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Spotlight on diabetic retinopathy

Introduction

Diabetic retinopathy (DR) has become increasingly common as the prevalence of diabetes has increased and is a major cause of vision loss in middle-aged and elderly people. Prevention of vision loss relies on early detection and coordination between primary care and ophthalmology. Advances in the diagnosis and treatment of DR have had a major impact on the management of this disease but several important management questions remain unanswered.

This themed collection features a selection of recent full-text articles and chapters from the Springer Nature portfolio that discuss advances in our understanding of the mechanisms of DR, the epidemiology of DR and related vision loss, appropriate screening and diagnostic testing, and prevention and treatment approaches. Over time this collection will be enhanced by the addition of specially commissioned articles and resources that provide further guidance to healthcare practitioners, as well as selected full-text articles sourced from other prominent publishers.

Contents

  1. Overview
  2. Epidemiology
  3. Etiology and risk factors
  4. Pathophysiology
  5. Screening and diagnosis
  6. Treatment

Instructions

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  • Access the content via the blue title text.


Overview

Diabetic retinopathy

A comprehensive 'primer' article that provides an up-to-date overview of diabetic retinopathy.

Summary points

  • Diabetic retinopathy (DR) affects one-third of patients with diabetes and is a major cause of vision loss in middle-aged and elderly people.
  • The development of DR is strongly associated with diabetes duration, and systemic control of glycemia and blood pressure.
  • DR is classified as mild, moderate, and severe non-proliferative DR and proliferative DR, with proliferative DR further classified based on the location of the new vessels.
  • The impact of DR and associated visual impairment on health-related quality of life is substantial and patients with DR often have reduced physical, emotional and social well-being.
  • Optimal control of blood glucose and blood pressure in individuals with diabetes remains the cornerstone for preventing the development and arresting the progression of DR.
  • DR screening coupled with timely, pre-symptomatic intervention is a rational and cost-effective strategy that can reduce blindness by 30-50%.
  • Anti-vascular endothelial growth factor (VEGF) treatments have been a major breakthrough in the management of vision-threatening stages of DE and are now first-line therapies for diabetic macular edema (DME).

Wong TY et al. Nat Rev Dis Primers 2016; 2: 16012. doi: 10.1038/nrdp.2016.12


Epidemiology

Global estimates on the number of people blind or visually impaired by diabetic retinopathy: A meta-analysis from 1990 to 2010

This meta-analysis of published population studies from 1990 to 2012 aimed to estimate global and regional trends of the prevalence and number of persons visually impaired by diabetic retinopathy.

Summary points
  • This meta-analysis of published population studies from 1990 to 2012 for the Global Burden of Disease Study 2010 yielded estimated global regional trends in diabetic retinopathy (DR).
  • Globally in 2010, out of overall 32.4 million blind and 191 million visually impaired people, 0.8 million were blind and 3.7 million were visually impaired because of DR.
  • DR accounted for 2.6% of all blindness in 2010 and 1.9% of all moderate and severe vision impairment worldwide, increasing from 2.1% and 1.3%, respectively, in 1990.
  • The number of persons with visual impairment due to DR worldwide is rising and represents an increasing proportion of all blindness/visual impairment causes.

Leasher JL et al. Diabetes Care 2016;39:1643-1649. doi:10.2337/dc15-2171

Epidemiology of diabetic retinopathy, diabetic macular edema, and related vision loss

A review of the major trends in the prevalence, incidence, progression and regression of diabetic retinopathy and macular edema as well as the established and novel risk factors for both conditions.

Summary points
  • Of an estimated 285 million people with diabetes mellitus worldwide, approximately one-third have signs of diabetic retinopathy (DR) and of these, a further one-third have vision-threatening DR, including diabetic macular edema (DME).
  • DR is the leading cause of vision loss in adults aged 20–74 years and fifth most common cause of preventable blindness and moderate-to-severe visual impairment.
  • In general, patients with type 2 diabetes in Western communities have a higher prevalence of DR than their counterparts.
  • According to population-based studies, prevalence of DME among patients with type 1 diabetes is between 4.2 and 7.9 % and in patients with type 2 diabetes, it is between 1.4 and 12.8 %.
  • There is no observable difference between prevalence of DME between Western or Eastern populations but the epidemiology of DME is much less well studied than DR and more research is needed.
  • Hyperglycemia is the most important modifiable risk factor for DR, and intensive glycemic control has been proven to have potent and long-lasting protective effects against development and progression of DR and DME.

