Visualization of Cataract Surgery Steps With 4D Microscope-Integrated Swept-Source Optical Coherence Tomography in Ex Vivo Porcine Eyes.

Purpose: To investigate the visualization capabilities of high-speed swept-source optical coherence tomography (SS-OCT) in cataract surgery. Methods: Cataract surgery was simulated in wet labs with ex vivo porcine eyes. Each phase of the surgery was visualized with a novel surgical microscope-integrated SS-OCT with a variable imaging speed of over 1 million A-scans per second. It was designed to provide four-dimensional (4D) live-volumetric videos, live B-scans, and volume capture scans. Results: Four-dimensional videos, B-scans, and volume capture scans of corneal incision, ophthalmic viscosurgical device injection, capsulorrhexis, phacoemulsification, intraocular lens (IOL) injection, and position of unfolded IOL in the capsular bag were recorded. The flexibility of the SS-OCT system allowed us to tailor the scanning parameters to meet the specific demands of dynamic surgical steps and static pauses. The entire length of the eye was recorded in a single scan, and unfolding of the IOL was visualized dynamically. Conclusions: The presented novel visualization method for fast ophthalmic surgical microscope-integrated intraoperative OCT imaging in cataract surgery allowed the visualization of all major steps of the procedure by achieving large imaging depths covering the entire eye and high acquisition speeds enabling live volumetric 4D-OCT imaging. This promising technology may become an integral part of routine and advanced robotic-assisted cataract surgery in the future. Translational Relevance: We demonstrate the visualization capabilities of a cutting edge swept-source OCT system integrated into an ophthalmic surgical microscope during cataract surgery.

European Unmet Needs in the Management of Neovascular Age-Related Macular Degeneration in Daily Practice: Data from the Fight Retinal Blindness! Registry.

PURPOSE: To evaluate the proportion, predictors, and outcomes of patients with neovascular age-related macular degeneration (nAMD) treated with a high burden of VEGF inhibitor intravitreal (IVT) injections after 2 years in routine clinical practice. DESIGN: Retrospective analysis of data from a prospectively designed observational outcomes registry, the Fight Retinal Blindness! Project, of patients treated in European centers. PARTICIPANTS: Treatment-naïve eyes (1 eye per patient) starting VEGF inhibitors for nAMD from January 2017 to March 2020 with 24 months of follow-up. We analyzed the following 3 treatment-burden groups defined by the mean interval of the 3 closest injections to the 24-month visit: (1) those with a high-treatment burden had injection intervals ≤ 42 days, (2) those with a low-treatment burden had injection intervals between 43 and 83 days; and (3) those with tolerable treatment burden had injection intervals between 84 and 365 days. METHODS: Multinomial regression was used to evaluate baseline risk predictors of patients requiring a high-treatment burden. MAIN OUTCOME MEASURES: The proportion of patients that experienced a high-treatment burden at 2 years and its predictors. RESULTS: We identified 2038 eligible patients completing 2 years of treatment (2038/3943 patients [60%]) with a median (quartile 1, quartile 3) of 13 (10, 17) injections. The proportion of patients with a high-treatment burden was 25% (516 patients) at 2 years. Younger patients (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.96-0.99; P < 0.01) were more likely to have high-treatment burden, whereas eyes with type 3 choroidal neovascular lesions at baseline were significantly less likely (OR, 0.26; 95% CI, 0.13-0.52; P < 0.01). Regarding type of fluid, patients with subretinal fluid only at baseline (OR, 3.85; 95% CI, 1.34-11.01; P = 0.01) and persistent active intraretinal (OR, 1.56; 95% CI, 1.18-2.06; P < 0.01) or subretinal fluid only (OR, 2.21; 95% CI, 1.52-3.21; P < 0.01) after the loading phase had a higher risk of high treatment burden at 2 years. CONCLUSIONS: High treatment burden is a common issue in routine clinical practice in Europe, with a quarter of patients requiring injections of conventional VEGF inhibitors every 6 weeks at 2 years and 40% discontinuing treatment within 2 years. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Volumetric Reconstruction of a Human Retinal Pigment Epithelial Cell Reveals Specialized Membranes and Polarized Distribution of Organelles.

