Deep learning for automatic prediction of early activation of treatment naïve non-exudative MNVs in AMD.

BACKGROUND: Around 30% of non-exudative macular neovascularizations(NE-MNVs) exudate within 2 years from diagnosis in patients with age-related macular degeneration(AMD).The aim of the study is to develop a deep learning classifier based on optical coherence tomography(OCT) and OCT angiography(OCTA) to identify NE-MNVs at risk of exudation. METHODS: AMD patients showing OCTA and fluorescein angiography (FA) documented NE-MNV with a 2-years minimum imaging follow-up were retrospectively selected. Patients showing OCT B-scan-documented MNV exudation within the first 2 years formed the EX-GROUP while the others formed QU-GROUP.ResNet-101, Inception-ResNet-v2 and DenseNet-201 were independently trained on OCTA and OCT B-scan images. Combinations of the 6 models were evaluated with major and soft voting techniques. RESULTS: Eighty-nine (89) eyes of 89 patients with a follow-up of 5.7 ± 1.5 years were recruited(35 EX GROUP and 54 QU GROUP). Inception-ResNet-v2 was the best performing among the 3 single convolutional neural networks(CNNs).The major voting model resulting from the association of the 3 different CNNs resulted in improvement of performance both for OCTA and OCT B-scan (both significantly higher than human graders' performance). Soft voting model resulting from the combination of OCTA and OCT B-scan based major voting models showed a testing accuracy of 94.4%. Peripheral arcades and large vessels on OCTA enface imaging were more prevalent in QU GROUP. CONCLUSIONS: Artificial intelligence shows high performances in identifications of NE-MNVs at risk for exudation within the first 2 years of follow up, allowing better customization of follow up timing and avoiding treatment delay. Better results are obtained with the combination of OCTA and OCT B-scan image analysis.

NONEXUDATIVE INTRARETINAL FLUID IN INTERMEDIATE AGE-RELATED MACULAR DEGENERATION.

BACKGROUND: To describe the occurrence of nonexudative intraretinal fluid (IRF) in intermediate age-related macular degeneration. METHODS: A retrospective study was designed to include consecutive cases with intermediate age-related macular degeneration associated with IRF. A multimodal imaging approach was used to confirm diagnosis of IRF in intermediate age-related macular degeneration. Multimodal imaging included color fundus photograph, fundus autofluorescence, fluorescein angiography, indocyanine green angiography, optical coherence tomography, and optical coherence tomography angiography. RESULTS: Ten eyes of 10 patients (2 male and 8 female patients, ages 68-80 years) showing IRF in intermediate age-related macular degeneration were included in the study. The mean best-corrected visual acuity was 20/40 Snellen equivalent. Multimodal imaging including fluorescein angiography/indocyanine green angiography and optical coherence tomography demonstrated the absence of macular neovascularization in all cases; optical coherence tomography-angiography did not detect any abnormal flow signal associated with IRF. Seven of 10 patients developed IRF in correspondence of pigment epithelium detachment. Three of 10 patients presented IRF in correspondence of an area of nascent geographic atrophy. CONCLUSION: Nonexudative intraretinal fluid in intermediate age-related macular degeneration is a novel, distinctive feature that is characterized by the presence of IRF with no evidence of macular neovascular lesions. The authors described different phenotypes of IRF in intermediate age-related macular degeneration. The definite diagnosis of this condition requires further studies with thorough application of multimodal imaging.

PHENOTYPIC CHARACTERIZATION OF PREDICTORS FOR DEVELOPMENT AND PROGRESSION OF GEOGRAPHIC ATROPHY USING OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To evaluate the impact of optical coherence tomography phenotypes preceding atrophy related to age-related macular degeneration on the progression of atrophic lesions. METHODS: In this observational retrospective cohort study, a total of 70 eyes of 60 consecutive patients with intermediate age-related macular degeneration with a minimum follow-up of 24 months were included. The atrophy was quantified using fundus autofluorescence, also considering the directionality of atrophy as centrifugal and centripetal progression rates. The main outcome measures were geographic atrophy (GA) progression rate (mm 2 /year) and square root transformation of GA (mm 2 /year). RESULTS: The best-fit model for GA (odds ratio: 1.81, P < 0.001) and square root transformation of GA (odds ratio: 1.36, P < 0.001) areas revealed that the main baseline predictor was the presence of a retinal pigment epithelium-basal lamina-Bruch membrane splitting. Large drusen at baseline appeared protective for the GA area lesion expansion over time (odds ratio: 0.52, P < 0.001) when considered with other confounders. CONCLUSION: A thin retinal pigment epithelium-basal lamina-Bruch membrane splitting without evidence of neovascularization on optical coherence tomography angiography likely represents an optical coherence tomography signature for late basal laminar deposits. Identifying this phenotype can help identify individuals with a higher risk of rapid progression and atrophy expansion.