Lee R et al. Eye and Vis 2015;2:17. doi:10.1186/s40662-015-0026-2


Etiology and risk factors

The role of systemic risk factors in diabetic retinopathy

This review article examines the effects that systemic health factors and their management have on the risk of development of diabetic retinopathy.

Summary points
  • In the United States an estimated 5.5 million people over the age of 40 have diabetic retinopathy (DR) and over 20% of diabetes expenditure is spent on ophthalmic complications.
  • Patients with diabetes are more likely to have components of the metabolic syndrome (abdominal obesity, dyslipidemia, hypertension, prothrombotic state, and a proinflammatory state), which are associated with a higher risk of developing DR.
  • Patients’ risks of developing DR and retinopathy progression are affected by glycemic control, hypertension, cholesterol levels, and lifestyle management efforts (eg, obesity, sleep hygiene and activity levels).
  • Ophthalmologists are in a unique position to help motivate patients to control their diabetes, as the threat of vision loss can be a critical wake-up call for patients to invest in their health.

Atchison E, Barkmeier A. Curr Ophthalmol Rep 2016; 4: 84–89. doi: 10.1007/s40135-016-0098-8

Genetics of diabetic retinopathy

This review summarizes the findings of investigations aimed at uncovering the underlying genetic architecture of diabetic retinopathy susceptibility and discusses current efforts in the field.

Summary points
  • Diabetic retinopathy (DR) is a polygenic disorder and heritability has been estimated to be as high as 27% for DR and 52% for proliferative diabetic retinopathy (PDR), an advanced form of the disease.
  • The frequency and severity of DR among patients with diabetes mellitus is heterogeneous and known risk factors such as diabetes duration and glycemic control do not fully explain this observed heterogeneity.
  • There is a high concordance of DR severity among twins with both type 1 diabetes and type 2 diabetes, and siblings and relatives of diabetic patients with DR have approximately a 2- to 3-fold risk of DR when compared with relatives of diabetic patients without DR.
  • While there is strong evidence to suggest that DR is a heritable trait, linkage studies, candidate gene association studies and genome-wide association studies have not yet revealed any reproducible loci for DR.

Cho H, Sobrin L. Curr Diab Rep 2014; 14: 515. doi: 10.1007/s11892-014-0515-z


Pathophysiology

A basic scientific understanding of diabetic retinopathy

An expert review of the current understanding of the pathophysiology of diabetic retinopathy.

Summary points
  • Diabetic retinopathy (DR) is classified into nonproliferative diabetic retinopathy and proliferative diabetic retinopathy, with the latter identified by the growth of new retinal blood vessels.
  • Although DR has been extensively studied, a complete understanding of the pathophysiology remains to be described.
  • Multiple pathways such as ‘metabolic memory’ and epigenetic modification are involved in the pathogenesis of this complex disease process.
  • Anti-vascular endothelial growth factor agents can reduce diabetic macular edema and the progression of DR.
  • Although unifying themes are beginning to emerge such as the role of epigenetics and oxidative stress, it is likely that successful treatment of DR will involve targeting multiple pathways.

Sear N, Yuan A. In: Managing Diabetic Eye Disease in Clinical Practice. Edited by Singh RP. Springer International Publishing, 2015. doi: 10.1007/978-3-319-08329-2_2


Screening and diagnosis

Feasibility and efficacy of diabetic retinopathy screening among youth with diabetes in a pediatric endocrinology clinic: A cross-sectional study

This study highlights the feasibility and efficacy of using a non-mydriatic fundus camera for screening of diabetic retinopathy in a youth population with diabetes.

