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.

Lens extraction versus laser peripheral iridotomy for acute primary angle closure.

BACKGROUND: Acute primary angle closure (APAC) is a potentially blinding condition. It is one of the few ophthalmic emergencies and carries high rates of visual morbidity in the absence of timely intervention. Laser peripheral iridotomy (LPI) has been the standard of care thus far. However, LPI does not eliminate the long-term risk of chronic angle closure glaucoma and other associated sequelae. There has been increasing interest in lens extraction as the primary treatment for the spectrum of primary angle closure disease, and it is as yet unclear whether these results can be extrapolated to APAC, and whether lens extraction provides better long-term outcomes. We therefore sought to evaluate the effectiveness of lens extraction in APAC to help inform the decision-making process.  OBJECTIVES: To assess the effect of lens extraction compared to LPI in the treatment of APAC. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2022, Issue 1), Ovid MEDLINE, Ovid MEDLINE E-pub Ahead of Print, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily (January 1946 to 10 January 2022), Embase (January 1947 to 10 January 2022), PubMed (1946 to 10 January 2022), Latin American and Caribbean Health Sciences Literature Database (LILACS) (1982 to 10 January 2022), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search. We last searched the electronic databases on 10 January 2022. SELECTION CRITERIA: We included randomized controlled clinical trials comparing lens extraction against LPI in adult participants ( ≥ 35 years) with APAC in one or both eyes. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and assessed the certainty of the body of evidence for prespecified outcomes using the GRADE approach. MAIN RESULTS: We included two studies conducted in Hong Kong and Singapore, comprising 99 eyes (99 participants) of predominantly Chinese origin. The two studies compared LPI with phacoemulsification performed by experienced surgeons. We assessed that both studies were at high risk of bias. There were no studies evaluating other types of lens extraction procedures.  Phacoemulsification may result in an increased proportion of participants with intraocular pressure (IOP) control compared with LPI at 18 to 24 months (risk ratio (RR) 1.66, 95% confidence interval (CI) 1.28 to 2.15; 2 studies, n = 97; low certainty evidence) and may reduce the need for further IOP-lowering surgery within 24 months (RR 0.07, 96% CI 0.01 to 0.51; 2 studies, n = 99; very low certainty evidence). Phacoemulsification may result in a lower mean IOP at 12 months compared to LPI (mean difference (MD) -3.20, 95% CI -4.79 to -1.61; 1 study, n = 62; low certainty evidence) and a slightly lower mean number of IOP-lowering medications at 18 months (MD -0.87, 95% CI -1.28 to -0.46; 1 study, n = 60; low certainty evidence), but this may not be clinically significant. Phacoemulsification may have little to no effect on the proportion of participants with one or more recurrent APAC episodes in the same eye (RR 0.32, 95% CI 0.01 to 7.30; 1 study, n = 37; very low certainty evidence). Phacoemulsification may result in a wider iridocorneal angle assessed by Shaffer grading at six months (MD 1.15, 95% CI 0.83 to 1.47; 1 study, n = 62; very low certainty evidence). Phacoemulsification may have little to no effect on logMAR best-corrected visual acuity (BCVA) at six months (MD -0.09, 95% CI -0.20 to 0.02; 2 studies, n = 94; very low certainty evidence). There was no evidence of a difference in the extent of peripheral anterior synechiae (PAS) (clock hours) between intervention arms at 6 months (MD -1.86, 95% CI -7.03 to 3.32; 2 studies, n = 94; very low certainty evidence), although the phacoemulsification group may have less PAS (degrees) at 12 months (MD -94.20, 95% CI -140.37 to -48.03; 1 study, n = 62) and 18 months (MD -127.30, 95% CI -168.91 to -85.69; 1 study, n = 60).  In one study, there were 26 adverse events in the phacoemulsification group: intraoperative corneal edema (n = 12), posterior capsular rupture (n = 1), intraoperative bleeding from iris root (n = 1), postoperative fibrinous anterior chamber reaction (n = 7), and visually significant posterior capsular opacification (n = 5), and no cases of suprachoroidal hemorrhage or endophthalmitis. There were four adverse events in the LPI group: closed iridotomy (n = 1) and small iridotomies that required supplementary laser (n = 3). In the other study, there was one adverse event in the phacoemulsification group (IOP > 30 mmHg on day 1 postoperatively (n = 1)), and no intraoperative complications. There were five adverse events in the LPI group: transient hemorrhage (n = 1), corneal burn (n = 1), and repeated LPI because of non-patency (n = 3).  Neither study reported health- or vision-related quality of life measures. AUTHORS' CONCLUSIONS: Low certainty evidence suggests that early lens extraction may produce more favorable outcomes compared to initial LPI in terms of IOP control. Evidence for other outcomes is less clear. Future high-quality and longer-term studies evaluating the effects of either intervention on the development of glaucomatous damage and visual field changes as well as health-related quality of life measures would be helpful.