Anti-vascular endothelial growth factor for diabetic macular oedema: a network meta-analysis.

Background: Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) can reduce oedema, improve vision, and prevent further visual loss. These drugs have replaced laser photocoagulation as the standard of care for people with DMO. In the previous update of this review, we found moderate-quality evidence that, at 12 months, aflibercept was slightly more effective than ranibizumab and bevacizumab for improving vision in people with DMO, although the difference may have been clinically insignificant (less than 0.1 logarithm of the minimum angle of resolution (logMAR), or five Early Treatment Diabetic Retinopathy Study (ETDRS) letters, or one ETDRS line). Objectives: The objective of this updated review was to compare the effectiveness and safety of the different anti-VEGF drugs in RCTs at longer followup (24 months). Search methods: We searched various electronic databases on 8 July 2022. Selection criteria: We included randomised controlled trials (RCTs) that compared any anti-angiogenic drug with an anti-VEGF mechanism of action versus another anti-VEGF drug, another treatment, sham, or no treatment in people with DMO. Data collection and analysis: We used standard Cochrane methods for pairwise meta-analysis and we augmented this evidence using network meta-analysis (NMA) methods. We used the Stata 'network' meta-analysis package for all analyses. We used the CINeMA (Confidence in Network Meta-Analysis) web application to grade the certainty of the evidence. Main results: We included 23 studies (13 with industry funding) that enrolled 3513 people with DMO (median central retinal thickness (CRT) 460 microns, interquartile range (IQR) 424 to 482) and moderate vision loss (median best-corrected visual acuity (BCVA) 0.48 logMAR, IQR 0.42 to 0.55. One study that investigated ranibizumab versus sham and one study that mainly enrolled people with subclinical DMO and normal BCVA were not suitable for inclusion in the efficacy NMA. Consistent with the previous update of this review, we used ranibizumab as the reference drug for efficacy, and control (including laser, observation, and sham) as the reference for systemic safety. Eight trials provided data on the primary outcome (change in BCVA at 24 months, in logMAR: lower is better). We found no evidence of a difference between the following interventions and ranibizumab alone: aflibercept (mean difference (MD) -0.05 logMAR, 95% confidence interval (CI) -0.12 to 0.02; moderate certainty); bevacizumab (MD -0.01 logMAR, 95% CI -0.13 to 0.10; low certainty), brolucizumab (MD 0.00 logMAR, 95% CI -0.08 to 0.07; low certainty), ranibizumab plus deferred laser (MD 0.00 logMAR, 95% CI -0.11 to 0.10; low certainty), and ranibizumab plus prompt laser (MD 0.03 logMAR, 95% CI -0.04 to 0.09; very low certainty). We also analysed BCVA change at 12 months, finding moderate-certainty evidence of increased efficacy with brolucizumab (MD -0.07 logMAR, 95%CI -0.10 to -0.03 logMAR), faricimab (MD -0.08 logMAR, 95% CI -0.12 to -0.05), and aflibercept (MD -0.07 logMAR, 95 % CI -0.10 to -0.04) compared to ranibizumab alone, but the difference could be clinically insignificant. Compared to ranibizumab alone, NMA of six trials showed no evidence of a difference with aflibercept (moderate certainty), bevacizumab (low certainty), or ranibizumab with prompt (very low certainty) or deferred laser (low certainty) regarding improvement by three or more ETDRS lines at 24 months. There was moderate-certainty evidence of greater CRT reduction at 24 months with brolucizumab (MD -23 microns, 95% CI -65 to -1 9) and aflibercept (MD -26 microns, 95% CI -53 to 0.9) compared to ranibizumab. There was moderate-certainty evidence of lesser CRT reduction with bevacizumab (MD 28 microns, 95% CI 0 to 56), ranibizumab plus deferred laser (MD 63 microns, 95% CI 18 to 109), and ranibizumab plus prompt laser (MD 72 microns, 95% CI 25 to 119) compared with ranibizumab alone. Regarding all-cause mortality at the longest available follow-up (20 trials), we found no evidence of increased risk of death for any drug compared to control, although effects were in the direction of an increase, and clinically relevant increases could not be ruled out. The certainty of this evidence was low for bevacizumab (risk ratio (RR) 2.10, 95% CI 0.75 to 5.88), brolucizumab (RR 2.92, 95% CI 0.68 to 12.58), faricimab (RR 1.91, 95% CI 0.45 to 8.00), ranibizumab (RR 1.26, 95% CI 0.68 to 2.34), and very low for conbercept (RR 0.33, 95% CI 0.01 to 8.81) and aflibercept (RR 1.48, 95% CI 0.79 to 2.77). Estimates for Antiplatelet Trialists Collaboration arterial thromboembolic events at 24 months did not suggest an increase with any drug compared to control, but the NMA was overall incoherent and the evidence was of low or very low certainty. Ocular adverse events were rare and poorly reported and could not be assessed in NMAs. Authors' conclusions: There is limited evidence of the comparative efficacy and safety of anti-VEGF drugs beyond one year of follow-up. We found no clinically important differences in visual outcomes at 24 months in people with DMO, although there were differences in CRT change. We found no evidence that any drug increases all-cause mortality compared to control, but estimates were very imprecise. Evidence from RCTs may not apply to real-world practice, where people in need of antiangiogenic treatment are often under-treated, and the individuals exposed to these drugs may be less healthy than trial participants.

