Patients with epilepsy are at an increased risk of subsequent stroke: A population-based cohort study

Seizure 23 (2014) 377–381

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Patients with epilepsy are at an increased risk of subsequent stroke: A population-based cohort study Chen-Shu Chang a,b,1, Chun-Hui Liao c,d,1, Che-Chen Lin e, Hsien-Yuan Lane c,d, Fung-Chang Sung d,e,*, Chia-Huang Kao d,f,** a

Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan Department of Medical Laboratory Science and Biotechnology, and Medical Imaging and Radiological Sciences, Central Taiwan University of Science and Technology, Taichung, Taiwan c Department of Psychiatry, China Medical University Hospital, Taichung, Taiwan d Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan e Management Office for Health Data, China Medical University, Taichung, Taiwan f Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan b

A R T I C L E I N F O

A B S T R A C T

Article history: Received 3 October 2013 Received in revised form 17 January 2014 Accepted 14 February 2014

Purpose: Epilepsy is well known as a disorder in poststroke patients. However, studies that have investigated the association between epilepsy and the risk of subsequent stroke are limited. This population-based study investigated the incidence and risk of stroke in patients with epilepsy by using the Taiwan National Health Insurance claims data. Methods: We identified 3812 patients newly diagnosed with epilepsy in 2000–2008 and 15,248 nonepilepsy comparisons frequency matched according to sex, age, and index year. We searched for subsequent stroke diagnoses in both cohorts until the end of 2009. The incidence rates and hazard ratios of stroke were estimated based on sex, age, the average defined daily doses (DDDs) of antiepilepsy drugs, and comorbidity. Results: The stroke incidence of the epilepsy cohort was 3-fold higher than that of the comparison cohort. The age-specific results indicated that in the epilepsy cohort and the comparison cohort, the risk was the highest for the youngest group (20–39 years). Conclusion: The patients with epilepsy exhibited a higher incidence of cerebral stroke than the general population did. In addition, younger patients with epilepsy and patients who took a high doses of antiepileptic drugs exhibited a high risk of stroke. ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Keywords: Comorbidity Epilepsy Stroke Insurance claims data Retrospective cohort study

1. Introduction Previous studies have determined that patients with epilepsy developed a wider range of medical and neurologic disorders, compared with the general population.1,2 The comorbidities include somatic disorders, such as cardiac, gastrointestinal, and respiratory disorders, metabolic and endocrine disorders, stroke,

* Corresponding author at: Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan. ** Corresponding author at: Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. Tel.: +886 4 22052121x7412; fax: +886 4 22336174. E-mail address: [email protected] (C.-H. Kao). 1 Both authors contributed equally.

dementia, and migraines.3–7 Numerous epidemiological studies have reported that patients with epilepsy exhibited a higher mortality rate than did the general population. Stroke was one of the major fatal causes.8–11 Using certain antiepileptic drugs (AEDs) has been associated with an increased risk of atherosclerosis,12 suggesting that these drugs could be responsible for increased cardiovascular risk in patients with epilepsy.13 According to a review of relevant literature, we concluded that patients with epilepsy are at a higher risk of stroke than the general population is.14,15 However, previous studies might have been limited by a cross-sectional design, small sample sizes, or confounding effects. Epilepsy is well known as a disorder in poststroke patients.16–18 Studies that have investigated the association of epilepsy with the risk of subsequent stroke are limited.3,5 This study used the UK General Practice Research Database, which indicated a relative

http://dx.doi.org/10.1016/j.seizure.2014.02.007 1059-1311/ß 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

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hazard of 2.89 for stroke in patients presenting with seizers in late-life.5 The risk remains unclear regarding young patients with epilepsy. We used the National Health Insurance (NHI) Research Database to evaluate the risk of stroke among adult patients with epilepsy in a 10-year follow-up period. This population-based retrospective cohort study addressed the epilepsy-cerebral stroke link, considering the associations with sex, age, the average defined daily doses (DDDs) of antiepilepsy drugs, and comorbidities.

recategorized into 3 subcohorts according to the tertile cutpoint of the average DDDs. Information on potential confounders, such as demographic factors or the comorbidity of stroke, were also collected in this study. The comorbidities used in this study were hypertension (ICD-9-CM 401–405) and hyperlipidemia (ICD-9-CM 272), both of which were diagnosed at least 3 times; diabetes mellitus (DM)(ICD-9-CM 250), diagnosed at least 2 times; coronary artery disease (CAD)(ICD-9-CM 410–413, 414.0, 414.8, and 414.9); and AF (ICD-9-CM 427.3), diagnosed once.

