The effect of stiffened diabetic red blood cells on wall shear stress in a reconstructed 3D microaneurysm.

Blood flow within the vasculature of the retina has been found to influence the progression of diabetic retinopathy. In this research cell resolved blood flow simulations are used to study the pulsatile flow of whole blood through a segmented retinal microaneurysm. Images were collected using adaptive optics optical coherence tomography of the retina of a patient with diabetic retinopathy, and a sidewall (sacciform) microaneurysm was segmented from the volumetric data. The original microaneurysm neck width was varied to produce two additional aneurysm geometries in order to probe the influence of neck width on the transport of red blood cells and platelets into the aneurysm. Red blood cell membrane stiffness was also increased to resolve the impact of rigid red blood cells, as a result of diabetes, in blood flow. Wall shear stress and wall shear stress gradients were calculated throughout the aneurysm domains, and the quantification of the influence of the red blood cells is presented. Average wall shear stress and wall shear stress gradients increased due to the increase of red blood cell membrane stiffness. Stiffened red blood cells were also found to induce higher local wall shear stress and wall shear stress gradients as they passed through the leading and draining parental vessels. Stiffened red blood cells were found to penetrate the aneurysm sac more than healthy red blood cells, as well as decreasing the margination of platelets to the vessel walls of the parental vessel, which caused a decrease in platelet penetration into the aneurysm sac.

Longitudinal analysis of microvascular perfusion and neurodegenerative changes in early type 2 diabetic retinal disease.

AIM: To prospectively monitor subclinical changes in capillary perfusion and retinal layer thickness in patients with type 2 diabetes and early diabetic retinal disease over 2 years. METHODS: In this longitudinal study we performed biannual retinal vascular imaging using optical coherence tomography angiography (RTVue) to analyse the foveal avascular zone (FAZ) area, perimeter, acircularity index (AI) and parafoveal superficial/deep vessel density (VD). Spectral-domain optical coherence tomography (Spectralis) was used to measure the thickness of nine macular layers and the peripapillary nerve fibre layer. RESULTS: Among 117 eyes (58 left) of 59 patients (21 female), 105 had no diabetic retinopathy (DR), 6 mild and 6 moderate non-proliferative DR at baseline. We found DR progression in 13 eyes at year 2. The FAZ area (+0.008±0.002 mm2/year, p<0.0001), perimeter (+0.036±0.010 mm/year, p=0.006) and AI (+0.005±0.002/year, p=0.0280) increased significantly. A pronounced decrease was found in the superficial (-1.425±0.290%/year, p<0.0001) but not the deep VD. Inner neuroretinal loss was confined to the ganglion cell (-0.539±0.150 µm/year, p=0.0004) and the inner plexiform layer (-0.361±0.127 µm/year, p=0.0045). In the outer retina, we observed a statistically significant decrease in thickness in the outer plexiform, photoreceptor layer and pigment epithelium of -0.921±0.161 µm/year, -0.325±0.139 µm/year and -0.385±0.084 µm/year, respectively. CONCLUSION: Subclinical signs of microangiopathy and neurodegeneration appear in parallel and are highly progressive even in the earliest stages of diabetic retinal disease. Trial registration number EudraCT20156000239634.

Microvasculature Segmentation and Intercapillary Area Quantification of the Deep Vascular Complex Using Transfer Learning.

Purpose: Optical coherence tomography angiography (OCT-A) permits visualization of the changes to the retinal circulation due to diabetic retinopathy (DR), a microvascular complication of diabetes. We demonstrate accurate segmentation of the vascular morphology for the superficial capillary plexus (SCP) and deep vascular complex (DVC) using a convolutional neural network (CNN) for quantitative analysis. Methods: The main CNN training dataset consisted of retinal OCT-A with a 6 × 6-mm field of view (FOV), acquired using a Zeiss PlexElite. Multiple-volume acquisition and averaging enhanced the vasculature contrast used for constructing the ground truth for neural network training. We used transfer learning from a CNN trained on smaller FOVs of the SCP acquired using different OCT instruments. Quantitative analysis of perfusion was performed on the resulting automated vasculature segmentations in representative patients with DR. Results: The automated segmentations of the OCT-A images maintained the distinct morphologies of the SCP and DVC. The network segmented the SCP with an accuracy and Dice index of 0.8599 and 0.8618, respectively, and 0.7986 and 0.8139, respectively, for the DVC. The inter-rater comparisons for the SCP had an accuracy and Dice index of 0.8300 and 0.6700, respectively, and 0.6874 and 0.7416, respectively, for the DVC. Conclusions: Transfer learning reduces the amount of manually annotated images required while producing high-quality automatic segmentations of the SCP and DVC that exceed inter-rater comparisons. The resulting intercapillary area quantification provides a tool for in-depth clinical analysis of retinal perfusion. Translational Relevance: Accurate retinal microvasculature segmentation with the CNN results in improved perfusion analysis in diabetic retinopathy.

