Diabetic Macular Edema and Diode Subthreshold Micropulse Laser: A Randomized Double-Masked Noninferiority Clinical Trial.

PURPOSE: To determine clinical effectiveness, safety, and cost-effectiveness of subthreshold micropulse laser (SML), compared with standard laser (SL), for diabetic macular edema (DME) with central retinal thickness (CRT) < 400 µm. DESIGN: Pragmatic, multicenter, allocation-concealed, double-masked, randomized, noninferiority trial. PARTICIPANTS: Adults with center-involved DME < 400 µm and best-corrected visual acuity (BCVA) of > 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters in one/both eyes. METHODS: Randomization 1:1 to 577 nm SML or SL treatment. Retreatments were allowed. Rescue with intravitreal anti-vascular endothelial growth factor therapies or steroids was permitted if 10 or more ETDRS letter loss occurred, CRT increased > 400 µm, or both. MAIN OUTCOME MEASURES: Primary outcome was mean change in BCVA in the study eye at 24 months (noninferiority margin 5 ETDRS letters). Secondary outcomes were mean change from baseline to month 24 in binocular BCVA; CRT and mean deviation of Humphrey 10-2 visual field in the study eye; percentage meeting driving standards; EuroQoL EQ-5D-5L, 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), and Vision and Quality of Life Index (VisQoL) scores; cost per quality-adjusted life-years (QALYs) gained; adverse effects; and number of laser and rescue treatments. RESULTS: The study recruited fully (n = 266); 87% of SML-treated and 86% of SL-treated patients had primary outcome data. Mean ± standard deviation BCVA change from baseline to month 24 was -2.43 ± 8.20 letters and -0.45 ± 6.72 letters in the SML and SL groups, respectively. Subthreshold micropulse laser therapy was deemed not only noninferior but also equivalent to SL therapy because the 95% confidence interval (CI; -3.9 to -0.04 letters) lay wholly within both upper and lower margins of the permitted maximum difference (5 ETDRS letters). No statistically significant difference was found in binocular BCVA (0.32 ETDRS letters; 95% CI, -0.99 to 1.64 ETDRS letters; P = 0.63); CRT (-0.64 µm; 95% CI, -14.25 to 12.98 µm; P = 0.93); mean deviation of the visual field (0.39 decibels (dB); 95% CI, -0.23 to 1.02 dB; P = 0.21); meeting driving standards (percentage point difference, 1.6%; 95% CI, -25.3% to 28.5%; P = 0.91); adverse effects (risk ratio, 0.28; 95% CI, 0.06-1.34; P = 0.11); rescue treatments (percentage point difference, -2.8%; 95% CI, -13.1% to 7.5%; P = 0.59); or EQ-5D, NEI-VFQ-25, or VisQoL scores. Number of laser treatments was higher in the SML group (0.48; 95% CI, 0.18-0.79; P = 0.002). Base-case analysis indicated no differences in costs or QALYs. CONCLUSIONS: Subthreshold micropulse laser therapy was equivalent to SL therapy, requiring slightly higher laser treatments.

Standard threshold laser versus subthreshold micropulse laser for adults with diabetic macular oedema: the DIAMONDS non-inferiority RCT.

