Retinopathy

Diabetes is the leading cause of new cases of blindness in individuals between the ages of 20 and 74 years. Ninety percent of patients with diabetes will have retinopathy after 15 years of known duration of disease, and 21% of patients will have retinopathy at the time of diagnosis. Retinopathy is responsible for 12,000-24,000 cases of blindness each year. It is critical for the primary care physician to realize that waiting until the diabetic patient complains of blurred vision may be too late, because permanent retinal injury with visual loss may have already occurred.

There are several interesting theories as to how hyperglycemia wreaks havoc on the retina (4). These include the following:

1. Neovascularization. In response to local tissue ischemia, vascular endothelial growth factor (VEGF) stimulates the growth of new blood vessels in nonperfused areas. This

From: Type 2 Diabetes, Pre-Diabetes, and the Metabolic Syndrome: The Primary Guide to Diagnosis and Management By: R. A. Codario © Humana Press Inc., Totowa, NJ

neovascularization causes blood vessels to grow between the internal surface of the retina and the vitreous gel.

2. Capillary occlusion. In the hyperglycemic state, the white blood cells may express more molecules on their surfaces, called integrins. Integrins can interact with the capillary endothelial cells that express intercellular adhesion molecules (ICAMS), which make the white cells adhere to the capillary walls. This adhesion causes the capillaries to become plugged and interferes with white-cell passage, progressively depriving larger areas of the retina of perfusion. Initially, surrounding capillaries can compensate by accepting increased flow, but this autoregulation eventually fails and wider retinal areas become compromised.

3. Exudative edema and leakage. White cells that have adhered to the endothelial surface release products that increase permeability. With increased permeability of the endo-thelium, production of VEGF is increased, which allows fluid to leak into the retina, resulting in tissue edema. This edematous fluid and cholesterol begins to accumulate in the retina, impairing visual acuity.

4. Fibrosis. With neovascularization there is a proliferation of fibrous tissue, which causes local and widespread vitreous gel retraction, tearing additional blood vessels and resulting in hemorrhage between the vitreous gel and the retina. This can result in floaters or diffuse visual loss. Hemorrhaging can produce more fibrosis, which can cause further retinal distortion and detachment and additional visual loss.

Diabetic retinopathy can be divided into background and proliferative retinopathy. Background retinopathy involves microaneurysms, intraretinal hemorrhages, clinically significant macular edema, venous beading, cotton mole spots, intraretinal microvascular abnormalities, and circinate retinal abnormalities. Proliferative diabetic neuropathy can include surface neovascularization, dysneovascularization, and subsequent complications of proliferation (including vitreous hemorrhaging and fraction retinal detachments). Although the retina may appear to be normal on clinical examination, several biological and physiological changes are occurring at the cellular level, accompanied by alterations in retinal blood flow and leukocyte adhesion.

Diabetic retinopathy tends to progress from the mild nonproliferative form, simply manifesting increased vascular permeability, to the moderate and severe non-proliferative form, which involves vascular alterations closer to the finer proliferative form, and is characterized by neovascularizations on the retina and the posterior portion of the vitreous.

Visual loss from diabetic retinopathy can occur as a result of preretinal or vitreous hemorrhaging from neovascularization, distortion of the retina from new blood vessel formation and contraction of fibrous tissue resulting in retinal detachment and subsequent irreversible vision loss, and capillary nonperfusion or macular edema (5).

The primary physician should understand the importance of preventing or delaying the onset of progression of diabetic retinopathy, particularly while the individual is asymptomatic. Referral to an ophthalmologist is important at the time of diagnosis of diabetes. Timely intervention with laser photocoagulation can prevent visual loss in a large percentage of patients who have severe nonproliferative or early proliferative diabetic retinopathy.

Clinical presentations of diabetic retinopathy can be varied, with the most common presentation being asymptomatic individuals. However, other presentations can include sudden visual loss, marked retinal lipid exudation in association with increased hyperlipidemia, marked vascular narrowing in small vessels (usually asso ciated with hypertension), and transient worsening of retinopathy, which can occur despite tight control.

Sudden visual loss is usually the result of the following:

1. Retinal vascular occlusion.

2. Vitreous hemorrhaging, which usually presents as strings or spots in the vision.

3. Central nervous system stroke.

4. Sudden onset of bilateral macular edema, usually associated with cardiac or renal decompensation or severe anemia.

5. Lens changes caused by blood sugar alterations.

Clinical trials have shown the relationship of glycemia to the progression of diabetic retinopathy; progression to proliferative retinopathy is more likely with the highest A1-C quartiles. The DCCT trial in patients with type 1 diabetes demonstrated that intensive glycemic control can significantly reduce the risk of retinopathy compared with conventional therapy, and that this benefit also extends to existing retinopathy ( 6).

The UKDPS trial (7) showed a similarly decreased risk, with a relative onset of 21% with a 12-year follow-up.

Recent research has shown that vasoactive endothelial-derived growth factor and protein kinase C play important roles in the progression of diabetic retinopathy. Clinical trials using inhibitors of protein kinase C for both prevention and treatment are in progress.

Laser photocoagulation therapy performed by an ophthalmological surgeon plays an important role in patients with nonproliferative diabetic retinopathy. This is why it is essential for diabetic patients to undergo regular ophthalmological examination, even when their vision seems to be normal. Ophthalmological examination should be performed at diagnosis of diabetes and yearly thereafter.

Nonproliferative or background retinopathy is usually characterized by the microaneurysms and intraretinal hemorrhaging that appear similar to dots and blots. Macular edema can occur in these individuals if a significant amount of fluid leaks into the macular area where central vision originates. The presence of macular edema is suggested by the presence of hard exudates in the macular area.

Advanced background retinopathy is sometimes referred to as preproliferative retin-opathy. Individuals with preproliferative retinopathy have an increased risk of progression to fine proliferative retinopathy. This stage is characterized by soft cotton-wool exudates, irregularly dilated and tortuous retinal capillaries, intraretinal neovascularization, and beading of the retinal veins (8).

Proliferative retinopathy imparts the most serious threats to vision. The neovascularization in this abnormality usually involves more than one-third of the optic disc, and these fragile vessels are prone to bleeding and disruption of retinal function. This bleeding can cause cobwebs or floaters, or retinal detachments that result from contraction of fibrous tissue.

In symptomatic patients with hard exudates near the macula, any proliferative or preproliferative characteristics in the first trimester of pregnancy should have a careful ophthalmological evaluation. Alarm symptoms include blurry vision (persisting for >1-2 days when not associated with a change in blood glucose), cobwebs, flashing lights or black spots in the field of vision, or sudden loss of vision in one or both eyes.

Retinal hemorrhaging, neovascularization covering more than one-third of the optic disc, or macular edema places patients at extremely high risk. The Early Treatment

Diabetic Retinopathy Study (ETDRS) (9) revealed that argon laser photocoagulation applied locally can be extremely effective in stabilizing vision and treating macular edema.

Photocoagulation has slowed the progression of visual loss in cases of macular edema and improved vision by as much as 50% when used as a preventative measure. Patients with proliferative retinopathy and high-risk characteristics are usually given panretinal laser treatments with a scattered pattern of 1200-1600 burns applied uniformly throughout the periphery of the retina, avoiding the macular area (10).

Significant retinal detachments and large vitreous hemorrhages may require vitrectomy. This is usually reserved for patients with poor vision. Hypertension can be a significant independent risk factor in causing and aggravating retinopathy in patients with type 2 diabetes as well as increasing the risk for macular edema.

Clinical trials have shown that elevated systolic blood pressure may significantly increase the risk of retinopathy in patients with type 2 diabetes. Most studies confirm an association not only with systolic but also with diastolic hypertension. In the UKPDS trial, blood pressure decreases of 10 mmHg systolic and 5 mmHg diastolic reduced diabetic microvascular complications after approximately 8 years by 37%.

Several mechanisms are postulated for the aggravation and promotion of diabetic retinopathy by hypertension. These include the following:

1. Increased retinal endothelial damage.

2. Loss of retinal vascular autoregulation.

3. Increased expression of VEGF, resulting in proliferation of small vessels and worsening of retinopathy.

Several clinical trials have confirmed that microalbuminuria, macroalbuminuria, and/ or proteinuria is related to progression of retinopathy. Close to 70% of patients with type 2 diabetes on dialysis have some form of retinopathy. This is important to keep in mind, particularly in patients with impaired renal function, because retinopathy may also be progressing (11).

An interesting association has been found between anemia and retinopathy, particularly because anemia is more common in patients with renal failure. Next to hyperglycemia, anemia has now been found to be the second highest risk factor for subsequent development of diabetic retinopathy; patients with hemoglobins less than 12 were twice as likely to develop diabetic retinopathy in a recently completed Finnish trial.

The ETDRS trial (9) showed that severe visual loss and iris peripheral retinopathy were associated with a low hematocrit, and that increases in hematocrit from 29.6 to 39.5% after treatment with erythropoietin (Procrit, Epogen) resolved macular edema in three of five patients evaluated.

Although there is some literature to support the association between smoking and diabetic retinopathy, the association is much stronger with macrovascular disease and nephropathy. Lipid disturbances can also aggravate prognosis in diabetic retinopathy; elevated triglyceride levels were associated with vision loss and proliferative diabetic retinopathy in the ETDRS trial.

All intensive glucose therapeutic maneuvers (except for chlorpropamide) were associated with a clear reduction in the risk of diabetic retinopathy progression in the UKPDS trial. Lisinopril has been beneficial in slowing retinopathy progression in patients with type 1 diabetes; and captopril and the ^-blocker atenolol were beneficial in patients with type 2 diabetes in the UKPDS trial.

The antiangiogenic effects at the cellular level of the thiazolidinediones has been shown to be beneficial in neovascularization. Rosiglitazone (Avandia) inhibited VEGF-induced proliferation and migration of retinal pigment epithelial cells and directly inhibited neovascularization, thus, the thiazolidinediones might be important in preventing retinopathy (12).

The Wisconsin Epidemiologic Study of Diabetic Retinopathy (13) showed no association between aspirin use and the severity of retinopathy. This study further provided evidence that aspirin therapy did not increase the risk of vitreous hemorrhaging in diabetics with proliferative retinopathy. Thus, there is no contraindication for the use of aspirin in patients with diabetic retinopathy, although more evidence needs to be established to determine whether aspirin can actually alter the course of the disease.

Although there is insufficient data regarding the effects of clopidogrel on retinopathy, both the Ticlopidine Microangiopathy of Diabetes Study and the Aspirin Microangiopathy of Diabetes Study (14) confirmed that these agents can be used safely in the presence of retinopathy, and fewer microaneurysms were found in the aspirin group. The use of antiplatelet agents has not been associated with an excess number of hemorrhagic complications in patients with diabetes; therefore, there is no contraindication for this approach for diabetic patients with acute myocardial infarctions (15).

Further investigation shows that emerging agents may be effective in treating retin-opathy. These agents include aldose reductase inhibitors, somatostatin analog, and VEGF inhibitors. Whether vitamin E therapy can delay the onset of progression of diabetic retinopathy is currently unclear.

Indications for surgery in diabetic retinopathy include the following (16):

1. