Comparison of two ultra-widefield color-fundus imaging devices for visualization of retinal periphery and microvascular lesions in patients with early diabetic retinopathy.

Comparison of two ultra-widefield (UWF) color-fundus (CF) imaging devices in diabetic patients for visualization of retinal periphery and detection of early microvascular lesions. The total gradable areas (TGA) seen on non-mydriatic CF-images of two UWF-imaging devices (Optos Daytona P200T; Zeiss Clarus 700) were compared and differences in projected area measured. Retinal periphery outside the 7 standard fields (7SF) was divided into: F3 temporal, F4 superotemporal, F5 inferotemporal, F6 superonasal, F7 inferonasal. DR stage was evaluated in the 7SF and the TGA on images of both devices and compared using Cohens κ. 67 eyes of 67 patients (52.5 ± 15.3 years) were analysed. DR stages in the 7SF were no (n = 36 Optos, n = 35 Clarus), mild (n = 16 Optos, n = 17 Clarus), and moderate DR (n = 15). Optos depicted significantly more area in F3 (median [interquartile range]; 2.41% [1.06-4.11] vs 0% [0-0], P < 0.001) and Clarus in F7 (3.29% [0-7.69] vs 0% [0-3.27], P = 0.002). In 4 eyes DR-stage was higher using Optos due to peripheral lesions not seen on the Clarus. Interrater reliability of DR-stage on both devices was almost perfect in the 7SF (κ = 0.975) and the TGA (κ = 0.855). Reliability in detecting signs of early DR is high on both devices. Clarus allowed for better visualization of the inferonasal field, Optos of the temporal field.

Intraprocedural OCT monitoring of the immediate treatment response during indocyanine green angiography-guided laser therapy of teleangiectatic capillaries in diabetic macular edema.

In this retrospective study the morphological response of teleangiectatic capillaries (TCs) to focal laser treatment and the functional and morphological outcome after Indocyanine green angiography (ICGA)-guided laser therapy was evaluated. TCs in eyes with diabetic macular edema (DME) were treated with laser therapy. The immediate and subsequent reaction of the TCs lumina to direct photocoagulation was monitored with customized OCT single scans. Additionally, patients were treated with intravitreal anti-VEGF as needed. 12 eyes of 9 patients with treatment naive (6 eyes) and pretreated (6 eyes) DME were followed-up for a mean of 24 months (± 8.1SD). Best-corrected visual acuity improved from 0.25 logMar (± 0.2SD) to 0.12 (± 0.10SD; p = 0.06) at each patient's last visit. During laser treatment a darkening of the TCs lumina was achieved in 91.3% of lesions. All these lesions fully resolved, whereas TCs, which showed no darkening of their lumen in OCT persisted and required re-treatment with laser. Additional anti-VEGF injections were indicated in only one eye (8.3%). The darkening of the TCs lumina visible in OCT might provide an image-biomarker that indicates successful coagulation of aneurysmatic lesions. Consequently, a significant functional and morphological improvement with need for anti-VEGF treatment in only one eye, was achieved.Information concerning the registration of the trial: date of registration: 11th of december, 2019. Trial registration number: 107/2019.

Comparison of early diabetic retinopathy staging in asymptomatic patients between autonomous AI-based screening and human-graded ultra-widefield colour fundus images.

INTRODUCTION: Comparison of diabetic retinopathy (DR) severity between autonomous Artificial Intelligence (AI)-based outputs from an FDA-approved screening system and human retina specialists' gradings from ultra-widefield (UWF) colour images. METHODS: Asymptomatic diabetics without a previous diagnosis of DR were included in this prospective observational pilot study. Patients were imaged with autonomous AI (IDx-DR, Digital Diagnostics). For each eye, two 45° colour fundus images were analysed by a secure server-based AI algorithm. UWF colour fundus imaging was performed using Optomap (Daytona, Optos). The International Clinical DR severity score was assessed both on a 7-field area projection (7F-mask) according to the early treatment diabetic retinopathy study (ETDRS) and on the total gradable area (UWF full-field) up to the far periphery on UWF images. RESULTS: Of 54 patients included (n = 107 eyes), 32 were type 2 diabetics (11 females). Mean BCVA was 0.99 ± 0.25. Autonomous AI diagnosed 16 patients as negative, 28 for moderate DR and 10 for having a vision-threatening disease (severe DR, proliferative DR, diabetic macular oedema). Based on the 7F-mask grading with the eye with the worse grading defining the DR stage 23 patients were negative for DR, 11 showed mild, 19 moderate and 1 severe DR. When UWF full-field was analysed, 20 patients were negative for DR, while the number of mild, moderate and severe DR patients were 12, 21, and 1, respectively. CONCLUSIONS: The autonomous AI-based DR examination demonstrates sufficient accuracy in diagnosing asymptomatic non-proliferative diabetic patients with referable DR even compared to UWF imaging evaluated by human experts offering a suitable method for DR screening.

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.

Identification of Subclinical Microvascular Biomarkers in Coronary Heart Disease in Retinal Imaging.