BACKGROUND: The National Institute for Health and Care Excellence recommends macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm on optical coherence tomography. The DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial compared standard threshold macular laser with subthreshold micropulse laser to treat diabetic macular oedema suitable for macular laser. OBJECTIVES: Determining the clinical effectiveness, safety and cost-effectiveness of subthreshold micropulse laser compared with standard threshold macular laser to treat diabetic macular oedema with a central retinal subfield thickness of < 400 µm. DESIGN: A pragmatic, multicentre, allocation-concealed, double-masked, randomised, non-inferiority, clinical trial. SETTING: Hospital eye services in the UK. PARTICIPANTS: Adults with diabetes and centre-involving diabetic macular oedema with a central retinal subfield thickness of < 400 µm, and a visual acuity of > 24 Early Treatment Diabetic Retinopathy Study letters (Snellen equivalent > 20/320) in one/both eyes. INTERVENTIONS: Participants were randomised 1 : 1 to receive 577 nm subthreshold micropulse laser or standard threshold macular laser (e.g. argon laser, frequency-doubled neodymium-doped yttrium aluminium garnet 532 nm laser); laser treatments could be repeated as needed. Rescue therapy with intravitreal anti-vascular endothelial growth factor therapies or steroids was allowed if a loss of ≥ 10 Early Treatment Diabetic Retinopathy Study letters between visits occurred and/or central retinal subfield thickness increased to > 400 µm. MAIN OUTCOME MEASURES: The primary outcome was the mean change in best-corrected visual acuity in the study eye at 24 months (non-inferiority margin 5 Early Treatment Diabetic Retinopathy Study letters). Secondary outcomes included the mean change from baseline to 24 months in the following: binocular best-corrected visual acuity; central retinal subfield thickness; the mean deviation of the Humphrey 10-2 visual field in the study eye; the percentage of people meeting driving standards; and the EuroQol-5 Dimensions, five-level version, National Eye Institute Visual Function Questionnaire - 25 and Vision and Quality of Life Index scores. Other secondary outcomes were the cost per quality-adjusted life-years gained, adverse effects, number of laser treatments and additional rescue treatments. RESULTS: The DIAMONDS trial recruited fully (n = 266); 87% of participants in the subthreshold micropulse laser group and 86% of participants in the standard threshold macular laser group had primary outcome data. Groups were balanced regarding baseline characteristics. Mean best-corrected visual acuity change in the study eye from baseline to month 24 was -2.43 letters (standard deviation 8.20 letters) in the subthreshold micropulse laser group and -0.45 letters (standard deviation 6.72 letters) in the standard threshold macular laser group. Subthreshold micropulse laser was deemed to be not only non-inferior but also equivalent to standard threshold macular laser as the 95% confidence interval (-3.9 to -0.04 letters) lay wholly within both the upper and lower margins of the permitted maximum difference (5 Early Treatment Diabetic Retinopathy Study letters). There was no statistically significant difference between groups in any of the secondary outcomes investigated with the exception of the number of laser treatments performed, which was slightly higher in the subthreshold micropulse laser group (mean difference 0.48, 95% confidence interval 0.18 to 0.79; p = 0.002). Base-case analysis indicated no significant difference in the cost per quality-adjusted life-years between groups. FUTURE WORK: A trial in people with ≥ 400 µm diabetic macular oedema comparing anti-vascular endothelial growth factor therapy alone with anti-vascular endothelial growth factor therapy and macular laser applied at the time when central retinal subfield thickness has decreased to < 400 µm following anti-vascular endothelial growth factor injections would be of value because it could reduce the number of injections and, subsequently, costs and risks and inconvenience to patients. LIMITATIONS: The majority of participants enrolled had poorly controlled diabetes. CONCLUSIONS: Subthreshold micropulse laser was equivalent to standard threshold macular laser but required a slightly higher number of laser treatments. TRIAL REGISTRATION: This trial is registered as EudraCT 2015-001940-12, ISRCTN17742985 and NCT03690050. FUNDING: This project was funded by the National Institute for Health and Care Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 50. See the NIHR Journals Library website for further project information.

The retina is a layer at the back of the eye. Its centre is called the macula and is responsible for central vision. Some people with diabetes develop diabetic macular oedema. In diabetic macular oedema fluid leaks from retinal blood vessels and builds up at the macula, resulting in sight loss. Diabetic macular oedema can be mild or severe; this can be determined measuring the thickness of the macula, which is measured in micrometres (µm). One micrometre is one thousandth of a millimetre. In mild diabetic macular oedema, the thickness of the macula increases, but is less than 400 µm. Patients with mild diabetic macular oedema can be treated with a laser and there are two laser types. The standard threshold macular laser has been available for many years. It clears the diabetic macular oedema but produces a 'burn' in the retina. The subthreshold micropulse laser is newer. It does not produce a burn but also clears the diabetic macular oedema. The lack of a burn, however, has led to doubts about whether or not this laser works as well as the standard threshold macular laser because 'no burn' was taken to mean 'less benefit'. These doubts led to our establishing the DIAMONDS (DIAbetic Macular Oedema aNd Diode Subthreshold micropulse laser) trial, which compared these two lasers for people with mild diabetic macular oedema. A total of 266 people suitable for either laser joined the study at 16 NHS hospitals across the UK; 133 received standard threshold macular laser and 133 received subthreshold micropulse laser. The choice of laser was determined by chance. The DIAMONDS trial found that the subthreshold micropulse laser was as good as the standard threshold macular laser (i.e. 'clinically equivalent') in terms of improving people's vision, reducing macula thickness, allowing people to meet driving standards and maintaining their quality of life, both in general terms and for vision in particular. There was a small increase (less than one session on average per person) in the number of laser treatment sessions needed with subthreshold micropulse laser. The costs of both laser treatments were about the same.

