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To determine longitudinal changes in choriocapillaris (CC) measures in eyes with reticular pseudodrusen (RPD) using optical coherence tomography angiography (OCTA). In this observational prospective study, 20 patients with exclusively RPD and no other alteration due to age-related macular degeneration were included. Eight RPD patients were re-examined at 5-year follow-up. Multimodal imaging was performed at baseline and at 5-year follow-up. OCTA CC images were analyzed for number, size and total area of flow deficits (FD), mean signal intensity, signal intensity standard deviation and kurtosis of signal intensity distribution in the ring area between a circle of 4 mm diameter and a circle of 6 mm diameter and in the superior ring quadrant. Area affected by RPD increased from 19.36 ± 8.39 mm2 at baseline to 37.77 ± 9.03 mm2 at 5-year follow-up. At baseline, percent of CC FD area was greater in RPD eyes (quadrant: p < 0.001; ring: p < 0.001) compared to controls. Besides, RPD eyes revealed a lower mean intensity signal (quadrant: p < 0.001; ring: p < 0.001). Evaluation of CC parameters suggested significant group × time interaction effects for CC FD (p = 0.04) and mean intensity signal (p = 0.004), in that RPD eyes presented increased CC FD and decreased mean intensity signal at follow-up. OCTA CC decorrelation signal further decreases in RPD patients over 5 years in both RPD-affected and RPD-unaffected macular areas. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is genetically associated with complement. Dendritic cells (DCs) play key roles during innate and adaptive immunity, and express complement components and their receptors. We investigated ocular DC heterogeneity and the role of DCs in the laser-induced choroidal neovascularization (CNV) model. In order to determine the function of DCs, we used two models of DC deficiency: the Flt3−/− and Flt3l−/− mouse. We identified three types of ocular DCs: plasmacytoid DC, classical DC-1, and classical DC-2. At steady-state, classical DCs were found in the iris and choroid but were not detectable in the retina. Plasmacytoid DCs existed at very low levels in iris, choroid, and retina. After laser injury, the number of each DC subset was up-regulated in the choroid and retina. In Flt3−/− mice, we found reduced numbers of classical DCs at steady-state, but each DC subset equally increased after laser injury between wildtype and Flt3−/− mice. In Flt3l−/− mice, each DC subsets was severely reduced after laser injury. Neither Flt3−/− or Flt3l−/− mice demonstrated reduced CNV area compared to wildtype mice. DCs do not play any significant role during the laser-induced CNV model of neovascular AMD. [ABSTRACT FROM AUTHOR]

Non-vascularized pigment epithelial detachments (PED) are usually associated with dry age-related macular degeneration (AMD). In this study, we aimed to investigate the correlation between visual function and morphologic parameters. Seventeen eyes of eleven patients with non-vascularized AMD were enrolled. In addition to conventional optical coherence tomography (OCT), polarization-sensitive optical coherence tomography (PS-OCT) measurements were performed by evaluating the regularity of retinal pigment epithelium (RPE) entropy within the PED area. Retinal sensitivity was measured with MP-3 microperimetry, and retinal sensitivities within (RSin) and outside (RSout) the PED area were calculated. The relationship between OCT parameters and visual function was analyzed. As a result, there was a significant difference between the RSin and RSout (p < 0.001, Wilcoxon signed rank test). Moreover, RSin was significantly related to logMAR VA (p = 0.033, linear mixed model). The regularity of RPE entropy was significantly related to visual acuity and RSin (p = 0.00038, p = 0.031, linear mixed model), although neither the height nor area of PED correlated with visual function. Our results suggest that retinal sensitivity is significantly deteriorated within the PED area and RPE entropy measured with PS-OCT was closely related to visual function in eyes with non-vascularized PED. [ABSTRACT FROM AUTHOR]

Evidence indicates that age-related macular degeneration (AMD) is associated with the prior presence of allergic diseases; however, large-scale studies in the literature are limited. A case–control study was conducted to describe the relationship between premorbid allergic diseases and AMD using Taiwan's National Health Insurance database. Eligibility criteria for inclusion of new adult AMD cases from 2000 to 2013 were set up. We defined the year of diagnosis as the index year. Age-, gender-, index year- matched controls who were drawn from the same database. The case control ratio was 1:4. For all participants, all premorbid conditions staring 1996 to index year were documented. Binary logistic regression was used to describe factors related to AMD occurrence. The AMD group consisted of 10,911 patients, and the comparison group consisted of 43,644 individuals. Patients with AMD showed significant associations with premorbid allergic diseases (aOR 1.54, 95% CI 1.47–1.61), specifically with allergic conjunctivitis (aOR 2.07, 95% CI 1.94–2.20), allergic rhinitis (aOR 1.32, 95% CI 1.25–1.39), asthma (aOR 0.99, 95% CI 0.93–1.06), and atopic dermatitis (aOR 1.04, 95% CI 0.94–1.17). Further analyses indicated that patients with more concurrent allergic diseases have higher associations with AMD than those with fewer concurrent diseases. Patients with more annual medical visits for their allergic diseases also showed higher associations with AMD than those with fewer visits. AMD is significantly associated with premorbid allergic diseases. The underlying mechanisms must be further investigated. [ABSTRACT FROM AUTHOR]

Melanosomes, lipofuscin, and melanolipofuscin are the three principal types of pigmented granules found in retinal pigment epithelium (RPE) cells. Changes in the density of melanosomes and lipofuscin in RPE cells are considered hallmarks of various retinal diseases, including Stargardt disease and age-related macular degeneration (AMD). Herein, we report the potential of an in vivo multimodal imaging technique based on directional back-scattering and short-wavelength fundus autofluorescence (SW-FAF) to study disease-related changes in the density of melanosomes and lipofuscin granules in RPE cells. Changes in the concentration of these granules in Abca4−/− mice (a model of Stargardt disease) relative to age-matched wild-type (WT) controls were investigated. Directional optical coherence tomography (dOCT) was used to assess melanosome density in vivo, whereas the autofluorescence (AF) images and emission spectra acquired with a spectrometer-integrated scanning laser ophthalmoscope (SLO) were used to characterize lipofuscin and melanolipofuscin granules in the same RPE region. Subcellular-resolution ex vivo imaging using confocal fluorescence microscopy and electron microscopy was performed on the same tissue region to visualize and quantify melanosomes, lipofuscin, and melanolipofuscin granules. Comparisons between in vivo and ex vivo results confirmed an increased concentration of lipofuscin granules and decreased concentration of melanosomes in the RPE of Abca4−/− mice, and provided an explanation for the differences in fluorescence and directionality of RPE scattering observed in vivo between the two mouse strains. [ABSTRACT FROM AUTHOR]

Age‐related macular degeneration (AMD) is a blinding eye disease with no unifying theme for its etiology. We used single-cell RNA sequencing to analyze the transcriptomes of ~ 93,000 cells from the macula and peripheral retina from two adult human donors and bulk RNA sequencing from fifteen adult human donors with and without AMD. Analysis of our single-cell data identified 267 cell-type-specific genes. Comparison of macula and peripheral retinal regions found no cell-type differences but did identify 50 differentially expressed genes (DEGs) with about 1/3 expressed in cones. Integration of our single-cell data with bulk RNA sequencing data from normal and AMD donors showed compositional changes more pronounced in macula in rods, microglia, endothelium, Müller glia, and astrocytes in the transition from normal to advanced AMD. KEGG pathway analysis of our normal vs. advanced AMD eyes identified enrichment in complement and coagulation pathways, antigen presentation, tissue remodeling, and signaling pathways including PI3K-Akt, NOD-like, Toll-like, and Rap1. These results showcase the use of single-cell RNA sequencing to infer cell-type compositional and cell-type-specific gene expression changes in intact bulk tissue and provide a foundation for investigating molecular mechanisms of retinal disease that lead to new therapeutic targets. [ABSTRACT FROM AUTHOR]

