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To develop a classification system of visual field (VF) abnormalities in highly myopic eyes with and without glaucoma.Secondary analysis of VF data from a longitudinal cohort study.One thousand eight hundred ninety-three VF tests from 1302 eyes (825 individuals).All participants underwent VF testing (Humphrey 24-2 Swedish interactive threshold algorithm standard program; Carl Zeiss Meditec) and detailed ophthalmic examination. A comprehensive set of VF defect patterns was defined via observation of the 1893 VF reports, literature review, and consensus meetings. The classification system comprised 4 major types of VF patterns, including normal type, glaucoma-like defects (paracentral defect, nasal step, partial arcuate defect, arcuate defect), high myopia-related defects (enlarged blind spot, vertical step, partial peripheral rim, nonspecific defect), and combined defects (nasal step with enlarged blind spot). A subset (n = 1000) of the VFs was used to evaluate the interobserver and intraobserver agreement and weighted κ values of the classification system by 2 trained readers. The prevalence of various VF patterns and their associated factors were determined.The classification of VF in highly myopic eyes and its associated risk factors.We found that normal type, glaucoma-like defects, high myopia-related defects, and combined defects accounted for 74.1%, 10.8%, 15.0%, and 0.1% of all unique VF tests, respectively. The interobserver and intraobserver agreements were89%, and the corresponding κ values were 0.86 or more between readers. Both glaucoma-like and high myopia-related VF defects were associated with older age (odds ratios [ORs], 1.07 [95% confidence interval (CI), 1.04-1.10; P0.001] and 1.06 [95% CI, 1.04-1.10; P0.001]) and longer axial length (ORs, 1.65 [95% CI, 1.32-2.07; P0.001] and 1.37 [95% CI, 1.11-1.68; P = 0.003]). Longer axial length showed a stronger effect on the prevalence of glaucoma-like VF defects than on the prevalence of high myopia-related VF defects (P = 0.036).We propose a new and reproducible classification system of VF abnormalities for nonpathologic high myopia. Applying a comprehensive classification system will facilitate communication and comparison of findings among studies.

To compare real-world 24-month outcomes of phacoemulsification combined with either iStent inject or Hydrus Microstent.Analysis of data from the Fight Glaucoma Blindness (FGB) international registry. Anonymized data from 344 eyes with mild-to-moderate open-angle glaucoma, normal-tension glaucoma or ocular hypertension that underwent phacoemulsification combined with either iStent inject (224) or Hydrus Microstent (120) were included. Data were adjusted for baseline characteristics using linear regression and propensity score matching. The primary endpoint was a comparison of mean intraocular pressure (IOP) at 24 months.At 24 months, there was no significant difference in IOP reduction between the two groups, consistent across all analyses. The matched cohort showed iStent inject achieved 3.1 mmHg reduction and Hydrus a 2.3 mmHg reduction (p = 0.530) and a mean medication reduction of 1.0 for iStent inject versus 0.5 for Hydrus (p = 0.081). 5.4% of eyes in the iStent inject group and 7.5% of eyes in the Hydrus group required subsequent procedures to improve IOP control within 24 months. Complications were rare with no significant differences between the groups.Twenty-four-month outcomes showed sustained IOP reduction with a good safety profile for both groups. There was no significant difference in IOP outcomes between the groups. There may be a small additional reduction in glaucoma medication usage following cataract surgery with iStent inject compared to Hydrus.

BACKGROUND Ophthalmoscopy and its interpretation are complex. We aimed to compare the diagnostic accuracy of smartphone fundoscopy with traditional direct ophthalmoscopy for optic disc interpretation, with e-learning support. METHODS We conducted a randomised, crossover study of 102 medical students. Students were offered e-learning for optic disc interpretation. A fundoscopy objective structured clinical examination was conducted after an introductory lecture and 10-min practical training session on smartphone fundoscopy and traditional ophthalmoscopy. Participants examined patients and simulator slides with a randomised crossover between smartphone [D-eye (Padova, Italy) or iExaminer (Welch Allyn, Macquarie Park, Australia)] and traditional ophthalmoscopy (Welch Allyn). Optic discs were graded independently by three masked ophthalmologists. The primary outcome was the ability to interpret an optic disc as normal or abnormal. Secondary outcomes included other optic disc aspects; student preferences; and e-learning performance. RESULTS Students' agreement with the gold standard for an abnormal or normal disc was significantly greater using a smartphone (74.4%) than with direct ophthalmoscopy (68.1%, p = 0.032). More students preferred smartphone (74%) over direct ophthalmoscopy (26%, p

Purpose To investigate corneal stiffness parameters (SPs) as predictors of future progression risk in glaucoma suspect eyes. Design Prospective, longitudinal study. Participants Three hundred seventy-one eyes from 228 primary open-angle glaucoma suspects, based on optic disc appearance, with normal baseline Humphrey Visual Field (HVF; Carl Zeiss Meditec) results. Methods Baseline corneal SPs were measured using Corvis ST (Oculus Optikgerate GmbH). Participants were followed up every 6 months with clinical examination, HVF testing, and OCT. The baseline SP at first applanation (SP-A1) and highest concavity predicted the prospective outcome measures. Main Outcome Measures Structural progression was measured by the OCT rate of thinning of the retinal nerve fiber layer (RNFL) and ganglion cell–inner plexiform layer (GCIPL). Functional progression was assessed by permutation analysis of pointwise linear regression criteria on HVF testing. Results Stiffness parameters correlated positively with central corneal thickness (CCT), which was adjusted for in all analyses. A higher SP-A1, suggestive of a stiffer cornea, was associated with a faster rate of RNFL thinning (P Conclusions Glaucoma suspect eyes with higher corneal SPs and lower CCT, suggestive of thin and stiff corneas, are at greater risk of progression. Corneal SPs seem to act synergistically with CCT as risk factors for glaucoma progression.

Purpose Intraocular pressure (IOP) elevations may occur in early morning or outside office hours and can be missed during routine in-clinic IOP measurements. Such fluctuations or peaks likely contribute to glaucoma progression. We sought to investigate the relationship between an IOP polygenic risk score (PRS) and short-term IOP profile. Design Cross-sectional study. Participants Four hundred seventy-three eyes from 239 participants with suspected or established primary open-angle glaucoma sampled from 4 outpatient clinics in Australia between August 2016 and December 2019. Methods Participants underwent Icare HOME (Icare Oy, Vanda, Finland) tonometer measurements to record IOP 4 times daily for 5 days. Unreliable measurements were excluded. A minimum of 2 days with at least 3 reliable measurements were required. We used a validated IOP PRS derived from 146 IOP-associated variants in a linear regression model adjusted for central corneal thickness and age. Main Outcome Measures Highest recorded early morning IOP and mean IOP within and outside office hours. Early morning IOP spikes were defined by a higher early morning IOP than the maximum in-office hours IOP. Results Reliable measurements were obtained from 334 eyes of 176 participants (mean age, 64 ± 9 years). Eyes in the highest IOP PRS quintile showed an early morning IOP increase of 4.3 mmHg (95% confidence interval [CI], 1.4–7.3; P = 0.005) and mean increase in IOP outside office hours of 2.7 mmHg (95% CI, 0.61–4.7; P = 0.013) than the lowest quintile, which were significant independently after accounting for a recent in-clinic IOP measured by Goldmann applanation tonometry. Eyes in the highest PRS quintile were 5.4-fold more likely to show early morning IOP spikes than the lowest quintile (odds ratio 95% CI, 1.3–23.6; P = 0.023). Conclusions A validated IOP PRS was associated with higher early morning IOP and mean IOP outside office hours. These findings support a role for genetic risk prediction of susceptibility to elevated IOP that may not be apparent during in-clinic hours, requiring more detailed clinical phenotyping using home tonometry, the results of which may guide additional interventions to improve IOP control.

To investigate the association between cardiovascular disease and baseline structural defects and disease progression in glaucoma.Prospective, longitudinal study of preperimetric and perimetric glaucoma.Two thousand six hundred twenty-eight eyes from 1314 participants recruited to the Progression Risk of Glaucoma: Relevant SNPs with Significant Association (PROGRESSA) study were evaluated for baseline and longitudinal structural thinning using spectral-domain OCT and for visual field progression on Humphrey visual field (HVF) assessment.Patients were classified as either predominantly macula ganglion cell-inner plexiform layer (mGCIPL), predominantly peripapillary retinal nerve fiber layer (pRNFL), or both mGCIPL and pRNFL structural change at enrollment, and then evaluated for longitudinal OCT or HVF progression. Cardiovascular disease and medication characteristics of the participants were compared with a reference group of stable patients.OCT and HVF baseline status and longitudinal progression.After accounting for age and cardiovascular characteristics, patients with predominantly mGCIPL thinning at baseline showed a higher prevalence of hypertension (odds ratio [OR], 2.70; 95% confidence interval [CI], 1.66-4.41; P0.001), antihypertensive use (OR, 2.03; 95% CI, 1.20-3.46; P = 0.008), and statin use (OR, 1.98; 95% CI, 1.07-3.66; P = 0.029) than reference patients. Patients with predominantly pRNFL thinning exhibited a comparable prevalence of cardiovascular disease or medication with reference patients. Review of longitudinal OCT and HVF data (mean follow-up, 5.34 ± 1.29 years) showed that hypertension was associated with an increased risk of both OCT (OR, 1.79; 95% CI, 1.17-2.75; P = 0.006) and HVF progression (OR, 1.92; 95% CI, 1.18-3.15; P = 0.013). A 1-standard deviation (approximately 21 mmHg) increase in systolic blood pressure at baseline was associated with a greater risk of OCT progression (OR, 1.27; 95% CI, 1.01-1.63; P = 0.041) and HVF progression (OR, 1.32; 95% CI, 1.01-1.73; P = 0.043). The association between systolic blood pressure and structural progression was comparable to that observed between intraocular pressure and structural progression (OR, 1.30; 95% CI, 1.01-1.67; P = 0.039).Cardiovascular disease is an important risk factor for glaucoma progression.

To investigate the association between the apolipoprotein E (Retrospective analysis of prospective cohort data.This study included all available eyes from participants recruited to the Progression Risk of Glaucoma: Relevant SNPs [single nucleotide polymorphisms] with Significant Association (PROGRESSA) study with genotyping data from whichApolipoprotein E alleles and genotypes were determined in PROGRESSA, and their distributions were compared with an age-matched and ancestrally matched normative cohort, the Blue Mountains Eye Study. Structural parameters of neuroretinal atrophy measured using spectral-domain OCT were compared within the PROGRESSA cohort on the basis ofLongitudinal rates of thinning in the macular ganglion cell-inner plexiform layer (mGCIPL) complex and the peripapillary retinal nerve fiber layer (pRNFL).Rates of mGCIPL complex thinning were faster in participants harboring ≥1 copies of theThe

To evaluate the relationship between body mass index (BMI) and glaucoma progression.Multicohort observational study.This study combined a retrospective longitudinal analysis of suspect and early manifest primary open angle glaucoma cases from the Progression Risk of Glaucoma: RElevant SNPs with Significant Association (PROGRESSA) study with 2 replication cohorts from the UK Biobank and the Canadian Longitudinal Study of Ageing (CLSA). In the PROGRESSA study, multivariate analysis correlated BMI with longitudinal visual field progression in 471 participants. The BMI was then associated with glaucoma diagnosis and cross-sectional vertical cup-disc ratio (VCDR) measurements in the UK Biobank, and finally prospectively associated with longitudinal change in VCDR in the CLSA study.In the PROGRESSA study, a lower BMI conferred a faster rate of visual field progression (mean duration of monitoring (5.28 ± 1.80 years (10.6 ± 3.59 visits) (β 0.04 dB/year/SD95% CI [0.005, 0.069]; P = .013). In the UK Biobank, a 1 standard deviation lower BMI was associated with a worse cross-sectional VCDR (β -0.048/SD 95% CI [-0.056, 0.96]; P.001) and a 10% greater likelihood of glaucoma diagnosis, as per specialist grading of retinal fundus imaging (OR 0.90 95% CI [0.84, 0.98]; P = .011). Similarly, a lower BMI was associated with a greater risk of glaucoma diagnosis as per International Classification of Disease data (OR 0.94/SD; 95% CI [0.91, 0.98]; P = .002). Body mass index was also positively correlated with intraocular pressure (β 0.11/SD; 95% CI [0.06, 0.15]; P.001). Finally, a lower BMI was then associated with greater VCDR change in the CLSA (β -0.007/SD; 95% CI [-0.01, -0.001]; P = .023).Body mass index correlated with longitudinal and cross-sectional glaucomatous outcomes. This supports previous work illustrating a correlation between BMI and glaucoma.

Introduction Fundoscopy can be of great clinical value, yet remains underutilised. Educational attempts to improve fundoscopy utilisation have had limited success. We aimed to explore the barriers and facilitators underlying the uptake of clinical direct ophthalmoscopy across a spectrum of medical specialties and training levels. Methods Ten focus groups were conducted with medical students (n = 42), emergency department doctors (n = 24), basic physician trainees (n = 7), hospital physicians (n = 6) and general practitioners (n = 7). Independent thematic analysis of transcripts was conducted by three investigators. A consensus thematic framework was developed, and transcripts were reanalysed using this framework. Results Thematic analysis identified seven main themes: (1) technical barriers to performing fundoscopy examinations; (2) clinical culture and expectations regarding fundoscopy; (3) the influence of fundoscopy on clinical management; (4) motivation to perform the examination; (5) novel technology including smartphone fundoscopy, and the value of a digital fundus image; (6) training requirements, and; (7) use of limited resources. Conclusion Our results build a more nuanced picture of the factors which determine fundoscopy utilisation. As current barriers limit practice by clinicians and medical students, expertise and confidence performing and interpreting fundoscopy are lost. This shifts the balance of perceived clinical utility to futility in changing patient management, and reinforces a cycle of reducing fundoscopy utilisation. We identified important cultural barriers such as accepted incompetence, and misperceptions of senior discouragement. Emerging technologies reduce the technical barriers to fundoscopy. Therefore education should: focus on detecting pathology from digital images; clarify the role of fundoscopy in patient management, and; be targeted at key career progression points.

