Comparison of intraocular pressure and anterior segment parameters in subjects with asymmetrical primary angle closure disease.

BACKGROUND: To compare intraocular pressure (IOP) and anterior segment parameters between eyes with unilateral primary angle closure glaucoma (PACG) and their fellow eyes with primary angle closure (PAC) or primary angle closure suspect (PACS). METHODS: Subjects underwent anterior segment imaging using 360-degree swept-source optical coherence tomography (SS-OCT, CASIA Tomey, Nagoya, Japan) and ocular investigations including gonioscopy and IOP measurement. Each SS-OCT scan (divided into 8 frames, 22.5 degrees apart) was analysed and an average was obtained for the following anterior segment parameters: iridotrabecular contact (ITC), angle opening distance (AOD750), iris thickness and curvature, anterior chamber width, depth and area (ACW, ACD and ACA) and lens vault (LV). RESULTS: Among 132 unilateral PACG subjects (mean age: 62.91 ± 7.2 years; 59.1% male), eyes with PACG had significantly higher presenting IOP (24.81 ± 0.94 vs. 18.43 ± 0.57 mmHg, p < 0.001), smaller gonioscopic Shaffer grade (2.07 ± 0.07 vs. 2.31 ± 0.07, p < 0.001) and a greater extent of peripheral anterior synechiae (PAS, 1.21 ± 0.21 vs. 0.54 ± 0.16 clock hours, p = 0.001). PACG eyes also exhibited increased ITC, ITC area, greater LV and smaller AOD750, ACD and ACA (all p < 0.05). Using the forward stepwise regression model, an increase in 1 mmHg in presenting IOP before laser peripheral iridotomy (LPI) increases the odds of having PACG by 9% (95% confidence interval 5%-14%). CONCLUSIONS: PACG eyes have higher presenting IOP, smaller anterior segment parameters, greater extent of PAS, and larger LV compared to their fellow eyes with angle closure. Narrower anterior chamber dimensions and higher presenting IOP before LPI may increase risk of chronic elevated IOP and glaucomatous optic neuropathy after LPI.

Mendelian Randomization Implicates Bidirectional Association between Myopia and Primary Open-Angle Glaucoma or Intraocular Pressure.

PURPOSE: Observational studies suggest that myopic eyes carry a greater risk of primary open-angle glaucoma (POAG); however, the evidence for this association is inconsistent. This may be the result of confounding factors that arise from myopia that complicate clinical tests for glaucoma. This study used Mendelian randomization (MR) analysis to determine genetic causal associations among myopia, glaucoma, and glaucoma-related traits that overcome the effects of external confounders. DESIGN: Bidirectional genetic associations between myopia and refractive spherical equivalent (RSE), POAG, and POAG endophenotypes were investigated. PARTICIPANTS: Data from the largest publicly available genetic banks (n = 216,257-542,934) were analyzed. METHODS: Multiple MR models and multivariate genomic structural modeling to identify significant mediators for the relationship between myopia and POAG. MAIN OUTCOME MEASURES: Genetic causal associations between myopia and POAG and POAG endophenotypes. RESULTS: We found consistent bidirectional genetic associations between myopia and POAG and between myopia and intraocular pressure (IOP) using multiple MR models at Bonferroni-corrected levels of significance. Intraocular pressure showed the most significant mediation effect on RSE and POAG (Sobel test, 0.13; 95% confidence interval, 0.09-0.17; P = 1.37 × 10-8). CONCLUSIONS: A strong bidirectional genetic causal link exists between myopia and POAG that is mediated mainly by IOP. Our findings suggest that IOP-lowering treatment for glaucoma may be beneficial in myopic eyes, despite the challenges of establishing a clear clinical diagnosis. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Differing Associations between Optic Nerve Head Strains and Visual Field Loss in Patients with Normal- and High-Tension Glaucoma.

