eMedicine Specialties > Ophthalmology > Retina

Retinopathy, Diabetic, Background

Author: Abdhish R Bhavsar, MD, Adjunct Assistant Professor, Department of Ophthalmology, University of Minnesota Medical School; Director of Clinical Research, Retina Center, PA; Past Chair, Consulting Staff, Department of Ophthalmology, Phillips Eye Institute
Coauthor(s): 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: Oct 6, 2009

Introduction

Background

Diabetes mellitus (DM) is a major medical problem throughout the world. 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.^4,5

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

The variety of hematologic abnormalities seen 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. 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 affected by this increased level of sorbitol, 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.

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).

Another theory to explain the development of macular edema deals with the increased levels of diacylglycerol (DAG) from the shunting of excess glucose. This is thought to activate protein kinase C (PKC), which, in turn, affects retinal blood dynamics, especially permeability and flow, leading to fluid leakage and retinal thickening.

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 to act as shunts through areas of nonperfusion.

Further increases in retinal ischemia trigger the production of vasoproliferative factors that stimulate new vessel formation. 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.

Neovascularization most commonly is observed at the borders of perfused and nonperfused retina and most commonly occur along the vascular arcades and at the optic nerve head. The new vessels break through and grow along the surface of the retina and into the scaffold of the posterior hyaloid face. By themselves, these vessels rarely cause visual compromise. However, they are fragile and highly permeable. These delicate vessels are disrupted easily by vitreous traction, which leads to hemorrhage into the vitreous cavity or the preretinal space.

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 degree of 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 16 million Americans have diabetes, with 50% of them not even aware that they have it. Of those that know, 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, responsible for more than 8000 cases of new blindness each year.⁶ This means that diabetes is responsible for 12% of blindness; the rate is even higher among certain ethnic groups.

International

The incidence of diabetes appears to be increasing throughout the world, at least in part due to the increasing incidence of obesity and sedentary lifestyle. Dietary changes involving diets with higher fat and carbohydrate intake as well as the increasing size of portions of food and drinks over the past several decades may also be responsible.

Mortality/Morbidity

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

An increased risk of diabetic retinopathy appears to exist in patients with Native American, Hispanic, and African American 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 more advanced stages of the disease, patients may experience symptoms, including blurred vision, distortion, or visual acuity loss.

Physical

• Microaneurysms
  • Earliest clinical sign of diabetic retinopathy
  • Secondary to capillary wall outpouching due to pericyte loss
  • Appear as small red dots in the superficial retinal layers
  • Fibrin and RBC accumulation in the microaneurysm lumen
  • Rupture produces blot/flame hemorrhages
  • May appear yellowish in time as endothelial cells proliferate and produce basement membrane
• Dot and blot hemorrhages
  • Occur as microaneurysms rupture in the deeper layers of the retina such as the inner nuclear and outer plexiform layers
  • Appear similar to microaneurysms if they are small; may need fluorescein angiography to distinguish between the two
• Flame-shaped hemorrhages - Splinter hemorrhages that occur in the more superficial nerve fiber layer
• Retinal edema and hard exudates - Caused by the breakdown of the blood-retina barrier, allowing leakage of serum proteins, lipids, and protein from the vessels
• Cotton-wool spots
  • Nerve fiber layer infarction from occlusion of precapillary arterioles
  • Fluorescein angiography - No capillary perfusion
  • Frequently bordered by microaneurysms and vascular hyperpermeability
• Venous loops, venous beading
  • Frequently adjacent to areas of nonperfusion
  • Reflects increasing retinal ischemia
  • Most significant predictor of progression to PDR
• Intraretinal microvascular abnormalities
  • Remodeled capillary beds without proliferative changes
  • Collateral vessels that do not leak on fluorescein angiography
  • Usually can be found on the borders of the nonperfused retina
• Macular edema
  • This condition is the leading cause of visual impairment in patients with diabetes. A reported 75,000 new cases of macular edema are diagnosed annually.
  • Possibly due to functional damage and necrosis of retinal capillaries
  • Clinically significant macular edema (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
• Mild nonproliferative diabetic retinopathy - Presence of at least 1 microaneurysm
• Moderate nonproliferative diabetic retinopathy
  • Presence of hemorrhages, microaneurysms, and hard exudates
  • Soft exudates, venous beading, and IRMA less than that of severe NPDR
• Severe nonproliferative diabetic retinopathy (4-2-1)
  • Hemorrhages and microaneurysms in 4 quadrants
  • Venous beading in at least 2 quadrants
  • IRMA in at least 1 quadrant
• Mild NPDR reflects structural changes in the retina caused by the physiological and anatomical effects of diabetes. On the other hand, the more advanced stages of NPDR reflect the increasing retinal ischemia setting up the stage for proliferative changes.

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 is made. After 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.
  • In patients with type II diabetes, the incidence of diabetic retinopathy 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.
• Glucose control
  • The Diabetic Control and Complications Trial (DCCT) has demonstrated that intensive glucose control reduced the incidence and the progression of diabetic retinopathy in patients with insulin-dependent diabetes mellitus (IDDM).
  • Although no similar trials for patients with non–insulin–dependent diabetes mellitus (NIDDM) have been completed, the American Diabetes Association (ADA) has suggested that glycosylated hemoglobin levels of less than 7% (reflecting long-term glucose levels) should be the goal in all patients to prevent or slow down the onset of diabetes-related complications.
• Renal disease, as evidenced by proteinuria and elevated BUN/creatinine levels, is an excellent predictor of the presence of retinopathy. This probably is due to 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.

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