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Purpose We hypothesized that the effect of blood lipid–related metabolites on primary open-angle glaucoma (POAG) would differ according to specific lipoprotein particles and lipid sub-fractions. We investigated the associations of blood levels of lipoprotein particles and lipid sub-fractions with POAG. Design Cross-sectional study. Participants Individuals recruited for the baseline visit of the population-based Singapore Epidemiology of Eye Disease study (n = 8503). Methods All participants underwent detailed standardized ocular and systemic examinations. A total of 130 blood lipid–related metabolites were quantified using a nuclear magnetic resonance metabolomics platform. The analyses were conducted in 2 stages. First, we investigated whether and which lipid-related metabolites were directly associated with POAG using regression analyses followed by Bayesian network modeling. Second, we investigated if any causal relationship exists between the identified lipid-related metabolites, if any, and POAG using 2-sample Mendelian randomization (MR) analysis. We performed genome-wide association studies (GWAS) on high-density lipoprotein (HDL) 3 cholesterol (after inverse normal transformation) and used the top variants associated with HLD3 cholesterol as instrumental variables (IVs) in the MR analysis. Main Outcome Measure Primary open-angle glaucoma. Results Of the participants, 175 (2.1%) had POAG. First, a logistic regression model showed that total HDL3 cholesterol (negatively) and phospholipids in very large HDL (positively) were associated with POAG. Further analyses using a Bayesian network analysis showed that only total HDL3 cholesterol was directly associated with POAG (odds ratio [OR], 0.72 per 1 standard deviation increase in HDL3 cholesterol; 95% confidence interval [CI], 0.61–0.84), independently of age, gender, intraocular pressure (IOP), body mass index (BMI), education level, systolic blood pressure, axial length, and statin medication. Using 5 IVs identified from the GWAS and with the inverse variance weighted MR method, we found that higher levels of HDL3 cholesterol were associated with a decreased odds of POAG (OR, 0.91; 95% CI, 0.84–0.99, P = 0.021). Other MR methods, including weighted median, mode-based estimator, and contamination mixture methods, derived consistent OR estimates. None of the routine lipids (blood total, HDL, or low-density lipoprotein [LDL] cholesterol) were associated with POAG. Conclusions Overall, these results suggest that the relationship between HDL3 cholesterol and POAG might be causal and specific, and that dysregulation of cholesterol transport may play a role in the pathogenesis of POAG.

Summary Background Excessive use of digital smart devices, including smartphones and tablet computers, could be a risk factor for myopia. We aimed to review the literature on the association between digital smart device use and myopia. Methods In this systematic review and meta-analysis we searched MEDLINE and Embase, and manually searched reference lists for primary research articles investigating smart device (ie, smartphones and tablets) exposure and myopia in children and young adults (aged 3 months to 33 years) from database inception to June 2 (MEDLINE) and June 3 (Embase), 2020. We included studies that investigated myopia-related outcomes of prevalent or incident myopia, myopia progression rate, axial length, or spherical equivalent. Studies were excluded if they were reviews or case reports, did not investigate myopia-related outcomes, or did not investigate risk factors for myopia. Bias was assessed with the Joanna Briggs Institute Critical Appraisal Checklists for analytical cross-sectional and cohort studies. We categorised studies as follows: category one studies investigated smart device use independently; category two studies investigated smart device use in combination with computer use; and category three studies investigated smart device use with other near-vision tasks that were not screen-based. We extracted unadjusted and adjusted odds ratios (ORs), β coefficients, prevalence ratios, Spearman's correlation coefficients, and p values for associations between screen time and incident or prevalent myopia. We did a meta-analysis of the association between screen time and prevalent or incident myopia for category one articles alone and for category one and two articles combined. Random-effects models were used when study heterogeneity was high (I2>50%) and fixed-effects models were used when heterogeneity was low (I2≤50%). Findings 3325 articles were identified, of which 33 were included in the systematic review and 11 were included in the meta-analysis. Four (40%) of ten category one articles, eight (80%) of ten category two articles, and all 13 category three articles used objective measures to identify myopia (refraction), whereas the remaining studies used questionnaires to identify myopia. Screen exposure was measured by use of questionnaires in all studies, with one also measuring device-recorded network data consumption. Associations between screen exposure and prevalent or incident myopia, an increased myopic spherical equivalent, and longer axial length were reported in five (50%) category one and six (60%) category two articles. Smart device screen time alone (OR 1·26 [95% CI 1·00–1·60]; I2=77%) or in combination with computer use (1·77 [1·28–2·45]; I2=87%) was significantly associated with myopia. The most common sources of risk of bias were that all 33 studies did not include reliable measures of screen time, seven (21%) did not objectively measure myopia, and nine (27%) did not identify or adjust for confounders in the analysis. The high heterogeneity between studies included in the meta-analysis resulted from variability in sample size (range 155–19 934 participants), the mean age of participants (3–16 years), the standard error of the estimated odds of prevalent or incident myopia (0·02–2·21), and the use of continuous (six [55%] of 11) versus categorical (five [46%]) screen time variables Interpretation Smart device exposure might be associated with an increased risk of myopia. Research with objective measures of screen time and myopia-related outcomes that investigates smart device exposure as an independent risk factor is required. Funding None.

Aging and elevated intraocular pressure (IOP) are two major risk factors for glaucomatous optic neuropathy; a condition characterized by the selective, progressive injury, and subsequent loss of retinal ganglion cells (RGCs). We examined how age modified the capacity for RGCs to functionally recover following a reproducible IOP elevation (50 mmHg for 30 min). We found that RGC functional recovery (measured using electroretinography) was complete by 7 days in 3-month-old mice but was delayed in 12-month-old mice until 14 days. At the 7-day recovery endpoint when RGC function had recovered in young but not older eyes, we examined RGC structural responses to IOP-related stress by analyzing RGC dendritic morphology. ON-RGC cell volume was attenuated following IOP elevation in both young and older mice. We also found that following IOP elevation OFF-RGC dendritic morphology became less complex per cell volume in young mice, an effect that was not observed in older eyes. Our data suggest that adaptations in OFF-RGCs in young eyes were associated with better functional recovery 7 days after IOP elevation. Loss of RGC cellular adaptations may account for delayed functional recovery in older eyes.