Purpose: Despite the centrality of the retinal pigment epithelium (RPE) in vision and retinopathy our picture of RPE morphology is incomplete. With a volumetric reconstruction of human RPE ultrastructure, we aim to characterize major membranous features including apical processes and their interactions with photoreceptor outer segments, basolateral infoldings, and the distribution of intracellular organelles. Methods: A parafoveal retinal sample was acquired from a 21-year-old male organ donor. With serial block-face scanning electron microscopy, a tissue volume from the inner-outer segment junction to basal RPE was captured. Surface membranes and complete internal ultrastructure of an individual RPE cell were achieved with a combination of manual and automated segmentation methods. Results: In one RPE cell, apical processes constitute 69% of the total cell surface area, through a dense network of over 3000 terminal branches. Single processes contact several photoreceptors. Basolateral infoldings facing the choriocapillaris resemble elongated filopodia and comprise 22% of the cell surface area. Membranous tubules and sacs of endoplasmic reticulum represent 20% of the cell body volume. A dense basal layer of mitochondria extends apically to partly overlap electron-dense pigment granules. Pores in the nuclear envelope form a distinct pattern of rows aligned with chromatin. Conclusions: Specialized membranes at the apical and basal side of the RPE cell body involved in intercellular uptake and transport represent over 90% of the total surface area. Together with the polarized distribution of organelles within the cell body, these findings are relevant for retinal clinical imaging, therapeutic approaches, and disease pathomechanisms.

Microaneurysm detection using high-speed megahertz optical coherence tomography angiography in advanced diabetic retinopathy.

PURPOSE: To compare detection rates of microaneurysms (MAs) on high-speed megahertz optical coherence tomography angiography (MHz-OCTA), fluorescein angiography (FA) and colour fundus photography (CF) in patients with diabetic retinopathy (DR). METHODS: For this exploratory cross-sectional study, MHz-OCTA data were acquired with a swept-source OCT prototype (A-scan rate: 1.7 MHz), and FA and CF imaging was performed using Optos® California. MA count was manually evaluated on en face MHz-OCTA/FA/CF images within an extended ETDRS grid. Detectability of MAs visible on FA images was evaluated on corresponding MHz-OCTA and CF images. MA distribution and leakage were correlated with detectability on OCTA and CF imaging. RESULTS: 47 eyes with severe DR (n = 12) and proliferative DR (n = 35) were included. MHz-OCTA and CF imaging detected on average 56% and 36% of MAs, respectively. MHz-OCTA detection rate was significantly higher than CF (p < 0.01). The combination of MHz-OCTA and CF leads to an increased detection rate of 70%. There was no statistically significant association between leakage and MA detectability on OCTA (p = 0.13). For CF, the odds of detecting leaking MAs were significantly lower than non-leaking MAs (p = 0.012). Using MHz-OCTA, detection of MAs outside the ETDRS grid was less likely than MAs located within the ETDRS grid (outer ring, p < 0.01; inner ring, p = 0.028). No statistically significant difference between rings was observed for CF measurements. CONCLUSIONS: More MAs were detected on MHz-OCTA than on CF imaging. Detection rate was lower for MAs located outside the macular region with MHz-OCTA and for leaking MAs with CF imaging. Combining both non-invasive modalities can improve MA detection.

Macular Microvascular Perfusion Status in Hypertensive Patients with Chronic Kidney Disease.

To compare retinal microvascular perfusion between the eyes of hypertensive patients with and without chronic kidney disease (CKD), the vessel density (VD) and fractal dimension (FD) of the superficial (SVP) and deep retinal vascular plexus (DVP) were analyzed on 6 × 6 mm fovea-centered optical coherence tomography angiography (OCTA) images of patients with hypertension. The retina was divided into an inner ring (IR) and outer ring (OR) according to the Early Treatment of Diabetic Retinopathy Study grid. The glomerular filtration rate (GFR) was determined and CKD was diagnosed (GFR < 60 mL/min/1.73 m2). Ninety-six eyes from 52 patients with hypertension were included in this analysis. Twenty patients (n = 37 eyes) were diagnosed with CKD. The mean age was 69 ± 11.7 years and 60.4 ± 9.2 years in the CKD group and in the control group, respectively. The univariate model revealed a significant difference in VD between patients without and with CKD in the superficial IR (0.36 ± 0.03 vs. 0.34 ± 0.04, p = 0.03), the superficial OR (0.35 ± 0.02 vs. 0.33 ± 0.04, p = 0.02), the deep OR (0.24 ± 0.01 vs. 0.23 ± 0.02, p = 0.003), and the FD in the SVP (1.87 ± 0.01 vs. 1.86 ± 0.02, p = 0.02) and DVP (1.83 ± 0.01 vs. 1.82 ± 0.01, p = 0.006). After adjusting for age and sex, these differences did not remain statistically significant. Similar results were observed for the FD in the SVP and DVP. In our cohort, patients with hypertension and CKD did not differ from patients without CKD in regard to microvascular perfusion status in the macular area as assessed using OCTA.