Ensemble Deep Learning for Diabetic Retinopathy Detection Using Optical Coherence Tomography Angiography.

Purpose: To evaluate the role of ensemble learning techniques with deep learning in classifying diabetic retinopathy (DR) in optical coherence tomography angiography (OCTA) images and their corresponding co-registered structural images. Methods: A total of 463 volumes from 380 eyes were acquired using the 3 × 3-mm OCTA protocol on the Zeiss Plex Elite system. Enface images of the superficial and deep capillary plexus were exported from both the optical coherence tomography and OCTA data. Component neural networks were constructed using single data-types and fine-tuned using VGG19, ResNet50, and DenseNet architectures pretrained on ImageNet weights. These networks were then ensembled using majority soft voting and stacking techniques. Results were compared with a classifier using manually engineered features. Class activation maps (CAMs) were created using the original CAM algorithm and Grad-CAM. Results: The networks trained with the VGG19 architecture outperformed the networks trained on deeper architectures. Ensemble networks constructed using the four fine-tuned VGG19 architectures achieved accuracies of 0.92 and 0.90 for the majority soft voting and stacking methods respectively. Both ensemble methods outperformed the highest single data-type network and the network trained on hand-crafted features. Grad-CAM was shown to more accurately highlight areas of disease. Conclusions: Ensemble learning increases the predictive accuracy of CNNs for classifying referable DR on OCTA datasets. Translational Relevance: Because the diagnostic accuracy of OCTA images is shown to be greater than the manually extracted features currently used in the literature, the proposed methods may be beneficial toward developing clinically valuable solutions for DR diagnoses.

Evaluating Signs of Microangiopathy Secondary to Diabetes in Different Areas of the Retina with Swept Source OCTA.

Purpose: The purpose of this study was to compare perfusion parameters of the parafovea with scans outside the parafovea to find an area most susceptible to changes secondary to diabetic retinopathy (DR). Methods: Patients with different DR severity levels as well as controls were included in this cross-sectional clinical trial. Seven standardized 3 × 3 mm areas were recorded with Swept Source Optical Coherence Tomography Angiography: one centered on the fovea, three were temporal to the fovea, and three nasally to the optic disc. The capillary perfusion density (PD) of the superficial capillary complex (SCC) and deep capillary complex (DCC) as well as the fractal dimension (FD) were generated. Statistical analyses were done with R software. Results: One hundred ninety-two eyes (33 controls, 51 no-DR, 41 mild DR, 37 moderate/severe DR, and 30 proliferative DR), of which 105 patients with diabetes and 25 healthy controls were included (59 ± 15 years; 62 women). Mean PD of the DCC was significantly less in patients without DR (parafovea = 0.48 ± 0.03; temporal = 0.48 ± 0.02; and nasal = 0.48 ± 0.03) compared to controls (parafovea = 0.49 ± 0.02; temporal = 0.50 ± 0.02; and nasal = 0.50 ± 0.03). With increasing DR severity, PD and FD of the SCC and DCC further decreased. Conclusions: Capillary perfusion of the retina is affected early by diabetes. PD of the DCC was significantly reduced in patients with diabetes who did not have any clinical signs of DR. The capillary network outside the parafovea was more susceptible to capillary perfusion deficits compared to the capillaries close to the fovea. Trial Registration: clinicaltrial.gov, NCT03765112, https://clinicaltrials.gov/ct2/show/NCT03765112?term=NCT03765112&rank=1.

