RELIABILITY OF CLINICAL GRADING OF DIABETIC RETINOPATHY COMPARED WITH GRADING OF ULTRA-WIDEFIELD IMAGES.

PURPOSE: To evaluate the reliability of clinical grading of diabetic retinopathy (DR) severity compared with grading on ultra-widefield pseudocolor fundus (UWF-CF) and ultra-widefield fluorescein angiography (UWF-FA) images and their relative detection of sight-threatening DR and referable DR. METHODS: A total of 184 diabetic eyes were analyzed. UWF-CF and UWF-FA images were graded based on the International Clinical Diabetic Retinopathy severity scale. Agreement between clinical and UWF-based severity grading was evaluated using Cohen's kappa coefficient. The rate of sight-threatening DR and referable DR was evaluated for each grading method. RESULTS: Moderate agreement was found between clinical grading and UWF-CF (k = 0.456, P < 0.001) and between UWF-CF and UWF-FA (k = 0.443, P < 0.001). The agreement between clinical grading and UWF-FA was fair (k = 0.397, P < 0.001). UWF-based grading identified a higher DR grade in 56 eyes (30%) on UWF-CF and 85 eyes (46.2%) on UWF-FA. Compared with clinical grading, UWF-FA detected a higher rate of sight-threatening DR (44%; 81/184 vs. 22.3%; 41/184), while UWF-CF detected more referable eyes (58.1%; 107/184 vs. 45.65%; 84/184). CONCLUSION: Ultra-widefield pseudocolor fundus is a valuable tool for identifying referable eyes and can be a useful, noninvasive adjunct to clinical grading. The results suggest that UWF-FA is particularly useful for detecting unsuspected sight-threatening DR in eyes with clinically referable DR.

Macular Perfusion Deficits on OCT Angiography Correlate with Nonperfusion on Ultrawide-field Fluorescein Angiography in Diabetic Retinopathy.

OBJECTIVE: To evaluate the correlation between nonperfusion parameters on OCT angiography (OCTA) and ultrawide-field fluorescein angiography (UWF-FA) in subjects with diabetes mellitus (DM). DESIGN: Prospective, cross-sectional study. SUBJECTS: Subjects with DM and a wide range of diabetic retinopathy (DR) severity seen at a tertiary referral center. METHODS: We used averaged 3 × 3 mm OCTA scans to measure geometric perfusion deficit (GPD), vessel density, and vessel length density in the full retina, superficial capillary plexuses (SCPs), and deep capillary plexuses (DCPs). Nonperfusion was manually delineated on UWF-FA to quantify central, peripheral, and total retinal nonperfusion (mm2 and % area). MAIN OUTCOME MEASURES: Correlation between OCTA parameters and UWF-FA nonperfusion, and accuracy of these OCTA and UWF-FA parameters in detecting clinically referable eyes, using receiver operating characteristic (ROC) curve analysis, sensitivity, specificity, and area under the ROC curve (AUC). RESULTS: The study included 67 eyes (12 eyes with no signs of DR, 8 mild, 22 moderate, 14 severe nonproliferative DR, and 11 treatment-naive proliferative DR). There was a fair-to-moderate correlation between either central or total retinal nonperfusion on UWF-FA (mm2) and GPD in the SCP (r = 0.482 and r = 0.464, respectively) and DCP (r = 0.470 and r = 0.456, respectively). Receiver operating characteristic analysis showed the DCP GPD significantly superior to other OCTA parameters at the DCP with the largest overall AUC on OCTA for distinguishing referable DR (0.905). Furthermore, the GPD parameter had the largest AUC in each respective capillary layer compared with other parameters. Overall, the total UWF-FA nonperfusion area showed a comparable AUC (0.907) and performed significantly better than peripheral nonperfusion (P = 0.041). Comparing the AUC values between GPD and UWF-FA nonperfusion parameters showed no significant difference in discerning referable DR. CONCLUSIONS: Nonperfusion as quantified on OCTA (3 × 3 mm) correlated with UWF-FA parameters and both were comparable in detecting referable DR. These macular OCTA metrics, particularly DCP GPD, have the potential for gauging the overall ischemic status of the retina, with an important clinical role in identifying eyes with clinically referable DR. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Association between macrophage-like cell density and ischemia metrics in diabetic eyes.

