bmj open€¦ · risk of epilepsy in stroke patients receiving acupuncture treatment: a nationwide...

For peer review only

Risk of epilepsy in stroke patients receiving acupuncture treatment: a nationwide retrospective matched-cohort

study

Journal: BMJ Open

Manuscript ID bmjopen-2015-010539

Article Type: Research

Date Submitted by the Author: 13-Nov-2015

Complete List of Authors: Weng, Shu-Wen; Taichung Hospital, Ministry of Health and Welfare, Department of Chinese Medicine Liao, Chien-Chang; Taipei Medical University Hospital, Department of

Anesthesiology Yeh, Chun-Chieh; University of Illinois, Department of Surgery Chen, Ta-Liang; Taipei Medical University Hospital, Department of Anesthesiology Lane, Hsin-Long; I-Shou University, School of Chinese Medicine for Post-Baccalaureate Lin, Jaung-Geng; China Medical University, School of Chinese Medicine Shih, Chun-Chuan; I-Shou University, School of Chinese Medicine for Post-Baccalaureate

<b>Primary Subject Heading</b>:

Complementary medicine

Secondary Subject Heading: Epidemiology, Public health, Neurology, Health services research

Keywords: Acupuncture, Stroke < NEUROLOGY, Epilepsy < NEUROLOGY

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Risk of epilepsy in stroke patients receiving acupuncture treatment: a nationwide

retrospective matched-cohort study

Short title: Acupuncture reduces post-stroke epilepsy

Shu-Wen Weng,1,2 Chien-Chang Liao,1,3,4,5 Chun-Chieh Yeh,6,7 Ta-Liang Chen,3,4,5,

Hsin-Long Lane,8 Jaung-Geng Lin,1 Chun-Chuan Shih8,9

1School of Chinese Medicine, China Medical University, Taichung, Taiwan

2Department of Chinese Medicine, Taichung Hospital, Ministry of Health and Welfare,

Taichung, Taiwan

3Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan

4School of Medicine, Taipei Medical University, Taipei, Taiwan

5Health Policy Research Center, Taipei Medical University Hospital, Taipei, Taiwan

6Department of Surgery, China Medical University Hospital, Taichung, Taiwan

7Department of Surgery, University of Illinois, Chicago, Illinois, USA

8School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung City,

Taiwan

9Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei

Medical University

*Chien-Chang Liao contributed equally with first author; Jaung-Geng Lin contributed equally

with the corresponding author.

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Correspondence:

Chun-Chuan Shih, MD, PhD

Associate professor

School of Chinese Medicine for Post-Baccalaureate, I-Shou University

No.8, Yida Rd., Jiaosu Village, Yanchao District, Kaohsiung 82445, Taiwan

Tel: 886-2-2765-1125

Fax: 886-2-2765-3230

E-mail: [email protected]; [email protected]; [email protected]

Abstract: 250 words; Text: 2184; Tables: 3; Figures: 1

Keywords: Stroke, epilepsy, acupuncture

List of abbreviations: CI=confidence intervals; HR=hazard ratio; ICD-9-CM=International

Classification of Diseases, 9th Revision, Clinical Modification; NHIRD=National Health

Insurance Research Database

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ABSTRACT

Objective: To investigate the risk of epilepsy for stroke patients with and without receiving of

acupuncture treatment.

Design: Retrospective cohort study.

Setting: This study was based on Taiwan’s National Health Insurance Research Database that

included stroke patients who hospitalized between January 1, 2000 and December 31, 2004.

Participants: We identified 60820 patients with new-diagnosed stroke hospitalization who

aged 20 years and older.

Primary and secondary outcome measures: We compared the incident epilepsy during the

follow-up period until the end of 2009 in stroke patients with and without receiving

acupuncture. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of epilepsy

associated with acupuncture were calculated in multivariate Cox proportional hazard

regressions.

Results: Stroke patients who received acupuncture treatment (11.2 per 1,000 person-years)

experienced a reduced incidence of epilepsy compared to those who did not receive

acupuncture treatment (13.4 per 1,000 person-years), with a HR of 0.81 (95% CI, 0.76 to 0.86)

after adjustment for sociodemographics and coexisting medical conditions. Acupuncture

treatment was associated with a decreased risk of epilepsy, particularly among stroke patients

aged 20-59 years and individuals with hemorrhagic stroke. The probability curve with

log-rank test indicated that stroke patients receiving acupuncture treatment experienced a

reduced probability of epilepsy compared with individuals who did not receive acupuncture

treatment during the follow-up period (p<0.0001).

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Conclusions: Stroke patients who received acupuncture treatment experienced a reduced risk

of epilepsy compared with those without receiving acupuncture treatment. However, these

protective effects associated with acupuncture treatment require further validation using

randomized clinical trials.

Key Words: Acupuncture, epilepsy, stroke, cohort study

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Strengths of this study

First, we used matching procedure with propensity score to reduce the confounding effects.

Second, the multivariate Cox proportional hazard models were use to control the residual

confounding bias. Third, our study had no selection bias because all hospitalized stroke

patients in 2000-2004 in Taiwan were analyzed.

Limitations of this study

First, our data lack of clinical risk scores (such as the National Institute of Health Stroke Scale

or the Barthel index), lesion characteristics (location or size), biochemical measures, and

patients’ lifestyles. Second, preventive administration of antiepileptic medications or other

rehabilitation programs were not considered during the follow-up period. Third, the validity

of diagnostic codes of diseases is also a limitation of the study. In addition, our study could

not validate the actual acupuncture points used in treatment. Finally, the mode of acupuncture

treatment for stroke patients varied among TCM physicians.

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INTRODUCTION

Stroke remains the leading cause of adult disability and death worldwide.[1,2]

Approximately global 5.8 million deaths were attributed to stoke and the one-year cost of

stroke is approximately 30,000 US dollars per patient in 2010 in countries worldwide.[2,3]

Given that strokes occur in 2.8% of adults in the United States, the economic burden of stroke

was $36.5 billion in 2010.[4] In Taiwan, the average of the first-year medical costs after

stroke was 5,679 US dollars per patient.[5] Epilepsy, depression, headache, acute myocardial

infarction, sleep disorders, pneumonia, gastrointestinal bleeding, urinary tract infection,

musculoskeletal pain, recurrent stroke, and post-stroke falls are common medical

complications observed after stroke.[6-8]

Acupuncture plays a major role in traditional Chinese medicine (TCM), and it is widely

used in many countries.[9] A previous study found that TCM is commonly used for stroke

patients in Asian countries,[10] and several investigations have demonstrated that acupuncture

treatment may improve dysphagia,[11] shoulder pain,[12] spasticity,[13] disability, and

quality of life in stroke patients.[14,15] Epilepsy frequently occurs after patients suffer from

hemorrhagic stroke, with an estimated prevalence ranging from 4.1% to 11.3%.[16,17] After

the first seizure, patients may develop recurrent seizures and exhibit increased fatality.[17,18]

Although acupuncture treatment is helpful and potentially reduces seizure frequency in

epilepsy patients,[19] limited information is available regarding whether acupuncture

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treatment is beneficial in reducing epilepsy in stroke patients.

Using the Taiwan National Health Insurance Research Database (NHIRD), we conducted a

nationwide, propensity score-matched, population-based, retrospective cohort study to

investigate the risk of epilepsy for stroke patients with and without receiving of acupuncture

treatment.

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METHODS

Source of data

Research data were obtained from reimbursement claims of the Taiwan National Health

Insurance Program, which was implemented in March 1995 and insures greater than 99% of

the 23 million Taiwan residents. The National Health Research Institute in Taiwan established

the National Health Insurance Research Database (NHIRD); this database records all

beneficiaries’ medical services, including inpatient and outpatient demographics, primary and

secondary diagnoses, procedures, prescriptions, and medical expenditures, for public research

interest. The validity of this database has been favorably evaluated, and research articles that

have used this database have been published in prominent scientific journals

worldwide.[10,20-23]

Ethical statements

The insurance reimbursement claims used in this study were from Taiwan’s National

Health Insurance Research Database. To ensure privacy, the patients were de-identified in the

electronic database. This study was evaluated and approved by the Institutional Review Board

of Taiwan’s National Health Research Institutes (NHIRD-100-122) and E-DA Hospital,

Kaohsiung, Taiwan (2014012). Informed consent was not required because the patients’

identities were decoded and scrambled. This study was conducted in accordance with the

Declaration of Helsinki.[10,20-23]

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Study design

We identified patients ≥20 years in age with newly diagnosed stroke who were hospitalized

between 2000 and 2004 as eligible study subjects. Each subject either received follow-up

from the index date until December 31, 2009 or was censored. To confirm that all stroke

patients in our study were incident cases, only new-onset stroke cases were included in this

study; patients with a diagnosis of stroke within a 4-year period prior to the study were not

included. Overall, we identified 226,699 new-onset stroke survivors ≥20 years in age among

the 23 million people in Taiwan; 37,687 of these patients had received at least two courses

(one course including six consecutive treatments) of acupuncture treatment after being

discharged. We compared stroke patients receiving at least two courses of acupuncture

treatment with patients not receiving acupuncture treatment. We randomly selected stroke

patients who had not received acupuncture treatment as controls; these patients were matched

according to age, sex, low income, urbanization, intensive care unit stay, neurosurgery, and

coexisting medical conditions, such as diabetes mellitus, hypertension, hyperlipidemia, head

injury, malignant neoplasm of brain, mental disorder, Parkinson’s disease, and stroke subtype.

Criteria and definition

We defined stroke according to the International Classification of Diseases, 9th Revision,

Clinical Modification (ICD-9-CM 430-438). The eligible study participants included 226,699

patients in the stroke cohort. Coexisting medical conditions included diabetes (ICD-9-CM

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250), hypertension (ICD-9-CM 401-405), hyperlipidemia (ICD-9-CM 272.0–272.4), mental

disorder (ICD-9-CM 290-319), head injury (ICD-9-CM 800-805, 850-854), malignant

neoplasm of brain (ICD-9-CM 191), Parkinson’s disease (ICD-9-CM 332), and Alzheimer’s

disease (ICD-9-CM 331). Regular renal dialysis (including hemodialysis and/or peritoneal

dialysis), which was identified from the individuals’ health reimbursement claims, was also

considered a medical condition among stroke patients in this study. Under the condition of not

experiencing previous epilepsy before stroke admission through January 1, 1996, cases of

newly diagnosed epilepsy (ICD-9-CM 345) were further defined as at least one medical visit

(including inpatient and outpatient care) with a physician’s diagnosis after stroke admission.

Statistical analysis

We conducted our analysis using a propensity score matched-pair procedure. A

nearest-neighbor algorithm was applied to construct matched pairs, assuming that a

proportion of 0.95 to 1.0 is perfect. The follow-up time, in person-years, was calculated for

each subject until the diagnosis of epilepsy or until being censored because of death,

withdrawal from the insurance system, or loss to follow-up. The outcome of this study was

the person-years of new-onset epilepsy for stroke patients. This study’s objective was to

determine whether using acupuncture was associated with reduced the incidence of epilepsy

in stroke patients.

We first compared the distribution of sociodemographic factors and coexisting medical

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conditions between the stroke cohorts with and without acupuncture treatment using

chi-square tests and t-tests. We calculated hazard ratios (HRs) with 95% confidence intervals

(CIs) for the risk of epilepsy after stroke associated with acupuncture treatment, adjusting for

age, sex, low income, and urbanization in multivariate Cox proportional hazard regression

models. The duration of observation for each person was calculated until the individual was

diagnosed with epilepsy or censored for death, migration, or discontinued enrollment in the

insurance system. Adjusted HRs with 95% CIs for epilepsy associated with acupuncture

treatment were calculated using multivariate Cox proportional hazard analyses with the

variables categorized. We also performed age- and sex-stratified analyses to investigate the

association between epilepsy and the use of acupuncture. SAS software version 9.1 (SAS

Institute, Inc.) was used for data analyses with a two-tailed probability, and P<.05 was

considered statistically significant.

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RESULTS

After the propensity score matching procedure, no significant differences in sex, age, stroke

subtype, low income, urbanization, coexisting medical condition, ICU stay, neurosurgery, or

length of stay were noted between stroke patients with and without acupuncture treatment

(Table 1). Compared to stroke patients who did not receive acupuncture treatment, stroke

patients receiving acupuncture treatment exhibited a reduced epilepsy incidence (7.5% vs.

5.5%, p<0.0001).

After adjustment for sex, age, stroke subtype, low income, urbanization, coexisting medical

condition, ICU stay, neurosurgery, and length of stay (Table 2), stroke patients receiving

acupuncture treatment exhibited a decreased risk of epilepsy (HR=0.81; 95% CI 0.76 to 0.86)

compared with those not receiving acupuncture treatment. The association between

acupuncture treatment and reduced risk of post-stroke epilepsy was significant in men

(HR=0.86; 95% CI 0.79 to 0.93) and women (HR=0.74; 95% CI 0.69 to 0.82) 20 to 59 years

of age as well as in individuals who had suffered from hemorrhagic stroke (HR=0.70; 95% CI

0.61 to 0.80). The HR values of post-stroke epilepsy were 0.21 (95% CI 0.10 to 0.43), 0.61

(95% CI 0.43 to 0.85), 0.61 (95% CI 0.51 to 0.73), and 0.72 (95% CI 0.63 to 0.83) in stroke

patients aged 20-29 years, 30-39 years, 40-49 years, and 50-59 years, respectively.

As shown in Table 2, patients who had suffered from hemorrhagic stroke and received

acupuncture treatment exhibited a decreased risk of post-stroke epilepsy (HR=0.70; 95% CI

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0.61 to 0.80). Among stroke patients, the risk of epilepsy exhibited a dose-dependent decrease

with increasing use of acupuncture treatment (Table 3). Figure 1 shows that the probability of

epilepsy in patients receiving acupuncture was reduced compared to that in patients not

receiving acupuncture.

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DISCUSSION

In this nationwide, propensity score-matched, retrospective cohort study, we observed that

stroke patients receiving acupuncture treatment exhibited a significantly lower risk of

epilepsy during the follow-up period compared to those not receiving acupuncture treatment.

A decreased risk of epilepsy after receiving acupuncture treatment was exclusively noted only

among hemorrhagic stroke patients 20 to 59 years of age. To our knowledge, this study is the

first to report the association between using acupuncture and reduced risk of post-stroke

epilepsy.

Older age, male sex, urbanization, hypertension, diabetes mellitus, mental disorders,

Parkinson’s disease and Alzheimer’s disease are known risk factors associated with

stroke.[24,25] These sociodemographics and coexisting medical conditions are also

associated with epilepsy.[6-28] Neurosurgery, ICU stay, and length of hospital stay have also

been shown to exhibit impacts on post-stroke epilepsy.[7,29] To reduce bias, we used

propensity score matching and multivariate regression to control for potential confounders.

Our study demonstrated that acupuncture treatment is associated with a decreased risk of

epilepsy among male and female stroke patients aged 20 to 59 and among those who have

experienced hemorrhagic stroke. Age and sex have been previously shown to determine the

medical conditions and complications of individuals suffering from stroke.[20] For instance,

older populations exhibit an increased mortality rate and poorer outcomes after stroke.[30]

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Young and middle-aged adults have less coexisting medical conditions; have better

knowledge, attitudes, and practice; and more commonly use TCM or acupuncture treatment

compared with older individuals.[10,31] These findings may partly explain why we observed

enhanced effects of acupuncture treatment on decreasing the risk of post-stroke epilepsy in

young and middle-aged adults.

