eMedicine Specialties > Ophthalmology > Retina

Retinopathy, Diabetic, Proliferative

Author: Abdhish R Bhavsar, MD, Adjunct Assistant Professor, Department of Ophthalmology, University of Minnesota; Director of Clinical Research, Retina Center, PA; Past Chair, Consulting Staff, Department of Ophthalmology, Phillips Eye Institute
Coauthor(s): Neal H Atebara, MD, Clinical Assistant Professor, Department of Surgery, Division of Ophthalmology, University of Hawaii School of Medicine; John H Drouilhet, MD, FACS, Clinical Professor, Department of Surgery, Section of Ophthalmology, University of Hawaii, John A Burns School of Medicine
Contributor Information and Disclosures

Updated: Mar 11, 2009

Introduction

Background

Diabetes mellitus (DM) is a major medical problem throughout the world. The incidence appears to be increasing not only among adults but also among children. Diabetes causes an array of long-term systemic complications, which have considerable impact on both the patient and the society because it typically affects individuals in their most productive years.¹ Ophthalmic complications of diabetes include corneal abnormalities, glaucoma, iris neovascularization, cataracts, and neuropathies. However, the most common and potentially most blinding of these complications is diabetic retinopathy.^2,3

Pathophysiology

The exact mechanism by which diabetes causes retinopathy remains unclear, but several theories have been postulated to explain the typical course and history of the disease.⁴

Growth hormone

Growth hormone appears to play a causative role in the development and progression of diabetic retinopathy. It was noted that diabetic retinopathy was reversed in women who had postpartum hemorrhagic necrosis of the pituitary gland (Sheehan syndrome). This led to the controversial practice of pituitary ablation to treat or prevent diabetic retinopathy in the 1950s. This technique has been abandoned because of numerous systemic complications and the discovery of the effectiveness of laser treatment.

Platelets and blood viscosity

Several hematologic abnormalities in diabetes, such as increased erythrocyte aggregation, decreased RBC deformability, increased platelet aggregation, and adhesion, predispose to sluggish circulation, endothelial damage, and focal capillary occlusion.⁵ This leads to retinal ischemia, which, in turn, contributes to the development of diabetic retinopathy.

Aldose reductase and vasoproliferative factors

Fundamentally, diabetes mellitus (DM) causes abnormal glucose metabolism as a result of decreased levels or activity of insulin. Increased levels of blood glucose are thought to have a structural and physiologic effect on retinal capillaries causing them to be both functionally and anatomically incompetent.

A persistent increase in blood glucose levels shunts excess glucose into the aldose reductase pathway in certain tissues, which converts sugars into alcohol (eg, glucose into sorbitol, galactose to dulcitol). Intramural pericytes of retinal capillaries seem to be particularly affected by this increased level of glucose because of its high aldose reductase content, eventually leading to the loss of its primary function (ie, autoregulation of retinal capillaries).

Loss of function of pericytes results in weakness and eventual saccular outpouching of capillary walls. These microaneurysms are the earliest detectable signs of DM retinopathy.

Ruptured microaneurysms (MA) result in retinal hemorrhages either superficially (flame-shaped hemorrhages) or in deeper layers of the retina (blot and dot hemorrhages).

Increased permeability of these vessels results in leakage of fluid and proteinaceous material, which clinically appears as retinal thickening and exudates. If the swelling and exudation would happen to involve the macula, a diminution in central vision may be experienced. Macular edema is the most common cause of vision loss in patients with nonproliferative diabetic retinopathy (NPDR). However, it is not exclusively seen only in patients with NPDR, but it also may complicate cases of proliferative diabetic retinopathy (PDR).

As the disease progresses, eventual closure of the retinal capillaries occurs, leading to hypoxia. Infarction of the nerve fiber layer leads to the formation of cotton-wool spots (CWS) with associated stasis in axoplasmic flow.

More extensive retinal hypoxia triggers compensatory mechanisms within the eye to provide enough oxygen to tissues. Venous caliber abnormalities, such as venous beading, loops, and dilation, signify increasing hypoxia and almost always are seen bordering the areas of capillary nonperfusion.

Intraretinal microvascular abnormalities (IRMA) represent either new vessel growth or remodeling of preexisting vessels through endothelial cell proliferation within the retinal tissues that act as shunts through areas of nonperfusion.

Further increases in retinal ischemia trigger the production of vasoproliferative factors, such as vascular endothelial growth factor (VEGF), that stimulate new vessel formation.⁶ The extracellular matrix is broken down first by proteases, and new vessels arising mainly from the retinal venules penetrate the internal limiting membrane and form capillary networks between the inner surface of the retina and the posterior hyaloid face.

These new blood vessels initially are associated with a small amount of fibroglial tissue formation. However, as the density of the neovascular frond increases, so does the fibrous tissue formation. In later stages, the vessels may regress leaving only networks of avascular fibrous tissue adherent to both the retina and the posterior hyaloid face. As the vitreous contracts, it may exert tractional forces on the retina via these fibroglial connections. Traction may cause retinal edema, retinal heterotropia, and both tractional retinal detachments and retinal tear formation with subsequent detachment.

Frequency

United States

Approximately 700,000 Americans have PDR with an annual incidence of 65,000. Approximately 500,000 persons have clinically significant macular edema (CSME) with an annual incidence of 75,000.