ImportanceIrreversible vision loss from primary open-angle glaucoma (POAG) can be prevented through timely diagnosis and treatment, although definitive diagnosis can be difficult in early-stage disease. As a consequence, large numbers of individuals with suspected glaucoma require regular monitoring, even though many of these may never develop disease and other high-risk individuals with suspected glaucoma may have delayed or inadequate treatment. POAG is one of the most heritable common diseases, and this provides an opportunity to use genetic instruments in risk-stratified screening, diagnosis, and treatment of early glaucoma.ObjectiveTo assess the association of glaucoma polygenic risk with glaucoma progression in early-stage disease.Design, Setting, and ParticipantsThis cohort study used clinical and genetic data obtained from a longitudinal cohort study, Progression Risk of Glaucoma: Relevant SNPs With Significant Association (PROGRESSA). Participants of European ancestry with characteristic optic nerve head changes suggestive of glaucoma were included. Data were collected between February 2012 and June 2020. Analysis took place between July 2020 and April 2022.Main Outcomes and MeasuresThe association of a glaucoma polygenic risk score (PRS) (2673 uncorrelated variants) with rate of peripapillary retinal nerve fiber layer thinning on optical coherence tomography and progression of visual field loss on 24-2 Humphrey visual fields.ResultsA total of 1777 eyes from 896 individuals had sufficient data for structural progression analyses and 1563 eyes from 808 individuals for functional progression analyses. The mean (SD) age was 62.1 (9.9) years, 488 (44%) were male, and 1087 of 1103 individuals (98.5%) had European ancestry. An ancestrally matched normative population cohort (n = 17 642) was used for PRS reference. Individuals in the top 5% PRS risk group were at a higher risk of visual field progression compared with the remaining 95% after 5 years (hazard ratio, 1.5; 95% CI, 1.13-1.97; P = .005). Conversely, those in the bottom 20% PRS risk group were at a lower risk of visual field progression compared with an intermediate risk group over 3 years (hazard ratio, 0.52; 95% CI, 0.28-0.96; P = .04).Conclusions and RelevanceIn this study, high polygenic risk was associated with more rapid structural and functional progression in early POAG, despite more intensive treatment. A PRS may serve as a valuable adjunct to identify individuals who stand to benefit the most from more frequent surveillance and earlier or more intensive treatment.

The aim of this study was to determine whether insertion of a trabecular bypass device (TBD) is a cost-effective intervention for the treatment of open-angle glaucoma (OAG) with mild to moderate vision loss in the Australian setting.We performed a cost-utility analysis of TBD implantation in conjunction with cataract surgery or as a standalone procedure in patients with OAG. The model used a Monte Carlo simulation to follow individual patients through a glaucoma treatment algorithm that included TBD and compared the costs and outcomes with those of patients simulated through an algorithm without TBD (usual care). The model tracked the intraocular pressure (IOP) of individual patients and then, based on this IOP, tracked the progression of the patient's glaucoma. Utility values were assigned dependent on severity of glaucoma. The analysis took the perspective of the Australian health care system. The main outcome was incremental cost per quality-adjusted life-year (QALY) of TBD versus usual care for the treatment of OAG.In the cataract surgery population, TBD surgery was associated with incremental healthcare costs of A$177 and 0.0726 QALYs per patient, resulting in an incremental cost per QALY gained of A$2430. In the standalone population, the overall incremental cost of TBD surgery versus usual care was A$2234. With QALYs gained of 0.1526 per patient, this equated to an incremental cost per QALY gained ratio of A$14,644.The incremental cost per QALY estimates for TBD were below thresholds generally accepted by Australian healthcare payers, suggesting that TBD is a cost-effective intervention for patients with primary OAG in the Australian setting.

Background/AimsTo determine if selective laser trabeculoplasty (SLT) is superior to topical medication as a first-line treatment for glaucoma on quality of life (QoL) and clinical outcomes.MethodsIn this international, longitudinal, multisite randomised controlled trial, treatment naïve mild-to-moderate primary open angle or exfoliation glaucoma patients were randomised 1:1 to SLT or topical medication. Glaucoma-specific QoL (primary outcome) was measured using the Glaucoma Outcomes Assessment Tool (GOAT; 342 items, 12 domains). Secondary outcomes included rate of successful intraocular pressure (IOP) reduction (>25% reduction from baseline) and presence of ocular surface disease including conjunctival hyperaemia and eyelid erythema. Our intention-to-treat analysis was performed at months 12 and 24.ResultsOf 167 enrolled patients, 83 and 84 were randomised to SLT and topical medication, respectively; and 145 (n=75 SLT, n=70 medication) completed 24-month follow-up. While both treatment arms achieved significant within-group gains in GOAT outcomes at both endpoints, SLT patients reported a greater between-group improvement in ‘social well-being’ compared with medication patients (mean±SE=0.28±0.13; p=0.034) at 24 months. At month 24, the rate of successful IOP reduction was 18.6% (95% CI 3.0% to 34.3%, p=0.022) higher (absolute difference) in the medication compared with SLT group. More individuals in the medication group had conjunctival hyperaemia and eyelid erythema compared with SLT at 24 months.ConclusionOverall, we did not find evidence that SLT was superior to medication in improving glaucoma-specific QoL. While we found superior IOP reduction in the medication arm, eyelid erythema and conjunctival hyperaemia were more prevalent in these patients compared with the SLT group.Trial registrationACTRN12611000720910.

To investigate which clinical measures influence whether an individual demonstrates earliest glaucomatous structural progression on peripapillary retinal nerve fiber layer (pRNFL) or macular ganglion cell-inner plexiform layer (mGCIPL).Prospective, longitudinal cohort study.Two hundred seventy-one eyes from 207 individuals with statistically significant evidence of glaucomatous progression on OCT Guided Progression Analysis (GPA) software were drawn from a total of 1271 eyes from 686 individuals categorized as glaucoma suspect or having early manifest glaucoma undergoing glaucoma surveillance.Individuals demonstrating earliest evidence of longitudinal progression on mGCIPL GPA event analysis were compared with individuals demonstrating evidence of earliest longitudinal progression on pRNFL GPA event analysis.Correlation of OCT event change analysis with intraocular pressure (IOP), clinical variables, and baseline thickness of the pRNFL and mGCIPL.Intraocular pressure, baseline pRNFL thickness, baseline mGCIPL thickness, and systemic hypertension were associated with location of first progression. Eyes demonstrating earliest longitudinal progression on mGCIPL had significantly lower maximum-recorded pretreatment IOP (mean difference, 3.90 mmHg; 95% confidence interval [CI], 2.37-5.43 mmHg; P0.001). The interval between progression on pRNFL and progression on mGCIPL increased by 12.4 months for every 5-mmHg increase in IOP (95% CI, 10.32-15.72 months). Eyes demonstrating earliest longitudinal progression on mGCIPL showed significantly lower baseline average pRNFL thickness than eyes progressing on pRNFL first (mean difference, 7.07 μm; 95% CI, 4.38-9.77 μm; P0.001). Eyes progressing first on mGCIPL parameters were 3.03 times more likely to demonstrate a new paracentral field defect than eyes progressing first on pRNFL parameters (odds ratio, 3.03; 95% CI, 1.26-7.28; P = 0.01).Clinical features, particularly pretreatment IOP, influence whether structural glaucoma progression is detected earlier with mGCIPL or pRNFL imaging. These data support the usefulness of mGCIPL imaging in addition to pRNFL analysis for detection of glaucoma progression, particularly in patients with normal IOP.

Background Fundoscopy outside ophthalmology is in decline, and the technical demands of the traditional direct ophthalmoscope examination are likely contributing. Alternative fundoscopy technologies are increasingly available, yet valid comparisons between fundoscopy technologies are lacking. We aimed to assess medical students’ perceptions of usefulness and ease of use of traditional and contemporary fundus-viewing technologies including smartphone fundoscopy. Methods One hundred forty-six second-year medical students participated in a cross-sectional, randomised, cross-over study of fundoscopy methods. Medical students completed small group training sessions using six current fundoscopy technologies including: a non-mydriatic fundus camera; two types of direct fundoscopy; and three types of smartphone fundoscopy. A novel survey of perceived usefulness and ease of use was then completed by students. Results Repeated-measures ANOVA found students rated both the perceived usefulness (pp Conclusions Smartphone fundoscopy was found to be significantly more useful and easier to use than other modalities. Educators should optimise student access to novel fundoscopy technologies such as smartphone fundoscopy which may mitigate the technical challenges of fundoscopy and reinvigorate use of this valuable clinical examination.