PURPOSE: To study the associations between optic nerve head (ONH) strains under intraocular pressure (IOP) elevation with retinal sensitivity in patients with glaucoma. DESIGN: Clinic-based cross-sectional study. PARTICIPANTS: Two hundred twenty-nine patients with primary open-angle glaucoma (subdivided into 115 patients with high-tension glaucoma [HTG] and 114 patients with normal-tension glaucoma [NTG]). METHODS: For 1 eye of each patient, we imaged the ONH using spectral-domain OCT under the following conditions: (1) primary gaze and (2) primary gaze with acute IOP elevation (to approximately 35 mmHg) achieved through ophthalmodynamometry. A 3-dimensional strain-mapping algorithm was applied to quantify IOP-induced ONH tissue strain (i.e., deformation) in each ONH. Strains in the prelaminar tissue (PLT), the retina, the choroid, the sclera, and the lamina cribrosa (LC) were associated (using linear regression) with measures of retinal sensitivity from the 24-2 Humphrey visual field test (Carl Zeiss Meditec). This was performed globally, then locally according to a previously published regionalization scheme. MAIN OUTCOME MEASURES: Associations between ONH strains and values of retinal sensitivity from visual field testing. RESULTS: For patients with HTG, we found (1) significant negative linear associations between ONH strains and retinal sensitivity (P < 0.001; on average, a 1% increase in ONH strains corresponded to a decrease in retinal sensitivity of 1.1 decibels [dB]), (2) that high-strain regions colocalized with anatomically mapped regions of high visual field loss, and (3) that the strongest negative associations were observed in the superior region and in the PLT. In contrast, for patients with NTG, no significant associations between strains and retinal sensitivity were observed except in the superotemporal region of the LC. CONCLUSIONS: We found significant negative associations between IOP-induced ONH strains and retinal sensitivity in a relatively large glaucoma cohort. Specifically, patients with HTG who experienced higher ONH strains were more likely to exhibit lower retinal sensitivities. Interestingly, this trend in general was less pronounced in patients with NTG, which could suggest a distinct pathophysiologic relationship between the two glaucoma subtypes.

Measuring glaucoma quality of life in an Asian population using item banking: psychometric evaluation and computerized adaptive testing simulations.

PURPOSE: To assess the psychometric properties of glaucoma-specific health-related quality of life (HRQoL) item banks (IBs), and explore their efficiency using computerized adaptive testing (CAT) simulations. METHODS: In this cross-sectional, clinical study, 300 Asian glaucoma patients answered 221 items within seven IBs: Ocular Comfort Symptoms (OS); Activity Limitation (AL); Lighting (LT); Mobility (MB); Glaucoma Management (GM); Psychosocial (PSY); and Work (WK). Rasch analysis was conducted to assess each IB's psychometric properties (e.g., item "fit" to the construct; unidimensionality) and a set of analytic performance criteria guiding decision making relating to retaining or dropping domains and items was employed. CAT simulations determined the mean number of items for 'high' and 'moderate' measurement precision (stopping rule: SEM 0.3 and 0.387, respectively). RESULTS: Participants' mean age was 67.2 ± 9.2 years (62% male; 87% Chinese). LT, MB, and GM displayed good psychometric properties overall. To optimize AL's psychometric properties, 16 items were deleted due to poor "fit", high missing data, item bias, low discrimination and/or a low clinical/patient importance rating. To resolve multidimensionality in PSY, we rehomed 16 items into a "Concern (CN)" domain. PSY and CN required further amendment, including collapsing of response categories, and removal of poorly functioning items (N = 7). Due to poor measurement precision, low applicability and high ceiling effect, low test information indices, and low item separation index the WK IB was not considered further. In CAT simulations on the final seven IBs (n = 182 items total), an average of 12.1 and 15.7 items per IB were required for moderate and high precision measurement, respectively. CONCLUSIONS: After reengineering our seven IBs, they displayed robust psychometric properties and good efficiency in CAT simulations. Once finalized, GlauCAT™-Asian may enable comprehensive assessment of the HRQoL impact of glaucoma and associated treatments.

Six-Year Incidence and Risk Factors for Primary Angle-Closure Disease: The Singapore Epidemiology of Eye Diseases Study.

PURPOSE: To determine the incidence and risk factors of primary angle-closure disease (PACD) over 6 years in a multi-ethnic Asian population. DESIGN: Population-based, longitudinal study. PARTICIPANTS: The Singapore Epidemiology of Eye Diseases study is a population-based cohort study conducted among adults aged 40 years or more. The baseline examination was conducted between 2004 and 2010, and the 6-year follow-up visit was conducted between 2011 and 2017. Of 6762 participants who attended the follow-up examination, 5298 at risk for primary angle-closure glaucoma (PACG) and 5060 at risk for PACD were included for analyses. METHODS: Standardized examinations including slit-lamp biomicroscopy, indentation gonioscopy, intraocular pressure (IOP) measurement, and static automated perimetry were performed. In this study, PACD includes primary angle-closure suspect (PACS), primary angle-closure (PAC), and PACG. MAIN OUTCOME MEASURES: The 6-year PACD incidence was evaluated among an at-risk population excluding adults with baseline glaucoma, PACS, PAC, pseudophakia at baseline or follow-up, or laser peripheral iridotomy or iridectomy at baseline visit. Logistic regression analysis adjusting for age, gender, and ethnicity was performed to evaluate associations between PACD development and demographic or ocular characteristics. Forward selection based on the Quasi-likelihood Information Criterion was used in multivariable analysis to reduce potential multicollinearity. RESULTS: The 6-year age-adjusted PACD incidence was 3.50% (95% confidence interval [CI], 2.94-4.16). In multivariable analysis, increasing age per decade (odds ratio [OR], 1.35; 95% CI, 1.15-1.59), higher IOP (OR, 1.04; 95% CI, 1.00-1.08), and shallower anterior chamber depth (OR, 1.11; 95% CI, 1.08-1.14) at baseline were associated with higher odds of PACD, whereas late posterior subcapsular cataract (PSC) (OR, 0.60; 95% CI, 0.48-0.76) was associated with lower odds of PACD. The 6-year age-adjusted incidences of PACG, PAC, and PACS were 0.29% (95% CI, 0.14-0.55), 0.46% (95% CI, 0.29-0.75), and 2.54% (95% CI, 2.07-3.12), respectively. CONCLUSIONS: Our study showed that the 6-year incidence of PACD was 3.50%. Increasing age, higher IOP, and shallower anterior chamber were associated with a higher risk of incident PACD, whereas late PSC was associated with a lower odds of PACD. These findings can aid in future projections and formulation of health care policies for screening of at-risk individuals for timely intervention.

