Screening for diabetic retinopathy: new perspectives and challenges.

Although the prevalence of all stages of diabetic retinopathy has been declining since 1980 in populations with improved diabetes control, the crude prevalence of visual impairment and blindness caused by diabetic retinopathy worldwide increased between 1990 and 2015, largely because of the increasing prevalence of type 2 diabetes, particularly in low-income and middle-income countries. Screening for diabetic retinopathy is essential to detect referable cases that need timely full ophthalmic examination and treatment to avoid permanent visual loss. In the past few years, personalised screening intervals that take into account several risk factors have been proposed, with good cost-effectiveness ratios. However, resources for nationwide screening programmes are scarce in many countries. New technologies, such as scanning confocal ophthalmology with ultrawide field imaging and handheld mobile devices, teleophthalmology for remote grading, and artificial intelligence for automated detection and classification of diabetic retinopathy, are changing screening strategies and improving cost-effectiveness. Additionally, emerging evidence suggests that retinal imaging could be useful for identifying individuals at risk of cardiovascular disease or cognitive impairment, which could expand the role of diabetic retinopathy screening beyond the prevention of sight-threatening disease.

The Usefulness of Serum Biomarkers in the Early Stages of Diabetic Retinopathy: Results of the EUROCONDOR Clinical Trial.

The main aim of this study was to evaluate the ability of serum biomarkers to predict the worsening of retinal neurodysfunction in subjects with type 2 diabetes. For this purpose, we measured selected molecules (N-epsilon-carboxy methyl lysine (CML), laminin P1 (Lam-P1), and asymmetric dimethylarginine (ADMA)) in the serum of 341 participants of the EUROCONDOR study at baseline, 24, and 48 weeks. Retinal neurodysfunction was assessed by measuring implicit time (IT) using multifocal electroretinography, and structural changes were examined by spectral domain-optical coherence tomography. The values of IT at baseline were directly correlated with baseline serum concentrations of CML (r = 0.135, p = 0.013). Furthermore, in the placebo group, increase in CML concentration throughout follow-up correlated with the IT (r = 0.20; p = 0.03). Baseline serum levels of CML also correlated with macular retinal thickness (RT) (r = 0.231; p < 0.001). Baseline Lam-P1 levels correlated with the increase of the RT at the end of follow-up in the placebo group (r = 0.22; p = 0.016). We provide evidence that CML may be a biomarker of both retinal neurodysfunction and RT, whereas Lam-P1 was associated with RT only. Therefore, circulating levels of these molecules could provide a complementary tool for monitoring the early changes of diabetic retinopathy (DR).

Effects of Topically Administered Neuroprotective Drugs in Early Stages of Diabetic Retinopathy: Results of the EUROCONDOR Clinical Trial.

The primary objective of this study was to assess whether the topical administration of two neuroprotective drugs (brimonidine and somatostatin) could prevent or arrest retinal neurodysfunction in patients with type 2 diabetes. For this purpose, adults aged between 45 and 75 years with a diabetes duration ≥5 years and an Early Treatment of Diabetic Retinopathy Study (ETDRS) level of ≤35 were randomly assigned to one of three arms: placebo, somatostatin, or brimonidine. The primary outcome was the change in implicit time (IT) assessed by multifocal electroretinography between baseline and at the end of follow-up (96 weeks). There were 449 eligible patients allocated to brimonidine (n = 152), somatostatin (n = 145), or placebo (n = 152). When the primary end point was evaluated in the whole population, we did not find any neuroprotective effect of brimonidine or somatostatin. However, in the subset of patients (34.7%) with preexisting retinal neurodysfunction, IT worsened in the placebo group (P < 0.001) but remained unchanged in the brimonidine and somatostatin groups. In conclusion, the topical administration of the selected neuroprotective agents appears useful in preventing the worsening of preexisting retinal neurodysfunction. This finding points to screening retinal neurodysfunction as a critical issue to identify a subset of patients in whom neuroprotective treatment might be of benefit.

Functional and Structural Findings of Neurodegeneration in Early Stages of Diabetic Retinopathy: Cross-sectional Analyses of Baseline Data of the EUROCONDOR Project.