Angle surgery has always been the basis of the surgical management of angle closure and angle closure glaucoma. After iridectomy, cyclodialysis was the most effective surgery at the beginning of the twentieth century and by the 1930s, trabecular surgery in the form of goniotomy was popularised for open-angle disease. These operations have been rediscovered in the twenty-first century, forming the cornerstone of the MIGS procedures. Little modern evidence exists as to their utility in angle closure disease but what little there is suggests they may have a role once pupil block, lens crowding and synechial mechanisms have been controlled.

Globalization is a comprehensive phenomenon with significant implications for global health. The globalization of minimally invasive glaucoma surgery (MIGS) is currently still a work in progress, with these devices slowly making inroads into Asia, Australasia, South America, and South Africa. Although MIGS companies can enjoy a quantum leap in economies of scale by serving global markets rather than only a confined domestic market, there are considerable economic, logistical, training, legal, and regulatory challenges that they need to overcome. The globalization of MIGS may benefit glaucoma patients worldwide, by reducing medication burden, improving the quality of life, and potentially decreasing the global incidence of glaucoma-related blindness.

Precis Standalone trabecular micro-bypass glaucoma surgery with the iStent devices is associated with clinically relevant reductions in intraocular pressure (IOP) sustained over a reasonably long-term while simultaneously reducing medication burden and a relatively favorable safety profile. Purpose While there is a relatively large body of evidence supporting the implantation of the iStent trabecular micro-bypass devices during phacoemulsification in patients with open-angle glaucoma (OAG), its efficacy as a standalone procedure has been less widely reported. The aims of this study were to systematically identify and quantitatively evaluate the efficacy of iStent devices (iStent and iStent inject) when performed independently of cataract surgery in patients with OAG. Methods A systematic review of the literature was undertaken in August 2019 to identify studies of standalone trabecular micro-bypass glaucoma surgery with iStent devices in patients with OAG. All randomized trials were considered and nonrandomized studies that included at least 6 months of follow-up or more than 10 eyes. Key efficacy analyses included postoperative IOP and medication use, which were used to evaluate weighted mean differences from baseline, and the proportion of eyes free of ocular medication. Postoperative adverse events were descriptively summarized. Results A total of 13 studies were identified including 4 randomized controlled trials and 9 nonrandomized or single-arm studies providing data for 778 eyes. In eyes implanted with iStent devices, a weighted mean IOP reduction of 31.1% was observed at 6 to 12 months. In studies reporting longer-term outcomes (36 to 48 mo or 60 mo), the weighted mean IOP reduction was 30.4% and 32.9%, respectively. The pooled weighted mean reduction in IOP from baseline across all studies at 6 to 12 months and 36 to 60 months poststent implantation was 7.01 mm Hg (95% confidence interval: 5.91, 8.11) and 6.59 mm Hg (95% confidence interval: 5.55, 7.63), respectively. Medication burden was reduced by ~1.0 medication at 6 to 18 months and 1.2 medications at 36 to 60 months. Adverse events reported in more than 5% of participants were progression of pre-existing cataract/cataract surgery and loss of best-corrected visual acuity but these rates were no different to those reported in comparator medical therapy study arms. Conclusions The results from these studies support the independent effect of the iStent trabecular bypass devices on IOP and medication burden over a duration of follow-up of up to 5 years.

PURPOSE: To examine the combined effects of common genetic variants associated with intraocular pressure (IOP) on primary open-angle glaucoma (POAG) phenotype using a polygenic risk score (PRS) stratification.DESIGN: Cross-sectional study.PARTICIPANTS: For the primary analysis, we examined the glaucoma phenotype of 2154 POAG patients enrolled in the Australian and New Zealand Registry of Advanced Glaucoma, including patients recruited from the United Kingdom. For replication, we examined an independent cohort of 624 early POAG patients.METHODS: Using IOP genome-wide association study summary statistics, we developed a PRS derived solely from IOP-associated variants and stratified POAG patients into 3 risk tiers. The lowest and highest quintiles of the score were set as the low- and high-risk groups, respectively, and the other quintiles were set as the intermediate risk group.MAIN OUTCOME MEASURES: Clinical glaucoma phenotype including maximum recorded IOP, age at diagnosis, number of family members affected by glaucoma, cup-to-disc ratio, visual field mean deviation, and treatment intensity.RESULTS: A dose-response relationship was found between the IOP PRS and the maximum recorded IOP, with the high genetic risk group having a higher maximum IOP by 1.7 mmHg (standard deviation [SD], 0.62 mmHg) than the low genetic risk group (P = 0.006). Compared with the low genetic risk group, the high genetic risk group had a younger age of diagnosis by 3.7 years (SD, 1.0 years; P < 0.001), more family members affected by 0.46 members (SD, 0.11 members; P < 0.001), and higher rates of incisional surgery (odds ratio, 1.5; 95% confidence interval, 1.1-2.0; P = 0.007). No statistically significant difference was found in mean deviation. We further replicated the maximum IOP, number of family members affected by glaucoma, and treatment intensity (number of medications) results in the early POAG cohort (P ≤ 0.01).CONCLUSIONS: The IOP PRS was correlated positively with maximum IOP, disease severity, need for surgery, and number of affected family members. Genes acting via IOP-mediated pathways, when considered in aggregate, have clinically important and reproducible implications for glaucoma patients and their close family members.

Contains fulltext : 218893.pdf (Publisher’s version ) (Closed access) Glaucoma, a disease characterized by progressive optic nerve degeneration, can be prevented through timely diagnosis and treatment. We characterize optic nerve photographs of 67,040 UK Biobank participants and use a multitrait genetic model to identify risk loci for glaucoma. A glaucoma polygenic risk score (PRS) enables effective risk stratification in unselected glaucoma cases and modifies penetrance of the MYOC variant encoding p.Gln368Ter, the most common glaucoma-associated myocilin variant. In the unselected glaucoma population, individuals in the top PRS decile reach an absolute risk for glaucoma 10 years earlier than the bottom decile and are at 15-fold increased risk of developing advanced glaucoma (top 10% versus remaining 90%, odds ratio = 4.20). The PRS predicts glaucoma progression in prospectively monitored, early manifest glaucoma cases (P = 0.004) and surgical intervention in advanced disease (P = 3.6 x 10(-)(6)). This glaucoma PRS will facilitate the development of a personalized approach for earlier treatment of high-risk individuals, with less intensive monitoring and treatment being possible for lower-risk groups.

IMPORTANCE: Cataract and primary open-angle glaucoma (POAG) commonly co-exist, and cataract surgery is thought to reduce intraocular pressure (IOP), the major modifiable risk factor of POAG. BACKGROUND: Previous studies exploring the effect of cataract surgery on IOP are limited by retrospective design, lack of a control group, medication use and washout and loss to follow up. DESIGN: Prospective, multicentre, matched case-control Australian study. PARTICIPANTS: 171 eyes of 108 POAG patients who underwent cataract surgery, matched to 171 control eyes. METHODS: Serial longitudinal IOP measurements were compared before and after cataract surgery, and relative to the controls. A mixed-effect model was used for the longitudinal data. MAIN OUTCOME MEASURES: Change in IOP. RESULTS: The mean follow-up time was 4.8 (1.4) years. Cataract surgery reduced mean IOP by 2.22 mmHg (95% confidence interval: 1.93-2.52 mmHg, P

Background Genome-wide association studies (GWAS) have identified association of common alleles with primary open-angle glaucoma (POAG) and its quantitative endophenotypes near numerous genes. This study aims to determine whether rare pathogenic variants in these disease-associated genes contribute to POAG. Methods Participants fulfilled strict inclusion criteria of advanced POAG at a young age of diagnosis. Myocilin mutation carriers were excluded using direct sequencing. Whole exome sequencing was performed on 187 glaucoma cases and 103 local screened nonglaucoma controls then joint-called with exomes of 993 previously sequenced Australian controls. GWAS-associated genes were assessed for enrichment of rare predicted pathogenic variants in POAG. Significantly enriched genes were compared against Exome Aggregation Consortium (ExAC) public control. Results Eighty-six GWAS disease or trait-associated glaucoma genes were captured and sequenced. CARD10 showed enrichment after Bonferroni correction for rare variants in glaucoma cases (OR = 13.2, P = 6.94 9 10�5) with mutations identified in 4.28% of our POAG cohort compared to 0.27% in controls. CARD10 was significantly associated with optic disc parameters in previous GWAS. The whole GWAS gene set showed no enrichment in POAG overall (OR = 1.12,P = 0.51). Conclusion We report here an enrichment of rare predicted pathogenic coding variants within a GWAS-associated locus in POAG (CARD10). These findings indicate that both common and rare pathogenic coding variants in CARD10 may contribute to POAG pathogenesis.

