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To investigate the association of peripheral anterior synechiae (PAS) with intraocular pressure (IOP) and anterior-segment parameters in subjects with primary angle-closure glaucoma (PACG). A total of 267 subjects with PACG were recruited and underwent gonioscopy and anterior-segment optical coherence tomography (ASOCT). Customized software was used to measure ASOCT parameters, including angle opening distance (AOD750) and trabecular-iris-space-area (TISA750) at 750 µm from the scleral spur, anterior chamber depth, width, area and volume (ACD, ACW, ACA, ACV), iris thickness (IT750), iris area (IAREA), and lens vault (LV). Presenting IOP was defined as the first IOP reading before the initiation of IOP-lowering treatment. The mean age of the 267 subjects was 67.0 ± 8.9 years, 140 (52.4%) were male, and 246 (92.1%) were of Chinese ethnicity. PAS was present in 122 (45.7%) subjects, and was most frequently found in the superior quadrant (79.5%). Subjects with PAS had greater presenting IOP (28.7 ± 12.9 vs 22.4 ± 9.7 mmHg, p < 0.001), narrower AOD750 (p < 0.001), smaller TISA750 (p < 0.001), ACD (p = 0.04), ACA (p = 0.02), ACV (p = 0.01) and larger LV (p = 0.01) compared to PACG eyes without PAS. No significant differences were noted for iris parameters. A multivariate logistic regression analysis showed that higher presenting IOP (β = 0.20, p < 0.001), worse visual field mean deviation (β = - 0.20, p = 0.01) and narrower AOD750 (β = - 0.25, p = 0.03) were the only parameters that significantly correlated with the extent of PAS in clock hours. Almost one-half of the subjects with PACG demonstrated PAS; these eyes were associated with higher presenting IOP, smaller anterior segment dimensions and more severe disease.

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., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: Aquaporins (AQPs) facilitate transmembrane osmotic water transport and may play a role in iris fluid conductivity, which is implicated in the pathophysiology of glaucoma. In this study, we compared the iris expression of AQPs and aqueous osmolality between primary angle closure glaucoma (PACG), primary open-angle glaucoma (POAG), and nonglaucoma eyes., Methods: AQP1-5 transcripts from a cohort of 36 PACG, 34 POAG and 26 nonglaucoma irises were measured by quantitative real-time PCR. Osmolality of aqueous humor from another cohort of 49 PACG, 50 POAG, and 50 nonglaucoma eyes were measured using an osmometer. The localization of AQP1 in both glaucoma and nonglaucoma irises was determined by immunofluorescent analysis., Results: Of the five AQP genes evaluated, AQP1 and AQP2 transcripts were significantly upregulated in both PACG (3.48- and 8.07-fold, respectively) and POAG (3.12- and 11.58-fold, respectively) irises relative to nonglaucoma counterparts. The aqueous osmolalities of PACG (303.68 mmol/kg) and POAG (300.79 mmol/kg) eyes were significantly lower compared to nonglaucoma eyes (312.6 mmol/kg). There was no significant difference in expression of AQP transcripts or aqueous osmolality between PACG and POAG eyes., Conclusions: PACG and POAG eyes featured significant increase in AQP1 and AQP2 expression in the iris and reduced aqueous osmolality compared to nonglaucoma eyes. These findings suggest that the iris may be involved in altered aqueous humor dynamics in glaucoma pathophysiology. Because PACG did not differ from POAG in both properties studied, it is likely that they are common to glaucoma disease in general.

