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Purpose Estimates of diabetic eye disease in American Indian and Alaska Natives (AI/AN) vary over time, region, and methods. This article reports recent prevalence of diabetic retinopathy (DR) and diabetic macular edema (DME) in AI/AN served by the Indian Health Services' (IHS) teleophthalmology program, as identified using ultrawide field imaging (UWFI). Methods This was a retrospective analysis of 2016-2019 clinical data (n = 53,900). UWF images were acquired by certified imagers using a validated protocol, and graded by licensed, certified optometrists supervised by an ophthalmologist. Graders evaluated the extent/severity of retinal lesions in comparison to standard photographs. DR lesions predominantly in any peripheral field were considered "predominantly peripheral lesions" (PPL). The analyses calculated prevalence of any DR, any DME, DR and DME severity, sight-threatening disease, and PPL. Results Patients averaged 56 years of age with a 68 mmol/mol A1c and 55% had had diabetes for 5+ years. Prevalence of any DR, any DME, and sight-threatening disease was 28.6%, 3.0%, and 3.0%. In patients with mild nonproliferative DR, PPL was seen in 25.3%. PPL suggested a more severe level of DR in 8.7% of patients. DR increased with age. DME decreased with age. Males and patients in the Nashville IHS area had more diabetic eye disease. Conclusion AI/AN have a high burden of diabetes and its complications. The IHS is resource-constrained, making accurate disease estimates necessary for resource allocation and budget justifications to Congress. These data update the estimates of diabetic eye disease in Indian Country and suggest that UWFI identifies early DR.

Purpose To evaluate the association of retinal nonperfusion and diabetic retinopathy (DR) severity with location of vascular caliber measurement using ultrawide field (UWF) imaging. Design Retrospective image review. Participants Adults with diabetes mellitus. Methods All images from subjects with same-day UWF fluorescein angiography (FA) and color imaging were evaluated. Predominantly peripheral lesions (PPL) and DR severity were graded from UWF color images. Nonperfusion was quantified using UWF-FA in defined retinal regions [posterior pole (PP), mid-periphery (MP), far-periphery (FP)]. Retinal vessel calibers were measured at an optic disc centered inner and outer zone. Main Outcome Measures Nonperfusion index (NPI) in the PP, MP and FP. Mean arteriole and venule diameter in the inner and outer zones. Results Two hundred eighty-five eyes of 193 patients (24.9% mild nonproliferative DR [NPDR], 22.8% moderate NPDR, 37.5% severe NPDR and 14.7% proliferative DR [PDR]) were reviewed. No significant associations between inner zone arteriolar diameter and retinal NPI overall or in any retinal region. In the outer zone, eyes with thinnest arteriolar calibers (quartile 1) were associated with a 1.7- to 2.4-fold nonperfusion increase across all retinal regions compared to the remaining eyes (P = 0.002 [PP] to 0.048 [FP]). In the outer zone, the percentage of eyes in the thinnest quartile of retinal arteriolar diameter increased with worsening DR severity (mild NPDR: 10% vs PDR: 31%, P = 0.007). This association was not observed when measured within the inner zone (P = 0.129). All venular caliber associations were not statistically significant when corrected for potentially confounding factors. Thinner outer zone retinal arteriolar caliber (quartile 1) was more common in eyes with PPL compared to eyes without PPL (34.1% vs 20.8%, P = 0.017) as were thicker outer venular calibers (quartile 4) (33% vs 21.3%, P = 0.036). Presence of PPL was associated with thinner outer zone arteriolar caliber (109.7 ± 26.5μm vs 123.0 ± 29.5μm, P = 0.001). Conclusions The association of vascular caliber with nonperfusion and DR severity differs based upon the retinal location at which vascular caliber is measured. Peripheral arterial narrowing is associated with increasing nonperfusion, worsening DR severity and presence of PPL. In contrast, inner zone retinal arteriolar caliber is not associated with these findings.

Background: The severity and extent of microaneurysms (MAs) have been used to determine diabetic retinopathy (DR) severity and estimate the risk of DR progression over time. The recent introduction...

The goal of personalized diabetes eye care is to accurately predict in real-time the risk of diabetic retinopathy (DR) progression and visual loss. The use of electronic health records (EHR) provides a platform for artificial intelligence (AI) algorithms that predict DR progression to be incorporated into clinical decision-making. By implementing an algorithm on data points from each patient, their risk for retinopathy progression and visual loss can be modeled, allowing them to receive timely treatment. Data can guide algorithms to create models for disease and treatment that may pave the way for more personalized care. Currently, there exist numerous challenges that need to be addressed before reliably building and deploying AI algorithms, including issues with data quality, privacy, intellectual property, and informed consent.

Purpose The purpose of this study was to determine factors affecting predominantly peripheral lesion (PPL) grading, such as qualitative versus quantitative assessment, device type, and severity of diabetic retinopathy (DR) in ultrawide field color images (UWF-CIs). Methods Patients with DR had UWF-CI qualitatively graded for PPL using standardized techniques and had hemorrhages/microaneurysms (H/Mas) individually annotated for quantitative PPL grading on two different ultrawide field devices. Results Among 791 eyes of 481 patients, 38.2% had mild nonproliferative DR (NPDR), 34.7% had moderate NPDR, and 27.1% had severe NPDR to proliferative DR (PDR). The overall agreement between qualitative and quantitative PPL grading was moderate (ĸ = 0.423, P < 0.001). Agreement rates were fair in eyes with mild NPDR (ĸ = 0.336, P < 0.001) but moderate in eyes with moderate NPDR (ĸ = 0.525, P < 0.001) and severe NPDR-PDR (ĸ = 0.409, P < 0.001). Increasing thresholds for quantitative PPL determination improved agreement rates, with peak agreements at H/Ma count differences of six for mild NPDR, five for moderate NPDR, and nine for severe NPDR-PDR. Based on ultrawide field device type (California = 412 eyes vs. 200Tx = 379 eyes), agreement between qualitative and quantitative PPL grading was moderate for all DR severities in both devices (ĸ = 0.369-0.526, P < 0.001) except for mild NPDR on the 200Tx, which had poor agreement (ĸ = 0.055, P = 0.478). Conclusions Determination of PPL varies between standard qualitative and quantitative grading and is dependent on NPDR severity, device type, and magnitude of lesion differences used for quantitative assessment. Translational Relevance Prior UWF studies have not accounted for imaging and grading factors that affect PPL, such factors need to be reviewed when assessing thresholds for DR progression rates.

Vision-threatening DR (vtDR) is commonly defined as moderate nonproliferative or more severe DR, or the presence of diabetic macular edema (DME). Modifiable risk factors of DR and vtDR are well-established in adults. This study identified risk factors associated with DR and vtDR in a large pediatric cohort with T1D. Medical chart review was performed of baseline visits of pediatric (≤21 yrs old) patients at an academic eye center from 2005-2020 to collect demographic characteristics, medical history and DR severity. Analyses were adjusted for correlation between eyes of the same person. In total, 1735 subjects (3454 eyes) were included with mean±SD age 15.4±4.6 years, T1D duration 7.1±5.3 years, T1D onset 8.3±5.4 years, and A1c 8.4±1.3; 50.7% were female, 30.7% were overweight/obese and 4.1% had elevated/high BP. Any DR was present in 8.5% and vtDR in 2.4% of eyes. Unadjusted analyses found DR presence associated with higher A1c (p Disclosure C. Jacoba: None. K. Sampani: None. C. Gilbert: None. P. S. Silva: Research Support; Self; Hillrom, Optomed, Optos plc. J. Keady: None. L. M. Laffel: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Dompe, Insulogic LLC, Janssen Pharmaceuticals, Inc., Laxmi Therapeutic Devices, LifeScan, Lilly Diabetes, Medtronic, Provention Bio, Inc. L. P. Aiello: Consultant; Self; KalVista Pharmaceuticals, Novo Nordisk, Regeneron Pharmaceuticals Inc., Stock/Shareholder; Self; KalVista Pharmaceuticals. J. Sun: Other Relationship; Self; Novo Nordisk, Roche Pharma, Research Support; Self; Adaptive Sensory Technology, Boehringer Ingelheim Pharmaceuticals, Inc., KalVista Pharmaceuticals, Optovue, Roche Pharma.

Diabetes mellitus has profound effects on multiple organ systems; however, the loss of vision caused by diabetic retinopathy might be one of the most impactful in a patient's life. The retina is a highly metabolically active tissue that requires a complex interaction of cells, spanning light sensing photoreceptors to neurons that transfer the electrochemical signal to the brain with support by glia and vascular tissue. Neuronal function depends on a complex inter-dependency of retinal cells that includes the formation of a blood-retinal barrier. This dynamic system is negatively affected by diabetes mellitus, which alters normal cell-cell interactions and leads to profound vascular abnormalities, loss of the blood-retinal barrier and impaired neuronal function. Understanding the normal cell signalling interactions and how they are altered by diabetes mellitus has already led to novel therapies that have improved visual outcomes in many patients. Research highlighted in this Review has led to a new understanding of retinal pathophysiology during diabetes mellitus and has uncovered potential new therapeutic avenues to treat this debilitating disease.

IMPORTANCE: Studies have not yet determined whether the distribution of lesions in the retinal periphery alters the association between the severity of diabetic retinopathy (DR) and macular vessel density. OBJECTIVE: To evaluate the association of DR lesion distribution with optical coherence tomography angiography (OCTA) metrics and DR severity. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional observational study was conducted at a tertiary care center for diabetic eye disease among 225 patients with type 1 or 2 diabetes who had undergone imaging between February 15, 2016, and December 31, 2019. EXPOSURES: Optical coherence tomography angiography 3 × 3-mm macular scans and ultra-widefield color imaging. MAIN OUTCOMES AND MEASURES: Optical coherence tomography angiography vessel density in the superficial capillary plexus, intermediate capillary plexus, and deep capillary plexus and choriocapillaris flow density. The severity of DR and the predominantly peripheral lesions (PPL) were evaluated from ultra-widefield color imaging. RESULTS: The study evaluated 352 eyes (225 patients; 125 men [55.6%]; mean [SD] age, 52.1 [15.1] years), of which 183 eyes (52.0%) had mild nonproliferative diabetic retinopathy (NPDR), 71 eyes (20.2%) had moderate NPDR, and 98 eyes (27.8%) had severe NPDR or proliferative diabetic retinopathy (PDR). In eyes with no PPL (209 [59.4%]), the mean (SD) vessel density in the superficial capillary plexus (mild NPDR, 38.1% [4.7%]; moderate NPDR, 36.4% [4.6%]; severe NPDR or PDR, 34.1% [4.1%]; P

The introduction of ultrawide field imaging has allowed the visualization of approximately 82% of the total retinal area compared to only 30% using 7-standard field Early Treatment Diabetic Retinopathy (ETDRS) photography. This substantially wider field of view, while useful in many retinal vascular diseases, is particularly important in diabetic retinopathy where eyes with predominantly peripheral lesions or PPL have been shown to have significantly greater progression rates compared to eyes without PPL. In telemedicine settings, ultrawide field imaging has substantially reduced image ungradable rates and increased rate of disease identification allowing care to be delivered more effectively. Furthermore, the use of ultrawide field fluorescein angiography allows the visualization of significantly more diabetic retinal lesions and allows more accurate quantification of total retinal nonperfusion, with potential implications in the management of diabetic retinopathy and diabetic macular edema. The focus of this paper is to review the current role of ultrawide field imaging in diabetic retinopathy and its possible future role in innovations for retinal image analysis such as artificial intelligence and vessel caliber measurements.

PURPOSE: Assess systemic vascular endothelial growth factor-A (VEGF) levels after treatment with intravitreous aflibercept, bevacizumab or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab following a retreatment algorithm. PARTICIPANTS: Participants with available plasma samples (N=436) METHODS: Plasma samples were collected before injections at baseline, 4-week, 52-week and 104-week visits. In a pre-planned secondary analysis, systemic free-VEGF levels from an ELISA immunoassay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free-VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were −0.30±0.61, −0.31±0.54, −0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted CI; P-value) were −0.01 (−0.12, +0.10; P=0.89), −0.31 (−0.44, −0.18; P

Despite recent advances in the medical management of diabetic retinal disease, there remain established indications for vitreoretinal surgery in the treatment of severe proliferative diabetic retinopathy. These include non-clearing vitreous hemorrhage and tractional retinal detachment. Advances in surgical instrumentation, technique, and experience have led to improved visual outcomes, as well as a corresponding decrease in the incidence of postoperative complications. However, the presence of systemic and ocular factors in diabetic patients increases the risk of adverse events compared to non-diabetic individuals. This review will focus on the most important postoperative complications following pars plana vitrectomy, with specific considerations for the diabetic patient.

Objective To describe the characteristic retinal features of lipemia retinalis when using ultrawide field scanning laser ophthalmoscopy. Main Points We report a case series of three subjects with ultrawide field retinal images showing cream discoloration of the fundus, light salmon-coloured posterior retinal vessels and greyish pink peripheral vasculature. On green-only imaging, many of the vessels appear light rather than typically dark. Conclusion Lipemia retinalis is readily apparent on ultrawide field imaging and illustrates the alterations that systemic diseases may induce in the posterior and peripheral retinal vasculature. Ultrawide field imaging highlights the disparate vascular appearance of the posterior pole and retinal periphery in this condition.

Purpose The purpose of this study was to assess how projection artifact removal (PAR) alters optical coherence tomography angiography (OCTA) assessment of superficial capillary plexus (SCP) and deep capillary plexus (DCP) in eyes of patients with diabetes. Methods We acquired 3 × 3 mm scans with RTVue-XR Avanti (Optovue, Inc., Fremont, CA), which were analyzed with PAR software (PAROCTA) and without (non-PAROCTA). SCP, DCP, and full thickness retina vascular density (VD) and vessel linear density (VLD) were manually calculated using ImageJ (version 1.51). Adjusted flow index (AFI) was manually assessed for full thickness images. Results Among 323 eyes of 194 patients (no diabetic retinopathy [DR]: 28 eyes; mild nonproliferative DR (NPDR): 96 eyes; moderate: 82 eyes; severe: 32 eyes; and proliferative DR [PDR]: 81 eyes), SCP VD and VLD were lower with PAROCTA than with non-PAROCTA only in eyes with moderate (VD: P = 0.017; VLD: P = 0.046), severe (P = 0.016; P = 0.009), and PDR (P < 0.001; P = 0.002). DCP VD and VLD were higher with PAROCTA as compared to non-PAROCTA only in eyes with no DR (VD and VLD: P < 0.001), mild (VD and VLD: P < 0.001), moderate (VD: P = 0.005; and VLD: P < 0.001), and severe (VD: P = 0.009; VLD: P < 0.001). Full thickness PAROCTA and non-PAROCTA VD and VLD differed only in eyes with no DR where PAROCTA estimates were higher (VD: P = 0.009; VLD: P = 0.02). PAROCTA AFI was lower than non-PAROCTA AFI for all DR severity levels (P < 0.001) except no DR. Conclusions Although differential effects of PAROCTA software are expected on SCP versus DCP measurements, these findings also suggest an interaction between PAROCTA and DR severity on assessment of VD. Conclusions from previous studies that have not corrected VD with PAR software should be carefully reviewed with regard to the role of specific vascular layers in DR. Translational Relevance Previous OCTA studies that have not corrected VD with PAR software should be carefully reviewed with regard to the role of individual vascular layers in differing severity levels of DR.