2. Methods 2.3. Statistical analysis 2.1. Data source Taiwan officially commenced the NHI program in March 1995, providing universal health insurance to 99% of the population and 92% of the medical institutions in Taiwan were included in the system.19–21 This study used the Longitudinal Health Insurance Database, which includes historical claims data from 1996 to 2009 for 1 million people randomly sampled by the National Health Research Institute (NHRI) from the entire insured population registered in 2000. Disease diagnoses were coded using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) for the diagnosis of disease. The outpatient claims data consisted of 3 diagnoses, and the inpatient claims data consisted of 5 diagnoses, accompanied by detailed pharmaceutical prescriptions and treatment procedures. The NHRI scrambled patient identifications and used surrogate numbers to secure patient privacy. The present study was approved by the ethics committee at China Medical University and Hospital. 2.2. Study population To increase the validity of the diagnoses, we selected patients newly diagnosed with epilepsy in 2000–2008 (ICD-9-CM, code 345), who were prescribed antiepileptic drugs, as the epilepsy cohort.18 The index date of the epilepsy cohort was set as the epilepsy diagnosis date. Patients in the comparison cohort were randomly selected from individuals who were free from epilepsy in 1996–2008 and frequency matched according to sex, age (per 5 years), and all comorbidities, except for atrial fibrillation (AF) (AF was not included in the frequency criteria because of low AF prevalence in individuals without epilepsy; however, the proportion of AF in the epilepsy cohort was 2.0%, and that in the comparison cohort was 1.0%), yielding a 4-fold sample size. The index date for the comparison cohort was randomly assigned the same month and day as the index year of the matched case. The follow-up time was terminated on the date of stroke event diagnosis, withdrawal from the insurance program, or on December 31, 2009. The event of interest in the study was a subsequent new stroke event (ICD-9-CM 430–438), which was determined by brain imaging, that was identified using the inpatient file. We also distinguished the stroke events as either ischemic strokes (ICD-9-CM 433–438) or hemorrhagic strokes (ICD-9-CM 430–432), excluding stroke patients aged less than 20 years. We also calculated the average DDDs of AEDs in the epilepsy cohort as the total sum of AEDs used during the observation time divided by the total follow-up duration (DDD/year). The AEDs were phenytoin (ATC code: N03AB02), carbamazepine (ATC code: N03AF01), gabapentin (ATC code: N03AX12), levetiracetam (ATC code: N03AX14), oxcarbazepine (ATC code: N03AF02), tiagabine (ATC code: N03AG06), topiramate (ATC code: N03AX11), vigabatrin (ATC code: N03AG04), phenobarbital (ATC code: N03AA02), and valproate (ATC code: N03AG01). The epilepsy cohort was

We used Chi-square tests to examine the categorical variables and t tests to examine the continuous variables to compare the characteristics between the epilepsy and comparison cohorts. The incidence of stroke in the 2 groups was determined. Compared with the comparison cohort, the hazard ratio (HR) and 95% confidence interval (CI) of stroke for the epilepsy cohort were estimated using the Cox proportional hazards regression model after adjusting for AF. The Kaplan–Meier method was used to evaluate the stroke-free curves of stroke for the epilepsy and comparison cohorts, and the variations in the curves were examined using logrank tests. Statistical analysis and data management were performed using the Statistical Analysis System (SAS) 9.3 (SAS Institute Inc., Cary, NC, USA), and the survival curve was determined using R 2.13.0 (The R Foundation for Statistical Computing, Vienna, Austria). A P value less than 0.05 was considered significant. 3. Results This study used 15,248 comparison individuals and 3812 patients with epilepsy, yielding a mean age of 50 years, and 41.7% of the participants were women (Table 1). Except for AF, the distribution of all the comorbidities between the epilepsy and comparison cohorts was similar (P > .99). The results of using the Kaplan–Meier model shown in Fig. 1 indicated that the cumulative incidence of stroke for the epilepsy cohort was significantly higher than that for the comparison cohort (logrank test < 0.0001). The incidence of stroke was approximately 3-fold higher in the epilepsy cohort than in the comparison cohort (24.08 vs. 7.96 per 1000 person-year), yielding an HR of 2.92 (95% CI = 2.58–3.30) after adjusting for AF (Table 2). The incidence of ischemic stroke was nearly 3-fold higher than that of hemorrhagic stroke for both cohorts. Compared with the comparison cohort, the epilepsy cohort exhibited HRs of 2.85 (95% CI = 2.49–3.26) for ischemic stroke and 3.30 (95% CI = 2.46–4.43) for hemorrhagic Table 1 Characteristic of the study population. Variable

