Diabetic Eye Disease

Lee WJ, Sobrin L, Kang MH, Seong M, Kim YJ, Yi J-H, Miller JW, Cho HY. Ischemic diabetic retinopathy as a possible prognostic factor for chronic kidney disease progression. Eye (Lond) 2014;28(9):1119-25.Abstract
PURPOSE: To assess the value of diabetic retinopathy (DR) severity as a possible predictive prognostic factor for the progression of chronic kidney disease (CKD). PATIENTS AND METHODS: Retrospective cohort study. Patients (51) who were initially diagnosed with DR and CKD were enrolled and their medical records were evaluated. The following ophthalmic factors were assessed by fluorescein angiography at the initial visit: area of capillary nonperfusion, presence of neovascularization and vitreous hemorrhage, and DR grade. The effect of these factors on CKD progression over the 2-year period of the study, defined as doubling of serum creatinine or the development of end-stage renal disease requiring dialysis or renal transplant, was evaluated. RESULTS: The study included 51 patients with DR and CKD; of these, 11 patients (21.6%) were found to have proliferative DR (PDR) and seven patients (13.7%) had high-risk PDR at baseline. Patients with ischemic DR, who showed extensive capillary nonperfusion (≥ 10 optic disc areas) in the retina, had a greater risk for CKD progression (hazard ratio = 6.64; P = 0.002). CONCLUSION: We found that extensive capillary nonperfusion in the retina greatly increased the risk of progression of CKD in patients with DR. This suggests that the retina and the kidney may have shared risk factors for microvascular disease secondary to diabetes mellitus, and emphasizes the need for a team approach to diabetes care.
Pemp B, Deák G, Prager S, Mitsch C, Lammer J, Schmidinger G, Scholda C, Schmidt-Erfurth U, Bolz M, Bolz M. Distribution of intraretinal exudates in diabetic macular edema during anti-vascular endothelial growth factor therapy observed by spectral domain optical coherence tomography and fundus photography. Retina 2014;34(12):2407-15.Abstract
PURPOSE: To evaluate changes in the distribution and morphology of intraretinal microexudates and hard exudates (HEs) during intravitreal anti-vascular endothelial growth factor therapy in patients with persistent diabetic macular edema. METHODS: Twenty-four patients with persistent diabetic macular edema after photocoagulation were investigated in this prospective cohort study. Each eye was assigned to a loading dose of three anti-vascular endothelial growth factor treatments at monthly intervals. Additional single treatments were performed if diabetic macular edema persisted or recurred. Intraretinal exudates were analyzed over 6 months using spectral domain optical coherence tomography (SD-OCT) and fundus photography. RESULTS: Before treatment, microexudates were detected by SD-OCT as hyperreflective foci in 24 eyes, whereas HEs were seen in 22 eyes. During therapy, HE increased significantly in number and size. This was accompanied by accumulation of microexudates in the outer retina. Enlargement of hyperreflective structures in SD-OCT was accompanied by enlargement of HE at corresponding fundus locations. A rapid reduction in diabetic macular edema was seen in all patients, but to varying degrees. Patients with hemoglobin A1c levels <7% and serum cholesterol <200 mg/dL formed fewer HEs and featured more edema reduction and visual acuity gain. CONCLUSION: Diabetic macular edema reduction during intravitreal anti-vascular endothelial growth factor therapy was accompanied by dynamic rearrangement of intraretinal exudates at corresponding locations in fundus photography and SD-OCT. Intraretinal aggregates of microexudates detectable as hyperreflective foci by SD-OCT may compose and precede HE before they become clinically visible.
Valdez CN, Arboleda-Velasquez JF, Amarnani DS, Kim LA, D'Amore PA. Retinal microangiopathy in a mouse model of inducible mural cell loss. Am J Pathol 2014;184(10):2618-26.Abstract
Diabetes can lead to vision loss because of progressive degeneration of the neurovascular unit in the retina, a condition known as diabetic retinopathy. In its early stages, the pathology is characterized by microangiopathies, including microaneurysms, microhemorrhages, and nerve layer infarcts known as cotton-wool spots. Analyses of postmortem human retinal tissue and retinas from animal models indicate that degeneration of the pericytes, which constitute the outer layer of capillaries, is an early event in diabetic retinopathy; however, the relative contribution of specific cellular components to the pathobiology of diabetic retinopathy remains to be defined. We investigated the phenotypic consequences of pericyte death on retinal microvascular integrity by using nondiabetic mice conditionally expressing a diphtheria toxin receptor in mural cells. Five days after administering diphtheria toxin in these adult mice, changes were observed in the retinal vasculature that were similar to those observed in diabetes, including microaneurysms and increased vascular permeability, suggesting that pericyte cell loss is sufficient to trigger retinal microvascular degeneration. Therapies aimed at preventing or delaying pericyte dropout may avoid or attenuate the retinal microangiopathy associated with diabetes.