Background Many CpGs become hyper or hypo-methylated with age. Multiple methods have been developed by Horvath et al. to estimate DNA methylation (DNAm) age including Pan-tissue, Skin & Blood, PhenoAge, and GrimAge. Pan-tissue and Skin & Blood try to estimate chronological age in the normal population whereas PhenoAge and GrimAge use surrogate markers associated with mortality to estimate biological age and its departure from chronological age. Here, we applied Horvath’s four methods to calculate and compare DNAm age in 499 subjects with type 1 diabetes (T1D) from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study using DNAm data measured by Illumina EPIC array in the whole blood. Association of the four DNAm ages with development of diabetic complications including cardiovascular diseases (CVD), nephropathy, retinopathy, and neuropathy, and their risk factors were investigated. Results Pan-tissue and GrimAge were higher whereas Skin & Blood and PhenoAge were lower than chronological age (p < 0.0001). DNAm age was not associated with the risk of CVD or retinopathy over 18–20 years after DNAm measurement. However, higher PhenoAge (β = 0.023, p = 0.007) and GrimAge (β = 0.029, p = 0.002) were associated with higher albumin excretion rate (AER), an indicator of diabetic renal disease, measured over time. GrimAge was also associated with development of both diabetic peripheral neuropathy (OR = 1.07, p = 9.24E−3) and cardiovascular autonomic neuropathy (OR = 1.06, p = 0.011). Both HbA1c (β = 0.38, p = 0.026) and T1D duration (β = 0.01, p = 0.043) were associated with higher PhenoAge. Employment (β = − 1.99, p = 0.045) and leisure time (β = − 0.81, p = 0.022) physical activity were associated with lower Pan-tissue and Skin & Blood, respectively. BMI (β = 0.09, p = 0.048) and current smoking (β = 7.13, p = 9.03E−50) were positively associated with Skin & Blood and GrimAge, respectively. Blood pressure, lipid levels, pulse rate, and alcohol consumption were not associated with DNAm age regardless of the method used. Conclusions Various methods of measuring DNAm age are sub-optimal in detecting people at higher risk of developing diabetic complications although some work better than the others.

AimsTo compare microaneurysm (MA) counts using ultrawide field colour images (UWF-CI) and ultrawide field fluorescein angiography (UWF-FA).MethodsRetrospective study including patients with type 1 or 2 diabetes mellitus receiving UWF-FA and UWF-CI within 2 weeks. MAs were manually counted in individual Early Treatment Diabetic Retinopathy Study (ETDRS) and extended UWF zones. Fields with MAs ≥20 determined diabetic retinopathy (DR) severity (0 fields=mild, 1–3=moderate, ≥4=severe). UWF-FA and UWF-CI agreement was determined and UWF-CI DR severity sensitivity analysis adjusting for UWF-FA MA counts performed.ResultsIn 193 patients (288 eyes), 2.4% had no DR, 29.9% mild non-proliferative DR (NPDR), 32.6% moderate (NPDR), 22.9% severe NPDR and 12.2% proliferative DR. UWF-FA MA counts were 3.5-fold higher (pConclusionsUWF-FA detects threefold to fivefold more MAs than UWF-CI and identifies 1.6–3.5-fold more fields affecting DR severity. Differences exist at all DR severity levels, thus limiting direct comparison between the modalities. However, correcting UWF-FA MA counts substantially improves DR severity agreement between the modalities.

Ultrawide field imaging (UWF) has allowed the visualization of a significantly greater area of the retina than previous standard approaches. In diabetic retinopathy (DR), significantly more lesions are seen on UWF imaging compared to the seven-standard ETDRS fields. In addition, some eyes have lesions that are located predominantly in the peripheral retina that are associated with an increased risk of DR progression. The current DR severity scales are still largely based on clinically visible retinal microvascular lesions and do not incorporate retinal periphery, neuroretinal, or pathophysiologic changes. Thus, current scales are not well suited for documenting progression or regression in eyes with very early or advanced DR, nor in the setting of vascular endothelial growth factor inhibitors (antiVEGF). In addition, the categorical system is highly subjective, and grading is variable between different graders based on experience level and training background. Recently, there have been efforts to quantify DR lesions on UWF imaging in an attempt to generate objective metrics for classification, disease prognostication and prediction of treatment response. The purpose of this review is to examine current quantitative metrics derived from UWF fluorescein angiograms and UWF color imaging to determine their feasibility in any potential future DR classification.

Diabetes mellitus is a chronic disease that affects 415 million people worldwide. Despite treatment advances, diabetic eye disease remains a leading cause of vision loss worldwide. Diabetic macular edema (DME) is a common cause of vision loss in diabetic patients. The pathophysiology is complex and involves multiple pathways that ultimately lead to central retinal thickening and, if untreated, visual loss. First-line treatment of DME has evolved from focal/grid laser established by the Early Treatment of Diabetic Retinopathy Study (ETDRS) to intravitreous pharmacologic therapy. Landmark prospective clinical trials examining the effect of intravitreous injections of vascular endothelial growth factor (VEGF) inhibitors in the treatment of DME have demonstrated improved visual outcomes over focal grid laser. This review focuses on the scientific evidence treatment of DME, disease pathophysiology, clinical disease course, current treatment standards, and emerging novel therapeutic approaches.

To compare diabetic retinopathy (DR) identification and ungradable image rates between nonmydriatic ultrawide field (UWF) imaging and nonmydriatic multifield fundus photography (NMFP) in a large multistate population-based DR teleophthalmology program.Multiple-site, nonrandomized, consecutive, cross-sectional, retrospective, uncontrolled imaging device evaluation.Thirty-five thousand fifty-two eyes (17 526 patients) imaged using NMFP and 16 218 eyes (8109 patients) imaged using UWF imaging.All patients undergoing Joslin Vision Network (JVN) imaging with either NMFP or UWF imaging from May 1, 2014, through August 30, 2015, within the Indian Health Service-JVN program, which serves American Indian and Alaska Native communities at 97 sites across 25 states, were evaluated. All retinal images were graded using a standardized validated protocol in a centralized reading center.Ungradable rate for DR and diabetic macular edema (DME).The ungradable rate per patient for DR and DME was significantly lower with UWF imaging compared with NMFP (DR, 2.8% vs. 26.9% [P0.0001]; DME, 3.8% vs. 26.2% [P0.0001]). Identification of eyes with either DR or referable DR (moderate nonproliferative DR or DME or worse) was increased using UWF imaging from 11.7% to 24.2% (P0.0001) and from 6.2% to 13.6% (P0.0001), respectively. In eyes with DR imaged with UWF imaging (n = 3926 eyes of 2402 patients), the presence of predominantly peripheral lesions suggested a more severe level of DR in 7.2% of eyes (9.6% of patients).In a large, widely distributed DR ocular telehealth program, as compared with NMFP, nonmydriatic UWF imaging reduced the number of ungradable eyes by 81%, increased the identification of DR nearly 2-fold, and identified peripheral lesions suggesting more severe DR in almost 10% of patients, thus demonstrating significant benefits of this imaging method for large DR teleophthalmology programs.

