Persistent diabetic macular edema: Definition, incidence, biomarkers, and treatment methods.

Intravitreal antivascular endothelial growth factor (anti-VEGF) treatment has drastically improved the visual and anatomical outcomes in patients with diabetic macular edema (DME); however, success is not always guaranteed, and a proportion of these eyes demonstrate persistent DME (pDME) despite intensive treatment. While standardized criteria to define these treatment-resistant eyes have not yet been established, many studies refer to eyes with no clinical response or an unsatisfactory partial response as having pDME. A patient is considered to have pDME if the retinal thickness improves less than 10-25% after 6 months of treatment. A range of treatment options have been recommended for eyes with pDME, including switching anti-VEGF agents, using corticosteroids and/or antioxidant drugs in adjunct with anti-VEGF therapy, and vitrectomy. In addition, multimodal imaging of DME eyes may be advantageous in predicting the responsiveness to treatment; this is beneficial when initiating alternative therapies. We explore the literature on persistent DME regarding its defining criteria, incidence, the baseline biological markers that may be useful in anticipating the response to treatment, and the available treatment options.

Retinal Imaging Using a Confocal Scanning Laser Ophthalmoscope-Based High-Magnification Module.

PURPOSE: To evaluate the usefulness of a high-magnification module (HMM) lens to visualize retinal photoreceptors, retinal nerve fiber layer (RNFL), and superficial retinal vasculature in physiologic and pathologic retinal conditions. DESIGN: Observational descriptive study. PARTICIPANTS: Thirty-two participants with normal and pathologic retina examination results. METHODS: Normal and pathologic maculae were imaged in vivo using still and video HMM lens modes, with fixation and contrast adjustments to enhance visualization. The HMM images were classified qualitatively based on structures identified as either good (photoreceptors seen), average (photoreceptor mosaic cannot be visualized clearly, retinal vessels and other retinal changes can be seen), or poor (no identifiable structures). Selected eyes were imaged with fundus photography, OCT, OCT angiography, indocyanine green angiography, and fluorescein angiography for comparison with the pathologic maculae. MAIN OUTCOMES MEASURES: Description of HMM module-obtained macula images. RESULTS: From 32 eyes imaged (16 normal and 16 pathologic retinas), 12 of 16 normal and 11 of 16 pathologic retinas demonstrated at least average image quality, in which retinal vasculature and landmarks could be visualized. The mosaic pattern of hexagonal shapes representing photoreceptors could not be resolved in most pathologic retinas. For the retinas in which the photoreceptor mosaics were visualized (12 of 16 normal and 2 of 16 pathologic retinas), parafoveal mosaic patterns appeared denser with better image quality for all participants compared with foveal photoreceptors. Difficulty in resolving the photoreceptors in the umbo, fovea, and perifovea was encountered, similar to what has been reported with adaptive optics devices. The RNFL was seen as arcuate hyperreflective bundles. Flow was observed in the macular microvasculature. Poorly resolved photoreceptors and scattered hyperreflective foci were correlated with changes in the retinal pigment epithelium in eyes with age-related macular degeneration or central serous chorioretinopathy. Macular striae were seen in eyes with epiretinal membrane. CONCLUSIONS: In most eyes, regardless of whether retinal pathologic features were present, it was challenging to obtain average quality (or better) images. In the few participants with good-quality imaging, the parafoveal photoreceptor mosaic, vascular flow, and various features of pathologic eyes could be visualized.

Repeatability of binarization thresholding methods for optical coherence tomography angiography image quantification.

