ORIGINAL ARTICLE

Cataract surgery is associated with a reduced risk of dementia: a nationwide population-based cohort study W.-K. Yua,*, Y.-T. Chenb,c,*, S.-J. Wangc,d,e,f, S.-C. Kuog,h,i, B.-C. Shiaj,k and C. J.-L. Liua,c a

EUROPEAN JOURNAL OF NEUROLOGY

Department of Ophthalmology, Taipei Veterans General Hospital, Taipei; bDepartment of Medicine, Taipei City Hospital Heping Fuyou Branch, Taipei; cFaculty of Medicine, National Yang Ming University School of Medicine, Taipei; dDepartment of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei; eInstitute of Brain Science, National Yang-Ming University, Taipei; f Brain Research Center, National Yang-Ming University, Taipei; gDivision of Infectious Diseases, Department of Medicine, Taipei Veterans General Hospital, Taipei; hInstitute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei; iNational Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli; jGraduate School of Business Administration, Fu Jen Catholic University, Taipei; and kDepartment of Statistics and Information Science and Applied Statistics, Fu Jen Catholic University, Taipei, Taiwan

Keywords:

cataract, cataract surgery, dementia Received 15 January 2014 Accepted 25 July 2014 European Journal of Neurology 2015, 22: 1370– 1379 doi:10.1111/ene.12561

Background and purpose: Our purpose was to determine the association of cataract surgery with subsequent development of dementia in older adults with newly diagnosed cataract. Methods: By using data from Taiwan National Health Insurance Research Database (NHIRD), a population-based cohort study including 491 226 subjects aged 70 or older with first-time diagnosis of cataract coded from 2000 to 2009 was conducted. After matching cataract patients receiving cataract surgery with cataract patients without receiving cataract surgery for age, sex, index date, Charlson Comorbidity Index score, interval between first coding of cataract diagnosis and index date, hypertension and diabetes mellitus, 113 123 patients in each cohort were enrolled. The main outcome measure was newly diagnosed dementia coded by neurologists or psychiatrists more than 365 days after cataract surgery. Incidence rate and hazard ratio of dementia were compared between the cataract surgery and cataract diagnosis cohorts. Results: The incidence rate of dementia was 22.40 per 1000 person-years in the cataract surgery cohort and 28.87 per 1000 person-years in the cataract diagnosis cohort. The rate of dementia was significantly lower in the cataract surgery group (hazard ratio 0.77, 95% confidence interval 0.75 0.79, P < 0.001). Female gender (P < 0.001) and a shorter interval between the date of first coding of a cataract diagnosis and the date of cataract surgery (P = 0.009) were significantly associated with a lower incidence rate of dementia. Conclusion: In an NHIRD cohort of Taiwanese aged 70 years and older with a diagnosis of cataract, patients undergoing cataract surgery were associated with a reduced risk of subsequent dementia compared with those without cataract surgery.

Introduction Correspondence: C. J.-L. Liu, Department of Ophthalmology, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Road, Taipei, 11217 Taiwan (tel.: +886 2 28757325; fax: +886 2 28761351; e-mail: [email protected]) and S.-J. Wang, Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, 201, Sec. 2, Shih-Pai Road, Taipei, 11217 Taiwan (tel.: +886 2 28757578; fax: +886 2 28757762; e-mail: [email protected]). *These authors contributed equally to this work.

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Dementia is an important age-related disorder of cognitive and behavioral impairment that markedly interferes with social and occupational functioning. It is estimated that there were 24.3 million and 35.6 million patients with dementia worldwide in 2001 and 2010, respectively, and the number is estimated to nearly double every 20 years, to 65.7 million in 2030 and

