Variation of Angle Parameters in Asians: An Anterior Segment Optical Coherence Tomography Study in a Population of Singapore Malays

Abstract

purpose. To assess variations in angle parameters using anterior segment optical coherence tomography (AS-OCT) and to investigate demographic, ocular and systemic associations of angle width.

methods. This was a substudy of a population based, cross-sectional survey of 3280 (78.7% response rate) Malay people aged 40 to 80 years in Singapore. All participants underwent a standardized interview and ocular and systemic examination. AS-OCT was performed on 291 consecutive patients in standardized dark conditions. Angle opening distance (AOD-500) and trabecular–iris space area (TISA-500) 500 μm from the scleral spur were determined for the nasal and temporal angles. Anterior chamber depth (ACD) was also measured.

results. AS-OCT measurements were analyzed in 239 (82.1%) right eyes. Mean AOD 500 was smaller in women than in men, both nasally (0.255 vs. 0.293 mm, P = 0.026) and temporally (0.245 vs. 0.286 mm, P = 0.023). Mean TISA-500 was smaller in women in the nasal quadrant only (0.104 vs. 0.117 mm, P = 0.035). Mean ACD was smaller in women than in men (2.71 vs. 2.87 mm, P = 0.001). Multiple linear regression showed that axial length and ACD were significantly associated with AOD-500 and TISA-500 both nasally (adjusted R ² = 0.34 for AOD-500 and 0.20 for TISA-500) and temporally (adjusted R ² = 0.35 for AOD-500 and 0.24 for TISA-500). Body mass index, HbA_1c, systolic blood pressure, intraocular pressure, cup-to-disc ratio, and central corneal thickness were not significantly associated with AOD-500, TISA-500, or ACD.

conclusions. In this Malay population, angle width measured by AS-OCT was smaller in women than in men, and in eyes with shorter axial length and shallower ACD.

Primary angle-closure glaucoma (PACG) is a leading cause of blindness, particularly in Asian countries. Gonioscopy is the current reference standard for the assessment of the anterior chamber angle. However, a skilled clinician is needed to perform this procedure. The technique is semiquantitative and subject to inter- and intraobserver discrepancies. Anterior segment optical coherence tomography (AS-OCT) is a new method of imaging the angle. AS-OCT uses the principle of low-coherence interferometry to assess ocular tissues and may be used to obtain quantitative morphometric information. The longer wavelength (1310 nm) of AS-OCT allows deeper tissue penetration, resulting in higher resolution imaging of the anterior chamber and angle compared with the original AS- OCT, which uses a wavelength of 830 nm. ¹ An additional advantage of AS-OCT is that it is a rapid, noncontact technique that can be performed with various levels of illumination. 

It has been shown that compared with normal eyes, eyes with occludable angles and with PACG have smaller anterior chamber depth (ACD), thicker lenses, and shorter axial length. ^{2 3 4 5 6 7 8 9} However, many of these studies have used A-scan ultrasound biometry ^{2 3 4 6 9} or ultrasound biomicroscopy (UBM) ⁵ and most study samples were hospital based. ^{2 3 4 5 6} Both UBM and A-scan biometry are contact techniques, with the UBM further requiring a water bath with the patient supine. 

There is little literature investigating the distribution of angle parameters in a population using AS-OCT. In the Beijing Eye Study, slit lamp–based AS-OCT performed on a population of Chinese adults found that a shallow anterior chamber and a narrow chamber angle in Chinese adults is associated with older age, female sex, hyperopia, nuclear cataract, small optic discs, short body stature, increased central corneal thickness, and chronic angle-closure glaucoma. ¹⁰  

The purpose of this study was to assess the variations of angle parameters in a normal Asian population by using AS-OCT, and to investigate demographic, ocular, and systemic associations of angle width. 

Methods

Study Population

The current analysis is a substudy of the Singapore Malay Eye Study (SiMES), a population-based, cross-sectional study of 3280 Malay men and women, aged 40 to 80 years, living in Singapore (78.7% participation rate). The study design and details of sample recruitment of the SiMES have been described elsewhere. ^{11 12} All 291 consecutive subjects attending the SiMES between the dates of September 12 and November 25, 2005, were included in this substudy. The SiMES adhered to the principles of the Declaration of Helsinki, and ethics approval was granted from the Institutional Review Board of the Singapore Eye Research Institute. Written informed consent in either in the Malay or English language was obtained from each participant. 