Purpose: Cardiovascular disease and foremost coronary heart disease (CHD) are the worldwide leading causes of death. The aim of this study was to use non-invasive, multimodel retinal imaging to define microvascular features in patients with and without coronary angiography (CA)-confirmed CHD. Methods: In this prospective, cross-sectional pilot study we included adult patients who presented to a tertiary referral center for elective CA due to suspected CHD. All patients underwent widefield fundus photography for retinopathy grading. Optical coherence tomography angiography was used to measure vessel density (VD) of the individual capillary plexuses in 6 × 6-mm macular volume scans. Adaptive optics imaging was performed to assess the first-order arteriolar lumen diameter (LD), total diameter (TD), wall-to-lumen ratio (WLR), and wall cross-section area, as well as to qualitatively describe vessel morphology. Results: Of the included 45 patients (13 females; 65 ± 10 years old), 27 were confirmed with CHD in elective CA. The most prevalent retinal vascular pathologies were arteriovenous nickings, focal arterial narrowings, and microaneurysms. VD in the superficial capillary plexus, deep capillary plexus, and choriocapillaris was lower in CHD patients, although the odds ratios were not significantly different from 1 (P = 0.06-0.92). Median arterial LD, TD, and WLR values were 98.3 µm (interquartile range [IQR] = 13.0), 122.9 µm (IQR = 17.6), and 0.26 µm (IQR = 0.07), respectively, with a trend toward a higher WLR in CHD patients. Conclusions: In a cardiovascular risk population, high-resolution quantitative and qualitative microvascular phenotyping in the retina may provide valuable subclinical indicators for coronary artery impairment, although larger clinical trials are needed. Translational Relevance: Subclinical retinal microvascular changes may serve as non-invasive, cost-effective biomarkers for risk stratification of patients with CHD.

Assessment of Detailed Photoreceptor Structure and Retinal Sensitivity in Diabetic Macular Ischemia Using Adaptive Optics-OCT and Microperimetry.

Purpose: The purpose of this study was to assess density and morphology of cone photoreceptors (PRs) and corresponding retinal sensitivity in ischemic compared to nonischemic retinal capillary areas of diabetic eyes using adaptive optics optical coherence tomography (AO-OCT) and microperimetry (MP). Methods: In this cross-sectional, observational study five eyes of four patients (2 eyes with proliferative diabetic retinopathy (DR) and 3 eyes moderate nonproliferative DR) were included. PR morphology and density was manually assessed in AO-OCT en face images both at the axial position of the inner-segment outer segment (IS/OS) and cone outer segment tips (COSTs). Retinal sensitivity was determined by fundus-controlled microperimetry in corresponding areas (MP-3, Nidek). Results: In AO-OCT, areas affected by capillary nonperfusion showed severe alterations of cone PR morphology at IS/OS and COST compared to areas with intact capillary perfusion (84% and 87% vs. 9% and 8% of area affected for IS/OS and COST, respectively). Mean reduction of PR signal density in affected areas compared to those with intact superficial capillary plexus (SCP) and deep capillary plexus (DCP) perfusion of similar eccentricity was -38% at the level of IS/OS (P = 0.01) and -39% at the level of COST (P = 0.01). Mean retinal sensitivity was 10.8 ± 5.4 in areas affected by DCP nonperfusion and 28.2 ± 1.5 outside these areas (P < 0.001). Conclusions: Cone PR morphology and signal density are severely altered in areas of capillary nonperfusion. These structural changes are accompanied by a severe reduction of retinal sensitivity, indicating the importance of preventing impaired capillary circulation in patients with DR.

Early Identification of Retinal Neuropathy in Subclinical Diabetic Eyes by Reduced Birefringence of the Peripapillary Retinal Nerve Fiber Layer.

Purpose: To study birefringence of the peripapillary retinal nerve fiber layer (RNFL) of diabetic eyes with no clinical signs of diabetic retinopathy (DR) or mild to moderate DR stages using spectral-domain polarization-sensitive (PS) optical coherence tomography (OCT). Methods: In this observational pilot study, circular PS-OCT scans centered on the optic nerve head were recorded in prospectively recruited diabetic and age-matched healthy eyes. From averaged circumpapillary intensity and retardation tomograms plots of RNFL birefringence were obtained by a linear fit of retardation versus depth within the RNFL tissue for each A-scan position and mean birefringence values for RNFL calculated. Spectral-domain OCT imaging (Heidelberg Engineering) was performed to assess peripapillary RNFL thickness and macular ganglion cell complex (GCC). Results: Out of 70 eyes of 43 diabetic patients (mean ± SD age: 50.86 ± 15.71) 36 showed no signs of DR, 17 mild and 17 moderate nonproliferative DR with no diabetic macular edema. Thirty-four eyes of 34 healthy subjects (53.21 ± 13.88 years) served as controls. Compared with healthy controls (0.143° ± 0.014°/µm) mean total birefringence of peripapillary RNFL was significantly reduced in subclinical diabetic eyes (0.131° ± 0.014°/µm; P = 0.0033), as well as in mild to moderate DR stages (0.125° ± 0.018°/µm, P < 0.0001) with borderline statistically significant differences between diabetic patients (P = 0.0049). Mean birefringence values were significantly lower in inferior compared with superior RNFL sectors (P < 0.0001) of diabetic eyes with no such difference detected in the healthy control group. Conclusions: We identified evidence of early neuroretinal alteration in diabetic eyes through reduced peripapillary RNFL birefringence assessed by PS-OCT occurring before appearance of clinical microvascular lesions or GCC alterations.

