Diabetic Eye Disease

Diabetic Eye Disease Publications

Ashraf M, AbdelAl O, Shokrollahi S, Pitoc CM, Aiello LP, Silva PS. Evaluation of diabetic retinopathy severity on ultrawide field colour images compared with ultrawide fluorescein angiograms. Br J Ophthalmol 2023;Abstract
PURPOSE: To compare Early Treatment Diabetic Retinopathy Study (ETDRS) diabetic retinopathy (DR) severity on ultrawide field (UWF) colour imaging (CI) and UWF fluorescein angiography (FA). DESIGN: Cross-sectional retrospective review. SUBJECTS: Patients with diabetes mellitus and at least mild non-proliferative DR on UWF-CI. METHODS: UWF-CI and UWF-FA images acquired within 1 month of each other were evaluated independently using ETDRS DR Severity Scale (DRSS) for colour photography adapted for UWF-CI and UWF-FA. Extent of non-perfusion (NP, mm2) was determined from UWF-FA images. MAIN OUTCOME MEASURES: Agreement rate between DRSS on UWF-CI and UWF-FA. RESULTS: Images from 218 eyes of 137 patients with diabetes were evaluated. Agreement rate for DRSS between UWF-CI and UWF-FA was moderate to substantial (K=0.46, Kw=0.65). Over-all, DRSS was worse in 73 (33.5%) eyes on UWF-FA and in 16 (7.3%) on UWF-CI. Compared to UWF-CI, UWF-FA identified more severe DRSS in 26.5% (1 step) and 7.34% (≥2 steps) of eyes. DRSS was worse than UWF-FA in 56 (51.4%) in early DR (ETDRS levels 20-47, N=109) and 17 (15.6%) in eyes with severe DR (53 and higher, N=109). In this cohort, the extent of NP significantly increased as eyes approach moderate non-proliferative DR (levels 43-47, p=0.0065). CONCLUSION: When evaluating UWF-FA images using the ETDRS colour severity scale, DRSS is graded as more severe in a substantial number of eyes than when evaluating UWF-CI. It is uncertain how the DRSS levels using UWF-FA translate to clinical outcomes, but the additional lesions detected might provide added prognostic value. These and other recent data emphasise the need of obtaining outcome data based on UWF-FA and the potential need to develop DRSS specifically tailored for UWF-FA images.
Le R, Cui Y, Lu ES, Zhu Y, Garg I, Wang JC, Lu Y, Zeng R, Katz R, Laíns I, Eliott D, Husain D, Kim LA, Miller JB. Prevalence of venous loops and association with retinal ischemia in diabetic retinopathy using widefield swept-source OCT angiography. Graefes Arch Clin Exp Ophthalmol 2023;Abstract
PURPOSE: To investigate the prevalence and clinical characteristics of diabetic patients with retinal venous loops (RVLs) and to assess the association with retinal ischemia using widefield swept-source optical coherence tomography angiography (WF SS-OCTA). METHODS: In this retrospective, cross-sectional study, a total of 195 eyes of 132 diabetic patients (31 eyes with no diabetic retinopathy (DR), 76 eyes with nonproliferative DR (NPDR), and 88 eyes with proliferative DR (PDR)) were imaged with WF SS-OCTA using Angio 6 × 6 mm and Montage 15 × 15 mm scans. Quantitative ischemia-related parameters, including ischemia index (ratio of nonperfusion area to total retinal area), foveal avascular zone (FAZ), and neovascularization features, were evaluated. RVLs were classified as type I or type II according to the branching level of the feeder vessel. A multivariate generalized estimating equations (GEE) logistic regression model was used to analyze the association of systemic parameters and ischemia-related metrics with RVLs in PDR eyes. RESULTS: Forty-eight RVLs were identified in 22 eyes (11.28%). The prevalence of RVLs was higher in PDR compared to NPDR eyes (21.59% vs. 3.95%, P < 0.05). Type II RVLs accounted for a higher proportion than type I (89.58% vs. 10.42%, P < 0.001). RVLs were more likely to originate from superior (vs. inferior) and temporal (vs. nasal) veins (P < 0.05). The GEE model showed that neovascularization (NV) flow area and diastolic blood pressure were associated with RVLs in the PDR group (P < 0.05). CONCLUSION: WF SS-OCTA is useful for the identification of RVLs in patients with DR. NV flow area and diastolic blood pressure were associated with the presence of RVLs in eyes with PDR. Ischemia index, FAZ, and other WF SS-OCTA parameters were not associated with RVLs. Further longitudinal studies are needed to identify the role of RVLs in DR progression.
