Lavanya R, Wong T, Friedman DS, Aung HT, Alfred T, Gao H, Seah SK, Kashiwagi K, Foster PJ, Aung T. Determinants of Angle Closure in Older Singaporeans. Arch Ophthalmol. 2008;126(5):686-691. doi:10.1001/archopht.126.5.686
Copyright 2008 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2008
To investigate systemic and ocular risk factors for angle closure (AC) in older Singaporeans and to determine if these risk factors are different in men vs women and in Chinese vs non-Chinese persons.
A cross-sectional study of 2042 subjects with phakia 50 years or older recruited from a primary care clinic in Singapore. Subjects completed a detailed questionnaire and underwent refraction, biometry, and gonioscopy. Univariate and multivariate analyses were performed to determine risk factors for AC.
The prevalence of AC among this study population was 19.3% (n = 395); 89.4% (n = 1826) of the study population were Chinese. In univariate analysis, patients with AC were older, female, and of Chinese descent and had shorter axial length, lower body mass index, higher intraocular pressure, and shallower anterior chamber depth. In multivariate analysis, female sex (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.06-1.92; P =.02), Chinese race/ethnicity (OR, 3.58; 95% CI, 2.03-6.29; P < .001), axial length (OR per millimeter increase, 0.69; 95% CI, 0.58-0.81; P<.001), and central anterior chamber depth of less than 2.80 mm vs at least 3.00 mm (OR, 42.5; 95% CI, 27.4-66.2; P<.001) were independently associated with AC.
In this community-based study of older Singaporeans, statistically significant independent predictors of AC were female sex, shorter axial length, shallower central anterior chamber depth, and Chinese race/ethnicity. Sex and racial/ethnic differences in the risk of AC were not fully explained by sex and racial/ethnic variations in axial length or anterior chamber depth.
Primary angle-closure (AC) glaucoma is a leading cause of blindness, particularly in Asia.1- 3 It is responsible for most bilateral glaucoma blindness in Mongolia,4 Singapore,5 China,6,7 and India.8- 11 Risk factors for primary AC glaucoma have been previously studied and include a shallow anterior chamber depth (ACD) and other ocular biometric characteristics such as short axial length (AL).12- 15 However, the main mechanism for AC is unclear and may vary among different racial/ethnic groups in Asia. For example, in Mongolia the main underlying mechanism for AC seems to be pupil block,16 and the role of non–pupil block AC in other Asians is debatable.17- 19
It has been suggested that population screening for AC would be useful to identify subjects at risk of primary AC glaucoma, allowing potential earlier intervention (eg, prophylactic laser iridotomy). However, it is unclear if screening is effective. In addition, with more than 3 billion people in Asia, screening and prophylactic treatment may pose an impossible burden on health resources. Therefore, it is important to identify high-risk groups that may be targeted for glaucoma screening and blindness prevention efforts.
Singapore has a multiethnic Asian population with Chinese, Indian, and Malayan residents. It was previously reported that the incidence of acute AC was 12.2 cases per 100 000 per year, with women and Chinese persons having 3 times higher risk compared with men and non-Chinese persons.20,21 The objectives of this study were to investigate systemic and ocular risk factors for AC in older Singaporeans and to determine if these risk factors are different in men vs women and in Chinese vs non-Chinese persons.
A cross-sectional study of 2114 persons 50 years and older were recruited between December 2005 and July 2006 from a government-run polyclinic that provides primary health care services for residents living in the area around the clinic. Subjects were participants of a study evaluating new screening instruments for AC and did not have any ophthalmic complaints at the time of consultation. Written informed consent was obtained from all participants, and the study had the approval of the institutional review board of Singapore Eye Research Institute and was performed in accord with the tenets of the Declaration of Helsinki.
Exclusion criteria were the use of contact lenses or topical glaucoma medications, corneal disorders preventing anterior chamber assessment, and a history of glaucoma, penetrating eye injury, or prior intraocular surgery. Height was measured using a wall-mounted measuring tape, and weight was measured using an automatic weighing scale. Body mass index (BMI) was calculated as the weight in kilograms divided by height in meters squared.2 A standardized questionnaire, similar to a survey used in a previous population-based study22 on Chinese Singaporeans, was administered to all participants and inquired about demographic and socioeconomic details and medical and ocular history. Education was ascertained and was categorized as follows: (1) no formal education, (2) primary education, (3) secondary education, or (4) tertiary education. Occupation was categorized into 6 groups as follows: (1) managers, professionals, and officer workers; (2) salespersons; (3) machine operators and production workers; (4) laborers, cleaners, and agricultural workers; (5) homemakers; or (6) other. Housing type was classified as the following: (1) government flat (1-2 rooms, 3 rooms, or 4-5 rooms), (2) executive government flat, or (3) private housing. Individual monthly income was recorded in Singapore dollars (approximate exchange rate Sing$1.5=US$1). A history of symptoms suggestive of attacks of AC was ascertained by asking for a history of redness with eye pain or headache associated with blurred vision, nausea, or vomiting.