Assessment of Ocular Parameters

Participants had a standardized examination procedure at a centralized clinic. Slit lamp examination (BQ-900; Haag-Streit, Köniz, Switzerland) was performed before and after pupil dilation. Intraocular pressure (IOP) was measured using Goldmann applanation tonometry (Haag-Streit) ¹¹ and the optic disc was examined through a +78-D lens at ×10 magnification. ^{13 14} Cataract was graded clinically using the Lens Opacity Classification System III (LOCS), grading nuclear opalescence. ¹⁵ Gonioscopy was performed by an examiner experienced in gonioscopy, who was masked to the AS-OCT findings. The test was performed in low ambient light with a Goldmann 2-mirror lens, at ×16 magnification, with the eye in the primary position. A 1-mm beam of light was used, and care was taken to avoid having light fall on the pupil. Minimal movement of the lens was allowed to enable an over-the-hill view with a convex iris; however, care was taken not to distort the view of the angle. A four-mirror (Sussman) lens was used to determine whether angle closure was due to apposition or peripheral anterior synechiae. The angle width for all four quadrants was graded using the modified Shaffer grading system. ¹⁶ Under this convention, the angle width is graded 4 for wide open, with the ciliary body being visible, and 0 for no visible angle structures. Axial length was measured with noncontact partial coherence laser interferometry (IOL Master; Carl Zeiss Meditec, Jena, Germany). 

AS-OCT

AS-OCT (Visante; Carl Zeiss Meditec, Dublin, CA) was performed under standardized dark conditions on 291 consecutive patients before any procedures that involved contact with the eye. ¹⁷ The details of AS-OCT imaging and the technology have been described previously. ¹⁸ Exclusion criteria were previous eye surgery or penetrating eye injury and inability to fixate for an OCT examination. With the participant in the sitting position and fixating on an internal target, images of the nasal and temporal angle quadrants (3 and 9 o’clock meridians) were captured by a single examiner (HTA), masked to other test results. To obtain the best-quality image, the examiner adjusted the saturation and noise as well as optimizing the polarization for each scan during the examination. Three images were taken for each eye and the best-quality image from each eye was selected for analyses. 

To correct for errors caused by the different refractive indices of the cornea and aqueous, the software integral to the AS-OCT, initially de-warps the image at the air–tear interface and at the corneal–aqueous interface. The AS-OCT images were analyzed with customized software (the Zhongshan Angle Analysis Program [ZAAP], Guangzhou, China) by a single examiner (NA) who was masked to other test results. ZAAP is a semiautomated angle assessment software that requires the examiner to identify the position of the scleral spur. The software then uses algorithms to define the borders of the corneal epithelium and endothelium and the anterior surface of the iris and then calculates the measurements automatically. ¹⁹ The angle opening distance (AOD) and trabecular–iris space area (TISA) in the temporal and nasal quadrants were measured 500 μm from the scleral spur in all AS-OCT images (Fig. 1) . The anterior chamber depth ACD was also measured as the distance between the endothelial surface of the cornea and the anterior surface of the lens along the visual axis. 

Assessment of Systemic Factors

Participants underwent a standardized interview, examination and collection of non-fasting venous blood samples. Height was measured in centimeters using a wall-mounted measuring tape. Weight was measured in kilograms with a digital scale (SECA, model 782 2321009; Vogel and Halke, Hamburg, Germany). Body mass index (BMI) was calculated as kilograms divided by square meters. Systolic and diastolic blood pressures (BP) as well as pulse rate were measured with a digital automatic blood pressure monitor (Dinamap model Pro Series DP110X-RW, 100V2; GE Medical Systems Information Technologies, Inc., Hillsboro, OR). Venous blood samples were analyzed for serum lipids, HbA1_C, creatinine, and casual glucose on the same day. Urine was collected to determine levels of microalbuminuria and creatinine. A detailed interviewer-administrated questionnaire was used to collect information about medical history, cigarette smoking, alcohol consumption, current medication, and socioeconomic status indicators such as education level, income, and type of domicile. ¹¹ Diabetes was diagnosed in a subject who had a nonfasting glucose level of ≥200 mg/dL (11.1 mmol/L) at examination, or had a physician diagnosis of diabetes and was using diabetic medications. Hypertension was defined as a systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg at examination or a physician diagnosis of hypertension. ¹¹  

