Is the disease risk and penetrance in Leber hereditary optic neuropathy actually low?

Pedigree analysis showed that a large proportion of Leber hereditary optic neuropathy (LHON) family members who carry a mitochondrial risk variant never lose vision. Mitochondrial haplotype appears to be a major factor influencing the risk of vision loss from LHON. Mitochondrial variants, including m.14484T>C and m.11778G>A, have been added to gene arrays, and thus many patients and research participants are tested for LHON mutations. Analysis of the UK Biobank and Australian cohort studies found more than 1 in 1,000 people in the general population carry either the m.14484T>C or the m.11778G>A LHON variant. None of the subset of carriers examined had visual acuity at 20/200 or worse, suggesting a very low penetrance of LHON. Haplogroup analysis of m.14484T>C carriers showed a high rate of haplogroup U subclades, previously shown to have low penetrance in pedigrees. Penetrance calculations of the general population are lower than pedigree calculations, most likely because of modifier genetic factors. This Matters Arising Response paper addresses the Watson et al. (2022) Matters Arising paper, published concurrently in The American Journal of Human Genetics.

A multinational survey of potential participant perspectives on ocular gene therapy.

Amidst rapid advancements in ocular gene therapy, understanding patient perspectives is crucial for shaping future treatment choices and research directions. This international cross-sectional survey evaluated knowledge, attitudes, and perceptions of ocular genetic therapies among potential recipients with inherited retinal diseases (IRDs). Survey instruments included the Attitudes to Gene Therapy-Eye (AGT-Eye), EQ-5D-5L, National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25), and Patient Attitudes to Clinical Trials (PACT-22) instruments. This study included 496 participant responses (89% adults with IRDs; 11% parents/guardians/carers) from 35 countries, with most from the United States of America (USA; 69%) and the United Kingdom (11%). Most participants (90%) indicated they would likely accept gene therapy if it was available, despite only 45% agreeing that they had good knowledge of gene therapy. The main sources of information were research registries (60% of participants) and the internet (61%). Compared to data from our recently published Australian national survey of people with IRDs (n = 694), USA respondents had higher knowledge of gene therapy outcomes, and Australian respondents indicated a higher perceived value of gene therapy treatments. Addressing knowledge gaps regarding outcomes and financial implications will be central to ensuring informed consent, promoting shared decision-making, and the eventual clinical adoption of genetic therapies.

Establishing risk of vision loss in Leber hereditary optic neuropathy.

We conducted an updated epidemiological study of Leber hereditary optic neuropathy (LHON) in Australia by using registry data to establish the risk of vision loss among different LHON mutations, sex, age at onset, and mitochondrial haplogroup. We identified 96 genetically unrelated LHON pedigrees, including 56 unpublished pedigrees, and updated 40 previously known pedigrees, comprising 620 affected individuals and 4,948 asymptomatic carriers. The minimum prevalence of vision loss due to LHON in Australia in 2020 was one in 68,403 individuals. Although our data confirm some well-established features of LHON, the overall risk of vision loss among those with a LHON mutation was lower than reported previously-17.5% for males and 5.4% for females. Our findings confirm that women, older adults, and younger children are also at risk. Furthermore, we observed a higher incidence of vision loss in children of affected mothers as well as in children of unaffected women with at least one affected brother. Finally, we confirmed our previous report showing a generational fall in prevalence of vision loss among Australian men. Higher reported rates of vision loss in males with a LHON mutation are not supported by our work and other epidemiologic studies. Accurate knowledge of risk is essential for genetic counseling of individuals with LHON mutations. This knowledge could also inform the detection and validation of potential biomarkers and has implications for clinical trials of treatments aimed at preventing vision loss in LHON because an overestimated risk may lead to an underpowered study or a false claim of efficacy.

Survey of perspectives of people with inherited retinal diseases on ocular gene therapy in Australia.

Many gene therapies are in development for treating people with inherited retinal diseases (IRD). We hypothesized that potential recipients of gene therapy would have knowledge gaps regarding treatment. We aimed to assess knowledge, attitudes, and perceptions of genetic therapies among potential recipients with IRD, using a novel instrument we designed (Attitudes to Gene Therapy-Eye (AGT-Eye)) and their associations with demographic data, self-reported visual status, and tools assessing quality of life and attitudes toward clinical trials using a community-based cross-sectional survey of Australian adults with IRD. AGT-Eye, overall quality of life EQ-5D-5L, National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25) and Patient Attitudes to Clinical Trials (PACT-22) instruments were administered. Six hundred and eighty-one people completed the study, 51.7% women of mean age 53.5 years (SD ± 15.8). Most participants (91.6%) indicated they would likely accept gene therapy if it was available to them or family members. However, only 28.3% agreed that they had good knowledge of gene therapy. Most obtained information about gene therapy from the internet (49.3%). Respondents with post-graduate degrees scored highest compared to other educational levels on methods (p < 0.001) and outcomes (p = 0.003) and were more likely to see economic value of treatment (p = 0.043). Knowledge gaps were present regarding methods and outcomes of gene therapy. This survey has shown high level of interest in the IRD community for gene therapies, and highlights areas for improved clinician and patient education.

Self-rated eyesight among healthy older Australians: Baseline results of the ASPREE Longitudinal Study of Older Persons.

BACKGROUND: We aimed to describe the self-reported level of eyesight amongst a cohort of relatively healthy older Australian adults, and to investigate associations between poorer self-rated eyesight and demographic, health, and functional characteristics METHODS: The ASPirin in Reducing Events in the Elderly (ASPREE) Longitudinal Study of Older Persons (ALSOP) study was embedded in a multisite trial which recruited independently living Australians from general practices (2010-2014). Self-rated eyesight was recorded on a paper-based questionnaire as Excellent, Good, Fair, Poor, Very poor, or Completely blind at the baseline study wave RESULTS: Data from 14 592 participants (aged 70-95 years, 54.61% female) were included in this cross-sectional analysis. Eighty percent of participants reported excellent or good eyesight (n = 11 677). People with complete blindness were precluded from enrolling but 299 participants (2.0%) reported poor or very poor eyesight, and 2616 rated their eyesight as fair (17.9%). Lower levels of eyesight were associated with being older, female, fewer years of formal education, a primary language other than English, smoking, and self-reported macular degeneration, glaucoma, retinopathy, cataracts, and hearing problems (each p ≤ 0.021). People with lower levels of eyesight had a higher number of falls, frailty characteristics, and depressive symptoms, and lower mental and physical health functioning scores (each p < 0.001) CONCLUSIONS: Whilst most of these healthy older Australians reported good or excellent eyesight, a notable minority reported poor or very poor eyesight, and this was associated with a range of poorer health measures. These findings support the need for additional resources to prevent vision loss and associated sequelae.

Interventions for the Management of Computer Vision Syndrome: A Systematic Review and Meta-analysis.

TOPIC: To evaluate the efficacy and safety of interventions for treating eye strain related to computer use relative to placebo or no treatment. CLINICAL RELEVANCE: Computer use is pervasive and often associated with eye strain, referred to as computer vision syndrome (CVS). Currently, no clinical guidelines exist to help practitioners provide evidence-based advice about CVS treatments, many of which are marketed directly to patients. This systematic review and meta-analysis was designed to help inform best practice for eye care providers. METHODS: Eligible randomized controlled trials (RCTs) were identified in Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and trial registries, searched from inception through November 23, 2021. Eligible studies were appraised for risk of bias and were synthesized. The certainty of the body of evidence was judged using the Grading of Recommendations, Assessment, Development, and Evaluation system. Standardized mean differences (SMDs) were used when differently scaled measures were combined. RESULTS: Forty-five RCTs, involving 4497 participants, were included. Multifocal lenses did not improve visual fatigue scores compared with single-vision lenses (3 RCTs; SMD, 0.11; 95% confidence interval [CI], -0.14 to 0.37; P = 0.38). Visual fatigue symptoms were not reduced by blue-blocking spectacles (3 RCTs), with evidence judged of low certainty. Relative to placebo, oral berry extract supplementation did not improve visual fatigue (7 RCTs; SMD, -0.27; 95% CI, -0.70 to 0.16; P = 0.22) or dry eye symptoms (4 RCTs; SMD, -0.10; 95% CI, -0.54 to 0.33; P = 0.65). Likewise, berry extract supplementation had no significant effects on critical flicker-fusion frequency (CFF) or accommodative amplitude. Oral omega-3 supplementation for 45 days to 3 months improved dry eye symptoms (2 RCTs; mean difference [MD], -3.36; 95% CI, -3.63 to -3.10 on an 18 unit scale; P < 0.00001) relative to placebo. Oral carotenoid supplementation improved CFF (2 RCTs; MD, 1.55 Hz; 95% CI, 0.42 to 2.67 Hz; P = 0.007) relative to placebo, although the clinical significance of this finding is unclear. DISCUSSION: We did not identify high-certainty evidence supporting the use of any of the therapies analyzed. Low-certainty evidence suggested that oral omega-3 supplementation reduces dry eye symptoms in symptomatic computer users.

Diagnostic accuracy of Immulite® TSI immunoassay for thyroid-associated orbitopathy in patients with recently diagnosed Graves' hyperthyroidism.

PURPOSE: The Immulite® thyroid stimulating immunoglobulin (TSI) immunoassay is a relatively new commercial assay that has shown good diagnostic accuracy in Graves' hyperthyroidism (GH). However, its clinical utility in thyroid-associated orbitopathy (TAO) is less clear. The purpose of this study was to assess the diagnostic accuracy of the Immulite® TSI immunoassay for TAO and investigate the associations between TSI and other clinical measures. METHODS: One hundred and forty patients that had been diagnosed with GH within the previous 12 months were recruited. Identification and grading of TAO were performed at enrolment and serum samples were analysed using the Immulite® TSI immunoassay. RESULTS: Of the 140 participants recruited, 75 (53.6%) had TAO. Age, sex and time since GH diagnosis were similar between those with and without TAO (p ≥ 0.300). TSI level tended to decrease with increasing time from GH diagnosis (Spearman's ρ - 0.28, 95% CI - 0.43, - 0.12). TSI levels were higher among those with than those without TAO (median 4.0 vs. 2.7 IU/L, respectively, p = 0.037). There was no correlation between TSI level and inflammatory index score (ρ = 0.14, 95% CI - 0.03, 0.30) or clinical severity (p = 0.527) among those with TAO. TSI level showed poor diagnostic accuracy for TAO (area under the receiver operating characteristic curve 0.60, 95% CI 0.51, 0.70). CONCLUSIONS: Although Immulite® TSI level was higher in the presence of TAO, it showed poor diagnostic accuracy and no correlation with clinical markers of TAO severity or activity.

A scoping review of studies using observational data to optimise dynamic treatment regimens.

BACKGROUND: Dynamic treatment regimens (DTRs) formalise the multi-stage and dynamic decision problems that clinicians often face when treating chronic or progressive medical conditions. Compared to randomised controlled trials, using observational data to optimise DTRs may allow a wider range of treatments to be evaluated at a lower cost. This review aimed to provide an overview of how DTRs are optimised with observational data in practice. METHODS: Using the PubMed database, a scoping review of studies in which DTRs were optimised using observational data was performed in October 2020. Data extracted from eligible articles included target medical condition, source and type of data, statistical methods, and translational relevance of the included studies. RESULTS: From 209 PubMed abstracts, 37 full-text articles were identified, and a further 26 were screened from the reference lists, totalling 63 articles for inclusion in a narrative data synthesis. Observational DTR models are a recent development and their application has been concentrated in a few medical areas, primarily HIV/AIDS (27, 43%), followed by cancer (8, 13%), and diabetes (6, 10%). There was substantial variation in the scope, intent, complexity, and quality between the included studies. Statistical methods that were used included inverse-probability weighting (26, 41%), the parametric G-formula (16, 25%), Q-learning (10, 16%), G-estimation (4, 6%), targeted maximum likelihood/minimum loss-based estimation (4, 6%), regret regression (3, 5%), and other less common approaches (10, 16%). Notably, studies that were primarily intended to address real-world clinical questions (18, 29%) tended to use inverse-probability weighting and the parametric G-formula, relatively well-established methods, along with a large amount of data. Studies focused on methodological developments (45, 71%) tended to be more complicated and included a demonstrative real-world application only. CONCLUSIONS: As chronic and progressive conditions become more common, the need will grow for personalised treatments and methods to estimate the effects of DTRs. Observational DTR studies will be necessary, but so far their use to inform clinical practice has been limited. Focusing on simple DTRs, collecting large and rich clinical datasets, and fostering tight partnerships between content experts and data analysts may result in more clinically relevant observational DTR studies.

NATURAL HISTORY OF QUANTITATIVE AUTOFLUORESCENCE IN INTERMEDIATE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate differences in quantitative autofluorescence (qAF) imaging measurements between eyes with and without large drusen, and whether qAF measurements change over time in the eyes with large drusen. METHODS: Eighty-five eyes from participants with bilateral large drusen and 51 eyes from healthy participants underwent qAF imaging at least once, and the age-related macular degeneration participants were reviewed 6-monthly. Normalized grey values at 9° to 11° eccentricity from the fovea were averaged to provide a summary measure of qAF values (termed qAF8). RESULTS: In a multivariable model, qAF8 measurements were not significantly different between age-related macular degeneration eyes with large drusen and healthy eyes (P = 0.130), and qAF8 measurements showed a decline over time in the age-related macular degeneration eyes (P = 0.013). CONCLUSION: These findings add to the body of evidence that qAF levels are not increased in eyes with large drusen compared with healthy eyes, and qAF levels show a significant decline over time in the age-related macular degeneration eyes. These findings highlight how the relationship between qAF levels and retinal pigment epithelium health does not seem to be straightforward. Further investigation is required to better understand this relationship, especially if qAF levels are to be used as an outcome measure in intervention trials.

Correction to: A comparison of methods to estimate the survivor average causal effect in the presence of missing data: a simulation study.

In the original publication of this article [1], the incorrect causal diagram was submitted as Fig. 1.

Prevalence, associations and characteristics of severe uncorrected refractive error in the Australian National Eye Health Survey.

IMPORTANCE: In Australia, nationally representative data of the burden and associations of severe uncorrected refractive error are scarce. BACKGROUND: To report the prevalence and characteristics of severe uncorrected refractive error in Indigenous and non-Indigenous Australians. DESIGN: Population-based cross-sectional study. PARTICIPANTS: A total of 3098 non-Indigenous Australians aged 50 to 98 and 1738 Indigenous Australians aged 40 to 92 living in 30 randomly selected Australian sites were examined. METHODS: Severe uncorrected refractive error was defined as an improvement of ≥2 lines on the logMAR chart in one or both eyes in participants with a presenting visual acuity <6/12. MAIN OUTCOME MEASURE: Severe uncorrected refractive error RESULTS: Prevalence of severe uncorrected refractive error was 11.0% (95% confidence interval 9.3-13.0) in non-Indigenous and 14.5% (12.5-16.7) in Indigenous Australians. Eighty-two percent of non-Indigenous and 77% of Indigenous participants had a spherical equivalent refraction between -2.00D and +2.00D. Indigenous Australians who were older (odds ratio [OR] for 70-79 years vs 40-49 years = 3.59), resided in outer regional areas (OR = 1.78) and did not have an eye examination in the previous 2-years (OR = 1.50) were associated with higher odds of severe uncorrected refractive error. Geographical remoteness (OR = .68 for inner regional), male gender (OR = 1.30), older age (OR for 70-79 years vs 50-59 years = 1.51) and failure to have an eye examination in the previous 2-years (OR = 2.06) were associated with severe uncorrected refractive error among non-Indigenous participants. CONCLUSIONS AND RELEVANCE: Increased public awareness of the importance of regular optometric examinations may be required in groups at high risk of severe uncorrected refractive error.

Gram-negative endophthalmitis: A prospective study examining the microbiology, clinical associations and visual outcomes following infection.