Age, mean (SD)a 20–39 40–59 360 Sex Female Male Comorbidity Hypertension AF CAD Diabetes Hyperlipidemia a

t-Test.

Comparison cohort

Epilepsy cohort

N = 15,248 (%)

N = 3812 (%)

50.0 (18.2) 5116 (33.6) 5436 (35.7) 4696 (30.8)

50.1 (18.3) 1279 (33.6) 1359 (35.7) 1174 (30.8)

6352 (41.7) 8896 (58.3)

1588 (41.7) 2224 (58.3)

5540 145 2084 2284 2916

1385 78 521 571 729

P-Value

0.9082 >0.99

>0.99

(36.3) (1.0) (13.7) (15.0) (19.1)

(36.3) (2.0) (13.7) (15.0) (19.1)

>0.99 <0.0001 >0.99 >0.99 >0.99

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Fig. 1. The Kaplan–Meier model used to measure the cumulative incidence curve for stroke in the study cohort.

stroke. Relative to the comparison cohort, the epilepsy patient who had the lowest dose of AED exposure exhibited a 1.30-fold increased risk of developing stroke (HR = 1.30, 95% CI = 1.03–1.64), and the epilepsy patient who had the highest dose of AED exposure exhibited the greatest increased risk of stroke (HR = 5.84, 95% CI = 5.02–6.80). The results also indicated that the risk of overall stroke, ischemic stroke, and hemorrhagic stroke occurrences increased as AED exposure increased (P for trend < .0001). Table 3 shows the stratification analysis for the risk of subsequent stroke and the demographic factor and comorbidity statuses of the study cohorts. The stroke risk was higher for men than for women and increased as age increased. However, the age-specific HR for the epilepsy cohort, compared with that of the comparison cohort, was highest in the young patients aged 20– 39 years (HR = 8.88, 95% CI = 5.71–13.82). Regarding the patients not presenting with comorbidities, the epilepsy cohort exhibited an adjusted HR of 5.88 (95% CI = 4.58–7.56) for stroke, compared with the comparison cohort. The comorbidity-specific adjusted HR for the epilepsy cohort ranged between 1.93 and 2.66, compared with the comparison cohort. 4. Discussion After adjusting for potential confounding factors, including demographic factors and the comorbidity of stroke, the results of the present study indicated that the incidence of ischemic stroke