Digital Gonioscopy Based on Three-dimensional Anterior-Segment OCT: An International Multicenter Study.

PURPOSE: To develop and evaluate the performance of a 3-dimensional (3D) deep-learning-based automated digital gonioscopy system (DGS) in detecting 2 major characteristics in eyes with suspected primary angle-closure glaucoma (PACG): (1) narrow iridocorneal angles (static gonioscopy, Task I) and (2) peripheral anterior synechiae (PAS) (dynamic gonioscopy, Task II) on OCT scans. DESIGN: International, cross-sectional, multicenter study. PARTICIPANTS: A total of 1.112 million images of 8694 volume scans (2294 patients) from 3 centers were included in this study (Task I, training/internal validation/external testing: 4515, 1101, and 2222 volume scans, respectively; Task II, training/internal validation/external testing: 378, 376, and 102 volume scans, respectively). METHODS: For Task I, a narrow angle was defined as an eye in which the posterior pigmented trabecular meshwork was not visible in more than 180° without indentation in the primary position captured in the dark room from the scans. For Task II, PAS was defined as the adhesion of the iris to the trabecular meshwork. The diagnostic performance of the 3D DGS was evaluated in both tasks with gonioscopic records as reference. MAIN OUTCOME MEASURES: The area under the curve (AUC), sensitivity, and specificity of the 3D DGS were calculated. RESULTS: In Task I, 29.4% of patients had a narrow angle. The AUC, sensitivity, and specificity of 3D DGS on the external testing datasets were 0.943 (0.933-0.953), 0.867 (0.838-0.895), and 0.878 (0.859-0.896), respectively. For Task II, 13.8% of patients had PAS. The AUC, sensitivity, and specificity of 3D DGS were 0.902 (0.818-0.985), 0.900 (0.714-1.000), and 0.890 (0.841-0.938), respectively, on the external testing set at quadrant level following normal clinical practice; and 0.885 (0.836-0.933), 0.912 (0.816-1.000), and 0.700 (0.660-0.741), respectively, on the external testing set at clock-hour level. CONCLUSIONS: The 3D DGS is effective in detecting eyes with suspected PACG. It has the potential to be used widely in the primary eye care community for screening of subjects at high risk of developing PACG.

Evaluation of Primary Angle-Closure Glaucoma Susceptibility Loci for Estimating Angle Closure Disease Severity.

PURPOSE: To investigate whether recently identified genetic loci for primary angle-closure glaucoma (PACG) are associated with disease severity. DESIGN: Case-control study. PARTICIPANTS: Eight hundred four PACG patients and 943 control participants of Chinese ethnicity from Singapore. METHODS: The 8 PACG-associated single nucleotide polymorphisms (SNPs; rs11024102 at PLEKHA7, rs3753841 at COL11A1, rs1015213 located between PCMTD1 and ST18 on chromosome 8q, rs3816415 at EPDR1, rs1258267 at CHAT, rs736893 at GLIS3, rs7494379 at FERMT2, and rs3739821 mapping in between DPM2 and FAM102A) identified from genome-wide association studies were tested for association with disease severity using logistic regression adjusted for age and gender. A P value of 0.006 was set as significant after Bonferroni correction for testing of 8 loci. We also calculated the weighted genetic risk score (GRS) weighted by the estimated individual SNP effect size on PACG calculated as logarithm of the odds ratio (OR). Disease severity was based on the visual field mean deviation (MD) and classified as early to moderate (MD, >-12 dB) and severe (MD, <-20 dB). MAIN OUTCOME MEASURES: Association of PACG loci with severe disease. RESULTS: Of the 804 PACG patients, genotyping data were available for 768 individuals and included 436 with mild-to-moderate PACG and 206 with severe PACG. The PACG patients were significantly older (mean age, 64.3 ± 9.1 years vs. 56.4 ± 8.9 years; P < 0.001) and there were proportionately more women compared with control participants (58.4% vs. 49.0%; P < 0.001). Of the 8 loci investigated, we observed significant evidence of association with severe PACG at 1 SNP, namely rs3816415 in EPDR1 (OR, 2.03; 95% confidence interval [CI], 1.49-2.78; P = 1 × 10-5). A higher-weighted GRS was associated significantly with severe PACG, with an OR of 3.11 (95% CI, 1.95-4.96) comparing the lowest quartile with the highest quartile. CONCLUSIONS: Our results show that EPDR1 is associated significantly with severe PACG, suggesting that it may predispose patients to more aggressive disease development. Individuals with PACG with a higher GRS were associated with a higher risk of severe PACG.