AIM: To determine the prevalence and associations of non-retinopathy ocular conditions among older Australian adults with diabetes. METHODS: Multistage random-cluster sampling was used to select 3098 non-indigenous Australians aged 50y or older (46.4% male) and 1738 indigenous Australians aged 40y or older (41.1% male) from all levels of geographic remoteness in Australia. Participants underwent a standardised questionnaire to ascertain diabetes history, and a clinical examination to identify eye disease. We determined the prevalence of uncorrected refractive error, visually significant cataract, cataract surgery, age-related macular degeneration, glaucoma, ocular hypertension, retinal vein occlusion and epiretinal membrane among those with and without self-reported diabetes. RESULTS: Participants with self-reported diabetes had a higher prevalence of cataract surgery than those without diabetes (28.8% vs 16.9%, OR 1.78, 95%CI: 1.35-2.34 among non-indigenous Australians, and 11.3% vs 5.2%, OR 1.62, 95%CI: 1.22-2.14 among indigenous Australians). Diabetic retinopathy (DR) increased the odds of cataract surgery among self-reported diabetic indigenous and non-indigenous Australians (OR 1.89, P=0.004 and OR 2.33, P

Importance: Deep learning (DL) networks require large data sets for training, which can be challenging to collect clinically. Generative models could be used to generate large numbers of synthetic optical coherence tomography (OCT) images to train such DL networks for glaucoma detection. Objective: To assess whether generative models can synthesize circumpapillary optic nerve head OCT images of normal and glaucomatous eyes and determine the usability of synthetic images for training DL models for glaucoma detection. Design, Setting, and Participants: Progressively growing generative adversarial network models were trained to generate circumpapillary OCT scans. Image gradeability and authenticity were evaluated on a clinical set of 100 real and 100 synthetic images by 2 clinical experts. DL networks for glaucoma detection were trained with real or synthetic images and evaluated on independent internal and external test data sets of 140 and 300 real images, respectively. Main Outcomes and Measures: Evaluations of the clinical set between the experts were compared. Glaucoma detection performance of the DL networks was assessed using area under the curve (AUC) analysis. Class activation maps provided visualizations of the regions contributing to the respective classifications. Results: A total of 990 normal and 862 glaucomatous eyes were analyzed. Evaluations of the clinical set were similar for gradeability (expert 1: 92.0%; expert 2: 93.0%) and authenticity (expert 1: 51.8%; expert 2: 51.3%). The best-performing DL network trained on synthetic images had AUC scores of 0.97 (95% CI, 0.95-0.99) on the internal test data set and 0.90 (95% CI, 0.87-0.93) on the external test data set, compared with AUCs of 0.96 (95% CI, 0.94-0.99) on the internal test data set and 0.84 (95% CI, 0.80-0.87) on the external test data set for the network trained with real images. An increase in the AUC for the synthetic DL network was observed with the use of larger synthetic data set sizes. Class activation maps showed that the regions of the synthetic images contributing to glaucoma detection were generally similar to that of real images. Conclusions and Relevance: DL networks trained with synthetic OCT images for glaucoma detection were comparable with networks trained with real images. These results suggest potential use of generative models in the training of DL networks and as a means of data sharing across institutions without patient information confidentiality issues. Agency for Science, Technology and Research (A*STAR) Nanyang Technological University National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This work was funded by grants from the National Medical Research Council (grants CG/C010A/2017_SERI, OFLCG/004c/2018-00, MOH-000249-00, MOH-000647-00, MOH-001001-00, MOH-001015-00, MOH-000500-00, and MOH-000707-00), National Research Foundation Singapore (grants NRF2019-THE002-0006 and NRF-CRP24-2020-0001), A*STAR (grant A20H4b0141), the Singapore Eye Research Institute & Nanyang Technological University (SERI-NTU Advanced Ocular Engineering [STANCE] Program), and the SERI-Lee Foundation (grant LF1019-1) in Singapore.

Importance: Retinal ganglion cells endure significant metabolic stress with ageing and glaucoma-related stressors. Injured cells require increased energy for repair but maintain capacity to recover function despite periods of functional loss. Nicotinamide, a precursor of redox co-factor and metabolite, NAD + , is low in serum of patients with primary open-angle glaucoma and its supplementation provides robust protection of retinal ganglion cells by targeting mitochondrial health in glaucoma models. However, the potential of nicotinamide to improve retinal ganglion cell function in humans with glaucoma is yet unknown. Objective: To determine whether nicotinamide supplementation taken in conjunction with conventional IOP-lowering therapy leads to early improvement in retinal ganglion cell function in people with glaucoma. Design: Crossover, double-masked, randomized clinical trial conducted between October 2017 to January 2019. Setting: Study participants recruited from two tertiary care centers in Melbourne, Australia. Participants: Adults diagnosed and treated for primary glaucoma. Ninety-four participants assessed for study eligibility. Intervention: Participants randomized to first receive oral placebo or nicotinamide and reviewed six-weekly. Accelerated dosing method utilized; participants commenced 6-week course of 1.5 grams/day followed by 6 weeks of 3.0 grams/day. After 12 weeks, participants crossed over to other intervention for 12 weeks without washout. At each visit, visual function measured using full-field flash electroretinography and white-on-white perimetry. Main outcome measures: Primary endpoint was change in inner retinal function determined a-priori as change in photopic negative response (PhNR) parameters: saturated PhNR amplitude (Vmax), ratio of PhNR/b-wave amplitude (Vmax ratio). Results: Fifty-seven participants (65.5±10.0 years, 39% female) enrolled. PhNR Vmax improved beyond 95% coefficient of repeatability (COR) in 23% of participants following 12 weeks of nicotinamide versus 9% on placebo. Conversely, PhNR Vmax deteriorated in 9% on placebo and 7% on nicotinamide. Overall, Vmax improved by 14.8% [95% CI: 2.8%, 26.9%], (p=0.02) on nicotinamide and 5.2% [-4.2%, 14.6%], (p=0.27) on placebo. Vmax ratio improved on average by 12.6% [5.0%, 20.2%], (p=0.002) following nicotinamide and 3.6% [-3.4%, 10.5%], (p=0.30) on placebo. A concomitant trend for improved visual field mean deviation was observed with 27% improving ≥1dB on nicotinamide and fewer deteriorating ≥1dB (4%) compared to placebo (p=0.02). Moderate correlation was observed between PhNR and visual field change with treatment. Participants demonstrated excellent treatment adherence rates (>94%) and nicotinamide was well tolerated with minimal side effects. Conclusions and Relevance: Nicotinamide supplementation can improve inner retinal function in patients receiving concurrent IOP-lowering glaucoma therapy. Further studies are underway to elucidate the effects of long-term nicotinamide supplementation on glaucoma progression.

Glaucoma filtration surgery plays an important role in achieving intraocular pressure (IOP) reduction in patients who have high IOP despite maximum medical therapy. Preclinical experimental models of glaucoma filtration surgery contribute a great deal to our knowledge of the wound healing processes that predispose to scarring and may lead to poor outcomes. However, this research needs to be interpreted in the light of the specific study design, animal model and methods used. We review the existing literature addressing various models of experimental glaucoma filtration surgery, discuss the considerations in assessing these models and describe future steps in evaluating potential therapeutics and bleb characteristics that could impact translational research in this field.