Background Endophthalmitis is a rare but devastating postoperative complication of cataract surgery. We aimed to describe the incidence of acute postoperative endophthalmitis in an Australian population over a 14-year period. Design This was a retrospective longitudinal cohort study performed at Westmead Hospital, a major tertiary hospital in Sydney, Australia. Participants Patients who had acute postoperative endophthalmitis within 6 weeks of their cataract surgery at Westmead Hospital were included. Methods Endophthalmitis cases from 2000 to 2014 were identified from computerized diagnostic coding. These were cross-referenced with the cataract surgery list over this time period. The routine use of intracameral vancomycin at the end of cataract surgery was introduced in Westmead Hospital in 2004. Main Outcome Measures We quantified the incidence of acute postoperative endophthalmitis pre and post the routine use of intracameral vancomycin. Results A total of 14 805 cataract cases were performed at Westmead Hospital from 2000 to 2014. Seventeen cases of endophthalmitis were within 6 weeks post cataract surgery performed at Westmead Hospital. In the period 2000 to 2003, the incidence of postoperative endophthalmitis was 0.43% (11/2539). From 2004 to 2014, there was a dramatic decrease in the incidence of postoperative endophthalmitis to 0.049% (6/12 266, P

Importance: The p.Gln368Ter (rs74315329) risk allele in the myocilin gene ( MYOC ) was initially reported to have high penetrance in glaucoma registry-based studies, but much lower estimates were recently obtained from population-based studies. We investigated this disparity using data from Australia and the United Kingdom. Objectives: To examine the penetrance and effect size of the MYOC p.Gln368Ter variant with glaucoma and ocular hypertension (OHT). Design, Setting, and Participants: This cross-sectional study within the UK Biobank (UKBB) included participants of white British ancestry. Glaucoma cases were defined by International Classification of Diseases, Ninth Revision (ICD-9) and Tenth Revision (ICD-10) diagnoses and self-reported questionnaires. Carriers of the MYOC p.Gln368Ter variant were identified using genotype imputation from arrays. In contrast, 2 Australian registry-based studies, the Australian and New Zealand Registry of Advanced Glaucoma and the Glaucoma Inheritance Study in Tasmania, ascertained glaucoma cases referred by eye care clinicians, with historic control participants recruited from other Australian studies. Samples were either directly sequenced or had genotypes determined by imputation (for the Australian registry and historic control participants). Recruitment to the UKBB occurred between 2006 and 2010, and data analysis occurred from September 2017 to July 2018. Main Outcomes and Measures: The penetrance and odds ratio (OR) were estimated for the MYOC p.Gln368Ter variants in participants with glaucoma and OHT. Results: A total of 411 337 UKBB participants of white British ancestry (mean [SD] age, 56.6 [8.0] years) were included, plus 3071 Australian registry and 6750 historic control participants. In the UKBB, the minor allele frequency of the MYOC p.Gln368Ter variant was 1 in 786 individuals (0.13%). The odds ratio of p.Gln368Ter in patients with primary open-angle glaucoma (POAG) was 6.76 (95% CI, 4.05-11.29); glaucoma (POAG, self-reported glaucoma, and unspecified glaucoma), 4.40 (95% CI, 3.38-5.71); OHT, 3.56 (95% CI, 2.53-4.92); and OHT and glaucoma combined, 4.18 (95% CI, 3.05-5.67). The penetrance of the MYOC p.Gln368Ter variant was 7.6% in patients with glaucoma, 24.3% in patients with OHT, and 30.8% in patients with OHT and glaucoma combined. In the Australian registry studies, the odds of MYOC p.Gln368Ter variant were 12.16 (95% CI, 6.34-24.97) in patients with advanced glaucoma and 3.97 (95% CI, 1.55-9.75) in those with nonadvanced glaucoma; the penetrance of glaucoma was 56.1%, and penetrance in those considered to have glaucoma or be glaucoma suspects was 69.5%. Conclusions and Relevance: The MYOC p.Gln368Ter variant confers a very high-risk effect size for advanced glaucoma; the risk is lower in nonadvanced glaucoma and OHT. In the general population sample, approximately 50% of MYOC p.Gln368Ter carriers 65 years and older had glaucoma or OHT, with higher prevalence in the Australian registry studies.

Purpose To evaluate the influence of different clinical examination techniques, including optic nerve head (ONH) photography, visual field tests, and adjunct imaging on the diagnosis of glaucoma by Australian and New Zealand optometrists. The effect of a short-term, didactic teaching module on these is also explored. Methods Clinical data of 30 patients previously seen at the Centre for Eye Health was collected and compiled into glaucoma diagnostic assessment modules. Each of six modules contained different combinations of clinical examination results and required a classification of the cases as normal, suspicious or glaucoma. A cohort of 54 Australian and New Zealand optometrists were recruited for the study and allocated into two cohorts. The intervention group completed a glaucoma training course prior to the assessment while the control group completed the assessment without additional training. Diagnostic accuracy was compared between modules and optometrist groups. Results High false negative rates were observed with ONH photography, which were drastically reduced with the addition of visual field, albeit at the cost of increased false positive rates. Addition of adjunct imaging techniques partially compensated for the increase in the false positive rate from the visual field, but had limited effect on false negative rate. Educational intervention resulted in larger improvement in the diagnostic ability when multiple imaging modalities were provided. Conclusion The study highlighted the importance of combining both structural and functional assessments in glaucoma. Current imaging technology demonstrated limited usefulness for event diagnosis due to the persistent difficulties of defining structural and functional loss in glaucoma, thus highlighting the need for new glaucoma assessment techniques. Short-term didactic teaching programs may only result in limited improvement of glaucoma diagnostic ability in optometrists, and hence, it may need to be combined with long-term and/or non-didactic training components to obtain a greater effect.

Open-angle glaucoma (OAG) is a major cause of blindness worldwide. To identify new risk loci for OAG, we performed a genome-wide association study in 3,071 OAG cases and 6,750 unscreened controls, and meta-analysed the results with GWAS data for intraocular pressure (IOP) and optic disc parameters (the overall meta-analysis sample size varying between 32,000 to 48,000 participants), which are glaucoma-related traits. We identified and independently validated four novel genome-wide significant associations within or near MYOF and CYP26A1, LINC02052 and CRYGS, LMX1B, and LMO7 using single variant tests, one additional locus (C9) using gene-based tests, and two genetic pathways - “response to fluid shear stress” and “abnormal retina morphology” - in pathway-based tests. Interestingly, some of the new risk loci contribute to risk of other genetically-correlated eye diseases including myopia and age-related macular degeneration. To our knowledge, this study is the first integrative study to combine genetic data from OAG and its correlated traits to identify new risk variants and genetic pathways, highlighting the future potential of combining genetic data from genetically-correlated eye traits for the purpose of gene discovery and mapping.

PurposeThe ganglion cell analysis (GCA) of the CIRRUSTM HD-OCT (Carl Zeiss, Meditec; Dublin, CA) provides measurement of the macular ganglion cell-inner plexiform layer (GCIPL) thickness. This study determined the frequency of scan artefacts and errors in GCIPL imaging in individuals undergoing HD-OCT surveillance for glaucoma.MethodA total of 1439 eyes from 721 subjects enrolled in a prospective study assessing predictors of glaucoma progression underwent macular GCIPL imaging with the CIRRUS HD-OCT at recruitment. The prevalence of acquisition errors, segmentation errors, and co-morbid macular pathology was determined.ResultsA total of 87 (6.0%) of the 1439 scans had either acquisition errors, segmentation artefacts, or other macular pathology. The most common co-morbid macular pathology was epiretinal membrane in 2.2% of eyes.ConclusionThe macular GCIPL scan was artefact free in 94% of eyes. However, epiretinal membrane and high myopia can cause scan artefact and should be considered when interpreting the results.

To assess the prevalence and associations of a notch in the optic disc neural rim.Stereo-photographs from the Blue Mountains Eye Study were graded for the presence of a notch (defined as focal reduction in neural rim width associated with a change in the curvature of the rim for no greater than 4 clock hours).A notch was found in at least 1 eye of 205 participants (5.7%), and was bilateral in 51 (1.4%). Notch prevalence increased with age from 2.48% in participants aged60 years, to 4.1% for ages 60 to 69 years, 7.98% for ages 70 to 79 years and 15.3% for ages 80 years or older. No sex differences were found. Notches were more frequent in eyes with myopia (odds ratio, OR, 1.98, 95% confidence interval, CI, 1.31-2.98) or beta-peripapillary atrophy (OR 2.20, CI 1.52-3.22). No associations were found with intraocular pressure, optic disc hemorrhage, or migraine history. After adjusting for other risk factors, a neural rim notch was strongly associated with glaucoma diagnosis (OR 21.2, CI 8.8-50.8). The sensitivity and specificity for glaucoma with visual field loss of finding a notch in either eye was 90.3% and 96.8%, respectively. The positive predictive value of a notch was 45.4% and negative predictive value 99.7%.A notch in the neural rim is a relatively infrequent sign in normal eyes but is very frequent in glaucoma. This sign has both good sensitivity and a positive predictive value for glaucoma.

Recent genome-wide association studies reported strong association of genetic variation at the CDKN2B/CDKN2B-AS1 locus on 9p21 with normal-tension glaucoma (NTG) in multiple populations. The mechanism by which this locus causes disease remains to be elucidated. We investigated the association of DNA methylation of CpG islands at this locus with NTG.We conducted a retrospective case-control study of 178 NTG cases and 202 unaffected controls from Australia. CDKN2B and CDKN2B-AS1 promoter methylation was measured quantitatively using the MassCleave assay, and assessed for association with the disease, and the genotype of the associated risk variants using IBM SPSS statistics 22.0 CpG sites at which methylation status was associated with NTG were validated using pyrosequencing.We identified one CpG site (F1:13-14) in the CDKN2B promoter which showed significant association with NTG (p = 0.001). The association was highly significant in female cases (p = 0.006) but not in male cases (p = 0.054). The association was validated using an independent method confirming the likely association of DNA methylation with NTG in females (p = 0.015), but not in males (p = 0.497). In addition, methylation at CpG sites in CDKN2B was also associated with genotype at rs1063192, which is known to confer risk for NTG.This study reveals an association of methylation status in the CDKN2B promoter with NTG, particularly in females. This suggests that the observed genetic association with the disease at this locus could be in part due to epigenetic mechanisms, and is likely to be independent of the association of nonsynonymous coding variation within the gene.

Purpose We investigate the effect of angiotensin receptor blockade on the migration of human Tenon fibroblasts (HTF), using irbesartan, an angiotensin II receptor type 1 (AT1R) blocker (ARB) as a potential antifibrotic agent in glaucoma filtration surgery. Methods Confluent HTF cultures were scratched with a 1 mL pipette tip and treated with either irbesartan (10, 50, and 100 μg/mL) or angiotensin II (2 μg/mL). The extent of HTF migration up to 30 hours, and cell number and morphology at 72 hours was evaluated. To assess the effect on reactive oxygen species (ROS) level, HTF were treated with either irbesartan (10 μg/mL) or angiotensin II (2 μg/mL) for 24 hours after scratching, and then stained with dihydroethidium (DHE) before evaluation by confocal microscopy. Results Irbesartan inhibited HTF migration by 50% to 70% compared to controls (P < 0.05). Levels of ROS were almost completely attenuated by irbesartan (DHE fluorescence intensity of 5.68E-09) (P < 0.05). Irbesartan reduced cell numbers by 50% and induced morphologic changes with loss of pseudopods (P < 0.05). Conversely, angiotensin II increased cell numbers up to 4-fold while retaining cell viability. Conclusions Irbesartan inhibited HTF migration and ROS production. It also reduced cell numbers and altered HTF morphology. Angiotensin II increased cell number without altering morphology. This initial study warrants future investigations for further potential antifibrotic effects of this drug. Translational Relevance This in vitro study focused on investigations of irbesartan's effects on HTF migration, ROS production, as well as HTF cell numbers and morphology. It suggests a potential therapeutic strategy worth further exploration with a view towards postoperative wound healing modulation in glaucoma filtration surgery.

Background To investigate the effects of current intraocular pressure-lowering medications on the efficacy of selective laser trabeculoplasty. Design Retrospective chart review of records from an urban glaucoma clinic in Sydney, Australia. Participants Patients who received their first selective laser trabeculoplasty between 2002 and 2005 were studied (grouped from 0 to 3 according to the number of pre-selective laser trabeculoplasty medications, and followed for 5 years). Those with previous argon laser therapy, trabeculectomy or angle-closure were excluded. Methods Selective laser trabeculoplasty (Ellex) used to deliver 180 or 360 degree of treatment, under the same protocol. Main Outcome Measures Responders were defined by ≥20% reduction from baseline intraocular pressure. Data were censored when pressure-lowering intervention was required. The mean intraocular pressure, survivor, response rate, number and type of medications were compared. Results There were 206 patients with ocular hypertension, primary, pseudo-exfoliation, or pigmentary glaucoma who used none (n = 20), one (n = 33), two (n = 61) or three or more (n = 92) pre-selective laser trabeculoplasty topical anti-glaucoma medications. The mean baseline intraocular pressures for each group was 23.7, 22.2, 20.7 and 20.4 mmHg, respectively (P = 0.061). Post-treatment mean intraocular pressure was 17.9, 17.7, 15.5, and 15.7 mmHg; percentage reduction was similar between groups (23.6–25.6%, P = 0.20). Kaplan–Meier survival analysis showed comparable survival rates across groups (P = 0.445). At 60 months, 11.1, 17.1, 30.5 and 11.5% of responders remained in each group. Higher proportions of patients in groups 2 and 3 required further laser or surgery. Conclusion The number of pre-selective laser trabeculoplasty medications did not affect the intraocular pressure-lowering effectiveness of selective laser trabeculoplasty; however, groups on more medications required more pressure-lowering interventions.