A Screening Tool for Self-Evaluation of Risk for Age-Related Macular Degeneration: Validation in a Spanish Population.

Purpose: The objectives of this study were the creation and validation of a screening tool for age-related macular degeneration (AMD) for routine assessment by primary care physicians, ophthalmologists, other healthcare professionals, and the general population. Methods: A simple, self-administered questionnaire (Simplified Théa AMD Risk-Assessment Scale [STARS] version 4.0) which included well-established risk factors for AMD, such as family history, smoking, and dietary factors, was administered to patients during ophthalmology visits. A fundus examination was performed to determine presence of large soft drusen, pigmentary abnormalities, or late AMD. Based on data from the questionnaire and the clinical examination, predictive models were developed to estimate probability of the Age-Related Eye Disease Study (AREDS) score (categorized as low risk/high risk). The models were evaluated by area under the receiving operating characteristic curve analysis. Results: A total of 3854 subjects completed the questionnaire and underwent a fundus examination. Early/intermediate and late AMD were detected in 15.9% and 23.8% of the patients, respectively. A predictive model was developed with training, validation, and test datasets. The model in the test set had an area under the curve of 0.745 (95% confidence interval [CI] = 0.705-0.784), a positive predictive value of 0.500 (95% CI = 0.449-0.557), and a negative predictive value of 0.810 (95% CI = 0.770-0.844). Conclusions: The STARS questionnaire version 4.0 and the model identify patients at high risk of developing late AMD. Translational Relevance: The screening instrument described could be useful to evaluate the risk of late AMD in patients >55 years without having an eye examination, which could lead to more timely referrals and encourage lifestyle changes.

Use of Imaging Technology to Assess the Effect of COVID-19 on Retinal Tissues: A Systematic Review.

PURPOSE: To evaluate the effect of COVID-19 on retinal tissues by conducting a systematic review and meta-analysis of the current literature. BACKGROUND: The novel coronavirus disease is not yet well understood. The orbit provides a window into the body's microvasculature, and as such, it is a non-invasive opportunity to analyse the systemic circulation in vivo. By analysing the current literature, we test the hypothesis that non-invasive imaging of the retina could provide insight into the effect of COVID-19 on the retinal microvasculature. METHODS: For this systematic review and meta-analysis, we screened PubMed databases and LitCOVID19 using the search criteria: (OCTA or Optical Coherence Tomography Angiography) AND (COVID-19 or corona or SARS-CoV-2) AND (retina or fundus). Databases were searched on 11 January 2022. The primary study outcomes were studies that utilised OCTA to analyse the retina; secondary outcomes involved studies that involved other imaging modalities such as OCT, fundus photography, and fundus autofluorescence. FINDINGS: The total number of studies included in this review was 32. Optical coherence tomography angiography scans show reduced central retinal vascular density, a thinner ganglion cell layer, a thicker retinal nerve fibre layer, and an enlarged foveal avascular zone. Optical coherence tomography scans demonstrate a thicker central macular thickness and other changes to the macula, ganglion cell, and inner nuclear layers. Many fundus photographs depicted cotton wool spots, microhaemorrhages, and vascular occlusions. Non-invasive imaging technology has demonstrated that COVID-19 can profoundly affect the retina. Therefore, there is a requirement for long-term follow-up of COVID-19 patients to assess whether the retinal damage caused by COVID-19 is reversible.

The role of dark adaptation in understanding early AMD.