Silva PS, Diala PA, Hamam RN, Arrigg PG, Shah ST, Murtha TL, Schlossman DK, Cavallerano JD, Sun JK, Aiello LP. Visual outcomes from pars plana vitrectomy versus combined pars plana vitrectomy, phacoemulsification, and intraocular lens implantation in patients with diabetes. Retina 2014;34(10):1960-8.Abstract

PURPOSE: To compare visual acuity outcomes and diabetic retinopathy progression after pars plana vitrectomy (PPV) versus combined pars plana vitrectomy and phacoemulsification (PPVCE) in patients with diabetes. METHODS: Retrospective review of 222 consecutive diabetic patients undergoing PPV or PPVCE. RESULTS: A total of 251 eyes of 222 patients were evaluated (PPV = 122, PPVCE = 129). Four-year follow-up was 64% (161 eyes). Overall, patients undergoing PPVCE had better preoperative visual acuity (PPVCE = 20/80, PPV = 20/160, P = 0.03). At 4-year follow-up, visual acuity improved (PPV = +22, PPVCE = +11 letters) compared with baseline in both groups. After correcting for baseline differences in visual acuity, no statistically significant difference in final visual acuity was observed (PPVCE = 20/32, PPV = 20/50, P = 0.09). Results did not differ substantially by surgical indication (vitreous hemorrhage, traction retinal detachment, epiretinal membrane, and/or diabetic macular edema). Cataract progression occurred in 64%, and cataract surgery was performed in 39% of phakic eyes undergoing PPV. Rates of diabetic retinopathy progression, vitreous hemorrhage, and retinal detachment were not statistically different. Neovascular glaucoma developed in 2 patients (2%) after PPV and 6 patients (8%) after PPVCE (P = 0.07). CONCLUSION: In diabetic patients, equivalent visual acuity improvement over 4 years was observed after PPV or PPVCE. Visual outcomes and retinopathy progression rates were not significantly different after either intervention, suggesting that PPVCE may be appropriate when indicated in patients with diabetes.

Arboleda-Velasquez JF, Primo V, Graham M, James A, Manent J, D'Amore PA. Notch signaling functions in retinal pericyte survival. Invest Ophthalmol Vis Sci 2014;55(8):5191-9.Abstract
PURPOSE: Pericytes, the vascular cells that constitute the outer layer of capillaries, have been shown to have a crucial role in vascular development and stability. Loss of pericytes precedes endothelial cell dysfunction and vascular degeneration in small-vessel diseases, including diabetic retinopathy. Despite their clinical relevance, the cellular pathways controlling survival of retinal pericytes remain largely uncharacterized. Therefore, we investigated the role of Notch signaling, a master regulator of cell fate decisions, in retinal pericyte survival. METHODS: A coculture system of ligand-dependent Notch signaling was developed using primary cultured retinal pericytes and a mesenchymal cell line derived from an inducible mouse model expressing the Delta-like 1 Notch ligand. This model was used to examine the effect of Notch activity on pericyte survival using quantitative PCR (qPCR) and a light-induced cell death assay. The effect of Notch gain- and loss-of-function was analyzed in monocultures of retinal pericytes using antibody arrays to interrogate the expression of apoptosis-related proteins. RESULTS: Primary cultured retinal pericytes differentially expressed key molecules of the Notch pathway and displayed strong expression of canonical Notch/RBPJK (recombination signal-binding protein 1 for J-kappa) downstream targets. A gene expression screen using gain- and loss-of-function approaches identified genes relevant to cell survival as downstream targets of Notch activity in retinal pericytes. Ligand-mediated Notch activity protected retinal pericytes from light-induced cell death. CONCLUSIONS: Our results have identified signature genes downstream of Notch activity in retinal pericytes and suggest that tight regulation of Notch signaling is crucial for pericyte survival.