Precis Improvements in post-trabeculectomy visual field outcomes were found to be significantly associated with pre-operative nerve fiber layer thickness parameters extracted from the sectorized structure-function relationship, baseline visual field and severity of glaucoma. Objective To determine whether the pre-operative structure-function relationship helps to predict visual outcomes at one-year post-trabeculectomy. Patients and methods 91 eyes from 87 participants who successfully underwent trabeculectomy were included in our study. All eyes received optical coherence tomography imaging and visual field assessment using 30-2 standard automated perimetry pre-operatively at baseline and post-operatively one year after trabeculectomy. Linear mixed model analysis was used to assess the association of structure and function at baseline, and multivariate analysis to investigate factors associated with post-operative visual field outcomes. Results Results from multivariate and univariate analysis for visual field one year after trabeculectomy showed that a positive pre-operative retinal nerve fiber layer thickness deviation from the structure-function model was found to be significantly associated with improved post-operative visual field outcomes (β=0.06▒dB/μm; 95% CI, 0.03 to 0.09). Other significant factors included baseline visual field mean deviation (β=-0.18; 95% CI -0.23 to -0.13) and the presence of severe glaucoma (β=-1.69; 95% CI, -2.80 to -0.57). Intraocular pressure was positively associated with improved visual field outcomes only in univariate analysis (β=0.06; 95% CI, 0.01 to 0.11). Conclusions and relevance Characteristics derived from the baseline structure-function relationship were found to be strongly associated with post-operative visual field outcomes. These findings suggest that the structure-function relationship could potentially have a role in predicting visual field progression after trabeculectomy.

Purpose: Detection of early glaucoma remains limited with the conventional analysis of the retinal nerve fiber layer (RNFL). This study assessed whether compensating the RNFL thickness for multiple demographic and anatomic factors improves the detection of glaucoma. Design: Cross-sectional study. Participants: Three hundred eighty-seven patients with glaucoma and 2699 healthy participants. Methods: Two thousand six hundred ninety-nine healthy participants were enrolled to construct and test a multivariate compensation model, which then was applied in 387 healthy participants and 387 patients with glaucoma (early glaucoma, n = 219; moderate glaucoma, n = 97; and advanced glaucoma, n = 71). Participants underwent Cirrus spectral-domain OCT (Carl Zeiss Meditec) imaging of the optic disc and macular cubes. Compensated RNFL thickness was generated based on ethnicity, age, refractive error, optic disc (ratio, orientation, and area), fovea (distance and angle), and retinal vessel density. The RNFL thickness measurements and their corresponding areas under the receiver operating characteristic curve (AUCs) were obtained. Main Outcome and Measures: Measured and compensated RNFL thickness measurements. Results: After applying the Asian-specific compensation model, the standard deviation of RNFL thickness reduced, where the effect was greatest for Chinese participants (16.9%), followed by Malay participants (13.9%), and Indian participants (12.1%). Multivariate normative comparison outperformed measured RNFL for discrimination of early glaucoma (AUC, 0.90 vs. 0.85; P < 0.001), moderate glaucoma (AUC, 0.94 vs. 0.91; P < 0.001), and advanced glaucoma (AUC, 0.98 vs. 0.96; P < 0.001). Conclusions: The multivariate normative database of RNFL showed better glaucoma discrimination capability than conventional age-matched comparisons, suggesting that accounting for demographic and anatomic variance in RNFL thickness may have usefulness in improving glaucoma detection. Agency for Science, Technology and Research (A*STAR) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version Supported by the National Medical Research Council, Singapore, Republic of Singapore (grant nos.: CG/C010A/2017, OFIRG/0048/2017, OFLCG/004c/2018, TA/MOH-000249-00/2018, and MOH-OFIRG20nov-0014); the National Research Foundation, Singapore, Republic of Singapore (grant nos.: NRF-CRP24-2020-0001 and NRF2019-THE002-0006); A*STAR (grant no.: A20H4b0141); the Singapore Eye Research Institute & Nanyang Technological University (SERI-NTU Advanced Ocular Engineering [STANCE] Program); the Duke-NUS Medical School (grant no. Duke-NUS-KP(Coll)/2018/0009A); and the SERI-Lee Foundation, Singapore, Republic of Singapore (grant no.: LF1019-1).

Nicotinamide adenine dinucleotide (NAD) is a REDOX cofactor and metabolite essential for neuronal survival. Glaucoma is a common neurodegenerative disease in which neuronal levels of NAD decline. Repleting NAD via dietary supplementation of nicotinamide (a precursor to NAD) is effective in preventing retinal ganglion cell neurodegeneration in mouse models. Supporting this, short-term oral nicotinamide treatment in human glaucoma patients provides a recovery of retinal ganglion cell function implying a protection of visual function. Despite this, the mechanism of neuroprotection and full effects of nicotinamide on retinal ganglion cells is unclear. Glaucoma is a complex neurodegenerative disease in which a mix of healthy, stressed, and degenerating retinal ganglion cells co-exist, and in which retinal ganglion cells display compartmentalized degeneration across their visual trajectory. Therefore, we assess the effects of nicotinamide on retinal ganglion cells in normal physiological conditions and across a range of glaucoma relevant insults. We confirm neuroprotection afforded by nicotinamide in rodent models which represent isolated ocular hypertensive, axon degenerative, and mitochondrial degenerative insults. We define a small molecular weight metabolome for the retina, optic nerve, and superior colliculus which demonstrates that ocular hypertension induces widespread metabolic disruption that can be prevented by nicotinamide. Nicotinamide provides these neuroprotective effects by increasing oxidative phosphorylation, buffering and preventing metabolic stress, and increasing mitochondrial size and motility whilst simultaneously dampening action potential firing frequency. These data support continued determination of the utility of long-term NAM treatment as a neuroprotective therapy for human glaucoma.One Sentence SummaryThe NAD precursor nicotinamide has a potent neuroprotective effect in the retina and optic nerve, targeting neuronal function, metabolism, and mitochondrial function.

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.

Mitochondrial complex I dysfunction is the most common respiratory chain defect in human disorders and a hotspot for neurodegenerative diseases. Amyloid precursor protein (APP) and its non-amyloidogenic processing products, in particular soluble APP α (sAPPα), have been shown to provide neuroprotection in models of neuronal injury; however, APP-mediated protection from acute mitochondrial injury has not been previously reported. Here, we use the plant-derived pesticide rotenone, a potent complex I-specific mitochondrial inhibitor, to discover neuroprotective effects of APP and sAPPα in vitro, in neuronal cell lines over-expressing APP, and in vivo, in a retinal neuronal rotenone toxicity mouse model. Our results show that APP over-expression is protective against rotenone toxicity in neurons via sAPPα through an autocrine/paracrine mechanism that involves the Pi3K/Akt pro-survival pathway. APP−/− mice exhibit greater susceptibility to retinal rotenone toxicity, while intravitreal delivery of sAPPα reduces inner retinal neuronal death in wild-type mice following rotenone challenge. We also show a significant decrease in human retinal expression of APP with age. These findings provide insights into the therapeutic potential of non-amyloidogenic processing of APP in complex I-related neurodegeneration. Electronic supplementary material The online version of this article (10.1007/s12035-018-1460-7) contains supplementary material, which is available to authorized users.

Glaucoma is a leading cause of blindness worldwide. In glaucoma, a progressive dysfunction and death of retinal ganglion cells occurs, eliminating transfer of visual information to the brain. Currently, the only available therapies target the lowering of intraocular pressure, but many patients continue to lose vision. Emerging pre-clinical and clinical evidence suggests that metabolic deficiencies and defects may play an important role in glaucoma pathophysiology. While pre-clinical studies in animal models have begun to mechanistically uncover these metabolic changes, some existing clinical evidence already points to potential benefits in maintaining metabolic fitness. Modifying diet and exercise can be implemented by patients as an adjunct to intraocular pressure lowering, which may be of therapeutic benefit to retinal ganglion cells in glaucoma.

