Prediction of treatment response in patients with neovascular age-related macular degeneration

Neovascular age-related macular degeneration (nAMD) is a common cause of visual impairment, and is currently treated with intravitreal anti-vascular endothelial growth factor agents such as aflibercept. While these treatments may improve visual acuity (VA) in some patients, clinicians cannot currently predict who is likely to benefit before treatment starts. The aim of this study is to explore the effectiveness of using Deep Learning approaches to train models for predicting whether a patient’s VA will respond favourably to three months of aflibercept therapy, using pre-treatment OCT images and clinical/demographic variables. We train a number of models using standard machine learning, Deep Learning transfer learning, and fully trained Deep Learning approaches in two experiments using outcomes based on the VA at 4- 10 weeks after the final dose. In experiment one, we trained models to predict whether the VA will be at least 54 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, while in experiment two we trained them to predict whether the VA will have increased by 10 or more letters. Model prediction quality was assessed using the Area Under the Curve (AUC) of the Receiver-Operating-Characteristic (ROC) curves. We found that all models performed significantly better than chance in both experiments, except for the fully trained Deep Learning model using just images in experiment two. The best performing model for experiment one was the Deep Learning transfer model using images and clinical/demographic variables (AUC=0.901), while in experiment two, none of the Deep Learning approaches performed better than a random forest using only clinical/demographic variables (AUC=0.751). Our experiments suggest that different Deep Learning approaches are required for predicting the second outcome if we want the models to perform better than those that use clinical/demographic variables alone

Pegaptanib sodium for neovascular age-related macular degeneration: clinical experience in the UK

The pathogenesis of age-related macular degeneration (AMD) is unclear, but it can take either a neovascular/exudative/wet form, characterized by choroidal neovascularization (CNV), or a dry form. No treatments are available for the dry form, but there are a number of pharmacological interventions that inhibit vascular endothelial growth factor (VEGF), which is central to the pathogenesis of CNV and neovascular AMD. Available anti-VEGF agents either target all active VEGF isoforms (eg, ranibizumab), or take a more selective approach and inhibit only VEGF165 (eg, pegaptantib sodium). Current guidance on their use is equivocal and restrictive at best, resulting in associated difficulties in securing adequate, timely funding for treatment. The Moorfields Eye Hospital undertook an audit of 70 patients receiving intravitreal (ITV) pegaptanib sodium on a pro re nata (prn) dosing schedule. Despite initial funding delays, the audit recorded superior treatment outcomes compared with those reported in the VISION trials at 12 weeks: 88% of audit patients maintained stable vision, 29% gained vision and 6% experienced severe vision loss compared with 70%, ≥6% and ≤10% of patients in VISION at 54 weeks, respectively. The audit indicates a positive correlation between patients with better baseline visual acuity (VA) and improved therapeutic benefits, including a greater likelihood of both vision gain and vision preservation. Experience at Moorfields also suggests that pegaptanib sodium is more useful in occult lesions than minimally classic lesions, and clinical experience suggests that combination therapies may offer the best approach with anti-VEGF therapies. Further randomized clinical trials will help better determine the optimal treatment strategies with pegaptanib sodium in neovascular AMD

Autofluorescence and high-definition optical coherence tomography of retinal artery occlusions

BACKGROUND: The purpose of this study is to illustrate the fundus autofluorescence and high-definition optical coherence tomography (HD-OCT) features of acute and long-standing retinal artery occlusions. DESIGN: Retrospective case series. PARTICIPANTS: Patients with acute and chronic retinal and cilioretinal artery occlusions are included in this series. METHODS: A detailed clinical examination, color fundus photographs, autofluorescence, and HD-OCT of the subjects were performed. RESULTS: HD-OCT demonstrates the localized and well-demarcated thickening of the inner retina in the acute phase of arterial occlusions that correlates with the areas of blocked autofluorescence caused by the cloudy swelling of the retina. The areas of blocked autofluorescence disappear with chronicity of the disease and this corresponds to the thinning of the inner retinal layers on HD-OCT. CONCLUSION: Heidelberg OCT and autofluorescence are useful tools to assess retinal arterial occlusions especially in subjects with unexplained visual field loss

Watching the human retina breath in real time and the slowing of mitochondrial respiration with age

The retina has the greatest metabolic demand in the body particularly in dark adaptation when its sensitivity is enhanced. This requires elevated level of perfusion to sustain mitochondrial activity. However, mitochondrial performance declines with age leading to reduced adaptive ability. We assessed human retina metabolism in vivo using broad band near-infrared spectroscopy (bNIRS), which records colour changes in mitochondria and blood as retinal metabolism shifts in response to changes in environmental luminance. We demonstrate a significant sustained rise in mitochondrial oxidative metabolism in the first 3 min of darkness in subjects under 50 years old. This was not seen in those over 50 years. Choroidal oxygenation declines in  50 s. Significant group differences in blood oxygenation are apparent in the first 6 min, consistent with mitochondrial demand leading hemodynamic changes. A greater coupling between mitochondrial oxidative metabolism with hemodynamics is revealed in subjects older than 50, possibly due to reduced capacity in the older retina. Rapid in vivo assessment of retinal metabolism with bNIRS provides a route to understanding fundamental physiology and early identification of retinal disease before pathology is established