Purpose The purpose of this study was to evaluate differences in optical coherence tomography angiography (OCTA) metrics in the superficial (SCP), intermediate (ICP), and deep (DCP) vascular plexuses across diabetic retinopathy (DR) severity levels. Methods This was a cross sectional observational retrospective chart review study. Eligible patients with diabetes who underwent same day RTVue XR Avanti OCTA, spectral-domain optical coherence tomography (SD-OCT), and 200-degree Optos ultrawide field color imaging. SCP, ICP, and DCP vessel density (VD) and vessel length density (VLD) were assessed using 3-D projection artifact removal software (PAROCTA) software. Results Of 396 eyes (237 patients), 16.1% had no DR, 26.9% mild nonproliferative DR (NPDR), 21.1% moderate NPDR, 12.1% severe NPDR, 10.1% proliferative DR (PDR) without panretinal photocoagulation (PRP), and 13.4% PDR with PRP. When comparing mild NPDR to no DR eyes, ICP and DCP VD and VLD were significantly lower, but there was no difference for SCP metrics. In eyes with more severe DR, there were significant differences in SCP VD and VLD between DR severity levels (mild versus moderate NPDR: VD 35.45 ± 3.31 vs. 34.14 ± 3.38, P = 0.008 and VLD 17.59 ± 1.83 vs. 16.80 ± 1.83, P = 0.003; moderate versus severe NPDR: VLD 16.80 ± 1.83 vs. 15.79 ± 1.84, P = 0.019), but no significant differences in ICP or DCP. Conclusions Although VD of each of the three individual layers decreases with increasing DR severity, DR severity has a substantially different effect on OCTA parameters within each layer. Vascular changes in eyes with no to early DR were present primarily in the deeper vascular layers, whereas in eyes with advanced DR the opposite was observed. This study highlights the effects of ICP and the importance of assessing SCP and DCP changes independently across each DR severity level.

Purpose To assess grading reproducibility of disorganization of the retinal inner layers (DRIL) and other morphologic features of diabetic macular edema (DME) across spectral domain optical coherence tomography (SDOCT) instruments and scan types. Methods A cross-sectional study enrolled participants with current or recent center-involved DME. In group A (27 eyes), we obtained two Cirrus scans (512 × 128 macular cube [Cube] and high-definition five-line raster [HD 5-Line]) and two Spectralis scans (high-resolution [HR] and high-speed [HS]). In group B, 26 eyes underwent HR scans and Optovue AngioVue (OP) 3 × 3-mm scans. All scans were graded for type and extent of DRIL, intraretinal cysts, cone outer segment tip visibility, and subretinal fluid (SRF). Results In the total cohort, mean central subfield thickness was 342.9 ± 83.4 µm. Intraclass correlations were high for DRIL extent across the four different imaging settings (HR vs. HS, r = 0.93; HR vs. Cube, r = 0.84, HR vs. HD 5-Line, r = 0.76, HR vs. OP, r = 0.87) and ranged from good to excellent for intraretinal cyst and SRF area. There were significantly smaller mean normalized differences between HR/HS scans versus HR and all other scan modalities (HR/HS vs. HR/Cube, P = 0.02; HR/HD 5-Line, P = 0.0005; HR/OP, P < 0.0001). Conclusions Our data suggest that the reproducibility for SDOCT parameters of DRIL and intraretinal cysts was high across all five SDOCT scan types; thus, evaluation of DRIL is feasible using multiple SDOCT models in eyes with DME. Translational Relevance DME morphological changes can be evaluated on multiple SDOCT devices with good reproducibility, allowing clinicians and researchers flexibility in DME assessment for clinical care and research.

Importance Moderate to substantial agreement between Early Treatment Diabetic Retinopathy Study (ETDRS) 7-field imaging and ultrawide-field (UWF) imaging has been suggested in single-center studies. Comparing images obtained by multiple centers could increase confidence that UWF images can be used reliably in place of ETDRS imaging in future clinical trials. Objective To compare diabetic retinopathy (DR) severity from modified ETDRS 7-field imaging and UWF imaging. Design, Setting, and Participants This preplanned, cross-sectional analysis included modified ETDRS 7-field images obtained using the Diabetic Retinopathy Clinical Research Network acquisition protocol and UWF images obtained captured with the Optos 200Tx system (Optos, PLC) from adult participants (≥18 years old) with type 1 or type 2 diabetes. Both image types were evaluated by trained graders masked to clinical data. Data collection occurred from February 2015 to December 2015, and data analysis from June 2016 to December 2017. Main Outcomes and Measures Agreement between UWF images, UWF images masked to include only the ETDRS 7-field area, and ETDRS 7-field images were calculated using κ statistics. Results A total of 764 eyes from 385 participants were included; participants had a median (IQR) age of 62.2 (53.6-69.2) years, 194 (50.4%) were women, and 256 (66.5%) were white. Of 742 eyes with both ETDRS 7-field images and UWF masked images graded, 359 (48.4% [95% CI, 44.4%-52.4%]) eyes had exact agreement, and 653 eyes (88.0% [95% CI, 85.2%-90.3%]) agreed within 1 step (weighted κ, 0.51 [95% CI, 0.44-0.58]). After open adjudication by an independent senior grader of all images with more than a 2-step discrepancy, perfect agreement was found in 435 eyes (59.0% [95% CI, 55.1%-62.8%]) and agreement within 1 step in 714 eyes (96.9% [95% CI, 95.1%-98.0%]; κ, 0.77 [95% CI, 0.73-0.82]). Ability of the imaging modalities to detect retinopathy severity in an individual eye was considered similar in 59 eyes (50.9% [95% CI, 41.3%-60.4%]), better for ETDRS 7-field imaging in 22 eyes (19.0% [95% CI, 12.5%-27.7%]), and better for UWF-masked images in 31 eyes (26.7% [95% CI 18.8%-36.5%]). Comparing UWF masked and unmasked images, 94 of 751 eyes (12.5%) had DR graded as at least 1 step more severe on UWF unmasked images vs UWF masked images. Predominantly peripheral DR lesions were present in 308 of 751 eyes (41.0%); this suggested increased DR severity by 2 or more steps in 34 eyes (11.0%). Conclusions and Relevance Imaging by the ETDRS 7-field and UWF imaging systems have moderate to substantial agreement when determining the severity of DR within the 7 standard fields. Disparities in an individual eye are equivalently distributed between imaging modalities and can be better or worse on 1 or the other. Longitudinal follow-up will evaluate the primary outcome of this study to determine if peripheral retinal findings are associated with future retinopathy outcomes.