Background The aim of the study was to investigate, using a native mitomycin-C-resistant human Tenon's fibroblast cell line, the possibility that interferon-alpha and gamma could be used with Fas agonists as an alternative anti-fibrotic strategy to mitomycin-C in trabeculectomy. Methods A clinically resistant and in vitro verified mitomycin-C-resistant human Tenon's fibroblast cell line was pretreated with interferon-alpha and interferon-gamma for 48 h before stimulation with an agonistic Fas antibody (CH11) for 2 days to induce cell death. Cell death assays were undertaken. Changes in apoptosis-related proteins were determined by flow cytometry and Western blot. Results Pretreatment with interferon-alpha or interferon-gamma for 48 h increased Fas, Fas-associated protein with death domain and caspase-8 expression. Protein expression was further increased by combined exposure to interferon-alpha and gamma. Pretreatment with cytokines had no effect on Fas-L and Bcl-2. Interferon-alpha alone did not change the rate of induced cell death. A combination of interferon-alpha and gamma synergistically increased the sensitivity of mitomycin-C-resistant human Tenon's fibroblast cell line to induced cell death. An antagonistic anti-Fas antibody (ZB4) completely blocked induced cell death. Broad caspase inhibitors specific for caspases-8 and -3 reduced induced deaths in interferon pretreated mitomycin-C-resistant human Tenon's fibroblast cell line in a dose-dependent manner. Conclusions Interferon-alpha and interferon-gamma render mitomycin-C-resistant human Tenon's fibroblast cell line sensitive to Fas-mediated apoptosis. The mechanism involves increased death-inducing signalling complex formation by upregulation of Fas, Fas-associated protein with death domain and caspase-8 expression.

Background The aim of this study was to assess the effect of goniosynechialysis on intraocular pressure and medication requirement in patients with angle closure. Design A retrospective chart review. Participants 51 eyes from 42 patients were included in the study. 17 had documented evidence of acute angle closure while 34 had chronic angle closure. Methods Examination of the medical records of patients with synechial primary angle closure who underwent combined phacoemulsification and goniosynechialysis from 2003–2011 at 3 centres. Main Outcome Measures Intraocular pressure and requirement for drops were the main outcome measures. Results Mean follow-up was 25.9 months for the acute group and 25.4 months for the chronic group. Mean preoperative intraocular pressure was 23.33 ± 14.41 mmHg on an average of 2.51 ± 1.3 medications. Mean postoperative intraocular pressure was lowered to 13.67 ± 2.41 (p ≤ 0.01) and medication usage was significantly lowered to 0.65 ± 0.87 (p ≤ 0.01). Subjects with documented acute symptomatic angle closure had higher preoperative intraocular pressure and a larger intraocular pressure fall post goniosynechialysis (from 30.41 mmHg ± 23 mmHg to 12.12 mmHg ± 2.32 mmHg) compared to those without such a documented episode (19.79 mmHg ± 4.37 mmHg to 14.44 mmHg ± 2.08 mmHg, p = 0.007). Both groups have similar postoperative need for glaucoma medication, 0.65 ± 0.93 vs 0.65 ± 0.85. Conclusions Combined phacoemulsififcation and goniosynechialysis reduces intraocular pressure, medication requirements and need for further surgery in subjects with angle closure. The procedure is more effective in eyes with a previously documented acute symptomatic presentation of angle closure.

PURPOSE. Primary open-angle glaucoma (POAG) and primary congenital glaucoma (PCG) with Mendelian inheritance are caused by mutations in at least nine genes. Utilizing whole-exome sequencing, we examined the disease burden accounted for by these known Mendelian glaucoma genes in a cohort of individuals with advanced early-onset POAG. METHODS. The cases exhibited advanced POAG with young age of diagnosis. Cases and examined local controls were subjected to whole-exome sequencing. Nine hundred ninetythree previously sequenced exomes of Australian controls were called jointly with our dataset. Qualifying variants were selected based on predicted pathogenicity and rarity in public domain gene variant databases. Case-control mutational burdens were calculated for glaucoma-linked genes. RESULTS. Two hundred eighteen unrelated POAG participants and 103 nonglaucomatous controls were included in addition to 993 unexamined controls. Fifty-eight participants (26.6%) harbored rare potentially pathogenic variants in known glaucoma genes. Enrichment of qualifying variants toward glaucoma was present in all genes except WDR36, in which controls harbored more variants, and TBK1, in which no qualifying variants were detected in cases or controls. After multiple testing correction, only MYOC showed statistically significant enrichment of qualifying variants (odds ratio [OR] = 16.62, P = 6.31310-16). CONCLUSIONS. Rare, potentially disease-causing variants in Mendelian POAG genes that showed enrichment in our dataset were found in 22.9% of advanced early-onset POAG cases. MYOC variants represented the largest monogenic cause in POAG. The association between WDR36 and POAG was not supported, and the majority of POAG cases did not harbor a potentially disease-causing variant in the remaining Mendelian genes. © 2017 The Authors.

Background Genome‐wide association studies (GWAS) have identified association of common alleles with primary open‐angle glaucoma (POAG) and its quantitative endophenotypes near numerous genes. This study aims to determine whether rare pathogenic variants in these disease‐associated genes contribute to POAG. Methods Participants fulfilled strict inclusion criteria of advanced POAG at a young age of diagnosis. Myocilin mutation carriers were excluded using direct sequencing. Whole exome sequencing was performed on 187 glaucoma cases and 103 local screened nonglaucoma controls then joint‐called with exomes of 993 previously sequenced Australian controls. GWAS‐associated genes were assessed for enrichment of rare predicted pathogenic variants in POAG. Significantly enriched genes were compared against Exome Aggregation Consortium (ExAC) public control. Results Eighty‐six GWAS disease or trait‐associated glaucoma genes were captured and sequenced. CARD10 showed enrichment after Bonferroni correction for rare variants in glaucoma cases (OR = 13.2, P = 6.94 × 10−5) with mutations identified in 4.28% of our POAG cohort compared to 0.27% in controls. CARD10 was significantly associated with optic disc parameters in previous GWAS. The whole GWAS gene set showed no enrichment in POAG overall (OR = 1.12, P = 0.51). Conclusion We report here an enrichment of rare predicted pathogenic coding variants within a GWAS‐associated locus in POAG (CARD10). These findings indicate that both common and rare pathogenic coding variants in CARD10 may contribute to POAG pathogenesis.

Background: Glaucoma is a sight-threatening disease affecting 3% of the population over the age of 50. Glaucoma is treatable, and severe vision loss can usually be prevented if diagnosis is made at an early stage. Genetic factors play a major role in the pathogenesis of the condition, and therefore, genetic testing to identify asymptomatic at-risk individuals is a promising strategy to reduce the prevalence of glaucoma blindness. Furthermore, unravelling genetic risk factors for glaucoma would also allow a better understanding of the pathogenesis of the condition and the development of new treatments. Design: The Australian and New Zealand Registry of Advanced Glaucoma is a prospective study that aims to develop a large cohort of glaucoma cases with severe visual field loss to identify novel genetic risk factors for glaucoma blindness. Methods: Clinical information and blood are collected from participants after referral by eye practitioners. Samples are collected across Australia and New Zealand using postage kits. Participants: Our registry has recruited just over 2000 participants with advanced glaucoma, as well as secondary and developmental glaucomas. Results: A positive family history of glaucoma is present in more than half of the advanced glaucoma cases and the age at diagnosis is significantly younger for participants with affected relatives, which reinforces the involvement of genetic factors in glaucoma. Conclusions: With the collection of glaucoma cases recruited so far, our registry aims to identify novel glaucoma genetic risk factors to establish risk profiling of the population and protocols for genetic testing.

