Early Treatment Diabetic Retinopathy Study Scale Research Articles

Comparison of quantitative assessment and efficiency of diabetic retinopathy diagnosis using ETDRS seven-field imaging and two ultra-widefield imaging.

This study compared the efficiency of diabetic retinopathy (DR) diagnosis and differences in the relative visible retinal area among the Early Treatment Diabetic Retinopathy Study (ETDRS) seven-field, ultra-widefield (UWF)-Optos, and UWF-Clarus fundus imaging methods. This was a prospective and clinic-based comparative study. All patients underwent three fundus examinations, and all images were graded using the ETDRS severity scale. We compared and analysed the agreement of DR severity and the relative visible retinal area among the three fundus examination methods, and the number and type of lesions outside the ETDRS seven-field (peripheral lesions) between the two UWF imaging methods. A total of 202 patients (386 eyes) were included. Weighted kappa for the agreement between ETDRS seven-field and blinded Optos images was 0.485; between ETDRS seven-field and blinded Clarus images, 0.924; and between blinded Optos and Clarus images, 0.461. Blinded Clarus showed excellent performance when a ETDRS scale was used for grading the images. The relative visible retinal area for ETDRS seven-field images was 195 ± 28 disc area (DA); single Optos images, 371 ± 69 DA; single Clarus images, 261 ± 65 DA; two-montage Clarus images, 462 ± 112 DA; and four-montage Clarus images, 598 ± 139 DA. The relative visible retinal area was statistically significant between any two of the imaging systems used. In total, 2015 and 4200 peripheral lesions were detected in single Optos and Clarus images, respectively (P < 0.001). These peripheral lesions on two UWF images suggested a more severe DR level in approximately 10% and 12% of eyes, respectively. UWF-Clarus fundus imaging offers a suitable assessment approach for DR severity; it could improve DR diagnosis and has the potential to replace ETDRS seven-field imaging after additional clinical trials.

Development and Progression of Diabetic Retinopathy in Adolescents and Young Adults With Type 2 Diabetes: Results From the TODAY Study.

The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study reported a 13.9% prevalence of diabetic retinopathy (DR) in youth with mean ± SD type 2 diabetes duration of 4.9 ± 1.5 years. After 7 years of additional follow-up, we report the risk factors for progression of DR in the TODAY cohort. Retinal photographs (n = 517) were obtained in 2010-2011 and again in 2017-2018 (n = 420) with standard stereoscopic seven-field digital fundus photography. Photographs were graded centrally using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. A total of 367 patients with gradable fundus photographs in at least one eye at both assessments were included in analyses of progression of DR, defined as an increase of three or more steps on the ETDRS scale. With mean ± SD age of 25.4 ± 2.5 years and diabetes duration of 12.0 ± 1.5 years, there was a 49% prevalence of any DR among participants. Prevalence by DR stage was as follows: 39% for very mild or mild nonproliferative DR (NPDR), 6% moderate to severe NPDR, and 3.8% proliferative DR. Compared with nonprogressors, participants who progressed three or more steps had significantly lower BMI, higher HbA1c, higher blood pressure, increased triglycerides, decreased C-peptide, and higher prevalence of other comorbidities. Multivariate analysis demonstrated that HbA1c was the dominant factor impacting DR progression. Poor glycemic control of youth-onset type 2 diabetes imparts a high risk for progression of DR, including advanced, sight-threatening disease by young adulthood.

Comparison of Ultra-Widefield Imaging and Standard Imaging in Assessment of Early Treatment Diabetic Retinopathy Severity Scale