Disturbances in choroidal microcirculation may lead to the onset and progression of age-related macular degeneration (AMD). We aimed to assess changes in the choroidal volume and thickness in the macular region in AMD eyes and to investigate whether coexisting vascular risk factors alter choroidal status. We enrolled 354 AMD patients (175 dry, 179 wet AMD) and 121 healthy controls. All participants underwent a complete ophthalmologic examination and assessment of choroidal thickness and volume. A multivariate analysis adjusted for age, sex, and smoking status revealed that wet AMD was an independent factor associated with higher average thickness of the central ring area (ATC) and average volume of the central ring area (AVC) and lower choroidal vascularity index (CVI) compared to controls (β = + 0.18, p = 0.0007, β = + 0.18, p = 0.0008, respectively) and to dry AMD (β = + 0.17, p = 0.00003 for both ATC and AVC and β = − 0.30 p < 0.0001 for CVI). ATC, AVC and average volume (AV) were lower in AMD patients with hypertension and ischaemic heart disease (IHD). The duration of hypertension was inversely correlated with ATC, AVC and AV (Rs = − 0.13, p < 0.05; Rs = − 0.12; p < 0.05, Rs = − 0.12; p < 0.05, respectively) while IHD duration negatively correlated with AV (Rs = − 0.15, p < 0.05). No such associations were observed in the control group. Our findings show that the choroidal vascular system in eyes with AMD is much more susceptible to damage in the presence than in the absence of systemic vascular disease. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) and age-related macular degeneration (AMD) are both common diseases of the elderly people. COPD induced systemic inflammation and hypoxia may have an impact on the development of AMD. This study investigated the possible association between COPD and subsequent risk of AMD. A retrospective cohort study was conducted based on the data from the National Health Insurance Research Database in Taiwan. The COPD cohort comprised 24,625 adult patients newly diagnosed during 2000–2012, whereas age-, gender-, and the year of diagnosis-matched non-COPD cohort comprised 49,250 individuals. Incident AMD was monitored to the end of 2013. A Cox proportional hazards model was applied to evaluate the risk of AMD. The COPD cohort showed 1.25 times higher AMD incidence than the non-COPD cohort (4.80 versus 3.83 per 1000 person-years, adjusted hazard ratio (HR) = 1.20 [95% confident interval (CI) = 1.10–1.32]). Stratified analyses for age, gender, and presence of comorbidity resulted in significant adjusted HRs in most subgroups. Further analysis revealed that the COPD group had an increased risk of both the exudative and non-exudative types of AMD (adjusted HRs = 1.49 [95% CI = 1.13–1.96] and 1.15 [95% CI = 1.05–1.26], respectively). COPD patients have an increased risk for AMD development. Clinicians should provide adequate care for the ocular health to these patients. [ABSTRACT FROM AUTHOR]

Outer retinal tubulations (ORT) are a relatively new finding characterizing outer retinal atrophy. The main aim of the present study was to describe ORT development in advanced age-related macular degeneration (AMD) and to assess its relationship with disease's severity. Patients with advanced AMD characterized either by macular neovascularization or geographic atrophy, showing signs of outer retinal disruption or retinal pigment epithelium atrophy on structural optical coherence tomography (OCT) at the inclusion examination were prospectively recruited. All the patients underwent complete ophthalmologic evaluation, structural OCT scans and fundus autofluorescence imaging. The planned follow-up was of 3-years. Main outcome measures were ORT prevalence, mechanism of ORT formation, mean time needed for complete ORT formation, best-corrected visual acuity (BCVA), definitely decreased autofluorescence (DDAF) area, questionably decreased autofluorescence (QDAF) area, retinal layer thickness, foveal sparing, number of intravitreal injections. We also assessed the possible role of external limiting membrane (ELM) and Müller cells in ORT pathogenesis. Seventy eyes (70 patients) were included; 43 showed dry AMD evolving to geographic atrophy, while 27 displayed the features of wet AMD. Baseline BCVA was 0.5 ± 0.5 LogMAR, decreasing to 0.9 ± 0.5 LogMAR at the 3-year follow-up (p < 0.01). We detected completely formed ORT in 26/70 eyes (37%), subdivided as follows: 20 eyes (77%) wet AMD and 6 eyes (23%) dry AMD (p < 0.01). ORT took 18 ± 8 months (range 3–35 months) to develop fully. We described the steps leading to ORT development, characterized by progressive involvement of, and damage to the photoreceptors, the ELM and the RPE. Eyes displaying ORT were associated with a smaller QDAF area, less retinal layers damage and lower rate of foveal sparing than eyes free of ORT (p < 0.01). We also described pigment accumulations simulating ORT, which were detected in 16/70 eyes (23%), associated with a greater loss of foveal sparing, increased DDAF area and smaller QDAF area at the 3-year follow-up (p < 0.01). In conclusion, this study provided a description of the steps leading to ORT development in AMD. ELM and Müller cells showed a role in ORT pathogenesis. Furthermore, we described a subtype of pigment hypertrophy mimicking ORT, evaluating its clinical utility. [ABSTRACT FROM AUTHOR]

The purpose of this study was to report the incidence of elevated intraocular pressure (IOP) after intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF) in Japanese patients with age-related macular degeneration (AMD). A retrospective study of chart review of patients who underwent ≥ 10 intravitreal anti-VEGF injections between April 2009 and December 2019 was conducted. Elevated IOP was defined as IOP ≥ 25 mmHg at one visit. Cases with elevated IOP resulting from IVI were identified. Furthermore, the association between elevated IOP and some parameters, as the risk factors that influence elevated IOP, was investigated. A total of 402 eyes of 370 patients were included in this study. Twenty-eight eyes of 26 patients (7.0%) were identified as cases with elevated IOP after IVI. The mean time of elevation after baseline was 50.6 ± 26.5 months. History of glaucoma (p = 0.021; odds ratio, 5.85), treatment modality (p = 0.019; odds ratio, 6.32), and total number of injections (p = 0.003; odds ratio, 1.03) were significantly associated with elevated IOP. A late complication of elevated IOP is associated with IVI in patients with AMD. Particularly, history of glaucoma and treat and extend regimen with frequent injections were found to be risk factors of elevated IOP. [ABSTRACT FROM AUTHOR]

To compare the long-term effectiveness of intravitreal anti-vascular endothelial growth factor (VEGF) treatment for pachychoroid neovasculopathy (PNV), polypoidal choroidal vasculopathy/aneurysmal type 1 neovascularization (PCV/AT1), and typical neovascular age-related macular degeneration (nAMD). Forty-one eyes with PNV, 68 eyes with PCV/AT1, and 56 eyes with typical nAMD were retrospectively included for analysis. All patients were treatment-naïve and received a three-monthly loading injection of anti-VEGF, followed by further injections, as required. The visual and anatomical outcomes after treatment were evaluated up to 36 months from baseline. No significant intergroup difference was found in terms of best-corrected visual acuity (BCVA) and changes in central foveal thickness at 12, 24, and 36 months after the baseline. In addition, no significant difference was found between the groups regarding the proportions of improved or worsened (increased or decreased more than 3-lines) visual acuity. However, the PNV group participants received significantly fewer anti-VEGF injections (11.7 ± 6.9) than those in the PCV/AT1 (12.4 ± 7.0; P = 0.031) and typical nAMD groups (13.2 ± 7.4; P = 0.016). The incidence of macular atrophy (MA) development was also significantly lower for the PNV (4/41 eyes, 9.8%) than the typical nAMD (15/56 eyes, 26.8%; P = 0.033) eyes. There was no significant difference between PNV, PCV/AT1, and typical nAMD regarding visual acuity improvement after anti-VEGF treatment over 36 months. However, the number of injections for PNV was significantly lower compared to that for PCV/AT1 and typical nAMD, and the incidence of MA development was significantly lower than in typical nAMD. [ABSTRACT FROM AUTHOR]

Epithelial–mesenchymal transition (EMT) in retinal pigment epithelial (RPE) cells plays a key role in proliferative retinal diseases such as age-related macular degeneration by contributing to subretinal fibrosis. To investigate the potential role of retinoic acid receptor-α (RAR-α) signaling in this process, we have now examined the effects of the RAR-α agonist Am580 on EMT induced by transforming growth factor-β2 (TGF-β2) in primary mouse RPE cells cultured in a three-dimensional type I collagen gel as well as on subretinal fibrosis in a mouse model. We found that Am580 inhibited TGF-β2-induced collagen gel contraction mediated by RPE cells. It also attenuated the TGF-β2-induced expression of the mesenchymal markers α-smooth muscle actin, fibronectin, and collagen type I; production of pro-matrix metalloproteinase 2 and interleukin-6; expression of the focal adhesion protein paxillin; and phosphorylation of SMAD2 in the cultured RPE cells. Finally, immunofluorescence analysis showed that Am580 suppressed both the TGF-β2-induced translocation of myocardin-related transcription factor-A (MRTF-A) from the cytoplasm to the nucleus of cultured RPE cells as well as subretinal fibrosis triggered by laser-induced photocoagulation in a mouse model. Our observations thus suggest that RAR-α signaling inhibits EMT in RPE cells and might attenuate the development of fibrosis associated with proliferative retinal diseases. [ABSTRACT FROM AUTHOR]

To evaluate the effect of aging, intra- and intersession repeatability and regional scotopic sensitivities in healthy and age-related macular degeneration (AMD) eyes. Intra- and intersession agreement and effect of age was measured in healthy individuals. The mean sensitivity (MS) and pointwise retinal sensitivities (PWS) within the central 24° with 505 nm (cyan) and 625 nm (red) stimuli were evaluated in 50 individuals (11 healthy and 39 AMD eyes). The overall intra- and intersession had excellent reliability (intraclass correlation coefficient, ICC > 0.90) and tests were highly correlated (Spearman rs = 0.75–0.86). Eyes with subretinal drusenoid deposit (SDD) had reduced PWS centrally, particularly at inferior and nasal retinal locations compared with controls and intermediate AMD (iAMD) without SDD. There was no difference in MS or PWS at any retinal location between iAMD without SDD and healthy individuals nor between iAMD with SDD and non-foveal atrophic AMD groups. Eyes with SDD have reduced rod function compared to iAMD without SDD and healthy eyes, but similar to eyes with non-foveal atrophy. Our results highlight rod dysfunction is not directly correlated with drusen load and SDD location. [ABSTRACT FROM AUTHOR]

