most of the seizures hap-
pened in therst3 years even though theincreased incidenceof epilep-
sy was found within 6 years after occurence of HE. This pattern is
similar to that of epilepsy after a traumatic brain injury. Approximately
40% of individuals with epilepsy after head trauma have onset within
6 months, 50% within 1 year, and 80% within 2 years [17,18]. The
more severe the head injury, the longer the patient is at risk for late sei-
zures. This information has implications in the follow-up strategy and
management of patients with HE.
A particular strength of this study is the use of a nationwide
population-based data set that provides a suf cient samplesize and sta-
tistical power to explore the link between HE and epilepsy. In addition,
thepatients in our study displayed a wide range of demographic charac-
teristics, which allowed us to perform strati
ed analyses according tosex, age, and comorbidities. Nevertheless, some insuf ciencies in our
study should be addressed. First, additional theoretically relevant con-
founding variables such as smoking, diabetes, and a family history of
epilepsy could not be included in our analysis because they were not in-
cluded in our data set. Further study is needed to clarify the effects
of these factors. Second, we might not be able to completely exclude
study subject “misclassication”. A patient with HE, with symptoms of
headache, visual disturbance, and altered mental status but no seizure,
might not seek medical advice and may thus be misclassied as having
hypertension only and be included in the comparison cohort. We be-
lieved that this probability was extremely low because few patients
would tolerate acute HE symptoms without medical intervention.
Moreover, our patients could seek medical advice easily because of the
high accessibility of medical services in Taiwan.
5. Conclusion
We found that the risk for epilepsy in Taiwan was approximately
2.24-fold greater among patients who had been previously diagnosed
with HE compared to those who had not and that this association was
entirely independent of age, sex, head injury, meningitis, encephalitis,
alcoholism, and multiple sclerosis. Thus, physicians should be aware
of HE's link to epilepsy when assessing patients with HE. Furthermore,
because approximately half of the epilepsy diagnoses occurred within
3 years from the onset of HE, routine follow-up examinations and con-
trol of blood pressure should be performed for at least 3 years.
Contributors
Conception/design: Tzu-Tsao Chung, Chi-YuLin, and Chia-Hung Kao.
Provision of study material or patients: Wen-Yen Huang, Cheng-Li
Lin, and Fung-Chang Sung.
Collection and/or assembly of data: Cheng-Li Lin and Fung-Chang
Sung.
Data analysis and interpretation: Tzu-Tsao Chung, Chi-Yu Lin,
Wen-Yen Huang, Fung-Chang Sung, and Chia-Hung Kao.
Manuscript writing: All authors.
Final approval of manuscript: All authors.
Conict of interest
All authors state that they have no conicts of interest.
Acknowledgments
The study was supported in part by the study projects (DMR-101-
061 and DMR-100-076) in China Medical University hospital, the
Taiwan Department of Health Clinical Trial and Research Center and
for Excellence (DOH102-TD-B-111-004), and the Taiwan Department
of Health Cancer Research Center for Excellence (DOH102-TD-C-111-
005). The funders had no role in study design, data collection and anal-
ysis, decision to publish, or preparation of the manuscript.
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Fig. 1. Cumulative incidence of epilepsy compared between cohorts with and without
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377T.-T. Chung et al. / Epilepsy & Behavior 29 (2013) 374– 378
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