Binarization is a critical step in analysis of retinal optical coherence tomography angiography (OCTA) images, but the repeatability of metrics produced from various binarization methods has not been fully assessed. This study set out to examine the repeatability of OCTA quantification metrics produced using different binarization thresholding methods, all of which have been applied in previous studies, across multiple devices and plexuses. Successive 3 × 3 mm foveal OCTA images of 13 healthy eyes were obtained on three different devices. For each image, contrast adjustments, 3 image processing techniques (linear registration, histogram normalization, and contrast-limited adaptive histogram equalization), and 11 binarization thresholding methods were independently applied. Vessel area density (VAD) and vessel length were calculated for retinal vascular images. Choriocapillaris (CC) images were quantified for VAD and flow deficit metrics. Repeatability, measured using the intra-class correlation coefficient, was inconsistent and generally not high (ICC < 0.8) across binarization thresholds, devices, and plexuses. In retinal vascular images, local thresholds tended to incorrectly binarize the foveal avascular zone as white (i.e., wrongly indicating flow). No image processing technique analyzed consistently resulted in highly repeatable metrics. Across contrast changes, retinal vascular images showed the lowest repeatability and CC images showed the highest.

Using the Pathophysiology of Dry AMD to Guide Binarization of the Choriocapillaris on OCTA: A Model.

Especially since the incorporation of swept laser sources, optical coherence tomography angiography (OCTA) has enabled quantification of choriocapillaris perfusion. A critical step in this process is binarization, which makes angiographic images quantifiable in terms of perfusion metrics. It remains challenging to have confidence that choriocapillaris perfusion metrics reflect the reality of pathophysiologic flow, largely because choice of binarization method can result in significantly different perfusion metric outcomes. This commentary discusses a proof-of-concept case involving comparative assessment of binarization methods for a set of dry age-related macular degeneration OCTA data. One of these methods was deemed preferable based on superior agreement with suspected physiologic and pathophysiologic characteristics, thus demonstrating the principle that, in the absence of gold standards for measurement of choriocapillaris perfusion, the best available approximations of pathophysiology may be used to guide choice of binarization method.

Model-to-Data Approach for Deep Learning in Optical Coherence Tomography Intraretinal Fluid Segmentation.

Importance: Amid an explosion of interest in deep learning in medicine, including within ophthalmology, concerns regarding data privacy, security, and sharing are of increasing importance. A model-to-data approach, in which the model itself is transferred rather than data, can circumvent many of these challenges but has not been previously demonstrated in ophthalmology. Objective: To determine whether a model-to-data deep learning approach (ie, validation of the algorithm without any data transfer) can be applied in ophthalmology. Design, Setting, and Participants: This single-center cross-sectional study included patients with active exudative age-related macular degeneration undergoing optical coherence tomography (OCT) at the New England Eye Center from August 1, 2018, to February 28, 2019. Data were primarily analyzed from March 1 to June 20, 2019. Main Outcomes and Measures: Training of the deep learning model, using a model-to-data approach, in recognizing intraretinal fluid (IRF) on OCT B-scans. Results: The model was trained (learning curve Dice coefficient, >80%) using 400 OCT B-scans from 128 participants (69 female [54%] and 59 male [46%]; mean [SD] age, 77.5 [9.1] years). In comparing the model with manual human grading of IRF pockets, no statistically significant difference in Dice coefficients or intersection over union scores was found (P > .05). Conclusions and Relevance: A model-to-data approach to deep learning applied in ophthalmology avoided many of the traditional hurdles in large-scale deep learning, including data sharing, security, and privacy concerns. Although the clinical relevance of these results is limited at this time, this proof-of-concept study suggests that such a paradigm should be further examined in larger-scale, multicenter deep learning studies.

Visual and anatomic outcomes of sustained single agent anti-VEGF treatment versus double anti-VEGF switching in the treatment of persistent diabetic macular edema.

BACKGROUND: To compare the anatomical and visual outcomes in eyes with persistent diabetic macular edema (DME) after initial anti-VEGF therapy that were retreated continuously with the same anti-VEGF drug versus those that underwent two successive cycles of medication change in anti-VEGF drugs (double anti-VEGF switch). METHODS: Retrospective review of eyes with persistent DME after 3 initial consecutive monthly anti-VEGF injections. This cohort was divided into two groups: Group 1 continued to receive the same initial anti-VEGF drug for at least 18 months while group 2 eyes were switched to different anti-VEGF medications twice. Group 1 was further subdivided into: Group 1A composed of eyes with less than 20% reduction in central subfield thickness (CRT) at month 3; and group 1B eyes with greater than or equal to 20% reduction in CRT. The percentage of eyes that achieved greater than 10 letters visual acuity (VA) gain or loss was recorded as the primary end point (through month 18 in group 1 and month 6 after 2nd switch in group 2). RESULTS: Group 1A, 1B and group 2 were composed of 24, 18, and 14 eyes respectively. 34.7%, 56.2% and 36.3% of eyes achieved > 10 letters gain, while 4.3%, 6.2% and 27.2% of eyes lost > 10 letters in groups 1A, 1B, and 2, respectively. Analysis of the visual acuity (VA) letter change in this time interval revealed no significant difference between all groups (p = 0.11). Mean VA and CRT measurements at the primary endpoint in all groups were 0.5, 0.39, and 0.47 logMAR (p = 0.44), and 369.7, 279.9, 321 µm, (p = 0.01) respectively. CONCLUSIONS: There was no difference in the visual outcomes between the two treatment strategies in eyes with persistent DME after 3 consecutive anti-VEGF injections. This may indicate that anti-VEGF switching-even if it is done twice-may have comparable clinical outcomes to sustained treatment with one agent.

Morphological changes in intraretinal microvascular abnormalities after anti-VEGF therapy visualized on optical coherence tomography angiography.

BACKGROUND: To examine the baseline morphological characteristics and alterations in intraretinal microvascular abnormalities (IRMAs) in response to anti-vascular endothelial growth factor (anti-VEGF) treatment, documented by optical coherence tomography angiography (OCTA) in diabetic eyes. METHODS: In this retrospective study, IRMAs were evaluated with multimodal imaging (fundus photography, fluorescein angiography, OCTA) in treatment-naïve diabetic eyes before and after anti-VEGF treatment for diabetic macular edema (DME) and/or proliferative diabetic retinopathy (PDR) and compared to diabetic control eyes with similar diabetic retinopathy (DR) severity that did not receive anti-VEGF therapy. The morphological characteristics of IRMAs on enface OCTA imaging were graded by masked readers at baseline, then after anti-VEGF therapy in treated eyes or after observation in control eyes. Characterization of interval changes in an IRMA were based on the following parameters: branching, vessel caliber and area of adjacent capillary non-perfusion. RESULTS: The treated group included 45 IRMA foci from 15 eyes of 11 patients, while the control group included 27 IRMA foci from 15 eyes of 14 patients. Following anti-VEGF treatment, enface OCTA demonstrated that 14 foci of IRMA (31%) demonstrated regression with normalization of appearance of the capillary bed, 20 IRMAs (44%) remained unchanged, six IRMAs (13%) progressed with enlargement or development of new IRMAs and five IRMAs (11%) demonstrated complete obliteration defined as IRMA disappearance with advancing capillary drop-out. In the control group, 17 IRMA (63%) remained stable, 8 IRMAs (29.6%) progressed and 2 experienced total obliteration (7.4%). The difference in rank order between the two groups was statistically significant (p = 0.022). CONCLUSIONS: In eyes with DR status post anti-VEGF therapy, foci of IRMAs have a variable course demonstrating one of four possible outcomes: regression, stability, progression or complete obliteration. In contrast, none of the untreated control diabetic eyes demonstrated regression of IRMAs, consistent with known progression of DR severity in high risk eyes. Morphologic evaluation of IRMAs with OCTA may help to monitor changes in retinal blood flow as well as the response to anti-VEGF treatment.

Repeatability and Reproducibility of Photoreceptor Density Measurement in the Macula Using the Spectralis High Magnification Module.