The main aim of the paper is to discuss current knowledge on how Age Related Macular Degeneration (AMD) affects Dark Adaptation (DA). The paper is divided into three parts. Firstly, we outline some of the molecular mechanisms that control DA. Secondly, we review the psychophysical issues and the corresponding analytical techniques. Finally, we characterise the link between slowed DA and the morphological abnormalities in early AMD. Historically, DA has been regarded as too cumbersome for widespread clinical application. Yet the technique is extremely useful; it is widely accepted that the psychophysically obtained slope of the second rod-mediated phase of the dark adaptation function is an accurate assay of photoreceptor pigment regeneration kinetics. Technological developments have prompted new ways of generating the DA curve, but analytical problems remain. A simple potential solution to these, based on the application of a novel fast mathematical algorithm, is presented. This allows the calculation of the parameters of the DA curve in real time. Improving current management of AMD will depend on identifying a satisfactory endpoint for evaluating future therapeutic strategies. This must be implemented before the onset of severe disease. Morphological changes progress too slowly to act as a satisfactory endpoint for new therapies whereas functional changes, such as those seen in DA, may have more potential in this regard. It is important to recognise, however, that the functional changes are not confined to rods and that building a mathematical model of the DA curve enables the separation of rod and cone dysfunction and allows more versatility in terms of the range of disease severity that can be monitored. Examples are presented that show how analysing the DA curve into its constituent components can improve our understanding of the morphological changes in early AMD.

IMAGE ANALYSIS OF OPTICAL COHERENCE TOMOGRAPHY SCANS TO EXPLORE ESTABLISHED AND NOVEL CHOROIDAL FEATURES IN PATIENTS WITH CENTRAL SEROUS CHORIORETINOPATHY.

PURPOSE: To explore the characteristics of choroidal tissue in patients with and without central serous chorioretinopathy (CSC) using an automated system of image analysis to determine known and novel metrics. METHODS: This was a retrospective case-control analysis of optical coherence tomography scans of patients seen at Manchester Royal Eye Hospital, UK, comparing patients with active CSC to an age-matched and gender-matched group with no CSC using a purpose-built automated system of image analysis. The expert system segments and measures established and novel features of choroid using a combination of thresholding, noise removal, and morphological techniques. RESULTS: A total of 72 patients were included in this study, with 40 included in the group with CSC and 32 patient controls with no CSC. There were significant increases from normal to CSC of median choroidal vascularity index, 54.7(median absolute deviation = 9.8) to 61.2(4.3), and all choroidal thickness indices including maximum depth, from 249.0(90.1) µm to 372.3(80.3) µm. For novel measures, there was a significant increase in tissue entropy from 6.68(0.28) to 6.95(0.17) and area of the largest five vessels from 6.28(3.04) mm2 to 9.10(3.49) mm2. The ratio of vessel lumen to stromal tissue intensity was conversely significantly reduced from 0.674(0.11) in normal patients to 0.59(0.06) in CSC. CONCLUSION: The automated system of choroidal analysis expands on the utility of known measures and introduces novel metrics. These findings contribute pathophysiological insights and metrics for further assessment and research on conditions affecting choroidal tissue.

Translating the Machine: Skills that Human Clinicians Must Develop in the Era of Artificial Intelligence.

In coming decades, artificial intelligence (AI) platforms are expected to build on the profound achievements demonstrated in research papers towards implementation in real-world medicine. The implementation of AI systems is likely to be as an adjunct to clinicians rather than a replacement, but it still has the potential for a revolutionary impact on ophthalmology specifically and medicine in general in terms of addressing crucial scientific, socioeconomic and capacity challenges facing populations worldwide. In this paper we discuss the broad range of skills that clinicians should develop or refine to be able to fully embrace the opportunities that this technology will bring. We highlight the need for an awareness to identify AI systems that might already be in place and the need to be able to properly assess the utility of their outputs to correctly incorporate the AI system into clinical workflows. In a second section we discuss the need for clinicians to cultivate those human skills that are beyond the capabilities of the AI platforms and which should be just as important as ever. We describe the need for such an awareness by providing clinical examples of situations that might in the future arise in human interactions with machine algorithms. We also envisage a harmonious future in which an educated human and machine interaction can be optimised for the best possible patient experience and care.

Exploring Consensus on Preventive Measures and Identification of Patients at Risk of Age-Related Macular Degeneration Using the Delphi Process.

BACKGROUND: Early identification of AMD can lead to prompt and more effective treatment, better outcomes, and better final visual acuity; several risk scores have been devised to determine the individual level of risk for developing AMD. Herein, the Delphi method was used to provide recommendations for daily practice regarding preventive measures and follow-up required for subjects at low, moderate, and high risk of AMD evaluated with the Simplified Test AMD Risk-assessment Scale (STARS®) questionnaire. METHODS: A steering committee of three experts drafted and refined 25 statements on the approach to be recommended in different clinical situations [general recommendations (n = 2), use of evaluation tools (n = 4), general lifestyle advice (n = 3), and AREDS-based nutritional supplementation (n = 5)] with the help of a group of international experts, all co-authors of this paper. Thirty retinal specialists from Europe and the US were chosen based on relevant publications, clinical expertise, and experience in AMD, who then provided their level of agreement with the statements. Statements for which consensus was not reached were modified and voted upon again. RESULTS: In the first round of voting, consensus was reached for 24 statements. After modification, consensus was then reached for the remaining statement. CONCLUSION: An interprofessional guideline to support preventive measures in patients at risk of AMD based on STARS® scoring has been developed to aid clinicians in daily practice, which will help to optimize preventive care of patients at risk of AMD.