Association of Diabetic Lesions and Retinal Nonperfusion Using Widefield Multimodal Imaging.

PURPOSE: To evaluate the association of microvascular lesions on ultrawidefield (UWF) color fundus (CF) images with retinal nonperfusion (RNP) up to the midperiphery on single-capture widefield (WF) OCT angiography (OCTA) in patients with diabetic retinopathy (DR). DESIGN: Cross-sectional study. SUBJECTS: Seventy-five eyes of 50 patients with mild to severe nonproliferative DR (NPDR) and proliferative DR (PDR) were included in this analysis. METHODS: ETDRS level and presence of predominantly peripheral lesions (PPLs) were assessed on UWF-CF images acquired with a Zeiss Clarus 700. Single-capture 65°-WF-OCTA was performed using a PlexElite prototype (Carl Zeiss Meditec, Inc.). A custom grid consisting of a central ETDRS grid extended by 2 rings reaching up to the midperiphery was overlaid to subdivide retinal areas visible on WF-OCTA en face images. Retinal nonperfusion was measured in each area and in total. Nonperfusion index (NPI) was calculated from total RNP. On UWF-CF images, the number of microaneurysms, hemorrhages, neovascularizations, and areas with intraretinal microvascular abnormalities (IRMAs) were evaluated using the same grid. MAIN OUTCOME MEASURES: Association of diabetic lesions with RNP was calculated using Spearman correlations (rs). RESULTS: Median RNP on WF-OCTA was 0 mm2 (0-0.9), 4.9 mm2 (1.9-5.4), 23.4 mm2 (17.8-37), and 68.4 mm2 (40.8-91.7) in mild, moderate, and severe NPDR and PDR, respectively. We found a statistically significant correlation (P < 0.01) of overall RNP (rs = 0.96,) and NPI (rs = 0.97) on WF-OCTA with ETDRS level. Number of grid-fields affected by IRMAs on CF images was highly associated with NPI (rs = 0.86, P < 0.01). Intraretinal microvascular abnormalities and RNPs had similar topographic distributions with high correlations in affected areas. Eyes with PPLs (n = 43 eyes, 57%) on CF images had a significantly higher NPI (P = 0.014) than eyes without PPLs. CONCLUSION: The combination of UWF-CF imaging and single-capture WF-OCTA allows precise and noninvasive analysis of the retinal vasculature up to the midperiphery in patients with DR. The presence and extent of IRMAs on CF images may serve as an indicator for underlying RNP, which is more pronounced in eyes with PPLs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Multiple instance learning based classification of diabetic retinopathy in weakly-labeled widefield OCTA en face images.

Diabetic retinopathy (DR), a pathologic change of the human retinal vasculature, is the leading cause of blindness in working-age adults with diabetes mellitus. Optical coherence tomography angiography (OCTA), a functional extension of optical coherence tomography, has shown potential as a tool for early diagnosis of DR through its ability to visualize the retinal vasculature in all spatial dimensions. Previously introduced deep learning-based classifiers were able to support the detection of DR in OCTA images, but require expert labeling at the pixel level, a labor-intensive and expensive process. We present a multiple instance learning-based network, MIL-ResNet,14 that is capable of detecting biomarkers in an OCTA dataset with high accuracy, without the need for annotations other than the information whether a scan is from a diabetic patient or not. The dataset we used for this study was acquired with a diagnostic ultra-widefield swept-source OCT device with a MHz A-scan rate. We were able to show that our proposed method outperforms previous state-of-the-art networks for this classification task, ResNet14 and VGG16. In addition, our network pays special attention to clinically relevant biomarkers and is robust against adversarial attacks. Therefore, we believe that it could serve as a powerful diagnostic decision support tool for clinical ophthalmic screening.