This cross-sectional study aimed to build a deep learning model for detecting neovascular age-related macular degeneration (AMD) and to distinguish retinal angiomatous proliferation (RAP) from polypoidal choroidal vasculopathy (PCV) using a convolutional neural network (CNN). Patients from a single tertiary center were enrolled from January 2014 to January 2020. Spectral-domain optical coherence tomography (SD-OCT) images of patients with RAP or PCV and a control group were analyzed with a deep CNN. Sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUROC) were used to evaluate the model's ability to distinguish RAP from PCV. The performances of the new model, the VGG-16, Resnet-50, Inception, and eight ophthalmologists were compared. A total of 3951 SD-OCT images from 314 participants (229 AMD, 85 normal controls) were analyzed. In distinguishing the PCV and RAP cases, the proposed model showed an accuracy, sensitivity, and specificity of 89.1%, 89.4%, and 88.8%, respectively, with an AUROC of 95.3% (95% CI 0.727–0.852). The proposed model showed better diagnostic performance than VGG-16, Resnet-50, and Inception-V3 and comparable performance with the eight ophthalmologists. The novel model performed well when distinguishing between PCV and RAP. Thus, automated deep learning systems may support ophthalmologists in distinguishing RAP from PCV. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a highly prevalent degenerative disease and a leading cause of vision loss worldwide. Evidence for an inflammatory component in the development of AMD exists, yet the exact mechanisms remain unclear. Bisretinoid N-retinylidene-N-retinylethanolamine (A2E) in retinal pigmental epithelial (RPE) cells, and in extracellular deposits constitutes a hallmark of AMD, but its role in the pathology of AMD is elusive. Here, we tested the hypothesis that A2E is responsible for the heightened inflammatory activity in AMD. To this end, we measured ex vivo mRNA expression of the cytokines TNF-α, IL-6, and IL-10 in whole blood samples after stimulation with A2E in a clinical sample of 27 patients with neovascular AMD and 24 patients with geographic atrophy secondary to AMD. Patients' spouses (n = 30) were included as non-affected controls. After stimulation with A2E, no statistical differences were found in the median expression level of TNF-α, IL-6, IL-10 between the control group, and the neovascular AMD and the geographic atrophy group. Our findings do not support evidence for the hypothesis, that A2E per se contributes to heightened inflammatory activity in AMD. [ABSTRACT FROM AUTHOR]

In age-related macular degeneration (AMD) research, dark adaptation has been found to be a promising functional measurement. In more severe cases of AMD, dark adaptation cannot always be recorded within a maximum allowed time for the test (~ 20–30 min). These data are recorded either as censored data-points (data capped at the maximum test time) or as an estimated recovery time based on the trend observed from the data recorded within the maximum recording time. Therefore, dark adaptation data can have unusual attributes that may not be handled by standard statistical techniques. Here we show time-to-event analysis is a more powerful method for analysis of rod-intercept time data in measuring dark adaptation. For example, at 80% power (at α = 0.05) sample sizes were estimated to be 20 and 61 with uncapped (uncensored) and capped (censored) data using a standard t-test; these values improved to 12 and 38 when using the proposed time-to-event analysis. Our method can accommodate both skewed data and censored data points and offers the advantage of significantly reducing sample sizes when planning studies where this functional test is an outcome measure. The latter is important because designing trials and studies more efficiently equates to newer treatments likely being examined more efficiently. [ABSTRACT FROM AUTHOR]

Deep learning (DL) has the potential to transform medical diagnostics. However, the diagnostic accuracy of DL is uncertain. Our aim was to evaluate the diagnostic accuracy of DL algorithms to identify pathology in medical imaging. Searches were conducted in Medline and EMBASE up to January 2020. We identified 11,921 studies, of which 503 were included in the systematic review. Eighty-two studies in ophthalmology, 82 in breast disease and 115 in respiratory disease were included for meta-analysis. Two hundred twenty-four studies in other specialities were included for qualitative review. Peer-reviewed studies that reported on the diagnostic accuracy of DL algorithms to identify pathology using medical imaging were included. Primary outcomes were measures of diagnostic accuracy, study design and reporting standards in the literature. Estimates were pooled using random-effects meta-analysis. In ophthalmology, AUC's ranged between 0.933 and 1 for diagnosing diabetic retinopathy, age-related macular degeneration and glaucoma on retinal fundus photographs and optical coherence tomography. In respiratory imaging, AUC's ranged between 0.864 and 0.937 for diagnosing lung nodules or lung cancer on chest X-ray or CT scan. For breast imaging, AUC's ranged between 0.868 and 0.909 for diagnosing breast cancer on mammogram, ultrasound, MRI and digital breast tomosynthesis. Heterogeneity was high between studies and extensive variation in methodology, terminology and outcome measures was noted. This can lead to an overestimation of the diagnostic accuracy of DL algorithms on medical imaging. There is an immediate need for the development of artificial intelligence-specific EQUATOR guidelines, particularly STARD, in order to provide guidance around key issues in this field. [ABSTRACT FROM AUTHOR]

Polypoidal choroidal vasculopathy (PCV) and neovascular age-related macular degeneration (nAMD) share some similarity in clinical imaging manifestations. However, their disease entity and treatment strategy as well as visual outcomes are very different. To distinguish these two vision-threatening diseases is somewhat challenging but necessary. In this study, we propose a new artificial intelligence model using an ensemble stacking technique, which combines a color fundus photograph-based deep learning (DL) model and optical coherence tomography-based biomarkers, for differentiation of PCV from nAMD. Furthermore, we introduced multiple correspondence analysis, a method of transforming categorical data into principal components, to handle the dichotomous data for combining with another image DL system. This model achieved a robust performance with an accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve of 83.67%, 80.76%, 84.72%, and 88.57%, respectively, by training nearly 700 active cases with suitable imaging quality and transfer learning architecture. This work could offer an alternative method of developing a multimodal DL model, improve its efficiency for distinguishing different diseases, and facilitate the broad application of medical engineering in a DL model design. [ABSTRACT FROM AUTHOR]

A remarkable proportion of neovascular age-related macular degeneration (nAMD) patients respond rather poorly to ranibizumab treatment, in spite of the minimum 4-week follow-up and treatment interval. Usually, retreatments are based on nAMD activity as evaluated by Spectral-domain Optical coherence Tomography (SD-OCT), biomicroscopic fundus examination and visual acuity changes. In this prospective pilot study, we aimed to study SD-OCT changes in a high-frequent follow-up manner (weekly (month 0–6), biweekly (month 7–12)) throughout the first year, which consequently led to intravitreal ranibizumab being administered up to biweekly. Best corrected visual acuity (BCVA) was already significantly improved at week 2. Central retinal thickness (CRT), intraretinal and subretinal fluid (SRF) were significantly improved from week 1 onwards. Half of the patients showed nAMD activity at week 2 or 3 and received the first retreatment earlier than 4 weeks after baseline injection. In total, 46% of retreatments were already applied 2 or 3 weeks after the previous treatment. Greater range of CRT and SRF fluctuation during follow-up was associated with lower final BCVA. Lower baseline BCVA and better SRF improvement at week 2 was associated with greater BCVA improvement. In conclusion, high-frequency SD-OCT follow-up provided a good option for adapting treatment in nAMD individually. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is the predominant cause of vision loss in the elderly with a major impact on ageing societies and healthcare systems. A major challenge in AMD management is the difficulty to determine the disease stage, the highly variable progression speed and the risk of conversion to advanced AMD, where irreversible functional loss occurs. In this study we developed an optical coherence tomography (OCT) imaging based spatio-temporal reference frame to characterize the morphologic progression of intermediate age-related macular degeneration (AMD) and to identify distinctive patterns of conversion to the advanced stages macular neovascularization (MNV) and macular atrophy (MA). We included 10,040 OCT volumes of 518 eyes with intermediate AMD acquired according to a standardized protocol in monthly intervals over two years. Two independent masked retina specialists determined the time of conversion to MNV or MA. All scans were aligned to a common reference frame by intra-patient and inter-patient registration. Automated segmentations of retinal layers and the choroid were computed and en-face maps were transformed into the common reference frame. Population maps were constructed in the subgroups converting to MNV (n=135), MA (n=50) and in non-progressors (n=333). Topographically resolved maps of changes were computed and tested for statistical significant differences. The development over time was analysed by a joint model accounting for longitudinal and right-censoring aspect. Significantly enhanced thinning of the outer nuclear layer (ONL) and retinal pigment epithelium (RPE)–photoreceptorinner segment/outer segment (PR-IS/OS) layers within the central 3 mm and a faster thinning speed preceding conversion was documented for MA progressors. Converters to MNV presented an accelerated thinning of the choroid and appearance changes in the choroid prior to MNV onset. The large-scale automated image analysis allowed us to distinctly assess the progression of morphologic changes in intermediate AMD based on conventional OCT imaging. Distinct topographic and temporal patterns allow to prospectively determine eyes with risk of progression and thereby greatly improving early detection, prevention and development of novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