Background and objective The photopic negative response (PhNR) of the electroretinogram (ERG) can be useful in the diagnosis and management of glaucoma. Its utility is limited by its large degree of measurement variability, which can be caused by low frequency oscillations and baseline wander. In this work we show a new denoising strategy using the empirical mode decomposition (EMD) which improves repeatability. Methods ERGs were performed on both eyes of 56 patients using red-on-blue stimulus after 2 min of preadaptation, capturing 10 sweeps per recording. Two recordings were obtained to provide intrasession test–retest estimates. Denoising was performed by removing the residue after the decomposition with the EMD, the Ensemble EMD (EEMD) and the Complete ensemble EMD with adaptive noise (CEEMDAN). The PhNR was measured as the amplitude, relative to the prestimulus baseline, of the first negative going trough after the b wave. The coefficient of repeatability (CoR) was calculated to represent 95% of the test–retest differences for the PhNR between sessions. Results Denoising with all of the varieties of the EMD improved the test–retest repeatability of the PhNR. The best results were achieved with the CEEMDAN algorithm, which for the PhNR amplitude improved the coefficient of repeatability relative to the effective dynamic range from 20.2% to 8.3%. Conclusions The EMD can be used to remove low frequency baseline drift and oscillation from the ERG and improve the test–retest repeatability of PhNR measurements. This technique could be deployed for a range of visual and other electrophysiological tests.

Myopia is an emerging public health issue with potentially significant economic and social impact, especially in East Asia. However, many uncertainties about myopia and its clinical management remain. The International Myopia Summit workgroup was convened by the Singapore Eye Research Institute, the WHO Regional Office for the Western Pacific and the International Agency for the Prevention of Blindness in 2019. The aim of this workgroup was to summarise available evidence, identify gaps or unmet needs and provide consensus on future directions for clinical research in myopia. In this review, among the many ‘controversies in myopia’ discussed, we highlight three main areas of consensus. First, development of interventions for the prevention of axial elongation and pathologic myopia is needed, which may require a multifaceted approach targeting the Bruch’s membrane, choroid and/or sclera. Second, clinical myopia management requires co-operation between optometrists and ophthalmologists to provide patients with holistic care and a tailored approach that balances risks and benefits of treatment by using optical and pharmacological interventions. Third, current diagnostic technologies to detect myopic complications may be improved through collaboration between clinicians, researchers and industry. There is an unmet need to develop new imaging modalities for both structural and functional analyses and to establish normative databases for myopic eyes. In conclusion, the workgroup’s call to action advocated for a paradigm shift towards a collaborative approach in the holistic clinical management of myopia.

We evaluated the changes in visual field mean deviation (VF MD) and retinal nerve fibre layer (RNFL) thickness in glaucoma patients undergoing trabeculectomy. One hundred patients were examined with VF and spectral-domain optical coherence tomography (OCT) before trabeculectomy and 4 follow-up visits over one year. Linear mixed models were used to investigate factors associated with VF and RNFL. VF improved during the first 3 months of follow-up (2.55 ± 1.06 dB/year) and worsened at later visits (−1.14 ± 0.29 dB/year). RNFL thickness reduced by −4.21 ± 0.25 µm/year from 1st month of follow-up. Eyes with an absence of initial VF improvement (β = 0.64; 0.30–0.98), RNFL thinning (β = 0.15; 0.08–0.23), increasing intraocular pressure (IOP; β = −0.11; −0.18 to −0.03) and severe glaucoma (β = −10.82; −13.61 to −8.02) were associated with VF deterioration. Eyes with VF deterioration (β = 0.19; 0.08–0.29), increasing IOP (β = −0.09; −0.17 to −0.01), and moderate (β = −6.33; −12.17 to −0.49) or severe glaucoma (β = −19.58; −24.63 to −14.52) were associated with RNFL thinning. Changes in RNFL structure and function occur over a 1-year follow-up period after trabeculectomy. Early VF improvement is more likely to occur in patients with mild/moderate glaucoma, whereas those with severe glaucoma show greater decline over one year. Our findings indicate that progression is observable using OCT, even in late-stage glaucoma. National Medical Research Council (NMRC) Published version The study is funded by National Medical Research Council (NMRC CG/C010A/2017 and OFIRG/0048/2017 and TA/MOH-000249-00/2018) and the Duke-NUS Medical School (Duke-NUS-KP(Coll)/2018/0009A), Singapore. The sponsor or funding organization had no role in the design or conduct of this research.

There is accumulating evidence that aging shifts the central nervous system milieu towards a proinflammatory state, with increased reactivity of microglia in the aging eye and brain having been implicated in the development of age-related neurodegenerative conditions. Indeed, alterations to microglial morphology and function have been recognized as a part of normal aging. Here, we sought to assess the effects of age on the retinal microglial and macrophage response to acute intraocular pressure (IOP) elevation. Further, we performed experiments whereby bone marrow from young or middle-aged mice was used to reconstitute the bone marrow of whole-body irradiated 12 month old mice. Bone marrow chimeric mice then underwent cannulation and IOP elevation 8 weeks after whole-body irradiation and bone marrow transplantation in order to determine whether the age of bone marrow alters the macrophage response to retinal injury. Our data show retinal macrophage reactivity and microglial morphological changes were enhanced in older mice when compared to younger mice in response to injury. When IOP elevation was performed after whole-body irradiation and bone marrow rescue, we noted subretinal macrophage accumulation and glial reactivity was reduced compared to non-irradiated mice that had also undergone IOP elevation. This effect was evident in both groups of chimeric mice that had received either young or middle-aged bone marrow, suggesting irradiation itself may alter the macrophage and glial response to injury rather than the age of bone marrow.

Retinal ganglion cell (RGC) degeneration causes vision loss in patients with glaucoma, and this has been generally considered to be irreversible due to RGC death. We question this assertion and summarise accumulating evidence that points to visual function improving in glaucoma patients with treatment, particularly in the early stages of disease. We propose that prior to death, RGCs enter periods of dysfunction but can recover with relief of RGC stress. We first summarise the clinical evidence for vision improvement in glaucoma and then detail our experimental work that points to the underlying processes that underpin clinical improvement. We show that functional recovery can occur following a prolonged course of RGC dysfunction and demonstrate how the capacity for recovery can be modified. Detecting RGC dysfunction and augmenting recovery of such ‘comatosed’ RGCs holds clinical potential to improve early detection of glaucoma and improve visual function.