Primary angle closure glaucoma genomic associations and disease mechanism.

PURPOSE OF REVIEW: The genetic basis of primary angle closure (PAC) glaucoma is slowly being elucidated. In recent years, genome-wide association studies have identified eight new susceptibility loci for PAC. Our purpose in this review is to summarize our current knowledge of genetics in angle closure, to take a closer look at the eight novel loci and what we have learned about their function, and consider what they might teach us about angle closure disease. RECENT FINDINGS: Multiple novel loci associated with PAC glaucoma have been identified in large genome-wide association studies. Moreover, primary open angle glaucoma and PAC glaucoma are found to have partly overlapping genetic features. SUMMARY: The genetic basis of PAC glaucoma is being deciphered. Even though there is still much more to be uncovered, this process has already provided new insights in the pathogenesis of this blinding disease. A better understanding of the pathogenic mechanisms through genomics may be valuable for the development of novel therapies.

Primary angle closure glaucoma (PACG) susceptibility gene PLEKHA7 encodes a novel Rac1/Cdc42 GAP that modulates cell migration and blood-aqueous barrier function.

PLEKHA7, a gene recently associated with primary angle closure glaucoma (PACG), encodes an apical junctional protein expressed in components of the blood aqueous barrier (BAB). We found that PLEKHA7 is down-regulated in lens epithelial cells and in iris tissue of PACG patients. PLEKHA7 expression also correlated with the C risk allele of the sentinel SNP rs11024102 with the risk allele carrier groups having significantly reduced PLEKHA7 levels compared to non-risk allele carriers. Silencing of PLEKHA7 in human immortalized non-pigmented ciliary epithelium (h-iNPCE) and primary trabecular meshwork cells, which are intimately linked to BAB and aqueous humor outflow respectively, affected actin cytoskeleton organization. PLEKHA7 specifically interacts with GTP-bound Rac1 and Cdc42, but not RhoA, and the activation status of the two small GTPases is linked to PLEKHA7 expression levels. PLEKHA7 stimulates Rac1 and Cdc42 GTP hydrolysis, without affecting nucleotide exchange, identifying PLEKHA7 as a novel Rac1/Cdc42 GAP. Consistent with the regulatory role of Rac1 and Cdc42 in maintaining the tight junction permeability, silencing of PLEKHA7 compromises the paracellular barrier between h-iNPCE cells. Thus, downregulation of PLEKHA7 in PACG may affect BAB integrity and aqueous humor outflow via its Rac1/Cdc42 GAP activity, thereby contributing to disease etiology.

Permeability of the porcine iris stroma.

Current literature has not considered or provided any data on the permeability of the iris stroma. In this study, we aimed to determine the hydraulic permeability of porcine irides from the isolated stroma. Fifteen enucleated porcine eyes were acquired from the local abattoir. The iris pigment epithelium was scraped off using a pair of forceps and the dilator muscles were pinched off using a pair of colibri toothed forceps. We designed an experimental setup, based on Darcy's law, and consisting of a custom 3D-printed pressure column using acrylonitrile butadiene styrene (ABS) plastic. PBS solution was passed through the iris stroma in a 180° arc shape, with a column height of approximately 204 mm (2000 Pa). Measurements of iris stromal thickness were conducted using optical coherence tomography (OCT). To measure flow rate, we measured the mass (volume) of PBS solution using a mass balance in approximately 1 min. Histology was performed using hematoxylin and eosin (H&E) and anti-smooth muscle antibody (anti-α-SMA) for validation. The permeability experiments demonstrated that the iris stroma is a biphasic tissue that allows fluid flow. Our image processing results determined the area of flow to be 7.55 mm2 and the tissue thickness to be between 180 and 430 µm. The hydraulic permeability of the porcine stroma, calculated using Darcy's law, was 5.13 ±â€¯2.39 × 10-5 mm2/Pa•s. Histological and immunochemical studies confirmed that the tissues used for this permeability study were solely iris stroma. Additionally, anti-α-SMA staining revealed staining specific for stromal blood vessels, with the notable absence of dilator and sphincter muscle staining. Our study combined experimental microscopic data with the theory of biphasic materials to investigate the hydraulic permeability of the iris stroma. This work will serve as a basis on which to validate future biomechanical studies of human irides with which may ultimately aid disease diagnosis and inform the design of novel treatments.

Evaluation of Primary Angle-Closure Glaucoma Susceptibility Loci in Patients with Early Stages of Angle-Closure Disease.

PURPOSE: To investigate whether newly identified genetic loci for primary angle-closure glaucoma (PACG) are associated with early stage angle-closure disease defined as primary angle closure suspect (PACS). DESIGN: Case-control study. PARTICIPANTS: A total of 1397 PACS patients and 943 controls of Chinese ethnicity from Singapore and 604 PACS patients and 287 controls of Indian ethnicity. METHODS: The 8 PACG single nucleotide polymorphisms (SNPs; rs11024102 at PLEKHA7, rs3753841 at COL11A1, rs1015213 located between PCMTD1 and ST18 son chromosome 8q, rs3816415 at EPDR1, rs1258267 at CHAT, rs736893 at GLIS3, rs7494379 at FERMT2, and rs3739821 mapping in between DPM2 and FAM102A) were genotyped by Taqman assays. The association between SNP genotypes and PACS status was measured using logistic regression. A P value of 0.006 was set to account for the testing of 8 genetic loci using a Bonferroni correction. A meta-analysis was conducted to calculate the overall P value and accompanying per-allele odds ratios for each SNP analyzed. MAIN OUTCOME MEASURES: Association of PACG loci with PACS status. RESULTS: The PACS patients were significantly older in both cohorts (Chinese, P < 0.001; Indian, P = 0.002), and there were also more women (P < 0.001, both Chinese and Indian cohorts). In the Chinese cohort, significant evidence of association was noted at 3 SNPs: rs1015213 [A] in PCMTD1-ST18 (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.36-4.11; P = 0.002), rs3816415 [A] in EPDR1 (OR, 1.49; 95% CI, 1.19-1.85; P < 0.001), and rs3739821 [G] in DPM2-FAM102A (OR, 1.40; 95% CI, 1.18-1.65; P < 0.001). Only PCMTD1-ST-18 was replicated modestly in the Indian population (P = 0.056). Meta-analysis showed significant evidence of association for PCMTD1-ST-18 (OR, 1.55; 95% CI, 1.18-2.04; P = 0.002) and DPM2-FAM102A (OR, 1.27; 95% CI, 1.12-1.45; P = 0.0002). CONCLUSIONS: In this study, 2 of 8 PACG-associated loci were associated significantly with PACS status, the earliest stage in the angle-closure glaucoma disease course. The association of these PACG loci with PACS status suggests that these loci may confer susceptibility to a narrow angle configuration.

A common variant near TGFBR3 is associated with primary open angle glaucoma.

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

Visual Field Progression in Patients with Primary Angle-Closure Glaucoma Using Pointwise Linear Regression Analysis.

PURPOSE: To evaluate visual field (VF) progression and rate of glaucomatous VF loss in patients with primary angle-closure glaucoma (PACG) using pointwise linear regression (PLR) trend analysis. DESIGN: Clinic-based retrospective study. PARTICIPANTS: Primary angle-closure glaucoma patients with 5 or more reliable VF tests and with 5 years or more of follow-up. METHODS: Visual field progression was assessed by PROGRESSOR software version 3.7 (Medisoft, Leeds, United Kingdom) and was defined by the presence of at least 2 adjacent testing points located within the same hemifield that showed progression with a change of -1 dB/year or more (P < 0.01) for inner points or -2 dB/year or more (P < 0.01) for edge points. We also performed a logistic regression analysis to determine the variables associated with rapid progression (defined as mean slope of progressing points ≥-1.5 dB/year). MAIN OUTCOME MEASURES: Visual field progression and rate of VF loss. RESULTS: Of the 1296 patients who were assessed, 398 (30.7%) fulfilled the inclusion criteria of 5 or more VFs and 5 years or more of follow-up. Visual field progression was observed in 63 of 398 eyes (15.8%) according to the PLR criteria. The overall mean rate of VF change for these patients was -0.12±0.51 dB/year over a mean follow-up period of 10.4±3.7 years. There were no significant differences in the age, gender distribution, follow-up duration, or number of VFs between those who showed progression and those who did not (all P > 0.05). The most common sector of VF progression was the superior arcuate area (65%). Rapid progression was found in 36 patients (57%). Multiple logistic regression analysis revealed older age and higher vertical cup-to-disc ratio (VCDR) at presentation as predictors of rapid progression (all P < 0.005) in the progressing group (n = 63). CONCLUSIONS: In patients with PACG being managed in a hospital setting, VF progression was noted in 15.8%, and the overall rate of VF loss was -0.12±0.51 dB/year. The superior arcuate was the most common sector of progression. Older age and higher VCDR at presentation were associated with rapid progression.

Comparison of Corneal Biomechanical Properties between Indian and Chinese Adults.

PURPOSE: To investigate the difference in corneal hysteresis (CH) and corneal resistance factor (CRF) between Indian and Chinese populations. DESIGN: Population-based cross-sectional study. PARTICIPANTS: Three hundred eighty-two Singaporean Indian persons and 764 Singaporean Chinese 50 years of age or older were included from the Singapore Indian Eye Study and Singapore Chinese Eye Study, respectively. METHODS: Participants underwent standardized systemic and ocular examinations and interviewer-administered questionnaires for risk factor assessment. The CH and CRF were measured with the Ocular Response Analyzer (Reichert Ophthalmic Instruments, Buffalo, NY). Information on genetic ancestry was derived using principal component analysis. Linear regression models were used to investigate the association of CH and CRF with potential risk factors. MAIN OUTCOME MEASURES: Corneal hysteresis and CRF. RESULTS: After excluding participants with a history of intraocular surgery, a diagnosis of glaucoma suspect or glaucoma, refractive surgery, or presence of corneal abnormalities, CH and CRF readings were available for 382 Indian persons. For each Indian participant, 2 Chinese participants were selected and matched for age and gender (n = 764). There were no differences in the clinical measurements of CH (10.6±1.6 mmHg; P = 0.670) or CRF (10.3±1.7 mmHg; P = 0.103) between the ethnic groups. However, after adjusting for covariates, Indian persons had, on average, 0.18-mmHg higher CH levels than in Chinese (95% confidence interval [CI], 0.02-0.38; P = 0.031). Consistently, CH level was correlated significantly with genetic ancestry in the Southeast Asian population. Corneal resistance factor level was not associated independently with self-reported ethnicity (95% CI, -0.10 to 0.29; P = 0.335). CONCLUSIONS: Chinese have lower CH than Indian persons, and this disparity may reflect biomechanical differences of the cornea.

ABCC5, a gene that influences the anterior chamber depth, is associated with primary angle closure glaucoma.

Anterior chamber depth (ACD) is a key anatomical risk factor for primary angle closure glaucoma (PACG). We conducted a genome-wide association study (GWAS) on ACD to discover novel genes for PACG on a total of 5,308 population-based individuals of Asian descent. Genome-wide significant association was observed at a sequence variant within ABCC5 (rs1401999; per-allele effect size =  -0.045 mm, P = 8.17 × 10(-9)). This locus was associated with an increase in risk of PACG in a separate case-control study of 4,276 PACG cases and 18,801 controls (per-allele OR = 1.13 [95% CI: 1.06-1.22], P = 0.00046). The association was strengthened when a sub-group of controls with open angles were included in the analysis (per-allele OR = 1.30, P = 7.45 × 10(-9); 3,458 cases vs. 3,831 controls). Our findings suggest that the increase in PACG risk could in part be mediated by genetic sequence variants influencing anterior chamber dimensions.

Investigation of the variability of anterior chamber scan protocol with Cirrus high definition optical coherence tomography.

IMPORTANCE: The evaluation of anterior chamber scan of Cirrus optical coherence tomography for routine clinical use. BACKGROUND: To assess the variability of anterior chamber angle measurements. DESIGN: This was a cross-sectional study. PARTICIPANTS: Forty subjects aged 40-80 years were included. METHODS: One randomly selected eye from 40 subjects was imaged with Cirrus optical coherence tomography (Carl Zeiss Meditec, Dublin, CA) by two different operators (expert vs. non-expert) with a 15-min interval for inter-observer and intra-observer variability of image acquisition. For image grading, the angle opening distance (AOD750) and the trabecular iris space area (TISA750) of nasal and temporal quadrants were measured with a customized algorithm (ImageJ, NIH, Bethesda, MD) by two different graders in a masked and random fashion. Bland Altman analysis and intraclass correlation coefficient (ICC) were calculated. MAIN OUTCOME MEASURES: ICC and limit of agreements (LOA). RESULTS: There were 15 (37.5%) eyes with closed angles. For inter-observer variability, the mean difference (95% LOA) of AOD750 for image acquisition and grading were -0.0039 mm (-0.0486, 0.0408) and 0.0011 mm (-0.0228, 0.025), respectively. The mean difference (95% LOA) of AOD750 for intra-observer variability for image acquisition and grading were 0.0013 mm (-0.0362, 0.0389) and -0.0013 mm (-0.0482, 0.0457), respectively. The ICCs were all ≥0.9. There was no significant difference in measurement variability between open and closed angles (P > 0.05). CONCLUSIONS AND RELEVANCE: Anterior chamber scan had low inter-observer and intra-observer variability in quantitative evaluation that was not affected by the angle status or the experience of an operator.

Pattern of Visual Field Loss in Primary Angle-Closure Glaucoma Across Different Severity Levels.

PURPOSE: To investigate the patterns of visual field (VF) defects in primary angle-closure glaucoma (PACG) across different severity levels and to assess hemifield differences within each severity level. DESIGN: Cross-sectional study. PARTICIPANTS: Three hundred four patients diagnosed with PACG were recruited from glaucoma clinics at a Singapore hospital. METHODS: Point-wise total deviation values were recorded from the static automated perimetry (Swedish interactive threshold algorithm standard program 24-2; Humphrey model 750 [Carl Zeiss Meditec, Dublin, CA]) printouts. Patients were excluded if they had unreliable VFs (fixation losses >33% and false-positive responses >15%), had undergone only 10-2 VF testing, had VF defects not typical of glaucoma, or had undergone cataract extraction. Mild, moderate, and severe VF loss were defined by a mean deviation of -6.00 dB or more, -6.01 to -12.00 dB, and -12.01 dB or less, respectively. Each hemifield was divided into regions according to glaucoma hemifield test sectors. The average mean deviation (MD) of each region was obtained using total deviation values. MAIN OUTCOME MEASURES: Between- and within-hemifield differences of the regions across the severity levels. RESULTS: After excluding ineligible cases, 249 patients with PACG were included in the analysis. Mean age of the patients was 65.7±8.6 years, with a 1:1 gender ratio. The number of patients who had mild, moderate, and severe VFs was 72 (28.9%), 78 (31.3%), and 99 (39.8%), respectively. For between-hemifield comparisons, all regions in the superior hemifield had worse MDs compared with their counterparts in the inferior hemifield across the severity spectrum. Likewise, for within-hemifield comparisons, MDs of the regions gradually worsened with increasing distance from the fixation point. CONCLUSIONS: In this group of clinic-based PACG patients, the superior hemifield was found to be affected more severely than the inferior hemifield, and the differences between them increased with worsening disease severity. The damage was consistently more pronounced in the nasal area.

Changes in Anterior Segment Morphology and Predictors of Angle Widening after Laser Iridotomy in South Indian Eyes.

PURPOSE: To compare anterior segment optical coherence tomography (ASOCT) angle morphology before and after laser peripheral iridotomy (LPI) in a cohort of South Indian subjects with primary angle-closure suspect (PACS) or primary angle-closure/primary angle-closure glaucoma (PAC/PACG) and to examine baseline parameters associated with angle widening. DESIGN: Prospective observational study. PARTICIPANTS: A total of 244 subjects aged ≥30 years with PACS or PAC/PACG in at least 1 eye. METHODS: The ASOCT images and angle gonioscopic grades were analyzed for all subjects at baseline and 2 weeks after LPI. Multivariable linear and logistic regression models were used to determine predictors of angle widening (change in mean angle opening distance [AOD750]) and angle opening (all 4 quadrants with trabecular meshwork [TM] visible on gonioscopy after LPI). MAIN OUTCOME MEASURES: Change in ASOCT parameters with LPI and baseline predictors of angle widening. RESULTS: Laser peripheral iridotomy resulted in angle widening on ASOCT with significant increases in AOD750, angle recess area, and trabecular iris surface area (P < 0.05 for all). Gonioscopically, 44.7% of all subjects had open angles in all 4 quadrants after LPI, with a greater percentage of angles open in the PACS group compared with the PAC/PACG group (52.4% vs. 36.4%; P = 0.01). In multivariable regression analyses, greater postoperative angle widening as defined by change in AOD750 was associated with shorter baseline AOD750 and axial length, and greater baseline anterior chamber depth, iris curvature, and lens vault (P ≤ 0.002 for all). Gonioscopic angle opening after LPI was more common with wider baseline angle width (modified Shaffer grade) and lower cup-to-disc ratio (P < 0.001 for both). CONCLUSIONS: In a South Indian population with PACS or PAC/PACG, LPI results in significant anterior chamber angle widening seen on both ASOCT and gonioscopy, although some degree of persistent iridotrabecular contact was present in approximately half of PACS eyes and approximately two thirds of PAC/PACG eyes on gonioscopy. The greatest widening by ASOCT was observed in eyes with features most consistent with greater baseline pupillary block.