Statistical Analysis

Statistical analysis was performed with commercial software (Statistical Package for Social Sciences, ver. 15.0; SPSS Inc., Chicago, IL). If both eyes were eligible for the study, only the right eye was analyzed. Results were reported as the mean, with differences between women and men tested by independent sample t-test. A χ² test was used for analyzing group differences for nominal data. Multiple linear regression analyses were performed to determine the independent relationship between the ocular and systemic factors with AOD-500 and TISA-500. Final multiple linear regression models included only age and sex (as other variables were not significant). Statistical significance was set at P < 0.05. The strength of the correlation coefficient was set at ≥0.8, very strong; 0.6 to 0.8, moderately strong; 0.3 to 0.5, fair; and <0.3, poor. ²⁰  

Results

AS-OCT measurements were analyzed in right eye images of 239 (of 291 subjects who had AS-OCT, 82.1%); 122 subjects were men (51%) and the mean age was 56.9 years (range, 40–80). Five of the subjects had a diagnosis of primary open-angle glaucoma. The remaining 52 subjects’ images were not analyzed due to poor image quality or pseudophakia; compared with the 52 excluded from analysis, the 239 subjects included were younger (56.9 vs. 62.8 years), had lower systolic blood pressure (145.6 vs. 156.7 mm Hg), were less likely to have diabetes (19.2% vs. 34.7%), and had shallower ACD (3.1 vs. 3.5 mm; data not shown). 

Table 1shows the characteristics of these 239 participants compared with the overall SiMES population who did not undergo AS-OCT (n = 3041). Included participants were younger (56.9 vs. 58.8 years), less likely to be smokers (69 vs. 593 participants), and more likely to have a higher IOP (16.0 vs. 15.3 mm Hg). 

The mean gonioscopic angle grade was 3.76 ± 0.48 (mean ± SD) nasally and 3.77 ± 0.48 temporally. There were no eyes that had closed angles (Shaffer, grade 0 or 1) in both nasal and temporal quadrants. 

Table 2shows the distribution of the AS-OCT measurement according to sex. The mean AOD-500 was significantly smaller in the women compared with the men, both nasally (P = 0.026) and temporally (P = 0.023). The mean ACD was also significantly smaller in the women (P = 0.001). The mean TISA-500 was only significantly smaller in the women for the nasal quadrant (P = 0.035). 

Table 3shows the relationship of systemic and ocular factors with AOD-500 and TISA-500 (univariate analysis). Associations were sought with serum lipids, HbA1_C, serum and urine creatinine, casual glucose, cigarette smoking, alcohol consumption, and socioeconomic factors, but none were found. Greater nasal and temporal AOD-500s and TISA-500s were significantly associated with a greater gonioscopic angle grade (P < 0.001) in the respective quadrants. A greater nasal and temporal AOD-500s were significantly associated with younger age (P = 0.01 and P = 0.022, respectively), male sex (P = 0.033 and P = 0.023 respectively), greater ACD (P < 0.001 and P < 0.001, respectively), longer axial length (P < 0.001 and P < 0.001, respectively), smaller spherical equivalent refraction (P < 0.001 and P < 0.001, respectively) and less lens opacity, measured by LOCS score (P = 0.007 and P = 0.009, respectively). Greater nasal and temporal TISA-500s were significantly associated with greater ACD and longer axial length (P < 0.001 in all cases) and with a more negative refractive error (P = 0.004 nasally and P < 0.001 temporally). 