SUBRETINAL LIPID GLOBULES AN EARLY BIOMARKER OF MACULAR NEOVASCULARIZATION IN EYES WITH INTERMEDIATE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To explore the association between subretinal lipid globules (SLGs) detected in eyes with intermediate age-related macular degeneration with the presence of nonexudative macular neovascularization. METHODS: This was a retrospective analysis of 113 consecutive patients with bilateral intermediate age-related macular degeneration (226 eyes) followed for a least 6 months. All eyes underwent multimodal imaging with fundus autofluorescence, spectral-domain optical coherence tomography, and optical coherence tomography angiography. Subretinal lipid globules were identified on spectral-domain optical coherence tomography as round hyporeflective lesions measuring 31 to 157 µ m located between the ellipsoid zone and the retinal pigment epithelium/Bruch membrane complex. Nonexudative macular neovascularization was detected with optical coherence tomography angiography. The features of NE-MNV lesions detected in eyes with SLGs were compared with those in eyes without SLGs. RESULTS: Subretinal lipid globules were identified in 15 eyes of which 14 eyes (93.3%) demonstrated NE-MNV on optical coherence tomography angiography. In the remaining 98 eyes without SLGs, 18 (18.4%) displayed NE-AMD on optical coherence tomography angiography. The macular neovascularization area was larger in the SLG subgroup (+0.38 vs. +0.21 mm 2 , P = 0.008) and showed faster horizontal growth (+727 µ m, CI 95% 250.4, 1,205.4) than MNV in eyes without SLGs (+64.9 µ m, CI 95%, 24.3, 154) on optical coherence tomography B-scans. After a mean of 11.6 months, the conversion rate to exudative MNV was similar between eyes with SLGs and those without SLGs [8/26 (38.5%) versus 3/13 (27.3%), P = 0.56)]. CONCLUSION: The detection of SLGs in eyes with intermediate age-related macular degeneration was strongly correlated with the presence of NE-MNV. Although these MNV lesions were larger and grew faster than NE-MNV detected in eyes lacking SLGs, the rates of conversion to exudative MNV appeared similar.

ARTIFICIAL INTELLIGENCE'S ROLE IN DIFFERENTIATING THE ORIGIN FOR SUBRETINAL BLEEDING IN PATHOLOGIC MYOPIA.

PURPOSE: To identify salient imaging features to support human-based differential diagnosis between subretinal hemorrhage (SH) due to choroidal neovascularization (CNV) onset and SH without CNV (simple bleeding [SB]) in pathologic myopia eyes using a machine learning (ML)-based step-wise approach. METHODS: Four different methods for feature extraction were applied: GradCAM visualization, reverse engineering, image processing, and human graders' measurements. GradCAM was performed on a deep learning model derived from Inception-ResNet-v2 trained with OCT B-scan images. Reverse engineering consisted of merging U-Net architecture with a deconvolutional network. Image processing consisted of the application of a local adaptive threshold. Available OCT B-scan images were divided in two groups: the first group was classified by graders before knowing the results of feature extraction and the second (different images) was classified after familiarization with the results of feature extraction. RESULTS: Forty-seven and 37 eyes were included in the CNV group and the simple bleeding group, respectively. Choroidal neovascularization eyes showed higher baseline central macular thickness ( P = 0.036). Image processing evidenced in CNV eyes an inhomogeneity of the subretinal material and an interruption of the Bruch membrane at the margins of the SH area. Graders' classification performance improved from an accuracy of 76.9% without guidance to 83.3% with the guidance of the three methods ( P  = 0.02). Deep learning accuracy in the task was 86.0%. CONCLUSION: Artificial intelligence helps identifying imaging biomarkers suggestive of CNV in the context of SH in myopia, improving human ability to perform differential diagnosis on unprocessed baseline OCT B-scan images. Deep learning can accurately distinguish between the two causes of SH.