Mortality/Morbidity

Approximately 16 million Americans have diabetes, with 50% of them not even aware that they have it. Of these, only one half receives appropriate eye care. Thus, it is not surprising that diabetic retinopathy is the leading cause of new blindness in persons aged 25-74 years in the United States.

Approximately 8,000 eyes become blind yearly because of diabetes. The treatment of diabetic retinopathy entails tremendous costs, but it has been estimated that this represents only one eighth of the costs of social security payments for vision loss. This cost does not compare to the cost in terms of loss of productivity and quality of life.

Race

There appear to be some genetic and racial influences on the risk of developing diabetes. Some factors that can increase one's risk of developing diabetes include Native American, African American, or Hispanic heritage.

Sex

Sex does not appear to have any affect on the development of diabetes or diabetic retinopathy.

Age

With increasing duration of diabetes, or with increasing age since the onset of diabetes, there is a higher risk of developing diabetic retinopathy and the complications of diabetic retinopathy, including diabetic macular edema or proliferative diabetic retinopathy.

Clinical

History

In the initial stages, patients are generally asymptomatic; however, in the advanced stages of the disease, patients may experience floaters, blurred vision, or progressive visual acuity loss.

Physical

These findings occur in addition to all the findings that can be seen in nonproliferative or background diabetic retinopathy. See Retinopathy, Diabetic, Background.

• Neovascularization
  • Hallmark of proliferative diabetic retinopathy (PDR)
  • Most often occurs near the optic disc (neovascularization of the disc [NVD]) or within 3 disc diameters of the major retinal vessels (neovascularization elsewhere [NVE])
• Preretinal or vitreous hemorrhage
  • Preretinal hemorrhages appear as pockets of blood within the potential space between the retina and the posterior hyaloid face. As the blood pools within this space, they may appear boat shaped.

• Hemorrhage into the vitreous may appear as a diffuse haze or as clumps of blood clots within the gel.
• Fibrovascular tissue proliferation is usually seen associated with the neovascular complex and also may appear avascular when the vessels have already regressed.
• Traction retinal detachments usually appear tented up, immobile, and concave compared to rhegmatogenous retinal detachments, which are bullous, mobile, and convex. However, a combination of both mechanisms is not an uncommon finding.
• Macular edema
  • Leading cause of visual impairment in patients with diabetes
  • Possibly due to functional damage and necrosis of retinal capillaries
  • In cases of PDR, edema also may be caused by retinal traction if the retina is sufficiently elevated away from the retinal pigment epithelium (RPE).
  • CSME is defined as any of the following:
    • Retinal thickening located 500 µm or less from the center of the foveal avascular zone (FAZ)
    • Hard exudates with retinal thickening 500 µm or less from the center of the FAZ
    • Retinal thickening 1 disc area or larger in size located within 1 disc diameter of the FAZ
• Classification of proliferative diabetic retinopathy⁷
  • Early proliferative diabetic retinopathy - Presence of new vessels but not meeting the criteria for high-risk PDR
  • High-risk proliferative diabetic retinopathy
    • NVD greater than or equal to one-third to one-half disc area (DA)
    • Any amount of NVD with vitreous or preretinal hemorrhage
    • NVE greater than or equal to one-half DA with preretinal or vitreous hemorrhage

Causes

Risk factors

• Duration of the diabetes
  • In patients with type I diabetes, no clinically significant retinopathy can be seen in the first 5 years after the initial diagnosis of diabetes. In 10-15 years, 25-50% of patients show some signs of retinopathy. This prevalence increases to 75-95% after 15 years and approaches 100% after 30 years of diabetes. PDR is rare within the first decade of diagnosis but increases to 14-17% by 15 years, rising steadily thereafter.
  • In patients with type II diabetes, the incidence of diabetic retinopathy likewise increases with the duration of the disease. Of patients with type II diabetes, 23% have NPDR after 11-13 years, 41% have NPDR after 14-16 years, and 60% have NPDR after 16 years. PDR was found in 3% of patients 11 or more years after the diagnosis.
• Renal disease, as evidenced by proteinuria and elevated BUN/creatinine levels, is an excellent predictor of the presence of retinopathy. This is probably because of the fact that both conditions are caused by DM-related microangiopathies such that the presence and severity of one reflects that of the other. Evidence suggests that aggressive treatment of the nephropathy may have a beneficial effect on the progression of diabetic retinopathy and neovascular glaucoma.
• Systemic hypertension, in the setting of diabetic nephropathy, correlates well with the presence of retinopathy. Independently, hypertension also may complicate diabetes in that it may result in hypertensive retinal vascular changes superimposed on the preexisting diabetic retinopathy, further compromising retinal blood flow.
• Proper management of hyperlipidemia (elevated serum lipids) may result in less retinal vessel leakage and hard exudate formation. The reason behind this is unclear.
• Pregnant women without any diabetic retinopathy run a 10% risk of developing NPDR during their pregnancy. Of those with preexisting NPDR, 4% progress to the proliferative type. Those with proliferative retinopathy do poorly without treatment, but those who have had prior panretinal photocoagulation (PRP) remain stable throughout their pregnancy.

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