Wu M, Matar DY, Yu Z, Chen Z, Knoedler S, Ng B, Darwish O, Haug V, Friedman L, Orgill DP, Panayi AC. Modulation of Lymphangiogenesis in Incisional Murine Diabetic Wound Healing Using Negative Pressure Wound Therapy. Adv Wound Care (New Rochelle) 2023;Abstract
Objective: Despite the significant function of lymphatics in wound healing, and frequent clinical use of Negative Pressure Wound Therapy (NPWT), the effect of mechanical force application on lymphangiogenesis remains to be elucidated. We utilize a murine incisional wound healing model to assess the mechanisms of lymphangiogenesis following NPWT. Approach: Dorsal incisional skin wounds were created on diabetic mice (genetically obese leptin receptor-deficient mice [db/db]; n = 30) and covered with an occlusive dressing (Control, n = 15) or NPWT (-125 mmHg, continuous, 24 h for 7 days; NPWT, n = 15). The wounds were macroscopically assessed for 28 days. Tissue was harvested on day 10 for analysis. Qualitative functional analysis of lymphatic drainage was performed on day 28 using Evans Blue staining (n = 2). Results: NPWT increased lymphatic vessel density (40 ± 20 vs. 12 ± 6 podoplanin [PDPN]+ and 25 ± 9 vs. 14 ± 8 lymphatic vessel endothelial receptor 1 [LYVE-1]+) and vessel diameter (28 ± 9 vs. 12 ± 2 μm). Western blotting verified the upregulation of LYVE-1 with NPWT. Leukocyte presence was higher with NPWT (22% ± 3.7% vs. 9.1% ± 4.1% lymphocyte common antigen [CD45]+) and the leukocytes were predominately B cells clustered within vessels (8.8% ± 2.5% vs. 18% ± 3.6% B-lymphocyte antigen CD20 [CD20]+). Macrophage presence was lower in the NPWT group. Lymphatic drainage was increased in the NPWT group, which exhibited greater Evans Blue positivity. Innovation: The lymphangiogenic effects take place independent of macrophage infiltration, appearing to correlate with B cell presence. Conclusion: NPWT promotes lymphangiogenesis in incisional wounds, significantly increasing the lymph vessel density and diameter. This study highlights the potential of NPWT to stimulate lymphatic drainage and wound healing of surgical incisions.
Fickweiler W, Mitzner M, Jacoba CMP, Sun JK. Circulatory Biomarkers and Diabetic Retinopathy in Racial and Ethnic Populations. Semin Ophthalmol 2023;:1-11.Abstract
Clinical staging systems for diagnosis and treatment of diabetic retinopathy (DR) must closely relate to endpoints that are both relevant for patients and feasible for physicians to implement. Current DR staging systems for clinical eye care and research provide detailed phenotypic characterization to predict patient outcomes in diabetes but have limitations. Biochemical biomarkers provide a rich pool of potential candidates for new DR staging systems that can be readily measured in accessible fluids. Circulating biomarkers that are specific to the retina and relate to angiogenesis and inflammation have been suggested as relevant for DR. Although there is a lack of multi-ethnic studies evaluating circulatory biomarkers in DR, variability in circulatory biomarkers have been reported in people from different ethnic and racial backgrounds. Therefore, there is a need for future studies to evaluate individual or combinations of biomarkers in diverse populations with DR from different ethnic and racial backgrounds.
Lin LY, Lee NG, Yoon MK, Stagner AM. Clear Cell Syringoma of the Eyelids, a Distinctive Histopathologic Variant Associated with Diabetes Mellitus. Ophthalmic Plast Reconstr Surg 2023;39(1):e20-e22.Abstract
The authors describe the clinical and histologic findings of the clear cell variant of syringoma. Three adult female patients (age range 39-76 years old) were found to have multiple, flesh-colored lower eyelid papules, clinically consistent with syringomas, but histologically displaying abundant clear cell change. Two patients had known diagnoses of uncontrolled diabetes.