The incidence of post-stroke epilepsy varied based on the stroke type.[16,32] Consistent

with previous reports,[16,17] the present study also demonstrated that patients who

experienced hemorrhagic stroke exhibited an increased risk for developing seizures compared

to those who experienced ischemic stroke or other stroke subtypes. Nevertheless, our

investigation indicated the beneficial effects of acupuncture treatment in reducing the risk of

epilepsy for patients with every stroke subtype.

Acupuncture treatment is one option among rehabilitation programs,[33] particularly for

stroke patients.[34] We propose three possible explanations for the association between

acupuncture treatment and the decreased risk of post-stroke epilepsy that was demonstrated in

this study. First, acupuncture intervention involves multiple levels of differential activities

over a wide range of brain networks.[35] and this modulation and sympathovagal response

may relate to acupuncture analgesia and other potential therapeutic effects.[35] Second,

depression is a frequent co-existing condition in stroke patients. Indeed, a meta-analysis

reported that acupuncture exhibits a beneficial effect on patients with depression.[36] Stroke

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patients with coexisting medical conditions, such as dementia or Alzheimer’s disease, are also

more likely to develop epilepsy,[37] and an interventional trial reported that acupuncture

treatment potentially improves cognitive function and quality of life in vascular dementia

patients.[38] Third, stroke patients who receive acupuncture treatment may possess more

knowledge about and better attitudes toward physical rehabilitation, which are helpful in

reducing post-stroke epilepsy, compared to patients not receiving acupuncture treatment.

The first advantage of this study was its large sample size and reduced selection bias.

Second, our study consisted of a retrospective cohort design using the NHIRD; this design

provides stronger causal inference than case-control and cross-sectional designs. Third, to

eliminate the interference of sociodemographics and coexisting medical conditions between

stroke patients receiving acupuncture treatment and those not receiving such treatment, we

used a propensity score matched-pair procedure to select acupuncture and non-acupuncture

treatment controls. To control for residual confounding effects in the association between a

decreased risk of post-stroke epilepsy and acupuncture treatment, we applied multivariable

Cox proportional hazard models to calculate adjusted HRs and 95% CIs of epilepsy

associated with acupuncture treatment. Finally, immortal time in observational studies may

bias the results in favor of the treatment group, thereby overestimating the beneficial effects.

To reduce such bias, we calculated person-years by correcting for immortal time in the

acupuncture treatment group.

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Nevertheless, this study had certain limitations. First, we used insurance claims data, which

lack information on clinical risk scores (such as the National Institute of Health Stroke Scale


patients’ lifestyles, which have been reported as predictors of post-stroke epilepsy. Thus, this

study does not provide information regarding the severity-dependent relationship between

epilepsy and stroke. Second, preventive administration of antiepileptic medications or other

rehabilitation programs were not considered during the follow-up period. Thus, we were

unable to evaluate the influence of these factors on the association between acupuncture and

the decreased risk of post-stroke epilepsy. Third, although the accuracy of diagnosis codes in

the database has been validated in previous studies,[10] the validity of co-morbidity codes is

one potential limitation of the study. The prevalence of epilepsy may also have been

underestimated, given that patients experiencing mild symptoms may not seek medical

treatment; however, these effects appear minimal in our population-based study. In addition,

our study could not validate the actual acupuncture points used in treatment, given the limited

information provided by the reimbursement claims of Taiwan’s NHIRD. Finally, the mode of

acupuncture treatment for stroke patients varied among TCM physicians. Thus, we could not

confirm that all TCM physicians performed the same procedures and used the same

acupuncture points for stroke patients.

In conclusion, stroke patients receiving acupuncture treatment exhibited a reduced risk of

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epilepsy compared to patients not receiving acupuncture treatment. The association between

decreased epilepsy risk and acupuncture use was observed in men, women, younger adults,

and patients suffering from hemorrhagic stroke. However, this associated protective effect

must be further assessed in randomized clinical trials to provide direct evidence regarding the

effectiveness and mechanisms of acupuncture treatment on post-stroke epilepsy.

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2010;9:105-18.

26. De Herdt V, Dumont F, Hénon H, et al. Early seizures in intracerebral hemorrhage:

incidence, associated factors, and outcome. Neurology 2011;77:1794-1800.

27. Roivanen R, Haapaniemi E, Putaala J, et al. Young adult ischaemic stroke related acute

symptomatic and late seizures: risk factors. Eur J Neurol 2013;20:1247-55.

28. Addo J, Ayerbe L, Mohan KM, et al. Socioeconomic status and stroke: an updated review.

Stroke 2012;43:1186-91.

29. Burneo JG, Fang J, Saposnik G. Impact of seizures on morbidity and mortality after stroke:

a Canadian multi-centre cohort study. Eur J Neurol 2010;17:52-8.

30. van Wijk I, Kappelle LJ, van Gijn J, et al. Long-term survival and vascular event risk after

transient ischaemic attack or minor ischaemic stroke: a cohort study. Lancet

2005;365:2098-104.

31. Shih CC, Liao CC, Su YC, et al. Gender Differences in Traditional Chinese Medicine Use

among Adults in Taiwan. PLoS One 2012;7:e32540.

32. Beghi E, D'Alessandro R, Beretta S, et al. Incidence and predictors of acute symptomatic

seizures after stroke. Neurology 2011;77:1785-93.

33. Wong V, Cheuk DK, Lee S, et al. Acupuncture for acute management and rehabilitation

of traumatic brain injury. Eur J Phys Rehabil Med 2012;48:71-86.

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34. Yam W, Wilkinson JM. Is acupuncture an acceptable option in stroke rehabilitation? A

survey of stroke patients. Complement Ther Med 2010;18:143-9.

35. Li QQ, Shi GX, Xu Q, et al. Acupuncture effect and central autonomic regulation. Evid

Based Complement Alternat Med 2013;2013:267959.

36. Wang H, Qi H, Wang BS, et al. Is acupuncture beneficial in depression: a meta-analysis

of 8 randomized controlled trials? J Affect Disord 2008;111:125-34.

37. Imfeld P, Bodmer M, Schuerch M, et al. Seizures in patients with Alzheimer's disease or

vascular dementia: a population-based nested case-control analysis. Epilepsia

2013;54:700-7.

38. Shi GX, Liu CZ, Li QQ, et al. Influence of acupuncture on cognitive function and markers

of oxidative DNA damage in patients with vascular dementia. J Tradit Chin Med

2012;32:199-202.

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Acknowledgments: This study is based in part on data obtained from the National Health

Insurance Research Database provided by the Bureau of National Health Insurance, Ministry

of Health and Welfare, and managed by the National Health Research Institutes. The

interpretation and conclusions contained herein do not represent those of the Bureau of

National Health Insurance, Ministry of Health and Welfare, or National Health Research

Institutes.

Competing interests: None.

Financial support: This research was supported in part by Shuang Ho Hospital, Taipei

Medical University (104TMU-SHH-23), and by Taiwan’s Ministry of Science and

Technology (MOST104-2314-B-038-027-MY2; MOST103-2320-B-214-010-MY2;

NSC102-2314-B-038-021-MY3).

Contributorship Statement: The conception or design of the work: SWW, CCL, CCS; The

acquisition and analysis of data: CCL, HLL, CCS; Interpretation of data: SWW, CCL, CCY,

TLC, HLL, JGL, CCS; Drafting the work: SWW, CCL; Revising it critically for important

intellectual content: SWW, CCL, CCY, TLC, HLL, JGL, CCS; Final approval of the version

to be published: SWW, CCL, CCY, TLC, HLL, JGL, CCS; Agreement to be accountable for

all aspects of the work in ensuring that questions related to the accuracy or integrity of any

part of the work are appropriately investigated and resolved: SWW, CCL, CCY, TLC, HLL,

JGL, CCS.

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Data sharing statement: dataset available from the Taiwan’s National Health Research

Institutes (http://nhird.nhri.org.tw/index1.php).

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Fig 1 The epilepsy-free proportions estimated for post-stroke patients with and without

acupuncture treatment using the Kaplan-Meier method.