Purpose: To compare the distribution of plateau iris in eyes across varying severity of primary angle closure glaucoma (PACG) using standardized ultrasound biomicroscopy (UBM) criteria., Design: Cross-sectional study., Methods: UBM was performed on 210 patients with PACG who had previously undergone laser peripheral iridotomy. Plateau iris was defined as the presence of all the following UBM criteria in ≥2 quadrants of the angle: anteriorly directed ciliary body, absent ciliary sulcus, iris angulation, flat iris plane, and iridotrabecular contact. Disease severity was based on the visual field mean deviation (MD) and classified as early-to-moderate (MD ≥ -12 dB), advanced (-12.01 dB to -20 dB), and severe (MD < -20 dB)., Results: Of 210 subjects recruited, 23 were excluded because of poor quality UBM images. The remaining 187 patients were categorized as having early-to-moderate (n = 103), advanced (n = 38), and severe PACG (n = 46). Of these subjects, 48.1% were male, and 90.9% were of Chinese ethnicity. The overall proportion of plateau iris was 36.9%, with 32.0% (33/103) in early-to-moderate, 34.2% (13/38) in advanced, and 50% (23/46) in severe PACG (P = .03, comparing severe PACG with early-to-moderate groups). Among the severe PACG group, those with plateau iris configuration had significantly smaller anterior chamber area (P = .03) and volume (P = .01) compared with those without plateau iris., Conclusion: The higher proportion of plateau iris configuration in eyes with severe PACG compared with early-to-moderate PACG suggest that this may be a contributory factor for disease severity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: The purpose of this study was to investigate whether the addition of primary angle closure glaucoma (PACG)-associated genetic loci allows improved detection of PACG, compared to anterior segment parameters measured by imaging., Design: Case-control study., Methods: Genotype data of the 8 PACG 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) were available. Customized software was used to measure anterior segment optical coherence tomography (ASOCT) parameters, namely, anterior chamber depth, width, and area (ACD, ACW, and ACA) and lens vault (LV). Statistical analysis for positive predictive values was modeled using the receiver operating characteristic curve (AUC). Statistical significance comparing predictive power of the different parameters was calculated using permutation., Results: A total of 388 PACG subjects and 751 controls with both ASOCT and genetic data were available for analysis. Anterior segment parameters including ACD, ACA, and LV had excellent predictive value (AUCs >0.94), except ACW (AUC=0.65), for identifying PACG. The inclusion of genetic risk alleles (either singly or as a composite genetic risk score for 8 genomewide association study SNPs) to ACD only provided a +0.50% improvement in reclassifying PACG cases and controls over and above the discriminatory value of ACD. This +0.50% improvement was not statistically significant (P > .05)., Conclusions: Although significant on their own, the incorporation of genetic data in the context of anterior segment imaging parameters like ACD provided only a marginal improvement of PACG detection., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the biomechanical properties (Young's modulus) of normal (control) and glaucomatous human iris using atomic force microscopy (AFM)., Methods: Iris tissue obtained from eighteen glaucomatous subjects (equal number of eyes with primary angle closure glaucoma (PACG) and primary open angle glaucoma (POAG) and five normal subjects who underwent elective eye surgery were subjected to the estimation of Young's modulus by AFM. Force measurements were done at room temperature using Nanowizard II BioAFM. The iris samples were immersed in the liquid media (PBS with 0.1% BSA) during force measurements. Young's modulus values were calculated for each recorded curve using JPK Data Processing Software, which uses a Hertz's contact model for spherical indenters fitted to the extend curves., Results: The iris from the normal controls had the least Young's modulus (0.85 ± 0.31 kPa) while those from PACG patients had the highest Young's modulus (2.40 ± 0.82 kPa). The Young's modulus of PACG iris was significantly higher compared to that of the normal controls (P = 0.005) and POAG iris (P = 0.001). However, there was no significant difference in the Young's modulus of POAG iris (1.13 ± 0.36 kPa) compared to that of the normal controls (P = 0.511)., Conclusions: Variations in biomechanical properties of iris tissue may have a significant role in the pathogenesis of angle closure glaucoma. This study suggests the existence of fundamental biomechanical differences in eyes with angle closure versus open angle glaucoma. An understanding of this basis creates a new platform to understand disease pathology better and work on therapeutic strategies that will address the same.

Purpose: To evaluate the corneal endothelial characteristics across the primary angle closure (PAC) disease spectrum amongst patients diagnosed as PAC suspects (PACS), PAC, PAC glaucoma (PACG), and previous acute PAC (APAC)., Methods: We analyzed a total of 529 subjects (51 PACS, 170 PAC, 234 PACG, and 74 with previous APAC). All subjects had undergone laser peripheral iridotomy prior to study recruitment. Corneal endothelial parameters were measured using a noncontact specular microscope and the following parameters were obtained: mean central endothelial cell density (ECD; cells/mm2), coefficient of variation (CV) in cell area, and percentage of hexagonal cells., Results: The mean age of the subjects was 65.1 ± 8.2 years, and 55.2% were females. The mean central ECD was 2582.0 ± 472.8 cells/mm2 in PACS, 2566.0 ± 408.3 cells/mm2 in PAC, 2523.8 ± 406.8 cells/mm2 in PACG, and 2504.0 ± 558.1 cells/mm2 in APAC, with no significant differences in ECD across the subgroups (P = 0.61). The CV was lowest in PACS (34.38 ± 6.05 μm2/cell), and highest in APAC (37.61 ± 7.98 μm2/cell), but the differences were not significant (P = 0.07). Likewise, the percentage of hexagonality was not significantly different between the groups. A subgroup analysis on the eyes with previous APAC with their fellow eye also showed no significant differences in the corneal endothelial characteristics., Conclusions: The corneal ECD and morphological characteristics such as CV and hexagonality are not significantly different across the PAC disease spectrum. This may reflect the lack of a sustained and/or dramatic IOP insult and/or an insignificant deleterious effect from medications, age, and chronicity on corneal endothelial parameters.