Ashraf M, Hock KM, Cavallerano JD, Wang FL, Silva PS. Comparison of Widefield Laser Ophthalmoscopy and ETDRS Retinal Area for Diabetic Retinopathy. Ophthalmol Sci 2022;2(4):100190.Abstract
PURPOSE: To evaluate agreement of nonmydriatic confocal scanning laser ophthalmoscopy (SLO; EIDON [CenterVue]) and the 7-standard field ETDRS area on ultrawide-field (UWF) SLO imaging for identification of diabetic retinopathy (DR) severity. DESIGN: Single-site, prospective, comparative, instrument validation study. PARTICIPANTS: One hundred ten eyes of 55 patients with diabetes mellitus were evaluated. METHODS: Each patient underwent nonmydriatic, nonsimultaneous stereoscopic imaging using the EIDON camera and 4 fields of 60° × 55° were acquired (macula centered, disc centered, temporal macula, superotemporal). Mydriatic UWF retinal images were acquired using a nonsimultaneous stereographic protocol with UWF imaging (California; Optos plc). Before grading, a standardized ETDRS 7-field image mask was applied to all UWF retinal images. Images from each device were graded independently by 2 masked graders using the ETDRS clinical DR classification. Any discrepancy in DR grading between the devices was adjudicated by a third grader. MAIN OUTCOME MEASURES: κ Levels of agreement, sensitivity, and specificity for DR thresholds. RESULTS: Severity by ETDRS grading was as follows: no DR, 10.9%; mild nonproliferative DR (NPDR), 45.5%; moderate NPDR, 16.5%; severe NPDR, 11.8%; proliferative DR, 12.7%; high-risk proliferative DR, 2.7%; and ungradable, 0%. After adjudication, the level of DR identified on EIDON images agreed exactly with that of UWF ETDRS imaging in 87% of eyes (n = 96) and was within 1 step in 99.1% of eyes (n = 109) with a simple κ value of 0.8244 ± 0.0439 (95% confidence interval [CI], 0.7385-0.9104) and weighted (linear) κ value of 0.9041 ± 0.0257 (95% CI, 0.8537-0.9545). Sensitivity and specificity compared with ETDRS field grading for any DR were 0.96 and 0.75, for moderate NPDR or worse were 0.96 and 0.97, and for severe NPDR or worse were 0.91 and 1.00, respectively. CONCLUSIONS: Nonmydriatic 4-field stereoscopic widefield imaging using the EIDON device was comparable with the DR severity identified within the ETDRS 7-standard field area of UWF images. Future studies will need to evaluate the applicability of this device as a clinical and research tool and the impact of different widefield coverage areas.
Malone JI, Gao X, Lorenzi GM, Raskin P, White NH, Hainsworth DP, Das A, Tamborlane W, Wallia A, Aiello LP, Bebu I, and of and Group DCCT (DCCT)-EDIC (EDIC) R. Retinopathy During the First 5 Years of Type 1 Diabetes and Subsequent Risk of Advanced Retinopathy. Diabetes Care 2022;Abstract
OBJECTIVE: To determine whether individuals with type 1 diabetes (T1D) who develop any retinopathy at any time prior to 5 years of diabetes duration have an increased subsequent risk for further progression of retinopathy or onset of proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), diabetes-related retinal photocoagulation, or anti-vascular endothelial growth factor injections. Additionally, to determine the influence of HbA1c and other risk factors in these individuals. RESEARCH DESIGN AND METHODS: Diabetic retinopathy (DR) was assessed longitudinally using standardized stereoscopic seven-field fundus photography at time intervals of 6 months to 4 years. Early-onset DR (EDR) was defined as onset prior to 5 years of T1D duration. Cox models assessed the associations of EDR with subsequent risk of outcomes. RESULTS: In unadjusted models, individuals with EDR (n = 484) had an increased subsequent risk of PDR (hazard ratio [HR] 1.51 [95% CI 1.12, 2.02], P = 0.006), CSME (HR 1.44 [1.10, 1.88], P = 0.008), and diabetes-related retinal photocoagulation (HR 1.48 [1.12, 1.96], P = 0.006) compared with individuals without EDR (n = 369). These associations remained significant when adjusted for HbA1c, but only the association with PDR remained significant after adjustment for age, duration of T1D, HbA1c, sex, systolic/diastolic blood pressure, pulse, use of ACE inhibitors, albumin excretion rate, and estimated glomerular filtration rate (HR 1.47 [95% CI 1.04, 2.06], P = 0.028). CONCLUSIONS: These data suggest that individuals with any sign of retinopathy within the first 5 years of T1D onset may be at higher risk of long-term development of advanced DR, especially PDR. Identification of early-onset DR may influence prognosis and help guide therapeutic management to reduce the risk of future visual loss in these individuals.