This study aimed to identify the clinical characteristics and longitudinal changes in exudative pachychoroid neovasculopathy (PNV) and non-exudative PNV. This retrospective cohort study involved 81 eyes of PNV diagnosed by multimodal imaging including optical coherence tomography angiography. At baseline, they were divided into exudative PNV group and non-exudative PNV group depending on the presence of subretinal fluid. The clinical features of both groups and the longitudinal changes were investigated and compared. There were 55 eyes with non-exudative PNV and 26 eyes with exudative PNV. Individuals with non-exudative PNV were older, more frequently asymptomatic and had a higher prevalence of polypoidal choroidal vasculopathy in the opposite eye (all P's < 0.05). Whereas individuals with exudative PNV showed thicker choroid and more frequent history of central serous chorioretinopathy (all P's < 0.001). During about 12 months of longitudinal observation, the transformation into polypoidal choroidal vasculopathy was noted in 4 eyes of non-exudative PNV group, whereas in none of the exudative PNV group. Exudative PNV and non-exudative PNV seem to be separate entities with different epidemiological parameters. Non-exudative PNV, which is frequently found without symptoms at an older age, is suspected to be the significant precursor lesion of polypoidal choroidal vasculopathy. In contrast, exudative PNV may share the same pathophysiology as central serous chorioretinopathy. [ABSTRACT FROM AUTHOR]

Polypoidal choroidal vasculopathy (PCV) is a distinctive type of neovascular age-related macular degeneration prevalent in many Asian countries. However, there is still some controversy in how the subtypes of PCV are classified. This post-hoc study redefined the branching vascular network (BVN) and PCV subtypes through retrospective review of indocyanine green angiography (ICGA) and fluorescein angiography images from two observational studies (RENOWNED/REAL). Of the visual outcomes for each angiographic subtype and treatment pattern investigated, BVN was identified in 56.3% of PCV patients. The proportions and features of the re-defined PCV subtypes were 43.8%, 10.4%, and 45.8% for subtype A (without distinctive features of BVN), B (with BVN but no leakage), and C (with BVN and leakage), respectively. Subtype A had better visual outcomes when compared to subtype C. This possibly resulted from a better baseline visual acuity in subtype A. Moreover, combination therapy [photodynamic therapy plus anti-vascular endothelial growth factor (VEGF)] may lead to better visual improvement than mono-anti-VEGF treatment alone. This study provides the prevalence of PCV subtypes in Taiwan and may serve as a reference for PCV treatment strategies in a real-world setting, especially for the combination therapy and patients without distinctive features of BVN. [ABSTRACT FROM AUTHOR]

The aim of this observational study was to assess the use and outcome of intravitreal aflibercept in a treat and extend regimen in treatment-naïve neovascular AMD patients in routine practice. This both retrospective and prospective study was conducted in four larger Swiss retina clinics (ASTERIA study). The primary endpoint was the mean change in best-corrected visual acuity (BCVA) in ETDRS letters from baseline to 12 months. Between December 2017 and August 2018, 160 patients were included. For patients with available data, the mean change in BCVA was + 8.4 (± 14.4) letters at month 12 (n = 139) and + 5.0 (± 11.4) letters at month 24 (n = 95). A mean number of 8.3 (± 2.4) injections were administered within the first year and 5.4 (± 2.9) injections during the second year. On average, the observed treatment interval at month 12 was 63.3 (± 22.0) days and increased to 69.1 (± 28.6) days at month 24. For 37% of the patients, a treatment interval ≥ 12 weeks was attained at month 24. In conclusion, intravitreal aflibercept in a Swiss real-life treat and extend regimen resulted in comparable anatomic and functional outcomes as were observed in the prospective registration trials of aflibercept for nAMD treatment. [ABSTRACT FROM AUTHOR]

Polymorphisms in the Complement Factor H (CFH) gene, coding for the Factor H protein (FH), can increase the risk for age-related macular degeneration (AMD). AMD-associated CFH risk variants, Y402H in particular, impair FH function leading to complement overactivation. Whether this alone suffices to trigger AMD pathogenesis remains unclear. In AMD, retinal homeostasis is compromised due to the dysfunction of retinal pigment epithelium (RPE) cells. To investigate the impact of endogenous FH loss on RPE cell balance, we silenced CFH in human hTERT-RPE1 cells. FH reduction led to accumulation of C3, at both RNA and protein level and increased RPE vulnerability toward oxidative stress. Mild hydrogen-peroxide exposure in combination with CFH knock-down led to a reduction of glycolysis and mitochondrial respiration, paralleled by an increase in lipid peroxidation, which is a key aspect of AMD pathogenesis. In parallel, cell viability was decreased. The perturbations of energy metabolism were accompanied by transcriptional deregulation of several glucose metabolism genes as well as genes modulating mitochondrial stability. Our data suggest that endogenously produced FH contributes to transcriptional and metabolic homeostasis and protects RPE cells from oxidative stress, highlighting a novel role of FH in AMD pathogenesis. [ABSTRACT FROM AUTHOR]

Wet age-related macular degeneration (AMD), which can cause progressive blindness, is characterised by choroid neovascularization (CNV) in the macular area. Although close attention has been paid to AMD, and anti-vascular endothelial growth factor (VEGF) drugs are available, its complex pathogenesis is still elusive. Tie2-expressing macrophages (TEMs) have been found to promote angiogenesis in remodel tissues and tumours. This study aimed to elucidate the role of macrophage Tie2 signalling in laser-induced CNV (LCNV). We observed that TEMs were responsible for the severity of CNV. Mechanistically, TEM deletion resulted in impaired LCNV due to the suppression of inflammatory angiogenesis and the promotion of apoptosis. We also observed that TEMs prevented apoptosis of b.End3 cells, but promoted their migration, proliferation and tube formation via VEGF, extracellular signal-regulated kinase (ERK) and v-akt murine thymoma viral oncogene (AKT)-dependent signalling pathways. The flow cytometry results comparing dry AMD patients and healthy controls with wet AMD patients showed that the percentage of Tie2+CD14+ cells was higher in the wet AMD patients' peripheral blood. This study demonstrates that Tie2 expression by macrophages intensifies CNV in LCNV murine models, thereby proposing an additional intervention option to inhibit CNV. [ABSTRACT FROM AUTHOR]

We investigated the association of visual outcome in typical neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV) with or without pachychoroid with lesion areas on optical coherence tomography (OCT) quantified by convolutional neural network (CNN) analysis. Treatment-naïve 132 nAMD and 45 PCV eyes treated with ranibizumab or aflibercept for at least 12 months were retrospectively reviewed. Significant factors, including intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachment (PED) and subretinal hyperreflective material (SHRM) area quantified by CNN at baseline and 12 months, were analyzed by logistic regression analyses for 3-line visual gain or maintenance of 20/30 Snellen vision. Visual gain at the final visit in nAMD was associated with a smaller SHRM at baseline (OR 0.167, P = 0.03), greater decrease in SRF and SHRM from baseline to month 12 (OR 1.564, P = 0.02; OR 12.877, P = 0.01, respectively). Visual gain in nAMD without pachychoroid was associated with a greater decrease in SRF and SHRM (OR 1.574, P = 0.03, OR 1.775, P = 0.04). No association was found in nAMD with pachychoroid and any type of PCV. Greater decrease in SRF and SHRM from baseline to month 12 was associated with favorable visual outcomes in nAMD without pachychoroid but not in nAMD with pachychoroid and PCV. [ABSTRACT FROM AUTHOR]

Neovascular age-related macular degeneration (nAMD) is a complex and multi-factorial disease, and low-grade inflammation is associated with pathogenesis of nAMD. Aqueous humor could reflect intraocular immune environments in various eye diseases. The research so far used aqueous humor samples and revealed that inflammation is involved in pathophysiology of nAMD, although immunological roles of cytokines were evaluated inadequately with aspect to individual effects. Here we used 27 kinds of cytokines covering general immunologic reactions, examined specific expression patterns of cytokines, and assessed relationships between inflammation and pathophysiology of nAMD by multivariate analyses. In nAMD eyes, principal component analysis showed that IL-7, MCP-1, MIP-1β and VEGF had high principal component loadings of over 0.6 in the first principal component constituting 32.6% of all variability of the data. In exploratory factor analysis, IL-6, MCP-1 and MIP-1β had high factor loadings (FL) of over 0.5 in Factor 1 constituting 32.6% of all variability, while VEGF had FL of over 1.0 in Factor 3 constituting 10.7% of all variability. In hierarchical cluster analysis, MCP-1 and VEGF were located in the cluster of first proximate mutual distance to central retinal thickness. These data could suggest that low-grade inflammation is a principal contributor in nAMD. [ABSTRACT FROM AUTHOR]

The advent of anti-vascular endothelial growth factor (VEGF) therapies has remarkably improved the functional outcomes of neovascular age-related macular degeneration (nAMD) patients. However, there are guidelines on how to start treatment, the guidelines for discontinuing treatment are not yet clear. In this respect, the treat-extend-stop (TES) protocol have showed us the possibility of discontinuing treatment. In this study, we tried to investigate optical coherence tomography angiography (OCTA) biomarkers related to recurrence of neovascular activity in eyes with nAMD undergoing treatment using TES protocol. A total of 134 eyes with nAMD were divided into two groups (stop, non-stop) depending on whether they met criteria for stopping anti-VEGF treatment. Quantitative and qualitative OCTA parameters including the morphologic pattern of choroidal neovascularization (CNV) were compared between groups. Of these, 44 eyes (32.8%) were in the stop group and 90 eyes (67.2%) were in the non-stop group. In multivariate regression analysis, closed-circuit pattern of CNV and the presence of peripheral loop were associated with the non-stop group (all p < 0.001). Our results imply that the morphologic appearance of CNV on OCTA after anti-VEGF treatment may be a useful biomarker to predict weaning from treatment. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a multifactorial retinal disease characterized by a progressive loss of central vision. Retinal pigment epithelium (RPE) degeneration is a critical event in AMD. It has been associated to A2E accumulation, which sensitizes RPE to blue light photodamage. Mitochondrial quality control mechanisms have evolved to ensure mitochondrial integrity and preserve cellular homeostasis. Particularly, mitochondrial dynamics involve the regulation of mitochondrial fission and fusion to preserve a healthy mitochondrial network. The present study aims to clarify the cellular and molecular mechanisms underlying photodamage-induced RPE cell death with particular focus on the involvement of defective mitochondrial dynamics. Light-emitting diodes irradiation (445 ± 18 nm; 4.43 mW/cm2) significantly reduced the viability of both unloaded and A2E-loaded human ARPE-19 cells and increased reactive oxygen species production. A2E along with blue light, triggered apoptosis measured by MC540/PI-flow cytometry and activated caspase-3. Blue light induced mitochondrial fusion/fission imbalance towards mitochondrial fragmentation in both non-loaded and A2E-loaded cells which correlated with the deregulation of mitochondria-shaping proteins level (OPA1, DRP1 and OMA1). To our knowledge, this is the first work reporting that photodamage causes mitochondrial dynamics deregulation in RPE cells. This process could possibly contribute to AMD pathology. Our findings suggest that the regulation of mitochondrial dynamics may be a valuable strategy for treating retinal degeneration diseases, such as AMD. [ABSTRACT FROM AUTHOR]

Introduction: To report 12-month pharmacoepidemiologic data on aflibercept and ranibizumab use in treatment-naïve eyes with neovascular age-related macular degeneration (nAMD).Methods: Participants were treatment-naïve eyes with nAMD tracked by the Fight Retinal Blindness! registry starting therapy with aflibercept or ranibizumab treatment between January 1st, 2013 and 31st December, 2016. Demographic and clinical characteristics were compared between treatment groups.Results: During the study period, 689 eyes initiated treatment with ranibizumab compared to 568 with aflibercept. We found a similar rate of use of both drugs. Ranibizumab-treated patients were older than aflibercept-treated patients (overall mean [SD] 82.0 [8.4] vs. 78.6 [8.1], P < 0.001). Median (Q1, Q3) lesion size was significantly larger in aflibercept-treated patients (2450 μm [1242, 3000]) compared with ranibizumab patients (2000 μm [1148, 2890], P = 0.008). Eyes treated with ranibizumab and aflibercept received a similar mean number of injections in the first 3 months (3.1 [0.7] vs. 3.0 [0.6]; P = 0.233) and at 12 months (7.3 [2.4] vs. 7.2 [2.2]; P = 0.139). The 12-month switching rates from 2013 onwards for eyes completing 12 months of follow-up were much higher for switching from ranibizumab to aflibercept (19.2%) compared with switching from aflibercept to ranibizumab (5.4%). The proportion of eyes that did not complete 12 months of treatment was 23.2% for ranibizumab and 22.2% for aflibercept-treated groups.Conclusion: A similar rate of use for ranibizumab and aflibercept among Australian practitioners was observed between 2013 and 2016. Ranibizumab was used more often in older patients while aflibercept tended to be used more often in eyes with larger lesions. [ABSTRACT FROM AUTHOR]

Purpose: Pneumatic displacement of submacular hemorrhages (SMHs) with intravitreal injection of sulfur hexafluoride (SF6) gas with or without tissue plasminogen activator (tPA) and prone posturing is an effective minimally invasive treatment. We observed some cases in which simultaneous flattening of hemorrhagic pigment epithelial detachments (PEDs) occurred after prone posturing. This study evaluated the impact of pneumatic displacement using tPA to treat PEDs and visual outcomes in eyes with SMHs secondary to neovascular age-related macular degeneration (AMD).Methods: This retrospective analysis reviewed the medical records of 32 patients (33 eyes) who underwent pneumatic displacement for AMD-associated SMHs. The SMHs were related to polypoidal choroidal vasculopathy (PCV) in 24 eyes and typical AMD in nine eyes and treated with intravitreal injection of SF6 gas with tPA. We assessed the postoperative best-corrected visual acuities (BCVAs), prevalence and flattening rates of the PEDs, and the number of additional treatments.Results: The mean follow-up period was 35.4 ± 19.8 months. The BCVAs improved significantly in eyes with PCV compared with eyes with typical AMD. Thirty-one (93.9%) of 33 eyes had an accompanying PED. The PEDs flattened in 14 (58.3%) of 24 eyes with PCV but in only one (14.3%) of seven eyes with typical AMD (p = 0.04). A mean of one additional treatment was administered during the first year in 15 eyes with flattened PEDs, which was significantly (p < 0.05) fewer than the 3.6 additional treatments in 16 eyes with persistent PEDs.Conclusions: PEDs often accompany SMHs secondary to neovascular AMD. Pneumatic displacement of the SMHs using tPA unexpectedly flattened the PEDs, especially in eyes with PCV, and was associated with fewer additional treatments. [ABSTRACT FROM AUTHOR]

Purpose: To assess the prevalences of segmentation errors and motion artifacts in optical coherence tomography angiography (OCT-A) in different retinal diseasesMethods: In a retrospective analysis, multimodal retinal imaging including OCT-A was performed in one eye of 57 healthy controls (50.96 ± 22.4 years) and 149 patients (66.42 ± 14.1 years) affected by different chorioretinal diseases: early/intermediate age-related macular degeneration (AMD; n = 26), neovascular AMD (nAMD; n = 22), geographic atrophy due to AMD (GA; n = 6), glaucoma (n = 28), central serous chorioretinopathy (CSC; n = 14), epiretinal membrane (EM; n = 26), retinal vein occlusion (RVO; n = 11), and retinitis pigmentosa (RP; n = 16). Central 3 × 3 mm2 OCT-A imaging was performed with active eye-tracking (AngioVue, Optovue). Best-corrected visual acuity (BCVA) and signal strength index (SSI) were recorded. Images were independently evaluated by two graders using the OCT-A motion artifact score (MAS; scores I-IV) as well as a newly introduced segmentation accuracy score (SAS; score I-IIB).Results: Mean SSI was 63.67 ± 9.2 showing a negative correlation with increasing age (rSp = − 0.42, p < 0.001, n = 206). In the healthy cohort, mean MAS was 1.45 ± 0.8 and segmentation was accurate (SAS I) in all eyes. In eyes with retinal pathologies, mean MAS was 2.1 ± 0.9 (p < 0.001). Lowest MAS was observed in GA (2.67 ± 0.5) and RVO (2.45 ± 1.1). Compared to an accurate segmentation in 100% in healthy subjects, 34.2% (n = 51) of all patients showed highest segmentation quality (p < 0.001). 63.8% showed segmentation errors in more than 5% of all single b-scans in one (SAS IIA, n = 58) or at least two (SAS IIB, n = 40) segmentation boundaries. Highest percentages of inaccurate segmentation (SAS IIA or IIB) were observed in the nAMD group (90.1%). The inner plexiform layer was the segmentation boundary most prone to inaccurate segmentation in all pathologies compared to the inner limiting membrane (ILM) and retinal pigment epithelium (RPE) segmentation layer. Incorrect ILM segmentation was only seen in patients with EM.Conclusions: Prior to both qualitative and quantitative analysis, OCT-A images must be carefully reviewed as motion artifacts and segmentation errors in current OCT-A technology are frequent particularly in pathologically altered maculae. [ABSTRACT FROM AUTHOR]

Purpose: To determine factors predictive of visual outcomes in eyes treated with intravitreal aflibercept injections (IAIs) for typical neovascular age-related macular degeneration (AMD) or polypoidal choroidal vasculopathy (PCV).Study design: Retrospective, multicenter, institutional, consecutive, interventional case series.Methods: One hundred nine eyes (107 patients) with treatment-naïve neovascular AMD at 3 university hospitals were studied. After a loading phase of 3 monthly 2.0-mg IAIs, injections were administered every 2 months. The baseline clinical characteristics were investigated in relation to the 12-month visual outcomes. Changes in the mean best-corrected visual acuity (BCVA) were measured at 12 months after initiation of aflibercept therapy.Results: Forty-five eyes (41.3%) had typical neovascular AMD, and 64 eyes (58.7%) had PCV. The changes in the mean BCVA at 12 months compared with baseline did not differ significantly (P =.737) between the 2 groups. Stepwise analysis showed that larger gains in the BCVA at 12 months were associated with poor BCVA (P <.001), no pigment epithelial detachment (P =.004), and subretinal fluid (P =.039) at baseline in eyes with typical neovascular AMD; larger gains in the BCVA were associated with poorer BCVA (P <.001), presence of choroidal vascular hyperpermeability (CVH) (P =.013), and subretinal fluid (P =.044) at baseline in eyes with PCV.Conclusions: Although poorer BCVA and the presence of subretinal fluid predicted larger gains in BCVA in both subtypes treated with aflibercept, eyes with typical neovascular AMD had greater improvement if no pigment epithelial detachment was present, while eyes with PCV had greater improvement if CVH was present. [ABSTRACT FROM AUTHOR]