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., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: We previously identified three distinct subgroups of patients with primary angle closure glaucoma (PACG) based on anterior segment optical coherence tomography (ASOCT) imaging. Group 1 was characterized by a large iris area with deepest anterior chambers, group 2 by a large lens vault (LV) and shallow anterior chamber depth (ACD), and group 3 displayed intermediate values across iris area, LV, and ACD. The purpose of the present study was to determine the distribution of plateau iris in these subgroups using ultrasound biomicroscopy (UBM) features., Methods: UBM images of the 210 subjects who were previously enrolled for the ASOCT subgrouping analysis and had undergone laser peripheral iridotomy were assessed and graded by a single glaucoma fellowship trained clinician. Plateau iris was defined as the presence of all the following UBM criteria in at least two quadrants: anteriorly directed ciliary body, absent ciliary sulcus, iris angulation, flat iris plane, and iridoangle touch., Results: Of 210 subjects, 23 were excluded due to poor-quality images. Based on standardized UBM criteria, the overall prevalence of plateau iris was 36.9% (n = 187). The proportion of plateau iris was similar across the three groups (subgroup 1:35.4% (n = 29); subgroup 2:39.0% (n = 32); subgroup 3:34.8% (n = 8), P = 0.87). On multiple logistic regression analysis, iris thickness at 750 μm from the scleral spur (IT750) was the only variable associated with plateau iris (odds ratio: 1.5/100 μm increase in iris thickness [IT], P = 0.04)., Conclusions: The proportion of plateau iris was similar across the three ASOCT-based PACG subgroups and more than one-third of subjects with PACG were diagnosed with plateau iris based on standardized UBM criteria. In addition, we noted that eyes with increased peripheral IT have an increased likelihood of plateau iris.

Purpose: To evaluate the intraocular pressure (IOP) change and associated factors 6 months after phacoemulsification in eyes with primary angle-closure suspect (PACS) and eyes with primary angle closure (PAC) that had no medical therapy., Setting: Singapore National Eye Center, Singapore, Singapore., Design: Retrospective case series., Methods: Patients with PACS or PAC (with corrected distance visual acuity <20/40) who had uneventful phacoemulsification were recruited. Patients were excluded if they were on IOP-lowering medications within 6 months preoperatively and postoperatively. Preoperative gonioscopy, A-scan biometry, anterior segment optical coherence tomography, and automated refraction were reviewed. Factors related to the percentage of and absolute IOP change were assessed using multiple linear regression analyses after adjusting for age, sex, and diagnosis., Results: The study evaluated 85 patients (85 eyes; 52 PACS, 33 PAC) after 7 eyes (1 PACS, 6 PAC) were excluded because of poor quality imaging. Overall, IOP decreased by 19.9% from the preoperative mean of 16.1 mm Hg ± 3.1 (SD) to 12.9 ± 2.7 mm Hg. The IOP change between the PACS group (-3.3 ± 2.8 mm Hg; -20.6%) and the PAC group (-3.2 ± 4.7 mm Hg; -19.6%) was similar (P > .05). In multiple linear regression analyses, a higher preoperative IOP (β = 0.68, P < .001) and fewer clock hours of peripheral anterior synechiae (PAS) (β = -0.30, P = .03) predicted a greater absolute change in and percentage of reduction in IOP, respectively., Conclusions: The mean IOP reduction 6 months after phacoemulsification was 20%. Less IOP reduction was observed in the presence of lower preoperative IOP and more extensive PAS., (Copyright © 2017 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)

Background: This study aimed to evaluate differences in iris gene expression profiles between primary angle closure glaucoma (PACG) and primary open angle glaucoma (POAG) and their interaction with biometric characteristics., Design: Prospective study., Participants: Thirty-five subjects with PACG and thirty-three subjects with POAG who required trabeculectomy were enrolled at the Singapore National Eye Centre, Singapore., Methods: Iris specimens, obtained by iridectomy, were analysed by real-time polymerase chain reaction for expression of type I collagen, vascular endothelial growth factor (VEGF)-A, -B and -C, as well as VEGF receptors (VEGFRs) 1 and 2. Anterior segment optical coherence tomography (ASOCT) imaging for biometric parameters, including anterior chamber depth (ACD), anterior chamber volume (ACV) and lens vault (LV), was also performed pre-operatively., Main Outcome Measures: Relative mRNA levels between PACG and POAG irises, biometric measurements, discriminant analyses using genes and biometric parameters., Results: COL1A1, VEGFB, VEGFC and VEGFR2 mRNA expression was higher in PACG compared to POAG irises. LV, ACD and ACV were significantly different between the two subgroups. Discriminant analyses based on gene expression, biometric parameters or a combination of both gene expression and biometrics (LV and ACV), correctly classified 94.1%, 85.3% and 94.1% of the original PACG and POAG cases, respectively. The discriminant function combining genes and biometrics demonstrated the highest accuracy in cross-validated classification of the two glaucoma subtypes., Conclusions: Distinct iris gene expression supports the pathophysiological differences that exist between PACG and POAG. Biometric parameters can combine with iris gene expression to more accurately define PACG from POAG., (© 2016 The Authors. Clinical & Experimental Ophthalmology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Ophthalmologists.)