PURPOSE: To evaluate the repeatability and reproducibility of photoreceptor density assessment with manual cell counting in healthy participants imaged with the Heidelberg Spectralis High Magnification Module (HMM). DESIGN: Precision study, evaluation of diagnostic test or technology. PARTICIPANTS: Eleven eyes of 8 participants. METHODS: Images were acquired using the Spectralis HMM by a single operator during 2 separate imaging sessions. The 3 highest-quality images of each eye from each session were selected for analysis and coregistered. For a subset of participants, a second operator acquired images in 1 session, and images with the best quality were selected for analysis. Photoreceptor densities were obtained by manual counts in squares of 0.0625 mm2 located in the parafovea. Repeatability (intragrader and intrasession) and reproducibility (interoperator, intergrader, and intersession) were assessed by calculating the intraclass correlation coefficient (ICC) from linear mixed effects models. Bland-Altman plots, coefficients of repeatability, and Pearson correlation results were reported. MAIN OUTCOME MEASURES: Intragrader, intrasession, intersession, interoperator, and intergrader ICC estimates and their 95% confidence intervals for photoreceptor density measurements in the parafovea. RESULTS: Twenty-four eyes of 13 healthy participants were imaged initially. Of these, 11 eyes (45.83%) of 8 participants that had at least 3 acceptable images in each session were included in this study. Mean parafoveal photoreceptor density was 14 988 cells/mm2 (standard deviation, 1403.15 cells/mm2). Intragrader ICC was 0.84 (95% confidence interval, 0.57-0.95), intrasession ICC was 0.69 (95% confidence interval, 0.17-0.86), intersession ICC was 0.88 (95% confidence interval, 0.53-0.96), interoperator ICC was 0.70 (95% confidence interval, 0-0.95), and intergrader ICC was 0.22 (95% confidence interval, 0-0.71). CONCLUSIONS: Images obtained with the HMM allow for photoreceptor mosaic visualization in the macular area, mainly in the parafovea. Although densities obtained are in accordance with other reported methods in the literature, variability within and between images of the apparent cell mosaic were observed, and this study did not demonstrate high repeatability or reproducibility for quantitative assessments using the manual counting method.

Topographic analysis of macular choriocapillaris flow deficits in diabetic retinopathy using swept-source optical coherence tomography angiography.

BACKGROUND: The purpose of this study was to investigate the association between diabetic retinopathy (DR) severity and macular choriocapillaris (CC) flow deficit percentage (FD %) in different macular regions using swept-source optical coherence tomography angiography (SS-OCTA). METHODS: Diabetic patients with SS-OCTA images were graded by severity and retrospectively assessed. CC FD % was calculated in four different regions of the OCTA image: inner, middle, outer, and full-field region. The generalized estimating equations (GEE) approach for clustered eye data was used to determine effect size and significance of age and disease severity on FD % for each region. RESULTS: 160 eyes from 90 total diabetic patients met inclusion criteria. Out of 90 patients, 33 had no DR, 17 had mild nonproliferative DR (NPDR), 8 had moderate NPDR, 10 had severe NPDR and 22 had proliferative DR. Age and DR severity had a significant positive association with FD % for each region studied with a greater effect in the two centermost regions. The increase in flow deficit percentage per year of age by region was: inner 0.12 (p < 0.001), middle 0.09 (p < 0.001), outer 0.05 (p < 0.001, full-field 0.06 (p < 0.001). The increase in flow deficit percentage per increase in diabetic retinopathy severity stage by region was: inner 0.65 (p < 0.0087), middle 0.56 (p < 0.0012), outer 0.33 (p < 0.045), full-field 0.36 (p < 0.018). CONCLUSIONS: Topographic analysis of the CC FD % in diabetic eyes suggests that CC flow impairment corresponds to DR severity, with all studied regions of the CC significantly affected. There was greater regional impairment due to age and disease severity in the inner and middle regions.

Global Analysis of Macular Choriocapillaris Perfusion in Dry Age-Related Macular Degeneration using Swept-Source Optical Coherence Tomography Angiography.

