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.

LONGITUDINAL CHANGES IN QUANTITATIVE AUTOFLUORESCENCE DURING PROGRESSION FROM INTERMEDIATE TO LATE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To prospectively investigate the development of quantitative autofluorescence (qAF) during progression from intermediate to late age-related macular degeneration (AMD). METHODS: Quantitative autofluorescence images from patients with intermediate AMD were acquired every three months with a Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany) using a built-in autofluorescence reference. The association between changes in longitudinal qAF and progression toward late AMD was assessed using Cox regression models with time-dependent covariates. RESULTS: One hundred and twenty-one eyes of 71 patients were included, and 653 qAF images were acquired. Twenty-one eyes of 17 patients converted to late AMD (median follow-up: 21 months; 12 eyes: atrophic AMD; nine eyes: neovascular AMD). The converting patients' mean age was 74.6 ± 4.4 years. Eleven eyes in the converting group (52.4%) were pseudophakic. The presence of an intraocular lens did not affect the qAF regression slopes (P > 0.05). The median change for atrophic AMD was -2.34 qAF units/3 months and 0.78 qAF units/3 months for neovascular AMD. A stronger decline in qAF was significantly associated with an increased risk of developing atrophic AMD (hazard ratio = 1.022, P < 0.001). This association, however, was not present in the group progressing toward neovascular AMD (hazard ratio = 1.001, P = 0.875). CONCLUSION: The qAF signal declines with progression to atrophy, contrary to developing neovascularization. Quantitative autofluorescence may allow identification of patients at risk of progressing to late AMD and benefits individualized patient care in intermediate AMD.

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.

Three-dimensional assessment of para- and perifoveal photoreceptor densities and the impact of meridians and age in healthy eyes with adaptive-optics optical coherence tomography (AO-OCT).

An adaptive optics optical coherence tomography (AO-OCT) system is used to assess sixty healthy eyes of thirty subjects (age 22 to 75) to evaluate how the outer retinal layers, foveal eccentricity and age effect the mean cone density. The cone mosaics of different retinal planes (the cone inner segment outer segment junction (IS/OS), the cone outer segment combined with the IS/OS (ISOS+), the cone outer segment tips (COST), and the full en-face plane (FEF)) at four main meridians (superior, nasal, inferior, temporal) and para- and perifoveal eccentricities (ecc 2.5° and 6.5°) were analyzed quantitatively. The mean overall cone density was 19,892/mm2 at ecc 2.5° and 13,323/mm2 at ecc 6.5°. A significant impact on cone density was found for eccentricity (up to 6,700/mm2 between ecc 2.5° and 6.5°), meridian (up to 3,700/mm2 between nasal and superior meridian) and layer (up to 1,400/mm2 between FEF and IS/OS). Age showed only a weak negative effect. These factors as well as inter-individual variability have to be taken into account when comparing cone density measurements between healthy and pathologically changed eyes, as their combined effect on density can easily exceed several thousand cones per mm2 even in parafoveal regions.

PRESENCE OF PERIPHERAL LESIONS AND CORRELATION TO MACULAR PERFUSION, OXYGENATION AND NEURODEGENERATION IN EARLY TYPE II DIABETIC RETINAL DISEASE.