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., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10(-15)), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10(-16)), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10(-14)), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10(-11)), and DPM2-FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10(-12)). We also confirmed significant association at three previously described loci (P < 5 × 10(-8) for each sentinel SNP at PLEKHA7, COL11A1, and PCMTD1-ST18), providing new insights into the biology of PACG.

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., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Importance: Selective laser trabeculoplasty (SLT) should be explored as a therapeutic option in eyes with angle closure., Objective: To assess the intraocular pressure (IOP)-lowering efficacy of SLT in eyes with primary angle closure (PAC) and PAC glaucoma (PACG)., Design, Setting, and Participants: Randomized clinical trial at tertiary eye care institutions of 100 patients diagnosed as having PAC or PAC glaucoma in which the angles had opened at least 180° (visible posterior trabecular meshwork on gonioscopy) after laser iridotomy. Recruitment and baseline were completed from June 2009 to April 2012 and 6-month follow-up was completed from December 2009 to November 2012., Interventions: Eligible patients with a baseline IOP greater than 21 mm Hg were randomized to either SLT or prostaglandin analog (PGA; travoprost, 0.004%). The SLT was repeated if the IOP reduction was less than 20.0% from baseline at the 1- or 3-month follow-up visit., Main Outcomes and Measures: The primary outcome measure was the change in IOP from baseline to the final follow-up visit (at 6 months). The frequency of additional postoperative treatments and complications were secondary outcomes., Results: Fifty patients (96 eyes) were randomized to SLT and 50 patients (99 eyes) to PGA medical therapy. At 6 months, 49 patients in the SLT group and 47 in the PGA group completed follow-up. Analysis was based on intent to treat. At 6 months, IOP decreased by 4.0 mm Hg (95% CI, 3.2-4.8) in the SLT group (P < .001) and by 4.2 mm Hg (95% CI, 3.5-4.9) in the PGA group (P < .001). There were no differences between the SLT and PGA groups in the absolute mean reduction of IOP (4.0 vs 4.2 mm Hg, respectively; P = .78) or in the percentage of reduction in IOP (16.9% vs 18.5%, respectively; P = .52). Complete success (IOP ≤21 mm Hg without medications) was achieved in 60.0% eyes of the SLT group, compared with 84.0% of eyes in the PGA group (P = .008). No patients required glaucoma surgery. Additional medications were required in 22.0% of patients in the SLT group compared with 8.0% in the PGA group (P = .05). One patient in the SLT group (2.0%) had a transient posttreatment IOP spike greater than 5 mm Hg. The mean endothelial cell count showed a significant decrease from baseline in the SLT arm (4.8% decrease; P = .001). No other events such as persistent uveitis or increase in peripheral anterior synechiae were noted in eyes that underwent SLT. Two patients in the PGA group exited owing to drug-related complications (1 patient with uveitis and 1 with allergic conjunctivitis)., Conclusions and Relevance: Eyes with PAC or PACG respond to SLT in the short term, but the overall long-term therapeutic effectiveness needs further evaluation., Trial Registration: clinicaltrials.gov Identifier: NCT01004900.

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.

Objective: To report the 8-year outcomes of Asian subjects who underwent trabeculectomy augmented by intraoperative 5-fluorouracil (5-FU) or placebo., Design: Retrospective review of a randomized controlled trial., Participants: Subjects with primary open-angle or angle-closure glaucoma., Methods: Study subjects were prospectively followed up for 3 years. After the last subject recruited had completed 8 years of follow-up, the charts of all subjects were reviewed to capture data from the year 3 visit onward. Kaplan-Meier survival function with Cox regression was performed to identify risk factors associated with trabeculectomy failure at 8 years., Main Outcome Measures: The primary outcome was trabeculectomy failure defined as intraocular pressure (IOP) >21 or <6 mmHg on 2 consecutive occasions after the first 6 weeks after surgery, repeat glaucoma surgery, or loss of light perception. Further end points were defined at IOP levels >17 and >14 mmHg. Secondary outcomes included IOP at 8 years and number of glaucoma medications. Complete success was defined using IOP end points ≤ 21, ≤ 17, or ≤ 14 mmHg at 8 years without medications., Results: Of the 243 enrolled subjects, 170 (70.0%) completed 8 years follow-up, 86 in the 5-FU and 84 in the placebo group. There was no significant difference in failure rates at 8 years for the failure definitions of IOP >21 mmHg (11.6% of the 5-FU group vs. 16.7% of the placebo group; P = 1.00), IOP >17 mmHg (23.3% of the 5-FU group vs. 31% of the placebo group; P = 0.78), and IOP >14 mmHg (46.5% of the 5-FU group vs. 58.3% of the placebo group; P = 0.37). Mean IOP at 8 years was 13.7 mmHg in the 5-FU versus 14.4 mmHg in the placebo group (P = 0.24). Mean number of medications was 0.65 drops in the 5-FU versus 0.93 drops in the placebo group (P = 0.06). Complete success with IOP ≤ 21 mmHg at 8 years was achieved in 48 subjects (55.8%) in the 5-FU and 33 subjects (39.3%) in the placebo group (P = 0.09). Absence of bleb microcysts at 1 year, preoperative IOP, and number of bleb needlings performed within the first year were significantly associated with failure., Conclusions: There was no significant difference in IOP between the 5-FU and the placebo group at 8 years., Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the impact of bilateral primary glaucoma on glaucoma-specific functioning in Asians., Methods: Patients with bilateral primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) aged 40 years or above of Chinese ethnicity in Singapore were recruited. All underwent a comprehensive clinical assessment of glaucoma. Glaucoma was diagnosed with a standard criteria including optic disc abnormality and visual field defect. The Glaucoma Quality of Life-15, a glaucoma-specific questionnaire, was used to evaluate the impact of glaucoma, and Rasch analysis was used to validate the Glaucoma Quality of Life-15., Results: A total of 192 patients (mean±SD age, 65.73±17.6 y and 65.1% male) were recruited, of which 56.2% (n=108) and 43.8% (n=84) had POAG and PACG, respectively. Fifty-four (28.1%), 85 (44.3%), and 53 (27.6%) had bilateral mild glaucoma, mild glaucoma in 1 eye and moderate/severe glaucoma in the other, and bilateral moderate/severe glaucoma, respectively. In multivariate analyses, compared with patients with mild glaucoma in both eyes, those with (a) mild glaucoma in 1 eye and moderate/severe in other; and (b) moderate/severe glaucoma in both eyes, reported significantly poorer functioning (β-coefficient=-8.20; confidence interval, -14.36 to -2.04; P<0.05) and (β=-21.05; confidence interval, -28.06 to -14.04; P<0.05), respectively. A similar independent association was found for POAG and PACG. These associations were also considered to be clinically significant while comparing bilateral mild glaucoma with bilateral moderate/severe glaucoma. We however, found no significant difference for functioning and severity of glaucoma between PACG and POAG patients (P<0.05)., Conclusions: Bilateral glaucoma is worse than the mild form in any eye and is significantly associated with poor glaucoma-specific functioning in this Singaporean Chinese sample. These data emphasize the need for strategies to identify patients early and prevent deterioration beyond the mild form of the condition.

Purpose: Nonadherence to glaucoma medications may be a major cause of treatment failure. We examined the acceptance of glaucoma patients toward a possible new route of administering glaucoma medication by subconjunctival injection., Patients and Methods: Patients were recruited from specialist glaucoma clinics on a voluntary basis. Trained interviewers administered a 30-item questionnaire and an information sheet with details of an alternative subconjunctival injection route involving injections at 3-month intervals. Outcome measures regarding acceptance of the new procedure, social situational factors, disease factors, and treatment factors were assessed., Results: A total of 151 patients participated in this study. Of the 151 patients 112 (74.2%) were willing to have their glaucoma medication given by the new method of subconjunctival injection, 101 of 112 (90.2%) were willing to accept it at the same cost as their present medication, and 87 of 101 (86.1%) were willing to accept it even at a higher cost. These patients tended to be on a greater number of medications (P=0.006), and medicating more frequently in a day (P=0.003). Nine of 10 (90%) patients who were admitted to nonadherence were willing to accept subconjunctival injections at 3-month intervals in place of their topical medication., Conclusions: Our study found that 74% of glaucoma patients were willing to accept an alternative form of glaucoma treatment through 3-monthly subconjunctival injections. A large proportion of patients who were admitted to nonadherence to topical medication were willing to consider this alternative method of medication. Our findings are helpful when developing patient-acceptable drug-delivery regimes, which may alleviate the need for daily medication.

Purpose: We investigated patients' attitudes and perceptions toward a subconjunctival implant as a novel ocular drug delivery method for glaucoma., Methods: We recruited 344 Chinese patients with primary open angle or angle closure glaucoma currently on topical antiglaucoma medication for a minimum of six months from specialist glaucoma clinics. Sociodemographic data, and information about patients' general and ocular health were collected. Beliefs about medicines, glaucoma, eye drops, and self-reported adherence were assessed by trained interviewers using validated questionnaires. A description about the implant was provided and patients subsequently were assessed on their understanding and acceptance., Results: Of the 344 Chinese patients enrolled, 216 (62.8%) would accept the implant as a replacement for their current eye drops. Of those who accepted the implant, 99 (45.8%) were willing to accept it at similar costs, while 40 (18.5%) and 20 (9.3%) patients were willing to pay 1.5 and 2 times the cost of their present medication, respectively. Patients who accepted the implant had more severe glaucoma (P = 0.015) and felt that the implant was more helpful than eye drops (P < 0.001). Beliefs toward medicines, glaucoma, eye drops, self-reported adherence, and sociodemographic factors did not have a significant impact on the patients' decisions., Conclusions: An ocular drug implant would be an acceptable alternative to topical eye drops for subgroups of glaucoma patients.