IMPORTANCE: This is the largest Gram-negative endophthalmitis specific series and provides important evidence to guide management. BACKGROUND: Endophthalmitis is a sight-threatening emergency. Gram-negative infections are associated with poorer visual outcomes; however, there is limited literature pertaining to this uncommon condition. DESIGN: Prospective case series. PARTICIPANTS: All patients presenting with endophthalmitis to a tertiary institution over a 20-year period. METHODS: Data were collected prospectively and entered into a registry. Patients with microbiological evidence of Gram-negative infection were included in the analysis. MAIN OUTCOMES MEASURES: Final visual acuity (VA), precipitating events, causative organisms, antibiotic sensitivity profiles and risk factors for poor visual outcomes were reported. RESULTS: One hundred Gram-negative organisms were isolated in 97 eyes. Final VA was worse than 6/60 in 65 (67.0%) eyes at follow-up and 29 (29.9%) eyes were eviscerated or enucleated. Microbial keratitis (26.8%, n = 26) and Pseudomonas aeruginosa (34.0%, n = 34) were the most common precipitating event and causative organism, respectively. Eight (8.0%) isolates were third-generation cephalosporin resistant; of which, 7 (88.0%) were sensitive to ciprofloxacin. Preceding microbial keratitis (OR = 13.16, P = .015) or P. aeruginosa infections (OR = 3.40, P = .045) were strongly associated with poorer visual outcomes (worse than 6/60). CONCLUSIONS AND RELEVANCE: Visual outcomes following Gram-negative endophthalmitis are extremely poor, with almost 30% of patients being eviscerated or enucleated. A majority of ceftazidime resistant organisms are sensitive to ciprofloxacin, providing evidence to support the empirical use of quinolones. Clinicians should be mindful that infections secondary to P. aeruginosa or microbial keratitis carry a particularly poor prognosis.

Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: A crossover randomized clinical trial.

IMPORTANCE: Retinal ganglion cells endure significant metabolic stress in glaucoma but maintain capacity to recover function. Nicotinamide, a precursor of NAD+ , is low in serum of glaucoma patients and its supplementation provides robust protection of retinal ganglion cells in preclinical models. However, the potential of nicotinamide in human glaucoma is unknown. BACKGROUND: To examine the effects of nicotinamide on inner retinal function in glaucoma, in participants receiving concurrent glaucoma therapy. DESIGN: Crossover, double-masked, randomized clinical trial. Participants recruited from two tertiary care centres. PARTICIPANTS: Fifty-seven participants, diagnosed and treated for glaucoma. METHODS: Participants received oral placebo or nicotinamide and reviewed six-weekly. Participants commenced 6 weeks of 1.5 g/day then 6 weeks of 3.0 g/day followed by crossover without washout. Visual function measured using electroretinography and perimetry. MAIN OUTCOME MEASURES: Change in inner retinal function, determined by photopic negative response (PhNR) parameters: saturated PhNR amplitude (Vmax), ratio of PhNR/b-wave amplitude (Vmax ratio). RESULTS: PhNR Vmax improved beyond 95% coefficient of repeatability in 23% of participants following nicotinamide vs 9% on placebo. Overall, Vmax improved by 14.8% [95% CI: 2.8%, 26.9%], (P = .02) on nicotinamide and 5.2% [-4.2%, 14.6%], (P = .27) on placebo. Vmax ratio improved by 12.6% [5.0%, 20.2%], (P = .002) following nicotinamide, 3.6% [-3.4%, 10.5%], (P = .30) on placebo. A trend for improved visual field mean deviation was observed with 27% improving ≥1 dB on nicotinamide and fewer deteriorating (4%) compared to placebo (P = .02). CONCLUSIONS: Nicotinamide supplementation can improve inner retinal function in glaucoma. Further studies underway to elucidate the effects of long-term nicotinamide supplementation.

Subthreshold Nanosecond Laser Intervention in Age-Related Macular Degeneration: The LEAD Randomized Controlled Clinical Trial.