POSTOPERATIVE MOVEMENT OF THE FOVEA AFTER SUCCESSFUL SURGERY IN PATIENTS WITH IDIOPATHIC EPIRETINAL MEMBRANES.

PURPOSE: To evaluate the change in the fovea's postoperative location after successful pars plana vitrectomy with combined epiretinal and internal limiting membrane peeling in patients with idiopathic epiretinal membranes (iERMs). METHODS: In this prospective study 32 eyes of 32 patients with iERMs were followed from baseline before until 3 months after surgery. Study measures included 4-m Early Treatment Diabetic Retinopathy Study best-corrected visual acuity, enhanced-depth imaging-optical coherence tomography, and intraoperative fundus photographs. Foveal movement was assessed by measuring the change in the papillofoveal distance (∆PFD). RESULTS: Mean ∆PFD in the study eye was -124 µm (±138) and -272 µm (±213) one day and 3 months after surgery, respectively. Mean ∆PFD after 3 months was greater in the study than in the fellow eye (P < 0.001). ∆PFD at Month 3 did not correlate with the internal limiting membrane area peeled (P = 0.78). CONCLUSION: Foveal movement starts immediately after surgery and causes a statistically significant reduction in PFD after uneventful macular pucker surgery. ∆PFD correlates statistically significantly with baseline best-corrected visual acuity and baseline central retinal thickness. The internal limiting membrane peeling size had no significant effect on the amount of postoperative foveal dislocation.

Association of macular perfusion status with microvascular parameters up to the far periphery in diabetic retinopathy using multimodal imaging.

BACKGROUND: The aim of our study was to investigate a possible association between macular perfusion status and retinal ischemia and leakage up to far peripheral retinal areas in eyes with early to advanced stages of diabetic retinopathy (DR). METHODS: In a retrospective, cross sectional analysis ultrawide field (UWF) color fundus photos (Optos, Optomap California) were graded for DR severity. Foveal avascular zone (FAZ) and vessel density from the superficial (SCP) and deep capillary plexus (DCP) were assessed on optical coherence tomography angiography (OCTA) scans (Topcon, DRI-OCT Triton). UWF angiography images were used to quantify leakage/ischemic index and number of microaneurysms (MA). Age, gender, disease duration, type of diabetes, HbA1C, hypertension, complications of diabetes and ocular history were recorded. Univariate mixed models and Spearman correlation analysis were used for statistical testing. RESULTS: 24 eyes of 17 laser-naive diabetic patients with different stages of DR were analyzed. The mean age was 59.56 ± 8.46 years and the mean disease duration 19.65 ± 12.25 years. No statistically significant associations between FAZ size, macular vessel density of SCP/DCP and peripheral retinal ischemia, leakage and MA number were demonstrated. Higher stages of DR were associated with ischemic index (estimate [95% CI]: 13.04 [1.5; 24.5], p = 0.033) and MA count (estimate [95% CI]: 43.7 [15.6; 71.8], p = 0.01), but no association with leakage index was observed. Only weak correlations between DR severity and anamnestic data were found. CONCLUSION: Retinal ischemic index and the amount of MAs assessed on UWFA up to peripheral areas are indicators of DR severity but not related to microvascular perfusion status in the macular region. Significance and timely sequence of macular vessel density in DR progression may need to be re-evaluated in future studies.

Analysis of retinal nerve fiber layer birefringence in patients with glaucoma and diabetic retinopathy by polarization sensitive OCT.

The retinal nerve fiber layer (RNFL) is a fibrous tissue that shows form birefringence. This optical tissue property is related to the microstructure of the nerve fiber axons that carry electrical signals from the retina to the brain. Ocular diseases that are known to cause neurologic changes, like glaucoma or diabetic retinopathy (DR), might alter the birefringence of the RNFL, which could be used for diagnostic purposes. In this pilot study, we used a state-of-the-art polarization sensitive optical coherence tomography (PS-OCT) system with an integrated retinal tracker to analyze the RNFL birefringence in patients with glaucoma, DR, and in age-matched healthy controls. We recorded 3D PS-OCT raster scans of the optic nerve head area and high-quality averaged circumpapillary PS-OCT scans, from which RNFL thickness, retardation and birefringence were derived. The precision of birefringence measurements was 0.005°/µm. As compared to healthy controls, glaucoma patients showed a slightly reduced birefringence (0.129 vs. 0.135°/µm), although not statistically significant. The DR patients, however, showed a stronger reduction of RNFL birefringence (0.103 vs. 0.135°/µm) which was highly significant. This result might open new avenues into early diagnosis of DR and related neurologic changes.