Lee WJ, Sobrin L, Lee MJ, Kang MH, Seong M, Cho H. The relationship between diabetic retinopathy and diabetic nephropathy in a population-based study in Korea (KNHANES V-2,3). Invest Ophthalmol Vis Sci 2014;Abstract

PURPOSE. To determine the risk factors for and relationship between diabetic retinopathy (DR) and diabetic nephropathy (DN), including microalbuminuria and overt nephropathy, in a population-based study of diabetes mellitus (DM) patients in Korea. METHODS. This was a population-based, cross-sectional study. From the fifth (2011, 2012) Korea National Health and Nutrition Examination Survey (KNHANES), 971 participants with type 2 DM were included. The prevalence of DR and DN was determined. Multivariate logistic regression was performed to determine risk factors, including DR, associated with DN in the Korean population. RESULTS. In DM patients, we observed a prevalence of 20.0% for any DR and 3.8% for proliferative diabetic retinopathy (PDR). Microalbuminuria prevalence was 19.3% and overt nephropathy prevalence was 5.5%. The risk factors of microalbuminuria were presence of hypertension, higher systolic blood pressure, serum hemoglobin A1c (HbA1c) and serum blood urea nitrogen level as well as the presence of PDR. The risk factors of overt nephropathy were long duration of DM, high levels of HbA1c, systolic blood pressure, total cholesterol and serum creatinine as well as the presence of DR. CONCLUSIONS. PDR is associated with microalbuminuria and DR is associated with overt nephropathy in Korean DM patients. Our findings suggest that when an ophthalmologist finds the presence of DR or PDR, timely evaluation of the patient's renal status should be recommended.

Bressler SB, Almukhtar T, Aiello LP, Bressler NM, Ferris FL, Glassman AR, Greven CM, Greven CM. Green or yellow laser treatment for diabetic macular edema: exploratory assessment within the Diabetic Retinopathy Clinical Research Network. Retina 2013;33(10):2080-8.Abstract
PURPOSE: Explore differences in green compared with yellow focal/grid laser treatment on functional and anatomical endpoints in eyes with diabetic macular edema. METHODS: Data from two randomized clinical trials were evaluated for differences in visual acuity and optical coherence tomography parameters for eyes assigned to sham injection + prompt laser, ranibizumab + prompt laser, or prompt laser only: among subgroups of eyes treated exclusively and electively with either green or yellow laser. RESULTS: In the sham injection + prompt laser group, the mean visual acuity letter score change for eyes receiving green and yellow laser treatment, respectively, was +2.4 ± 14 and +5.1 ± 13 at the 52-week visit (P = 0.06) and +2.4 ± 15 and +6.0 ± 13 at the 104-week visit (P = 0.13), with no corresponding evidence of differences in optical coherence tomography thickness. When comparing wavelength groups in the ranibizumab + prompt laser and prompt laser-only groups, meaningful differences in visual acuity and optical coherence tomography thickness were not detected at 1 year or 2 years. CONCLUSION: A trend toward improved vision outcome with yellow laser observed in one trial was not corroborated by anatomical outcomes or by the other trial. In this study, without random assignment to different wavelengths controlling for bias and confounding, it is not possible to determine whether one wavelength is better than the other.