A decision-support tool for funding health innovations at a tertiary academic medical center.

OBJECTIVES: To report the processes used to design and implement an assessment tool to inform funding decisions for competing health innovations in a tertiary hospital. METHODS: We designed an assessment tool for health innovation proposals with three components: "value to the institution," "novelty," and "potential for adoption and scaling." The "value to the institution" component consisted of twelve weighted value attributes identified from the host institution's annual report; weights were allocated based on a survey of the hospital's leaders. The second and third components consisted of open-ended questions on "novelty" and "barriers to implementation" to support further dialogue. Purposive literature review was performed independently by two researchers for each assessment. The assessment tool was piloted during an institutional health innovation funding cycle. RESULTS: We used 17 days to evaluate ten proposals. The completed assessments were shared with an independent group of panellists, who selected five projects for funding. Proposals with the lowest scores for "value to the institution" had less perceived impact on the patient-related value attributes of "access," "patient centeredness," "health outcomes," "prevention," and "safety." Similar innovations were reported in literature in seven proposals; potential barriers to implementation were identified in six proposals. We included a worked example to illustrate the assessment process. CONCLUSIONS: We developed an assessment tool that is aligned with local institutional priorities. Our tool can augment the decision-making process when funding health innovation projects. The tool can be adapted by others facing similar challenges of trying to choose the best health innovations to fund.

The Singapore Asymptomatic Narrow Angles Laser Iridotomy Study: Five-Year Results of a Randomized Controlled Trial.

PURPOSE: To examine the efficacy of laser peripheral iridotomy (LPI) in patients who received a diagnosis of primary angle-closure suspect (PACS). DESIGN: Prospective, randomized controlled trial. PARTICIPANTS: This multicenter, randomized controlled trial (ClinicalTrials.gov identifier, NCT00347178) enrolled 480 patients older than 50 years from glaucoma clinics in Singapore with bilateral asymptomatic PACS (defined as having ≥2 quadrants of appositional angle closure on gonioscopy). METHODS: Each participant underwent prophylactic LPI in 1 randomly selected eye, whereas the fellow eye served as a control. Patients were followed up yearly for 5 years. MAIN OUTCOME MEASURES: The primary outcome measure was development of primary angle closure (PAC; defined as presence of peripheral anterior synechiae, intraocular pressure [IOP] of >21 mmHg, or both or acute angle closure [AAC]) or primary angle-closure glaucoma (PACG) over 5 years. RESULTS: Of the 480 randomized participants, most were Chinese (92.7%) and were women (75.8%) with mean age of 62.8 ± 6.9 years. Eyes treated with LPI reached the end point less frequently after 5 years (n = 24 [5.0%]; incidence rate [IR], 11.65 per 1000 eye-years) compared with control eyes (n = 45 [9.4%]; IR, 21.84 per 1000 eye-years; P = 0.001). The adjusted hazard ratio (HR) for progression to PAC was 0.55 (95% confidence interval [CI], 0.37-0.83; P = 0.004) in LPI-treated eyes compared with control eyes. Older participants (per year; HR, 1.06; 95% CI, 1.03-1.10; P < 0.001) and eyes with higher baseline IOP (per millimeter of mercury; HR, 1.35; 95% CI, 1.22-1.50; P < 0.0001) were more likely to reach an end point. The number needed to treat to prevent an end point was 22 (95% CI, 12.8-57.5). CONCLUSIONS: In patients with bilateral asymptomatic PACS, eyes that underwent prophylactic LPI reached significantly fewer end points compared with control eyes over 5 years. However, the overall incidence of PAC or PACG was low.

Outcomes of surgical bleb revision at a tertiary Singapore eye hospital.