Response of Retinal Sensitivity to Intravitreal Anti-angiogenic Bevacizumab and Triamcinolone Acetonide for Patients with Diabetic Macular Edema over One Year.

AIM: The aim of this study was to evaluate and compare microperimetry changes in patients with clinically significant diabetic macular edema secondary to diabetes mellitus, following intravitreal injections of bevacizumab or triamcinolone during a follow-up of 1 year after treatment. MATERIALS AND METHODS: 30 patients with clinically significant macular edema were randomized into two groups of 15 patients each. One group initially received three intravitreal injections of 2.5 mg bevacizumab at monthly intervals. The other received a single injection of 8 mg of triamcinolone followed by two sham interventions at monthly intervals. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) were measured. Macular function was documented by microperimetry at baseline, 3, 6, 9 months and at the last visit of each patient. RESULTS: In the bevacizumab group, the mean differential light threshold (±standard deviation) under therapy improved significantly from 8.40 (± 3.8) dB to 12.8 (±4.3) dB at the 12-month follow-up visit (p ≤ .05), whereas in the triamcinolone group it increased from 8.0 (± 2.4) dB at baseline to 9.3 (±3.6) dB at the last visit without reaching statistical significance (p > .05). The mean differential light thresholds between the two groups were not statistically significant at baseline or the last visit (p > .05). In the bevacizumab group, the improvement (slope) in mean differential light threshold was significantly superior to the Triamcinolone group (Estimate = 0.588, p ≤ .05). CONCLUSION: Central macular function as measured by microperimetry in patients with acute DME improved in addition to anatomical restoration after intravitreal bevacizumab and triamcinolone injection. In our clinical study, the measures of the variables in patients receiving bevacizumab were superior to those receiving triamcinolone throughout the one-year observation period.

Systematic ultrastructural comparison of swept-source and full-depth spectral domain optical coherence tomography imaging of diabetic macular oedema.

BACKGROUND/AIMS: Optical coherence tomography (OCT) is commonly used to diagnose and assess diabetic macular oedema (DME). Swept-source OCT (SS-OCT) promises improved imaging depth and more independence from media opacities. Heidelberg Spectralis full-depth imaging (FDI) combines details at different depths to one representation. The aim of this study was to determine the comparability of the imaging methods concerning DME ultrastructure. METHODS: Two graders assessed the presence of typical DME phenomena in eyes with centre-involving DME on Topcon Atlantis SS-OCT and Heidelberg Spectralis FDI spectral-domain OCT (SD-OCT) B-scans. Retinal layer segmentation was corrected and choroidal layers were manually segmented. Graders measured cyst and subretinal fluid (SRF) diameters and counted hyper-reflective foci (HRF). Findings were recorded and statistically analysed. RESULTS: Statistically significant systematic biases (Spectralis-Atlantis) were found for the HRF count (outside the central mm, -6.39, p=0.0338), chorioretinal thickness (central mm: -35.45 µm, p=0.00034), choroidal thickness (central mm: -60.97 µm, p=0.00004) and Sattler's layer thickness (-42.69 µm, p=0.0001). Intergrader agreement was excellent or very good for posterior vitreous detachment, vitreomacular attachment (central mm) and SRF presence in both devices. Manually delineated Sattler's layer thickness showed an intraclass correlation of 0.85 with FDI SD-OCT but 0.26 with SS-OCT (p=0.003). CONCLUSION: Prominent aspects such as cysts in the outer nuclear layer and SRF can be identified with comparable confidence, while a significant systematic bias underlies chorioretinal, choroidal and Sattler's layer thickness and HRF count. Specialists should use the same device at every examination during longitudinal clinical consideration or cross-sectional evaluation of these ultrastructural biomarkers.

Short-time effect of intravitreal injections on retinal vascular oxygenation and vessel diameter in patients with diabetic macular oedema or neovascular age-related macular degeneration.