PURPOSE: There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD. DESIGN: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy. METHODS: Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. MAIN OUTCOME MEASURES: The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events. RESULTS: Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant. CONCLUSIONS: In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT® laser, but they should not be extrapolated to other short-pulse lasers.

A comparison of methods to estimate the survivor average causal effect in the presence of missing data: a simulation study.

BACKGROUND: Attrition due to death and non-attendance are common sources of bias in studies of age-related diseases. A simulation study is presented to compare two methods for estimating the survivor average causal effect (SACE) of a binary exposure (sex-specific dietary iron intake) on a binary outcome (age-related macular degeneration, AMD) in this setting. METHODS: A dataset of 10,000 participants was simulated 1200 times under each scenario with outcome data missing dependent on measured and unmeasured covariates and survival. Scenarios differed by the magnitude and direction of effect of an unmeasured confounder on both survival and the outcome, and whether participants who died following a protective exposure would also die if they had not received the exposure (validity of the monotonicity assumption). The performance of a marginal structural model (MSM, weighting for exposure, survival and missing data) was compared to a sensitivity approach for estimating the SACE. As an illustrative example, the SACE of iron intake on AMD was estimated using data from 39,918 participants of the Melbourne Collaborative Cohort Study. RESULTS: The MSM approach tended to underestimate the true magnitude of effect when the unmeasured confounder had opposing directions of effect on survival and the outcome. Overestimation was observed when the unmeasured confounder had the same direction of effect on survival and the outcome. Violation of the monotonicity assumption did not increase bias. The estimates were similar between the MSM approach and the sensitivity approach assessed at the sensitivity parameter of 1 (assuming no survival bias). In the illustrative example, high iron intake was found to be protective of AMD (adjusted OR 0.57, 95% CI 0.40-0.82) using complete case analysis via traditional logistic regression. The adjusted SACE odds ratio did not differ substantially from the complete case estimate, ranging from 0.54 to 0.58 for each of the SACE methods. CONCLUSIONS: On average, MSMs with weighting for exposure, missing data and survival produced biased estimates of the SACE in the presence of an unmeasured survival-outcome confounder. The direction and magnitude of effect of unmeasured survival-outcome confounders should be considered when assessing exposure-outcome associations in the presence of attrition due to death.

Bleb-associated endophthalmitis: Proportion, presentation, management and outcomes in Victoria, Australia.

IMPORTANCE: Bleb-associated endophthalmitis is a potentially vision-threatening complication of trabeculectomy. With improvements in surgical technique and changing patterns of intraoperative antimetabolite use, a re-evaluation of the incidence of bleb-associated endophthalmitis is warranted. BACKGROUND: To investigate changes in the incidence, presentation, management and outcomes of bleb-associated endophthalmitis between 1997 and 2015 in Victoria, Australia. DESIGN: A retrospective cohort analysis. PARTICIPANTS: Consecutive cases of bleb-associated endophthalmitis managed at the Royal Victorian Eye and Ear Hospital (RVEEH) between 1997 and 2015. METHODS: Medical record review of consecutive cases of bleb-associated endophthalmitis and statistical analysis were performed. MAIN OUTCOME MEASURES: Visual acuity, including loss of light perception, intraocular pressure, and need for further surgery. RESULTS: Sixty-seven eyes with bleb-associated endophthalmitis (BAE) were identified. Of these, 41 had trabeculectomy performed in Victoria during the study period, over which time 11 129 trabeculectomies were performed. The proportion of BAE was stable over time (0.4%). The mean age at presentation was 73.7 ± 12.1 years old and the majority of patients were Caucasian (79.1%). The mean duration between glaucoma filtration surgery and the development of bleb-associated endophthalmitis was 3 years (Interquartile Range = 0.4-6.0 years). The cultures were positive in 71.6% of cases. Approximately 1 in 8 patients required enucleation. The final visual acuity was poor with a Snellen Visual Acuity (VA) of 6/60 or worse in two-thirds of patients. CONCLUSIONS AND RELEVANCE: Bleb-associated endophthalmitis is an uncommon complication following glaucoma filtration surgery. The proportion has remained stable over time. Visual outcomes remain poor.