Participants underwent visual acuity measurement using a logarithm of the minimum angle of resolution chart (Lighthouse Inc, Long Island, New York) and autorefraction (Autorefractometer RM-8000B; Topcon Corporation, Tokyo, Japan). A comprehensive eye examination was performed that included slitlamp examination, stereoscopic optic disc examination with a 78-diopter lens (Volk Optical Inc, Mentor, Ohio), and intraocular pressure (IOP) measurement using Goldmann applanation tonometry (Haag-Streit, Koniz, Switzerland). Gonioscopy was performed at a low level of ambient illumination using a Goldmann 2-mirror lens at high magnification (×16) with the eye in the primary position of gaze. A 1-mm light beam was reduced to a narrow slit, and the vertical beam was offset horizontally for assessing superior and inferior angles and vertically for assessing nasal and temporal angles. Care was taken to avoid light falling on the pupil during gonioscopy. Minimum adjustment of the lens or eye was allowed to enable a view “over the hill” of a steep iris, while avoiding excessive eye movement and manipulation so as to gain an undistorted view of the angle. Indentation gonioscopy with the Sussman 4-mirror lens was used to establish the presence or absence of peripheral anterior synechiae. The Scheie grading scheme,23 which is based on the angle structures visible during the examination, was used, and AC by gonioscopy was defined as the presence of at least 180° of angle in which the posterior pigmented trabecular meshwork was not visible on nonindentation gonioscopy in the primary position. The examination and gonioscopy were performed in all subjects by one of us (R.L.) with extensive experience in performing gonioscopy in epidemiologic studies, standardized against another of us (T.A.) with subspecialty glaucoma training. A weighted κ statistic of 0.82 was achieved for the assessment of AC.
Axial length and central ACD were measured (IOL Master; Carl Zeiss, Jena, Germany).24,25 A scanning peripheral ACD analyzer (SPAC; Takagi, Nagano, Japan) was used to assess corneal curvature.26- 28 The IOL Master and SPAC measurements were performed among all subjects in the dark by a single experienced operator (H.T.A.).
The association between a potential risk factor and the presence of AC was initially evaluated using logistic regression models to determine the odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for age and sex, with statistical significance determined by the Wald test or likelihood ratio test. For continuous variables, the linearity assumption of the relationship with the log odds of outcome was tested by including the square; where the assumption was not met, the variable was categorized into 3 groups with levels that were clinically relevant and contained adequate numbers of patients. Variables that were originally categorical and had their number of levels reduced (race/ethnicity, education, and occupation) were tested against their original formats for significant loss of information using likelihood ratio test.
Multiple logistic regression models were then constructed to assess the independent effects of the various risk factors that were statistically significant after age and sex adjustment. The multivariate analyses were performed as follows. Model A included all variables relating to IOP, medical history, and sociodemographic status. Model B contained all variables in model A plus AL and refraction (sphere). Model C had all the variables in model B plus ACD. Finally, all variables that were not statistically significant were removed 1 at a time to derive the final model. Age, sex, and BMI were maintained in the final model irrespective of their final P values, and BMI was considered for multivariate analysis instead of height and weight. The area under the receiver operating characteristic curve was used to evaluate the discriminative ability of variables in each of the models. Multiple imputation techniques were used for missing values based on information from all candidate variables. Regression coefficient estimates were pooled across 5 imputed data sets for all multivariate analyses.
The right eye of all subjects was used for the analysis. The 5% significance level was used. Analysis was performed using commercially available software (STATA 9.2; StataCorp LP, College Station, Texas).
During a 7-month period, 2114 subjects were recruited into the study. Twelve subjects were ineligible because they had pseudophakia in both eyes or had a history of glaucoma. Of the remaining 2102 subjects, 2042 completed the gonioscopy examination and were included in the analysis. Of these, 52.6% (n = 1074) were female, and 89.4% (n = 1826) were Chinese.
Three hundred ninety-five subjects (19.3%) had AC in their right eye by gonioscopy. Subjects with AC (mean [SD] age, 65.1 [7.8] years) were older than subjects without AC (mean [SD] age, 62.7 [7.9] years; P < .001) and were more likely to be female than male (Table 1). After adjusting for age and sex, subjects with AC had lower BMI (P = .005) and were more often of Chinese descent (P = .001). Furthermore, adjusting for age and sex, subjects with AC were more likely to be hyperopic, to have shorter AL and shallower ACD, and to have higher IOP than subjects without AC. There was no statistically significant difference in the radius of corneal curvature between the 2 groups (P = .52).
