Raghavan Lavanya

Assessment of the Scleral Spur in Anterior Segment Optical Coherence Tomography Images

OBJECTIVE To assess visibility of the scleral spur in anterior segment optical coherence tomography (AS-OCT) images. METHODS This cross-sectional observational study included 502 participants aged 50 years or older who had no previous ophthalmic problems and were recruited from a community clinic in Singapore. All participants underwent gonioscopy and AS-OCT (Visante; Carl Zeiss Meditec, Dublin, California). Scleral spur location was assessed in AS-OCT images by 2 examiners with glaucoma subspecialty training and was defined as the point where there was an inward protrusion of the sclera with a change in curvature of its inner surface. RESULTS Scleral spur location could be determined in 72% of the images of the right eye. Its location on AS-OCT images was less detectable in quadrants with a closed angle on gonioscopy and also in images obtained in the superior and inferior compared with the nasal and temporal quadrants (64%, 67%, 75%, and 80%, respectively; P < .001). CONCLUSIONS The inability to detect the scleral spur may hamper quantitative analysis of anterior chamber angle parameters that are dependent on the location of this anatomical structure, particularly in the superior and inferior quadrants. New parameters independent of the scleral spur may be useful for detecting eyes at risk of angle closure.

Quantitative Iris Parameters and Association with Narrow Angles

PURPOSE To investigate the relationship between quantitative iris parameters (iris curvature [I-Curv], iris area [I-Area], and iris thickness) and the presence of narrow angles. DESIGN Cross-sectional, community-based study. PARTICIPANTS We recruited 2047 subjects >50 years old without ophthalmic symptoms from a community clinic in Singapore. METHODS All subjects underwent gonioscopy and anterior segment optical coherence tomography (AS-OCT) under dark conditions. An eye was considered to have narrow angles if the posterior pigmented trabecular meshwork was not visible for >/=180 degrees on nonindentation gonioscopy with the eye in the primary position. Customized software was used on horizontal AS-OCT scans to measure I-Curv, I-Area, and iris thickness 750 mum (IT750) and 2000 mum (IT2000) from the scleral spur. The average of both temporal and nasal measured values of the right eye was used for analysis. MAIN OUTCOME MEASURES The association between iris parameters and narrow angles on gonioscopy. RESULTS Iris parameters from 1465 eyes (71.6%) were available for analysis. Of these, 315 subjects (21.5%) had narrow angles. The mean I-Curv (0.366 vs 0.259 mm; P<0.020), IT750 (0.476 vs 0.453 mm; P<0.001), and IT2000 (0.491 vs 0.482 mm; P = 0.010) were greater in persons with than without narrow angles. After adjusting for age, gender, anterior chamber depth, axial length, and pupil size, the greater I-Curv, I-Area, IT750, and IT2000 were significantly associated with narrow angles (odds ratio [OR] 2.5 and 95% confidence interval [CI], 1.3-5.1; OR, 2.7 and 95% CI, 1.6-4.8; OR, 2.6 and 95% CI, 1.6-4.1; OR, 2.7 and 95% CI, 1.5-4.7, comparing 4th with 1st quartile for each parameter, respectively). In stratified analysis, women and subjects aged >/=60 years had stronger associations for most iris parameters with narrow angles than men and younger subjects. CONCLUSIONS Quantitative iris parameters (I-Curv, I-Area, and iris thickness) are independently associated with narrow angles, particularly in women and older subjects. These data provide further insights into the pathogenesis of angle closure in Singaporeans. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Collagen-related genes influence the glaucoma risk factor, central corneal thickness

Central corneal thickness (CCT) is a risk factor of glaucoma, the most common cause of irreversible blindness worldwide. The identification of genetic determinants affecting CCT in the normal population will provide insights into the mechanisms underlying the association between CCT and glaucoma, as well as the pathogenesis of glaucoma itself. We conducted two genome-wide association studies for CCT in 5080 individuals drawn from two ethnic populations in Singapore (2538 Indian and 2542 Malays) and identified novel genetic loci significantly associated with CCT (COL8A2 rs96067, p(meta) = 5.40 × 10⁻¹³, interval of RXRA-COL5A1 rs1536478, p(meta) = 3.05 × 10⁻⁹). We confirmed the involvement of a previously reported gene for CCT and brittle cornea syndrome (ZNF469) [rs9938149 (p(meta) = 1.63 × 10⁻¹⁶) and rs12447690 (p(meta) = 1.92 × 10⁻¹⁴)]. Evidence of association exceeding the formal threshold for genome-wide significance was observed at rs7044529, an SNP located within COL5A1 when data from this study (n = 5080, P = 0.0012) were considered together with all published data (reflecting an additional 7349 individuals, p(Fisher) = 1.5 × 10⁻⁹). These findings implicate the involvement of collagen genes influencing CCT and thus, possibly the pathogenesis of glaucoma.

Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10−12), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10−10) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10−9). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

Novel Association of Smaller Anterior Chamber Width with Angle Closure in Singaporeans

PURPOSE To describe variations in anterior chamber width (ACW) and investigate its association with the presence of narrow angles. DESIGN Cross-sectional study. PARTICIPANTS We recruited 2047 subjects aged 50 years or more from a community polyclinic and 111 subjects with primary angle closure (PAC) or primary angle closure glaucoma (PACG) from an eye hospital in Singapore. METHODS All participants underwent gonioscopy, anterior chamber depth (ACD) and axial length (AL) measurement (IOLMaster; Carl Zeiss, Jena, Germany), and anterior-segment optical coherence tomography (AS-OCT, Visante, Carl Zeiss Meditec, Dublin, CA). Customized software was used to measure the ACW, defined as the distance between the scleral spurs in the horizontal (nasal-temporal) axis of AS-OCT scans. An eye was deemed to have narrow angles if the posterior trabecular meshwork was not visible for at least 180 degrees on non-indentation gonioscopy with the eye in the primary position. MAIN OUTCOME MEASURES Anterior chamber width and narrow angles. RESULTS Data on 1465 community-based subjects were available for analysis. Anterior chamber width was significantly smaller in women compared with men (11.70 mm vs. 11.81 mm, respectively, P<0.001) and decreased significantly with age (P for trend <0.001). Significant predictors of smaller ACW were lower educational level, lower body mass index, shorter AL, shallower ACD, and Chinese race. Of the 1465 subjects, 315 (21.5%) had narrow angles on gonioscopy. Mean ACW was smaller in eyes with narrow angles compared with those without narrow angles (11.60 mm vs. 11.80 mm, P<0.001). The age- and gender-adjusted odds ratio for the highest quartile compared with the lower 3 quartiles of ACW with the presence of narrow angles was 3.4 (95% confidence interval, 2.3-5.0; P for trend <0.001). Hospital-based subjects with PAC/PACG had even smaller ACW than community subjects with narrow angles (11.33 mm vs. 11.60 mm, P<0.001). CONCLUSIONS In this cross-sectional study, ACW was smaller in women, Chinese persons, and older persons, and was associated with narrow angles in 2 different study populations. These data suggest that a smaller ACW may represent a novel risk indicator for angle closure.

Determinants of Angle Closure in Older Singaporeans

OBJECTIVES 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.

Prevalence and Causes of Visual Impairment and Blindness in an Urban Indian Population: The Singapore Indian Eye Study

PURPOSE To describe the prevalence and causes of visual impairment and blindness in an urban Indian population. DESIGN Population-based study. PARTICIPANTS Ethnic Indians aged more than 40 years living in Singapore. METHODS Participants underwent standardized ophthalmic assessments for visual impairment and blindness, defined using best-corrected visual acuity (BCVA) and presenting visual acuity (PVA), according to US and modified World Health Organization (WHO) definitions. MAIN OUTCOME MEASURES Unilateral visual impairment or blindness was defined on the basis of the worse eye, and bilateral visual impairment or blindness was defined on the basis of the better eye. Primary causes of visual impairment were determined. RESULTS A total of 3400 eligible individuals (75.6% response rate) participated. On the basis of US definitions, the age-standardized prevalence was 0.4% for bilateral blindness (≤20/200, better eye) and 3.4% for bilateral visual impairment (<20/40 to >20/200, better eye). Another 0.3% of bilateral blindness and 13.4% of bilateral visual impairment were correctable with refraction. Cataract was the principal cause of best-corrected bilateral blindness (60.0%) and bilateral visual impairment (65.7%). Other major causes of blindness and visual impairment included diabetic retinopathy, age-related macular degeneration, glaucoma, corneal opacity, and myopic maculopathy. CONCLUSIONS The prevalence of bilateral blindness and visual impairment in Indians living in Singapore is lower than estimates from populations living in India, but similar to estimates obtained from Singapore Malay and Chinese populations. Cataract is the leading cause of blindness and visual impairment. One in 20 cases of bilateral blindness and 1 in 10 cases of bilateral visual impairment are attributable to diabetic retinopathy. These data may have relevance to many ethnic Indian persons living outside India.