PurposeTo compare Early Treatment Diabetic Retinopathy Study (ETDRS) severity levels between standard 7-field imaging and ultra-widefield (UWF) imaging and to incorporate peripheral diabetic retinopathy (DR) lesions into the ETDRS grading system.DesignCross-sectional Study.ParticipantsPaired images from 192 eyes (189 participants) with diabetic retinopathy were included.MethodsThe ETDRS levels were determined by masked graders in 3 ways: standard 7-field imaging, UWF within the 7-field region (7-field UWF imaging), and the entire UWF image (global ETDRS imaging).Main Outcome MeasuresPercentage agreement between 7-field and UWF imaging for ETDRS levels.ResultsOf the 166 paired images evaluated, exact agreement was found in 48.8% of eyes between standard 7-field and 7-field UWF ETDRS levels with a weighted κ value of 0.59 (95% confidence interval [CI], 0.5–0.68). Agreement rates varied with DR severity and were least in early DR (30.8%) and moderate nonproliferative DR (26.5%) groups. In 156 eyes with 7-field UWF ETDRS and global UWF ETDRS levels, exact agreement was found in 143 eyes (92%), with a weighted κ value of 0.9 (95% CI, 0.9–0.98). The peripheral lesions contributed to a higher DR severity in 8% and changed the eye to a proliferative DR level in 2%. Reproducibility of the 3 ETDRS evaluations was comparable with a weighted κ value of 0.57 with standard 7-field imaging, 0.65 with 7-field UWF imaging, and 0.60 with global ETDRS scale imaging.ConclusionsModerate agreement was found in the ETDRS DR severity scale between standard 7-field and UWF imaging, indicating caution in interchanging data from the 2 methods. Both methods showed good reproducibility for clinical trial outcome of 2-step change. The global ETDRS scale provides a comprehensive score to incorporate peripheral changes into the ETDRS scale. The implications of the global scale on progression rate are yet to be determined.

Screening eye exams in youth with type 1 diabetes under 18 years of age: Once may be enough?

Case series and registry data suggest that diabetic retinopathy requiring treatment is rare in youth with type 1 diabetes (T1D) prior to 18 years of age. We evaluated this question in the standardized clinical trial setting by retrospectively reviewing diabetic retinopathy examinations from participants in the Diabetes Control and Complications Trial (DCCT) who were 13 to <18 years of age at randomization. Standardized stereoscopic 7-field fundus photographs were obtained every 6 months during DCCT (1983-1993). Photographs were graded centrally using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Transitions in diabetic retinopathy status over time were described. A total of 195 participants with median baseline glycated hemoglobin (HbA1c) of 9.3% (103 in the conventional and 92 in the intensive treatment groups) had an average of 5.3 diabetic retinopathy assessments during 2.3 years of follow-up (range 1-11) while under 18 years of age during the DCCT. No participant developed severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy and only one participant (in the intensive group) reached clinically significant macular edema (CSME) while less than 18 years of age. In this incident case, baseline characteristics included diabetes duration 9.3 years, HbA1c 10.3%, LDL 131 mg/dL, and mild non-proliferative diabetic retinopathy (35/35 ETDRS scale); CSME resolved without treatment. Similar analyses using age cut-offs of <19, 20, or 21 years showed a slight rise in diabetic retinopathy requiring treatment over late adolescence. Clinical trial evidence suggests that frequent eye exams may not be universally necessary in youth <18 years of age with T1D.

Potent Oral Hypoglycemic Agents for Microvascular Complication: Sodium-Glucose Cotransporter 2 Inhibitors for Diabetic Retinopathy.

The purpose of this study was to investigate the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on the progression of diabetic retinopathy (DR) in patients with type 2 diabetes. The medical records of 21 type 2 diabetic patients who used a SGLT2i and 71 patients with sulfonylurea (control) were reviewed retrospectively. The severity of DR was assessed using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. Fewer patients who used a SGLT2i than control patients with sulfonylurea showed progression of DR based on ETDRS scale (44% versus 14%, P = 0.014). Moreover, treatment with a SGLT2i was associated with a significantly lower risk of DR progression (P = 0.021), and this effect remained significant after adjusting for the age, duration of diabetes, initial DR grade, and HbA1c level by propensity score matching (P = 0.013). Treatment of type 2 diabetic patients with a SGLT2i slowed the progression of DR compared to sulfonylurea, which is independent of its effect on glycemic control. This study provides a foundation for further evaluation of the effect of SGLT2i on the progression of DR.

Non-mydriatic ultrawide field scanning laser ophthalmoscopy compared with dilated fundal examination for assessment of diabetic retinopathy and diabetic macular oedema in Chinese individuals with diabetes mellitus

AimsTo evaluate the performance of ultrawide field scanning laser ophthalmoscopy (UWF-SLO) for assessing diabetic retinopathy (DR) and diabetic macular oedema (DME) in a Chinese population, compared with clinical examination.MethodsThis is...

Polymorphisms in the CTSH gene may influence the progression of diabetic retinopathy: a candidate-gene study in the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987).