AimTo estimate the prevalence of glaucoma in Australia.MethodsThis was a population-based study of 3098 non-Indigenous Australians (50–98 years) and 1738 Indigenous Australians (40–92 years) stratified by remoteness. Each participant underwent a standard examination that included visual field assessment, tonometry and non-mydriatic fundus photography. Two fellowship-trained glaucoma specialists independently assessed relevant case notes (past ocular history, best-corrected visual acuity, frequency doubling technology visual fields, Van Herick grade, intraocular pressure and optic disc-centred photographs) and assigned a diagnosis ranked on a scale of certainty: none, possible, probable or definite glaucoma.ResultsA total of 4792 (99.1%, 3062 non-Indigenous and 1730 Indigenous) participants had retinal photographs in at least one eye that were gradable for glaucoma. The weighted prevalence of glaucoma (definite) in non-Indigenous Australians and Indigenous Australians was 1.5% (95% CI 1.0 to 2.2) and 0.6% (95% CI 0.4 to 1.1), respectively. When definite and probable cases of glaucoma were combined, rates were 3.4% (95% CI 2.7 to 4.3) among non-Indigenous and 1.6% (95% CI 1.1 to 2.3) in Indigenous Australians. Only 52.4% of non-Indigenous Australians and 28.0% of Indigenous Australians with glaucoma self-reported a known history of glaucoma.ConclusionWe estimate that 198 923 non-Indigenous Australians aged 50 years and over and 2139 Indigenous Australians aged 40 years and over have glaucoma. Given the high rates of undiagnosed glaucoma coupled with a significant ageing of the Australian population, improvements in case detection and access to low vision rehabilitation services may be required to cope with the growing burden of glaucoma.

Numerous studies have demonstrated physical activity is a strong factor in overall health and well-being, and a growing body of literature, reviewed herein, suggests that several eye conditions, including glaucoma, age-related macular degeneration, and diabetic retinopathy, are associated with lower activity levels. Likewise, physical activity levels are lower in persons with worse vision. Research in this area has utilized both self-reported physical activity measures as well as objective measures of activity (i.e., accelerometers), each of which have their own strengths and limitations. Putative mechanisms explaining the association of various eye conditions with physical activity are discussed. It is possible that activity restriction occurs as a downstream consequence of eye disease/visual impairment, that activity restriction causes eye disease/visual impairment, or that causality is bidirectional; evidence supporting each of these theories is put forth. An improved understanding of the relationship between physical activity and eye disease will highlight potential secondary health risks resulting from eye disease, and can help determine whether activity might serve as a readily available preventative measure to prevent specific eye conditions.

Die Tatsache einer moglichen Visus- und Gesichtsfelderholung beim Glaukom ist ein bekanntes, wenn auch bisher wenig erforschtes Phanomen. Unser Ziel ist es, einen Einblick in die funktionelle Regeneration retinaler Ganglienzellen (RGZ) besonders nach einem zugefugten Schaden zu gewahren. Dabei mochten wir ein besonderes Augenmerk auf die Entwicklung therapeutischer Ansatze in diesem Bereich richten. Verwendet wurde ein Mausmodell zur Untersuchung der funktionellen Regeneration der RGZ nach einem durch kurzzeitige Augeninnendruck (IOP)-Erhohung gesetzten Schaden. Trotz prolongierten RGZ-Schadens, der durch eine akute IOP-Erhohung induziert wurde, zeigte sich eine fast vollstandige funktionelle Erholung der zunachst dysfunktionalen RGZ. Dabei wurde deutlich, dass ein fortgeschrittenes Alter der Mause sowie eine fettreiche Kost die Regeneration der RGZ negativ beeinflussten, wohingegen korperliche Aktivitat die Regeneration der RGZ verbesserte. Es konnte bei alten, korperlich aktiven Mausen eine ahnlich ausgepragte RGZ-Regeneration nachgewiesen werden, wie sie in jungen untrainierten Mausen zu finden war. Geschadigte RGZ besitzen auch nach langerer Zeit die Kapazitat zu regenerieren. Therapeutische Interventionen, die speziell geschadigte RGZ identifizieren und ihre Regeneration fordern, konnten einen vielversprechenden neuen Ansatz in der Glaukomtherapie darstellen.

Purpose: To conduct a nationwide survey on the prevalence and causes of vision impairment and blindness in Indigenous and non-Indigenous Australians. \ud Design: Nationwide, cross-sectional, population-based field survey. Participants: Indigenous Australians aged 40 years or older and non-Indigenous Australians aged 50 years or more randomly sampled from all levels of geographic remoteness in Australia. \ud Methods: Multistage random-cluster sampling was used to select 3098 non-Indigenous Australians and 1738 Indigenous Australians from 30 sites across 5 remoteness strata with a response rate of 71.5%. Sociodemographic and health data were collected using an interviewer-administered questionnaire. Trained examiners conducted standardized eye examinations, including visual acuity, perimetry, slit-lamp examination, intraocular pressure, and fundus photography. The prevalence and main causes of bilateral presenting vision loss (visual acuity worse than 6/12 in the better eye) were determined, and risk factor analysis was conducted. \ud Main Outcome Measures: The prevalence and main causes of vision impairment and blindness. \ud Results: The overall prevalence of vision loss in Australia was 6.6% (95% confidence interval [CI], 5.4e7.8). The prevalence of vision loss was 11.2% (95% CI, 9.5e13.1) in Indigenous Australians and 6.5% (95% CI, 5.3e7.9) in non-Indigenous Australians. Vision loss was 2.8 times more prevalent in Indigenous Australians than in non-Indigenous Australians after age and gender adjustment (17.7%, 95% CI, 14.5e21.0 vs. 6.4%, 95% CI, 5.2e7.6, P < 0.001). In non-Indigenous Australians, the leading causes of vision loss were uncorrected refractive error (61.3%), cataract (13.2%), and age-related macular degeneration (10.3%). In Indigenous Australians, the leading causes of vision loss were uncorrected refractive error (60.8%), cataract (20.1%), and diabetic retinopathy (5.2%). In non-Indigenous Australians, increasing age (odds ratio [OR], 1.72 per decade; 95% CI, 1.40e2.10) and having not had an eye examination within the past year (OR, 1.61; 95% CI, 1.06e2.42) were risk factors for vision loss. Risk factors in Indigenous Australians included older age (OR, 1.61 per decade; 95% CI, 1.34e1.95), remoteness (OR, 2.02; 95% CI, 1.23e3.31), gender (OR, 0.60 for men; 95% CI, 0.42e0.84), and diabetes in combination with never having had an eye examination (OR, 14.47; 95% CI, 5.65e37.05). \ud Conclusions: Vision loss is more prevalent in Indigenous Australians than in non-Indigenous Australians, highlighting that improvements in eye healthcare in Indigenous communities are required. The leading causes of vision loss were uncorrected refractive error and cataract, which are readily treatable. Other countries with Indigenous communities may benefit from conducting similar surveys of Indigenous and non-Indigenous populations.