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.

Purpose: To determine the proinflammatory cytokine profile of aqueous humor from glaucomatous eyes., Methods: Aqueous humor samples were prospectively collected from 38 eyes (26 primary open angle glaucoma [POAG] and 12 primary angle closure glaucoma [PACG] eyes) of 37 medically treated glaucoma patients and 23 cataract subjects recruited in an institutional setting in this case-controlled study. The main outcome measure was to quantify the levels of 29 inflammatory cytokines in the aqueous of glaucoma and cataract subjects using a multiplexed cytokine analysis. Data on patient demographics, duration of glaucoma, preoperative intraocular pressure (IOP) as well as duration of anti-glaucoma therapy were also collected for correlation analysis., Results: Mean duration of glaucoma was 53.8 months (range 1-360 months). Aqueous obtained from the glaucoma patients showed increased concentration of interleukin (IL)-9 (p=0.032), IL-12 (p=0.003), interferon (IFN)-α (p=0.034), IFN-γ (p=0.002), monokine induced by interferon-gamma (MIG or CXCL9) (p=0.006), and IL-10 (p=0.050), compared to the cataract group. The POAG group had higher IL-12 (p=0.011), IFN-γ (p=0.005), and CXCL9 (p=0.047) levels than controls, while the PACG group had higher interleukin-8 (CXCL8) (p=0.015) and CXCL9 (p=0.023) levels than the controls. No significant correlation was observed between aqueous cytokine level and preoperative IOP and duration of glaucoma. Duration of topical Timolol and Alphagan therapy correlated negatively with CXCL8 (r=-0.588, p=0.035), respectively., Conclusions: Primary glaucoma is associated with an aqueous inflammatory response and this is different between POAG and PACG groups. Duration of glaucoma treatment may have an effect on cytokine profile in the aqueous.

Purpose: To investigate the long-term rates of blindness and visual field (VF) progression in treated primary angle-closure glaucoma (PACG) patients., Design: Retrospective observational case series., Methods: PACG patients with ≥10 years of follow-up were analyzed. All VFs (static automated perimetry, central 24-2 threshold test) performed were reviewed and reliable VFs (fixation losses <20%, false positives and false negatives <33%) were scored using the Advanced Glaucoma Intervention Study (AGIS) system. Progression of a VF defect was defined as a change of ≥4 from baseline on 2 consecutive VF tests., Results: From the 137 eyes of 87 patients with PACG with ≥10 years of follow-up identified, 6% and 30.1% were blind based on initial visual acuity (VA) and VF criteria respectively and 12.0% had an initial AGIS score of 20; these were excluded. Eighty-three eyes from 57 patients (all Chinese, mean age 59.9 ± 8.2 years, 67.5% female) were analyzed. The mean AGIS score was 5.14 ± 4.37 at baseline. VF deterioration was detected in 27 eyes (32.5%) of 21 patients, with 4.8% and 7.2% of eyes progressing to blindness based on VA and VF criteria respectively. On Cox regression, eyes with VF progression had higher mean overall IOP (P < .001), and higher prevalence of previous acute angle closure (AAC, P = .008)., Conclusions: Over 10 years, a third of PACG patients were found to have VF progression, with 7% progressing to blindness while on treatment. Eyes with higher mean overall IOP and a history of previous AAC were more likely to have VF progression., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objectives: To investigate the incidence of postoperative complications arising in the first year after trabeculectomy and combined phacotrabeculectomy in eyes with primary angle-closure glaucoma (PACG) vs those with primary open-angle glaucoma (POAG)., Methods: This was a retrospective study of all glaucoma operations done at a Singapore hospital from January 9, 2001, to December 30, 2004. The types of glaucoma surgery included trabeculectomy and phacotrabeculectomy, all with mitomycin C or fluorouracil. The incidences of postoperative complications and reoperations were analyzed. For those who underwent bilateral or repeated operations, only the first operated eye of each subject was included., Results: A total of 446 subjects with PACG (112 who underwent trabeculectomy and 334 who underwent phacotrabeculectomy) and 816 subjects with POAG (208 who underwent trabeculectomy and 608 who underwent phacotrabeculectomy) were analyzed. Postoperative complications occurred in 65 of 1262 eyes (5.2%) overall, with 27 eyes (8.4%) in the trabeculectomy group (PACG: 8.0%; 95% confidence interval [CI], 4.3%-14.6%; POAG: 8.7%; 95% CI, 5.5%-13.3%; P > .99) and 38 eyes (4.0%) in the phacotrabeculectomy group (PACG: 5.1%; 95% CI, 3.2%-8.0%; POAG: 3.5%; 95% CI, 2.3%-5.2%; P = .31). The rate of complications was significantly higher in the trabeculectomy group than the phacotrabeculectomy group overall (P = .003), but there was no significant difference between the POAG and PACG groups overall (POAG: 4.8%; 95% CI, 3.5%-6.5%; PACG: 5.8%; 95% CI, 4.0%-8.4%; P = .53). The commonest complication found was hypotony with overfiltration (23 cases [1.8%]), followed by bleb leak (11 cases [0.9%]). There was no significant difference in incidence of reoperations between POAG (2.7%; 95% CI, 1.8%-4.1%) and PACG (4.0%; 95% CI, 2.6%-6.3%) (P = .27)., Conclusion: The incidences of postoperative complications and reoperations in the first year after glaucoma surgery were similar for PACG and POAG.