Purpose To determine whether cone density, spacing, or regularity in eyes with and without diabetes (DM) as assessed by high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) correlates with presence of diabetes, diabetic retinopathy (DR) severity, or presence of diabetic macular edema (DME). Methods Participants with type 1 or 2 DM and healthy controls underwent AOSLO imaging of four macular regions. Cone assessment was performed by independent graders for cone density, packing factor (PF), nearest neighbor distance (NND), and Voronoi tile area (VTA). Regularity indices (mean/SD) of NND (RI-NND) and VTA (RI-VTA) were calculated. Results Fifty-three eyes (53 subjects) were assessed. Mean ± SD age was 44 ± 12 years; 81% had DM (duration: 22 ± 13 years; glycated hemoglobin [HbA1c]: 8.0 ± 1.7%; DM type 1: 72%). No significant relationship was found between DM, HbA1c, or DR severity and cone density or spacing parameters. However, decreased regularity of cone arrangement in the macular quadrants was correlated with presence of DM (RI-NND: P = 0.04; RI-VTA: P = 0.04), increasing DR severity (RI-NND: P = 0.04), and presence of DME (RI-VTA: P = 0.04). Eyes with DME were associated with decreased density (P = 0.04), PF (P = 0.03), and RI-VTA (0.04). Conclusions Although absolute cone density and spacing don't appear to change substantially in DM, decreased regularity of the cone arrangement is consistently associated with the presence of DM, increasing DR severity, and DME. Future AOSLO evaluation of cone regularity is warranted to determine whether these changes are correlated with, or predict, anatomic or functional deficits in patients with DM.

OBJECTIVE To evaluate the ability of trained nonphysician retinal imagers to perform diabetic retinopathy (DR) evaluation at the time of ultrawide field retinal (UWF) imaging in a teleophthalmology program. RESEARCH DESIGN AND METHODS Clinic patients with diabetes received Joslin Vision Network protocol retinal imaging as part of their standard medical care. Retinal imagers evaluated UWF images for referable DR at the time of image capture. Training of the imagers included 4 h of standardized didactic lectures and 12 h of guided image review. Real-time evaluations were compared with standard masked gradings performed at a centralized reading center. RESULTS A total of 3,978 eyes of 1,989 consecutive patients were imaged and evaluated. By reading center evaluation, 3,769 eyes (94.7%) were gradable for DR, 1,376 (36.5%) had DR, and 580 (15.3%) had referable DR. Compared with the reading center, real-time image evaluation had a sensitivity and specificity for identifying more than minimal DR of 0.95 (95% CI 0.94–0.97) and 0.84 (0.82–0.85), respectively, and 0.99 (0.97–1.00) and 0.76 (0.75–0.78), respectively, for detecting referable DR. Only three patients with referable DR were not identified by imager evaluation. CONCLUSIONS Point-of-care evaluation of UWF images by nonphysician imagers following standardized acquisition and evaluation protocols within an established teleophthalmology program had good sensitivity and specificity for detection of DR and for identification of referable retinal disease. With immediate image evaluation

The emergence of diabetes as a global epidemic is accompanied by the rise in diabetes‑related retinal complications. Diabetic retinopathy, if left undetected and untreated, can lead to severe visual impairment and affect an individual's productivity and quality of life. Globally, diabetic retinopathy remains one of the leading causes of visual loss in the working‑age population. Teleophthalmology for diabetic retinopathy is an innovative means of retinal evaluation that allows identification of eyes at risk for visual loss, thereby preserving vision and decreasing the overall burden to the health care system. Numerous studies worldwide have found teleophthalmology to be a reliable and cost‑efficient alternative to traditional clinical examinations. It has reduced barriers to access to specialized eye care in both rural and urban communities. In teleophthalmology applications for diabetic retinopathy, it is critical that standardized protocols in image acquisition and evaluation are used to ensure low image ungradable rates and maintain the quality of images taken. Innovative imaging technology such as ultrawide field imaging has the potential to provide significant benefit with integration into teleophthalmology programs. Teleophthalmology programs for diabetic retinopathy rely on a comprehensive and multidisciplinary approach with partnerships across specialties and health care professionals to attain wider acceptability and allow evidence‑based eye care to reach a much broader population.

Purpose. To characterize hallmark diabetic retinopathy (DR) lesions utilizing adaptive optics scanning laser ophthalmoscopy (AOSLO) and to compare AOSLO findings with those on standard imaging techniques. Methods. Cross-sectional study including 35 eyes of 34 study participants. AOSLO confocal and multiply scattered light (MSL) imaging were performed in eyes with DR. Color fundus photographs (CF), infrared images of the macula (Spectralis, Heidelberg), and Spectralis spectral domain optical coherence tomography SDOCT B-scans of each lesion were obtained and registered to corresponding AOSLO images. Main Outcome Measures. Individual lesion characterization by AOSLO imaging. AOSLO appearance was compared with CF and SDOCT imaging. Results. Characterized lesions encompassed 52 microaneurysms (MA), 20 intraretinal microvascular abnormalities (IRMA), 7 neovascularization (NV), 11 hard exudates (HE), 5 dot/blot hemorrhages (HEM), 4 cotton wool spots (CWS), and 14 intraretinal cysts. AOSLO allowed assessment of perfusion in vascular lesions and enabled the identification of vascular lesions that could not be visualized on CF or SDOCT. Conclusions. AOSLO imaging provides detailed, noninvasive in vivo visualization of DR lesions enhancing the assessment of morphological characteristics. These unique AOSLO attributes may enable new insights into the pathological changes of DR in response to disease onset, development, regression, and response to therapy.

Despite treatment advances, diabetic eye disease remains a leading cause of visual acuity (VA) loss worldwide. No methods to prospectively determine which patients will gain or lose vision exist, limiting individualized risk assessment and management. We investigated whether noninvasive, readily obtainable spectral domain optical coherence tomography parameters were correlated with VA in eyes with current or resolved center-involved diabetic macular edema (DME). Images were evaluated for disorganization of the retinal inner layers (DRIL), cysts, epiretinal membranes, microaneurysms, subretinal fluid, and outer layer disruption/reflectivity. DRIL affecting ≥50% of the 1-mm central retinal zone was associated with worse VA in all eyes, eyes with current edema, and eyes with resolved edema. Furthermore, early 4-month change in DRIL extent predicted VA change from baseline to 1 year. These data suggest that DRIL is a robust predictor of VA in eyes with present or previous DME and more highly correlated with VA than other widely used measures, such as retinal thickness. If further studies confirm DRIL as a predictive biomarker of future VA, physicians would gain a new tool of substantial clinical and investigative importance that could significantly change the approach to ophthalmic counseling and therapeutic management in patients with diabetes.

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.Retrospective review of 222 consecutive diabetic patients undergoing PPV or PPVCE.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).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.

Laser treatment for diabetic retinopathy was the first intraocular treatment to provide a highly effective means for preventing visual loss in patients with diabetes. Although inherently destructive, laser treatment is remarkably effective in preventing visual loss and preserving vision long-term. This review will describe briefly the current techniques and discuss in detail the reported side-effects and potential complications of laser treatment of diabetic retinal disease.

Diabetic patients are known to have an increased risk of cataract development and cataract surgery is a common surgical procedure for diabetic individuals. Cataract extraction (CE) in diabetic patients as compared to non-diabetic patients is associated with higher risks of reported complications such as capsular contraction and opacification as well as post-surgical worsening of macular edema (ME) and diabetic retinopathy (DR). In this paper, we review the pathogenesis of diabetic cataract, the risk factors contributing to cataract complications as well as DR progression, and assess preventive measures and treatment options for DR and ME following CE.