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115.4 million in 2050 [1,2]. Dementia has an enormous impact on affected families and creates a socioeconomic burden: the estimated costs of dementia totaled US$604 billion globally in 2010 [3]. The prevalence of dementia rises exponentially with advancing age, from 1% at age 65 to 15% at age 85, and up to more than 40% at age 95 [4,5]. Age-related cataract refers to acquired lens opacity with aging and is the leading cause of reversible visual impairment and blindness worldwide [6]. Visual prognosis is usually good after modern cataract extraction with implantation of an intraocular lens (IOL). The Beaver Dam Eye Study reported that the cumulative incidence of nuclear, cortical and subcapsular cataracts in right eyes increased from 2.9%, 1.9% and 1.4% in persons aged 43 54 years to 40.0%, 21.8% and 7.3% in those aged 75 years or older, respectively [7]. The Speedwell Eye Study, a cross-sectional survey of men aged 65 83 years, has shown that 25% of the participants had visual acuity of 6/24 or less attributable to cataract [8]. Previous studies have demonstrated a strong association between visual impairment and poor cognitive function, particularly in the elderly [9,10]. The Singapore Malay Eye Study, a population survey of subjects aged 60 80 years, found that older subjects with visual impairment, particularly that due to cataract, were more likely to have cognitive dysfunction [11]. Jefferis et al. [12] reviewed the association of cataract and cognitive impairment and proposed a need for a multidisciplinary approach for patients with visual symptoms, ophthalmology pathology and dementia. Several prospective interventional studies reported improvements in cognitive functions after cataract surgery in the elderly [13–15]. However, it is unknown whether cataract extraction is helpful in reducing the incidence or postponing the development of senile dementia. In the present study, the aim was to determine the association between cataract extraction with IOL implantation and subsequent development of senile dementia at least 1 year after the date of surgical intervention in a nationwide population-based cohort study.

Design Data source

In the current study, data from the National Health Insurance Research Database (NHIRD) of Taiwan were used. In 1995, a national health insurance program was launched in Taiwan, in which the enrollment is mandatory; thus it covered more than 98% of

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residents. In 1999, the Bureau of National Health Insurance began to release patient data in electronic form under the NHIRD project. The NHIRD consists of de-identified secondary data released for research purposes. Various extracted data sets are available to researchers, and hundreds of published papers have used the NHIRD as the basis for their studies. The accuracy of diagnoses in the NHIRD has been validated for several diseases [16–19]. The diseases were coded according to the International Classification of Disease, Ninth Revision, Clinical Modification (ICD9-CM) diagnosis codes, 2001 edition. Ethical approval for the study was obtained from the Institutional Review Board of Taipei Veterans General Hospital. Study design

This was a population-based, observational retrospective cohort study to determine the association between cataract surgery and the risk of subsequent dementia. Two cohorts, a cataract surgery cohort and a cataract diagnosis cohort, were enrolled in our study (Fig. 1). All subjects aged 70 years or older in 2000 were identified, and all their data were extracted regarding demographic variables, diagnosis codes, procedure codes and drug prescriptions for the period from January 2000 to December 2010, including information about outpatient visits and hospital admission. The database from January 1995 to December 1999 was further extracted to ensure that all individuals were available for at least a 5-year follow-up before enrollment, which would be used for definition of comorbidities and to validate that cataract diagnosis was first made after the year 2000. Participants

This study enrolled all individuals aged 70 years or older in January 2000 in Taiwan. Amongst them, patients with the diagnostic code of cataract (ICD-9CM code 366.x) made by ophthalmologists from 2000 to 2009 were selected. None of these patients had the diagnostic code of cataract during the 5-year period before 2000. The cataract surgery cohort comprised patients who had a diagnosis of cataract and received cataract surgery during the period between 2000 and 2009. The National Health Insurance Administration does not subsidize cataract surgery for eyes with a best corrected visual acuity equal to or better than 0.4, and more than one visit before cataract surgery is required, except for an emergency. Patients receiving cataract surgery without simultaneous implantation of IOL or receiving surgery on the day when cataract diagnosis was first coded were excluded from the

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Figure 1 Patient selection flow chart.