This cross-sectional study evaluated the relationship between 1) functional and structural measurements of neurodegeneration in the initial stages of diabetic retinopathy (DR) and 2) the presence of neurodegeneration and early microvascular impairment. We analyzed baseline data of 449 patients with type 2 diabetes enrolled in the European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) study (NCT01726075). Functional studies by multifocal electroretinography (mfERG) evaluated neurodysfunction, and structural measurements using spectral domain optical coherence tomography (SD-OCT) evaluated neurodegeneration. The mfERG P1 amplitude was more sensitive than the P1 implicit time and was lower in patients with Early Treatment of Diabetic Retinopathy Study (ETDRS) level 20-35 than in patients with ETDRS level <20 (P = 0.005). In 58% of patients, mfERG abnormalities were present in the absence of visible retinopathy. Correspondence between SD-OCT thinning and mfERG abnormalities was shown in 67% of the eyes with ETDRS <20 and in 83% of the eyes with ETDRS level 20-35. Notably, 32% of patients with ETDRS 20-35 presented no abnormalities in mfERG or SD-OCT. We conclude that there is a link between mfERG and SD-OCT measurements that increases with the presence of microvascular impairment. However, a significant proportion of patients in our particular study population (ETDRS ≤35) had normal ganglion cell-inner plexiform layer thickness and normal mfERG findings. We raise the hypothesis that neurodegeneration may play a role in the pathogenesis of DR in many but not in all patients with type 2 diabetes.

The influence of age, duration of diabetes, cataract, and pupil size on image quality in digital photographic retinal screening.

OBJECTIVE: To evaluate the effect of age, duration of diabetes, cataract, and pupil size on the image quality in digital photographic screening. RESEARCH DESIGN AND METHODS: Randomized groups of 3,650 patients had one-field, non-mydriatic, 45 degrees digital retinal imaging photography before mydriatic two-field photography. A total of 1,549 patients were then examined by an experienced ophthalmologist. Outcome measures were ungradable image rates, age, duration of diabetes, detection of referable diabetic retinopathy, presence of early or obvious central cataract, pupil diameter, and iris color. RESULTS: The ungradable image rate for non-mydriatic photography was 19.7% (95% CI 18.4-21.0) and for mydriatic photography was 3.7% (3.1-4.3). The odds of having one eye ungradable increased by 2.6% (1.6-3.7) for each extra year since diagnosis for nonmydriatic, by 4.1% (2.7-5.7) for mydriatic photography irrespective of age, by 5.8% (5.0-6.7) for non-mydriatic, and by 8.4% (6.5-10.4) for mydriatic photography for every extra year of age, irrespective of years since diagnosis. Obvious central cataract was present in 57% of ungradable mydriatic photographs, early cataract in 21%, no cataract in 9%, and 13% had other pathologies. The pupil diameter in the ungradable eyes showed a significant trend (P < 0.001) in the three groups (obvious cataract 4.434, early cataract 3.379, and no cataract 2.750). CONCLUSIONS: The strongest predictor of ungradable image rates, both for non-mydriatic and mydriatic digital photography, is the age of the person with diabetes. The most common cause of ungradable images was obvious central cataract.

Development of a cost-effectiveness model for optimisation of the screening interval in diabetic retinopathy screening.

BACKGROUND: The English NHS Diabetic Eye Screening Programme was established in 2003. Eligible people are invited annually for digital retinal photography screening. Those found to have potentially sight-threatening diabetic retinopathy (STDR) are referred to surveillance clinics or to Hospital Eye Services. OBJECTIVES: To determine whether personalised screening intervals are cost-effective. DESIGN: Risk factors were identified in Gloucestershire, UK using survival modelling. A probabilistic decision hidden (unobserved) Markov model with a misgrading matrix was developed. This informed estimation of lifetime costs and quality-adjusted life-years (QALYs) in patients without STDR. Two personalised risk stratification models were employed: two screening episodes (SEs) (low, medium or high risk) or one SE with clinical information (low, medium-low, medium-high or high risk). The risk factor models were validated in other populations. SETTING: Gloucestershire, Nottinghamshire, South London and East Anglia (all UK). PARTICIPANTS: People with diabetes in Gloucestershire with risk stratification model validation using data from Nottinghamshire, South London and East Anglia. MAIN OUTCOME MEASURES: Personalised risk-based algorithm for screening interval; cost-effectiveness of different screening intervals. RESULTS: Data were obtained in Gloucestershire from 12,790 people with diabetes with known risk factors to derive the risk estimation models, from 15,877 people to inform the uptake of screening and from 17,043 people to inform the health-care resource-usage costs. Two stratification models were developed: one using only results from previous screening events and one using previous screening and some commonly available GP data. Both models were capable of differentiating groups at low and high risk of development of STDR. The rate of progression to STDR was 5 per 1000 person-years (PYs) in the lowest decile of risk and 75 per 1000 PYs in the highest decile. In the absence of personalised risk stratification, the most cost-effective screening interval was to screen all patients every 3 years, with a 46% probability of this being cost-effective at a £30,000 per QALY threshold. Using either risk stratification models, screening patients at low risk every 5 years was the most cost-effective option, with a probability of 99-100% at a £30,000 per QALY threshold. For the medium-risk groups screening every 3 years had a probability of 43-48% while screening high-risk groups every 2 years was cost-effective with a probability of 55-59%. CONCLUSIONS: The study found that annual screening of all patients for STDR was not cost-effective. Screening this entire cohort every 3 years was most likely to be cost-effective. When personalised intervals are applied, screening those in our low-risk groups every 5 years was found to be cost-effective. Screening high-risk groups every 2 years further improved the cost-effectiveness of the programme. There was considerable uncertainty in the estimated incremental costs and in the incremental QALYs, particularly with regard to implications of an increasing proportion of maculopathy cases receiving intravitreal injection rather than laser treatment. Future work should focus on improving the understanding of risk, validating in further populations and investigating quality issues in imaging and assessment including the potential for automated image grading. STUDY REGISTRATION: Integrated Research Application System project number 118959. FUNDING DETAILS: The National Institute for Health Research Health Technology Assessment programme.