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Table 1 Baseline Characteristics of Stroke Patients With and Without Acupuncture

Treatment

Acupuncture use

No (N = 30410) Yes (N = 30410) P value

n (%) n (%)

Female 13615 (44.8) 13615 (44.8) 1.0000

Age, years 1.0000

20-29 186 (0.6) 186 (0.6)

30-39 723 (2.4) 723 (2.4)

40-49 3441 (11.3) 3441 (11.3)

50-59 6582 (21.6) 6582 (21.6)

60-69 9843 (32.4) 9843 (32.4)

70-79 8156 (26.8) 8156 (26.8)

≥80 1479 (4.9) 1479 (4.9)

Stroke subtype 1.0000

Hemorrhage 4014 (13.2) 4014 (13.2)

Ischemic 16597 (54.6) 16597 (54.6)

Other 9799 (32.2) 9799 (32.2)

Low income 546 (1.8) 546 (1.8) 1.0000

Urbanization 1.0000

Low 1108 (3.6) 1108 (3.6)

Moderate 10302 (33.9) 10302 (33.9)

High 19000 (62.5) 19000 (62.5)

Coexisting medical condition

Hypertension 22458 (73.9) 22458 (73.9) 1.0000

Mental disorder 12570 (41.3) 12570 (41.3) 1.0000

Diabetes mellitus 11755 (38.7) 11755 (38.7) 1.0000

Hyperlipidemia 5739 (18.9) 5739 (18.9) 1.0000

Head injury 3441 (11.3) 3441 (11.3) 1.0000

Parkinson’s disease 1389 (4.6) 1389 (4.6) 1.0000

Alzheimer’s disease 51 (0.2) 51 (0.2) 1.0000

Brain cancer 36 (0.1) 36 (0.1) 1.0000

ICU stay 3465 (11.4) 3465 (11.4) 1.0000

Neurosurgery 850 (2.8) 850 (2.8) 1.0000

Length of stay, days 7.74±6.12 7.77±6.15 0.4919

ICU = intensive care unit.

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Table 2 Incidence and Risk of Epilepsy for Stroke Patients With and Without Acupuncture Treatment by Age, Sex, and Stroke

Type

No acupuncture Acupuncture use

n Events Person-year Incidence n Events Person-year Incidence HR (95% CI)

All* 30,410 2,270 169,235 13.4 30,410 1,663 147,859 11.2 0.81 (0.76-0.86)

Female 13,615 907 79,068 11.5 13,615 592 67,584 8.0 0.74 (0.69-0.82)

Male 16,795 1,363 90,167 15.1 16,795 1,071 80,275 13.3 0.86 (0.79-0.93)

Age, years‡

20-29 186 38 1,000 38.0 186 9 913 9.9 0.21 (0.10-0.43)

30-39 723 89 4,046 22.0 723 56 3,474 16.1 0.61 (0.43-0.85)

40-49 3,441 346 20,733 16.7 3,441 199 17,419 11.4 0.61 (0.51-0.73)

50-59 6,582 489 39,817 12.3 6,582 320 33,835 9.5 0.72 (0.63-0.83)

60-69 9,843 654 56,976 11.5 9,843 537 48,718 11.0 0.95 (0.84-1.06)

70-79 8,156 566 40,936 13.8 8,156 457 37,720 12.1 0.90 (0.79-1.02)

≥80 1,479 88 5,726 15.4 1,479 85 5,779 14.7 1.04 (0.77-1.40)

Type of stroke§

Hemorrhage 4,014 559 20,851 26.8 4,014 389 19,766 19.7 0.70 (0.61-0.80)

Ischemic 16,597 1,137 91,134 12.5 16,597 934 80,840 11.6 0.93 (0.85-1.01)

Other 9,799 574 57,250 10.0 9,799 340 47,253 7.2 0.70 (0.61-0.81)

CI = confidence interval, HR = hazard ratio. *Adjusted for sociodemographics, hypertension, mental disorders, diabetes, hyperlipidemia, traumatic brain injury, Parkinson’s

disease, Alzheimer’s disease, brain cancer, type of stroke, admission to intensive care unit, neurosurgery, and length of stay. †Adjusted for covariates in the full model with the exception of sex. ‡Adjusted for covariates in the full model with the exception of age. §Adjusted for covariates in the full model with the exception of stroke subtype.

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Table 3 Risk of Epilepsy and Number of Acupuncture Treatment Packages in Stroke Patients

Number of packages n Events Person-years Incidence HR (95% CI)*

0 30410 2270 169235 10.9 1.00 (reference)

2 6118 316 25653 12.3 0.81 (0.72-0.91)

3 4051 235 17829 13.2 0.87 (0.76-0.99)

4 2888 157 13536 11.6 0.78 (0.66-0.91)

5 2203 114 10676 10.7 0.71 (0.59-0.86)

6 1673 82 8005 10.2 0.70 (0.56-0.87)

≥7 13477 759 72160 10.5 0.69 (0.63-0.74)

CI = confidence interval, HR = hazard ratio. *Adjusted for sociodemographics, hypertension, mental disorders, diabetes, hyperlipidemia,

traumatic brain injury, Parkinson’s disease, Alzheimer’s disease, brain cancer, type of stroke,

admission to intensive care unit, neurosurgery, and length of stay.

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STROBE 2007 (v4) checklist of items to be included in reports of observational studies in epidemiology*

Checklist for cohort, case-control, and cross-sectional studies (combined)

Section/Topic Item # Recommendation Reported on page #

Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 1, 3

(b) Provide in the abstract an informative and balanced summary of what was done and what was found 3

Introduction

Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 5

Objectives 3 State specific objectives, including any pre-specified hypotheses 6

Methods

Study design 4 Present key elements of study design early in the paper 7

Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data

collection 7, 8

Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of participants. Describe

methods of follow-up

Case-control study—Give the eligibility criteria, and the sources and methods of case ascertainment and control

selection. Give the rationale for the choice of cases and controls

Cross-sectional study—Give the eligibility criteria, and the sources and methods of selection of participants

8, 9

(b) Cohort study—For matched studies, give matching criteria and number of exposed and unexposed

Case-control study—For matched studies, give matching criteria and the number of controls per case 8, 9

Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic

criteria, if applicable 8, 9

Data sources/ measurement 8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe

comparability of assessment methods if there is more than one group 8, 9

Bias 9 Describe any efforts to address potential sources of bias 9, 10

Study size 10 Explain how the study size was arrived at 9, 10

Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen

and why 9, 10

Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 9, 10

(b) Describe any methods used to examine subgroups and interactions 9, 10

(c) Explain how missing data were addressed 9, 10

(d) Cohort study—If applicable, explain how loss to follow-up was addressed

Case-control study—If applicable, explain how matching of cases and controls was addressed 9, 10

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Cross-sectional study—If applicable, describe analytical methods taking account of sampling strategy

(e) Describe any sensitivity analyses 9, 10

Results

Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility,

confirmed eligible, included in the study, completing follow-up, and analysed 11, 12

(b) Give reasons for non-participation at each stage 11, 12

(c) Consider use of a flow diagram 11, 12

Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and

potential confounders 11, 12

(b) Indicate number of participants with missing data for each variable of interest 11, 12

(c) Cohort study—Summarise follow-up time (eg, average and total amount) 11, 12

Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time 11, 12

Case-control study—Report numbers in each exposure category, or summary measures of exposure 11, 12

Cross-sectional study—Report numbers of outcome events or summary measures 11, 12

Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95%

confidence interval). Make clear which confounders were adjusted for and why they were included 11, 12

(b) Report category boundaries when continuous variables were categorized 11, 12

(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period 11, 12

Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses 11, 12

Discussion

Key results 18 Summarise key results with reference to study objectives 13

Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction

and magnitude of any potential bias 16

Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results

from similar studies, and other relevant evidence 13-17

Generalisability 21 Discuss the generalisability (external validity) of the study results 13-17

Other information

Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on

which the present article is based 18

*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE

checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at

http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.