Summary points
  • Diabetic retinopathy (DR) is the leading cause of new cases of blindness among young adults in the United States.
  • Retinopathy may not produce apparent symptoms until visual loss develops and, thus, early detection and treatment is important in reducing rates of diabetes-related vision problems.
  • This study examined the feasibility and efficacy of using a non-mydriatic camera to screen for DR among youth with type 1 or type 2 diabetes.
  • Of the 236 youths with type 1 or type 2 diabetes screened with non-mydriatic camera in this study, DR was detected in 3.8% and 9.1% were visually impaired.
  • A non-mydriatic fundus camera is feasible and efficacious for DR screening in youth with diabetes.
  • DR screening at routine endocrinology visits may be beneficial in managing youth with diabetes and preventing irreversible vision loss, particularly for those in regions where diabetes rates are high.

Tapley​​​​​​​ JL et al. Diabetol Metab Syndr 2015; 7: 56. doi: 10.1186/s13098-015-0054-z

Diabetic retinopathy screening

This chapter provides an overview of screening approaches and modalities for monitoring and evaluating diabetic retinopathy.

Summary points
  • Diabetic retinopathy (DR) has become increasingly common as the prevalence of diabetes has increased and early detection of DR is crucial to preventing blindness.
  • Every patient with diabetes should have a comprehensive eye exam by an ophthalmologist or optometrist on at least an annual basis, and more frequently if the patient has significant DR.
  • Fundus photography is a useful tool in the evaluation and monitoring of diabetic retinopathy but should not be used in place of an ophthalmic exam by an eye care professional.
  • Fluorescein angiography is also a useful tool in the evaluation of ocular vasculature and can show areas of retinal nonperfusion in patients with diabetes.
  • Optical coherence tomography is a fast, non-invasive technology that can produce very detailed images of the retina and is useful in the evaluation and treatment of diabetic macular edema.

Reichel E, Salz D. In: Managing Diabetic Eye Disease in Clinical Practice. Edited by Singh RP. Springer International Publishing, 2015. doi:​​​​​​​ 10.1007/978-3-319-08329-2_3

Automated retinal image analysis for diabetic retinopathy in telemedicine

An evaluation of retinal image analysis systems currently used for diabetic retinopathy telemedicine programs.

Summary points

  • There will be an estimated 552 million persons with diabetes globally by the year 2030, with over half of these individuals expected to develop diabetic retinopathy (DR).
  • Telemedicine programs have the capability to distribute quality eye care to virtually any location and address the lack of access to ophthalmic services but there is a shortage of specially trained retinal image graders.
  • Automatic retinal image analysis (ARIA) systems designed for use in telemedicine have the potential to provide automated real-time patient evaluation, predictive patient and population analyses and possible identification of previously unrecognized novel markers of disease risk.
  • A major challenge to fully realizing the potential of this technology is the lack of a uniform validation for ARIA systems.
  • Large-scale implementation of ARIA systems for DR will require the involvement of primary care providers and a simple action-oriented process to allow easy detection of referable ocular disease and prompt access to appropriate eye care services.

Sim DA et al. Curr Diab Rep 2015; 15: 14. doi: 10.1007/s11892-015-0577-6

Ultra widefield fundus imaging for diabetic retinopathy

Ultra widefield fundus (UWF) imaging enhances screening, severity grading and physician understanding of diabetic eye disease in clinical practice. This article reviews the evolution of UWF imaging and its use in diabetic eye disease.

Summary points

  • Ultra widefield fundus imaging, with both color photography and fluorescein dye angiography, enables views of the central and far peripheral retina.
  • The ability to view areas not seen by standard photographic methods may enhance understanding of diabetic retinopathy (DR) severity and pathogenesis as well as allowing for future advances in treatment methods and decision-making.
  • Treatment for diabetic eye disease has also seen an increase in the use of intravitreal anti-vascular endothelial growth factor medications and a decrease in the use of retinal laser photocoagulation.
  • In this changing landscape, the role of peripheral retinal disease on DR progression, risk of vision loss, and indications for intervention becomes even more important to understand.
  • As the population of diabetic individuals continues to grow worldwide, the ability to capture a widefield image in a single photograph may lead to improved diagnosis, grading, and treatment of diabetic eye disease.

Kiss S, Berenberg TL. Curr Diab Rep 2014; 14: 514. doi: 10.1007/s11892-014-0514-0

Diabetic retinopathy

Optical coherence tomography (OCT) has revolutionized the diagnosis and management of patients with retinal diseases. Using illustrative cases, this chapter discusses OCT findings commonly encountered in patients with diabetic retinopathy.