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for the patients with epilepsy was significantly higher than that for the patients in the comparison cohort. The men were at a higher risk of ischemic stroke than the women were in this study. Cleary et al. determined that patients who presented with seizures after 60 years of age exhibited a substantial risk of stroke.5 Another study determined that epilepsy may increase the risk of cardiovascular disease and stroke.22 We also observed a sharp increase in the incidence of stroke as age increased. The incidence was 6.3-fold higher for the patients aged 60 years than for those aged 20–39 years in the epilepsy cohort. No previous comprehensive studies have compared the age-specific incidence of stroke in patients with epilepsy. Based on our research, this is the first study to document such findings by examining data that were based on a generalized population-based cohort. Cerebral stroke is a heterogeneous disease that comprises several subtypes consisting of different etiologies.23 Traditional cardiovascular risk assessments for each sex include standard lipid measurements (e.g., total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol) and assessments of nonlipid risk factors (e.g., hypertension or diabetes mellitus). These conditions interact to promote atherosclerosis formation, which is the artery-clogging process that causes heart attacks and strokes.24,25 Specific diseases, such as carotid stenosis, AF, and lifestyle-related factors (e.g., smoking, absence of regular exercise, and being overweight) are well-known stroke risk factors.26 Previous studies have determined that statin could potentially prevent epilepsy.27,28 No increase in vascular risk factors was observed in patients with epilepsy29; therefore, we attempted to control the comorbidities between the epilepsy and comparison cohorts in this study. In the data obtained in the present study, the comorbidity-specific HR of stroke risk suggested that the epilepsy cohort and control group presenting with hypertension, diabetes, CAD, and hyperlipidemia exhibited a significantly high risk of stroke. Several studies have reported that the plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, and its components increased in patients who were prescribed longterm carbamazepine (CBZ),30,31 phenobarbital, or VPA therapy.32,33 Dyslipidemia causes atherosclerosis in arterial vessels.34 Increased body weight, which is a frequently encountered side effect associated with long-term VPA use,35,36 plays a modulatory role in promoting these risks of vascular injury.37,38 Prospective studies have established that increased carotid artery intimamedia thickness (CIMT) is involved in subsequent hypertension and dyslipidemia in adults, and that increased CIMT typically occurs in association with an increased incidence of acute cardiovascular and cerebrovascular events.39 High CIMT values, increased plaque scores, the number of plaques, and the degree of carotid stenosis have been correlated with cerebrovascular disorder.40 This study determined that the relationship between the risk of stroke and AEDs was dose-dependent.

Table 2 The incidence and hazard ratio for stroke. All stroke Event 653 Comparison Epilepsy 427 Anti-epilepsy drug useda <5 DDD 78 5–69 DDD 121 370 DDD 228 P for trend

Ischemic

Hemorrhagic

Rate

aHR

Event

Rate

aHR

Event

Rate

aHR

7.96 24.08

Ref 2.92(2.58–3.30)

547 349

6.67 19.68

Ref 2.85(2.49–3.26)

106 78

1.29 4.40

Ref 3.30(2.46–4.43)

10.44 21.31 49.77

1.30(1.03–1.64) 2.58(2.13–3.14) 5.84(5.02–6.80) <0.0001

61 102 186

8.16 17.96 40.60

1.21(0.93–1.58) 2.60(2.10–3.21) 5.68(4.81–6.72) <0.0001

17 19 42

2.27 3.35 9.17

1.75(1.05–2.92) 2.51(1.54–4.10) 6.69(4.67–9.58) <0.0001

Model adjusted for AF. aHR: adjusted hazard ratio; rate: incidence rate, per 1000 person-year. a Average DDD, per year.

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Table 3 Cox proportional hazards regression estimated hazard ratio of stroke for study cohorts with/without comorbidity and demographic factors. Variables

Sex Female Male Age group 20–39 40–59 360 Without any comorbidity Hypertension No Yes AF No Yes CAD No Yes Diabetes No Yes Hyperlipidemia No Yes

Comparison cohort

Epilepsy cohort

aHR (95% CI)

Event

PYs

254 399

35,349 46,680

7.19 8.55

138 289

7925 9808

17.41 29.46

2.35(1.91–2.89) 3.32(2.85–3.87)

29 124 500 107

29,725 30,341 21,963 47,217

0.98 4.09 22.77 2.27

61 132 234 142

7002 6476 4256 10,521

8.71 20.38 54.99 13.50

8.88(5.71–13.82) 4.89(3.83–6.26) 2.32(1.99–2.71) 5.88(4.58–7.56)

154 499

54,958 27,071

2.80 18.43

180 247

12,172 5562

14.79 44.41

5.17(4.17–6.41) 2.33(2.00–2.71)

625 28

81,527 501

7.67 55.86

406 21

17,537 197

23.15 106.48

2.99(2.64–3.39) 1.93(1.09–3.42)

457 196

72,651 9377

6.29 20.9

339 88

15,745 1989

21.53 44.25

3.32(2.88–3.82) 2.04(1.59–2.63)

453 200

71,276 10,753

6.36 18.6

335 92

15,627 2107

21.44 43.66

3.26(2.83–3.76) 2.27(1.77–2.91)

462 191

67,571 14,457

6.84 13.21

317 110

14,687 3047

21.58 36.10

3.05(2.64–3.52) 2.66(2.10–3.36)

Rate

Event

PYs

Rate

Model adjusted for AF. aHR: adjusted hazard ratio; rate: incidence rate, per 1000 person-year.