To determine the influence of diabetes and diabetes type on ocular outcomes following central retinal vein occlusion (CRVO).Retrospective chart review of all patients evaluated over a 4-year period in a tertiary diabetes eye care center. Ophthalmic findings were recorded including visual acuity and the presence of retinal neovascularization at presentation, after 3-6 months, and at last follow-up.The records of 19,648 patients (13,571 diabetic; 6077 nondiabetic) were reviewed. The prevalence of CRVO in diabetic patients (N=72) and nondiabetic patients (N=27) were 0.5 and 0.4%, respectively. Disc neovascularization (21.3 vs 0.0%, P=0.05) and panretinal photocoagulation (PRP) (48.7 vs 21.4%, P=0.01) were more common in diabetic patients compared with nondiabetic patients. Compared with type 2 diabetic patients, retinal neovascularization (28.6 vs 3.7%, P=0.004) and subsequent PRP (78.6 vs 41.9%, P=0.01) were more likely in type 1 patients. Optic nerve head collateral vessels (CVs) were observed less than half as often (21.4 vs 56.5%, P=0.04) in patients with type 1 diabetes. Presence of optic nerve head CVs at baseline was associated with less likelihood of PRP (14.3 vs 46.1%, P=0.03).In this cohort, the rates of CRVO in diabetic and nondiabetic patients were similar to previously published population-based studies. Following CRVO, diabetic patients had higher rates of disc neovascularization and were more likely to require subsequent PRP than nondiabetic patients. As compared with CRVO patients with type 2 diabetes, patients with type 1 diabetes and CRVO had worse anatomic outcomes with substantially increased risks of retinal neovascularization and PRP; however, final visual acuity outcomes were similar.

OBJECTIVE To compare efficiency of nonmydriatic ultrawide field retinal imaging (UWFI) and nonmydriatic fundus photography (NMFP) in a diabetic retinopathy (DR) ocular telehealth program. RESEARCH DESIGN AND METHODS Patients in this retrospective, comparative cohort study underwent NMFP and UWFI between 1 November 2011 and 1 November 2012. Images were evaluated for DR and diabetic macular edema (DME) by certified graders using a standard protocol at a centralized reading center. Identification of DR, image evaluation time, and rate of ungradable eyes were compared. RESULTS NMFP and UWFI were performed in 1,633 and 2,170 consecutive patients, respectively. No statistically significant differences were found between groups regarding age, diabetes duration, sex, ethnicity, or insulin use. The ungradable rate per patient for DR (2.9 vs. 9.9%, P < 0.0001) and DME (3.8 vs. 8.8%, P < 0.0001) was lower with UWFI than with NMFP. With UWFI, the median image evaluation time per patient was reduced from 12.8 to 9.2 min (P < 0.0001). The identification of patients with DR (38.4 vs. 33.8%) and vision-threatening DR (14.5 vs. 11.9%) was increased with UWFI versus NMFP. In a consecutive subgroup of 502 eyes of 301 patients with DR, the distribution of peripheral retinal lesions outside Early Treatment Diabetic Retinopathy Study fields suggested a more severe DR level in 9.0% (45 eyes). CONCLUSIONS In a standardized DR ocular telehealth program, nonmydriatic UWFI reduced the ungradable rate by 71% (to

Multiple studies have shown that genetic factors may play an important role in determining an individual's risk for the development of diabetic retinopathy (DR) and progression to proliferative DR. However, consistent and definitive genetic associations with DR across broad populations have been not been established. Numerous genes have been studied for their association with DR and the results of these investigations have most specifically pointed to three specific genes that are likely involved in DR development and progression. The gene coding for vascular endothelial growth factor, aldose reductase, and the receptor for advanced glycation end products have been extensively evaluated, and specific polymorphisms of these genes have been suggested to potentially increase the risk of DR development. In this paper, we have reviewed the published literature on the genetics of DR and the potential implications for DR development and progression.

Ischemic retinal diseases, particularly diabetic retinopathy, continue to significantly impact vision and remain a leading cause of vision loss in working-aged adults. Identifying specific genetic risk factors for ischemic-driven pathways that increase susceptibility to developing diabetic retinopathy is a priority to allow development of accurate risk assessment algorithms, employ earlier intervention, and design novel treatment strategies to reduce the associated visual complications. Single nucleotide polymorphisms (SNPs) in the VEGF gene have been shown to influence the expression of the VEGF protein. Several studies suggest that SNPs in the VEGF gene mediate genetic predisposition to diabetic retinopathy. In addition, alterations in the vitreous proteome, including carbonic anhydrase mediated vascular permeability, have been found to be associated with sight-threatening proliferative diabetic retinopathy and macular edema. Inhibition of these factors could provide new therapeutic opportunities for the treatment of diabetic retinopathy.

Von Hippel-Lindau Disease (VHL) is an autosomal dominant inherited systemic cancer syndrome that gives rise to cystic and highly vascularized tumors in many organs, including the eye. Recent studies have contributed to the understanding of VHL pathophysiology, genetics, and the role of the VHL protein. This article reviews recent studies on VHL clinical findings, genetics and tumorigenesis.Literature review of articles on VHL genetics with correlation to clinical findings.Genotype-phenotype correlation studies show that patients with a complete deletion mutation of the VHL gene, relative to participants with a missense or protein-truncating mutation, had better visual acuity and decreased tumorigenesis incidence of retinal hemangioblastomas. It has also been documented that higher levels of vascular endothelial growth factor (VEGF), hypoxia induced factor (HIF), and ubiquitin are found in ocular hemangioblastomas. The stromal foamy vacuolated cells seem to be the true tumor cells of the disease acting on the surrounding endothelial cells in ocular hemangioblastomas. Tumor cells and ocular lesions have shown increased levels of Erythropoietin (Epo), Epo receptor (EpoR), and CD133. Also, CXCR4, a CXC chemokine receptor, is expressed in retinal VHL hemangioblastomas. Recent studies suggest that the VHL mutation alone may not be sufficient to develop VHL-associated neoplasms. Studies suggest that targeting various proteins along with anti-angiogenesis molecules may be a better therapeutic approach than targeting VEGF alone.Understanding of the mechanisms and genetics underlying VHL and its associated retinal hemangioblastomas has increased substantially in recent years. This knowledge suggests that future advances may include better identification of individuals at higher risk of vision loss and the development of novel individualized therapies.

Objective To evaluate detection of hemorrhage and/or microaneurysm (H/Ma) using ultrawide field (UWF) retinal imaging as compared with standard Early Treatment Diabetic Retinopathy Study (ETDRS) 7-field photographs (ETDRS photos). Design Single-site comparative study of UWF images and ETDRS photos. Participants One hundred twenty-six eyes of 69 patients with no diabetic retinopathy (DR) or mild or moderate nonproliferative DR (NPDR). Methods Stereoscopic 200° UWF images and stereoscopic 35mm 30° 7-field color photographs were acquired on the same visit. Images were graded for severity and distribution of H/Ma. H/Mas were counted in ETDRS fields 2 to 7 in both ETDRS photos and UWF images. H/Mas in the UWF peripheral fields were also counted. Main Outcome Measures Kappa (κ) and weighted κ statistics for agreement. Number of H/Ma within and outside ETDRS fields identified in UWF images and ETDRS photos. Results Distribution of DR severity by ETDRS photos was 24 (19.0%) no DR, 48 (38.1%) mild NPDR, and 54 (42.9%) moderate NPDR. A total of 748 of 756 fields (98.9%) were gradable for H/Mas on ETDRS photos and UWF images. Simple κ/weighted κ statistics for severity of H/Ma: all fields 0.61/0.69, field 2 0.70/0.77, field 3 0.62/0.73, field 4 0.50/0.62, field 5 0.54/0.65, field 6 0.64/0.70, and field 7 0.58/0.63 with overall exact agreement in 81.3% and within 1 step in 97.9% of fields. A greater proportion of fields was graded a more severe H/Ma level in UWF images than in the corresponding ETDRS photos (UWF: 12.7% vs. ETDRS: 6.5%). Evaluating comparable areas in UWF images and ETDRS photos (fields 2–7), a mean of 42.8 H/Mas were identified using ETDRS photos and 48.8 in UWF images ( P = 0.10). An additional mean of 21.3 H/Mas (49.8% increase, P Conclusions There is good to excellent agreement between UWF images and ETDRS photos in determining H/Ma severity, with excellent correlation of H/Ma counts within ETDRS photo fields. UWF peripheral fields identified 49.8% more H/Ma, suggesting a more severe H/Ma in 12.7% of eyes. Given the additional lesions detected in peripheral fields and the known risks associated with H/Ma and peripheral lesions, quantification of H/Ma using UWF images may provide a more accurate representation of DR disease activity and potential greater accuracy in predicting DR progression.