Purpose To evaluate the measurement of optic disc morphology using Heidelberg Retinal Tomography (HRT) with and without the aid of optic disc photos. Methods One hundred three children (aged 11 and 12 y, 52 boys) were selected randomly from the Singapore Cohort study of Risk Factors for Myopia. Optic nerve head topography and retinal nerve fiber layer thickness measurements were assessed using the HRT-II (Heidelberg, Germany) scanning laser ophthalmoscope. All contour lines were drawn by the same researcher on 2 occasions. The first drawing was made without optic disc photographs but using the 3-dimensional rotation assessment. The second drawing was made with the additional aid of digital monoscopic optic disc photographs. Results There was a high correlation between the measurements taken with and without optic disc photographs. For the global disc area, the difference between the mean readings was 0.67 mm2 and the intraclass correlation (ICC) was 0.81 [95% confidence interval (CI) 0.73-0.86]. The mean difference for the global cup-to-disc ratio was 0.03 [ICC 0.86 (95% CI 0.80-0.90)]. The ICCs were high across almost all of the readings except rim volume, in which the ICC was 0.57 (95% CI 0.43-0.69). Conclusions This study shows minimal differences in HRT measured optic disc parameters when optic disc photos are used to aid in the definition of the scleral ring. Omitting the use of disc photographs in measuring HRT outputs may translate into significant savings in time and logistics in simultaneously obtaining HRT and optic disc photographs in large population-based studies.

Objective To evaluate the Heidelberg Retina Tomograph II (HRTII; Heidelberg Engineering, Heidelberg, Germany) as a screening tool for open-angle glaucoma (OAG) in an older population. Design Population-based, cross-sectional study. Participants Participants from the 10-year follow-up Blue Mountains Eye Study (n = 1952; 75.6% of survivors). Methods Participants underwent optic nerve head imaging performed using the HRTII; OAG was diagnosed independently from optic disc photographs and Humphrey 24-2 visual fields. Main Outcome Measures The Moorfields Regression Analysis (MRA) was applied to scans using the default results of "normal," borderline," and "outside normal limits." Outcome classification was at the person level and used data from both eyes. Results Mean age was 73.7 years. The HRT scans could be acquired in 1644 participants, 95.9% of those fully examined; 87.4% of scans having a topography standard deviation (TSD) ≤40 μm. Larger TSD was associated with older age and OAG. The MRA sensitivity was 64.1%, specificity 85.7%, positive predictive value 21%, and negative predictive value 97.6% for detecting OAG. Including borderline results improved sensitivity (87.0%) but specificity dropped to 70.6%. Significant predictors of abnormal MRA included OAG (odds ratio [OR], 7.70; 95% confidence interval [CI] 4.79–12.35), age (OR, 1.05; 95% CI, 1.03–1.07), TSD (OR, 1.01; 95% CI, 1.003–1.020) and disc size (OR, 3.2; 95% CI, 2.31–4.49). Diagnostic accuracy was improved by restricting TSD Conclusions Diagnostic test evaluation studies of HRTII using single eye analyses or restrictive selection overestimate test accuracy compared with this population-based study. Although the specificity of the MRA was inadequate for use as a glaucoma screening test, the HRTII performed relatively well in an unselected older population with acceptable quality scans in most eyes. Financial Disclosure(s) The authors have no proprietary or commercial interest in any of the materials discussed in this article.

To measure and compare quality of life in patients with and without glaucoma using the Glaucoma Quality of Life-15 Questionnaire, and to determine the association between glaucoma-related quality of life and clinical indices of glaucoma.Using a prospective, cross-sectional study, we collected demographic information via interviews and administered the questionnaire to assess glaucoma-related quality of life in 121 patients with glaucoma and 31 subjects without glaucoma. Visual function was measured objectively by clinical examination. Group differences and the association between questionnaire scores and clinical indices were evaluated using nonparametric analysis of variance and correlation coefficients, respectively. The relationship between the likelihood of reporting vision-related dysfunction and glaucoma severity was examined using logistic regression.Patients with glaucoma had significantly poorer glaucoma-related quality of life than controls (P0.001). Summary scores differed significantly among patients with mild, moderate, and severe glaucoma demonstrating a trend of poorer quality of life with increasing disease severity. Activities involving glare and dark adaptation were most problematic for all, but patients with glaucoma felt significantly more compromised in central and near vision, peripheral vision, and outdoor mobility (all P0.001). Glaucoma-related quality of life scores correlated moderately and significantly with visual acuity, disease severity, and visual field measurements, but only severe glaucoma was a significant predictor of self-perceived deficits in glaucoma-related quality of life (P=0.038).The Glaucoma Quality of Life-15 Questionnaire correlated well with objective measures of visual function and discriminated between quality of life in patients with glaucoma and subjects without glaucoma.

Elevated plasma homocysteine has been associated with an increased risk of cardiovascular disease. The association between open-angle glaucoma and cardiovascular disease has recently stimulated interest in the role of homocysteine in the pathogenesis of glaucoma. Some studies report elevated plasma homocysteine in patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma (PXFG), but have not found this association consistently in other types of open-angle glaucoma. In this study, we have measured plasma homocysteine and C677T methylenetetrahydrofolate reductase (MTHFR) mutation, the commonest genetic cause of elevated plasma homocysteine, in patients with PXFG, primary open-angle glaucoma (POAG), and normal tension glaucoma (NTG).Prospective cross-sectional cohort study.Forty-eight patients with PXFG, 36 patients with POAG, 34 patients with NTG, and 42 controls without glaucoma.Fasting venous blood samples from each participant were analyzed for plasma homocysteine and the C677T MTHFR gene mutation. MAIN OUTCOME OF INTEREST: Mean plasma homocysteine levels, number of individuals with homocysteine above the reference range, and percentage of individuals with heterozygous or homozygous C677T MTHFR gene mutations.Mean plasma homocysteine was significantly higher in PXFG (11.77+/-4.18 micromol/L), POAG (11.21+/-2.84 micromol/L), and NTG (11.74+/-3.79 micromol/L) compared with control (9.82+/-1.75 micromol/L). Hyperhomocysteinemia was found in 27.1% of PXFG patients, 30.6% of POAG patients, and 29.4% of NTG patients. There was no significant difference in frequency of MTHFR C677T gene mutation between groups.Plasma homocysteine was elevated in PXFG, POAG, and NTG. Elevated plasma homocysteine seems to be associated with glaucoma in these patients.

Matrix perimetry uses frequency-doubling technology (FDT) incorporated into a 5 degrees test target. This permits testing of the same number of locations within a defined visual field as standard automated perimetry (SAP) and may improve performance compared with original FDT perimetry. This study investigates the performance of Humphrey Matrix perimetry for detecting glaucomatous visual-field loss.Prospective case control study.We recruited 115 participants with glaucomatous visual-field loss and 33 normal controls from an urban glaucoma practice. Each participant performed SITA 24-2 SAP then threshold 24-2 Matrix perimetry. Severity of visual-field loss was defined using SAP mean deviation (MD) as early (MD-6 dB), moderate (MD -6 to -12 dB) or advanced (MD-12 dB). The sensitivity and specificity of Humphrey Matrix perimetry were calculated for different automated indices.The matrix perimetry sensitivity and specificity were up to 100% for moderate and advanced glaucomatous visual-field loss. A receiver operator characteristic area under the curve (AUC) analysis revealed MD to be slightly better than pattern standard deviation (PSD) for defining moderate (AUC: MD 0.997; PSD 0.987) and advanced defects (AUC: MD 1.000; PSD 0.987). Matrix was less sensitive (up to 87.3%) for detecting early glaucomatous visual-field loss compared with SITA 24-2 SAP (AUC: PSD 0.948; MD 0.910).Matrix perimetry is excellent for detection of moderate to advanced glaucomatous visual-field loss but may miss some early defects. It may be well suited to following progression of early to moderate field loss because of a smaller target size compared with original FDT perimetry.