Choroidal vascularity index in eyes with central macular atrophy secondary to age-related macular degeneration and Stargardt disease.

PURPOSE: To compare macular atrophy (MA) secondary to age-related macular degeneration (AMD) and Stargardt disease (STGD) using the choroidal vascularity index (CVI). METHODS: In this multicentric retrospective study, two distinct cohorts were collected: patients with MA secondary to AMD and MA secondary to STGD. All patients were investigated using a multimodal imaging approach, including CVI in the subfoveal 1000 µm area. Of note, the CVI is not influenced by aging, which allows comparisons between different cohorts. RESULTS: Seventy eyes were included: 35 eyes of 35 patients (mean age 78 ± 7 years) in the AMD group and 35 eyes of 35 patients (mean age 41 ± 16 years, p < 0.001) in the STGD group. Choroidal thickness was significantly lower in the AMD group in comparison to the STGD group (151 ± 80 µm vs 353 ± 105 µm, p < 0.001). The total choroidal area (TCA) was significantly greater in the STGD group in comparison to the AMD group (1.734 ± 0.958 mm2 vs 0.538 ± 0.391 mm2, respectively, p < 0.001). Interestingly, the CVI was significantly lower in AMD patients in comparison to STGD patients (27.322 ± 15.320% vs 49.880 ± 7.217%, respectively, p < 0.001), and this difference was confirmed in the subgroup of patients over 50 years old. CONCLUSION: Our results corroborate the hypothesis that large choroidal vessels were impaired to a greater extent in AMD than in STGD. CVI may help in differentiating AMD from STGD in the presence of MA, better understanding of the pathogenesis, and monitoring of therapeutic response.

A COMMON FINDING IN FOVEAL-SPARING EXTENSIVE MACULAR ATROPHY WITH PSEUDODRUSEN IMPLICATES BASAL LAMINAR DEPOSITS.

PURPOSE: To characterize structural and clinical alterations preceding the diffuse macular atrophy in extensive macular atrophy with pseudodrusen (EMAP) and their evolution toward atrophic changes. METHODS: A retrospective chart review was performed of patients with early-onset reticular pseudodrusen (i.e., pre-EMAP) younger than 55 years and EMAP with foveal sparing. Patients were included if they had complete medical records and multimodal imaging. RESULTS: A total of 12 patients were reviewed, of whom 4 of 12 patients (7 eyes) presented a pre-EMAP stage, characterized by the presence of pseudodrusen-like deposits without atrophic changes, while the remaining 8 of 12 patients (10 eyes) exhibited EMAP with foveal sparing (60.1 ± 6.4 years). Subretinal deposits of various stages tended to fade, leaving subretinal pigment epithelium accumulation of hyperreflective material with a physical separation between the retinal pigment epithelium-basal lamina and the Bruch membrane, along with the persistence of hyperreflective material after retinal pigment epithelium loss. These findings preceded atrophy development in a pre-EMAP stage and the EMAP stage with foveal sparing. CONCLUSION: Our findings presented distinct multimodal imaging features in eyes with reticular pseudodrusen depicting a peculiar phenotype of rapidly progressing atrophy in midlife. The disease spectrum may include other forms of geographic atrophy allied by thickened basal laminar deposits.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY CHARACTERIZATION OF EVOLVING LESIONS IN FELLOW EYES OF EXUDATIVE TYPE 3 MACULAR NEOVASCULARIZATION PATIENTS.