Bebu I, Braffett BH, de Boer IH, Aiello LP, Bantle JP, Lorenzi GM, Herman WH, Gubitosi-Klug RA, Perkins BA, Lachin JM, Molitch ME, Molitch ME. Relationships Between the Cumulative Incidences of Long-term Complications in Type 1 Diabetes: the DCCT/EDIC Study. Diabetes Care 2022;Abstract
OBJECTIVE: To describe the relationships between the cumulative incidences of long-term complications in individuals with type 1 diabetes (T1D) and assess whether observed associations are independent of age, duration of diabetes, and glycemic levels. METHODS: Proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), reduced estimated glomerular filtration rate (eGFR), amputations, cardiovascular disease (CVD), and mortality were assessed in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study over ∼30 years. RESEARCH DESIGN AND RESULTS: The cumulative incidence of complications ranged from 3% (amputations) to 37% (CSME). There were large differences in the cumulative incidence of PDR between participants with versus without prior CSME (66% vs. 15%), reduced eGFR (59% vs. 29%), and amputation (68% vs. 32%); reduced eGFR with or without prior PDR (25% vs. 9%), amputation (48% vs. 13%), and CVD (30% vs. 11%); CVD with or without prior reduced eGFR (37% vs. 14%) and amputation (50% vs. 16%); and mortality with or without prior reduced eGFR (22% vs. 9%), amputation (35% vs. 8%), and CVD (25% vs. 8%). Adjusted for age, duration of T1D, and mean updated HbA1c, the complications and associations with higher risk included PDR with CSME (hazard ratio [HR] 1.88; 95% CI 1.42, 2.50), reduced eGFR (HR 1.41; 95% CI 1.01, 1.97), and CVD (HR 1.43; 95% CI 1.06, 1.92); CSME with higher risk of PDR (HR 3.94; 95% CI 3.18 4.89), reduced eGFR (HR 1.49; 95% CI 1.10, 2.01), and CVD (HR 1.35; 95% CI 1.03, 1.78); reduced eGFR with higher risk of CVD (HR 2.09; 95% CI 1.44, 3.03), and death (HR 3.40; 95% CI 2.35, 4.92); amputation(s) with death (HR 2.97; 95% CI 1.70, 2.90); and CVD with reduced eGFR (HR 1.59; 95% CI 1.08, 2.34) and death (HR 1.95; 95% CI 1.32, 2.90). CONCLUSIONS: Long-term micro- and macrovascular complications and mortality are highly correlated. Age, diabetes duration, and glycemic levels do not completely explain these associations.
Roh M, Tesfaye H, Kim SC, Zabotka LE, Patorno E. Cardiovascular and Mortality Risk with Intravitreal Vascular Endothelial Growth Factor Inhibitors in Patients with Diabetic Retinopathy. Ophthalmol Retina 2022;6(12):1145-1153.Abstract
OBJECTIVE: To investigate the cardiovascular (CV) safety associated with intravitreal anti-VEGF injections (IAVIs) in patients with diabetic retinopathy (DR). DESIGN: Population-based cohort study using Medicare and 2 commercial insurance claims databases in the United States from January 2009 to December 2017. SUBJECTS: Patients with DR aged ≥ 18 years in whom treatment with either IVAIs or laser procedure or intravitreal steroid injections was initiated. METHODS: We estimated the propensity score (PS) using multivariable logistic regression models, including 85 baseline covariates and PS-matched patients in a 1:1 ratio. We estimated the pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analyses based on prior history of CV events were also conducted. MAIN OUTCOME MEASURES: A composite CV outcome of myocardial infarction (MI) or stroke, its individual components, and all-cause mortality in 180 and 365 days after treatment initiation. RESULTS: We identified 61 508 PS-matched patients in a 1:1 ratio in whom either IVAIs or laser or steroid treatment was initiated. Compared with laser or steroid treatment, IAVIs were not associated with an increased risk of the composite CV outcome (HR, 0.95; 95% CI, 0.83-1.09), MI (HR, 0.93; 95% CI, 0.76-1.13), or stroke (HR, 0.98; 95% CI, 0.80-1.19) or the risk of all-cause mortality (HR, 1.25; 95% CI, 0.97-1.62) at 180 days of follow-up. At 365 days, the risk of the composite CV outcome, stroke, and MI remained similar between the 2 groups, although the risk of all-cause mortality was increased with IAVIs (HR, 1.35; 95% CI, 1.14-1.60). The subgroup analysis showed that the risk of all-cause mortality was increased in patients with a prior history of CV events. CONCLUSIONS: Among > 60 000 patients with DR, those who received IAVIs had a risk of CV events similar to those who received laser or steroid treatment. However, the risk of all-cause mortality was higher in patients who received IAVIs for DR.