PURPOSE: To investigate the short-time effect of intravitreal injections (IVI) of the vascular endothelial growth factor inhibitors ranibizumab and aflibercept on retinal arterial and venous oxygen saturation (SO2a and SO2v), arteriovenous oxygen saturation difference (AVD) and vessel diameter (VDa and VDv) in patients with diabetic macular oedema (DME) and patients with choroidal neovascularization (CNV) due to age-related macular degeneration. METHODS: Uncontrolled prospective observational study in 100 eyes. Retinal vessel oxygen saturation and diameters were assessed using a retinal oximeter before and minutes after IVI of ranibizumab or aflibercept. RESULTS: 40 eyes with CNV and 34 eyes with DME were included in the analysis. At baseline, SO2a and SO2v were significantly higher in DME (p = 0.043 and p = 0.009, respectively). After IVI, SO2a significantly decreased in CNV and DME eyes by 2.6% (p = 0.016) and 4.6% (p = 0.002) and SO2v decreased by 14.0% (p = 0.004) and 12.4% (p = 0.017), respectively. However, a significant increase in AVD was only found in CNV (15.7%, p = 0.001). VDa decreased significantly only in DME by 5.7% (p = 0.010). No medication-specific disease effect was found and vice versa. CONCLUSIONS: The observed changes can be interpreted as signs of increased metabolic demand during the physiological stress after an IVI. The abnormal arterial constriction and the abolished increase in AVD seen only in eyes with DME indicate an impairment of vascular autoregulation and oxygen distribution and a reduced neuroretinal metabolism in the diabetic retina with a significant impact on inner retinal oxygen consumption shortly after IVI.

Retinal and Choroidal Perfusion Status in the Area of Laser Scars Assessed With Swept-Source Optical Coherence Tomography Angiography.

Purpose: To evaluate the perfusion status of the retina and choriocapillaris in the area of laser scars on swept-source optical coherence tomography angiography (OCTA) images of eyes previously treated with panretinal photocoagulation (PRP). Methods: Cross-sectional exploratory analysis of swept-source OCTA images, which were retrospectively reviewed for laser scars. The appearance of the capillary networks in the area of previous laser were evaluated following a three-step grading system (normal/sparse/missing capillary network). The superficial and deep capillary plexus of the retina and the choriocapillaris were graded separately. Results: A total of 3140 laser scars in 54 eyes of 31 patients (13 female, mean age 57 ± 12 years) were included in this analysis. In the retina, 6.8% of the superficial and deep capillary network in the area evaluated appeared normal, 58% and 56% sparse, and 35% and 37% missing. Capillary dropout in the retina was not restricted to the area of prior laser treatment. The choriocapillaris decorrelation signal was either sparse (61%) or completely missing (38%) within the laser scar area. The perfusion of the choriocapillaris appeared normal in the area adjacent to laser scars. Conclusions: Capillary non-perfusion in the choriocapillaris was found within the laser scar area. Laser treatment seems to cause sustained non-perfusion of choriocapillaris in the area treated.

Application of optical coherence tomography angiography in diabetic retinopathy: a comprehensive review.

Optical coherence tomography angiography (OCTA) is a noninvasive method that enables visualization of blood flow within retinal vessels down to the size of capillaries by detecting motion contrast from moving blood cells. OCTA provides a fast and safe procedure to assess retinal microvasculature with higher contrast and resolution than conventional fluorescence angiography. The different capillary plexuses are displayed separately and their perfusion density can be quantified. Imaging capabilities such as these have led to an emerging field of clinical application for OCTA in vascular diseases such as diabetic retinopathy (DR). Evaluation of parameters such as parafoveal capillary perfusion density could be a biomarker for disease diagnosis and progression. Typical microvascular changes in DR such as capillary nonperfusion, microaneurysms, intraretinal microvascular abnormalities, and neovascularization can be reliably detected in optical coherence tomography angiograms, characterized in detail and attributed to the different capillary plexuses. Monitoring of these lesions in vivo gives potential novel insight into the pathophysiology in DR. The aim of this article is to summarize the potential applications/utility of OCTA in DR reported in the literature.

Atrophy of the central neuroretina in patients treated for diabetic macular edema.