Argon Laser Peripheral Iridoplasty for Primary Angle-Closure Glaucoma: A Randomized Controlled Trial.

PURPOSE: To determine the effectiveness of argon laser peripheral iridoplasty (ALPI) in primary angle closure (PAC) and primary angle-closure glaucoma (PACG). DESIGN: Randomized controlled trial. PARTICIPANTS: Eighty PAC or PACG subjects who underwent laser iridotomy (LI) and had at least 180° of persistent appositional angle closure and intraocular pressure (IOP) of more than 21 mmHg were enrolled. METHODS: Subjects were randomized to receive either 360° ALPI (Visulas 532s; Carl Zeiss Meditec, Jena, Germany) or medical therapy (Travoprost 0.004%; Alcon-Couvreur, Puurs, Antwerp, Belgium). Repeat ALPI was performed if the IOP reduction was less than 20% from baseline along with inadequate angle widening at the month 1 or month 3 visit. Intraocular pressure was controlled with systematic addition of medications when required. MAIN OUTCOME MEASURES: The primary outcome measure was success rates after ALPI at 1 year. Complete success was defined as an IOP of 21 mmHg or less without medication, and qualified success was defined as an IOP of 21 mmHg or less with medication. Failure was defined as an IOP more than 21 mmHg despite additional medications or requiring glaucoma surgery. RESULTS: Forty subjects (51 eyes) were randomized to ALPI and 40 subjects (55 eyes) were randomized to medical therapy. Complete success (IOP ≤21 mmHg without medication) was achieved in 35.0% eyes of the ALPI group compared with 85.0% of eyes in the prostaglandin analog (PGA) group (P < 0.001), and qualified success (IOP ≤21 mmHg with medication) was achieved in 35.0% and 7.5%, respectively (P = 0.003). The IOP decreased by 4.9 mmHg (95% confidence interval [CI], 3.5-6.3 mmHg) in the ALPI group (P < 0.001) and by 6.1 mmHg (95% CI, 5.1-7.1 mmHg) in the medication group (P < 0.001). A failure rate of 30.0% was noted in the ALPI group compared with 7.5% in the medication group (P = 0.01). No treatment-related complications were recorded in either group. CONCLUSIONS: After 1 year, ALPI was associated with higher failure rates and lower IOP reduction compared with PGA therapy in eyes with persistent appositional angle closure and raised IOP after LI.

Iris Crypts Influence Dynamic Changes of Iris Volume.

PURPOSE: To determine the association of iris surface features with iris volume change after physiologic pupil dilation in adults. DESIGN: Cross-sectional observational study. PARTICIPANTS: Chinese adults aged ≥ 50 years without ocular diseases. METHODS: Digital iris photographs were taken from eyes of each participant and graded for crypts (by number and size) and furrows (by number and circumferential extent) following a standardized grading scheme. Iris color was measured objectively, using the Commission Internationale de l'Eclairage (CIE) L* color parameter (higher value denoting lighter iris). The anterior segment was imaged by swept-source optical coherence tomography (SS-OCT) (Casia; Tomey, Nagoya, Japan) under bright light and dark room conditions. Iris volumes in light and dark conditions were measured with custom semiautomated software, and the change in iris volume was quantified. Associations of the change in iris volume after pupil dilation with underlying iris surface features in right eyes were assessed using linear regression analysis. MAIN OUTCOME MEASURES: Iris volume change after physiologic pupil dilation from light to dark condition. RESULTS: A total of 65 Chinese participants (mean age, 59.8±5.7 years) had gradable data for iris surface features. In light condition, higher iris crypt grade was associated independently with smaller iris volume (ß [change in iris volume in millimeters per crypt grade increment] = -1.43, 95% confidence interval [CI], -2.26 to -0.59; P = 0.001) and greater reduction of iris volume on pupil dilation (ß [change in iris volume in millimeters per crypt grade increment] = 0.23, 95% CI, 0.06-0.40; P = 0.010), adjusting for age, gender, presence of corneal arcus, and change in pupil size. Iris furrows and iris color were not associated with iris volume in light condition or change in iris volume (all P > 0.05). CONCLUSIONS: Although few Chinese persons have multiple crypts on their irides, irides with more crypts were significantly thinner and lost more volume on pupil dilation. In view that the latter feature is known to be protective for acute angle-closure attack, it is likely that the macroscopic and microscopic composition of the iris is a contributing feature to angle-closure disease.