Diabetic retinopathy is a leading cause of new-onset vision loss worldwide. Treatments supported by large clinical trials are effective in preserving vision, but many persons do not receive timely diagnosis and treatment of diabetic retinopathy, which is typically asymptomatic when most treatable. Telemedicine evaluation to identify diabetic retinopathy has the potential to improve access to care and improve outcomes, but incomplete implementation of published standards creates a risk to program utility and sustainability. In a prior article, we reviewed the literature regarding the impact of imaging device, number and size of retinal images, pupil dilation, type of image grader, and diagnostic accuracy on telemedicine assessment for diabetic retinopathy. This article reviews the literature regarding the impact of automated image grading, cost effectiveness, program standards, and quality assurance (QA) on telemedicine assessment of diabetic retinopathy. Telemedicine assessment of diabetic retinopathy has the potential to preserve vision, but greater attention to development and implementation of standards is needed to better realize its potential.

Diabetic retinopathy is a leading cause of new-onset vision loss worldwide. Treatments supported by large clinical trials are effective in preserving vision, but many persons do not receive timely diagnosis and treatment of diabetic retinopathy, which is typically asymptomatic when most treatable. Telemedicine evaluation to identify diabetic retinopathy has the potential to improve access to care, but there are no universal standards regarding camera choice or protocol for ocular telemedicine. We review the literature regarding the impact of imaging device, number and size of retinal images, pupil dilation, type of image grader, and diagnostic accuracy on telemedicine assessment for diabetic retinopathy. Telemedicine assessment of diabetic retinopathy has the potential to preserve vision, but further development of telemedicine specific technology and standardization of operations are needed to better realize its potential.

According to current projections, the number of Americans with diabetes mellitus will increase from 27.8 million in 2007 to 60.7 million in 2030. With the increasing gap between demand for eye care and supply of ophthalmologists and optometrists, and the non-uniform distribution of eye care providers in US counties, barriers to eye examinations will likely increase. Telemedicine assessment of diabetic retinal disease through remote retinal imaging and diagnosis has the potential to meet these growing demands. To establish evidence for a telemedicine program as an effective modality for diabetic retinopathy (DR) assessment, the interpretation of teleretinal images should compare favorably with Early Treatment Diabetic Retinopathy Study film or digital photographs. We review the current evidence on the critical features and characteristics of ocular telehealth programs for DR in the following categories: image gradability, mydriasis, sensitivity and specificity, cost-effectiveness, long-term effectiveness, patient comfort and satisfaction, and improvement of patient related outcomes.

Diabetic retinopathy (DR) is the most frequent microvascular complication from diabetes and requires annual screening and at least annual follow-up. A systemic approach to optimize blood glucose and blood pressure may halt progression to severe stages of DR and obviate the need for ocular treatment. Although there is evidence of benefit from fenofibrate or intravitreous antiVEGF treatment for eyes with nonproliferative DR (NPDR), these therapies are not standard care for NPDR at this time. Some patients with severe NPDR, especially those with type 2 diabetes, benefit from early panretinal photocoagulation (PRP). Once DR progresses to proliferative DR (PDR), treatment is often necessary to prevent visual loss. PRP remains mainstay treatment for PDR with high-risk characteristics. However, intravitreous antiVEGF injections appear to be a safe and effective treatment alternative for PDR through at least two years. Vitreoretinal surgery is indicated for PDR cases with non-clearing vitreous hemorrhage and/or tractional retinal detachment.

Diabetic retinal disease remains a leading cause of blindness among working-aged adults around the world. Until this decade, laser photocoagulation for both proliferative diabetic retinopathy and diabetic macular edema had been the standard of care for millions of patients. The introduction of vascular endothelial growth factor inhibitors (anti-VEGF) and subsequent clinical trials demonstrating their efficacy for treatment of diabetic eye disease have established a new standard in treatment of center-involved diabetic macular edema that is highly specific to the pathologic process and highly effective in preserving and improving vision. This review focuses on clinically relevant developments that led to the shift from focal/grid laser photocoagulation to anti-VEGF injections in the treatment of center-involved diabetic macular edema (DME), with an overview of the disease pathophysiology, clinical disease course, and available anti-VEGF agents. This article also reviews the scientific evidence exploring the use of anti-VEGF agents in nonproliferative and proliferative diabetic retinopathy.

Diabetic retinal disease is characterized by a series of retinal microvascular changes and increases in retinal vascular permeability that lead to development of diabetic retinopathy (DR) and diabetic macular edema (DME), respectively. Current treatment strategies for DR and DME are mostly limited to vascular endothelial growth factor (VEGF) inhibitors and laser photocoagulation. These treatment modalities are not universally effective in all patients, and potential side effects persist in a significant portion of patients. The plasma kallikrein-kinin system (KKS) is one of the pathways that has been identified in the vitreous in proliferative DR and DME. Preclinical studies have shown that the activation of intraocular KKS induces retinal vascular permeability, vasodilation, and retinal thickening. Proteomic analysis from vitreous of eyes with DME has shown that KKS and VEGF pathways are potentially independent biologic pathways. Furthermore, proteins associated with DME in the vitreous were significantly more correlated with the KKS pathway compared to VEGF pathway. Preclinical experiments on diabetic animals showed that inhibition of KKS components was found to be an effective approach to decrease retinal vascular permeability. An initial phase I human trial of a novel plasma kallikrein inhibitor for the treatment of DME is currently ongoing to test the safety of this approach and serves as an initial step in the translation of basic science discovery into an innovative clinical intervention.

More than half-a-billion individuals are projected to have diabetes by 2030, with the greatest increase in developing nations. Southeast Asian countries comprise a substantial proportion of this population and will need to prepare for both the rise in diabetes cases and the accompanying increase in diabetes related complications, most commonly diabetic retinopathy. Ocular telehealth programs utilizing retinal imaging for diabetic retinopathy have been established as an effective means to prevent visual loss due to diabetic retinal disease across multiple populations and in various settings. An additional value of ocular telehealth programs is their ability to integrate a multidisciplinary approach to diabetes eye care that incorporates patient education and fosters collaboration among multiple specialties. A program that provides a systematic and organized approach in delivering diabetes eye care is critically needed to successfully address this critical emerging health issue in this region of the world.