Analysis of individuals identified as having AC revealed that the mean (SD) age-adjusted AL in men was statistically significantly longer than that in women (23.29 [0.08] vs 22.99 [0.06] mm, P = .002), but this association was no longer present after adjusting for height (23.15 [0.08] vs 23.15 [0.07] mm, P = .99). There was no statistically significant difference in the mean (SD) age-adjusted ACD in men vs women among persons with AC (2.68 [0.02] vs 2.69 [0.01] mm, P = .55).
Table 2 gives the results of multiple logistic regression models of predictors of AC. Anterior chamber depth was strongly associated with AC in a multivariate model adjusting for age, sex, AL, IOP, and race/ethnicity. Eyes with ACD of less than 2.80 mm were more likely to have AC than eyes with ACD of at least 3.00 mm (OR, 42.5; 95% CI, 27.4-66.2). Other variables that remained associated with AC in the multivariate model include IOP, female sex, shorter AL, Chinese race/ethnicity, and a history of symptoms suggestive of AC. Being Chinese was statistically significantly associated with the presence of AC even after adjustment for AL, ACD, and other risk factors. Although age was associated with AC on univariate analysis, this association disappeared after adjusting for all other factors (OR, 0.94; 95% CI, 0.64-1.37; P = .91), suggesting that, although AC increases with age, it is likely to be due to the biometric changes occurring in the eye.
In an analysis stratified by age and race/ethnicity, symptoms suggestive of prior attacks of AC were risk factors for AC in men (OR, 17.80; 95% CI, 3.06-103.00) but not in women (OR, 3.52; 95% CI, 0.92-13.40) (eTable). Symptoms had similar predictive value for AC in Chinese persons (OR, 5.78; 95% CI, 1.83-18.30) and in non-Chinese persons (OR, 6.84; 95% CI, 0.43-108.40). Other factors seemed to have a similar magnitude of risk among men and women.
In this cross-sectional study of older Singaporeans, statistically significant independent predictors of AC were female sex, shorter AL, shallower ACD, and Chinese race/ethnicity, even after adjustment for age and height. These associations are consistent with previous studies.12- 15 The prevalence of AC in this population sample was 19.3%. A previous population-based study5 among Chinese Singaporeans older than 50 years estimated the prevalence of AC to be 10.6%. The higher prevalence in our population may be owing to differing definitions of AC in the 2 studies. The previous study used at least 270° of posterior pigmented trabecular meshwork not visible on nonindentation gonioscopy to define AC, whereas our study used at least 180°. Because subjects with a known history of glaucoma or laser iridotomy were excluded from the present study and because the study participants were attending general physicians with nonophthalmic complaints, it seems unlikely that the high prevalence of AC was owing to sample selection. In our study, the risk for AC increased with shallower ACD, and an ACD of less than 2.80 mm was associated with a 42 times higher odds of AC compared with an ACD of at least 3.00 mm after controlling for age and other factors (Table 2). Previous investigations in Mongolia and Singapore have also documented that shallow ACD is associated with a higher prevalence of glaucomatous optic neuropathy.29
Chinese (as opposed to Malayan and Indian) race/ethnicity was a strong determinant of risk of AC. Our study found no difference in the mean (SD) age-adjusted ACD when comparing Chinese subjects with non-Chinese subjects in the overall population (3.07 [0.01] vs 3.03 [0.02] mm, P=.11) or in the subgroup of subjects with AC (2.69 [0.01] vs 2.67 [0.05] mm, P =.73). However, Chinese subjects had longer mean age-adjusted AL compared with that in non-Chinese subjects (23.94 [0.03] vs 23.45 [0.09] mm, P < .001), although this difference was not statistically significant in the subgroup of subjects with AC (23.12 [0.05] vs 22.74 [0.21] mm, P =.08). In multivariate analysis adjusting for age, sex, IOP, and biometric factors, Chinese subjects remained 3 times more likely to have AC than non-Chinese subjects. Chinese persons in Singapore were previously reported to have twice the rate of hospital admissions for symptomatic AC compared with Malayans and Indians.21 An earlier study18 comparing biometric factors such as AL, ACD, refraction, and corneal curvature in Taiwanese Chinese, African Americans, and American subjects of white race/ethnicity found that there were no statistically significant differences between these 3 groups for AL and ACD. The present finding that AC remains more common among Chinese even after adjusting for AL and ACD suggests that mechanisms for AC may differ across racial/ethnic groups and that factors specific to the angle (such as thicker iris or ciliary body anatomy) may have an important role in causing AC.