PURPOSE: To investigate fellow eyes of newly diagnosed unilateral exudative Type 3 (T3) macular neovascularization (MNV) patients by assessing the presence and progression of a preclinical neovascular component during a 3-year follow-up. METHODS: This is a longitudinal study involving three retinal referral centers. Patients affected by unilateral exudative treatment-naive T3 MNV were enrolled. RESULTS: Twenty-four eyes of 24 patients (79 ± 6 years old) were enrolled. Nine eyes (37%) displayed a nonexudative T3 MNV at baseline that developed exudation after a mean of 9 ± 9 months. Fifteen eyes that did not display a nonexudative Type 3 MNV at baseline. Five eyes (21%) did not display neovessels at baseline, but showed a nonexudative T3 after 13 ± 9 months, and exudation after 8 ± 3 months. Five eyes (21%) developed active exudative T3 MNV after 23 ± 9 months, with no detectable nonexudative stage at baseline. Five eyes (21%) did not show MNV, but progressed to geographic atrophy by 36 months of follow-up. Overall, T3 MNV in the fellow eye accounted for 79%, all developing exudation over 3 years of follow-up. CONCLUSION: The occurrence of a nonexudative T3 MNV is a frequent event in the fellow eye of patients newly diagnosed with unilateral exudative T3 MNV and it precedes the development of exudation over 3 years (prevalence of 37% and cumulative incidence of 79%). Optical coherence tomography angiography approach may be used to perform an early diagnosis and treatment of patients with T3 MNV.

Branch retinal artery occlusion caught in the act by an optical coherence tomography angiography image: case report.

BACKGROUND: Retinal artery occlusion is a vascular entity caused by the temporary blockage of retinal arterioles. CASE PRESENTATION: We present the case of a 57-year-old woman a partial visual loss in the right eye due to a cilioretinal artery occlusion. Ophthalmoscopy revealed a focal area of retinal whitening superior to the optic nerve in the right eye, while the left eye was within the limit. Retinal imaging, in particular optical coherence tomography angiography (OCTA), showed a capillary drop out of the superficial capillary plexus and the corresponding b-scan showed a round hyporeflective grey dot (optical empty) corresponding to the dark grey spot on the enface view at the level of the retinal whitening area. CONCLUSION: Although the images did not allow the differentiation between vasospasm or retinal emboli, the OCTA imaging might help to identify and to caught in the act the specific region causing the retinal impairment. Also, the possible formation of small microcavity should be considered in case with branch retinal artery occlusion. The use of this new imaging technology might help to evaluate the efficacy of the therapy in vivo.

Optical Coherence Tomography Angiography in Central Retinal Vein Occlusion: Macular Changes and Their Correlation with Peripheral Nonperfusion at Ultra-Widefield Fluorescein Angiography.

INTRODUCTION: The aim of this study was to investigate the correlation between ischemic index (ISI) measured on ultra-widefield (UWF) fluorescein angiography (FA) images and macular parameters obtained by optical coherence tomography angiography (OCT-A) in eyes affected by central retinal vein occlusion (CRVO). METHODS: Retrospective study of data from 12 eyes affected by treatment-naïve CRVO. All patients underwent a comprehensive ocular examination including structural OCT, OCT-A, and UWF FA. Variables analyzed included best corrected visual acuity (BCVA) measured with the ETDRS chart; foveal avascular zone (FAZ) area at full-thickness OCT-A angiogram; perfusion density (PD) in the superficial (SCP) and deep capillary plexus (DCP); ISI; and central macular thickness (CMT). RESULTS: ISI showed a significant positive correlation with FAZ area (r = 0.63, p = 0.019) and a significant negative correlation with PD in the SCP (r = -0.62, p = 0.022), PD in the DCP (r = -0.66, p = 0.011), and BCVA (r = -0.75, p = 0.002). FAZ area also negatively correlated to PD in the SCP (r = -0.75, p = 0.002) and DCP (r = -0.64, p = 0.016). BCVA positively correlated to PD in the SCP (r = 0.67, p = 0.009) and DCP (r = 0.68, p = 0.008), while a negative correlation was found with FAZ area (r = -0.65, p = 0.013) and CMT (r = -0.70, p = 0.006). DISCUSSION/CONCLUSION: OCT-A macular parameters (namely, FAZ area and PD of SCP and DCP) significantly correlated with ISI, a quantitative way to assess peripheral retinal nonperfusion on UWF FA. Macular OCT-A analysis may help in assessing the need for additional UWF FA testing in eyes affected by CRVO.

Biallelic Inactivating TUB Variants Cause Retinal Ciliopathy Impairing Biogenesis and the Structure of the Primary Cilium.