Family practices' achievement of diabetes quality of care targets and risk of screen-detected diabetic retinopathy

Background: We aimed to determine whether family practices' achievement of diabetes quality of care targets is associated with diabetic retinal disease in registered patients. Methods: Data for achievement of diabetes quality of care targets, including the proportion of patients with HbA1c≤7.5%, for 144 family practices in London UK, for the years 2004/5 to 2007/8, were linked to data from a population-based diabetes eye screening programme collected from September 2007 to February 2009. Analyses were adjusted for age, sex, duration and type of diabetes, unadjusted diabetes prevalence, ethnicity and deprivation category. Results: Data were analysed for 24,458 participants with one or more eye screening results in the period. There were 9,332 (38%) with any diabetic retinopathy and 2,819 (11.5%) with sight threatening diabetic retinopathy (STDR), including 2,654 (10.9%) with maculopathy. Among participants registered at 13 family practices that were in the highest quartile for achievement of the HbA1c quality of care target for all four years of study, the relative odds of any diabetic retinopathy were 0.78 (0.69 to 0.88) P<0.001. For participants at 12 practices consistently in the lowest quartile of HbA1c achievement, the relative odds of any diabetic retinopathy were 1.16 (1.03 to 1.30), P = 0.015. In the highest achieving practices, the relative odds of maculopathy were 0.74 (0.62 to 0.89), P = 0.001 and STDR 0.77 (0.65 to 0.92), P = 0.004. Conclusions: The risk of diabetic retinopathy might be lower at family practices that consistently achieve highly on diabetes quality of care targets for HbA1c

The Role of Neuroglobin in Retinal Hemodynamics and Metabolism: A Real-Time Study

Purpose: In this study, we used broadband near-infrared spectroscopy, a non-invasive optical technique, to investigate in real time the possible role of neuroglobin in retinal hemodynamics and metabolism. / Methods: Retinae of 12 C57 mice (seven young and five old) and seven young neuroglobin knockouts (Ngb-KOs) were exposed to light from a low-power halogen source, and the back-reflected light was used to calculate changes in the concentration of oxygenated hemoglobin (HbO2), deoxygenated hemoglobin (HHb), and oxidized cytochrome c oxidase (oxCCO). / Results: The degree of change in the near-infrared spectroscopy signals associated with HHb, HbO2, and oxCCO was significantly greater in young C57 mice compared to the old C57 mice (P < 0.05) and the Ngb-KO model (P < 0.005). / Conclusions: Our results reveal a possible role of Ngb in regulating retinal function, as its absence in the retinae of a knockout mouse model led to suppressed signals that are associated with hemodynamics and oxidative metabolism. / Translational Relevance: Near-infrared spectroscopy enabled the non-invasive detection of characteristic signals that differentiate between the retina of a neuroglobin knockout mouse model and that of a wild-type model. Further work is needed to evaluate the source of the signal differences and how these differences relate to the presence or absence of neuroglobin in the ganglion, bipolar, or amacrine cells of the retina

Dosing Regimens of Intravitreal Aflibercept for Diabetic Macular Edema Beyond the First Year: VIOLET, a Prospective Randomized Trial.

INTRODUCTION The purpose was to compare two flexible regimens of intravitreal aflibercept (IVT-AFL) with fixed dosing every 8 weeks, beyond the first year of treatment, in patients with diabetic macular edema (DME). VIOLET was a 100-week, randomized, Phase IIIb, non-inferiority study in patients with center-involving DME previously treated with IVT-AFL for ≥ 1 year according to the European label. METHODS Patients received an initial dose of IVT-AFL at study baseline and were randomly assigned (1:1:1) to treat-and-extend (T&E), pro re nata (PRN), or fixed regimens. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline (randomization) to Week 52. RESULTS Full analysis set comprised 458 patients (baseline mean BCVA: 72.5, 71.0, and 72.7 letters in the T&E, PRN, and fixed-dose groups, respectively). Patients received a mean (min-max) of 10.0 (2-14; T&E), 11.5 (1-25; PRN), and 12.3 (3-13; fixed) injections over 100 weeks, with 13.3 (4-23), 25.0 (3-29), and 16.1 (5-25) clinic visits, respectively. At Week 52, mean (± standard deviation) BCVA changes from baseline were + 0.5 ± 6.7 (T&E), + 1.7 ± 6.8 (PRN), and + 0.4 ± 6.7 (fixed-dosing) letters (least squares mean difference [95% confidence interval]: T&E 0.01 [- 1.46, 1.47] and PRN 0.95 (- 0.52, 2.42) letters versus fixed dosing; p < 0.0001 for both non-inferiority tests [4-letter margin]). The IVT-AFL safety profile was consistent with previous studies. CONCLUSION The treatment burden associated with intravitreal injections for DME is lowest with T&E regimens, but there are a range of flexible IVT-AFL dosing regimens, allowing physicians to adopt an individualized treatment plan. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02818998