To evaluate the specificity of current definitions used to identify progressive change of the average peripapillary retinal nerve fiber layer (RNFL) thickness measurements obtained on optical coherence tomography (OCT) imaging.Prospective observational cohort study.Setting: University of California, San Diego.Seventy-five eyes from 45 normal participants.Patients were seen at an average of 5.7 visits over 3.2 years, to determine the age-related average RNFL thickness changes and longitudinal measurement variability. Slope and variability estimates were used to reconstruct "real-world" OCT imaging measurements with computer simulations.False-positive rates for progression in normal eyes using different definitions.The estimated normal average RNFL thickness change over time was -0.54 ± 0.23 μm/year (P .001). Even with a recent definition of progression that appeared to guarantee a high level of specificity by accounting for normal aging (requiring a significant negative slope that was more negative than the 5% lower limit of aging), 18% simulated normal eyes were still falsely identified as having progressed after 5 years of annual testing in a clinical practice scenario. However, this was reduced to 8% and 4% when trend-based analysis of progression was performed after adjustments using the mean and 5% lower limit of normal rates of aging, respectively.This study highlights how current definitions for detecting RNFL thinning have an unacceptably poor level of specificity, and that more stringent definitions are required to avoid misleading interpretations of progression on OCT imaging in clinical practice.

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Importance This study provides ophthalmologists who manage uveitic glaucoma with important information on factors that can affect the success of surgical management of this challenging disease. Background This study examines surgical outcomes of trabeculectomy and glaucoma device implant (GDI) surgery for uveitic glaucoma, in particular the effect of uveitis activity on surgical outcomes. Design Retrospective chart review at a tertiary institution. Samples 82 cases with uveitic glaucoma (54 trabeculectomies, 28 GDI surgeries) performed between 1 December 2006 and 30 November 2014. Methods Associations of factors with surgical outcomes were examined using univariate and multivariate analysis. Main Outcome Measures Surgical outcomes (failure, success and qualified success) as defined in Guidelines from World Glaucoma Association. Results Average follow up was 26.4 ± 21.5 months. Anterior uveitis was the most common uveitis type. Overall qualified success rate of the trabeculectomies was not statistically different to GDI, being 67% and 75% respectively (P = 0.60). Primary GDI and secondary GDI operations showed similar success rates. The most common post-operative complication was hypotony (~30%). Two cases of GDI developed endophthalmitis and none in trabeculectomies. Active uveitis at the time of operation was higher in trabeculectomy compared to GDI group (35% vs. 14%). Active uveitis at the time of surgery did not significantly increase risk of failure for trabeculectomies. Recurrence of uveitis was significantly associated with surgical failure in trabeculectomy group (odds ratio OR 4.8, P = 0.02) but not in GDI group. Conclusions and Relevance Surgical success rate of GDI was not significantly different to trabeculectomy for uveitic glaucoma in this study. Regular monitoring, early and prolonged intensive treatment of ocular inflammation is important for surgical success particularly following trabeculectomy.

As the myopia epidemic gathers pace, with 5 billion people expected to be myopic and 1 billion predicted to have sight-threatening high myopia by 2050, there is an urgent need to identify targets for early intervention to mitigate the onset and progression of myopia among children.1 Research has suggested that insufficient time spent outdoors in childhood is one of myopia’s major modifiable risk factors,2 and public health interventions that increase time spent outdoors may therefore be the most scalable and efficacious preventative strategies. However, much of the time children spend outdoors consists of moderate-to-vigorous physical activity, and studies on the effect of time spent outdoors have typically not accounted for potentially confounding protective effects of physical activity against myopia.3 There is a noteworthy lack of research on and understanding of the independent association between myopia and physical activity, which might be measured independently of time spent outdoors by objectively studying physical activity in exclusively indoor environments or including ambient light sensors in studies on physical activity. This knowledge gap may impede the optimisation of behavioural interventions for myopia prevention. Physical activity exerts myriad positive effects on paediatric health and may protect against other eye diseases including glaucoma,4 and there are compelling reasons to expect that it may also attenuate axial elongation independently of time spent outdoors, perhaps through promotion of choroidal perfusion and thickening,5 although this has been disputed.6 A 2017 systematic review by Suhr Thykjaer and colleagues attempted to clarify the relationship between physical activity and myopia, but the authors were unable to draw strong conclusions owing …

INTRODUCTION: The porosity of the fibrous capsule around a glaucoma drainage device (GDD) may be the most important functional attribute. The factors that determine capsular porosity are not well understood. Failed GDD surgeries are usually associated with thick impervious capsules and components of aqueous have been implicated in this process. PURPOSE: In this study, we interrogated the effect of passage of nonaqueous fluid on capsular porosity in mature (but aqueous naive) blebs in a previously reported GDD model (the "Center for Eye Research Australia Implant"). MATERIALS AND METHODS: The study was performed at two centers using 17 New Zealand White (NZW) rabbits. An experimental GDD was implanted into the subconjunctival space but without connection to the anterior chamber. After 28 days, balanced salt solution (BSS) was passed through the implant for 30 to 40 minutes at 12 mm Hg. Capsular porosity was measured as flow (μL/min) at a constant pressure. Porosity of the capsule was retested at 3 and 6 days. RESULTS: There was a marked reduction in capsular porosity within 3 days of exposure to BSS (fluid challenge). Even though the baseline porosity was significantly different in the two groups (3.00 ± 0.5 μL/min and 29.67 ± 12.12 μL/min, p < 0.001), the effect of passage of BSS was similar. Capsular porosity fell by approximately 80% in both groups from baseline after single BSS challenge. Capsular thickness was significantly less in Advanced Eye Center (AEC) rabbits at baseline. There was no change in the capsular thickness before and after single fluid challenge. CONCLUSION: Passage of BSS at physiological pressures for under 40 minutes caused marked reduction in the porosity of the fibrous capsule within 3 days. This was not associated with any significant thickening of the fibrous capsule within this time frame. HOW TO CITE THIS ARTICLE: Pandav SS, Ross CM, Thattaruthody F, Nada R, Singh N, Gautam N, Beirne S, Wallace GG, Sherwood MB, Crowston JG, Coote M. Porosity of Bleb Capsule declines rapidly with Fluid Challenge. J Curr Glaucoma Pract 2016;10(3):91-96.

Studies of rodent models of Alzheimer’s disease (AD) and of human tissues suggest that the retinal changes that occur in AD, including the accumulation of amyloid beta (Aβ), may serve as surrogate markers of brain Aβ levels. As Aβ has a wavelength-dependent effect on light scatter, we investigate the potential for in vivo retinal hyperspectral imaging to serve as a biomarker of brain Aβ. Significant differences in the retinal reflectance spectra are found between individuals with high Aβ burden on brain PET imaging and mild cognitive impairment (n = 15), and age-matched PET-negative controls (n = 20). Retinal imaging scores are correlated with brain Aβ loads. The findings are validated in an independent cohort, using a second hyperspectral camera. A similar spectral difference is found between control and 5xFAD transgenic mice that accumulate Aβ in the brain and retina. These findings indicate that retinal hyperspectral imaging may predict brain Aβ load., The use of PET for detection of Aβ in the brain in AD has limitations; studies also indicate that retinal changes, including Aβ deposition, occur in AD. Here the authors demonstrate the potential to use in vivo retinal hyperspectral imaging as a surrogate for brain accumulation of Aβ.

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.