Risks of progression of retinopathy and vision loss related to tight blood pressure control in type 2 diabetes mellitus: UKPDS 69.

OBJECTIVE: To determine the relationship between tight blood pressure (BP) control and the different aspects of diabetic retinopathy in patients with type 2 diabetes mellitus (DM). SETTING: Nineteen hospital-based clinics in England, Scotland, and Northern Ireland. DESIGN: Outcome of retinopathy status assessed by 4-field retinal photography related to allocation within a randomized controlled trial comparing a tight BP control policy aiming for a BP less than 150/85 mm Hg with a less tight BP control policy aiming for a BP less than 180/105 mm Hg. SUBJECTS: One thousand one hundred forty-eight hypertensive patients with type 2 DM were studied. These patients had type 2 DM for a mean duration of 2.6 years at the inception of the Hypertension in Diabetes Study, had a mean age of 56 years; and had a mean BP of 160/94 mm Hg. Seven hundred fifty-eight patients were allocated to a tight BP control policy with angiotensin-converting enzyme inhibitor or beta-blockers as the main therapy; 390 were allocated to a less tight BP control policy. MAIN OUTCOME MEASURES: Deterioration of retinopathy (>/=2-step change on a modified Early Treatment Diabetic Retinopathy Study [ETDRS] final scale), together with end points (photocoagulation, vitreous hemorrhage, and cataract extraction) and analysis of specific lesions (microaneurysms, hard exudates, and cotton-wool spots). Visual acuity was assessed at 3-year intervals using ETDRS logarithm of the minimum angle of resolution charts. Blindness was monitored as an end point with the criterion of Snellen chart assessment at 6/60 or worse. RESULTS: By 4.5 years after randomization, there was a highly significant difference in microaneurysm count with 23.3% in the tight BP control group and 33.5% in the less tight BP control group having 5 or more microaneurysms (relative risk [RR], 0.70; P = .003). The effect continued to 7.5 years (RR, 0.66; P<.001). Hard exudates increased from a prevalence of 11.2% to 18.3% at 7.5 years after randomization with fewer lesions found in the tight BP control group (RR, 0.53; P<.001). Cotton-wool spots increased in both groups but less so in the tight BP control group which had fewer cotton-wool spots at 7.5 years (RR, 0.53; P<.001). A 2-step or more deterioration on the ETDRS scale was significantly different at 4.5 years with fewer people in the tight BP control group progressing 2 steps or more (RR, 0.75; P = .02). Patients allocated to tight BP control were less likely to undergo photocoagulation (RR, 0.65; P = .03). This difference was driven by a difference in photocoagulation due to maculopathy (RR, 0.58; P = .02). The cumulative incidence of the end point of blindness (Snellen visual acuity, >/=6/60) in 1 eye was 18/758 for the tight BP control group compared with 12/390 for less tight BP control group. These equate to absolute risks of 3.1 to 4.1 per 1000 patient-years, respectively (P = .046; RR, 0.76; 99% confidence interval, 0.29-1.99). There was no detectable difference in outcome between the 2 randomized therapies of angiotensin-converting enzyme inhibition and beta-blockade. CONCLUSIONS: High BP is detrimental to each aspect of diabetic retinopathy; a tight BP control policy reduces the risk of clinical complications from diabetic eye disease.

Epidemiological issues in diabetic retinopathy.

There is currently an epidemic of diabetes in the world, principally type 2 diabetes that is linked to changing lifestyle, obesity, and increasing age of the population. Latest estimates from the International Diabetes Federation (IDF) forecasts a rise from 366 million people worldwide to 552 million by 2030. Type 1 diabetes is more common in the Northern hemisphere with the highest rates in Finland and there is evidence of a rise in some central European countries, particularly in the younger children under 5 years of age. Modifiable risk factors for progression of diabetic retinopathy (DR) are blood glucose, blood pressure, serum lipids, and smoking. Nonmodifiable risk factors are duration, age, genetic predisposition, and ethnicity. Other risk factors are pregnancy, microaneurysm count in an eye, microaneurysm formation rate, and the presence of any DR in the second eye. DR, macular edema (ME), and proliferative DR (PDR) develop with increased duration of diabetes and the rates are dependent on the above risk factors. In one study of type 1 diabetes, the median individual risk for the development of early retinal changes was 9.1 years of diabetes duration. Another study reported the 25 year incidence of proliferative retinopathy among population-based cohort of type 1 patients with diabetes was 42.9%. In recent years, people with diabetes have lower rates of progression than historically to PDR and severe visual loss, which may reflect better control of glucose, blood pressure, and serum lipids, and earlier diagnosis.

A simple risk stratification for time to development of sight-threatening diabetic retinopathy.

OBJECTIVE: The American Diabetes Association and the English NHS Diabetic Eye Screening Program recommend annual screening for diabetic retinopathy (DR) with referral to ophthalmology clinics of patients with sight-threatening DR (STDR). Using only longitudinal data from retinal photographs in the population-based NHS Diabetic Eye Screening Program in Gloucestershire, we developed a simple means to estimate risk of STDR. RESEARCH DESIGN AND METHODS: From 2005, 14,554 patients with no DR or mild nonproliferative DR only at two consecutive annual digital photographic screenings were categorized by the presence of DR in neither, one, or both eyes at each screening and were followed for a further median 2.8 years. RESULTS: Of 7,246 with no DR at either screening, 120 progressed to STDR, equivalent to an annual rate of 0.7%. Of 1,778 with no DR in either eye at first screening and in one eye at second screening, 80 progressed to STDR, equivalent to an annual rate of 1.9% and to a hazard ratio (HR) of 2.9 (95% CI 2.2-3.8) compared with those with no DR. Of 1,159 with background DR in both eyes at both screenings, 299 progressed to STDR equivalent to an annual rate of 11% and an HR of 18.2 (14.7-22.5) compared with individuals with no DR. CONCLUSIONS: Combining the results from 2 consecutive years of photographic screening enables estimation of the risk of future development of STDR. In countries with systematic screening programs, these results could inform decisions about screening frequency.

The influence of background diabetic retinopathy in the second eye on rates of progression of diabetic retinopathy between 2005 and 2010.

PURPOSE: The Gloucestershire Diabetic Eye Screening Programme offers annual digital photographic screening for diabetic retinopathy to a countywide population of people with diabetes. This study was designed to investigate progression of diabetic retinopathy in this programme of the English NHS Diabetic Eye Screening Programme. METHODS: Mydriatic digital retinal photographs of people with diabetes screened on at least 2 occasions between 2005 and 2010 were graded and included in this study if the classification at first screening was no DR (R0), background DR in one (R1a) or both eyes (R1b). Times to detection of referable diabetic retinopathy (RDR) comprising maculopathy (M1), preproliferative (R2) or proliferative retinopathy (R3) were analysed using survival models. RESULTS: Data were available on 19 044 patients, 56% men, age at screening 66 (57-74) years (median, 25th, 75th centile). A total of 8.3% of those with R1a and 28.2% of those with R1b progressed to any RDR, hazard ratios 2.9 [2.5-3.3] and 11.3 [10.0-12.8]. Similarly 7.1% and 0.11% of those with R1a progressed to M1 and R3, hazard ratios 2.7 [2.3-3.2] and 1.6 [0.5-5.0], compared to 21.8% and 1.07% of those with R1b, hazard ratio 9.1 [7.8-10.4] and 15.0 [7.1-31.5]. CONCLUSIONS: The risk of progression is significantly higher for those with background DR in both eyes than those with background retinopathy in only one or in neither eye.

Screening for diabetic retinopathy: developing a standardized photographic protocol for St. John's Hospital.

The management of people with diabetes involves input from many healthcare professionals including doctors, nurses, podiatrists and dieticians. In February 1999 at the request of the Consultant Diabetologist a diabetic screening service was established at St. John's Hospital using digital retinal photography. A preliminary photographic protocol was put into place immediately. In order to establish if the protocol was suitable, or at the level of a national standard, the author carried out an extensive literature search. There proved to be a paucity of published information specifically related to guidelines for diabetic retinopathy screening, using a photographic method. The author therefore issued questionnaires to randomly selected medical photography and diabetic screening units throughout the United Kingdom. The research and results of this study has enabled the provision of an effective and efficient retinopathy screening service. Medical photographers are now recognized as part of the diabetic clinic 'team' that care for patients at St. John's Hospital.