study to minimize bias caused by incorrect diagnosis coding, inaccurate preoperative visual acuity measurement and coexistent emergency eye condition. Since cases of newly diagnosed dementia that occurred within 365 days of cataract surgery were not considered to be an event relevant to the effect of surgical intervention in this study, the index date was defined as 366 days after cataract surgery in order to avoid immortal time bias. Immortal time refers to a period within 365 days of cataract surgery in which, by our design, the occurrence of dementia cannot occur. Patients who died, left the insurance program, or were

coded as dementia within 365 days of cataract surgery were excluded. Also excluded were patients who were diagnosed to have antecedent cerebrovascular disease (ICD-9-CM codes 430.x 438.x), dementia (ICD-9CM codes 290.x or 331.0), ocular disease which may hamper vision recovery after cataract surgery (ICD-9CM codes 42, 78.5, 131.6, 360.0x, 360.4x, 360.5, 360.6, 361.00 361.07, 361.81, 362.12, 362.30 362.33, 362.35, 362.36, 362.50 362.56, 362.7x, 363.0x 363.6x, 366.2, 368.0x, 369.x, 371.03, 371.05, 371.6x, 377.1x, 377.34, 377.41, 377.49, 379.31, 379.5x, 743.30 743.34, 870.3, 870.4871.2, 871.5, 871.6, 921.3), or other

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ophthalmic operations indicating a history of visionimpairing ocular diseases (Fig. 1). Matching

This study also included a matched control cohort comprising the remaining patients who had a diagnosis of cataract but not receiving cataract surgery during the study period (cataract diagnosis cohort). Since the cataract diagnosis cohort did not receive cataract surgery, they were assigned the same index dates as those of their surgical counterparts during the process of matching. After applying the same exclusion criteria as the cataract surgery cohort to the cataract diagnosis cohort, one cataract diagnosis case for each patient in the cataract surgery cohort was identified, which was individually matched by age (0.5 year), sex, Charlson Comorbidity Index (CCI) score (1 score), presence or absence of hypertension and diabetes mellitus, and interval (90 days) between the date of first coding of cataract and the index date. Outcomes

Both cohorts were followed until 31 December 2010, death, admission for cerebrovascular disease (ICD-9CM codes 430.x 438.x) or diagnosis of dementia (ICD-9-CM codes 290.x or 331.0). Dementia diagnosis was considered in this study only when it was coded by neurologists or psychiatrists. In Taiwan, patients can make an appointment with a neurologist or psychiatrist without referral. The concept of person-years was adopted to assess the risk of newly developed dementia. Viewing things in person-years allowed us to look at our cohort in a more general way, rather than trying to separate out and process data from each individual member of the study population. To obtain the number, all the years of follow-up of all participants during the study period were added up, and then the sum of years was divided by the occurrence of dementia. Statistical analysis

Descriptive statistics were used to describe the baseline characteristics of our cohort. Baseline characteristics of the two groups were compared using Pearson v2 tests for categorical variables and the independent t test for parametric continuous variables. The cumulative incidence of dementia was calculated by the Kaplan Meier method. The relative risk of dementia between the two groups was calculated with the hazard ratio (HR) from Cox regression models. Cox regression models were also performed on age, CCI,

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hypertension, diabetes mellitus, dyslipidemia, coronary artery disease and atrial fibrillation subgroups to examine their influences on the incidence of dementia 1 year after cataract surgery. Tests of interactions were performed for those subgroups by the likelihood ratio test. Microsoft SQL Server 2008 R2 (Microsoft Corp., Redmond, WA, USA) was used for data linkage, processing and sampling. All statistical analyses were conducted using STATA statistical software (version 12.0; StataCorp., College Station, TX, USA).

Results Characteristics of the study population

Of a total of 23 725 083 beneficiaries in Taiwan, 1 784 960 subjects aged 70 years or older were enrolled into the database that was evaluated. In all, 491 226 patients with a date of first-time diagnosis of cataract between January 2000 and December 2009 were identified: 236 894 patients in the cataract surgery group and 254 332 patients in the cataract diagnosis group, respectively. After excluding 15 182 patients who received cataract surgery on the day of first-time diagnosis of cataract, 9669 without simultaneous implantation of IOL, 4478 who were diagnosed as dementia within 365 days after cataract surgery, 7669 lost to follow-up within 365 days after cataract surgery, 27 300 who had a history of vision-impairing disease other than cataract or ophthalmic surgery indicating other vision-impairing diseases, 21 350 with antecedent cerebrovascular diseases and 6959 with a history of dementia, 144 287 patients who had received cataract surgery with IOL implantation during the study period were enrolled for further analyses (Fig. 1). After matching for age, sex, CCI score, interval between first coding of cataract diagnosis and index date, hypertension and diabetes mellitus, a total of 113 123 patients in the cataract surgery cohort and 113 123 matched patients in the cataract diagnosis cohort, i.e. without cataract surgery, were included in our analyses. The mean age of the cataract surgery cohort was 79.4 years (SD 4.9 years). Of these patients, 50.1% were female. In the cataract surgery cohort, the median interval between surgery and the date of first coding of cataract diagnosis was 165 days (interquartile range 12–885 days). The detailed results are shown in Table 1. Dementia incidence