We previously showed that macrophage-like cells (MLCs) are increased in eyes with advanced diabetic retinopathy (DR). Here, we hypothesized that MLC density was correlated with ischemia using optical coherence tomography angiography (OCTA) and ultra-widefield fluorescein angiography (UWF-FA). Treatment-naïve diabetic eyes were prospectively imaged with repeated OCTA (average 5.3 scans per eye) and UWF-FA imaging. OCTA images were registered and averaged to generate a superficial capillary plexus (SCP), deep capillary plexus (DCP), and MLC slab. We calculated geometric perfusion deficit (GPD), vessel length density, and vessel density for the SCP and DCP. MLC density was quantified by two masked graders and averaged. Ischemia on UWF-FA was measured to generate a non-perfusion area (NPA) and index (NPI). Since MLC density was non-parametrically distributed, MLC density was correlated with ischemia metrics using Spearman correlations. Forty-five treatment-naïve eyes of 45 patients (59 ± 12 years of age; 56% female) were imaged. We included 6 eyes with no DR, 7 eyes with mild non-proliferative DR (NPDR), 22 moderate NPDR, 4 severe NPDR, and 6 PDR eyes. MLC density between graders was highly correlated (r = 0.9592, p < 0.0001). MLC density was correlated with DCP GPD (r = 0.296, p = 0.049), but no other OCTA ischemia metrics. MLC density was also correlated with UWF-FA NPA (r = 0.330, p = 0.035) and NPI (r = 0.332, p = 0.034). MLC density was correlated with total ischemia on UWF-FA and local DCP GPD. Since both UWF-FA and DCP non-perfusion are associated with higher risk for DR progression, MLC density could be another potential biomarker for DR progression.

Topical delivery of a small molecule RUNX1 transcription factor inhibitor for the treatment of proliferative vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) is the leading cause of retinal detachment surgery failure. Despite significant advances in vitreoretinal surgery, it still remains without an effective prophylactic or therapeutic medical treatment. After ocular injury or retinal detachment, misplaced retinal cells undergo epithelial to mesenchymal transition (EMT) to form contractile membranes within the eye. We identified Runt-related transcription factor 1 (RUNX1) as a gene highly expressed in surgically-removed human PVR specimens. RUNX1 upregulation was a hallmark of EMT in primary cultures derived from human PVR membranes (C-PVR). The inhibition of RUNX1 reduced proliferation of human C-PVR cells in vitro, and curbed growth of freshly isolated human PVR membranes in an explant assay. We formulated Ro5-3335, a lipophilic small molecule RUNX1 inhibitor, into a nanoemulsion that when administered topically curbed the progression of disease in a novel rabbit model of mild PVR developed using C-PVR cells. Mass spectrometry analysis detected 2.67 ng/mL of Ro5-3335 within the vitreous cavity after treatment. This work shows a critical role for RUNX1 in PVR and supports the feasibility of targeting RUNX1 within the eye for the treatment of an EMT-mediated condition using a topical ophthalmic agent.

Characterization of a Murine Model of Oxazolone-Induced Orbital Inflammation.

Purpose: Acute orbital inflammation can lead to irreversible vision loss in serious cases. Treatment thus far has been limited to systemic steroids or surgical decompression of the orbit. An animal model that mimics the characteristic features of acute orbital inflammation as found in thyroid eye disease can be used to explore novel treatment modalities. Methods: We developed a murine model of orbital inflammation by injecting oxazolone into the mouse orbit. The mice underwent magnetic resonance imaging (MRI) and were euthanized at various time points for histologic examination. Immunofluorescence studies of specific inflammatory cells and cytokine arrays were performed. Results: We found clinical and radiographic congruity between the murine model and human disease. After 72 hours, sensitized mice exhibited periorbital dermatitis and inflammation in the eyelids of the injected side. By one week, increased proptosis in the injected eye with significant eyelid edema was appreciated. By four weeks, inflammation and proptosis were decreased. At all three time points, the mice demonstrated exophthalmos and periorbital edema. Histopathologically, populations of inflammatory cells including T cells, macrophages, and neutrophils shared similarities with patient samples in thyroid eye disease. Proteomic changes in the levels of inflammatory and angiogenic markers correlated to the expected angiogenic, inflammatory, and fibrotic responses observed in patients with thyroid eye disease. Conclusions: A murine model of orbital inflammation created using oxazolone recapitulates some of the clinical features of thyroid eye disease and potentially other nonspecific orbital inflammation, typified by inflammatory cell infiltration, orbital tissue expansion and remodeling, and subsequent fibrosis. Translational Relevance: This animal model could serve as a viable platform with which to understand the underlying mechanisms of acute orbital inflammation and to investigate potential new, targeted treatments.