Relationship between reticular pseudodrusen and choroidal thickness in intermediate age-related macular degeneration.

IMPORTANCE: Reticular pseudodrusen (RPD) is strongly associated with late age-related macular degeneration (AMD) but their aetiology remains unknown. RPD have been associated with reduced choroidal thickness (ChT) but most studies are limited by small sample size and varying severity of AMD. BACKGROUND: To investigate the relationship between choroidal thickness and RPD in eyes with intermediate AMD (iAMD), controlling for variables known to influence ChT. DESIGN: Retrospective cohort study. PARTICIPANTS: Participants were recruited from Centre for Eye Research Australia. METHODS: Colour fundus photographs, fundus auto fluorescence, near-infrared and spectral-domain ocular coherence tomography (OCT) were graded for RPD. ChT was measured from enhanced-depth imaging OCT scans at the centre of fovea, 1500 and 3000 µm nasal, temporal, superior and inferior from centre of fovea. MAIN OUTCOME MEASURES: ChT between RPD and non-RPD group. RESULTS: A total of 297 eyes from 152 subjects were included. A total of 84 (28%) had RPD and were older than non-RPD group (75.1 ± 5.4 years and 68.7 ± 6.9 years, respectively; P < 0.001). In unadjusted analysis, the RPD group was significantly associated with thinner choroids across all measured locations (P ≤ 0.022). After adjustment for variables, the presence of RPD was no longer associated with ChT (P ≥ 0.132 for all locations) but age (P < 0.001) and refractive error (P = 0.002) remained significantly associated with ChT. CONCLUSIONS AND RELEVANCE: Age and refractive error, rather than RPD, was significantly associated with reduced ChT in eyes with iAMD. Choroidal insufficiency may be a less important variable in RPD aetiology than previously considered.

Reticular Pseudodrusen and Their Association with Age-Related Macular Degeneration: The Melbourne Collaborative Cohort Study.

PURPOSE: To determine the prevalence of reticular pseudodrusen (RPD) and its association with age-related macular degeneration (AMD) and AMD risk factors in a large sample. DESIGN: Community-based cohort study in Melbourne, Victoria, Australia. PARTICIPANTS: A total of 21,130 participants 48 to 86 years of age available for ophthalmic assessment at follow-up from 2003 through 2007. METHODS: Lifestyle, diet, and anthropometric measurements were obtained at baseline and follow-up. At follow-up, digital macular color photographs were graded for early, intermediate, and late AMD as well as the presence of RPD. Data were analyzed using multinomial logistic regression controlling for age, gender, smoking, country of birth, and diet. MAIN OUTCOME MEASURES: Detection of RPD based on color fundus photographs. RESULTS: Prevalence of RPD was 0.41% (87 of 21,130 participants), with 51% having bilateral RPD. Patients with RPD were older compared with patients with large drusen (>125 µm; 76±4 vs. 68±9 years; P < 0.001). Increasing age, female gender, being a current smoker, as well as focal pigmentary abnormalities and large drusen (>125 µm) were associated with a higher prevalence of RPD. Presence of geographic atrophy (GA) was associated with the highest odds of having RPD (odds ratio [OR], 153; 95% confidence interval [CI], 53-442), followed by choroidal neovascularization (CNV; OR, 90; 95% CI, 26-310), intermediate AMD (OR, 33; 95% CI, 14-77), and early AMD (OR, 12; 95% CI, 5-31) compared with those with no AMD. The ARMS2 single nucleotide polymorphism (SNP) rs10490924, HTRA1 SNPs rs11200638 and rs3793917, and CFH SNPs rs393955, rs1061170, and rs2274700 were associated with increased prevalence of RPD (all P < 0.05). CONCLUSIONS: Reticular pseudodrusen are highly concurrent with AMD and have similar associations with known AMD risk factors such as age, gender, smoking, and genetic risk factors. Reticular pseudodrusen are associated more strongly with GA than with CNV. Although RPD are not specific to AMD, they are likely to be a strong risk factor for progression to late-stage AMD, similar to focal pigmentary abnormalities and large drusen.