PURPOSE: To examine the prevalence of central retinal atrophy in patients treated for diabetic macular edema (DME) in a clinical setting. METHODS: Retrospective data analysis of patients with DME, focusing on those who developed central retinal thinning after DME treatment at the Department of Ophthalmology, Medical University Vienna. Patient characteristics and clinical data including best-corrected visual acuity (BCVA), spectral domain optical coherence tomography and fluorescence angiography images were reviewed and DME treatment strategies analysed using descriptive statistics. The correlation between visual acuity and ocular, systemic or DME treatment factors was calculated using linear regression models and ancovas. RESULTS: A total of 6684 outpatient visits by 1437 patients with diabetes were analysed. Out of 149 patients, who had had a central subfield thickness (CST) below 200 µm, 32 (36 eyes) had previously been diagnosed with a centre involving DME with an average CST of 473 ± 103 µm and average visual acuity of 0.62 ± 0.44 logMAR at first presentation. At the time of central atrophy, 29 (81%) out of 36 eyes had a history of laser treatment, 11 (31%) a vitrectomy, 32 (88%) repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF; mean 5.3 ± 3.8) and 22 (61%) intravitreal corticosteroid injections (mean 2.5 ± 2.7). Visual function (0.67 ± 0.43 logMAR) at the time of atrophy was not significantly correlated to central retinal thickness (191 ± 7 µm) or any other ocular, systemic or treatment factors. CONCLUSIONS: Only 4% of patients treated for DME developed central retinal thinning in our observation period. On average, our atrophy patients had higher CST and lower BCVA when they first presented with DME compared to the overall DME cohort, and they received a combination of intravitreal injections and laser for DME treatment. Central retinal atrophy might not be attributed to excessive use of intravitreally applied anti-VEGF or any other DME therapy alone.

THREE-DIMENSIONAL ANALYSIS OF RETINAL MICROANEURYSMS WITH ADAPTIVE OPTICS OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To characterize retinal microaneurysms (MAs) in patients with diabetes using adaptive optics optical coherence tomography (AOOCT) and compare details found in AOOCT with those found in commercially available retinal imaging techniques. METHODS: Patients with diabetes and MA in the macular area were included in this pilot study. The area of interest, identified in standard fluorescein angiography, was imaged using an AO fundus camera and AOOCT. Microaneurysms were characterized in AOOCT (visibility, reflectivity, feeding/draining vessels, and intraretinal location) and compared with findings in AO fundus camera, OCT angiography, and fluorescein angiography. RESULTS: Fifty-three MAs were imaged in 15 eyes of 10 patients. Feeding and/or draining vessels from both capillary plexus could be identified in 34 MAs in AOOCT images. Of 45 MAs imaged with OCT angiography, 18 (40%) were visible in the superior plexus, 12 (27%) in the deep capillary plexus, and 15 MAs (33%) could not be identified at all. Intraluminal hyperreflectivity, commonly seen in AO fundus camera, corresponded only in 8 of 27 cases (30%) to intraluminal densities seen in AOOCT. CONCLUSION: Adaptive optics OCT imaging revealed that MAs located in the inner nuclear layer were connected to the intermediate and/or deep capillary plexus. Intraluminal hyperreflectivity seen on AO fundus camera images originated from a strong reflection from the vessel wall and only in a third of the cases from intraluminal clots. Currently, AOOCT is the most expedient in vivo imaging method to capture morphologic details of retinal microvasculature in 3D and in the context of the surrounding retinal anatomy.

Correlation between corneal and retinal neurodegenerative changes and their association with microvascular perfusion in type II diabetes.