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Risk of epilepsy in stroke patients receiving acupuncture treatment: a nationwide retrospective matched-cohort

study

Journal: BMJ Open

Manuscript ID bmjopen-2015-010539.R1

Article Type: Research

Date Submitted by the Author: 07-Apr-2016

Complete List of Authors: Weng, Shu-Wen; Taichung Hospital, Ministry of Health and Welfare, Department of Chinese Medicine Liao, Chien-Chang; Taipei Medical University Hospital, Department of

Anesthesiology Yeh, Chun-Chieh; University of Illinois, Department of Surgery Chen, Ta-Liang; Taipei Medical University Hospital, Department of Anesthesiology Lane, Hsin-Long; I-Shou University, School of Chinese Medicine for Post-Baccalaureate Lin, Jaung-Geng; China Medical University, School of Chinese Medicine Shih, Chun-Chuan; I-Shou University, School of Chinese Medicine for Post-Baccalaureate

<b>Primary Subject Heading</b>:

Complementary medicine

Secondary Subject Heading: Epidemiology, Public health, Neurology, Health services research

Keywords: Acupuncture, Stroke < NEUROLOGY, Epilepsy < NEUROLOGY


BMJ Open on O

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Risk of epilepsy in stroke patients receiving acupuncture treatment: a nationwide

retrospective matched-cohort study

Short title: Acupuncture reduces post-stroke epilepsy

Shu-Wen Weng,1,2

Chien-Chang Liao,1,3,4,5

Chun-Chieh Yeh,6,7

Ta-Liang Chen,3,4,5

,

Hsin-Long Lane,8 Jaung-Geng Lin,

1 Chun-Chuan Shih

8,9

1School of Chinese Medicine, College of Chinese Medicine, China Medical University,

Taichung, Taiwan

2Department of Chinese Medicine, Taichung Hospital, Ministry of Health and Welfare,

Taichung, Taiwan

3Department of Anesthesiology, Taipei Medical University Hospital, Taipei, Taiwan

4Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical

University, Taipei, Taiwan

5Health Policy Research Center, Taipei Medical University Hospital, Taipei, Taiwan

6Department of Surgery, China Medical University Hospital, Taichung, Taiwan

7Department of Surgery, University of Illinois, Chicago, Illinois, USA

8School of Chinese Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung City,

Taiwan

9Program for the Clinical Drug Discovery from Botanical Herbs, College of Pharmacy, Taipei

Medical University

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*Chien-Chang Liao contributed equally with first author; Jaung-Geng Lin contributed equally

with the corresponding author.

Correspondence:

Chun-Chuan Shih, MD, PhD

Associate professor

School of Chinese Medicine for Post-Baccalaureate, I-Shou University

No.8, Yida Rd., Jiaosu Village, Yanchao District, Kaohsiung 82445, Taiwan

Tel: 886-2-2765-1125

Fax: 886-2-2765-3230

E-mail: [email protected]; [email protected]; [email protected]

Abstract: 250 words; Text: 2184; Tables: 3; Figures: 1

Keywords: Stroke, epilepsy, acupuncture

List of abbreviations: CI=confidence intervals; HR=hazard ratio; ICD-9-CM=International

Classification of Diseases, 9th Revision, Clinical Modification; NHIRD=National Health

Insurance Research Database

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ABSTRACT

Objective: To investigate the risk of epilepsy for stroke patients with and without receiving of

acupuncture treatment.

Design: Retrospective cohort study.

Setting: This study was based on Taiwan’s National Health Insurance Research Database that

included stroke patients who hospitalized between January 1, 2000 and December 31, 2004.

Participants: We identified 42040 patients with new-diagnosed stroke hospitalization who

aged 20 years and older.

Primary and secondary outcome measures: We compared the incident epilepsy during the

follow-up period until the end of 2009 in stroke patients with and without receiving

acupuncture. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of epilepsy

associated with acupuncture were calculated in multivariate Cox proportional hazard

regressions.

Results: Stroke patients who received acupuncture treatment (11.2 per 1,000 person-years)

experienced a reduced incidence of epilepsy compared to those who did not receive

acupuncture treatment (13.4 per 1,000 person-years), with a HR of 0.81 (95% CI, 0.76 to 0.86)

after adjustment for sociodemographics and coexisting medical conditions. Acupuncture

treatment was associated with a decreased risk of epilepsy, particularly among stroke patients

aged 20-69 years. The probability curve with log-rank test indicated that stroke patients

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receiving acupuncture treatment experienced a reduced probability of epilepsy compared with

individuals who did not receive acupuncture treatment during the follow-up period

(p<0.0001).

Conclusions: Stroke patients who received acupuncture treatment experienced a reduced risk

of epilepsy compared with those without receiving acupuncture treatment. However, these

protective effects associated with acupuncture treatment require further validation using

randomized clinical trials.

Key Words: Acupuncture, epilepsy, stroke, cohort study

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Strengths of this study

(1) We used matching procedure with propensity score to reduce the confounding effects.

(2) The multivariate Cox proportional hazard models were use to control the residual

confounding bias.

(3) Our study had no selection bias because all hospitalized stroke patients in 2000-2004 in

Taiwan were analyzed.

Limitations of this study

(1) Our data lack of clinical risk scores, lesion characteristics, biochemical measures, and

lifestyles of stroke patients.

(2) Preventive administration of antiepileptic medications or other rehabilitation programs

were not considered during the follow-up period.

(3) The validity of diagnostic codes of diseases is also a limitation of the study.

(4) Our study could not validate the actual acupuncture points used in treatment.

(5) The mode of acupuncture treatment for stroke patients varied among TCM physicians.

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INTRODUCTION

Stroke remains the leading cause of adult disability and death worldwide.[1,2]

Approximately global 5.8 million deaths were attributed to stoke and the one-year cost of

stroke is approximately 30,000 US dollars per patient in 2010 in countries worldwide.[2,3]

Given that strokes occur in 2.8% of adults in the United States, the economic burden of stroke

was $36.5 billion in 2010.[4] In Taiwan, the average of the first-year medical costs after

stroke was 5,679 US dollars per patient.[5] Epilepsy, depression, headache, acute myocardial

infarction, sleep disorders, pneumonia, gastrointestinal bleeding, urinary tract infection,

musculoskeletal pain, recurrent stroke, and post-stroke falls are common medical

complications observed after stroke.[6-8]

Acupuncture plays a major role in traditional Chinese medicine (TCM), and it is widely

used in many countries.[9] A previous study found that TCM is commonly used for stroke

patients in Asian countries,[10] and several investigations have demonstrated that acupuncture

treatment may improve dysphagia,[11] shoulder pain,[12] spasticity,[13] disability, and

quality of life in stroke patients.[14,15] Epilepsy frequently occurs after patients suffer from

hemorrhagic stroke, with an estimated prevalence ranging from 4.1% to 11.3%.[16,17] After

the first seizure, patients may develop recurrent seizures and exhibit increased fatality.[17,18]

Although acupuncture treatment is helpful and potentially reduces seizure frequency in

epilepsy patients,[19] limited information is available regarding whether acupuncture

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treatment is beneficial in reducing epilepsy in stroke patients.

Using the Taiwan National Health Insurance Research Database (NHIRD), we conducted a

nationwide, propensity score-matched, population-based, retrospective cohort study to

investigate the risk of epilepsy for stroke patients with and without receiving of acupuncture

treatment.