Objective: To investigate diurnal intraocular pressure (IOP) fluctuation in eyes with angle closure in comparison with normal subjects and to look for associated risk factors for IOP fluctuation., Design: Prospective, cross-sectional study., Participants: Ninety-eight eyes of 98 Asian subjects with angle closure (consisting of 32 primary angle-closure suspects [PACS], 34 subjects with primary angle closure [PAC], and 32 subjects with primary angle-closure glaucoma [PACG]) and 21 eyes of 21 normal control subjects., Methods: All angle-closure subjects were enrolled after laser peripheral iridotomy but before commencement of any medical or surgical treatment. Ophthalmic examination, including dynamic gonioscopy and automated perimetry, were performed, and diurnal IOP measurements were obtained using noncontact air-puff tonometry at hourly intervals between 8:00 am and 5:00 pm. Mean diurnal IOP, peak diurnal IOP, trough IOP, and IOP fluctuation (peak IOP-trough IOP) were compared between groups. Multiple linear regression analysis was performed to study the association of IOP fluctuation with clinical variables such as age, extent of peripheral anterior synechiae (PAS), central corneal thickness, vertical cup-to-disc ratio, and pattern standard deviation (PSD) on automated perimetry., Main Outcome Measures: Mean diurnal IOP, peak IOP, and IOP fluctuation., Results: Most subjects were Chinese (89.1%) and female (61.3%). Intraocular pressure fluctuation was significantly higher in PACG (5.4+/-2.4 mmHg) and PAC (4.5+/-2.3 mmHg) subjects compared with PACS subjects (3.7+/-1.2 mmHg) and normal controls (3.8+/-1.1 mmHg; P = 0.005), with highest IOP found in the early morning. The combined PACG and PAC group had more than twice the risk (odds ratio, 2.38; 95% confidence interval, 1.1-5.1; P = 0.025) of having IOP fluctuation of more than 3 mmHg compared with the combined PACS and normal group. Extent of PAS (Pearson's correlation coefficient, r = 0.37; P = 0.0001) and visual field PSD (r = 0.34; P = 0.0002) were found to be associated with greater IOP fluctuation., Conclusions: The PACG and PAC eyes showed diurnal IOP fluctuation of 4 to 5 mmHg, and this fluctuation was higher than in PACS subjects and normal controls. The degree of PAS and visual field loss were associated with IOP fluctuation in PAC and PACG eyes.

Purpose: To report 3-year results of a randomized, controlled trial comparing the use of a single application of 5-fluorouracil (5-FU) with placebo in trabeculectomy surgery., Design: Prospective, randomized, double-blinded treatment trial., Participants: Two hundred forty-three Asian patients with primary open-angle or primary angle-closure glaucoma undergoing primary trabeculectomy., Methods: One eye of each patient was randomized to receive either intraoperative 5-FU or normal saline (placebo) during trabeculectomy., Main Outcome Measures: Primary outcome measure was the level of intraocular pressure (IOP). Secondary outcomes were progression of visual field loss, rates of adverse events, and interventions after surgery., Results: Of the 288 eligible patients, 243 were enrolled and 228 completed 3 years follow-up; 120 patients received 5-FU and 123 received placebo. Trial failure, according to predefined IOP criteria, was lower in the 5-FU group compared with the placebo group, although the difference was only significant with a failure criterion of IOP >17 mmHg (P = 0.0154). There was no significant difference in progression of optic disc and/or visual field loss over 36 months between 5-FU and placebo (relative risk [RR], 0.67; 95% confidence interval [CI], 0.34-1.31; P = 0.239). Uveitis occurred more often in the 5-FU-treated group (14/115 [12%] vs 5/120 [4%]; P = 0.032)., Conclusions: This is the first masked, prospective, randomized trial reporting the effect of adjunctive 5-FU in trabeculectomy surgery in an East Asian population. The trial shows that an increased success rate can be achieved for several years after a single intraoperative treatment with 5-FU. We conclude that 5-FU is relatively safe and can be routinely used in low-risk East Asian patients., Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article.