A marked observation in the present study was that, among the patients in both cohorts who did not present with any comorbidities, the patients in the epilepsy cohort exhibited a 3-fold increased stroke risk, compared with the patients in the comparison cohort. Regarding age, the cumulative data indicated that the young patients (20–39 years) in the epilepsy cohort exhibited a significantly increased stroke risk, compared with the patients in the comparison cohort who were in the same age range. This is a striking finding. The possible reason is the early onset of epilepsy and treatment resistance. We hypothesized that the harmful effects of recurrent epilepsy and vascular risk factors contribute to the overproduction of reactive oxygen species and the oxidation of low-density lipoproteins into atherogenic particles, which play a pivotal role in the pathogenesis of atherosclerosis.41,42 In addition, Hamed et al. provided evidence suggesting that CIMT may increase and various vascular risk factors may worsen in patients with chronic epilepsy and/or are provided treatment with antiepileptic medications.43 In addition, long-term AED therapy may cause low-grade systemic inflammation and increased oxidative stress, which is manifested by a substantially increased CIMT7,44 and high concentrations of highsensitivity C-reactive protein, which are recognized as activators of the extrinsic pathway of the coagulation system.40,45 A positive relationship has been observed between the duration of CBZ, PHT, or VPA monotherapy and the acceleration of atherosclerosis in the CIMT of patients with epilepsy, albeit by using different underlying mechanisms.46 Young epilepsy patients might have been suffering from seizure attacks since childhood and also might have undergone long-term AED therapy, which contribute to the risk of stroke. This population-based study used a large random sample of insured patients and provided a source for exploring the epidemiologic characteristics of cerebral stroke in patients with epilepsy. Nevertheless, the present study presented several limitations. First, the diagnosis of stroke might be overestimated among the epilepsy cohort because mimic stroke may have occurred among the patients with epilepsy,47,48 and no brain images were available to illustrate the unequivocal evidence of a stroke in the database. The evaluation process for identifying seizures and strokes might include brain

images taken by physicians to evaluate the possible etiology. Although image data were unavailable in the claims data that we obtained, we attempted to evaluate the incidence of stroke by referring to the inpatient database, which used a more careful survey for evaluating the diagnoses to prevent possible overestimation. Second, we could not estimate the precise temporal relationships between epilepsy and subsequent stroke occurrence because the index date for the diagnosis of epilepsy might not have been the onset date of the disease. This is because the diagnosis of epilepsy was based on the date registered in the claims data after the patients visited a physician, and because of a possible delay in the diagnosis of epilepsy from the time of initial symptoms.27 Thus, the onset of epilepsy might not be based on the date of diagnosis. We attempted to estimate the incidence of stroke after the diagnosis of epilepsy. Finally, the information on several cardiovascular risk factors, including smoking, body mass index, the actuarial concentrations of lipid profiles, blood glucose levels, blood pressure, the CIMT, education level, and occupation were also unavailable in the database. Furthermore, the DDD provides information on only the prescriptions received by patients; medication adherence and effect information was not available. 5. Conclusion The patients with epilepsy exhibited an increased risk of cerebral stroke even after controlling the comorbidities of stroke risk factors, compared with the patients in the general population. This finding indicates the key epidemiological concerns and risk factors that are involved in the development of stroke in patients with epilepsy. This finding may have implications for the development of prevention strategies that can be employed when treating patients with epilepsy, particularly for high-risk individuals. Author contributors The individual contributions of the authors were as follows. Conception and design: Chen-Shu Chang, Chun-Hui Liao, ChiaHuang Kao; Administrative support: Che-Chen Lin, Hsien-Yuan Lane, Fung-Chang Sung; Collection and assembly of data:

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Chen-Shu Chang, Chun-Hui Liao, Che-Chen Lin; Data analysis and interpretation: Chen-Shu Chang, Chun-Hui Liao, Che-Chen Lin; Manuscript writing: all authors; Final approval of manuscript: all authors. Conflict of interest All of the authors declare no conflict of interest. We confirm that we have read the journal’s position on topics involved in ethical publication and affirm that this report is consistent with those guidelines. Acknowledgments This study was supported by China Medical University Hospital (DMR-96-080, DMR-100-114 and 1MS1), in part by the Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (DOH102-TD-B-111-004), China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM102021169), Tseng-Lien Lin Foundation, Taichung, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. The funders had no role in the study design, data collection, analysis, decision to publish, or preparation of the manuscript. References 1. Boro A, Haut S. Medical comorbidities in the treatment of epilepsy. Epilepsy Behav 2003;4:S2–12. 2. Gaitatzis A, Sisodiya SM, Sander JW. The somatic comorbidity of epilepsy: a weighty but often unrecognized burden. Epilepsia 2012;53:1282–93. 3. Shinton RA, Gill JS, Zezulka AV, Beevers DG. The frequency of epilepsy preceding stroke: case–control study in 230 patients. Lancet 1987;1:11–3. 4. Bigal ME, Lipton RB, Cohen J, Silberstein SD. Epilepsy and migraine. Epilepsy Behav 2003;4:S13–24. 5. Cleary P, Shorvon S, Tallis R. Late-onset seizures as a predictor of subsequent stroke. Lancet 2004;363:1184–6. 6. Elliott JO, Lu B, Shneker B, Charyton C, Layne Moore J. Comorbidity, health screening, and quality of life among persons with a story of epilepsy. Epilepsy Behav 2009;14:125–9. 7. Mintzer S. Metabolic consequences of antiepileptic drugs. Curr Opin Neurol 2010;23:164–9. 8. Cockerell OC, Johnson AL, Sander JW, Hart YM, Goodridge DM, Shorvon SD. Mortality from epilepsy: results from a prospective population-based study. Lancet 1994;344:918–21. 9. Jallon P. Mortality in patients with epilepsy. Curr Opin Neurol 2004;17:141–6. 10. Mohanraj R, Norrie J, Stephen LJ, Kelly K, Hitiris N, Brodie MJ. Mortality in adults with newly diagnosed and chronic epilepsy: a retrospective comparative study. Lancet Neurol 2006;5:481–7. 11. Nilsson L, Tomson T, Farahmand BY, Diwan V, Persson PG. Cause-specific mortality in epilepsy: a cohort study of more than 9000 patients once hospitalized for epilepsy. Epilepsia 1997;38:1062–8. 12. Tan TY, Lu CH, Chuang HY, Lin TK, Liou CW, Chang WN, et al. Long-term antiepileptic drug therapy contributes to the acceleration of atherosclerosis. Epilepsia 2009;50:1579–86. 13. Lopinto-Khoury C, Mintzer S. Antiepileptic drugs and markers of vascular risk. Curr Treat Opt Neurol 2010;12:300–8. 14. Strine TW, Kobau R, Chapman DP, Thurman DJ, Price P, Balluz LS. Psychological distress, comorbidities, and health behaviors among U.S. adults with seizures: results from the 2002 National Health Interview Survey. Epilepsia 2005;46:1133–9. 15. Te´llez-Zenteno JF, Matijevic S, Wiebe S. Somatic comorbidity of epilepsy in the general population in Canada. Epilepsia 2005;46:1955–62. 16. Camilo O, Goldstein LB. Seizures and epilepsy after ischemic stroke. Stroke 2004;35:1769–75. 17. Chadehumbe MA, Khatri P, Khoury JC, et al. Seizures are common in the acute setting of childhood stroke: a population-based study. J Child Neurol 2009;24:9–12. 18. Chen CC, Chen LS, Yen MF, Chen HH, Liou HH. Geographic variation in the age- and gender-specific prevalence and incidence of epilepsy: analysis of Taiwanese National Health Insurance-based data. Epilepsia 2012;53:283–90. 19. Chiang TL. Taiwan’s 1995 health care reform. Health Policy 1997;39:225–39.

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