Current ultra-wide field (UWF) retinal imaging systems utilize scanning laser ophthalmoscope technology combined with an ellipsoidal mirror to capture up to 200 degrees of the retina in a single image. When compared with mydriatic ETDRS-protocol, 7 standard field photographs and clinical examination, nonmydriatic UWF images appear to have excellent agreement in allowing the detection and classification of diabetic retinopathy (DR), although larger, definitive validation studies are still forthcoming. UWF imaging and angiography allow visualization of peripheral retinal nonperfusion, vascular leakage and neovascularization in patients with DR that may not be captured on 7 standard fields. Prospective randomized controlled trials are needed to evaluate whether modified laser treatment algorithms based on improved visualization of the retinal periphery might improve patient outcomes. Nonmydriatic UWF imaging has potential applications for ocular diabetic telehealth programs, but validation of newer, more portable, and more affordable UWF imaging models is needed.

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.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.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.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.

Purpose We evaluate diabetic microaneurysm (MA) features on high-resolution adaptive optics scanning laser ophthalmoscopy (AOSLO) and their correlations with visual acuity (VA) and local retinal pathology on spectral domain optical coherence tomography (SDOCT). Methods Diabetic participants underwent VA testing and AOSLO and SDOCT imaging of MAs. AOSLO images were graded for MA dimension, wall hyperreflectivity (WH), intraluminal hyperreflectivity (IH), and perfusion pattern. SDOCTs centered on each MA were graded for disorganization of the retinal inner layers (DRIL) and other neuroretinal pathology. Results We imaged 109 MAs (30 eyes). Multivariate modeling, including statistically significant covariates from bivariate analyses, associated WH with greater MA size (P = 0.001) and DRIL (P = 0.04). IH was associated with perfusion (P = 0.003) and MA visibility on photographs (P = 0.0001), and larger MA size with partial perfusion (P = 0.03), MA ring signs (P = 0.0002), and photographic visibility (P = 0.01). Multivariate modeling revealed an association of WH and VA with DRIL. Conclusions AOSLO imaging demonstrates associations of hyperreflective MA walls with MA size and adjacent DRIL, as well as the presence of DRIL with lower VA. This study identifies a correlation between vascular and neural pathology associated with VA decline. Further studies of MA structure and neuroretinal disorganization may enable novel approaches to assess anatomic and functional outcomes in the diabetic eye.

Diabetic retinopathy remains a leading cause of visual loss worldwide. Patients with diabetes mellitus commonly have multiple comorbidities treated with a wide variety of medications. Systemic medications that target glycemic control and coexisting conditions may have beneficial or deleterious effects on the onset or progression of diabetic retinopathy. In addition, data is accumulating to suggest that the use of systemic therapy primarily to address ocular complications of diabetic retinopathy may be a promising therapeutic approach. This article reviews our current understanding of the ocular-specific effects of systemic medications commonly used by patients with diabetes mellitus, including those directed at control of hyperglycemia, dyslipidemia, hypertension, cardiac disease, anemia, inflammation and cancer. Current clinical evidence is strongest for the use of angiotensin-converting enzyme inhibitors and angiotensin-2 receptor blockers in preventing the onset or slowing the progression of early diabetic retinopathy. To a more limited extent, evidence of a benefit of fibrates for diabetic macular edema exists. Numerous other agents hold considerable promise or potential risk. Thus, these compounds must undergo further rigorous study to determine the actual clinical efficacy and adverse effects before definitive therapeutic care recommendations can be offered.

Ultrawide field imaging (UWFI) is increasingly being used in teleophthalmology settings. Given the greater area of the retina imaged, we evaluated the ability of UWFI vs nonmydriatic fundus photography (NMFP) to detect nondiabetic retinal findings in a teleophthalmology program.We conducted a retrospective single-center comparative cohort study from January 1, 2011, to June 30, 2013, imaging 3864 and 3971 consecutive teleophthalmology patients (7728 and 7942 eyes) using NMFP and UWFI, respectively. Standard diabetic retinopathy evaluation and nondiabetic findings were compared between the 2 imaging modalities. In patients without diabetic retinopathy (2243 by NMFP and 2252 by UWFI), the rate of identification of nondiabetic findings by NMFP (451 patients [20.1%]) and UWFI (490 [21.8%]) were comparable (P = .19). Ultrawide field imaging increased the identification of choroidal nevi by 27% (406 eyes [5.3%] by NMFP vs 545 eyes [6.9%] by UWFI; P.001) and chorioretinal atrophy or scarring by 116% (50 eyes [0.6%] by NMFP vs 101 eyes [1.3%] by UWFI; P.001). No peripheral retinal findings were identified with NMFP, while UWFI detected 25 retinal tears (0.3%; P.001), 54 lattice and peripheral degenerations (0.7%; P.001), and 142 cases of vitreous detachment or floaters (1.8%; P.001). Data analysis was performed from November 1, 2013, to May 1, 2014.In eyes without diabetic retinopathy, approximately 20% may have ocular findings identified on retinal imaging, which emphasizes the role of retinal imaging in patients with diabetes mellitus type 1 and type 2 regardless of the severity of retinopathy. In this cohort, UWFI increased the identification of peripheral retinal and vitreous pathologic findings.

Purpose To assess whether the presence of peripheral nonperfusion on ultrawide field (UWF) fluorescein angiography (FA) is associated with diabetic retinopathy (DR) severity and the presence of predominantly peripheral lesions (PPLs). Design Single-site, cross-sectional, retrospective study. Participants Sixty-eight eyes of 37 diabetic subjects with or without DR and no history of prior panretinal laser photocoagulation. Methods Both 200° UWF images and UWF FA images were acquired at the same visit. Early Treatment Diabetic Retinopathy Study (ETDRS) templates were overlaid digitally based on disc and macula location onto stereographically projected UWF images. Images were evaluated for the presence of PPLs, defined as more than 50% of the graded lesion located outside the ETDRS field in each of the 5 extended fields. The UWF-FA images were evaluated by 2 masked, independent graders for extent of retinal nonperfusion area (NPA) and nonperfusion index (NPI; nonperfused/total gradable area). Main Outcome Measures Association of NPA and NPI with DR severity and presence of PPLs. Results Distribution of DR severity was as follows: no DR, 8.8% eyes; mild nonproliferative DR (NPDR), 17.6%; moderate NPDR, 32.4%; severe NPDR, 17.6%; proliferative DR (PDR), 19.1%; and high-risk PDR, 4.4%; with PPL present in 61.8%. There was strong intragrader ( r = 0.95) and intergrader ( r = 0.86) agreement for NPA. Presence of PPLs was associated with increased NPA (191.8 mm 2 vs. 306.1 mm 2 ; P = 0.0019) and NPI (0.25 vs. 0.43; P = 0.0003). These relationships remained significant after adjusting for DR severity and diabetes duration. In eyes without PDR (n = 52), increasing NPA and NPI was associated with worsening DR (NPA, P = 0.001; NPI, P = 0.0003). NPA and NPI were not associated with clinically significant macular edema (NPA, P = 0.99; NPI, P = 0.67), nor correlated with visual acuity (NPA, r = 0.14, P = 0.23; NPI, r = 0.24, P = 0.05). Conclusions Following a standardized protocol, the evaluation of UWF FA for NPA and NPI is reproducible. Both parameters are correlated highly with the presence of PPLs and DR severity. Given that the presence and extent of PPLs have been associated with increased risks of DR progression, the clinical identification of PPLs may reflect closely the extent of nonperfusion and ischemia, thus accounting for the increased risk of progression.