The incidence of type 1 diabetes mellitus (T1DM) is increasing globally, and as a consequence, more patients are affected by microvascular complications such as diabetic retinopathy (DR). The aim of this study was to elucidate possible associations between diabetes-related single-nucleotide polymorphisms (SNP) and the development of DR. Three hundred and thirty-nine patients with T1DM from the Danish Cohort of Pediatric Diabetes 1987 (DCPD1987) went through an ophthalmic examination in 1995; 185 of these were reexamined in 2011. The development of DR was assessed by comparison of overall DR level between baseline and follow-up in the worst eye at baseline. Patients were graded on a modified version of the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and 20 SNPs were genotyped in 130 of the 185 patients. We found the CTSH/rs3825932 variant (C > T) was associated with reduced risk of progression to proliferative diabetic retinopathy (PDR) (OR [95 % CI] = 0.20 [0.07-0.56], p = 2.4 × 10(-3), padjust = 0.048) and ERBB3/rs2292239 variant (G > T) associated with increased risk of two-step progression (OR [95 % CI] = 2.76 [1.31-5.80], p = 7.5 × 10(-3), padjust = 0.15). The associations were independent of other known risk factors, such as HbA1c, sex, and diastolic blood pressure. In conclusion, CTSH/rs3825932 and ERBB3/rs2292239 SNPs were associated with reduced risk of progression to PDR and two-step progression of DR on the ETDRS scale accordingly. The variant CTSH remained statistically significant after adjusting for multiple testing. Our results suggest an overlap between genetic variants that confer risk of T1DM and progression of DR.

Functional and structural change in diabetic eyes. Interim results from an ongoing longitudinal prospective study

To presents results after 18 months of follow-up of a longitudinal study aiming at exploring the correlation between diabetic retinal vascular lesions and functional change. Patients were consecutively recruited from attendees to the screening program for diabetic retinopathy. Subjects are followed every sixth month for the first 3 years and thereafter annually up to 5 years. Progression of diabetic retinopathy is evaluated using the Early Treatment Diabetic Retinopathy Study (ETDRS) scale and improvement/deterioration in visual fields by predefined significance limits for change. Of 81 subjects, with no/mild/moderate diabetic retinopathy included, 76 have passed the 18-month visit. At that time, retinal progression by two steps according to the ETDRS scale had occurred in two subjects. Visual acuity was -0.14 logMAR and had decreased with two letters (0.04 logMAR) (p < 0.001) from baseline. The global visual field index mean deviation was almost unchanged with a negligible improvement of 0.03 dB (p = 0.79). In 21 subjects, repeated significant deterioration was seen in ≥10% of all points tested in the field, while almost no improved points were noted. The two subjects with retinal progression were not among those 21 with indication of perimetric progression. This is, to our knowledge, the first longitudinal study evaluating change of visual fields in a representative diabetic cohort with no or mild/moderate retinopathy. In this interim report, we demonstrate deteriorated perimetric sensitivity in subjects already at 18 months of follow-up. The results will have implications for evaluating change in visual function in future clinical trials.

Fenofibrate – A Potential Systemic Treatment for Diabetic Retinopathy?

To review clinical and experimental data for fenofibrate as a possible systemic treatment for diabetic retinopathy. Perspective. Review of clinical studies focused on 2 major randomized controlled trials: the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) and ACCORD (Action to Control Cardiovascular Risk in Diabetes)-Eye studies. Progression was defined in FIELD as laser treatment for proliferative retinopathy or macular edema or increase by ≥ 2 steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, and in ACCORD-Eye as ≥ 3 steps (ETDRS scale) or proliferative disease requiring laser or vitrectomy treatment. Experimental studies investigating the mode of action of fenofibrate were reviewed. The 2 trials included 11 388 patients with type 2 diabetes mellitus, of whom 5701 were treated with fenofibrate (± statin) for up to 5 years. Fenofibrate reduced first laser treatment by 31% (P = .0002), and progression of diabetic retinopathy with absolute reductions of 5.0% over 5 years (P = .022, FIELD) and 3.7% over 4 years (P = .006, ACCORD-Eye). There was greater benefit in patients with than without preexisting retinopathy. The putative mechanisms implicated in the mode of action of fenofibrate involve lipid and nonlipid pathways, including beneficial effects on apoptosis, oxidative stress, inflammation, blood-retinal barrier breakdown, and neuroprotection. There are now robust and consistent clinical data to recommend fenofibrate as an adjunctive treatment for early diabetic retinopathy in patients with type 2 diabetes mellitus, taking into account the risks vs benefits of therapy. Further elucidating its mode of action will help to refine how best to use fenofibrate in the management of diabetic retinopathy.

Comparison of Digital and Film Grading of Diabetic Retinopathy Severity in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study

To compare diabetic retinopathy (DR) severity as evaluated by digital and film images in a long-term multicenter study, as the obsolescence of film forced the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) to transition to digital after 25 years. At 20 clinics from 2007 through 2009, 310 participants with type 1 diabetes with a broad range of DR were imaged, per the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, with both film and digital cameras. Severity of DR was assessed centrally from film and tonally standardized digital cameras. For retinopathy outcomes with greater than 10% prevalence, we had 85% or greater power to detect an agreement κ of 0.7 or lower from our target of 0.9. Comparing DR severity, digital vs film yielded a weighted κ of 0.74 for eye level and 0.73 for patient level ("substantial"). Overall, digital grading did not systematically underestimate or overestimate severity (McNemar bias test, P=.14). For major DR outcomes (≥3-step progression on the ETDRS scale and disease presence at ascending thresholds), digital vs film κ values ranged from 0.69 to 0.96 ("substantial" to "nearly perfect"). Agreement was 86% to 99%; sensitivity, 75% to 98%; and specificity, 72% to 99%. Major conclusions were similar with digital vs film gradings (odds reductions with intensive diabetes therapy for proliferative DR at EDIC years 14 to 16: 65.5% digital vs 64.3% film). Digital and film evaluations of DR were comparable for ETDRS severity levels, DCCT/EDIC design outcomes, and major study conclusions, indicating that switching media should not adversely affect ongoing studies.

Retinal microaneurysm count predicts progression and regression of diabetic retinopathy. Post‐hoc results from the DIRECT Programme

To study the association between baseline retinal microaneurysm score and progression and regression of diabetic retinopathy, and response to treatment with candesartan in people with diabetes. This was a multicenter randomized clinical trial. The progression analysis included 893 patients with Type 1 diabetes and 526 patients with Type 2 diabetes with retinal microaneurysms only at baseline. For regression, 438 with Type 1 and 216 with Type 2 diabetes qualified. Microaneurysms were scored from yearly retinal photographs according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. Retinopathy progression and regression was defined as two or more step change on the ETDRS scale from baseline. Patients were normoalbuminuric, and normotensive with Type 1 and Type 2 diabetes or treated hypertensive with Type 2 diabetes. They were randomized to treatment with candesartan 32 mg daily or placebo and followed for 4.6 years. A higher microaneurysm score at baseline predicted an increased risk of retinopathy progression (HR per microaneurysm score 1.08, P < 0.0001 in Type 1 diabetes; HR 1.07, P = 0.0174 in Type 2 diabetes) and reduced the likelihood of regression (HR 0.79, P < 0.0001 in Type 1 diabetes; HR 0.85, P = 0.0009 in Type 2 diabetes), all adjusted for baseline variables and treatment. Candesartan reduced the risk of microaneurysm score progression. Microaneurysm counts are important prognostic indicators for worsening of retinopathy, thus microaneurysms are not benign. Treatment with renin-angiotensin system inhibitors is effective in the early stages and may improve mild diabetic retinopathy. Microaneurysm scores may be useful surrogate endpoints in clinical trials.

Rationale, Design, and Methods of the Action to Control Cardiovascular Risk in Diabetes Eye Study (ACCORD-EYE)

Diabetic retinopathy (DR) is a major microvascular complication of diabetes mellitus. The Action to Control Cardiovascular Risk in Diabetes Eye Study (ACCORD-EYE), a prospective study of a subset of patients in the randomized controlled clinical ACCORD trial, is being conducted at enrollment and after 4 years of follow-up to assess the progression of DR with standardized comprehensive eye exams and fundus photography of 7 standard stereoscopic fields. This study aims to assess the effects of the ACCORD medical treatment strategies of tight control of glycemia and blood pressure and management of dyslipidemia on the course of DR in patients with type 2 diabetes. Photographs will be evaluated at a centralized location using the modified Early Treatment Diabetic Retinopathy Study (ETDRS) classification. The primary outcome of ACCORD-EYE, which will measure the development and progression of DR, is a composite of (1) progression of DR (> or = 3 steps on the ETDRS scale), (2) photocoagulation for DR, or (3) vitrectomy for DR. Specifically, the following questions will be addressed: (1) Does a therapeutic strategy targeting a glycosylated hemoglobin (HbA(1c)) level <6.0% reduce development and progression of DR more than one targeting an HbA(1c) level of 7.0%-7.9% (target median level, 7.5%)? (2) In the context of good glycemic control, does a strategy using a fibrate to increase high-density lipoprotein cholesterol and lower triglyceride levels and a statin to maintain the level of low-density lipoprotein (LDL) cholesterol at <2.59 mmol/L (100 mg/dL) reduce development and progression of DR compared with one using placebo and a statin to treat LDL cholesterol? (3) In the context of good glycemic control, does a strategy targeting a systolic blood pressure level <120 mm Hg reduce development and progression of DR compared with one targeting a level <140 mm Hg? Secondary outcome variables include various levels of loss of visual acuity at 4 years versus baseline, cataract extraction, and the development or progression of diabetic macular edema. Methods to measure DR progression have been incorporated into ACCORD, and complete baseline data have been collected on 3,537 participants. These data will provide valuable information regarding the effects of medical treatment on the prevention and progression of DR.

Effectiveness and safety of screening for diabetic retinopathy with two nonmYdriatic digital images compared with the seven standard stereoscopic photographic fields

Background: The use of nonmydriatic cameras, which offer ease of screening and 45° immediate imaging of the fundus, is gaining increasing acceptance for screening programs tailored to diverse conditions. We performed a study to evaluate the effectiveness and safety of screening for diabetic retinopathy with two nonmydriatic camera images compared with the seven standard stereoscopic 30° fields (7SF). We also wished to determine whether safe screening guidelines could be established to identify patients needing referral to an ophthalmologist.Methods: In this prospective masked cross-sectional study, we evaluated agreement in the assessment of the severity of diabetic retinopathy by means of two 45° images centred on the optic disc and on the macula obtained with the Topcon CRW6 nonmydriatic camera and by means of 7SF photography and ophthalmologic slit-lamp biomicroscopy, both performed with pupil dilation. Between November 2000 and June 2001, 98 adult patients known to have type I or 2 diabetes mellitus who presented for the first time to the diabetic retinopathy clinic of a tertiary care centre in Montreal were enrolled consecutively. Thus, patient recruitment was weighted toward more severe retinopathy to ensure sufficient representation of less frequent but more severe levels. Each patient underwent nonmydriatic fundus photography of both eyes, followed by a complete ophthalmologic examination with pupil dilation by a single retina specialist and 7SF photography of both eyes with pupil dilation. The level of retinopathy was graded independently in each eye from the 7SF photographs according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale by two graders; an independent retina specialist adjudicated the rare instances of interreader disagreement in a masked fashion. Two months later, two graders independently graded the nonmydriatic images in a blinded fashion according to the ETDRS scale; a third observer adjudicated the rare instances of interreader disagreement. We measured concordance between grading results with the various screening techniques using the weighted and unweighted K statistic. We used sensitivity and specificity indices to determine safe screening guidelines to identify patients needing referral to an ophthalmologist.Results: There was substantial agreement in the grading of retinopathy with nonmydriatic camera imaging and with 7SF photography, both for all eyes (κ = 0.626 [standard deviation (SD) 0.045]) and for the eye with more severe disease (κ = 0.654 [SD 0.063]). With nonmydriatic camera imaging, screening thresholds for patient referral to an ophthalmologist of very mild retinopathy (ETDRS grade 20), mild retinopathy (ETDRS grade 35) and moderate retinopathy (EDTRS grade 43) had sensitivity values of 97.9%, 97.1% and 53.3% respectively and specificity values of 81.3%, 95.5% and 96.9% respectively. Screening thresholds of very mild or mild retinopathy both correctly identified 100% of eyes with severe nonproliferative or proliferative retinopathy. With a screening threshold of mild retinopathy, screening with the nonmydriatic camera would lead to referral to an ophthalmologist of 37.8% of patients because of detected disease and of an additional 17.3% because of insufficient image quality in at least one eye, for a total of 55.1%. The overall sensitivity and specificity of a two-field nonmydriatic screening strategy with a threshold of mild retinopathy for referral of patients with insufficient image quality in at least one eye are 97.7% and 84.0% respectively.Interpretation: Our results suggest that two-field nonmydriatic camera imaging is a safe screening strategy that may identify the patients with diabetes most in need of ophthalmologic care.