PURPOSE: To describe the outcomes of surgical bleb revisions from a tertiary glaucoma service in Singapore. METHODS: One hundred and thirty-one eyes of 129 patients who underwent surgical bleb revisions at the Singapore National Eye Centre between 2007 and 2014 were included in the study. The indications for bleb revision were: bleb-related infection (BRI), early and late bleb leak, early and late overfiltration, and bleb dysesthesia. Regression analysis was applied to elucidate risk factors. RESULTS: The mean age of the patients was 66 years, 62.6% were male, and 88.5% were Chinese. The majority of the eyes had primary glaucoma (79.4%). The mean interval from the initial trabeculectomy or phaco-trabeculectomy to the bleb revision was 58.8 months. The overall success rate was 69.5%. By Kaplan-Meier survival analysis, the overall cumulative success range fell from 78.6% to 49.1% over 10 years. Eyes with early bleb leak had lower surgical success compared to eyes with late bleb leak, early overfiltration and late overfiltration (P = 0.026, log-rank test). The IOP improved significantly post-operatively for eyes with BRI, early bleb leak, late bleb leak, early overfiltration and overfiltration (P < 0.05). Vision improved significantly in eyes with early overfiltration, but deteriorated in eyes with BRI (P < 0.05). CONCLUSION: The overall success rate for surgical bleb revisions was good with complete resolution of the primary problem in the majority of cases. However, eyes with early bleb leak were less likely to have successful outcomes and should be monitored more closely post-operatively.

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.

Evaluating CO2 laser-assisted sclerectomy surgery with mitomycin C combined with or without phacoemulsification in adult Asian glaucoma subjects.

PURPOSE: To evaluate and compare outcomes of CO2 laser-assisted sclerectomy surgery (CLASS) with mitomycin C (MMC) combined with or without phacoemulsification in adult Asian glaucoma patients. DESIGN: Retrospective, comparative study. METHODS: Adult Asian glaucoma patients who underwent CLASS alone or combined with phacoemulsification using standardized surgery by two trained glaucoma surgeons between 2014 and 2016 were identified. The main measures of outcome were: intraocular pressure (IOP), use of supplemental medical therapy, best-corrected visual acuity (BCVA), microperforations, macroperforations, and repeated intervention(s) for glaucoma. RESULTS: Forty-one eyes who underwent CLASS alone (13 eyes) or combined with phacoemulsification (28 eyes) were included. Overall, BCVA improved from 0.28 ± 0.19 to 0.14 ± 0.17, and 0.17 ± 0.19, 0.22 ± 0.24, and 0.18 ± 0.23 at 6, 12, 24, and 36 months, respectively. Mean IOP dropped from 17.9 ± 4.7 mmHg to 14.6 ± 5.5, 13.9 ± 3.3, 14.3 ± 3.6, and 14.1 ± 3.7 mmHg, and average number of medications reduced from 2.9 ± 0.9 to 0.2 ± 0.6, 0.5 ± 0.9, 1.0 ± 1.2, and 1.3 ± 1.4 at the same time points. There was no statistically significant difference in BCVA, IOP, and medication reduction between the two groups. CONCLUSIONS: CLASS combined with or without phacoemulsification was equally safe and effective, but yielded more modest results in our population.

Genome-wide association study identifies seven novel susceptibility loci for primary open-angle glaucoma.

Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide for which 15 disease-associated loci had been discovered. Among them, only 5 loci have been associated with POAG in Asians. We carried out a genome-wide association study and a replication study that included a total of 7378 POAG cases and 36 385 controls from a Japanese population. After combining the genome-wide association study and the two replication sets, we identified 11 POAG-associated loci, including 4 known (CDKN2B-AS1, ABCA1, SIX6 and AFAP1) and 7 novel loci (FNDC3B, ANKRD55-MAP3K1, LMX1B, LHPP, HMGA2, MEIS2 and LOXL1) at a genome-wide significance level (P < 5.0×10-8), bringing the total number of POAG-susceptibility loci to 22. The 7 novel variants were subsequently evaluated in a multiethnic population comprising non-Japanese East Asians (1008 cases, 591 controls), Europeans (5008 cases, 35 472 controls) and Africans (2341 cases, 2037 controls). The candidate genes located within the new loci were related to ocular development (LMX1B, HMGA2 and MAP3K1) and glaucoma-related phenotypes (FNDC3B, LMX1B and LOXL1). Pathway analysis suggested epidermal growth factor receptor signaling might be involved in POAG pathogenesis. Genetic correlation analysis revealed the relationships between POAG and systemic diseases, including type 2 diabetes and cardiovascular diseases. These results improve our understanding of the genetic factors that affect the risk of developing POAG and provide new insight into the genetic architecture of POAG in Asians.

New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics.

Primary open-angle glaucoma (POAG), the most common optic neuropathy, is a heritable disease. Siblings of POAG cases have a ten-fold increased risk of developing the disease. Intraocular pressure (IOP) and optic nerve head characteristics are used clinically to predict POAG risk. We conducted a genome-wide association meta-analysis of IOP and optic disc parameters and validated our findings in multiple sets of POAG cases and controls. Using imputation to the 1000 genomes (1000G) reference set, we identified 9 new genomic regions associated with vertical cup-disc ratio (VCDR) and 1 new region associated with IOP. Additionally, we found 5 novel loci for optic nerve cup area and 6 for disc area. Previously it was assumed that genetic variation influenced POAG either through IOP or via changes to the optic nerve head; here we present evidence that some genomic regions affect both IOP and the disc parameters. We characterized the effect of the novel loci through pathway analysis and found that pathways involved are not entirely distinct as assumed so far. Further, we identified a novel association between CDKN1A and POAG. Using a zebrafish model we show that six6b (associated with POAG and optic nerve head variation) alters the expression of cdkn1a. In summary, we have identified several novel genes influencing the major clinical risk predictors of POAG and showed that genetic variation in CDKN1A is important in POAG risk.

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.

Aqueous shunts with mitomycin C versus aqueous shunts alone for glaucoma.

BACKGROUND: Glaucoma affects more than 70 million people worldwide, with about 10% being bilaterally blind, making it the leading cause of irreversible blindness globally. In patients with advanced glaucoma or those who have failed medical treatment without achieving adequate intraocular pressure (IOP) control, trabeculectomy (glaucoma filtration surgery where an ostium is created into the anterior chamber from underneath a partial thickness scleral flap to allow for aqueous flow out of the anterior chamber intointo the subconjunctival space forming a filtering bleb) and aqueous shunt surgery for more complex and refractory cases remain the mainstay therapies. Proliferation of fibrous tissue around an implanted aqueous shunt may block the diffusion of aqueous humour. Mitomycin C (MMC) is one of two commonly used adjunct antifibrotic agents used during aqueous shunt surgery to prevent proliferation of fibrous tissue. However, the effectiveness and safety of the use of intraoperative MMC during aqueous shunt surgery has not been established. OBJECTIVES: To evaluate the effectiveness and safety of MMC versus no MMC used during aqueous shunt surgery for reducing IOP in primary and secondary glaucoma. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2018, Issue 2); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 13 February 2018. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which one group of participants received MMC during aqueous shunt surgery and another group did not. We did not exclude studies based on outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently reviewed titles and abstracts from the literature searches. We obtained full-text reports of potentially relevant studies and assessed them for inclusion. Two review authors independently extracted data related to study characteristics, risk of bias, and outcomes. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included five RCTs, with a total of 333 eyes with glaucoma randomized, and identified two ongoing trials. All included trials examined the effect of MMC versus no MMC when used during aqueous shunt surgery for glaucoma. The trials included participants with different types of uncontrolled glaucoma. One study was conducted in China, one in Saudi Arabia, two in the USA, and one study was a multicenter study conducted in Brazil, Canada, Scotland, and USA. We assessed all trials as having overall unclear risk of bias due to incomplete reporting of study methods and outcomes; two of the five trials were reported only as conference abstracts.None of the included trials reported mean decrease from baseline in IOP; however, all five trials reported mean IOP at 12 months post-surgery. At 12 months, the effect of MMC on mean IOP compared with no MMC was unclear based on a meta-analysis of trials (mean difference -0.12 mmHg, 95% CI -2.16 to 2.41; low-certainty evidence). Two trial did not report sufficient information to include in meta-analysis, but reported that mean IOP was lower in the MMC group compared with the no MMC group at 12 months.None of the included trials reported mean change from baseline in visual acuity; however, one trial reported lower mean LogMAR values (better vision) in the MMC group than in the no MMC group at 12 months post-surgery. None of the included studies reported the proportion of participants with stable best-corrected visual acuity. Three trials reported that loss of vision was not significantly different between groups (no data available for meta-analysis).None of the included studies reported the proportion of participants with a postoperative hypertensive phase, which is defined as IOP > 21 mmHg within 3 months after surgery. Two trials reported adverse events (choroidal effusion, corneal edema, flat anterior chamber, and retinal detachment); however, due to small numbers of events and sample sizes, no clear difference between MMC and placebo groups was observed. AUTHORS' CONCLUSIONS: We found insufficient evidence in this review to suggest MMC provides any postoperative benefit for glaucoma patients who undergo aqueous shunt surgery. Data across all five included trials were sparse and the reporting of study methods required to assess bias was inadequate. Future RCTs of this intervention should report methods in sufficient detail to permit assessment of potential bias and estimate target sample sizes based on clinically meaningful effect sizes.