Silva PS, Cavallerano JD, Sun JK, Soliman AZ, Aiello LM, Aiello LP. Peripheral lesions identified by mydriatic ultrawide field imaging: distribution and potential impact on diabetic retinopathy severity. Ophthalmology 2013;120(12):2587-2595.Abstract
OBJECTIVE: To assess diabetic retinopathy (DR) as determined by lesions identified using mydriatic ultrawide field imaging (DiSLO200; Optos plc, Scotland, UK) compared with Early Treatment Diabetic Retinopathy Study (ETDRS) 7-standard field film photography. DESIGN: Prospective comparative study of DiSLO200, ETDRS 7-standard field film photographs, and dilated fundus examination (DFE). PARTICIPANTS: A total of 206 eyes of 103 diabetic patients selected to represent all levels of DR. METHODS: Subjects had DiSLO200, ETDRS 7-standard field film photographs, and DFE. Images were graded for severity and distribution of DR lesions. Discrepancies were adjudicated, and images were compared side by side. MAIN OUTCOME MEASURES: Distribution of hemorrhage and/or microaneurysm (H/Ma), venous beading (VB), intraretinal microvascular abnormality (IRMA), and new vessels elsewhere (NVE). Kappa (κ) and weighted κ statistics for agreement. RESULTS: The distribution of DR severity by ETDRS 7-standard field film photographs was no DR 12.5%; nonproliferative DR mild 22.5%, moderate 30%, and severe/very severe 8%; and proliferative DR 27%. Diabetic retinopathy severity between DiSLO200 and ETDRS film photographs matched in 80% of eyes (weighted κ = 0.74,κ = 0.84) and was within 1 level in 94.5% of eyes. DiSLO200 and DFE matched in 58.8% of eyes (weighted κ = 0.69,κ = 0.47) and were within 1 level in 91.2% of eyes. Forty eyes (20%) had DR severity discrepancies between DiSLO200 and ETDRS film photographs. The retinal lesions causing discrepancies were H/Ma 52%, IRMA 26%, NVE 17%, and VB 4%. Approximately one-third of H/Ma, IRMA, and NVE were predominantly outside ETDRS fields. Lesions identified on DiSLO200 but not ETDRS film photographs suggested a more severe DR level in 10% of eyes. Distribution in the temporal, superotemporal, inferotemporal, superonasal, and inferonasal fields was 77%, 72%, 61%, 65%, and 59% for H/Ma, respectively (P<0.0001); 22%, 24%, 21%, 28%, and 22% for VB, respectively (P = 0.009); 52%, 40%, 29%, 47%, and 36% for IRMA, respectively (P<0.0001), and 8%, 4%, 4%, 8%, and 5% for NVE, respectively (P = 0.03). All lesions were more frequent in the temporal fields compared with the nasal fields (P<0.0001). CONCLUSIONS: DiSLO200 images had substantial agreement with ETDRS film photographs and DFE in determining DR severity. On the basis of DiSLO200 images, significant nonuniform distribution of DR lesions was evident across the retina. The additional peripheral lesions identified by DiSLO200 in this cohort suggested a more severe assessment of DR in 10% of eyes than was suggested by the lesions within the ETDRS fields. However, the implications of peripheral lesions on DR progression within a specific ETDRS severity level over time are unknown and need to be evaluated prospectively.
Al-Latayfeh M, Silva PS, Sun JK, Aiello LP. Antiangiogenic therapy for ischemic retinopathies. Cold Spring Harb Perspect Med 2012;2(6):a006411.Abstract
Neovascularization is a common pathological process in various retinal vascular disorders including diabetic retinopathy (DR), age-related macular degeneration (AMD) and retinal vein occlusion (RVO). The development of neovascular vessels may lead to complications such as vitreous hemorrhage, fibrovascular tissue formation, and traction retinal detachments. Ultimately, irreversible vision loss may result. Various proangiogenic factors are involved in these complex processes. Different antiangiogenic drugs have been formulated in an attempt treat these vascular disorders. One factor that plays a major role in the development of retinal neovascularization is vascular endothelial growth factor (VEGF). Anti-VEGF agents are currently FDA approved for the treatment of AMD and RVO. They are also extensively used as an off-label treatment for diabetic macular edema (DME), proliferative DR, and neovascular glaucoma. However, at this time, the long-term safety of chronic VEGF inhibition has not been extensively evaluated. A large and rapidly expanding body of research on angiogenesis is being conducted at multiple centers across the globe to determine the exact contributions and interactions among a variety of angiogenic factors in an effort to determine the therapeutic potential of antiangiogenic agent in the treatment of a variety of retinal diseases.
Gologorsky D, Thanos A, Vavvas D. Therapeutic interventions against inflammatory and angiogenic mediators in proliferative diabetic retinopathy. Mediators Inflamm 2012;2012:629452.Abstract
The global prevalence of diabetes is estimated to be 336 million people, with diabetic complications contributing to significant worldwide morbidity and mortality. Diabetic retinopathy results from cumulative microvascular damage to the retina and inflammation is recognized as a critical driver of this disease process. This paper outlines the pathophysiology leading to proliferative diabetic retinopathy and highlights many of the inflammatory, angiogenic, and cytokine mediators implicated in the development and progression of this disease. We focus a detailed discussion on the current targeted therapeutic interventions used to treat diabetic retinopathy.