Summary points
  • Diabetic retinopathy (DR) is the leading cause of new vision loss and legal blindness in working-aged patients in the United States and developed countries.
  • Of the varying manifestations of DR, diabetic macular edema (DME) is the most frequent mechanism of vision loss in these patients.
  • Optical coherence tomography (OCT) has allowed for characterization and monitoring of disease severity in DR, including DME, tractional retinal detachment, epiretinal membrane formation, and diabetic papillopathy.
  • In clinical studies investigating the efficacy of anti-vascular endothelial growth factor therapy for the treatment of DME, central macular thickness as determined by OCT is routinely used as a primary study outcome.
  • OCT has become integral in clinical decision-making in patients with DR. The case studies featured in this article reflect OCT findings commonly encountered in this patient population.

Ali Khan M, Juhn A. In: Optical Coherence Tomography. Edited by Girach A & Sergott RC. Springer International Publishing, 2016. doi: 10.1007/978-3-319-24817-2_3

Proliferative diabetic retinopathy

An overview of the definition, clinical manifestations, epidemiology and management recommendations for proliferative diabetic retinopathy.

Summary points
  • Proliferative diabetic retinopathy (PDR) is characterized by neovascularization of the disk or neovascularization elsewhere.
  • The prevalence of PDR in the United States has been reported as 1.5% in diabetics over 40 years of age. Type I diabetics have a higher prevalence of PDR.
  • Risk factors include: hyperglycemia, duration since diagnosis of diabetes, pregnancy, smoking, cardiovascular risk factors, and renal disease.
  • Anti-vascular endothelial growth factor (VEGF) drugs may be used as a temporizing measure to decrease vessel leakage and induce regression of neovascularization (both anterior segment and retinal).
  • Anti-VEGF therapy is beneficial as an adjunct to laser photocoagulation, either to cause regression of vessels prior to vitrectomy in treatment refractory PDR, or to expedite resolution of neovascularization of the angle.
  • Dilated fundus exam is recommended every 2–3 months for PDR not classified as high risk. More frequent follow-up is needed for high-risk PDR. Pregnant women with PDR should have dilated exams monthly.

Kodati S, Legarreta. In: Manual of Retinal Diseases. Edited by Medina CA, Townsend JH, Singh AD. Springer International Publishing, 2016. doi: 10.1007/978-3-319-20460-4_60

Nonproliferative diabetic retinopathy

An overview of the definition, clinical presentation, epidemiology, and management recommendations for nonproliferative diabetic retinopathy.

Summary points
  • Nonproliferative diabetic retinopathy (NPDR) is characterized by dot/blot hemorrhages, flame-shaped hemorrhages, microaneurysms, hard exudates, cotton wool spots, venous beading, venous loops, and intraretinal microvascular anomalies.
  • The major risk factor for development of diabetic retinopathy is duration of diabetes as well as poor control of blood glucose and systemic hypertension.
  • Diabetic retinopathy results from microvasculopathy believed to be related to the accumulation of advanced glycation end products.
  • Patients with diabetes mellitus (DM) type I should have comprehensive eye exam at 20 years of age. Patients with DM type II should be examined at time of diagnosis with diabetes.
  • Prognosis and management depend largely on severity of NPDR.
  • Treatment focuses on strict control of blood glucose, hypertension, and lipids. Further lifestyle modifications including diet, exercise, and smoking cessation should be encouraged.

Prensky CJ, Legarreta JE. In: Manual of Retinal Diseases. Edited by Medina CA, Townsend JH, Singh AD. Springer International Publishing, 2016. doi: 10.1007/978-3-319-20460-4_58


Treatment

Medical management of diabetic retinopathy

An accessible overview of the treatment goals for diabetic retinopathy (DR) and the evidence from clinical trials that glycemic control is associated with a reduction in the progression of DR.

Summary points
  • Controlling HbA1c is associated with a reduction in the progression of diabetic retinopathy (DR).
  • Clinicians should strive to achieve HbA1c values of <7% and blood pressure <140/80 mmHg to reduce the risk of microvascular and macrovascular complications.
  • However, HbA1c goals for patients must be individualized due to the complications associated with intensive glycemic control and patient characteristics.
  • Treating hypertension through lifestyle modification and medications is important in decreasing progression of DR.
  • Patients with diabetes who become pregnant need to set appropriate HbA1c and blood pressure goals due to the risk of progression of retinopathy during pregnancy.