Table 4shows the results of multiple linear regression models of the AS-OCT measurements with a model adjusted for age and sex. Significant determinants of greater nasal and temporal AOD-500s were a longer axial length (P < 0.001 and P = 0.005, respectively) and greater ACD (P < 0.001 in both cases). ACD (P < 0.001) and axial length (P = 0.049) were the significant determinants of TISA-500 nasally and with respect to TISA-500 temporally; the significant determinants were axial length (P = 0.042) and ACD (P < 0.001). Further adjustment for height did not change the results (data not shown). 

Discussion

AS-OCT is a new, noncontact method of imaging the angle. Previous studies that have compared AS-OCT with gonioscopy have found that the AS-OCT is highly sensitive in detecting angle closure when the AS-OCT images were assessed qualitatively, but specificity was lower at 55%. ^{21 22} However, correlation between quantitative measurement of the angle from AS-OCT and gonioscopy has not been examined. In this population-based study among Malay adults, greater nasal and temporal AOD-500s and TISA-500s were significantly associated with greater gonioscopic angle grades in the respective quadrants. We found that angle width, as measured by AS-OCT, was smaller in women than men and in eyes with shorter axial length and shallower ACD. 

Our data concur with those in several other studies, ^{23 24 25} including the most recent findings from the Beijing Eye Study. ¹⁰ Other studies have also shown that eyes with angle-closure have shorter axial lengths and shallower ACDs. ^{8 9 26 27} However, we found that axial length and ACD contributed to only approximately 34% of the variation in AOD-500 (adjusted R ² = 0.339 nasally and 0.345 temporally) and approximately 20% of the variation in TISA-500 (adjusted R ² = 0.200 nasally and 0.239 temporally), suggesting that other ocular and systemic factors are involved in determining the AOD-500 and TISA-500. Increased lens thickness has been found to be a significant determinant of angle closure. ^{8 9 26} Although we did not evaluate lens thickness, we looked at nuclear opalescence as graded by the LOCS system, and in the univariate analysis, increasing LOCS grade was significantly associated with smaller AOD-500 but TISA-500. However, in the multiple linear regression analysis adjusted for age and sex, LOCS grade was not found to be associated with either AOD-500 or TISA-500, probably indicating that age is a confounding intermediate phenotype in this relationship. Another determinant of angle-closure is lens position, ^{4 28 29} and studies have shown that a more anterior placed lens is found in people with angle closure. ^{4 28 29} Iris thickness has also been found to be a significant determinant of angle-closure, though data are somewhat contradictory, with Sihota et al. ⁵ finding that eyes with primary angle-closure glaucoma have thinner irises, but Ramani et al. ²⁹ finding no significant difference in iris thickness between those with suspected primary angle closure and normal subjects. These characteristics were not evaluated in this study. 

Of interest, of the two quantitative parameters, AOD-500 correlated more closely with the clinical gonioscopic assessment of angle width than did TISA-500, suggesting that AOD-500 reflects the gonioscopic findings more closely. The reasons for this are unclear. One possibility is that localized variations in iris contour or thickness in the region of the trabecular meshwork affects angle width, which in turn would affect the AOD-500, as AOD is a point distance. TISA-500, a measurement of area, may be less influenced by such variations in the iris, as these may average out over the area and the overall area may remain the same or is only slightly altered. As AOD-500 correlated more highly with clinical gonioscopic assessment of angle width than did TISA-500, it could be recommended that AOD-500 be used as an AS-OCT surrogate for gonioscopy. 

The Beijing Eye Study reported the association between age, ACD, and angle characteristics measured with slit lamp AS-OCT. The study found that older people had a narrower anterior chamber angle (measured in degrees) and shallower ACD (measured in millimeters). ¹⁰ We found that older persons had a smaller AOD-500, but age was not associated with TISA-500. The reasons for a lack of association in our study between older age and TISA-500 are unclear. Again, this may be related to the fact that TISA-500 is a measurement of area and not distance, and this parameter is less influenced by iris factors such as iris profile, which may change with age. Another possibility is that our sample size was underpowered for finding a significant association for TISA. The Beijing Eye study also found a narrower anterior chamber angle was significantly associated with short body stature ¹⁰ ; however, we did not find any association with height, perhaps because of racial differences between the two populations. 