Silva PS, Cavallerano JD, Sun JK, Noble J, Aiello LM, Aiello LP. Nonmydriatic ultrawide field retinal imaging compared with dilated standard 7-field 35-mm photography and retinal specialist examination for evaluation of diabetic retinopathy. Am J Ophthalmol 2012;154(3):549-559.e2.Abstract
PURPOSE: To compare nonmydriatic stereoscopic Optomap ultrawide field images with dilated stereoscopic Early Treatment Diabetic Retinopathy Study 7-standard field 35-mm color 30-degree fundus photographs (ETDRS photography) and clinical examination for determining diabetic retinopathy (DR) and diabetic macular edema (DME) severity. DESIGN: Single-site, prospective, comparative, instrument validation study. METHODS: One hundred three diabetic patients (206 eyes) representing the full spectrum of DR severity underwent nonmydriatic ultrawide field 100-degree and 200-degree imaging, dilated ETDRS photography, and dilated fundus examination by a retina specialist. Two independent readers graded images to determine DR and DME severity. A third masked retina specialist adjudicated discrepancies. RESULTS: Based on ETDRS photography (n = 200), the results were as follows: no DR (n = 25 eyes [12.5%]), mild nonproliferative DR (NPDR; 47 [23.5%]), moderate NPDR (61 [30.5%]), severe NPDR (11 [5.5%]), very severe NPDR (3 [1.5%]), and proliferative DR (52 [2.5%]). One (0.5%) eye was ungradable and 6 eyes did not complete ETDRS photography. No DME was found in 114 eyes (57.0%), DME was found in 28 eyes (14.0%), and clinically significant DME was found in 47 eyes (23.5%), and 11 (5.5%) eyes were ungradable. Exact DR severity agreement between ultrawide field 100-degree imaging and ETDRS photography occurred in 84%, with agreement within 1 level in 91% (K(W) = 0.85; K = 0.79). Nonmydriatic ultrawide field images exactly matched clinical examination results for DR in 70% and were within 1 level in 93% (K(W) = 0.71; K = 0.61). Nonmydriatic ultrawide field imaging acquisition time was less than half that of dilated ETDRS photography (P < .0001). CONCLUSIONS: Nonmydriatic ultrawide field images compare favorably with dilated ETDRS photography and dilated fundus examination in determining DR and DME severity; however, they are acquired more rapidly. If confirmed in broader diabetic populations, nonmydriatic ultrawide field imaging may prove to be beneficial in DR evaluation in research and clinical settings.
Liu Y, Biarnés Costa M, Gerhardinger C. IL-1β is upregulated in the diabetic retina and retinal vessels: cell-specific effect of high glucose and IL-1β autostimulation. PLoS One 2012;7(5):e36949.Abstract
Many molecular and cellular abnormalities detected in the diabetic retina support a role for IL-1β-driven neuroinflammation in the pathogenesis of diabetic retinopathy. IL-1β is well known for its role in the induction and, through autostimulation, amplification of neuroinflammation. Upregulation of IL-1β has been consistently detected in the diabetic retina; however, the mechanisms and cellular source of IL-1β overexpression are poorly understood. The aim of this study was to investigate the effect of high glucose and IL-1β itself on IL-1β expression in microglial, macroglial (astrocytes and Müller cells) and retinal vascular endothelial cells; and to study the effect of diabetes on the expression of IL-1β in isolated retinal vessels and on the temporal pattern of IL-1β upregulation and glial reactivity in the retina of streptozotocin-diabetic rats. IL-1β was quantified by RealTime RT-PCR and ELISA, glial fibrillar acidic protein, α2-macroglobulin, and ceruloplasmin by immunoblotting. We found that high glucose induced a 3-fold increase of IL-1β expression in retinal endothelial cells but not in macroglia and microglia. IL-1β induced its own synthesis in endothelial and macroglial cells but not in microglia. In retinal endothelial cells, the high glucose-induced IL-1β overexpression was prevented by calphostin C, a protein kinase C inhibitor. The retinal vessels of diabetic rats showed increased IL-1β expression as compared to non-diabetic rats. Retinal expression of IL-1β increased early after the induction of diabetes, continued to increase with progression of the disease, and was temporally associated with upregulation of markers of glial activation. These findings point to hyperglycemia as the trigger and to the endothelium as the origin of the initial retinal upregulation of IL-1β in diabetes; and to IL-1β itself, via autostimulation in endothelial and macroglial cells, as the mechanism of sustained IL-1β overexpression. Interrupting the vicious circle triggered by IL-1β autostimulation could limit the progression of diabetic retinopathy.