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METHODS

Source of data

Research data were obtained from reimbursement claims of the Taiwan National Health

Insurance Program, which was implemented in March 1995 and insures greater than 99% of

the 23 million Taiwan residents. The National Health Research Institute in Taiwan established

the National Health Insurance Research Database (NHIRD); this database records all

beneficiaries’ medical services, including inpatient and outpatient demographics, primary and

secondary diagnoses, procedures, prescriptions, and medical expenditures, for public research

interest. The validity of this database has been favorably evaluated, and research articles that

have used this database have been published in prominent scientific journals

worldwide.[10,20-23]

Ethical statements

The insurance reimbursement claims used in this study were from Taiwan’s National

Health Insurance Research Database. To ensure privacy, the patients were de-identified in the

electronic database. This study was evaluated and approved by the Institutional Review Board

of Taiwan’s National Health Research Institutes (NHIRD-100-122) and E-DA Hospital,

Kaohsiung, Taiwan (2014012). Informed consent was not required because the patients’

identities were decoded and scrambled. This study was conducted in accordance with the

Declaration of Helsinki.[10,20-23]

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Study design

We identified patients ≥20 years in age with newly diagnosed stroke who were hospitalized

between 2000 and 2004 as eligible study subjects. Each subject either received follow-up

from the index date until December 31, 2009 or was censored. To confirm that all stroke

patients in our study were incident cases, only new-onset stroke cases were included in this

study; patients with a diagnosis of stroke within a 4-year period prior to the study were not

included. Overall, we identified 226,699 new-onset stroke survivors ≥20 years in age among

the 23 million people in Taiwan; 21020 of these patients had received at least two courses

(one course including six consecutive treatments) of acupuncture treatment after being

discharged. We compared stroke patients receiving at least two courses of acupuncture

treatment with patients not receiving acupuncture treatment. We randomly selected stroke

patients who had not received acupuncture treatment as controls (case-control ratio=1:1);

these patients were matched according to age, sex, stroke subtype, low income, urbanization,

hypertension, mental disorder, diabetes, hyperlipidemia, head injury, Parkinson’s disease,

Alzheimer’s disease, brain cancer, renal dialysis, rehabilitation, anti-epilepsy drugs,

anticoagulant, anti-platelet agents, lipid-lowering agents, stay of intensive care unit,

neurosurgery, and length of stay.

Criteria and definition

We defined stroke according to the International Classification of Diseases, 9th Revision,

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Clinical Modification (ICD-9-CM 430-438). The eligible study participants included 226,699

patients in the stroke cohort. Coexisting medical conditions included hypertension

(ICD-9-CM 401-405), mental disorder (ICD-9-CM 290-319), diabetes (ICD-9-CM 250),

hyperlipidemia (ICD-9-CM 272.0–272.4), head injury (ICD-9-CM 800-805, 850-854),

Parkinson’s disease (ICD-9-CM 332), Alzheimer’s disease (ICD-9-CM 331), brain cancer

(ICD-9-CM 191), and. regular renal dialysis (administration code, D8, D9). Using

rehabilitation, anti-epilepsy drugs, anticoagulant, anti-platelet agents, lipid-lowering

agents,during the follow-up period were also considered in this study During the index stroke

admission, we identified stay of intensive care unit, neurosurgery, and length of stay as

potential confounding factors for the association between acupuncture treatment and

post-stroke epilepsy. Under the condition of not experiencing previous epilepsy before stroke

admission through January 1, 1996, cases of newly diagnosed epilepsy (ICD-9-CM 345) were

further defined as at least one medical visit (including inpatient and outpatient care) with a

physician’s diagnosis after stroke admission.

Statistical analysis

We used propensity score-matched pair method combined frequency matching to analyze

patients with and without acupuncture treatment. We developed a non-parsimonious

multivariable logistic regression model to estimate a propensity score for patients with and

without acupuncture treatment, irrespective of outcome. Clinical significance guided the

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initial choice of covariates in this model: age, sex, stroke subtype, low income, urbanization,

hypertension, mental disorder, diabetes, hyperlipidemia, head injury, Parkinson’s disease,

Alzheimer’s disease, brain cancer, renal dialysis, rehabilitation, anti-epilepsy drugs,

anticoagulant, anti-platelet agents, lipid-lowering agents, stay of intensive care unit,

neurosurgery, and length of stay. We matched patients with acupuncture to no-acupuncture

patients using a greedy-matching algorithm with best to next-best until no more match. In the

1:1 matching procedure, all cases are initially matched to their “best” control in the first

iteration of the 8 to 1 digit match. The set of matched cases is then matched to the set of

un-matched controls in N-1 additional iterations of the 8 to 1 Digit Match. If a case does not

have 1 matched controls, it is removed from the set of matches at the time it fails to receive a

matched control. The corresponding control is also removed from the set of matches. The

control is added back to the pool of un-matched controls, and allowed to match to another

case. This method could remove 98% of the bias from measured covariates. The chi-square

tests were used to measure covariate balance and a p-value <0.05 was suggested to represent

meaningful covariate imbalance.

The follow-up time, in person-years, was calculated for each subject until the diagnosis of

epilepsy or until being censored because of death, withdrawal from the insurance system, or

loss to follow-up. The outcome of this study was the person-years of new-onset epilepsy for

stroke patients. This study’s objective was to determine whether using acupuncture was

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associated with reduced the incidence of epilepsy in stroke patients.

We first compared the distribution of sociodemographic factors and coexisting medical

conditions between the stroke cohorts with and without acupuncture treatment using

chi-square tests and t-tests. We calculated hazard ratios (HRs) with 95% confidence intervals

(CIs) for the risk of epilepsy after stroke associated with acupuncture treatment, adjusting for

age, sex, low income, and urbanization in multivariate Cox proportional hazard regression

models. The duration of observation for each person was calculated until the individual was

diagnosed with epilepsy or censored for death, migration, or discontinued enrollment in the

insurance system. Adjusted HRs with 95% CIs for epilepsy associated with acupuncture

treatment were calculated using multivariate Cox proportional hazard analyses with the

variables categorized. We also performed age- and sex-stratified analyses to investigate the

association between epilepsy and the use of acupuncture. SAS software version 9.1 (SAS

Institute, Inc.) was used for data analyses with a two-tailed probability, and P<.05 was

considered statistically significant.

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RESULTS

After the propensity score matching procedure, no significant differences in sex, age, stroke

subtype, low income, urbanization, coexisting medical condition, ICU stay, neurosurgery, or

length of stay were noted between stroke patients with and without acupuncture treatment

(Table 1).

Compared to stroke patients who did not receive acupuncture treatment (Table 2), stroke

patients receiving acupuncture treatment exhibited a reduced epilepsy incidence (9.8 vs. 11.5

per 1000 person-years, p<0.0001). After adjustment for sex, age, stroke subtype, low income,

urbanization, coexisting medical condition, rehabilitation, anti-epilepsy drugs, anticoagulant,

anti-platelet agents, lipid-lowering agents, ICU stay, neurosurgery, and length of stay, stroke

patients receiving acupuncture treatment exhibited a decreased risk of epilepsy (HR=0.74;

95% CI 0.68 to 0.80) compared with those not receiving acupuncture treatment. The

association between acupuncture treatment and reduced risk of post-stroke epilepsy was

significant in men (HR=0.77; 95% CI 0.69 to 0.85) and women (HR=0.70; 95% CI 0.61 to

0.81), stroke patients aged 20-69 years as well as in individuals who had suffered from

hemorrhagic stroke (HR=0.60; 95% CI 0.50 to 0.73), ischemic stroke (HR=0.86; 95% CI 0.78

to 0.96) and other stroke (HR=0.62; 95% CI 0.52 to 0.74). The HR values of post-stroke

epilepsy were 0.16 (95% CI 0.04 to 0.68), 0.39 (95% CI 0.21 to 0.73), 0.51 (95% CI 0.39 to

0.66), 0.66 (95% CI 0.54 to 0.80) and 0.79 (95% CI 0.68 to 0.91) in stroke patients aged

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20-29 years, 30-39 years, 40-49 years, 50-59 years, and 60-69 years, respectively.

Among stroke patients, the risk of epilepsy exhibited a dose-dependent decrease with

increasing use of acupuncture treatment (Table 3). Figure 1 shows that the probability of

epilepsy in patients receiving acupuncture was reduced compared to that in patients not

receiving acupuncture.