Previous studies have shown that women are more likely to have angle closure. ^{4 9 24 26 27 30 31} The Liwan Eye Study, a population-based study in China, also found that women had narrower iridotrabecular angles as measured by gonioscopy. ³² With the anterior segment OCT, we are now able to quantify these differences. Our study found that the women had a significantly smaller AOD-500, nasal TISA-500, and ACD than did the men. The temporal TISA-500 was also smaller in the women but this was of borderline significance (P = 0.070). Our findings of reduced AOD-500 and nasal TISA-500 in women compared with men provide quantitative biometric evidence to explain the increased risk of angle-closure in women. ^{25 27 33 34 35}  

Limitations of this study should be discussed. The cross-sectional design limits causal inferences. In our study, only one cross-section AS-OCT image per quadrant was evaluated. This may result in an unrepresentative assessment of the AOD-500, TISA-500, or ACD, depending on where the cross-section is taken. The superior and inferior angle quadrants were not imaged because of technical difficulties in moving the eyelids out of the way and poor image quality. The results of our study may thus not be applicable to these vertical quadrants. Also our study involved a relatively small sample size, consisting of 291 patients from the original study cohort of 3280 randomly selected subjects from the community. The only patients with glaucoma in this substudy population had primary open-angle glaucoma; none had angle-closure glaucoma. In addition, it would have been interesting to examine the relationship between lens thickness and relative lens position with the AS-OCT measurements of angle width. This would help determine whether it is purely a bigger lens in a smaller eye that contributes to a narrower angle width or if there is a separate contribution from the lens position. Such a study would require A-scan ultrasound measurement, but this measurement was not performed in our study. These issues should be evaluated in further studies with a larger sample size. 

In conclusion, our population-based study in Asian Malays found that quantitative measures of anterior segment angles (AOD-500, TISA-500, and ACD) by AS-OCT were smaller in women than in men. Significant determinants of AOD-500 and TISA-500 were axial length and ACD, confirming previous associations of gonioscopic angle width with ocular biometry parameters. 

 Supported by National Medical Research Council Grants 0796/2003, 0863/2004, and CSI/0002/2005; and Biomedical Research Council Grant 501/1/25-5.

 Submitted for publication July 16, 2008; revised September 27 and November 3, 2008; accepted April 7, 2009.

 Disclosure: N. Amerasinghe, None; P.J. Foster, None; T.Y. Wong, None; H.M. Htoon, None; M. He, None; S.Y. Shen, None; H.T. Aung, None; S.-M. Saw, None; T. Aung, None

 The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.

 

Figure 1.

 

Cross-section through the angle structures illustrating AOD-500 and TISA-500. Modified from a diagram courtesy of Daniel Su, Singapore National Eye Centre.

Table 1.

 

Characteristics of Included Participants from the Singapore Malay Eye Study

Characteristic	Persons Included in AS-OCT Study (n = 239)	Persons Excluded from AS-OCT Study (n = 3041)	P *
Age (y)	56.9 (10.34)	58.8 (11.07)	0.005
Sex, male %	122 (51.0)	1454 (47.8)	0.335
Income, <S$1000	145 (60.7)	1685 (55.4)	0.115
Education, elementary or less	185 (77.4)	2276 (75.1)	0.425
HbA1c, %	6.4 (1.45)	6.5 (1.56)	0.779
Systolic blood pressure (mm Hg)	145.6 (22.17)	147.2 (23.89)	0.274
Body mass index, (kg/m2)	26.4 (5.32)	26.4 (5.09)	0.909
Diabetes	46 (19.2)	718 (23.6)	0.123
Hypertension	156 (65.3)	2090 (68.8)	0.265
Current smoker	69 (28.9)	593 (19.6)	0.001
Anterior chamber depth (mm)	3.1 (0.36)	3.1 (0.38)	0.298
Axial length (mm)	23.5 (1.09)	23.5 (1.05)	0.999
Intraocular pressure (mm Hg)	16.0 (3.32)	15.3 (3.71)	0.010
Central corneal thickness (μm)	543.0 (36.63)	541.0 (33.33)	0.424

 Data presented are the mean (SD) or number (%), as appropriate, for each variable. Data for ocular parameters are presented for right eye only.