Purpose There have been concerns that short-term clinical trials for evaluating new treatments in glaucoma would require prohibitively large sample sizes when using visual field end points, given that glaucoma often is a slowly progressing disease. This study sought to determine the required sample size for such trials using event-based analyses and whether it can be reduced using trend-based analyses. Design Longitudinal, observational study. Participants Three hundred twenty-one eyes of 240 glaucoma participants followed up under routine clinical care using 24-2 visual field testing for an average of 10 years. Methods Sample size requirements were derived using computer simulations that reconstructed real-world visual fields by combining estimates of pointwise variability according to different threshold levels and rates of change obtained from the clinical glaucoma cohort. A clinical trial lasting 2 years with testing every 3 months was simulated, assuming that the new treatment halted visual field change in various percentages of participants (or "responders"). Treatment efficacy was evaluated by: (1) difference in incidence of pointwise event-based progression (similar to the commercially available Guided Progression Analysis; Carl Zeiss Meditec, Dublin, CA) and (2) difference in rate of visual field mean deviation (MD) change between groups using linear mixed models (LMMs). Main Outcome Measures Sample size to detect a statistically significance difference between groups. Results Between-group trend-based analyses using LMMs reduced sample size requirements by 85% to 90% across the range of new treatment effects when compared with the conventional pointwise event-based analysis. For example, to detect the effect of a new treatment that halted progression in 30% of the participants under routine clinical care (equal to a 30% reduction in average rate of MD change) with 90% power, 1924 participants would be required per group using event-based analysis, but only 277 participants would be required per group if LMMs were used. Conclusions The feasibility of future glaucoma clinical trials can be improved substantially by evaluating differences in the rate of visual field change between groups.

Purpose: To compare the RETeval sensor strip and Dawson-Trick-Litzkow (DTL) electrodes for recording the photopic negative response (PhNR) using a portable electroretinogram (ERG) device in eyes with and without glaucoma. Methods: Twenty-six control and 31 glaucoma or glaucoma-suspect participants were recruited. Photopic ERGs were recorded with sensor strip and DTL electrodes in random order using the LKC RETeval device. Stimuli consisted of brief, red flashes (1.7 cd.s/m2) on a blue background (photopic 10 cd/m2). The PhNR amplitude was measured from baseline to trough and also expressed as a ratio over the b-wave amplitude. Results: The sensor strip-recorded PhNR amplitude was significantly attenuated (mean ± standard deviation [SD], 4.8 ± 2.1 vs. 12.7 ± 4.8 μV, P < 0.0001), with lower signal-to-noise ratio (SNR; 5.5 ± 2.1 vs. 8.1 ± 3.9, P < 0.0001), and a trend toward a larger PhNR/b-wave ratio compared with DTL electrodes. The PhNR amplitude, implicit time and PhNR/b-wave ratio correlated with visual field mean light sensitivity, although this fell short of significance for the sensor strip recorded PhNR amplitude. The electrodes demonstrated similar intersession repeatability with a coefficient of repeatability of ±27% and ±28% for the DTL and sensor strip, respectively. Conclusions: Sensor strip electrodes are a viable alternative for recording reproducible PhNRs, especially when values are normalized to the b-wave. However, DTL electrodes should be considered in cases of attenuated PhNR, or in elevated noise levels, due to its better signal-to-noise quality. Translational Relevance: Sensor strip electrodes can simplify PhNR recordings in the clinic, potentially eliminating the need for an experienced operator.

Energy metabolism refers to the processes by which life transfers energy to do cellular work. The retina's relatively large energy demands make it vulnerable to energy insufficiency. In addition, evolutionary pressures to optimize human vision have been traded against retinal ganglion cell bioenergetic fragility. Details of the metabolic profiles of the different retinal cells remain poorly understood and are challenging to resolve. Detailed immunohistochemical mapping of the energy pathway enzymes and substrate transporters has provided some insights and highlighted interspecies differences. The different spatial metabolic patterns between the vascular and avascular retinas can account for some inconsistent data in the literature. There is a consilience of evidence that at least some individuals with glaucoma have impaired RGC energy metabolism, either due to impaired nutrient supply or intrinsic metabolic perturbations. Bioenergetic-based therapy for glaucoma has a compelling pathophysiological foundation and is supported by recent successes in animal models. Recent demonstrations of visual and electrophysiological neurorecovery in humans with glaucoma is highly encouraging and motivates longer duration trials investigating bioenergetic neuroprotection.

Summary Retinal ganglion cells (RGCs) become increasingly vulnerable to injury with advancing age. We recently showed that this vulnerability can be strongly modified in mice by exercise. However, the characteristics and underlying mechanisms of retinal protection with exercise remain unknown. Hence, the aim of this study was to investigate cellular changes associated with exercise‐induced protection of aging retinal cells and the role of local and peripheral trophic signalling in mediating these effects. We focussed on two molecules that are thought to play key roles in mediating beneficial effects of exercise: brain‐derived neurotrophic factor (BDNF) and AMP‐activated protein kinase (AMPK). In middle‐aged (12 months old) C57BL/6J mice, we found that exercise protected RGCs against dysfunction and cell loss after an acute injury induced by elevation of intra‐ocular pressure. This was associated with preservation of inner retinal synapses and reduced synaptic complement deposition. Retinal expression of BDNF was not upregulated in response to exercise alone. Rather, exercise maintained BDNF levels in the retina, which were decreased postinjury in nonexercised animals. Confirming a critical role for BDNF, we found that blocking BDNF signalling during exercise by pharmacological means or genetic knock‐down suppressed the functional protection of RGCs afforded by exercise. Protection of RGCs with exercise was independent of activation of AMPK in either retina or skeletal muscle. Our data support a previously unidentified mechanism in which exercise prevents loss of BDNF in the retina after injury and preserves neuronal function and survival by preventing complement‐mediated elimination of synapses.

BACKGROUND The aim of the study is to measure the impact of age-related macular degeneration on vision-related activity limitation and preference-based status for glaucoma patients. DESIGN This was a cross-sectional study. PARTICIPANTS Two-hundred glaucoma patients of whom 73 had age-related macular degeneration were included in the research. METHODS Sociodemographic information, visual field parameters and visual acuity were collected. Age-related macular degeneration was scored using the Age-Related Eye Disease Study system. MAIN OUTCOME MEASURES The Rasch-analysed Glaucoma Activity Limitation-9 and the Visual Function Questionnaire Utility Index measured vision-related activity limitation and preference-based status, respectively. Regression models determined factors predictive of vision-related activity limitation and preference-based status. Differential item functioning compared Glaucoma Activity Limitation-9 item difficulty for those with and without age-related macular degeneration. RESULTS Mean age was 73.7 (±10.1) years. Lower better eye mean deviation (β: 1.42, 95% confidence interval: 1.24-1.63, P

Accumulating evidence from experimental and clinical studies suggest that retinal ganglion cells at least in the earlier stages of glaucoma have the capacity to recover function following periods of functional loss. The capacity for recovery may be negatively impacted by advancing age but can be boosted by interventions such as diet restriction and exercise.