Thomsen SL, Welch RJ, Do DV. In: Managing Diabetic Eye Disease in Clinical Practice. Edited by Singh RP. Springer International Publishing, 2015. doi: 10.1007/978-3-319-08329-2_4

Fenofibrate and diabetic retinopathy

This article reviews the clinical evidence and the mechanisms by which fenofibrate may reduce the progression of diabetic retinopathy.

Summary points
  • Diabetic retinopathy (DR) is a common microvascular complication in persons with types 1 and 2 diabetes and is the leading cause of vision loss in working-aged adults globally.
  • Medical therapies including intensive control of hyperglycemia and hypertension have been shown to reduce the incidence and progression of DR.
  • Two recent randomized clinical trials have demonstrated beneficial effects of systemic fenofibrate therapy in reducing the rate of progression of DR independently of serum lipid levels in patients with type 2 diabetes mellitus.
  • These findings suggest that fenofibrate may be an effective strategy for reducing the progression of DR, thus reducing the large and growing public health burden of treating the sight-threatening complications of DR.
  • However, despite an increased number of fenofibrate prescriptions in the USA over recent years, fenofibrate is still not routinely used for its beneficial effects on DR.
  • Further treatment trials with a focus on the primary outcome of DR progression are warranted prior to the general acceptance of fenofibrate for the treatment of DR, especially for those who are already affected with DR.

Knickelbein JE, Abbott AB, Chew EY. Curr Diab Rep 2016; 16: 90. doi: 10.1007/s11892-016-0786-7

Laser therapy in the management of diabetic retinopathy

A summary of laser treatment options, including subthreshold micropulse laser, beyond the established focal/grid laser photocoagulation protocol initially demonstrated in the Early Treatment of Diabetic Retinopathy Study.

Summary points
  • Diabetic macular edema is the major cause of decreased vision in diabetic patients. 
  • Laser treatment options beyond the established focal/grid laser photocoagulation protocol initially demonstrated in the Early Treatment of Diabetic Retinopathy Study are explored in this review.
  • Subthreshold micropulse laser seems to be an effective adjunctive therapy in conjunction with intravitreal anti-angiogenic injections in a subset of patients.
  • This treatment options is specifically effective in those with a retinal thickness of less than 400 μm, without the risk of scotomas and potential vision loss, which can occur with conventional laser treatment.
  • Given the absence of scarring from this “invisible” laser, the subthreshold micropulse laser may allow for earlier treatment prior to the onset of clinically significant macular edema, potentially preventing symptomatic vision loss and permanent photoreceptor damage.

Shah S, Fortun J. J Curr Ophthalmol Rep 2016; 4: 90–96. doi: 10.1007/s40135-016-0097-9

Surgery for diabetic eye complications

An overview of the indications, surgical objectives and techniques, adjunctive pharmacotherapy, and outcomes of vitrectomy for proliferative diabetic eye complications.

Summary points
  • New modalities for the treatment of diabetic eye complications have emerged in the past decade. Nevertheless, many severe diabetic retinopathy (DR) complications can only be treated with vitreoretinal surgery.
  • Complications from DR can result in severe pathologies that are very challenging to repair surgically and can carry a poor visual prognosis.
  • Early vitrectomy to remove the posterior hyaloid and early fibrovascular proliferation is ideal to prevent the progression to tractional retinal detachment and combined tractional and rhegmatogenous retinal detachment, particularly in young diabetics.
  • With the availability of new microincisional vitrectomy technology, wide angle microscope viewing systems, and pharmacologic agents, vitrectomy can improve visual acuity and achieve long-term anatomic stability in eyes with severe complications from proliferative DR.
  • As a result of these advances in technology, surgical intervention for complicated DR can be performed earlier than suggested by the Diabetic Retinopathy Vitrectomy Study, allowing for better visual and anatomical results. 

Berrocal MH, Acaba LA, Acaba A. Curr Diab Rep 2016; 16: 99. doi: 10.1007/s11892-016-0787-6