Background
Diabetes mellitus (DM) is a major medical problem throughout the world. Diabetes causes an array of long-term systemic complications that have considerable impact on the patient as well as society, as the disease typically affects individuals in their most productive years.[1] An increasing prevalence of diabetes is occurring throughout the world.[2] In addition, this increase appears to be greater in developing countries. The etiology of this increase involves changes in diet, with higher fat intake, sedentary lifestyle changes, and decreased physical activity.[3, 4]
Diabetic retinopathy is the leading cause of new blindness in persons aged 25-74 years in the United States. Approximately 700,000 persons in the United States have proliferative diabetic retinopathy, with an annual incidence of 65,000. A recent estimate of the prevalence of diabetic retinopathy in the United States showed a high prevalence of 28.5% among those with diabetes aged 40 years and older.[5] (See Epidemiology.)
Patients with diabetes often develop ophthalmic complications, such as corneal abnormalities, glaucoma, iris neovascularization, cataracts, and neuropathies. The most common and potentially most blinding of these complications, however, is diabetic retinopathy.[6, 7]
In the initial stages of diabetic retinopathy, patients are generally asymptomatic, but in more advanced stages of the disease patients may experience symptoms that include floaters, distortion, and/or and blurred vision. Microaneurysms are the earliest clinical sign of diabetic retinopathy. (See Clinical Presentation.)
Workup for diabetic retinopathy includes fasting glucose and hemoglobin A1c measurements. (See Workup.)
Renal disease, as evidenced by proteinuria and elevated BUN/creatinine levels, is an excellent predictor of retinopathy; both conditions are caused by DM-related microangiopathies, and the presence and severity of one reflects that of the other. Aggressive treatment of the nephropathy may slow progression of diabetic retinopathy and neovascular glaucoma. (See Treatment and Management.)
According to The Diabetes Control and Complications Trial controlling diabetes and maintaining the HbA1c level in the 6-7% range can substantially reduce the progression of diabetic retinopathy. (See Treatment and Management.)
One of the most important aspects in the management of diabetic retinopathy is patient education. Inform patients that they play an integral role in their own eye care. (See Patient Education.)
For more information, see Type 1 Diabetes Mellitus and Type 2 Diabetes Mellitus.
Pathophysiology
Fundus photograph of early background diabetic retinopathy showing multiple microaneurysms. 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.[8, 9]
Growth hormone
Growth hormone appears to play a causative role in the development and progression of diabetic retinopathy. Diabetic retinopathy has been shown to be reversible 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 since 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 red blood cell deformability, increased platelet aggregation, and adhesion, predispose the patient 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 their primary function (ie, autoregulation of retinal capillaries). This results in weakness and eventual saccular outpouching of capillary walls. These microaneurysms are the earliest detectable signs of DM retinopathy. (See the image below.)
Fundus photograph of early background diabetic retinopathy showing multiple microaneurysms. Using nailfold video capillaroscopy, a high prevalence of capillary changes is detected in patients with diabetes, particularly those with retinal damage. This reflects a generalized microvessel involvement in both type 1 and type 2 diabetes.[10]
Ruptured microaneurysms result in retinal hemorrhages either superficially (flame-shaped hemorrhages) or in deeper layers of the retina (blot and dot hemorrhages). (See the image below.)
Retinal findings in background diabetic retinopathy, including blot hemorrhages (arrowhead), microaneurysms (short arrow), and hard exudates (long arrow). 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 involve the macula, a diminution in central vision may be experienced.
Macular edema
Macular edema is the most common cause of vision loss in patients with nonproliferative diabetic retinopathy (NPDR). However, it is not exclusively seen in patients with NPDR; it may also complicate cases of proliferative diabetic retinopathy.
Fluorescein angiogram demonstrating foveal dye leakage caused by macular edema.
Fundus photograph of clinically significant macular edema demonstrating retinal exudates within the fovea. Another theory to explain the development of macular edema focuses on the increased levels of diacylglycerol from the shunting of excess glucose. This is thought to activate protein kinase C, which, in turn, affects retinal blood dynamics, especially permeability and flow, leading to fluid leakage and retinal thickening.
Hypoxia
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, with associated stasis in axoplasmic flow.
More extensive retinal hypoxia triggers compensatory mechanisms in 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 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.