Inherited retinal degeneration (IRD) represents a clinically variable and genetically heterogeneous group of disorders characterized by photoreceptor dysfunction. These diseases typically present with progressive severe vision loss and variable onset, ranging from birth to adulthood. Genomic sequencing has allowed to identify novel IRD-related genes, most of which encode proteins contributing to photoreceptor-cilia biogenesis and/or function. Despite these insights, knowledge gaps hamper a molecular diagnosis in one-third of IRD cases. By exome sequencing in a cohort of molecularly unsolved individuals with IRD, we identified a homozygous splice site variant affecting the transcript processing of TUB, encoding the first member of the Tubby family of bipartite transcription factors, in a sporadic case with retinal dystrophy. A truncating homozygous variant in this gene had previously been reported in a single family with three subjects sharing retinal dystrophy and obesity. The clinical assessment of the present patient documented a slightly increased body mass index and no changes in metabolic markers of obesity, but confirmed the occurrence of retinal detachment. In vitro studies using patient-derived fibroblasts showed the accelerated degradation of the encoded protein and aberrant cilium morphology and biogenesis. These findings definitely link impaired TUB function to retinal dystrophy and provide new data on the clinical characterization of this ultra-rare retinal ciliopathy.

USING THREE-DIMENSIONAL OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY METRICS IMPROVES REPEATABILITY ON QUANTIFICATION OF ISCHEMIA IN EYES WITH DIABETIC MACULAR EDEMA.

PURPOSE: Two-dimensional (2D) optical coherence tomography angiography (OCTA) is known to be prone to segmentation errors, especially in pathologic eyes. Therefore, our aim was to systematically compare intrasession repeatability between repeated scans for 2D and three-dimensional (3D) OCTA metrics in quantifying retinal perfusion in eyes with diabetic macular edema. METHODS: Diabetic patients with diabetic retinopathy and diabetic macular edema who had two consecutive OCTA imaging scans obtained during the same visit were retrospectively included. A previously validated algorithm was applied to OCTA volume data to measure the 3D vascular volume and perfusion density. Optical coherence tomography angiography en face images were also processed to obtain 2D perfusion density metrics. RESULTS: Twenty patients (20 eyes) with diabetic retinopathy and diabetic macular edema were included. The intraclass correlation coefficient ranged from 0.591 to 0.824 for 2D OCTA metrics and from 0.935 to 0.967 for 3D OCTA metrics. Therefore, compared with the 2D OCTA analysis, the intraclass correlation coefficients of the 3D OCTA analysis were higher (without overlapping of the 95% confidential intervals). Similarly, the coefficient of variation (ranging from 2.2 to 4.2 for 2D OCTA metrics and from 1.9 to 2.0 for 3D OCTA metrics) indicated that the 3D OCTA-based quantifications had the highest interscan intrasession agreements. Differences in interscan 2D OCTA metrics' values were associated with average macular volume. CONCLUSION: Three-dimensional OCTA metrics have higher values of intrasession repeatability, as compared with 2D OCTA metrics. The latter finding seems to be related to the high rate of segmentation errors occurring in diabetic macular edema eyes.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY ASSESSMENT OF THE DIABETIC MACULA: A Comparison Study Among Different Algorithms.

PURPOSE: To assess the impact of histogram adjustments and binarization thresholding selection on quantitative measurements of diabetic macular ischemia using optical coherence tomography angiography (OCTA). METHODS: Patients with diabetic retinopathy (DR) who had swept-source OCTA imaging obtained were enrolled. An additional group of 15 healthy control subjects was included for comparison. Previously used brightness/contrast changes and binarization thresholds were applied to original OCTA images to obtain and compare different binarized images. Qualitative and quantitative comparisons were performed. RESULTS: Thirty patients with DR (30 eyes) were included in the analysis. Fifteen eyes displayed the presence of diabetic macular edema. Qualitative grading revealed that binarized images obtained using a global threshold had better quality compared with local or multistep thresholds. The "median" filter was most frequently graded as the histogram adjustment resulting in binarized images with best quality. In the quantitative analysis, local thresholds tended to generate higher values of measured metrics. Differences in OCTA metrics between global and local thresholds were associated with presence of diabetic macular edema and signal strength index value. In the comparison between healthy and DR eyes, differences in OCTA metrics were significantly affected by binarization threshold selection. CONCLUSION: Quantitative OCTA parameters may be significantly influenced by strategies to quantify macular perfusion. Image quality and presence of macular edema can significantly impact OCTA-derived quantitative vascular measurements and differences between global and local binarization thresholds. These findings highlight the importance of consistent strategies to reliably generate quantitative OCTA metrics in patients with DR.

Standardization of Optical Coherence Tomography Angiography Imaging Biomarkers in Diabetic Retinal Disease.