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DISCUSSION

In this nationwide, propensity score-matched, retrospective cohort study, we observed that

stroke patients receiving acupuncture treatment exhibited a significantly lower risk of

epilepsy during the follow-up period compared to those not receiving acupuncture treatment.

A decreased risk of epilepsy after receiving acupuncture treatment was exclusively noted only

among stroke patients aged 20 to 69 years. To our knowledge, this study is the first to report

the association between using acupuncture and reduced risk of post-stroke epilepsy.

Older age, male sex, urbanization, hypertension, diabetes mellitus, mental disorders,

Parkinson’s disease and Alzheimer’s disease are known risk factors associated with

stroke.[24,25] These sociodemographics and coexisting medical conditions are also

associated with epilepsy.[6-28] Neurosurgery, ICU stay, and length of hospital stay have also

been shown to exhibit impacts on post-stroke epilepsy.[7,29] To reduce bias, we used

propensity score matching and multivariate regression to control for potential confounders.

Our study demonstrated that acupuncture treatment is associated with a decreased risk of

epilepsy among male and female stroke patients aged 20 to 69 years. Age and sex have been

previously shown to determine the medical conditions and complications of individuals

suffering from stroke.[20] For instance, older populations exhibit an increased mortality rate

and poorer outcomes after stroke.[30] Young and middle-aged adults have less coexisting

medical conditions; have better knowledge, attitudes, and practice; and more commonly use

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TCM or acupuncture treatment compared with older individuals.[10,31] These findings may

partly explain why we observed enhanced effects of acupuncture treatment on decreasing the

risk of post-stroke epilepsy in young and middle-aged adults.

The incidence of post-stroke epilepsy varied based on the stroke type.[16,32] Consistent

with previous reports,[16,17] the present study also demonstrated that patients who

experienced hemorrhagic stroke exhibited an increased risk for developing seizures compared

to those who experienced ischemic stroke or other stroke subtypes. Nevertheless, our

investigation indicated the beneficial effects of acupuncture treatment in reducing the risk of

epilepsy for patients with every stroke subtype.

Acupuncture treatment is one option among rehabilitation programs,[33] particularly for

stroke patients.[34] We propose three possible explanations for the association between

acupuncture treatment and the decreased risk of post-stroke epilepsy that was demonstrated in

this study. First, acupuncture intervention involves multiple levels of differential activities

over a wide range of brain networks and this modulation and sympathovagal response may

relate to acupuncture analgesia and other potential therapeutic effects.[35] Second, depression

is a frequent co-existing condition in stroke patients. Indeed, a meta-analysis reported that

acupuncture exhibits a beneficial effect on patients with depression.[36] Stroke patients with

coexisting medical conditions, such as dementia or Alzheimer’s disease, are also more likely

to develop epilepsy,[37] and an interventional trial reported that acupuncture treatment

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potentially improves cognitive function and quality of life in vascular dementia patients.[38]

Third, stroke patients who receive acupuncture treatment may possess more knowledge about

and better attitudes toward physical rehabilitation, which are helpful in reducing post-stroke

epilepsy, compared to patients not receiving acupuncture treatment.

By using functional magnetic resonance imaging, previous studies indicated that laser

acupuncture activated the precuneus relevant to mood in the posterior default mode network

while needle acupuncture activated the parietal cortical region associated with the primary

motor cortex.[39] In addition, laser stimulation of acupoints lead to activation of

frontal-limbic-striatal brainregions, with the pattern of neural activity somewhat different for

each acupuncture point.[40] The activation in under activated brain regions, deactivation

where there is overload and over activation and so on. This may be one of the reasons why

there is a reduction of epilepsy. Therefore, we believe that laser acupuncture may be also

helpful during the rehabilitation for stroke patients.

The first strength of this study was its large sample size and reduced selection bias. Second,

our study consisted of a retrospective cohort design using the NHIRD; this design provides

stronger causal inference than case-control and cross-sectional designs. Third, to eliminate the

interference of sociodemographics and coexisting medical conditions between stroke patients

receiving acupuncture treatment and those not receiving such treatment, we used a propensity

score matched-pair procedure to select acupuncture and non-acupuncture treatment controls.

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To control for residual confounding effects in the association between a decreased risk of

post-stroke epilepsy and acupuncture treatment, we applied multivariable Cox proportional

hazard models to calculate adjusted HRs and 95% CIs of epilepsy associated with

acupuncture treatment. Finally, immortal time in observational studies may bias the results in

favor of the treatment group, thereby overestimating the beneficial effects. To reduce such

bias, we calculated person-years by correcting for immortal time in the acupuncture treatment

group.

Nevertheless, this study had certain limitations. First, we used insurance claims data, which

lack information on clinical risk scores (such as the National Institute of Health Stroke Scale


patients’ lifestyles, which have been reported as predictors of post-stroke epilepsy. Thus, this

study does not provide information regarding the severity-dependent relationship between

epilepsy and stroke. Second, preventive administration of antiepileptic medications or other

rehabilitation programs were not considered during the follow-up period. Thus, we were

unable to evaluate the influence of these factors on the association between acupuncture and

the decreased risk of post-stroke epilepsy. Third, although the accuracy of diagnosis codes in

the database has been validated in previous studies,[10] the validity of co-morbidity codes is

one potential limitation of the study. The prevalence of epilepsy may also have been

underestimated, given that patients experiencing mild symptoms may not seek medical

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treatment; however, these effects appear minimal in our population-based study. In addition,

our study could not validate the actual acupuncture points used in treatment, given the limited

information provided by the reimbursement claims of Taiwan’s NHIRD. Finally, the mode of

acupuncture treatment for stroke patients varied among TCM physicians. Thus, we could not

confirm that all TCM physicians performed the same procedures and used the same

acupuncture points for stroke patients.

In conclusion, stroke patients receiving acupuncture treatment exhibited a reduced risk of

epilepsy compared to patients not receiving acupuncture treatment. The association between

decreased epilepsy risk and acupuncture use was observed in men, women, younger adults,

and patients suffering from any subtypes of stroke. However, this associated protective effect

must be further assessed in randomized clinical trials to provide direct evidence regarding the

effectiveness and mechanisms of acupuncture treatment on post-stroke epilepsy.

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Acknowledgments: This study is based in part on data obtained from the National Health

Insurance Research Database provided by the Bureau of National Health Insurance, Ministry

of Health and Welfare, and managed by the National Health Research Institutes. The

interpretation and conclusions contained herein do not represent those of the Bureau of

National Health Insurance, Ministry of Health and Welfare, or National Health Research

Institutes.

Competing interests: None.

Financial support: This research was supported in part by Shuang Ho Hospital, Taipei

Medical University (104TMU-SHH-23), Taiwan’s Ministry of Science and Technology

(MOST104-2314-B-038-027-MY2; MOST103-2320-B-214-010-MY2;

NSC102-2314-B-038-021-MY3), and Taiwan’s Ministry of Health and Welfare Clinical Trial

and Research Center of Excellence (MOHW105-TDU-B-212-133019).

Data sharing statement: dataset available from the Taiwan’s National Health Research

Institutes (http://nhird.nhri.org.tw/index1.php).

Author contribution: All the authors revised and approved the contents of the submitted

article. CCL and CCS created the idea of the manuscript. CCL and HLL conducted statistical

analysis of data. SWW and CCL wrote the manuscript. All the authors made substantial

contributions to interpretation of data and carried out a critical revision of the manuscript for

important intellectual content.

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Fig 1 The epilepsy-free proportions estimated for post-stroke patients with and without

acupuncture treatment using the Kaplan-Meier method.