PURPOSE: The impact of peripheral retinal lesions (PL) visualized with ultra-wide-field imaging on diabetic retinopathy (DR) remains unclear. The purpose of this study was to assess the presence of PL and their association with macular microvasculopathy, metabolic dysfunction, and neurodegeneration in patients with Type II diabetes and early retinal disease. METHODS: Forty-five degree color fundus (Topcon) and 200° ultra-wide-field images (Optos) were assessed for the presence and severity of DR. Lesions anterior to the 45° were considered peripheral. The foveal avascular zone area, perimeter and acircularity index, and foveal full-retina and parafoveal superficial/deep complex vessel density were evaluated with RTVue optical coherence tomography angiography. Vessel oxygen saturation was measured with oximetry. Peripapillary retinal nerve fiber and individual macular retinal layer thicknesses were measured with Spectralis optical coherence tomography. RESULTS: Among the 161 eyes (80 left eyes) of 81 patients (34 female), 64 (39.8%) showed higher levels of DR on ultra-wide-field than on 45° fundus images (P < 0.0001). PL were identified in 97 eyes (60.3%) and in 59 among 115 eyes without central signs of DR. No significant correlation to biomarkers of central microvascular disease (foveal avascular zone/vessel density variables), oxygen saturation, and retinal layer thickness was found. CONCLUSION: Ultra-wide-field imaging helps to detect more eyes with early DR due to the detection of PL, which appear independently of biomarkers of macular microvascular impairment, metabolic function, and neuropathy in eyes without central signs of DR. These results suggest that the evaluation of the retinal periphery may become crucial in DR screening if PL are proven to influence disease outcomes.

INVESTIGATING A GROWTH PREDICTION MODEL IN ADVANCED AGE-RELATED MACULAR DEGENERATION WITH SOLITARY GEOGRAPHIC ATROPHY USING QUANTITATIVE AUTOFLUORESCENCE.

PURPOSE: To investigate geographic atrophy (GA) progression using quantitative autofluorescence (qAF) in eyes with solitary GA. METHODS: Forty-three eyes of 26 patients (age 79.7 ± 7.2 years; 28 women; 16 pseudophakic) underwent spectral-domain optical coherence tomography and qAF imaging at baseline and after 12 months. The junctional zone (AJZ) and a nonaffected 300-µm-wide control area (AC) were delineated on spectral-domain optical coherence tomography scans and transferred to the qAF image. Linear mixed models were calculated to investigate the association between GA progression and qAF, age, and baseline GA area. Mixed model analyses of variance were used to investigate differences in qAF between areas. RESULTS: Quantitative autofluorescence of the three inferior sections of both the AJZ (P = 0.028; P = 0.014 and P = 0.032) and the AC (P = 0.043; P = 0.02 and P = 0.028) were significantly associated with GA progression after 12 months. However, qAF measurements were not associated with GA progression in the overall model (P > 0.05). Mean qAF was significantly lower in the AJZ and growth area (AG12) than in the AC (both P ≤ 0.001). CONCLUSION: The authors report a statistically significant association between GA growth area and qAF measurements at specific retinal locations and a significant difference in qAF between the GA border and unaffected areas outside the lesion. Quantitative autofluorescence measurements may be limitedly useful for predicting GA progression.

SWEPT SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY, FLUORESCEIN ANGIOGRAPHY, AND INDOCYANINE GREEN ANGIOGRAPHY COMPARISONS REVISITED: Using a Novel Deep-Learning-Assisted Approach for Image Registration.

PURPOSE: To compare area measurements between swept source optical coherence tomography angiography (SSOCTA), fluorescein angiography (FA), and indocyanine green angiography (ICGA) after applying a novel deep-learning-assisted algorithm for accurate image registration. METHODS: We applied an algorithm for the segmentation of blood vessels in FA, ICGA, and SSOCTA images of 24 eyes with treatment-naive neovascular age-related macular degeneration. We trained a model based on U-Net and Mask R-CNN for each imaging modality using vessel annotations and junctions to estimate scaling, translation, and rotation. For fine-tuning of the registration, vessels and the elastix framework were used. Area, perimeter, and circularity measurements were performed manually using ImageJ. RESULTS: Choroidal neovascularization lesion size, perimeter, and circularity delineations showed no significant difference between SSOCTA and ICGA (all P > 0.05). Choroidal neovascularization area showed excellent correlation between SSOCTA and ICGA (r = 0.992) and a Bland-Altman bias of -0.10 ± 0.24 mm. There was no significant difference in foveal avascular zone size between SSOCTA and FA (P = 0.96) and an extremely small bias of 0.0004 ± 0.04 mm and excellent correlation (r = 0.933). Foveal avascular zone perimeter was not significantly different, but foveal avascular zone circularity was significantly different (P = 0.047), indicating that some small cavities or gaps may be missed leading to higher circularity values representing a more round-shaped foveal avascular zone in FA. CONCLUSION: We found no statistically significant differences between SSOCTA and FA and ICGA area measurements in patients with treatment-naive neovascular age-related macular degeneration after applying a deep-learning-assisted approach for image registration. These findings encourage a paradigm shift to using SSOCTA as a first-line diagnostic tool in neovascular age-related macular degeneration.