During the follow-up period, there were 23 620 newly diagnosed cases of dementia: 10 829 amongst 483 343

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Table 1 Baseline characteristics of the patients

Mean age, yearsa Male Duration between the first-time diagnosis of cataract and cataract surgeryb Duration between the first-time diagnosis of cataract and index dateb Charlson Comorbidity Index score 0 1 2 3 ≥4 Hypertension Diabetes mellitus Dyslipidemia Coronary artery disease Atrial fibrillation

Cataract surgery cohort (N = 113 123)

Matched cataract diagnosis cohort (N = 113 123)

P value

79.4  4.9 56 443 (49.9) 165 (12–885)

79.4  4.9 56 443 (49.9) –

0.893 1.000

530 (377–1250)

526 (379–1244)c

0.05

14 067 20 565 23 460 21 291 33 740 83 346 38 487 37 317 53 694 5677

13 829 20 596 23 713 21 420 33 565 83 346 38 487 37 857 53 877 5667

0.373

(12.4) (18.2) (20.7) (18.8) (29.8) (73.7) (34.0) (33.0) (47.5) (5.0)

(12.2) (18.2) (21.0) (18.9) (29.7) (73.7) (34.0) (33.4) (47.6) (5.0)

1.000 1.000 0.124 0.441 0.923

Data are shown as no. (%) unless otherwise indicated. aShown as mean (standard deviation); bshown as median (interquartile range); cduration between the first-time diagnosis of cataract and matched date of cataract surgery.

person-years in the cataract surgery cohort and 12 791 amongst 443 051 person-years in the cataract diagnosis cohort. The incidence rate of dementia was 22.40 per 1000 person-years in the cataract surgery cohort and 28.87 per 1000 person-years in the cataract diagnosis cohort. Compared with the cataract diagnosis cohort, the cataract surgery group was associated with a decreased risk of dementia (Table 2 and Fig. 2). The adjusted HR (aHR) was 0.76 [95% confidence interval (CI) 0.74–0.78, P < 0.001]. Risk of dementia by subgroup analyses including age, sex and comorbid diseases

Tests of interactions were significant (P < 0.001) and for the interval between the first coding of cataract diagnosis and cataract surgery (P = 0.009) (Table

for gender the date of the date of 3). When

compared with patients of a different gender, the HR of dementia was lower in females (aHR 0.73, 95% CI 0.70–0.75) than in males (aHR 0.80, 95% CI 0.77– 0.83). When stratified by duration between the firsttime diagnosis of cataract and cataract surgery, patients receiving cataract surgery within 365 days had the lowest HR of dementia amongst all groups (aHR 0.75, 95% CI 0.73–0.77). There was no evidence that age, CCI score, hypertension, diabetes mellitus, dyslipidemia, coronary artery disease or atrial fibrillation modified the association of cataract surgery with subsequent risk of dementia (Table 3).

Discussion In this nationwide population-based cohort study of subjects aged 70 years or older, patients undergoing cataract surgery during the study period were associated

Table 2 Incidence rate and hazard ratios of dementia in the cataract surgery and cataract diagnosis cohorts, 2000–2009

All follow-up period Within 3 years 3–5 years Within 5 years 5–10 years a

Adjusteda

Cataract surgery cohort

Cataract diagnosis cohort

Crude

Personyears

No. of events

Incidence rateb

Personyears

No. of events

Incidence rateb

Hazard ratio (95% CI)

P value

Hazard ratio (95% CI)

P value

483 343

10 829

22.40

443 051

12 791

28.87

0.77 (0.75–0.79)