PURPOSE: The pathophysiology of diabetic neurodegeneration and microvasculopathy remains controversial. Neurosensory layer thickness and corneal nerve fibre loss represent potential biomarkers of neuropathy. The purpose of this cross-sectional study was to determine the correlation between these neurodegenerative features and their association with retinal microvascular integrity in patients with type II diabetes without retinopathy. METHODS: Nerve fibre length (NFL), density (NFD) and branch density (NBD) were assessed using corneal confocal microscopy. Spectralis optical coherence tomography (OCT) was used for peripapillary retinal nerve fibre layer (RNFL), and macular RNFL, ganglion cell (GCL), inner plexiform (IPL) and inner nuclear layer (INL) thicknesses. Parafoveal vessel density (PVD) was determined using OCT angiography. RESULTS: We analysed 118 eyes of 61 patients. Peripapillary RNFL, macular RNFL, GCL, IPL and INL were 101 ± 8, 29 ± 3, 43 ± 4, 36 ± 3 and 36 ± 3 µm. NFL, NFD and NBD were 12.3 ± 4.4 mm/mm2 , 17.8 ± 7.4/mm2 and 26.7 ± 15.2/mm2 . Corneal nerve fibre variables were neither associated with inner retinal thicknesses nor PVD. A significant positive correlation was found between macular GCL, IPL and peripapillary RNFL with deep capillary plexus PVD (p ≤ 0.05). CONCLUSION: Our results indicate that corneal and retinal neurodegeneration are independent changes early in type II diabetes and that distinct retinal, but not corneal neurodegenerative features, are associated with retinal microvascular perfusion.

Dynamic Changes of Retinal Microaneurysms in Diabetes Imaged With In Vivo Adaptive Optics Optical Coherence Tomography.

Purpose: To prospectively monitor microaneurysms (MAs) in three dimensions using adaptive optics optical coherence tomography (AOOCT). Methods: Patients with diabetes mellitus and parafoveal MAs were included in this longitudinal study. At baseline, MAs were identified in standard fluorescein angiography (FA) and subsequently imaged with an AOOCT prototype, incorporated into an AO fundus camera (RTX1, Imagine Eyes) device. Imaging was repeated every 3 months in each patient to explore the potential structural change of MAs over time including size, shape, intraretinal position, (intra-) luminal reflectivity, and other qualitative morphologic characteristics. Results: We imaged 18 MAs in seven eyes (two left eyes) of five patients (mean age: 69 ± 7 years) over 18 months. All MAs appeared as saccular in the en face imaging plane at baseline, and no change in shape was observed in any of the MAs during follow-up. Evaluation of the AOOCT volumes revealed dynamic changes of MAs during follow-up including intermittent growth (n = 2), progressive involution (n = 3), total disappearance (n = 2), and MA division (n = 1). Intraluminal hyperreflective material was visualized in 11 out of 18 MAs, which remained stable (n = 3), increased (n = 2), regressed (n = 1), or fluctuated (n = 5). Three MAs without intraluminal spots at baseline progressively developed distinct hyperreflectivities. Conclusions: AOOCT illustrates the structurally dynamic evolution of MAs in vivo in three dimensions. Despite a consistent saccular shape in the en face view, AOOCT volumes revealed a heterogeneous behavior in regard to size and reflective status of MAs over time.

Association of Microaneurysms on Adaptive Optics Scanning Laser Ophthalmoscopy With Surrounding Neuroretinal Pathology and Visual Function in Diabetes.

Purpose: We evaluate diabetic microaneurysm (MA) features on high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) and their correlations with visual acuity (VA) and local retinal pathology on spectral domain optical coherence tomography (SDOCT). Methods: Diabetic participants underwent VA testing and AOSLO and SDOCT imaging of MAs. AOSLO images were graded for MA dimension, wall hyperreflectivity (WH), intraluminal hyperreflectivity (IH), and perfusion pattern. SDOCTs centered on each MA were graded for disorganization of the retinal inner layers (DRIL) and other neuroretinal pathology. Results: We imaged 109 MAs (30 eyes). Multivariate modeling, including statistically significant covariates from bivariate analyses, associated WH with greater MA size (P = 0.001) and DRIL (P = 0.04). IH was associated with perfusion (P = 0.003) and MA visibility on photographs (P = 0.0001), and larger MA size with partial perfusion (P = 0.03), MA ring signs (P = 0.0002), and photographic visibility (P = 0.01). Multivariate modeling revealed an association of WH and VA with DRIL. Conclusions: AOSLO imaging demonstrates associations of hyperreflective MA walls with MA size and adjacent DRIL, as well as the presence of DRIL with lower VA. This study identifies a correlation between vascular and neural pathology associated with VA decline. Further studies of MA structure and neuroretinal disorganization may enable novel approaches to assess anatomic and functional outcomes in the diabetic eye.