Ophthalmology Going Greener: A Narrative Review.

The combined effects of fossil fuel combustion, mass agricultural production and deforestation, industrialisation and the evolution of modern transport systems have resulted in high levels of carbon emissions and accumulation of greenhouse gases, causing profound climate change and ozone layer depletion. The consequential depletion of Earth's natural ecosystems and biodiversity is not only a devastating loss but a threat to human health. Sustainability-the ability to continue activities indefinitely-underpins the principal solutions to these problems. Globally, the healthcare sector is a major contributor to carbon emissions, with waste production and transport systems being amongst the highest contributing factors. The aim of this review is to explore modalities by which the healthcare sector, particularly ophthalmology, can reduce carbon emissions, related costs and overall environmental impact, whilst maintaining a high standard of patient care.

Ophthalmology and Therapy: Reflecting on 2020 and Embracing the Challenges of 2021.

2020 will forever be marked as a year that brought with it an unprecedented number of challenges for the healthcare community. COVID-19 had monumental effects on all fields, including ophthalmology. Considering this we are truly thankful for all of the support we have received, despite the pressures brought about by the pandemic. We are very grateful to our Editorial and Advisory boards who have continued to offer their advice, to our authors for working with us to help publish their work, and to our readers for engaging with our content. The Editorial below has been authored by Ophthalmology and Therapy's EU Editor-in-Chief Professor Tariq Aslam. Professor Aslam writes about his aspirations for the healthcare and ophthalmology community in 2021, and how the journal hopes to play its part in facing these challenges.

Statistical Modelling of the Visual Impact of Subretinal Fluid and Associated Features.

INTRODUCTION: The aim of this study was to develop a statistical model to determine the visual significance of subretinal fluid (SRF) in combination with other constructed optical coherence tomography (OCT) features in patients with wet age-related macular degeneration. METHODS: The project used labelled data from 1211 OCTs of patients with neovascular macular degeneration (nAMD) attending the macular treatment centre of Manchester Royal Eye Hospital to build a statistical model to determine vision for any virtual, constructed OCT. A four-dimensional plot was created to represent the visual impact of SRF in OCTs in the context of the associated OCT characteristics of atrophy and subretinal hyperreflective material (SHRM). RESULTS: The plot illustrates that at levels of SRF below 150 µm, the impact of SRF on vision is very low. Increasing the amount of fluid to 200 µm and beyond increases the impact on vision, but only if there is little atrophy or SHRM. CONCLUSIONS: This study suggests that levels of SRF up to around 150 µm thickness on OCT have minimal impact on vision. Greater levels of SRF have greater impact on vision, unless associated with significant amounts of atrophy or SHRM, when the additional effect of the SRF on vision remains low.

Video Conferencing in the Intravitreal Injection Clinic in Response to the COVID-19 Pandemic.

PURPOSE: To share a useful intervention to minimize risk of COVID-19 infection to both healthcare workers and patients in the eye clinic. METHODS: We present our experience of virtual, within-clinic remote visual acuity assessment to reduce the risk of infection with COVID-19. RESULTS: Along with standard recommendations for personal protective equipment and hand hygiene to contain viral spread and treating only urgent cases, remote within-clinic visual acuity testing and consultations can be undertaken with minimal specialist equipment and appears to provide useful information whilst being acceptable to patients. CONCLUSION: Ophthalmology practice must adapt in order to combat COVID-19. This measure can easily be incorporated into daily practice to reduce both patient footfall within the department and close contact between patient and healthcare practitioners.

A Review of Macular Atrophy of the Retinal Pigment Epithelium in Patients with Neovascular Age-Related Macular Degeneration: What is the Link? Part II.