[Diagnosis, treatment and monitoring of diabetic eye disease (Update 2023)]. / Diagnostik, Therapie und Verlaufskontrolle der diabetischen Augenerkrankung (Update 2023).

Diabetes mellitus can cause diabetic retinopathy, diabetic macular edema, optic neuropathy, cataract or dysfunction of the eye muscles. The incidence of these disorders correlates with disease duration and quality of metabolic control. Regular ophthalmological examinations are needed to prevent sight-threatening advanced stages of diabetic eye diseases.

Comparative connectomics reveals noncanonical wiring for color vision in human foveal retina.

The Old World macaque monkey and New World common marmoset provide fundamental models for human visual processing, yet the human ancestral lineage diverged from these monkey lineages over 25 Mya. We therefore asked whether fine-scale synaptic wiring in the nervous system is preserved across these three primate families, despite long periods of independent evolution. We applied connectomic electron microscopy to the specialized foveal retina where circuits for highest acuity and color vision reside. Synaptic motifs arising from the cone photoreceptor type sensitive to short (S) wavelengths and associated with "blue-yellow" (S-ON and S-OFF) color-coding circuitry were reconstructed. We found that distinctive circuitry arises from S cones for each of the three species. The S cones contacted neighboring L and M (long- and middle-wavelength sensitive) cones in humans, but such contacts were rare or absent in macaques and marmosets. We discovered a major S-OFF pathway in the human retina and established its absence in marmosets. Further, the S-ON and S-OFF chromatic pathways make excitatory-type synaptic contacts with L and M cone types in humans, but not in macaques or marmosets. Our results predict that early-stage chromatic signals are distinct in the human retina and imply that solving the human connectome at the nanoscale level of synaptic wiring will be critical for fully understanding the neural basis of human color vision.

Effect of Changes in Surgical Strategies for the Treatment of Primary Rhegmatogenous Retinal Detachment on Functional and Anatomical Outcomes: A Retrospective Analysis of 812 Cases from the Years 2004 to 2012.

BACKGROUND: At the Department of Ophthalmology and Optometry at the MUV surgical method (scleral buckling, vitrectomy, combined vitrectomy/scleral buckling) and timing (daytime, nighttime) for the treatment of primary rhegmatogenous retinal detachment (RRD) changed continuously in the years 2004 to 2012. This study aims to evaluate changes in surgical strategies over time including their impact on functional and anatomical outcomes. METHODS: Retrospective evaluation of patients operated on primary RRD between the years 2004 and 2012. Baseline demographic data, month 3 best-corrected visual acuity (BCVA), surgical method, single success surgery, surgical timing, and intraoperative complications were analyzed. RESULTS: Overall, 812 eyes of 812 patients with a mean (±SD) age of 58.1 ± 13.3 years were included. A total of 413 (51%) patients presented with macula-on and 359 (44%) with macula-off RRD. Month 3 BCVA increased over time, both in macula-on or macula-off groups (p < 0.001). The rate of complete retinal reattachment 3 months postoperatively increased significantly from 65% in 2004 to 83% in 2012 in both groups. Scleral buckling surgeries decreased continuously from 95% to 16% with an appropriate increase in vitrectomies as well as a decrease in surgeries during nighttime (68% in 2004, 6% in 2012) with equal or better visual and functional outcomes. CONCLUSION: Our data showed that improving functional and single-success surgery outcomes in patients operated on for primary RRD. In the years 2004 to 2012, surgical techniques shifted from scleral buckling to primary vitrectomy and were increasingly scheduled during the daytime.

Detection of diabetic neovascularisation using single-capture 65°-widefield optical coherence tomography angiography.