Background: Intraocular injections of antivascular endothelial growth factor (VEGF) agents are currently the main therapy in age-related macular degeneration (AMD). The safety of bevacizumab, an anti-VEGF compound frequently delivered off label, is debated, particularly for high-group risks. We aim to analyze the mortality associated with intravitreal injections of bevacizumab for AMD in patients previously diagnosed with acute myocardial infarct (MI).Methods: In a national database, we identified bevacizumab-treated AMD patients with a diagnosis of MI prior to their first bevacizumab injection, delivered between September 2008 and October 2014 (n = 2100). We then generated sub-groups of patients treated within 3 months (n = 11), 6 months (n = 24), 12 months (n = 52), and 24 months (n = 124) after MI. Those patients were compared to age- and gender-matched members that had a MI at the same time and had never been exposed to anti-VEGF. Survival analysis was performed using propensity score-adjusted Cox regression.Results: Bevacizumab-treated patients were slightly and insignificantly older than controls (mean age 83.25 vs 83.19 year, P = .75). Gender distribution was similar. In a Cox regression adjusted with propensity score, the following differences in mortality were found: within 3 months between MI and initiation of bevacizumab treatment, OR = 6.22 (95% C.I 1.08-35.97, P < .05); within 6 months, OR = 2.37 (95% C.I 0.93-6.02, P = .071); within 12 months, OR = 3.00 (95% C.I 1.44-6.28, P < .01); within 24 months after MI, OR = 2.24 (95% C.I 1.35-3.70, P < .01); and MI any time prior to first bevacizumab injection, OR = 1.71 (95% C.I 1.53-1.92, P < .001).Conclusions: We report increased mortality associated with the use of intravitreal bevacizumab in AMD patients after MI, compared to age- and gender-matched post-MI patients with no exposure to any anti-VEGF agent. Caution should be taken while offering bevacizumab to AMD patients after MI. [ABSTRACT FROM AUTHOR]

Purpose: Real-life studies on long-term functional outcome of anti-VEGF treatment for wet age-related macular degeneration (wAMD) are limited. We therefore assessed the 10-year outcomes in our patients.Methods: In this retrospective study, all patients with newly diagnosed wAMD that had received minimally three intravitreal injections between 2007 and 2012 and a follow-up of ≥48 months were included. Primary outcome measure was the evolution of best-corrected visual acuity (BCVA) over time. For qualitative, quantitative and longitudinal data, Pearson's chi2 test, the Mann-Whitney U-test and Wilcoxon’s signed-rank test were applied at a significance level of p < 0.05.Results: Of 267 eyes (219 patients) with newly diagnosed wAMD treated during this period, 104 eyes (104 patients) had been followed for at least 48 months and were included. Fifty-nine eyes (57.8%) after 7 years were still under active treatment, 29 eyes (25.0%) had interrupted treatment [mean follow-up 7.5 years (4.0-10.1; SD 1.6)], whereas 16 patients had died. BCVA stabilized at −7.3 to −11.9 letters after 3-10 years of follow-up with a mean of 2.8 injections (median; 3.0, SD 1.0; 1-5) and 5.1 visits per year. In two thirds of eyes, treatment was switched to aflibercept or corticosteroid combinations without bearing on functional outcomes. Thirty-seven percent (37%) of eyes maintained driving vision for up to 10 years.Conclusions: Beyond 3 years of treatment, functional stability was maintained for up to 10 years. Further improvement of long-term outcomes might have required a more intensive treatment in the early phase. [ABSTRACT FROM AUTHOR]

Purpose: To report research participants’ baseline characteristics in the AMD2000 study, a prospective, multicenter, 5-year, observational cohort study of Japanese age-related macular degeneration (AMD). The characteristics were determined using multimodal imaging.Methods: Patients with AMD were recruited at 18 clinical sites in Japan between April 2006 and March 2009. Each patient underwent a complete ophthalmic examination, including measurement of best-corrected visual acuity (Landolt chart), indirect ophthalmoscopy, slit-lamp biomicroscopy with a contact lens, optical coherence tomography imaging, fundus photography, and fluorescein and indocyanine green angiography.Results: Four hundred sixty participants (326 men [70.9%]) were included in the study. At enrollment, 131 eyes (28.5%) had hard drusen and 125 eyes (27.2%) had soft drusen in the macular area. A total of 455 eyes (98.9%) were diagnosed as having wet AMD, and 5 eyes (1.1%), as having dry AMD. Of the 455 eyes with wet AMD, 209 eyes (45.4%) had typical AMD, 228 eyes (49.6%) had polypoidal choroidal vasculopathy (PCV), and 18 eyes (3.9%) had retinal angiomatous proliferation. The size of choroidal neovascularization (CNV) was significantly smaller with indocyanine green angiography than with fluorescein angiography (P < 0.001). Poor baseline visual acuity was associated with cystoid macular edema, older age, scar, extrafoveal macular edema, subfoveal CNV, large branching vascular network, and hard exudates.Conclusion: Japanese patients with AMD are predominantly male, lack drusen, and have a high rate of PCV. [ABSTRACT FROM AUTHOR]

Purpose: In this study (AMD2000), we aimed to determine the visual prognosis of Japanese patients with age-related macular degeneration (AMD).Methods: This was a multicenter prospective observational cohort study. In total, 460 patients with AMD were recruited from April 2006 to March 2009 from 18 clinical trial sites in Japan. They were followed up for 5 years, as they continued to receive medical treatment.Results: Of the 409 study eyes followed up for at least 1 year, 243 eyes (59.4%) were treated with photodynamic therapy (PDT) using verteporfin, and 58 eyes (14.2%) were treated with intravitreal injections of antivascular endothelial growth factor agents as the initial treatment. The mean best-corrected visual acuities (BCVA) for typical AMD (tAMD; 0.688 ± 0.498) and polypoidal choroidal vasculopathy (PCV; 0.451 ± 0.395) were significantly less at 2 years (tAMD, 0.779 ± 0.632, P < 0.05; PCV, 0.534 ± 0.618, P < 0.05) and at 5 years (AMD, 0.873 ± 0.718, P < 0.05; PCV, 0.635 ± 0.668, P < 0.05) than at baseline. In eyes with tAMD, absence of blocked fluorescence was associated with 5-year maintenance of the baseline BCVA. Regarding PCV, the presence of polypoidal lesions and cystoid macular edema as well as the lesion size was associated with 5-year maintenance of the baseline BCVA. In some patients, the diagnosis changed: of the 192 eyes initially diagnosed with typical AMD, 19 were newly diagnosed with PCV during follow-up.Conclusion: Maintaining the baseline BCVA over the long term is difficult in Japanese eyes with wet AMD. [ABSTRACT FROM AUTHOR]

Purpose: Our purpose was to use deep learning for the automated detection of age-related macular degeneration (AMD) in spectral domain optical coherence tomography (SD-OCT).Methods: A total of 1112 cross-section SD-OCT images of patients with exudative AMD and a healthy control group were used for this study. In the first step, an open-source multi-layer deep convolutional neural network (DCNN), which was pretrained with 1.2 million images from ImageNet, was trained and validated with 1012 cross-section SD-OCT scans (AMD: 701; healthy: 311). During this procedure training accuracy, validation accuracy and cross-entropy were computed. The open-source deep learning framework TensorFlow™ (Google Inc., Mountain View, CA, USA) was used to accelerate the deep learning process. In the last step, a created DCNN classifier, using the information of the above mentioned deep learning process, was tested in detecting 100 untrained cross-section SD-OCT images (AMD: 50; healthy: 50). Therefore, an AMD testing score was computed: 0.98 or higher was presumed for AMD.Results: After an iteration of 500 training steps, the training accuracy and validation accuracies were 100%, and the cross-entropy was 0.005. The average AMD scores were 0.997 ± 0.003 in the AMD testing group and 0.9203 ± 0.085 in the healthy comparison group. The difference between the two groups was highly significant (p < 0.001).Conclusions: With a deep learning-based approach using TensorFlow™, it is possible to detect AMD in SD-OCT with high sensitivity and specificity. With more image data, an expansion of this classifier for other macular diseases or further details in AMD is possible, suggesting an application for this model as a support in clinical decisions. Another possible future application would involve the individual prediction of the progress and success of therapy for different diseases by automatically detecting hidden image information. [ABSTRACT FROM AUTHOR]