INTRODUCTION: To explore the potential link between macular atrophy (MA) of the retinal pigment epithelium (RPE) in patients with neovascular age-related macular degeneration (nAMD) and anti-vascular endothelial growth factor (anti-VEGF) treatment. METHODS: Through a balanced overview of the field from a largely clinical perspective, we looked at available evidence on the topic of MA correlation with anti-VEGF therapy and examined possible risk factors for MA development in the context of nAMD treatment with anti-VEGF. RESULTS: Links have been reported to connect both MA incidence and progression to treatment frequency and to the anti-VEGF drug type. CONCLUSIONS: All reports agree on the fact that de novo development of MA in anti-VEGF-treated eyes is frequent and multifactorial. Research data shows an expansion of atrophy during anti-VEGF treatment. There are mixed conclusions about the correlation of MA incidence or progression with treatment-related risk factors. It mostly appears that there is no straightforward link. More clinical research is still needed to further understand this association.

Treatment decisions of UK hospital optometrists and ophthalmologists in patients with nAMD: a vignette study.

PURPOSE: A vignette study to examine treatment decisions made by UK hospital optometrists in patients with neovascular age-related macular degeneration (nAMD) and the effect of optometrists' experience on agreement. METHODS: Patients with nAMD attending Manchester Royal Eye Hospital, Manchester, UK were identified as potential candidates for the case series of vignettes. The cases were chosen to reflect a varied case-mix with respect to difficulty as well as ensuring good quality of the images. Each vignette included a history summary consisting of the number of previous injections given and visual acuity measurements at baseline, the previous visit, and the current visit. Images were compiled to show baseline fundus photographs and ocular coherence tomography (OCT) images with the current visit images on which the treatment decision was to be made along with the images from the previous visit. Hospital optometrists were recruited and asked to complete the series of vignettes, deciding if treatment was required at that visit and how confident they felt with that decision. Their responses were compared to the reference standard created by a consensus of consultant ophthalmologists with a sub-speciality interest in medical retina. RESULTS: Regarding treatment decision for optometrists, the percentage correct value was 75% with the sensitivity being 75.6% (95% CI 70.1-80.3) and the specificity as 75.1% (95% CI 72.1-77.8). No statistically significant difference was found between differing levels of experience. However, there was a significant difference in confidence levels between groups. Potentially sight threatening decisions accounted for 6.4% of the optometrists' decisions, 3.5% were made with a high confidence rating suggesting no discussion with an ophthalmologist was required. CONCLUSIONS: Although the optometrists showed modest agreement with the reference standard in a series of cases that have higher than average complexity, the optometrists showed a similar amount of variability within their treatment decisions compared to the reference standard. The optometrists were therefore not inferior in their performance compared to the ophthalmologists and this can be seen as supporting evidence for their extended role within this clinical area. Experience did not have an effect on 'correct' treatment decisions although there was a statistically significant effect on increasing confidence of treatment decision.

Macular Atrophy of the Retinal Pigment Epithelium in Patients with Neovascular Age-Related Macular Degeneration: What is the Link? Part I: A Review of Disease Characterization and Morphological Associations.

INTRODUCTION: The purpose of this review was to explore the potential link between macular atrophy (MA) of the retinal pigment epithelium in patients with neovascular age-related macular degeneration (nAMD) with the disease characteristics and morphological features. METHODS: To this end, we performed a search of peer-reviewed articles published on the PubMed database and included all relevant papers. We then examined these papers for possible risk factors for MA development in the context of nAMD treated with anti-vascular endothelial growth factor drugs, as well as possible protective factors. RESULTS: Our review of the relevant publications revealed that areas of MA can be directly visualized through multiple imaging modalities. Associations have been identified between MA of the retinal pigment epithelium and choroidal neovascular membrane characteristics, intra- and subretinal fluid, pigment epithelial detachment, choroidal thickness, subretinal hyperreflective material, outer retinal tubulations, hemorrhage, subretinal drusenoid deposits, refractile drusen, hyperreflective foci, retinal angiomatous proliferation, polypoidal choroidal vasculopathy, geographic atrophy in the fellow eye, genetic factors, and age. CONCLUSION: The findings of this review indicate that a multimodal approach is recommended for the assessment of MA. The conclusions drawn to date on the correlation between MA development or progression of MA and specific risk factors and possible protective factors are mixed. More clinical research is needed to reach a better understanding of this association.

Diabetic macular oedema and diode subthreshold micropulse laser (DIAMONDS): study protocol for a randomised controlled trial.