Diagnostic Performance of Anterior Chamber Angle Measurements for Detecting Eyes With Narrow Angles: An Anterior Segment OCT Study

OBJECTIVE To assess the diagnostic performance of angle measurements from anterior segment optical coherence tomography (AS-OCT) images for identifying eyes with narrow angles. METHODS We conducted a community-based cross-sectional study of individuals 50 years or older who had phakic eyes and who underwent AS-OCT imaging in the dark by a single operator and gonioscopy by an ophthalmologist masked to AS-OCT findings. An eye was considered to have narrow angles if the posterior pigmented trabecular meshwork was not visible for at least 180° on gonioscopy. Horizontal AS-OCT images were analyzed for the following measurements using customized software: angle opening distance (AOD) at 250, 500, and 750 μm from the scleral spur; trabecular-iris space area (TISA) at 500 and 750 μm; and angle recess area (ARA) at 750 μm. Areas under the receiver operating characteristic curves (AUCs) were generated for AOD, TISA, and ARA to assess the performance of these measurements in detecting eyes with narrow angles. RESULTS Of 2047 individuals examined, 582 were excluded mostly because of poor image quality or inability to locate the scleral spur. Of the remaining 1465 participants, 315 (21.5%) had narrow angles on gonioscopy. Mean (SD) age was 62.7 (7.7) years, 54.1% were women, and 90.0% were Chinese. The AUCs were highest for AOD750 in the nasal (0.90 [95% confidence interval, 0.89-0.92]) and temporal (0.91 [0.90-0.93]) quadrants. CONCLUSIONS The AOD750 is the most useful angle measurement for identifying individuals with gonioscopic narrow angles in gradable AS-OCT images. Poor definition of the scleral spur precludes quantitative analysis in approximately 25% of AS-OCT images.

Genome-wide association studies in Asians confirm the involvement of ATOH7 and TGFBR3, and further identify CARD10 as a novel locus influencing optic disc area

Damage to the optic nerve (e.g. from glaucoma) has an adverse and often irreversible impact on vision. Earlier studies have suggested that the size of the optic nerve head could be governed by hereditary factors. We conducted a genome-wide association study (GWAS) on 4445 Singaporean individuals (n = 2132 of Indian and n = 2313 of Malay ancestry, respectively), with replication in Rotterdam, the Netherlands (n = 9326 individuals of Caucasian ancestry) using the most widely reported parameter for optic disc traits, the optic disc area. We identified a novel locus on chromosome 22q13.1, CARD10, which strongly associates with optic disc area in both Singaporean cohorts as well as in the Rotterdam Study (RS; rs9607469, per-allele change in optic disc area = 0.051 mm(2); P(meta) = 2.73×10(-12)) and confirmed the association between CDC7/TGFBR3 (lead single nucleotide polymorphism (SNP) rs1192415, P(meta) = 7.57×10(-17)) and ATOH7 (lead SNP rs7916697, P(meta) = 2.00 × 10(-15)) and optic disc area in Asians. This is the first Asian-based GWAS on optic disc area, identifying a novel locus for the optic disc area, but also confirming the results found in Caucasian persons suggesting that there are general genetic determinants applicable to the size of the optic disc across different ethnicities.

Prevalence and Risk Factors for Refractive Errors in Indians: The Singapore Indian Eye Study (SINDI)

PURPOSE To determine the prevalence and risk factors for refractive errors in middle-aged to elderly Singaporeans of Indian ethnicity. METHODS A population-based, cross-sectional study of Indians aged over 40 years of age residing in Southwestern Singapore was conducted. An age-stratified (10-year age group) random sampling procedure was performed to select participants. Refraction was determined by autorefraction followed by subjective refraction. Myopia was defined as spherical equivalent (SE) < -0.50 diopters (D), high myopia as SE < -5.00 D, astigmatism as cylinder < -0.50 D, hyperopia as SE > 0.50 D, and anisometropia as SE difference > 1.00 D. Prevalence was adjusted to the 2000 Singapore census. RESULTS Of the 4497 persons eligible to participate, 3400 (75.6%) were examined. Complete data were available for 2805 adults with right eye refractive error and no prior cataract surgery. The age-adjusted prevalence was 28.0% (95% confidence interval [CI], 25.8-30.2) for myopia and 4.1% (95% CI, 3.3-5.0) for high myopia. There was a U-shaped relationship between myopia and increasing age. The age-adjusted prevalence was 54.9% (95% CI, 52.0-57.9) for astigmatism, 35.9% (95% CI, 33.7-38.3) for hyperopia, and 9.8% (95% CI, 8.6-11.1) for anisometropia. In a multiple logistic regression model, adults who were female, younger, taller, spent more time reading and writing per day, or had astigmatism were more likely to be myopic. Adults who were older or had myopia or diabetes mellitus had higher risk of astigmatism. CONCLUSIONS In Singapore, the prevalence of myopia in Indian adults is similar to those in Malays, but lower than those in Chinese. Risk factors for myopia are similar across the three ethnic groups in Singapore.