Purpose: Swept-source optical coherence tomography angiography (SS-OCTA) was used to investigate if the clinical stage of dry age-related macular degeneration (AMD) was correlated with global and regional macular choriocapillaris (CC) perfusion. Methods: In this retrospective, cross-sectional study, 6 × 6-mm SS-OCTA images from eyes with early, intermediate, and advanced dry AMD (56 eyes, 41 patients) were analyzed using algorithms described in the literature to assess regional flow deficit percentage (FD%) and average flow deficit size. Regions were defined by concentric areas centered on the fovea: a 1-mm-diameter area, 3-mm-diameter ring, 5-mm-diameter area, 5-mm-diameter ring, and 6 × 6-mm whole image. Data were modeled using the generalized estimating equations approach. Results: The relationship between age and CC FD% and average flow deficit size was statistically significant (P ≤ 0.05) in all regions of analysis by linear modeling. The relationship between dry AMD stage and FD% was statistically significant by linear modeling in the 5-mm ring, and between dry AMD stage and average flow deficit size in the 3-mm ring, 5-mm area, 5-mm ring, and 6 × 6-mm whole image. Conclusions: Linear modeling suggests a statistically significant relationship between dry AMD stage and CC perfusion, most prominent in the more peripheral regions of the macula.

Accuracy and Reliability in Differentiating Retinal Arteries and Veins Using Widefield En Face OCT Angiography.

PURPOSE: To evaluate the accuracy and reliability in differentiating retinal arteries from veins using widefield optical coherence tomography angiography (OCTA). METHODS: Ten healthy eyes and 12 eyes from diabetic patients were included. Foveal-centered swept-source OCTA images (12 × 12 mm) were obtained using the PLEX Elite 9000. Vessels were graded as arteries or veins by two independent, masked readers. Arteriovenous crossings were also evaluated in healthy eyes. The vessel identification gold standard was defined using color fundus photographs (CFP) for normal eyes and both CFP and fluorescein angiography for diabetic eyes. Grading accuracy was compared to the gold standard and reliability between readers assessed. RESULTS: The study evaluated 538 vessels (119 first order, 110 second, 309 third) in healthy eyes and 645 vessels (184 first order, 159 second, 302 third). In healthy eyes, the average accuracies identifying all, first-, second-, and third-order vessels were 98.61%, 99.16%, 100%, and 98.06%, respectively. Cohen's κ between graders in all vessels was 0.948. In diabetic eyes, the average accuracies identifying vessels were 96.90%, 99.46%, 97.77%, and 94.85%, respectively. Cohen's κ between graders for all vessels was 0.888. For crossing identification, the average accuracy and Cohen's κ were low (60.71% and 0.659, respectively). CONCLUSIONS: En face OCTA allows for accurate and reliable artery and vein identification; for small branches and crossings, identification by en face OCTA alone may be less accurate and reliable. TRANSLATIONAL RELEVANCE: Arteries and veins can be differentiated on OCTA, assisting in clinically identifying pathology as arterial or venous side.

Impact of Binarization Thresholding and Brightness/Contrast Adjustment Methodology on Optical Coherence Tomography Angiography Image Quantification.

PURPOSE: Binarization is a critical technique in optical coherence tomography angiography (OCTA) image analysis, but there is no consistency in the method used in published OCTA studies. This study assessed whether differences in OCTA binarization and brightness and contrast adjustments affect quantification measurements. DESIGN: Prospective cross-sectional validity study. METHODS: This was a single-center study examining 21 eyes of 11 healthy individuals. All eyes were imaged using a swept-source OCTA (Zeiss), and quantitative measurements resulting from five binarization thresholding and five brightness/contrast adjustment methods were compared. All measurements were calculated for the superficial plexus and choriocapillaris (CC), as well as unaveraged and averaged en face OCTA images. RESULTS: There were statistically significant differences between measurements from different binarization thresholding methods (P < 0.0001), as well as measurements from different histogram adjustments (P < 0.0001). The binarization thresholds yielded different measurements when combined with variable brightness/contrast adjustments. The method of analysis also affected the directionality of trends in imaging measurements between unaveraged and averaged CC images. CONCLUSIONS: The method of OCTA image binarization thresholding and histogram adjustment significantly alters quantitative measurements and the directionality of trends. Results obtained from different OCTA binarization methods should be seen as valid only for that given method. This has significant consequences for clinical trials using OCTA measurements as outcome measurements. A consensus is needed across the research community for a consistent method for OCTA image quantification and greater attention paid to fully describing methods in published studies.