Objective: To confirm the presence of uveal effusion in the eyes of Asian patients with primary angle closure glaucoma (PACG) using ultrasound biomicroscopy (UBM)., Methods: In this observational case series, 70 patients with PACG (28 untreated patients with newly diagnosed PACG and 42 patients who had undergone previous laser iridotomy and were being monitored) and 12 patients with acute primary angle closure (APAC) were recruited. Eyes of patients with newly diagnosed PACG and APAC underwent UBM before and after laser iridotomy, whereas eyes of patients with treated PACG underwent UBM at enrollment. Uveal effusion was defined as a clear space between the choroid and sclera and was graded as follows: grade 0, none; grade 1, slitlike; grade 2, bandlike; and grade 3, obvious., Results: Overall, uveal effusion was found in 11 of 70 eyes with PACG (15.7%; 95% confidence interval, 8.8%-26.2%) and in 3 of 12 eyes with APAC (25%; 95% confidence interval, 8.0%-53.4%). For patients with newly diagnosed PACG, uveal effusion was found in 4 of 28 eyes (14.2%; 95% confidence interval, 5.1%-32.1%) before laser iridotomy; 2 eyes had effusion after laser iridotomy. When present, the effusion was grade 1 in PACG eyes and grade 2 or 3 in APAC eyes., Conclusions: Uveal effusion was present in a significant proportion of Asian eyes with PACG and APAC, confirming a recent report of this finding.

Purpose: The genetic basis of primary angle closure glaucoma (PACG) has yet to be elucidated. Ocular characteristics related to PACG such as short hyperopic eyes with shallow anterior chambers suggest the involvement of genes that regulate ocular size. CHX10, a retinal homeobox gene associated with microphthalmia, and MFRP, the membrane-type frizzled-related protein gene underlying recessive nanophthalmos, represent good candidate genes for PACG due to the association with small eyes. To investigate the possible involvement of CHX10 and MFRP in PACG, we sequenced both genes in PACG patients with small ocular dimensions., Methods: One hundred and eight Chinese patients with axial lengths measuring 22.50 mm or less were selected for analysis. Ninety-three age- and ethnically-matched control subjects were also screened. Genomic DNA was extracted from leukocytes of peripheral blood samples, and the exons of CHX10 and MFRP were amplified by polymerase chain reaction (PCR) and subjected to bidirectional sequencing and analysis., Results: All study patients were Chinese with a mean age of 66.2+/-9.1 years (range 46-86). There were 77 females (71.3%). Forty-nine out of the one hundred and eight subjects had previous symptomatic PACG, and 59 had asymptomatic PACG. The mean axial length was 21.90+/-0.50 mm (range 19.98-22.50 mm). We identified a possible disease-causing variant in CHX10 (c.728G>A) resulting in Gly243Asp substitution in one patient. This variant was not found in 215 normal controls. Several CHX10 and MFRP polymorphisms were also identified., Conclusions: Our results do not support a significant role for CHX10 or MFRP mutations in PACG.

Purpose: SPARC (secreted protein, acidic, and rich in cysteine) is involved in extracellular matrix (ECM) organization. The purpose of this study was to evaluate the expression of SPARC in iris tissue from primary angle closure glaucoma (PACG) eyes., Methods: Iris tissue was obtained from peripheral iridectomies performed during trabeculectomy surgery in nine PACG and 16 primary open-angle glaucoma (POAG) eyes at the Singapore National Eye Centre. Three non-glaucoma control iris specimens were obtained from patients who underwent Descemet's stripping automated endothelial keratoplasty (DSAEK) procedure. SPARC and collagen I expression were quantified by real-time polymerase chain reaction (PCR). The histological distribution of collagen I and III in the iris stroma was determined using picrosirius red polarization. Density of the iris stromal vasculature was also calculated., Results: The mean age was 68.9+/-10.9 years and 65.7+/-12.2 years in POAG and PACG groups, respectively. The PACG iris expressed SPARC 13.6-fold more and collagen I 5.2 fold more compared to non-glaucoma control iris. The PACG iris also demonstrated 3.3 fold higher SPARC and 2.0 fold higher collagen I expression relative to the POAG iris. The density of collagen I was greater in PACG eyes than in POAG and control eyes (p<0.001). The mean density of iris stromal blood vessels per micron square area was similar in all three groups., Conclusions: SPARC was significantly increased in the PACG iris. The data suggest that SPARC could play a role in the development of PACG by influencing the biomechanical properties of the iris through a change in ECM organization.