Women have consistently been found to have a higher risk for AC glaucoma.1,12,30 In this study, we found that women had an overall age- and race/ethnicity–adjusted OR of 1.86 (95% CI, 1.43-2.42; P < .001) for the risk of AC. Although women in general had age-adjusted shorter AL and shallower ACD than men, there were no statistically significant differences in the mean age- and height-adjusted ACD values between men and women in the subgroup of subjects with AC (2.65 [0.02] vs 2.71 [0.02] mm, P =.06). Similarly, there were no differences in AL after controlling for age and height. After adjusting for age, BMI, IOP, race/ethnicity, and ocular biometric factors, women still had a higher risk for AC compared with men (OR, 1.43; 95% CI, 1.06-1.92; P =.02). On stratifying by age, race/ethnicity, and ocular biometric factors, Chinese women had 3 times the risk of AC compared with non-Chinese women (OR, 3.03; 95% CI, 1.36-6.72) (eTable). This suggests that women are more prone to AC, although the increased propensity cannot be explained by differences in height or ocular biometric factors.
A finding of the present study was the positive predictive value of a history of previous symptoms suggestive of AC. Eleven of 395 persons (2.8%) with AC reported previous symptoms (on direct questioning), while 22 of 1647 unaffected persons (1.3%) reported such symptoms (positive predictive value, 33.3%; 95% CI, 18.0%-51.8%) using a prevalence of 19.3%. Most subjects reported redness of the eyes with minimal headache or eye pain, and treatment was not sought owing to the mild nature of the symptoms. Although we found that symptoms were statistically significantly associated with the disease, the small proportion of those reporting these phenomena underlines the fact that most AC is asymptomatic. Because subjects with a known history of glaucoma or laser iridotomy were excluded from this study and because subjects were unaware of the diagnosis of AC when being interviewed, reporting bias or recall bias seems unlikely. Subjects included in this study were attending general physicians with complaints unrelated to their eyes and vision; consequently, it is unlikely that symptomatic AC was overrepresented. The few persons with symptoms also argues against this being the result of bias from earlier presentation among those with symptoms. Nevertheless, a positive history of possible subacute attacks was a statistically significant independent risk factor for AC (OR, 6.46; 95% CI, 2.29-18.20; P < .001). Although a positive history of symptoms was reported in men and women more or less equally (1.4% vs 1.8%, P =.56), such symptoms were stronger predictors of AC in men (OR, 17.80; 95% CI, 3.06-103.00) than in women (OR, 3.52; 95% CI, 0.92-13.40). This contrasts with a previous study21 in which women had twice the rates of symptomatic AC than men. Our findings demonstrate that symptoms suggestive of AC in women may not be as sensitive or specific as those in men. In women, these symptoms may have been confused with or associated with other medical conditions such as migraine or cluster headaches. Another observation was that height did not have any effect on the presence of AC on univariate analysis (OR, 0.99; 95% CI, 0.97-1.01; P = .24) or multivariate analysis (OR, 1.00; 95% CI, 0.99-1.04; P =.28). We also found that subjects who had higher BMI were less likely to have AC (OR, 0.96; 95% CI, 0.93-0.99; P = .005), although this association was not statistically significant on multivariate analysis (OR, 0.97; 95% CI, 0.93-1.01; P = .20).
Limitations of this study were that lens thickness was not measured and that the ciliary body was not imaged by ultrasound biomicroscopy. This would have provided a greater understanding of the pathophysiologic mechanisms of AC in this population. In addition, there were fewer numbers of non-Chinese subjects, which resulted in lower precision of the analysis among this group. Another limitation of the study was that it was not population based but was a community-based screening study of older Singaporeans without ophthalmic complaints at a general polyclinic. It is likely that there might have been some selection biases in the sample. For example, the participants may have concurrent ocular and general medical problems that would have made them more receptive to an eye examination. The study subjects may also be more aware, concerned, and motivated about health issues and for these reasons volunteered to take part in the study. Hence, the results of this study cannot be extrapolated to the entire population, and further research validating these findings in a population-based study would be useful.
In conclusion, in this community-based, large cross-sectional screening study of older Singaporeans, the statistically significant independent predictors of AC were female sex, shorter AL, shallower ACD, and Chinese race/ethnicity. Furthermore, the findings suggest that sex and racial/ethnic differences in the risk of AC are not fully explained by sex or racial/ethnic variations in AL or ACD.
Correspondence: Tin Aung, MBBS, PhD, FRCSEdin, Department of Glaucoma, Singapore National Eye Center and Eye Research Institute, 11 Third Hospital Ave, Singapore 168751 (email@example.com).
Submitted for Publication: May 17, 2007; final revision received September 19, 2007; accepted September 30, 2007.
Financial Disclosure: None reported.
Funding/Support: This study was supported by an unrestricted grant from SingHealth Foundation, Singapore.