Sapieha P, Chen J, Stahl A, Seaward MR, Favazza TL, Juan AM, Hatton CJ, Joyal J-S, Krah NM, Dennison RJ, Tang J, Kern TS, Akula JD, Smith LEH. Omega-3 polyunsaturated fatty acids preserve retinal function in type 2 diabetic mice. Nutr Diabetes 2012;2:e36.Abstract
OBJECTIVE: Diabetic retinopathy (DR) is associated with hyperglycemia-driven microvascular pathology and neuronal compromise in the retina. However, DR is also linked to dyslipidemia. As omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) are protective in proliferative retinopathy, we investigated the capacity of ω-3PUFAs to preserve retinal function in a mouse model of type 2 diabetes mellitus (T2DM). DESIGN: Male leptin-receptor-deficient (db/db) mice were maintained for 22 weeks (4 weeks-26 weeks of life) on calorically and compositionally matched diets, except for 2% enrichment in either ω-3 or ω-6PUFAs. Visual function was assessed at 9, 14 and 26 weeks by electroretinography. Retinal capillary and neuronal integrity, as well as glucose challenge responses, were assessed on each diet. RESULTS: The ω-3PUFA diet significantly preserved retinal function in the mouse model of T2DM to levels similar to those observed in nondiabetic control mice on normal chow. Conversely, retinal function gradually deteriorated in db/db mice on a ω-6PUFA-rich diet. There was also an enhanced ability of ω-3PUFA-fed mice to respond to glucose challenge. The protection of visual function appeared to be independent of cytoprotective or anti-inflammatory effects of ω-3PUFAs. CONCLUSION: This study identifies beneficial effects of dietary ω-3PUFAs on visual function in T2DM. The data are consistent with dyslipidemia negatively impacting retinal function. As ω-3PUFA lipid dietary interventions are readily available, safe and inexpensive, increasing ω-3PUFA intake in diabetic patients may slow the progression of vision loss in T2DM.
Maker MP, Noble J, Silva PS, Cavallerano JD, Murtha TJ, Sun JK, Aiello LM, Bursell S-E, Aiello LP. Automated Retinal Imaging System (ARIS) compared with ETDRS protocol color stereoscopic retinal photography to assess level of diabetic retinopathy. Diabetes Technol Ther 2012;14(6):515-22.Abstract
BACKGROUND: Early Treatment Diabetic Retinopathy Study (ETDRS) seven-standard-field color stereoscopic retinal photography (ETDRS photos) has been a gold standard for determining diabetic retinopathy (DR) severity. The Automated Retinal Imaging System (ARIS™, model 110, Visual Pathways, Inc., Prescott, AZ) acquires seven-sequential color stereoscopic digital images (ARIS images) by a semiautomated technician-run process generally corresponding to ETDRS photos. We assessed the correlation between a single semiautomated ARIS imaging session without any re-imaging and ETDRS photos performed by a certified photographer for the determination of DR severity. METHODS: Two independent masked readers graded mydriatic ARIS images and ETDRS photos. A third masked retinal specialist adjudicated discrepancies. Correlation between the two modalities was compared using weighted-κ statistics. RESULTS: We evaluated 211 eyes of 106 patients with varying levels of DR. Partially ungradable images were present in 3.4% of ETDRS photos versus 31.8% of ARIS images. Exact agreement and agreement within one level between ETDRS photos and ARIS images using only completely gradable image sets occurred in 69% (κ=0.81) and 90% of cases, respectively. Exact agreement for clinically significant macular edema was 92.1% (κ=0.59). There was 100% agreement for eyes with high-risk proliferative DR. Within one level of DR severity, 100% agreement occurred for the following: questionable nonproliferative DR (NPDR), moderate NPDR, and severe NPDR. CONCLUSIONS: Results suggest that semiautomated ARIS images compare favorably with ETDRS photos when full image sets can be obtained; however, partially ungradable image sets occurred almost 10 times more frequently with ARIS images than with ETDRS photos. In the two-thirds of cases where ARIS images can be utilized, ARIS can obtain retinal images comparable to ETDRS photos while requiring less highly trained personnel than generally needed for standard ETDRS photos.