Optical coherence tomography Angiography (OCT-A) represents a revolution in the noninvasive evaluation of retinal and choroidal circulation especially in detecting early clinical signs of diabetic retinal disease (DRD). With appropriate use, OCT-A characteristics and measurements have the potential to become new imaging biomarkers in managing and treating DRD. Major challenges include (a) provision of standardized outputs from different OCT-A instruments providing standardized terminology to correctly interpret data; (b) the presence of artifacts; (c) the absence of standardized grading or interpretation method in the evaluation of DRD, similar to that already established in fundus photography; and (d) establishing how OCT-A might be able to provide surrogate markers to demonstrate blood retinal barrier breakdown and vascular leakage, commonly associated with DRD. In fact, OCT-A guidelines for DRD are still evolving. The outputs of quantitative OCT-A data offer a unique opportunity to develop tools based on artificial intelligence to assist the clinicians in diagnosing, monitoring, and managing patients with diabetes. In addition, OCT-A has the potential to become a useful tool for the evaluation of cardiovascular diseases and different neurological diseases including cognitive impairment. This article written by the members of Diabetic Retinopathy expert committee of the European Vision Clinical Research network will review the available evidence on the use of OCT-A as an imaging biomarker in DRD and discuss the limits and the current application as well as future developments for its use in both clinical practice and research trials of DRD.

Multimodal imaging characterization of peripheral drusen.

PURPOSE: To provide an integrate multimodal imaging characterization of peripheral drusen in the eyes with and without macular signs of age-related macular degeneration (AMD) and to analyze their association with macular findings. METHODS: In this retrospective, cross-sectional study, subjects with peripheral drusen were imaged with the Optos (Optos PLC, Dunfermline, Scotland, UK) and Spectralis devices to obtain referenced spectral domain optical coherence tomography (SD-OCT) images. Two experienced graders independently graded the ultra-widefield (UWF) pseudocolor and fundus autofluorescence (FAF) images for the presence of peripheral drusen and analyzed peripheral druse features using OCT. Main outcome measures included quantitative and qualitative assessment of peripheral drusen. RESULTS: Fifty-seven eyes (30 subjects) were included in the analysis. Mean ± SD age was 77.6 ± 9.2 years (range 54-97 years). On pseudocolor images, graders identified the presence of drusen in all the enrolled eyes (Cohen's kappa was 1.0). On FAF images, Cohen's kappa was 0.71. In the topographical assessment, peripheral drusen were detected in 23 cases in the temporal region, in 40 cases in the nasal region, in 40 cases in the inferior region, and in 42 cases in the superior region. On SD-OCT images, peripheral drusen had a high reflective core in 97.1% of cases, while remaining drusen were characterized by a low reflective core. The macula was affected by early/intermediate AMD in 23 eyes (43.5%) and late AMD in 6 eyes (10.5%). CONCLUSIONS: We provided an integrate multimodal imaging assessment of peripheral drusen in the eyes with and without AMD. Peripheral drusen were characterized by distinguished features that may suggest that these lesions constitute a distinct disease, rather than representing an expansion of AMD.

Microvasculature Changes of Myopic Choroidal Neovascularization and the Predictive Value of Feeder Vessel Disappearance after Ranibizumab Treatment Revealed Using Optical Coherence Tomography Angiography.

AIM: To investigate vascular changes of myopic choroidal neovascularization (mCNV) after ranibizumab treatment using optical coherence tomography-angiography (OCTA). METHODS: Consecutive subjects with a diagnosis of mCNV were included. Patients underwent intravitreal injection of ranibizumab treatment with a 6-month follow-up. All patients underwent a complete ophthalmological examination and OCTA evaluation. The 3 × 3 OCTA en face images were analyzed for the absence/presence of mCNV, CNV area, and CNV network morphology. In particular, the morphology of the mCNV was analyzed in order to detect the presence/absence of feeder vessels. RESULTS: Eleven subjects were evaluated. At baseline, the mCNV was identified in all cases on OCTA. At 6 months, the mean mCNV area was not statically significantly reduced in comparison with baseline values (p > 0.05), while the morphologic analysis revealed a complete disappearance of the feeder vessel in 6 eyes. The subgroup analysis of these latter showed that the CNV area was significantly reduced, visual acuity had improved, and only one intravitreal injection was administrated over the entire follow-up period. CONCLUSIONS: OCTA allowed the detection of qualitative and quantitative vascular changes in mCNV. The disappearance of the feeder vessel was associated with better anatomical as well as functional outcomes at the last follow-up visit.

Treatment of Diabetic Macular Edema with Multiple Dexamethasone Intravitreal Implants: Evidence from Real-Life Experience.