Neovascularization
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. (See the images below.)
New vessel formation on the surface of the retina (neovascularization elsewhere)
An area of neovascularization that leaks fluorescein on angiography.
Boat-shaped preretinal hemorrhage associated with neovascularization elsewhere. In patients with proliferative diabetic retinopathy (PDR), nocturnal intermittent hypoxia/reoxygenation that results from sleep-disordered breathing may be a risk factor for iris and/or angle neovascularization.[11]
Neovascularization is most commonly observed at the borders of perfused and nonperfused retina and most commonly occurs 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, but 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.
Etiology
Duration of 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. Proliferative diabetic retinopathy (PDR) is rare within the first decade of type I diabetes diagnosis but increases to 14-17% by 15 years, rising steadily thereafter.
In patients with type II diabetes, the incidence of diabetic retinopathy increases with the disease duration. Of patients with type II diabetes, 23% have nonproliferative diabetic retinopathy (NPDR) after 11-13 years, 41% have NPDR after 14-16 years, and 60% have NPDR after 16 years.
Hypertension and hyperlipidemia
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, but the reason behind this is unclear.
Pregnancy
Pregnant women with proliferative diabetic retinopathy do poorly without treatment, but those who have had prior panretinal photocoagulation remain stable throughout pregnancy. Pregnant women without diabetic retinopathy run a 10% risk of developing NPDR during their pregnancy; of those with preexisting NPDR, 4% progress to the proliferative type.
For more information, see Diabetes Mellitus and Pregnancy.
Epidemiology
Of the approximately 16 million Americans with diabetes, 50% are unaware that they have it. Of those who know they have diabetes, only half receive 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 700,000 Americans have proliferative diabetic retinopathy, with an annual incidence of 65,000. Approximately 500,000 persons have clinically significant macular edema, with an annual incidence of 75,000.
Diabetes is responsible for approximately 8000 eyes becoming blinded each year, meaning that diabetes is responsible for 12% of blindness.[12] The rate is even higher among certain ethnic groups. An increased risk of diabetic retinopathy appears to exist in patients of Native American, Hispanic, and African American heritage.
With increasing duration of diabetes or with increasing age since its onset, there is a higher risk of developing diabetic retinopathy and its complications, including diabetic macular edema or proliferative diabetic retinopathy.
For more information, see Macular Edema.
Prognosis
Prognostic factors that are favorable for visual loss include the following:
- Circinate exudates of recent onset
- Well-defined leakage
- Good perifoveal perfusion
Prognostic factors that are unfavorable for visual loss include the following:
- Diffuse edema/multiple leaks
- Lipid deposition in the fovea
- Macular ischemia
- Cystoid macular edema
- Preoperative vision of less than 20/200
- Hypertension
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.
The Early Treatment for Diabetic Retinopathy Study has found that laser surgery for macular edema reduces the incidence of moderate visual loss (doubling of visual angle or roughly a 2-line visual loss) from 30% to 15% over a 3-year period. The Diabetic Retinopathy Study has found that adequate scatter laser panretinal photocoagulation reduces the risk of severe visual loss (< 5/200) by more than 50%.[13, 14]
Patient Education
One of the most important aspects in the management of diabetic retinopathy is patient education. Inform patients that they play an integral role in their own eye care.
Excellent glucose control is beneficial in any stage of diabetic retinopathy. It delays the onset and slows down the progression of the diabetic complications in the eye.
The following symptoms and/or health concerns must be addressed in any patient education program for those with diabetic retinopathy:
- Systemic problems (eg, hypertension, renal disease, and hyperlipidemia) may contribute to disease progression.
- Smoking, although not directly proven to affect the course of the retinopathy, may further compromise oxygen delivery to the retina. Therefore, all efforts should be made in the reduction, if not outright cessation, of smoking.
- Visual symptoms (eg, vision changes, floaters, distortion, redness, pain) could be manifestations of disease progression and should be reported immediately.
Diabetes mellitus, in general, and diabetic retinopathy, in particular, are progressive conditions, and regular follow-up care with a physician is crucial for detection of any changes that may benefit from treatment.
For excellent patient education resources, see eMedicine's Diabetes Center. Also, visit eMedicine's patient education article Diabetic Eye Disease.
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