Visualizing melanosomes, lipofuscin, and melanolipofuscin in human retinal pigment epithelium using serial block face scanning electron microscopy.

To assess serial section block-face scanning electron microscopy (SBFSEM) for retinal pigment epithelium (RPE) ultrastructure, we determined the number and distribution within RPE cell bodies of melanosomes (M), lipofuscin (L), and melanolipofuscin (ML). Eyes of 4 Caucasian donors (16M, 32F, 76F, 84M) with unremarkable maculas were sectioned and imaged using an SEM fitted with an in-chamber automated ultramicrotome. Aligned image stacks were generated by alternately imaging an epoxy resin block face using backscattered electrons, then removing a 125 nm-thick layer. Series of 249-499 sections containing 5-24 nuclei were examined per eye. Trained readers manually assigned boundaries of individual cells and x,y,z locations of M, L, and ML. A Density Recovery Profile was computed in three dimensions for M, L, and ML. The number of granules per RPE cell body in 16M, 32F, 76F, and 84M eyes, respectively, was 465 ± 127 (mean ± SD), 305 ± 92, 79 ± 40, and 333 ± 134 for L; 13 ± 9; 6 ± 7, 131 ± 55, and 184 ± 66 for ML; and 29 ± 19, 24 ± 12, 12 ± 7, and 7 ± 3 for M. Granule types were spatially organized, with M near apical processes. The effective radius, a sphere of decreased probability for granule occurrence, was 1 µm for L, ML, and M combined. In conclusion, SBFEM reveals that adult human RPE has hundreds of L, LF, and M and that granule spacing is regulated by granule size alone. When obtained for a larger sample, this information will enable hypothesis testing about organelle turnover and regulation in health, aging, and disease, and elucidate how RPE-specific signals are generated in clinical optical coherence tomography and autofluorescence imaging.

Candidatus Dirofilaria hongkongensis as Causative Agent of Human Ocular Filariosis after Travel to India.

We report a human case of ocular Dirofilaria infection in a traveler returning to Austria from India. Analysis of mitochondrial sequences identified the worm as Candidatus Dirofilaria hongkongensis, a close relative of Dirofilaria repens, which was only recently described in Hong Kong and proposed as a new species.

Intereye Microvascular Differences in Patients With Same-Stage Diabetic Retinopathy Revealed by OCTA.

Purpose: To evaluate microvascular intereye differences in diabetic patients with same-stage diabetic retinopathy (DR) in both eyes as assessed using optical coherence tomography angiography (OCTA). Methods: In this cross-sectional study, fovea-centered swept-source 6 × 6 mm OCTA scans were acquired using a 200 kHz OCTA device. Vessel density (VD) and fractal dimension were calculated on binarized, vessel-segmented images in the superficial capillary plexus (SCP) and deep capillary plexus (DCP). Foveal avascular zone (FAZ) area (FAZA) and perimeter (FAZP) was measured and FAZ circularity (FAZC) calculated. Absolute difference (δabs) and asymmetry index between eyes was assessed and compared across DR stages. Differences of VD, FD, and FAZ parameters between left and right eye were evaluated using linear mixed models. Results: A total of 336 eyes of 168 diabetic patients without DR and with DR stages ranging from mild nonproliferative to proliferative DR were included for analysis. The intereye comparison revealed significantly lower VD in the SCP (estimate [95% CI] = -0.009 [-0.01; -0.006], P < 0.01), as well as a significantly lower FD in the SCP (-0.007 [-0.009; -0.005], P < 0.01) of the left compared to the right eye. FAZC of the left compared to the right eye was lower in eyes without DR, moderate DR, and PDR (P < 0.05). FAZ δabs and asymmetry index were higher in more advanced disease stages (P < 0.05). Conclusions: OCTA metrics provide important information on the retinal microvasculature in systemic diseases such as DR. Our results reveal a significant intereye difference with lower VD and FD in the SCP as well as higher FAZ impairment of the left compared to the right eye.