OBJECTIVE: To gain information about multiple dexamethasone intravitreal implant (DEX-I) injections in diabetic macular edema (DME) eyes in real-life clinical settings. METHODS: Patients with DME treated with multiple (≥5) DEX-I injections between January 1, 2014, and December 31, 2018, were retrospectively enrolled regardless of previous treatment with anti-VEGF agents. All patients were evaluated with best-corrected visual acuity (BCVA) in logMAR, ocular fundus, and spectral domain optical coherence tomography (SD-OCT) at baseline and at 3 months after the last DEX-I injection. Multiple DEX-I injections were administered when necessary in case of DME recurrence. Main efficacy measures were changes in BCVA and central retinal thickness (CRT) from baseline to 3 months after the last DEX-I injection; main secondary measures were an increase in intraocular pressure (IOP), the need for cataract surgery, endophthalmitis, and vitreous hemorrhage. RESULTS: Seventeen patients (18 eyes) with DME and mean age (± SD) of 54.3 ± 8.16 years were treated with DEX-I injections between 2014 and 2018. The majority of eyes (77.8%) had been treated with a mean of 6.3 ± 3.2 anti-VEGF agents before switching to DEX-I. During a mean follow-up period of 37.6 months and after a mean number of 5.9 DEX-I injections, visual acuity improved or stabilized in 77.8% of all eyes, accompanied by a significant reduction in CRT. An increase in IOP was recorded in 38.8% of all patients, while a surgical procedure was needed for cataract in 73.3% of all phakic patients. CONCLUSIONS: In this real-life experience in Italy, multiple DEX-I treatments showed good efficacy with no new safety concerns. The follow-up duration of >3 years and a greater number of DEX-I intravitreal injections compared to other observations confirm the positive balance between risks and benefits of DEX-I in the long term.

Glutathione transferase P silencing promotes neuronal differentiation of retinal R28 cells.

Glutathione transferases (GSTs) play an important role in retinal pathophysiology. Within this family, the GSTP isoform is known as an endogenous regulator of cell survival and proliferation pathways and of cellular responses to oxidative stress. In the present study we silenced GSTP in R28 cells, a retinal precursor cell line with markers of both glial and neuronal origin, and obtained stable clones which were viable and, unexpectedly, characterized by a more neuronal phenotype. The degree of neuronal differentiation was inversely correlated with GSTP residual expression levels. The clone with the lowest expression of GSTP showed metabolic reprogramming, a more favorable redox status and, despite its neuronal phenotype, a sensitivity to glutamate and 4-hydroxynonenal toxicity comparable to that of control cells. Altogether, our evidence shows that near full depletion of GSTP in retinal precursor cells, triggers neuronal differentiation and prosurvival metabolic changes.

Inflammatory mediators in the vitreal reflux of patients with diabetic macular edema.

PURPOSE: To quantify inflammatory, growth/angiogenic, and tissue remodeling mediators in vitreal reflux (VR) in patients with diabetic macular edema (DME), as collected at first and third intravitreal anti-vascular endothelial growth factor (anti-VEGF, ranibizumab) injection. METHODS: Thirty (30) consecutive patients (type-2 diabetes mellitus) with visual impairments due to DME and undergoing the first (untreated DME) or the third (treated DME) intravitreal injection of anti-VEGF were included in the study. At the time of surgery, patients were subjected to clinical assessment and spectral domain-optical coherence tomography (SD-OCT), including central retinal thickness (CRT), macular volume, and outer nuclear layer/retinal pigment epithelial (ONL/RPE) measurements. VR sampling was performed at the time of needle removal and subjected to customized protein-array, Western blotting (WB), Ella™ microfluidic, and/or enzyme-linked immunosorbent assay (ELISA) analysis. Biostrumental and biochemical data were collected just prior to the surgery and are representative of disease state. Clinical, biostrumental, and numerous biomarkers and cytokines were statistically compared. RESULTS: Decreased CRT values were detected in treated DME retinas, as compared to untreated ones (p ≤ 0.05). Differences in VEGF and other mediator expressions between treated and untreated DME were detected in VR samples. Particularly, osteopontin (p ≤ 0.05), interleukin 6 (IL6) (p ≤ 0.05), and VEGF (p ≤ 0.1) values were decreased after treatment. Significant changes were validated by WB, ELISA, and Ella™ analysis. CONCLUSION: Overall, the biostrumental and biochemical data suggest the presence of a specific pattern of inflammation in VR after treatment. The data would suggest the presence of other mechanisms and mediators, in addition to VEGF, accountable for DME progression.