Patel NA, Al-Khersan H, Yannuzzi NA, Lin J, Smiddy WE. Aflibercept Monotherapy versus Bevacizumab First for Diabetic Macular Edema: A Cost Analysis based on DRCR Protocol AC Results. Ophthalmol Retina 2022;Abstract
PURPOSE: To calculate costs of treatment for diabetic macular edema (CI-DME) with bevacizumab-first (step therapy) compared to aflibercept monotherapy. DESIGN: Cost analysis of treatment arms based on a published study SUBJECTS: None METHODS: Published results from the Diabetic Retinopathy Clinical Research Network (DRCR.net) protocol AC were used to assess costs. Data incorporated in a usage and outcome model included frequency of injections, medication type, visits, and imaging. Costs were modeled based on 2022 Medicare reimbursement data for both facility (hospital-based) and non-facility settings in Miami. Outcomes were similar in Protocol AC so were not differentially studied. Results were extrapolated so as to estimate lifetime (17 years for the age of the cohort). RESULTS: Over the 2 years reported in protocol AC, the cost required to treat in the facility (nonfacility setting) was $42,000 ($32,000) in the aflibercept monotherapy group and $29,000 ($22,000) in the bevacizumab-first group. Extrapolated modeled lifetime costs were $158,000 ($136,000) and $125,000 ($103,000), respectively. The total cost with bevacizumab-first was 33% lower at year 2 and 21% lower at year 17 compared with aflibercept monotherapy. Savings per year for the 2 year results were $6,500 ($5000) in the facility (non-facility) setting. For the extrapolated 17 year model annual savings were $1900 ($1900) in the facility (non-facility) setting. The professional fees accounted for a minority of overall costs; in contrast, medication costs accounted for 82% of the total costs for the aflibercept monotherapy and 73% in the bevacizumab-first group at 2 years. Our model predicted an additional 15% lifetime cumulative savings if patients still not meeting threshold criteria after switching to aflibercept were placed back on bevacizumab, and a similar degree of improvement if those on not meeting threshold criteria on aflibercept monotherapy were switched to bevacizumab. MAIN OUTCOME MEASURES: Cost of treatment options. CONCLUSION: Medication is the dominant driver of the total expenses associated with the treatment of diabetic macular edema. While cost savings are realized with bevacizumab-first step therapy, the magnitude was not as much as might be intuited, probably due to the high (70%) incidence of patients switching to aflibercept within Protocol AC.
Kovoor E, Chauhan SK, Hajrasouliha A. Role of inflammatory cells in pathophysiology and management of diabetic retinopathy. Surv Ophthalmol 2022;67(6):1563-1573.Abstract
Diabetic retinopathy (DR) is a sight-threatening complication of diabetes mellitus. Several inflammatory cells and proteins, including macrophages and microglia, cytokines, and vascular endothelial growth factors, are found to play a significant role in the development and progression of DR. Inflammatory cells play a significant role in the earliest changes seen in DR including the breakdown of the blood retinal barrier leading to leakage of blood into the retina. They also have an important role in the pathogenesis of more advanced stage of proliferative diabetic retinopathy, leading to neovascularization, vitreous hemorrhage, and tractional retinal detachment. In this review, we examine the function of numerous inflammatory cells involved in the pathogenesis, progression, and role as a potential therapeutic target in DR. Additionally, we explore the role of inflammation following treatment of DR.