Purpose: Various hypoxia-related proteins are differentially expressed in the retina and secreted to the vitreous and/or aqueous humor of patients affected by dry or neovascular age-related macular degeneration (nAMD). To determine whether these conditions alter concentrations of cytokines also in the systemic circulation, we measured plasma levels of six hypoxia-related proteins.Methods: Plasma was prepared from EDTA blood that was collected from patients affected by dry AMD (n = 5), nAMD (n = 11), proliferative diabetic retinopathy (PDR; n = 9), and patients with an epiretinal membrane (ERM; n = 11). ERM samples served as negative controls, PDR samples as positive controls. Protein concentrations of vascular endothelial growth factor (VEGF), erythropoietin (EPO), angiopoietin-like 4 (ANGPTL4), placental growth factor (PlGF), tumor necrosis factor alpha (TNF-α), and pigment epithelium-derived factor (PEDF) were determined by enzyme-linked immunosorbent assay (ELISA).Results: The concentration of PlGF was significantly increased in plasma of patients affected by nAMD. Although no statistically significant differences were found for EPO, ANGPTL4, PlGF, TNF-α, and PEDF, the mean concentration of VEGF was lowest in the nAMD group. Plasma concentrations of the six factors did not correlate with gender or age of patients.Conclusions: nAMD may increase plasma concentrations of PlGF, making it a candidate as a biomarker for the neovascular form of AMD. Other factors, however, were not differentially regulated, suggesting that their systemic concentrations are not generally increased in hypoxia-related retinal diseases. [ABSTRACT FROM AUTHOR]

Purpose: To determine changes in quality of life measures when choroidal neovascularization (CNV) developed in the second eye of patients with initially unilateral neovascular age-related macular degeneration (AMD).Methods: We analyzed responses to the 39-item National Eye Institute Visual Function Questionnaire (NEI-VFQ), 36-item Short Form Health Survey (SF-36), and Hospital Anxiety and Depression Scale (HADS) at baseline, and prior to and following second eye CNV diagnosis in 92 participants enrolled in two Submacular Surgery Trials. Paired t-tests for sample sizes over 30 and Wilcoxon signed-rank tests for sample sizes <30 were performed to compare scores.Results: CNV development resulted in statistically and clinically significant changes in responses to 20 of 39 NEI-VFQ items, indicating visual function decline during a mean interval of 25 months. Little difference was noted between baseline scores and prior to CNV diagnosis, which averaged 8.9 months duration. Subscales demonstrated a statistically significant decline in general vision, near activities, distance activities, social functioning, role difficulties, dependency, and driving. There were minimal changes in the HADS and SF-36 scales.Conclusion: CNV development in the second eye had a dramatic effect on visual functioning based on patient responses to the NEI-VFQ questionnaire. Our investigation is believed to be the first study using data collected prospectively to demonstrate vision-related quality of life changes that resulted from development of CNV in AMD patients. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of our study was to investigate the clinical and genetic characteristics of pseudodrusen subtypes and their incidence in advanced age-related macular degeneration (AMD). Methods: We studied 84 eyes from 84 patients with pseudodrusen associated with advanced AMD, including typical AMD, polypoidal choroidal vasculopathy (PCV), retinal angiomatous proliferation (RAP), and geographic atrophy (GA). Multiple imaging modalities, including color fundus photography, spectral-domain optical coherence tomography (SD-OCT), near-infrared reflectance, and fundus autofluorescence, were employed to diagnose pseudodrusen and its subtypes. Subfoveal choroidal thickness was measured using SD-OCT. Subject eyes were classified into two subtypes, dot-dominant or ribbon-dominant, according to the maximum length of ribbon pseudodrusen. Genotyping was performed for ARMS2 A69S (rs10490924) and CFH I62V (rs800292) variants. Results: The percentage of ribbon-dominant type pseudodrusen was significantly higher in eyes with RAP (69.6%) and GA (78.6%) compared with those with typical AMD (31.1%) ( p = .0025 and .0017, respectively). Multivariate logistic regression analysis disclosed that incidence of female patients and coexisting large soft drusen was significantly higher in ribbon- than dot-dominant types ( P = 0.014 and P = 0.008, respectively), while age, subfoveal choroidal thickness, and risk allele frequency for both ARMS2 A69S (rs10490924) and CFH I62V (rs800292) were not different between the two pseudodrusen subtypes. Conclusions: Among eyes with advanced AMD associated with pseudodrusen, ribbon-dominant type pseudodrusen were more prevalent in eyes with GA or RAP and were associated with large soft drusen and female patients. [ABSTRACT FROM AUTHOR]

Purpose: To report the 1-year outcomes of every-4-weeks (Q4W) as-needed aflibercept treatment in resistant neovascular age-related macular degeneration (nAMD) patients who had been treated and failed prior bevacizumab or ranibizumab injections, and who also responded poorly to every-8-weeks (Q8W) aflibercept treatment. Methods: Forty-three eyes of 39 patients with persistent nAMD despite monthly bevacizumab and/or ranibizumab injections and who were switched to Q8W 2-mg aflibercept injections, but showed persistence of fluid were included. Patients were treated with as-needed Q4W aflibercept injections with monthly monitoring. Maximum retinal thickness (MRT), central macular thickness (CMT), maximum pigment epithelial detachment height (PED) and best-corrected visual acuity (BCVA) were assessed and compared to baseline when high-frequency aflibercept was initiated. Results: A mean of 8 (interquartile range, 4-11) Q4W injections were given during the follow-up. MRT and CMT significantly decreased at all follow-up visits ( p < 0.05); however, there was no significant change in maximum PED height ( p > 0.05) at any visit. Mean BCVA was 0.38 ± 0.28 (logMAR) (≈20/63, Snellen) at baseline, and 0.4 ± 0.34 (logMAR) (≈20/76, Snellen) at 1 year ( p = 0.76). Seventy-two percent of eyes maintained a final BCVA of 20/63 or better. Twelve eyes (28 %) had some subretinal scar tissue formation and 5 eyes (11.6 %) had evidence of atrophy at 1 year. Conclusion: A stepwise algorithm with Q4W as-needed aflibercept treatment led to anatomic improvement in previously treated eyes which failed other therapies, including aflibercept every 8 weeks. Lack of visual improvement may be due to a ceiling effect as our eyes generally had good visual acuity. [ABSTRACT FROM AUTHOR]

Purpose: The purpose was to evaluate the effects of long-term anti-VEGF treatment on the retinal nerve fiber layer (RNFL) and retinal ganglion cell layer (RGCL) thickness for patients with neovascular AMD and glaucoma. Methods: Medical records of respective patients who had received more than 15 anti-VEGF injections were reviewed. Initial and latest SD-OCT macular scans were segmented and changes of the RNFL and RGCL thickness at the four outer ETDRS quadrants were evaluated. Secondary outcome measures included changes of visual field parameters seen in automated perimetry. Results: Sixteen patients were included (mean age 78 ± 6 years). The mean total number of anti-VEGF injections was 39 ± 16. The mean treatment duration was 6.1 ± 2.1 years. The mean IOP decreased from 18 ± 5 mmHg at baseline to 15 ± 5 mmHg at the last visit ( p = 0.026). The mean RNFL thickness volume of the outer ETDRS quadrants (0.98 ± 0.18 mm to 0.97 ± 0.18 mm p = 0.61) and its average thickness (37.9 ± 7.3 μm to 37.2 ± 7.4 μm, p = 0.6) did not significantly change. However, the average RGCL thickness decreased significantly from 0.86 ± 0.12 mm to 0.79 ± 0.11 mm ( p = 0.01), and from 27.7 ± 4.2 to 25.9 ± 3.7 μm ( p = 0.01). Number of injections correlated with the RGCL change (r2 = 0.36, p = 0.01). The mean sensitivity, mean defect and absolute scotomata did not significantly change with p-values of 0.28, 0.21 and 0.07, respectively. Conclusion: Patients under long term treatment with anti-VEGF and concurrent glaucoma show significant decrease in macular RGLC volume. However, this decrease is comparable to reported RGCL decrease in patients under anti-VEGF treatment without underlying glaucoma and suggests that glaucoma patients may not be at a higher risk for losing macular RNFL and RGCL, at least if adequate control of intraocular pressure is maintained. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the characteristics and 6-month treatment outcome of polypoidal choroidal vasculopathy (PCV) in patients aged <50 years. Methods: This retrospective study included 22 eyes from 22 patients who were <50 years old and had been diagnosed with treatment naïve PCV. Analyses of treatment outcome were performed in eyes treated with anti-vascular endothelial growth factor (VEGF) therapy. Eyes that exhibited submacular hemorrhage of ≥1 disc diameter and involving the fovea were included in the hemorrhage group. The remaining eyes were included in the no-hemorrhage group. The baseline best-corrected visual acuity (BCVA) was compared with that at 6 months within each group. Results: The mean age of the 22 patients was 46.5 ± 1.8 (range, 43-49) years. Submacular hemorrhage was noted in ten eyes (45.5 %). The presence of drusen was noted in one eye and pseudodrusen was not noted in any of the eyes included. Treatment outcome was analyzed in 18 eyes. A mean number of 2.9 ± 0.5 intravitreal anti-VEGF injections were administered during the 6-month follow-up period. In the no-hemorrhage group ( n = 10), the BCVA at diagnosis and at 6 months was 0.55 ± 0.32 and 0.35 ± 0.22 respectively ( P = 0.011). In the hemorrhage group ( n = 8), the values were 0.99 ± 0.45 and 0.74 ± 0.63 respectively ( P = 0.128). Conclusions: A relatively high proportion of young PCV patients exhibited submacular hemorrhage at initial presentation. In those without submacular hemorrhage, intravitreal anti-VEGF therapy was found to be beneficial. [ABSTRACT FROM AUTHOR]

Inflammation is a cellular response to factors that challenge the homeostasis of cells and tissues. Cell-associated and soluble pattern-recognition receptors, e.g. Toll-like receptors, inflammasome receptors, and complement components initiate complex cellular cascades by recognizing or sensing different pathogen and damage-associated molecular patterns, respectively. Cytokines and chemokines represent alarm messages for leukocytes and once activated, these cells travel long distances to targeted inflamed tissues. Although it is a crucial survival mechanism, prolonged inflammation is detrimental and participates in numerous chronic age-related diseases. This article will review the onset of inflammation and link its functions to the pathogenesis of age-related macular degeneration (AMD), which is the leading cause of severe vision loss in aged individuals in the developed countries. In this progressive disease, degeneration of the retinal pigment epithelium (RPE) results in the death of photoreceptors, leading to a loss of central vision. The RPE is prone to oxidative stress, a factor that together with deteriorating functionality, e.g. decreased intracellular recycling and degradation due to attenuated heterophagy/autophagy, induces inflammation. In the early phases, accumulation of intracellular lipofuscin in the RPE and extracellular drusen between RPE cells and Bruch's membrane can be clinically detected. Subsequently, in dry (atrophic) AMD there is geographic atrophy with discrete areas of RPE loss whereas in the wet (exudative) form there is neovascularization penetrating from the choroid to retinal layers. Elevations in levels of local and systemic biomarkers indicate that chronic inflammation is involved in the pathogenesis of both disease forms. [ABSTRACT FROM AUTHOR]

Purpose: The macular degeneration quality of life (MacDQoL) instrument is a validated condition-specific measure of quality of life in patients with macular degeneration. This paper presents the first mapping algorithm to predict EQ-5D from responses to the MacDQoL instrument.Methods: Responses to the MacDQoL and EQ-5D-3L instruments from 482 patients were collected from the IVAN multicentre trial of two alternative drug treatments for neovascular age-related macular degeneration. Regression specifications were estimated using OLS, censored least absolute deviation, Tobit and two-part models. Their predictive performance was assessed using mean squared error. An internal validation sample based on a random selection of 25 % of patients was used to assess the performance of the model estimated on the remaining 75 % of patients.Results: A two-part model had the best predictive performance on the full sample. The covariates of this model include responses and weighted impact scores for all 23 condition-specific domains of the MacDQoL, and responses to a general MacDQoL quality of life question. The selected models were successful at predicting means and standard deviations of target populations, but prediction is weaker at the upper and lower extremes of the EQ-5D-3L distribution.Conclusion: The mapping algorithms provide a means of predicting EQ-5D-3L index scores from MacDQoL scores, and could facilitate cost-effectiveness analyses when the latter but not the former are available to researchers. Further validation of the performance of the algorithms using external data would provide a means of establishing the robustness of the algorithms. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the association of the ABCA1 rs1883025 polymorphism and susceptibility to age-related macular degeneration (AMD). Methods: A systematic search of the PubMed, EMBASE, and ISI web of science databases was performed to identify eligible published studies without language restrictions up to September 2015. Pooled odds ratios (ORs) with 95 % confidence intervals (CIs) were estimated under different genetic models using meta-analytic methods. Stratified analysis and sensitivity analysis were performed to explore potential sources of heterogeneity. Results: A total of 12 articles with 25,445 cases and 36,460 controls were eligible in this meta-analysis. The ABCA1 rs1883025 variant showed significant association with the lower risk of overall AMD under the allelic model ( OR= 0.81, 95 % CI=0.74-0.89). Stratified analysis based on ethnicity demonstrated a strong association between rs1883025 polymorphism and AMD in the Caucasian population, but not in Asian population. For late AMD, the ABCA1 rs1883025 variant was observed to have a significant association with the lower risk of this disease ( OR = 0.81, 95 % CI, 0.72-0.91). In early-stage AMD, significant associations of the rs1883025 polymorphism with lower risk of early AMD were observed in different genetic models (OR ranging from 0.45 to 0.65, all P < 0.05). Conclusions: The present meta-analysis indicated that the T allelic in rs1883025 variant was significantly associated with the risk of developing AMD, particularly at the early stage. The associations of the ABCA1 locus with AMD risk in various populations need further exploration. [ABSTRACT FROM AUTHOR]

The bis-retinoid N-retinylidene-N-retinylethanolamine (A2E) is one of the major components of lipofuscin, a fluorescent material that accumulates with age in the lysosomes of the retinal pigment epithelium (RPE) of the human eye. Lipofuscin, as well as A2E, exhibit a range of cytotoxic properties, which are thought to contribute to the pathogenesis of degenerative diseases of the retina such as Age-related Macular Degeneration. Consistent with such a pathogenic role, high levels of lipofuscin fluorescence are found in the central area of the human RPE, and decline toward the periphery. Recent reports have however suggested a surprising incongruence between the distributions of lipofuscin and A2E in the human RPE, with A2E levels being lowest in the central area and increasing toward the periphery. To appraise such a possibility, we have quantified the levels of A2E in the central and peripheral RPE areas of 10 eyes from 6 human donors (ages 75–91 years) with HPLC and UV/VIS spectroscopy. The levels of A2E in the central area were on average 3–6 times lower than in peripheral areas of the same eye. Furthermore, continuous accumulation of selected ions (CASI) imaging mass spectrometry showed the presence of A2E in the central RPE, and at lower intensities than in the periphery. We have therefore corroborated that in human RPE the levels of A2E are lower in the central area compared to the periphery. We conclude that the levels of A2E cannot by themselves provide an explanation for the higher lipofuscin fluorescence found in the central area of the human RPE. [ABSTRACT FROM AUTHOR]

Age-related macular degeneration (AMD) is a degenerative retinal disease that causes blindness in people 60–65 years and older, with the highest prevalence appearing in people 90 years-old or more. Epidemiological estimates indicate that the number of cases is increasing, and will almost double in the next 20 years. Preventive measures require precise etiological knowledge. This is quite difficult, since AMD is a multifactorial condition with intricate relationships between causes and risk factors. In this review, we describe the impact of light on the structure and physiology of the retina and the pigment epithelium, taking into account the continuous exposure to natural and artificial light sources along the life of an individual. A large body of experimental evidence demonstrates the toxic effects of some lighting conditions on the retina and the pigment epithelium, and consensus exists about the importance of photo-oxidation phenomena in the causality chain between light and retinal damage. Here, we analyzed the transmission of light to the retina, and compared the aging human macula in healthy and diseased retinas, as shown by histology and non-invasive imaging systems. Finally, we have compared the putative retinal photo-sensitive molecular structures that might be involved in the genesis of AMD. The relationship between these compounds and retinal damage supports the hypothesis of light as an important initiating cause of AMD. [ABSTRACT FROM AUTHOR]

PurposeTo compare the impact of sustained supplementation using different macular carotenoid formulations on macular pigment (MP) and visual function in early age-related macular degeneration (AMD).Patients and methodsSixty-seven subjects with early AMD were randomly assigned to: Group 1 (20 mg per day lutein (L), 0.86 mg per day zeaxanthin (Z); Ultra Lutein), Group 2 (10 mg per day meso-zeaxanthin (MZ), 10 mg per day L, 2 mg per day Z; Macushield; Macuhealth), Group 3 (17 mg per day MZ, 3 mg per day L, 2 mg per day Z). MP was measured using customised heterochromatic flicker photometry and visual function was assessed by measuring contrast sensitivity (CS) and best-corrected visual acuity (BCVA). AMD was graded using the Wisconsin Age-Related Maculopathy Grading System (AREDS 11-step severity scale).ResultsAt 3 years, a significant increase in MP from baseline was observed in all groups at each eccentricity (P<0.05), except at 1.75° in Group 1 (P=0.160). Between 24 and 36 months, significant increases in MP at each eccentricity were seen in Group 3 (P<0.05 for all), and at 0.50° in Group 2 (P<0.05), whereas no significant increases were seen in Group 1 (P>0.05 for all). At 36 months, compared with baseline, the following significant improvements (P<0.05) in CS were observed: Group 2-1.2, 6, and 9.6 cycles per degree (c.p.d.); Group 1-15.15 c.p.d.; and Group 3-6, 9.6, and 15.15 c.p.d. No significant changes in BCVA, or progression to advanced AMD, were observed.ConclusionIn early AMD, MP can be augmented with a variety of supplements, although the inclusion of MZ may confer benefits in terms of panprofile augmentation and in terms of CS enhancement. [ABSTRACT FROM AUTHOR]