*   P for the difference in characteristics by inclusion/exclusion from study, based on χ² test or t-test, as appropriate.

Table 2.

 

Distribution of the AS-OCT Measurements by Sex

AS-OCT Measurement	Male and Female (n = 239)			Male (n = 122)			Female (n = 117)			P	Absolute Difference (mm)	Relative Percentage Difference
		Mean	SD	Mean	SD	Mean	SD
AOD 500 nasal	0.274	0.131	0.293	0.144	0.255	0.114	0.026	0.038	13.0
AOD 500 temporal	0.266	0.138	0.286	0.141	0.245	0.132	0.023	0.041	14.3
ACD	2.789	0.365	2.867	0.338	2.707	0.375	0.001	0.160	5.6
TISA 500 nasal	0.111	0.049	0.117	0.058	0.104	0.037	0.035	0.013	11.1
TISA 500 temporal	0.103	0.049	0.109	0.052	0.097	0.045	0.070	0.012	11.0

Table 3.

 

Relationship of Systemic and Ocular Factors with AOD 500 and TISA 500

Systemic/Ocular Factor	AOD 500 Nasal			AOD 500 Temporal			TISA 500 Nasal			TISA 500 Temporal
		R	P	R	P	R	P	R	P
Age	−0.17	0.010	−0.16	0.015	−0.01	0.967	−0.03	0.589
Sex	−0.14	0.026	−0.15	0.023	−0.14	0.05	−0.12	0.070
Height in cm	0.13	0.045	0.13	0.051	0.08	0.221	0.08	0.221
BMI in kg/m2	0.11	0.085	0.04	0.552	0.13	0.046	0.07	0.279
Diabetes	0.01	0.837	0.03	0.625	0.02	0.734	0.04	0.559
HbA1c %	0.01	0.8443	0.03	0.647	0.01	0.880	0.07	0.293
Hypertension	0.11	0.088	0.09	0.172	0.04	0.587	0.03	0.639
Systolic BP (mm Hg)	0.01	0.837	0.08	0.208	0.01	0.952	0.02	0.742
Diastolic BP (mm Hg)	0.07	0.284	0.06	0.367	0.05	0.476	0.05	0.415
ACD (mm)	0.57	<0.001	0.58	<0.001	0.44	<0.001	0.49	<0.001
Axial length (mm)	0.40	<0.001	0.37	<0.001	0.28	<0.001	0.29	<0.001
Refraction spherical equivalent	−0.30	<0.001	0.29	<0.001	−0.19	0.004	−0.21	<0.001
IOP (mm Hg)	0.04	0.596	0.04	0.589	0.01	0.884	0.04	0.522
Vertical cup-to-disc ratio	0.03	0.707	0.06	0.345	0.04	0.590	0.08	0.228
Central corneal thickness (μm)	−0.001	0.992	−0.03	0.664	−0.06	0.398	−0.08	0.203
LOCS	−0.18	0.007	−0.17	0.009	−0.06	0.334	−0.05	0.456
Gonioscopy nasal	0.38	<0.001	—	—	0.25	<0.001	—	—
Gonioscopy temporal	—	—	0.33	<0.001	—	—	0.22	<0.001

  R, Pearson’s correlation coefficient; gonioscopy was graded using the modified Shaffer grading system.

Table 4.

 

Multivariate Linear Regression Analysis of AS-OCT Measurements

	All Persons
		β Coefficient	Standardized β	P
Adjusted AOD-500 nasal
Axial Length (mm)	0.025	0.203	0.001
ACD (mm)	0.171	0.474	<0.001
		Adjusted R 2 = 0.339
Adjusted AOD-500 temporal
Axial length (mm)	0.021	0.165	0.005
ACD (mm)	0.193	0.507	<0.001
		Adjusted R 2 = 0.345
Adjusted TISA 500 nasal
Axial length (mm)	0.006	0.128	0.049
ACD (mm)	0.054	0.406	<0.001
		Adjusted R 2 = 0.200
Adjusted TISA 500 temporal
Axial length (mm)	0.005	0.116	0.042
ACD (mm)	0.062	0.462	<0.001
		Adjusted R 2 = 0.239

 Models are adjusted for age and sex.