BACKGROUND: In the UK, macular laser is the treatment of choice for people with diabetic macular oedema with central retinal subfield thickness (CST) < 400 µm, as per National Institute for Health and Care Excellence guidelines. It remains unclear whether subthreshold micropulse laser is superior and should replace standard threshold laser for the treatment of eligible patients. METHODS: DIAMONDS is a pragmatic, multicentre, allocation-concealed, randomised, equivalence, double-masked clinical trial that aims to determine the clinical effectiveness and cost-effectiveness of subthreshold micropulse laser compared with standard threshold laser, for the treatment of diabetic macular oedema with CST < 400 µm. The primary outcome is the mean change in best-corrected visual acuity in the study eye from baseline to month 24 post treatment. Secondary outcomes (at 24 months) include change in binocular best corrected visual acuity; CST; mean deviation of the Humphrey 10-2 visual field; change in percentage of people meeting driving standards; European Quality of Life-5 Dimensions, National Eye Institute Visual Functioning Questionnaire-25 and VisQoL scores; incremental cost per quality-adjusted life year gained; side effects; number of laser treatments and use of additional therapies. The primary statistical analysis will be per protocol rather than intention-to-treat analysis because the latter increases type I error in non-inferiority or equivalence trials. The difference between lasers for change in best-corrected visual acuity (using 95% CI) will be compared to the permitted maximum difference of five Early Treatment Diabetic Retinopathy Study (ETDRS) letters. Linear and logistic regression models will be used to compare outcomes between treatment groups. A Markov-model-based cost-utility analysis will extend beyond the trial period to estimate longer-term cost-effectiveness. DISCUSSION: This trial will determine the clinical effectiveness and cost-effectiveness of subthreshold micropulse laser, when compared with standard threshold laser, for the treatment of diabetic macular oedema, the main cause of sight loss in people with diabetes mellitus. TRIAL REGISTRATION: International Standard Randomised Controlled Trials, ISRCTN17742985 . Registered on 19 May 2017 (retrospectively registered).

Swept-source optical coherence tomography angiography features of sub-retinal fibrosis in neovascular age-related macular degeneration.

IMPORTANCE: The study highlights the role of optical coherence angiography in the management of patients with neovascular age-related macular degeneration (nAMD) who have developed sub-retinal fibrosis. BACKGROUND: Development of sub-retinal fibrosis in the context of nAMD is known to adversely affect visual function. The aim of this study is to assess structure and flow features obtained through swept-source optical coherence tomography angiography (OCTA) in patients with sub-retinal fibrosis and associate these with visual acuity (VA). DESIGN: Institutional retrospective cohort study. PARTICIPANTS: A total 39 eyes of 39 patients with nAMD with sub-retinal fibrosis imaged with OCTA were included in this study. METHODS: Patients underwent swept-source OCTA. Thickness of sub-retinal hyper-reflective material (SHRM) and presence and configuration of a choroidal neovascular membrane were recorded in each case. MAIN OUTCOME MEASURES: A univariate multiple regression was performed seeking associations between VA and structural and flow OCTA features. RESULTS: Average VA on the date of OCTA was 53 ± 22 ETDRS letters. Average thickness of centre-involving SHRM was 157 ± 73 µm. A choroidal neovascular membrane was detectable in 26 cases and not detectable in 13. VA was independently influenced by thickness of SHRM (P = 0.034) and presence of a detectable choroidal neovascular membrane (P = 0.02) on OCTA. CONCLUSIONS AND RELEVANCE: Poorer VA in patients with nAMD and sub-retinal fibrosis is associated with presence of a detectable neovascular membrane on OCTA. The role of OCTA to guide nuanced management decisions in this patient population may be significant.

Slowed Dark Adaptation in Early AMD: Dual Stimulus Reveals Scotopic and Photopic Abnormalities.

Purpose: The recovery of visual sensitivity after a photobleach in early AMD is slowed in rods but cones also may be abnormal. The purpose of this article was to test different stimulus locations to investigate cone function and its relation to rod abnormalities. Methods: Stimuli were presented at two locations, 3.0° and 5.5°, in the inferior visual field. Post photobleach dark adaptation (DA) curves from 50 early-AMD patients were compared with those from 15 healthy controls of similar age. Curves were characterized in terms of four parameters: ct, cone threshold; α, the transition point from cone to rod function; S2, the slope of the second rod-mediated component; and ß, the transition from the second to the third rod-mediated component. Results: There were strong location effects for the healthy group and the AMD group. Cone threshold was higher for the outer compared with the inner stimulus (P = 0.001), S2 was steeper for outer compared with inner (P < 0.001), α was shorter for outer (P = 0.004), and ß was shorter for outer than inner (P = 0.002). The high variance in the patient data, particularly for α and ß, explained the absence of a group*location interaction in the statistics. Conclusions: The data provide a novel perspective on abnormal cone- and rod-sensitivity recovery in early dry AMD. The comparison of pairs of DA curves from different locations highlights the involvement of cones in the underlying pathology of AMD. Dynamic measures of visual function are particularly sensitive to early AMD.

Use of a Neural Net to Model the Impact of Optical Coherence Tomography Abnormalities on Vision in Age-related Macular Degeneration.

PURPOSE: To develop a neural network for the estimation of visual acuity from optical coherence tomography (OCT) images of patients with neovascular age-related macular degeneration (AMD) and to demonstrate its use to model the impact of specific controlled OCT changes on vision. DESIGN: Artificial intelligence (neural network) study. METHODS: We assessed 1400 OCT scans of patients with neovascular AMD. Fifteen physical features for each eligible OCT, as well as patient age, were used as input data and corresponding recorded visual acuity as the target data to train, validate, and test a supervised neural network. We then applied this network to model the impact on acuity of defined OCT changes in subretinal fluid, subretinal hyperreflective material, and loss of external limiting membrane (ELM) integrity. RESULTS: A total of 1210 eligible OCT scans were analyzed, resulting in 1210 data points, which were each 16-dimensional. A 10-layer feed-forward neural network with 1 hidden layer of 10 neurons was trained to predict acuity and demonstrated a root mean square error of 8.2 letters for predicted compared to actual visual acuity and a mean regression coefficient of 0.85. A virtual model using this network demonstrated the relationship of visual acuity to specific, programmed changes in OCT characteristics. When ELM is intact, there is a shallow decline in acuity with increasing subretinal fluid but a much steeper decline with equivalent increasing subretinal hyperreflective material. When ELM is not intact, all visual acuities are reduced. Increasing subretinal hyperreflective material or subretinal fluid in this circumstance reduces vision further still, but with a smaller gradient than when ELM is intact. CONCLUSIONS: The supervised machine learning neural network developed is able to generate an estimated visual acuity value from OCT images in a population of patients with AMD. These findings should be of clinical and research interest in macular degeneration, for example in estimating visual prognosis or highlighting the importance of developing treatments targeting more visually destructive pathologies.

Automated Measurement of Visual Acuity in Pediatric Ophthalmic Patients Using Principles of Game Design and Tablet Computers.

PURPOSE: To report on the utility of a computer tablet-based method for automated testing of visual acuity in children based on the principles of game design. We describe the testing procedure and present repeatability as well as agreement of the score with accepted visual acuity measures. DESIGN: Reliability and validity study. METHODS: Setting: Manchester Royal Eye Hospital Pediatric Ophthalmology Outpatients Department. PATIENT POPULATION: Total of 112 sequentially recruited patients. INTERVENTION: For each patient 1 eye was tested with the Mobile Assessment of Vision by intERactIve Computer for Children (MAVERIC-C) system, consisting of a software application running on a computer tablet, housed in a bespoke viewing chamber. The application elicited touch screen responses using a game design to encourage compliance and automatically acquire visual acuity scores of participating patients. Acuity was then assessed by an examiner with a standard chart-based near ETDRS acuity test before the MAVERIC-C assessment was repeated. MAIN OUTCOME MEASURE: Reliability of MAVERIC-C near visual acuity score and agreement of MAVERIC-C score with near ETDRS chart for visual acuity. RESULTS: Altogether, 106 children (95%) completed the MAVERIC-C system without assistance. The vision scores demonstrated satisfactory reliability, with test-retest VA scores having a mean difference of 0.001 (SD ±0.136) and limits of agreement of 2 SD (LOA) of ±0.267. Comparison with the near EDTRS chart showed agreement with a mean difference of -0.0879 (±0.106) with LOA of ±0.208. CONCLUSIONS: This study demonstrates promising utility for software using a game design to enable automated testing of acuity in children with ophthalmic disease in an objective and accurate manner.