Copyright 2020 The Authors iovs.arvojournals.org. PURPOSE. To evaluate the short-term changes in inner retinal function using the photopic negative response (PhNR) after intraocular pressure (IOP) reduction in glaucoma. METHODS. Forty-seven participants with glaucoma who were commencing a new or additional IOP-lowering therapy (treatment group) and 39 participants with stable glaucoma (control group) were recruited. IOP, visual field, retinal nerve fiber layer thickness, and electroretinograms (ERGs) were recorded at baseline and at a follow-up visit (3 ± 2 months). An optimized protocol developed for a portable ERG device was used to record the PhNR. The PhNR saturated amplitude (Vmax), Vmax ratio, semi-saturation constant (K), and slope of the Naka–Rushton function were analyzed. RESULTS. A significant percentage reduction in IOP was observed in the treatment group (28 ± 3%) compared to the control group (2 ± 3%; P < 0.0001). For PhNR Vmax, there was no significant interaction (F1,83 = 2.099, P = 0.15), but there was a significant difference between the two time points (F1,83 = 5.689, P = 0.019). Post hoc analysis showed a significant difference between baseline and 3 months in the treatment group (mean difference, 1.23 μV; 95% confidence interval [CI], 0.24–2.22) but not in the control group (0.30 μV; 95% CI, 0.78–1.38). K and slope were not significantly different in either group. Improvement beyond test–retest variability was seen in 17% of participants in the treatment group compared to 3% in the control group (P = 0.007, χ2 test). CONCLUSIONS. The optimized protocol for measuring the PhNR detected short-term improvements in a proportion of participants following IOP reduction, although the majority showed no change.

Purpose To describe a minimally invasive experimental model of acute ocular hypertension (OHT) with characteristics of acute angle closure (AAC). Methods Adult C57/Bl6 mice (n = 31) were subjected to OHT in one eye using a modified circumlimbal suture technique that elevated intraocular pressure (IOP) for 30 minutes. Contralateral un-operated eyes served as controls. IOP, anterior segment optical coherence tomography, and fundus fluorescein angiography (FFA) were performed. The positive scotopic threshold response (pSTR) and a-wave and b-wave amplitudes were also evaluated. Retinal tissues were immunostained for the retinal ganglion cell (RGC) marker RBPMS and the glial marker GFAP. Results OHT eyes developed shallower anterior chambers and dilated pupils. FFA showed focal leakage in 32.2% of OHT eyes, but in none of the control eyes. pSTR was significantly reduced at week 1 in OHT eyes compared to control eyes (57.3 ± 7.2 µV vs. 106.9 ± 24.8 µV; P < 0.05), but a- and b-waves were unaffected. GFAP was upregulated in OHT eyes but not in control eyes or eyes that had been sutured without OHT. RGC density was reduced in OHT eyes after 4 weeks (3857 ± 143.8) vs. control eyes (4469 ± 176.0) (P < 0.05). Conclusions Our minimally invasive model resulted in acute OHT with characteristics of AAC in the absence of non-OHT-related neuroinflammatory changes arising from ocular injury alone. Translational Relevance This model provides a valuable approach to studying specific characteristics of a severe blinding disease in an experimental setting. Focal areas of ischemia were demonstrated, consistent with clinical studies of acute angle closure patients elsewhere, which may indicate the need for further research into how this could affect visual outcome in these patients.

Purpose: The purpose of this study was to investigate the effect of interstimulus frequency on the photopic negative response (PhNR) in the clinical electroretinogram (ERG) in glaucoma and healthy eyes. Methods: Participants with open angle glaucoma (n = 15) and age-matched controls (n = 20) were recruited. Photopic ERGs were recorded in one eye using five frequencies (1-5 Hz) delivered in random order. ERGs were analyzed for changes to amplitude and timing between groups and interstimulus frequency. Coefficient of variation (CoV) was used to examine variability within recordings for each frequency. Results: While the a-wave and b-wave showed minimal alteration, the PhNR was highly sensitive to changes in interstimulus frequency. The PhNR signal was largest at 1 Hz and steadily diminished with higher frequencies in both control and glaucoma groups. Significant differences in PhNR amplitude were found between controls and glaucoma groups at 2 and 3 Hz. While 1 Hz delivered the largest PhNR, it also showed a significantly greater CoV compared to other frequencies. Conclusions: An interstimulus frequency of 2 Hz was optimal for recording the PhNR, creating a good balance between testing time and signal quality. A higher frequency could be used to further shorten clinical testing times; however, this may compromise its clinical utility by dampening the PhNR. Translational Relevance: Here we show the importance of considering flash interstimulus frequency when designing ERG protocols for recording the PhNR as while higher frequencies can shorten test times, they also have considerable effects on the PhNR.

Optic nerve head drusen are benign acellular calcium concretions that usually form early in life, just anterior to the lamina cribrosa. Improving imaging using optical coherence tomography suggests they are common and may be present in many clinically normal discs. These drusen may change in appearance in early life, but are generally stable in adulthood, and may be associated with visual field defects, anterior ischaemic optic neuropathy, or rarer complications. Based on long-term clinical data and optical coherence tomography, we propose a refined hypothesis as to the cause of optic disc drusen. Here we summarise recent findings and suggest future studies to better understand the forces involved.

Importance Studies have documented a higher disease burden in indigenous compared with nonindigenous populations, but no global data on the epidemiology of visual loss in indigenous peoples are available. A systematic review of literature on visual loss in the world’s indigenous populations could identify major gaps and inform interventions to reduce their burden of visual loss. Objective To conduct a systematic review on the prevalence and causes of visual loss among the world’s indigenous populations. Evidence Review A search of databases and alternative sources identified literature on the prevalence and causes of visual loss (visual impairment and blindness) and eye diseases in indigenous populations. Studies from January 1, 1990, through August 1, 2017, that included clinical eye examinations of indigenous participants and, where possible, compared findings with those of nonindigenous populations were included. Methodologic quality of studies was evaluated to reveal gaps in the literature. Findings Limited data were available worldwide. A total of 85 articles described 64 unique studies from 24 countries that examined 79 598 unique indigenous participants. Nineteen studies reported comparator data on 42 085 nonindigenous individuals. The prevalence of visual loss was reported in 13 countries, with visual impairment ranging from 0.6% in indigenous Australian children to 48.5% in native Tibetans 50 years or older. Uncorrected refractive error was the main cause of visual impairment (21.0%-65.1%) in 5 of 6 studies that measured presenting visual acuity. Cataract was the main cause of visual impairment in all 6 studies measuring best-corrected acuity (25.4%-72.2%). Cataract was the leading cause of blindness in 13 studies (32.0%-79.2%), followed by uncorrected refractive error in 2 studies (33.0% and 35.8%). Conclusions and Relevance Most countries with indigenous peoples do not have data on the burden of visual loss in these populations. Although existing studies vary in methodologic quality and reliability, they suggest that most visual loss in indigenous populations is avoidable. Improvements in quality and frequency of research into the eye health of indigenous communities appear to be required, and coordinated eye care programs should be implemented to specifically target the indigenous peoples of the world.