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Table 1 Baseline Characteristics of Stroke Patients With and Without Acupuncture

Treatment

Acupuncture use

No (N = 21020) Yes (N = 21020) P value

N (%) n (%)

Female 9272 (44.1) 9272 (44.1) 1.0000

Age, years 1.0000

20-29 75 (0.4) 75 (0.4)

30-39 284 (1.4) 284 (1.4)

40-49 1878 (8.9) 1878 (8.9)

50-59 4320 (20.6) 4320 (20.6)

60-69 7080 (33.7) 7080 (33.7)

70-79 6311 (30.0) 6311 (30.0)

≥80 1072 (5.1) 1072 (5.1)

Stroke subtype 1.0000

Hemorrhage 1775 (8.4) 1775 (8.4)

Ischemic 12285 (58.4) 12285 (58.4)

Other 6960 (33.1) 6960 (33.1)

Low income 184 (0.9) 184 (0.9) 1.0000

Urbanization 1.0000

Low 582 (2.8) 582 (2.8)

Moderate 7247 (34.5) 7247 (34.5)

High 13191 (62.8) 13191 (62.8)

Coexisting medical condition

Hypertension 15887 (75.6) 15887 (75.6) 1.0000

Mental disorder 8144 (38.7) 8144 (38.7) 1.0000

Diabetes mellitus 8048 (38.3) 8048 (38.3) 1.0000

Hyperlipidemia 3403 (16.2) 3403 (16.2) 1.0000

Head injury 1659 (7.9) 1659 (7.9) 1.0000

Parkinson’s disease 656 (3.1) 656 (3.1) 1.0000

Alzheimer’s disease 13 (0.1) 13 (0.1) 1.0000

Brain cancer 4 (0.0) 4 (0.0) 1.0000

Renal Dialysis 304 (1.5) 304 (1.5) 1.0000

Rehabilitation 13803 (46.6) 13803 (46.6) 1.0000

Anti-epilepsy drugs 6170 (29.4) 6170 (29.4) 1.0000

Anticoagulant 1599 (7.6) 1599 (7.6) 1.0000

Anti-platelet agents 20016 (95.2) 20016 (95.2) 1.0000

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Lipid-lowering agents 11307 (53.8) 11307 (53.8) 1.0000

ICU stay 1412 (6.7) 1412 (6.7) 1.0000

Neurosurgery 318 (1.5) 318 (1.5) 1.0000

Length of stay, days 6.92±5.19 6.93±5.25 0.7302

ICU = intensive care unit.

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Table 2 Incidence and Risk of Epilepsy for Stroke Patients With and Without Acupuncture Treatment by Age, Sex, and Stroke

Type

No acupuncture Acupuncture use

n Events Person-year Incidence n Events Person-year Incidence HR (95% CI)

All* 21020 1382 120164 11.5 21020 993 101044 9.8 0.74 (0.68-0.80)

Female 9272 525 55162 9.5 9272 343 45620 7.5 0.70 (0.61-0.81)

Male 11748 857 65001 13.2 11748 650 55424 11.7 0.77 (0.69-0.85)

Age, years‡

20-29 75 9 408 22.1 75 3 369 8.1 0.16 (0.04-0.68)

30-39 284 31 1632 19.0 284 16 1363 11.7 0.39 (0.21-0.73)

40-49 1878 165 11601 14.2 1878 90 9357 9.6 0.51 (0.39-0.66)

50-59 4320 263 26875 9.8 4320 166 22064 7.5 0.66 (0.54-0.80)

60-69 7080 444 42234 10.5 7080 332 34762 9.6 0.79 (0.68-0.91)

70-79 6311 403 33073 12.2 6311 341 29006 11.8 0.88 (0.76-1.02)

≥80 1072 67 4340 15.4 1072 45 4123 10.9 0.71 (0.48-1.04)

Type of stroke§

Hemorrhage 1775 253 9355 27.0 1775 179 8501 21.1 0.60 (0.50-0.73)

Ischemic 12285 764 68961 11.1 12285 615 59265 10.4 0.86 (0.78-0.96)

Other 6960 365 41848 8.7 6960 199 33277 6.0 0.62 (0.52-0.74)

CI = confidence interval, HR = hazard ratio. *Adjusted for all covariates in Table 1. †Adjusted for covariates in Table 1 except sex. ‡Adjusted for covariates in Table 1 except age. §Adjusted for covariates in Table 1 except stroke subtype.

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Table 3 Risk of Epilepsy and Number of Acupuncture Treatment Packages in Stroke Patients

Number of packages n Events Person-years Incidence HR (95% CI)*

0 21020 1382 120164 11.5 0.77 (0.66-0.90)

2 4385 182 18258 10.0 1.06 (0.91-1.25)

3 2907 164 12720 12.9 0.84 (0.69-1.02)

4 2040 104 9597 10.8 0.75 (0.59-0.95)

5 1545 72 7271 9.9 0.74 (0.55-0.98)

6 1168 48 5464 8.8 0.64 (0.57-0.71)

≥7 8975 423 47734 8.9 0.69 (0.63-0.74)

CI = confidence interval, HR = hazard ratio. *Adjusted for age, sex, stroke subtype, low income, urbanization, hypertension, mental

disorder, diabetes, hyperlipidemia, head injury, Parkinson’s disease, Alzheimer’s disease,

brain cancer, renal dialysis, rehabilitation, anti-epilepsy drugs, anticoagulant, anti-platelet

agents, lipid-lowering agents, stay of intensive care unit, neurosurgery, and length of stay.

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STROBE 2007 (v4) checklist of items to be included in reports of observational studies in epidemiology*

Checklist for cohort, case-control, and cross-sectional studies (combined)

Section/Topic Item # Recommendation Reported on page #

Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 1, 3

(b) Provide in the abstract an informative and balanced summary of what was done and what was found 3

Introduction

Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 5

Objectives 3 State specific objectives, including any pre-specified hypotheses 6

Methods

Study design 4 Present key elements of study design early in the paper 7

Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure, follow-up, and data

collection 7, 8

Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of participants. Describe

methods of follow-up

Case-control study—Give the eligibility criteria, and the sources and methods of case ascertainment and control

selection. Give the rationale for the choice of cases and controls

Cross-sectional study—Give the eligibility criteria, and the sources and methods of selection of participants

8, 9

(b) Cohort study—For matched studies, give matching criteria and number of exposed and unexposed

Case-control study—For matched studies, give matching criteria and the number of controls per case 8, 9

Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic

criteria, if applicable 8, 9

Data sources/ measurement 8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe

comparability of assessment methods if there is more than one group 8, 9

Bias 9 Describe any efforts to address potential sources of bias 9, 10

Study size 10 Explain how the study size was arrived at 9, 10

Quantitative variables 11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen

and why 9, 10

Statistical methods 12 (a) Describe all statistical methods, including those used to control for confounding 9, 10

(b) Describe any methods used to examine subgroups and interactions 9, 10

(c) Explain how missing data were addressed 9, 10

(d) Cohort study—If applicable, explain how loss to follow-up was addressed

Case-control study—If applicable, explain how matching of cases and controls was addressed 9, 10

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Cross-sectional study—If applicable, describe analytical methods taking account of sampling strategy

(e) Describe any sensitivity analyses 9, 10

Results

Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility,

confirmed eligible, included in the study, completing follow-up, and analysed 11, 12

(b) Give reasons for non-participation at each stage 11, 12

(c) Consider use of a flow diagram 11, 12

Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and

potential confounders 11, 12

(b) Indicate number of participants with missing data for each variable of interest 11, 12

(c) Cohort study—Summarise follow-up time (eg, average and total amount) 11, 12

Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time 11, 12

Case-control study—Report numbers in each exposure category, or summary measures of exposure 11, 12

Cross-sectional study—Report numbers of outcome events or summary measures 11, 12

Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95%

confidence interval). Make clear which confounders were adjusted for and why they were included 11, 12

(b) Report category boundaries when continuous variables were categorized 11, 12

(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period 11, 12

Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses 11, 12

Discussion

Key results 18 Summarise key results with reference to study objectives 13

Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss both direction

and magnitude of any potential bias 16

Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results

from similar studies, and other relevant evidence 13-17

Generalisability 21 Discuss the generalisability (external validity) of the study results 13-17

Other information

Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the original study on

which the present article is based 18

*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.

Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE

checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at

http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.

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