AIM: To assess the detection rate of retinal neovascularisation (NV) in eyes with proliferative diabetic retinopathy (PDR) using widefield optical coherence tomography angiography (WF-OCTA) in comparison to ultrawidefield fluorescein angiography (UWF-FA). METHODS: Single-capture 65°-WF-OCTA-imaging was performed in patients with NV at the disc or elsewhere (NVE) detected on UWF-FA using a modified PlexElite system and B-scans were examined for blood flow signals breaching the internal limiting membrane. Sensitivity of WF-OCTA and UWF colour fundus (UWF-CF) photography for correct diagnosis of PDR was determined and interdevice agreement (Fleiss' κ) between WF-OCTA and UWF-FA for detection of NV in the total gradable area and each retinal quadrant was evaluated. RESULTS: Fifty-nine eyes of 41 patients with PDR detected on UWF-FA were included. Sensitivity of detecting PDR on WF-OCTA scans was 0.95 in contrast to 0.78 on UWF-CF images. Agreement in detecting NVE between WF-OCTA and UWF-FA was high in the superotemporal (κ=0.98) and inferotemporal (κ=0.94) and weak in the superonasal (κ=0.24) and inferonasal quadrants (κ=0.42). On UWF-FA, 63% of NVEs (n=153) were located in the temporal quadrants with 93% (n=142) of them being detected on WF-OCTA scans. CONCLUSION: The high reliability of non-invasive WF-OCTA imaging in detecting PDR can improve clinical examination with the potential to replace FA as a single diagnostic tool.

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.

Evaluation of neuroretinal integrity in optical coherence tomography-graded eyes with partial-thickness macular holes.

PURPOSE: To evaluate neuroretinal integrity in different subtypes of optical coherence tomography (OCT)-graded partial-thickness macular holes. METHODS: Fovea-centred SD-OCT images (Cirrus, Carl Zeiss Meditec AG; Spectralis, Heidelberg Engineering GmbH) and visual acuity (VA) acquired at every visit were analysed by two retina specialists retrospectively in 71 eyes of 65 patients. Partial-thickness macular holes were classified as lamellar macular hole (LMH), epiretinal membrane foveoschisis (ERMF) or macular pseudohole (MPH). RESULTS: Lamellar macular hole, ERMF and MPH were diagnosed in 33 (47%), 31 (43%) and 7 (10%) eyes with a VA of 0.18 ± 0.25, 0.15 ± 0.2, and 0.06 ± 0.08 (p = 0.323), respectively. Median follow-up time was 11 (interquartile range 4-32.5), 10 (interquartile range 5-18) and 19 (interquartile range 8-24) months in LMH, ERMF and MPH. In all subgroups, VA remained stable during the follow-up (p = 0.652, p = 0.915 and p = 1.000). Epiretinal proliferations (EP) were present in 12 LMH and 3 ERMF. At baseline, eyes with EP had significantly worse VA (p < 0.001), wider foveal cavities (p = 0.007) and thinner foveal floors (p < 0.001) compared with eyes without EP. Twelve out of 15 eyes with EP showed exudative cystoid spaces. Among all 71 eyes, 51 remained morphologically and functionally stable during follow-up. CONCLUSION: In our study cohort, EP are associated with worse VA and advanced neuroretinal tissue loss presenting with wider foveal cavities and thinner foveal floors. During the follow-up period, VA remained stable in all entities of partial-thickness macular holes.

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.

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.

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.

Retinal adaptive optics imaging with a pyramid wavefront sensor.

The pyramid wavefront sensor (P-WFS) has replaced the Shack-Hartmann (SH-) WFS as the sensor of choice for high-performance adaptive optics (AO) systems in astronomy. Many advantages of the P-WFS, such as its adjustable pupil sampling and superior sensitivity, are potentially of great benefit for AO-supported imaging in ophthalmology as well. However, so far no high quality ophthalmic AO imaging was achieved using this novel sensor. Usually, a P-WFS requires modulation and high precision optics that lead to high complexity and costs of the sensor. These factors limit the competitiveness of the P-WFS with respect to other WFS devices for AO correction in visual science. Here, we present a cost-effective realization of AO correction with a non-modulated P-WFS based on standard components and apply this technique to human retinal in vivo imaging using optical coherence tomography (OCT). P-WFS based high quality AO imaging was successfully performed in 5 healthy subjects and smallest retinal cells such as central foveal cone photoreceptors are visualized. The robustness and versatility of the sensor is demonstrated in the model eye under various conditions and in vivo by high-resolution imaging of other structures in the retina using standard and extended fields of view. As a quality benchmark, the performance of conventional SH-WFS based AO was used and successfully met. This work may trigger a paradigm shift with respect to the wavefront sensor of choice for AO in ophthalmic imaging.

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.