Lee D, Tomita Y, Negishi K, Kurihara T. Therapeutic roles of PPARα activation in ocular ischemic diseases. Histol Histopathol 2022;:18542.Abstract
Ocular ischemia is one of the leading causes of blindness. It is related to various ocular diseases and disorders, including age-related macular degeneration, diabetic retinopathy, glaucoma, and corneal injury. Ocular ischemia occurs due to an abnormal supply of oxygen and nutrients to the eye, resulting in ocular metabolic dysfunction. These changes can be linked with pathologic conditions in the eye, such as inflammation, neovascularization, and cell death, ultimately leading to vision loss. The current treatment care for ocular ischemia is limited. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor protein functioning in regulating lipid metabolism, fatty acid oxidation, and glucose homeostasis. Recently, PPARα activation has been suggested as a useful therapeutic target in treating ocular ischemia. However, its applications have not been well summarized. In this review, we cover an overview of the therapeutic roles of PPARα activation in various ocular ischemic conditions with recent experimental evidence and further provide clinical implications of its therapeutic applications. Our review will enable more approaches to comprehensively understand the therapeutic roles of PPARα activation for preventing ocular ischemic diseases.
Marcus DM, Silva PS, Liu D, Aiello LP, Antoszyk A, Elman M, Friedman S, Glassman AR, Googe JM, Jampol LM, Martin DF, Melia M, Preston CM, Wykoff CC, Sun JK, Sun JK. Association of Predominantly Peripheral Lesions on Ultra-Widefield Imaging and the Risk of Diabetic Retinopathy Worsening Over Time. JAMA Ophthalmol 2022;140(10):946-954.Abstract
Importance: Ultra-widefield (UWF) imaging improves the ability to identify peripheral diabetic retinopathy (DR) lesions compared with standard imaging. Whether detection of predominantly peripheral lesions (PPLs) better predicts rates of disease worsening over time is unknown. Objective: To determine whether PPLs identified on UWF imaging are associated with increased disease worsening beyond the risk associated with baseline Early Treatment Diabetic Retinopathy Study (ETDRS) Diabetic Retinopathy Severity Scale (DRSS) score. Design, Setting, and Participants: This cohort study was a prospective, multicenter, longitudinal observational study conducted at 37 US and Canadian sites with 388 participants enrolled between February and December 2015. At baseline and annually through 4 years, 200° UWF-color images were obtained and graded for DRSS at a reading center. Baseline UWF-color and UWF-fluorescein angiography (FA) images were evaluated for the presence of PPL. Data were analyzed from May 2020 to June 2022. Interventions: Treatment of DR or diabetic macular edema was at investigator discretion. Main Outcomes and Measures: Predominantly peripheral lesions were defined as DR lesions with a greater extent outside vs inside the 7 standard ETDRS fields. Primary outcome was disease worsening defined as worsening 2 steps or more on the DRSS or receipt of DR treatment. Analyses were adjusted for baseline DRSS score and correlation between 2 study eyes of the same participant. Results: Data for 544 study eyes with nonproliferative DR (NPDR) were analyzed (182 [50%] female participants; median age, 62 years; 68% White). The 4-year disease worsening rates were 45% for eyes with baseline mild NPDR, 40% for moderate NPDR, 26% for moderately severe NPDR, and 43% for severe NPDR. Disease worsening was not associated with color PPL at baseline (present vs absent: 38% vs 43%; HR, 0.78; 95% CI, 0.57-1.08; P = .13) but was associated with FA PPL at baseline (present vs absent: 50% vs 31%; HR, 1.72; 95% CI, 1.25-2.36; P < .001). Conclusions and Relevance: Although no association was identified with color PPL, presence of FA PPL was associated with greater risk of disease worsening over 4 years, independent of baseline DRSS score. These results suggest that use of UWF-FA to evaluate retinas peripheral to standard ETDRS fields may improve the ability to predict disease worsening in NPDR eyes. These findings support use of UWF-FA for future DR staging systems and clinical care to more accurately determine prognosis in NPDR eyes.