Pupillary Responses to Full-Field Chromatic Stimuli Are Reduced in Patients with Early-Stage Primary Open-Angle Glaucoma.

PURPOSE: To evaluate the ability of chromatic pupillometry to reveal abnormal pupillary responses to light in patients with early-stage primary open-angle glaucoma (POAG) and to test whether the degree of pupillometric impairment correlates with structural hallmarks of optic nerve damage in the disease. DESIGN: Cross-sectional study. PARTICIPANTS: Forty-six patients with early-stage POAG (63.4±8.3 years, 63% male, 87% ethnic-Chinese) and 90 age-matched healthy controls (61.4±8.6 years, 34% male, 89% ethnic-Chinese). Patients with POAG had a visual field mean deviation (VFMD) of -6 decibels or better on automated perimetry. METHODS: Each participant underwent a monocular 2-minute exposure to blue light (462 nm) followed by another 2-minute exposure to red light (638 nm) using a modified Ganzfeld dome equipped with a light-emitting diode lighting system. The light stimuli intensity was increased logarithmically to evaluate the combined extrinsic and intrinsic response of intrinsically photosensitive retinal ganglion cells (ipRGCs). Light-induced changes in horizontal pupil diameter were assessed monocularly using infrared pupillography. MAIN OUTCOME MEASURES: Baseline-adjusted, light-induced pupillary constriction amplitudes were calculated, and individual irradiance-response curves were constructed for each stimulus. Pupillary constriction amplitudes were compared between groups and across light intensities using a linear mixed model analysis. The linear relationship between pupillometric parameters and different structural and functional features of glaucoma was assessed using Pearson's correlation analysis. RESULTS: Light-induced pupillary constriction was reduced in patients with early-stage POAG compared with controls at moderate to high irradiances (≥11 Log photons/cm2/s) of blue (P = 0.003) and red (P < 0.001) light. Maximal pupillary constriction amplitude was correlated with retinal nerve fiber layer thickness (RNFL) thickness (blue: r = 0.51, P < 0.001; red: r = 0.45, P = 0.002) in patients with POAG but not in controls. Conversely, pupillometric parameters were not correlated with visual field scores in patients with early-stage POAG. CONCLUSIONS: Patients with early-stage POAG exhibit reduced pupillary responses to moderate and high irradiances of blue and red lights. This wavelength-independent functional alteration correlates with structural thinning of the RNFL and could be the consequence of dysfunction or loss of melanopsin expressing ipRGCs in the early stages of the disease.

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.

Social, health and ocular factors associated with primary open-angle glaucoma amongst Chinese Singaporeans.

IMPORTANCE: There is limited literature on lifestyle and health factors related to primary open-angle glaucoma amongst Asians. BACKGROUND: This study evaluated the association of primary open-angle glaucoma with smoking, health and ocular factors amongst Chinese Singaporeans. DESIGN: Case-control study. PARTICIPANTS: The study used 711 primary open-angle glaucoma patients from a Singapore hospital and 2788 population-based controls. METHODS: Subjects underwent clinical examination and completed a questionnaire with details on family history of glaucoma, comorbidities, smoking and alcohol consumption. Glaucoma cases were subclassified as normal or high-tension glaucoma according to their untreated intraocular pressures. MAIN OUTCOME MEASURES: The association of various health and lifestyle factors, with normal-tension and high-tension glaucoma was evaluated. RESULTS: Using multiple logistic regression, primary open-angle glaucoma was associated with older age (odds ratio 1.12 per year older; 95% confidence interval 1.10-1.15; P < 0.001), family history of glaucoma (odds ratio 7.86; 95% confidence interval 4.48-13.79; P < 0.001), higher intraocular pressure (odds ratio 1.75 per 1 mmHg; 95% confidence interval 1.64-1.87; P < 0.001) and thinner central corneal thickness (odds ratio 1.01; 95% confidence interval 1.01-1.02; P < 0.001). Myopes were more likely to have primary open-angle glaucoma (P < 0.001). A current smoking habit was protective against normal-tension glaucoma (odds ratio 0.30; 95% confidence interval 0.10-0.92; P = 0.035). CONCLUSIONS AND RELEVANCE: Older age, family history of glaucoma, higher intraocular pressure, thinner central corneal thickness and myopia were significantly associated with primary open-angle glaucoma amongst Chinese Singaporeans.

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.

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.

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.