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.

Retinal pigment epithelium cells produce VEGF in response to oxidized phospholipids through mechanisms involving ATF4 and protein kinase CK2.

Oxidized phospholipids (OxPLs) are pleiotropic lipid mediators known to induce proangiogenic and proinflammatory cellular effects that are increasingly recognized to be involved in a number of physiologic and pathologic processes in the retina. Immunohistochemical studies have detected OxPLs in retinal structures, such as retinal pigment epithelium (RPE) or photoreceptor cells. This study analyzed whether OxPLs could play a role in upregulation of VEGF, which is a cause of pathological neovascularization characteristic of eye diseases such as age-related macular degeneration. We confirmed accumulation of OxPLs in the eye using reversed-phase liquid chromatography coupled to mass spectrometry. Multiple species of oxidized phosphatidylcholines (OxPCs) were detected in human vitreous, including biologically active fragmented species POVPC, PGPC, PONPC and PAzPC. In in vitro experiments human fetal RPE and primary RPE cells were stimulated with OxPLs. Primary RPE cells were transfected with small interfering RNAs targeting ATF4. mRNA levels of VEGF in fetal and primary RPE cells were determined by real-time quantitative PCR. VEGF protein concentrations were measured in culture medium by ELISA. We found that OxPCs and other classes of OxPLs upregulated the expression of VEGF in fetal and primary RPE cells, which critically depended on ATF4. In addition, upregulation of VEGF in primary RPE cells was blocked by a chemical inhibitor of protein kinase CK2 known to suppress induction of ATF4 and VEGF by OxPLs. Our data show that different species of OxPLs, which are present in the human eye are capable of stimulating expression of VEGF in fetal and primary RPE cells via ATF4-dependent mechanisms.

Quantitative proteomics of aqueous and vitreous fluid from patients with idiopathic epiretinal membranes.

The purpose of the study was to perform a detailed, quantitative protein analysis of the aqueous (AF) and vitreous fluids (VF) from human eyes with idiopathic epiretinal membranes (iERM). The complementary approaches of quantitative liquid chromatography mass spectrometry (LCMS) and multiplex protein assays were utilised to reveal the protein composition in ocular fluids of this retinal disorder. In a prospective clinical trial, AF and VF was collected during surgery from twenty four eyes corresponding to twenty four patients with iERM. VF and AF from eight patients were labelled with the 4-plex iTRAQ reagent and analysed by LCMS. Each iTRAQ 4-plex experiment consisted of the AH and VH from two patients. A total of 323 proteins were identified in the AF and VF from eyes with iERM. Grouping the proteins according to involvement in biological processes, showed that the majority were involved in the classical and alternative pathway of complement activation (n = 27), proteolysis (n = 26) and cell adhesion (n = 28). iTRAQ relative quantitation revealed minimal variation in the protein content between both ocular compartments with only 3.96% of the identified proteins significantly, differentially-expressed. Eight proteins were expressed at a higher level in the VF compared to the AF; and 4 proteins were expressed at a lower level in the VF compared to the AF. For the multiplex bead assays, 29 growth factors and cytokines were assessed in the AF and VF from 16 additional patients with iERM. The protein profile was shown to be similar between VF and AF for the majority of factors except PDGF-AA. This factor was expressed at a higher level in the VF compared to the AF. The data presented in this study revealed that the majority of the proteins identified by LCMS and multiplex bead assays were present in both ocular compartments in similar quantities. This study is a first step, 'discovery phase' towards revealing and quantitating the protein content in the aqueous and vitreous fluid in human eyes with iERM.

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.

[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.

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.