Characterization of In Vivo Retinal Lesions of Diabetic Retinopathy Using Adaptive Optics Scanning Laser Ophthalmoscopy.

PURPOSE: To characterize hallmark diabetic retinopathy (DR) lesions utilizing adaptive optics scanning laser ophthalmoscopy (AOSLO) and to compare AOSLO findings with those on standard imaging techniques. METHODS: Cross-sectional study including 35 eyes of 34 study participants. AOSLO confocal and multiply scattered light (MSL) imaging were performed in eyes with DR. Color fundus photographs (CF), infrared images of the macula (Spectralis, Heidelberg), and Spectralis spectral domain optical coherence tomography SDOCT B-scans of each lesion were obtained and registered to corresponding AOSLO images. MAIN OUTCOME MEASURES: Individual lesion characterization by AOSLO imaging. AOSLO appearance was compared with CF and SDOCT imaging. RESULTS: Characterized lesions encompassed 52 microaneurysms (MA), 20 intraretinal microvascular abnormalities (IRMA), 7 neovascularization (NV), 11 hard exudates (HE), 5 dot/blot hemorrhages (HEM), 4 cotton wool spots (CWS), and 14 intraretinal cysts. AOSLO allowed assessment of perfusion in vascular lesions and enabled the identification of vascular lesions that could not be visualized on CF or SDOCT. CONCLUSIONS: AOSLO imaging provides detailed, noninvasive in vivo visualization of DR lesions enhancing the assessment of morphological characteristics. These unique AOSLO attributes may enable new insights into the pathological changes of DR in response to disease onset, development, regression, and response to therapy.

Association of Changes in Macular Perfusion With Ranibizumab Treatment for Diabetic Macular Edema: A Subanalysis of the RESTORE (Extension) Study.

Importance: Anti-vascular endothelial growth factor treatment is the first-line therapy in the treatment of center-involving diabetic macular edema. Data on capillary perfusion changes under repeated treatment in a possibly compromised vascular network are limited. Objective: To evaluate the association of repeated ranibizumab injections on macular perfusion in patients with diabetic macular edema. Design, Setting, and Participants: This study analyzed prospectively collected data from the 12-month RESTORE core study and the 24-month open label RESTORE extension study, which assessed the efficacy and safety of ranibizumab in patients with visual impairment due to diabetic macular edema. Of 345 patients with center-involving diabetic macular edema who had enrolled in the 12-month RESTORE core study, 240 entered the 24-month RESTORE extension study. Of these, 83 (34.6%) received ranibizumab, 83 (34.6%) received ranibizumab and laser combination therapy, and 74 (30.8%) received laser monotherapy in the first year of the study; 208 completed the 24-month extension study. Fluorescence angiography images were taken from each participant twice each year graded by Vienna Reading Center on severity of capillary loss in the parafoveal area, regularity of the foveal avascular zone outline, and measurement of the size of the foveal avascular zone, following a standardized protocol. Data analysis took place from July 2014 through December 2017. Main Outcomes and Measures: Change in 3 fluorescence angiography perfusion parameters over the course of treatment. Results: Mean (SD) patient age was 62.6 (8.8) years; 124 of 208 (59.2%) were male and 197 of 208 (94.6%) were white. The number of patients with definite altered foveal avascular zone regularity at baseline was 103 of 240 patients (42.9%); another 118 patients (49.2%) had questionably altered regularity at baseline. Definitive capillary loss was found in 65 of 240 patients (27.1%) at baseline. Mean (SD) foveal avascular zone size at baseline was 0.261 (0.232) mm2 in ranibizumab monotherapy, 0.231 (0.219) mm2 in ranibizumab and macular laser combination therapy, and 0.201 (0.13) mm2 in laser monotherapy. No treatment arm experienced significant increase in foveal avascular zone size at any time in the study period. At month 36, ranibizumab monotherapy resulted in a mean increase of 0.073 mm2 (95% CI, 0.005-0.142 mm2) and combination therapy resulted in a mean increase of 0.117 mm2 (95% CI, 0.045-0.188 mm2), but no changes were statistically significant. No changes occurred in foveal avascular zone regularity in any treatment group, and no differences were found in capillary loss around the fovea in the 3 treatment groups; neither element could be correlated with visual acuity or central retinal thickness. Conclusions and Relevance: Repeated ranibizumab treatment was not associated with impaired macular perfusion in our study cohort. Because our data do not suggest a harmful effect of anti-vascular endothelial growth factor therapy on capillary integrity, patients with severe microangiopathy and advanced capillary dropout should not be denied these treatments.

Detailed analysis of retinal morphology in patients with diabetic macular edema (DME) randomized to ranibizumab or triamcinolone treatment.

PURPOSE: Our purpose was to compare the impact in diabetic macula edema (DME) of two intravitreal drugs (0.5 mg ranibizumab vs. 8 mg triamcinolone) on changes in retinal morphology in spectral-domain optical coherence tomography (SD OCT) images, color fundus photography (CF) and fluorescein angiography (FA) images during a 1-year follow-up. METHODS: Post hoc analysis was conducted of morphologic characteristics in OCT, FA and CF images of eyes with a center involving DME that were included in a prospective double-masked randomized trial. Eligible patients were divided at random into two groups receiving either pro re nata treatment with 0.5 mg ranibizumab or 8 mg triamcinolone after a fixed loading dose. OCT and CF images were acquired at monthly visits and FA images every three months. RESULTS: Twenty-five eyes of 25 patients (ranibizumab: n = 10; triamcinolone: n = 15) were included in this study. Patients treated with ranibizumab showed better visual acuity results after 12 months than patients receiving triamcinolone (p = 0.015) although edema reduction was similar (p = 0.426) in both groups. The initial effect on macular edema shedding after a single ranibizumab injection could be amplified with the following two injections of the loading dose. After a single injection of triamcinolone the beneficial initial effect on the macula edema faded within 3 months. Subretinal fluid and INL cystoid spaces diminished early in the course of treatment while fluid accumulation in the ONL seemed to be more persistent in both treatment arms. In FA, the area of leakage diminished significantly in both treatment arms. After repeated injections the morphologic OCT and FA characteristics of the treatment arms converged. CONCLUSIONS: Despite the higher dosage of triamcinolone, both therapies were safe and effective for treating diabetic macular edema. Fluid accumulation in the INL and subretinal space was more responsive to therapy than fluid accumulation in the ONL. Clinicaltrials.gov : NCT00682539.

Regional Patterns of Retinal Oxygen Saturation and Microvascular Hemodynamic Parameters Preceding Retinopathy in Patients With Type II Diabetes.

Purpose: Alterations in retinal oxygen metabolism and retinal microcirculation are signs of impending diabetic retinopathy (DR). However, if specific retinal regions are primarily affected is so far unknown. The purpose of this study was to investigate if retinal oxygen saturation (SO2) and microvascular hemodynamic parameters follow a distinct regional pattern in patients with diabetes but no DR. Methods: Patients with type II diabetes without clinically apparent DR were imaged as follows: SO2 in peripapillary vessels was assessed with dual-wavelength oximetry. Optical coherence tomography angiography (OCTA) scans were acquired with a prototype system using a swept-source laser with an effective 400 kHz A-scan rate and 16° field of view. Regional flow indices termed "flux" were calculated for the peripapillary microvasculature. Parafoveal capillary density was evaluated with the commercially available AngioVue OCTA. Results: Twenty-nine eyes of 16 consecutive patients (59 ± 10 years, 6 females) were included in this study. SO2 differed significantly between quadrants (P < 0.001), with a decreasing pattern from the upper nasal through the lower nasal, the upper temporal and the lower temporal quadrant in arterioles and venules. In contrast, peripapillary flux followed an increasing trend from nasally to temporally. Peripapillary and parafoveal microvascular hemodynamic parameters demonstrated no significant regional variability as observed for retinal oxygenation. Conclusions: Metabolic imaging identified regional differences in retinal SO2 without an associated topographic variance in microvascular hemodynamics in type II diabetes without DR. Future studies should focus on the mechanisms causing this heterogeneity in metabolic demand.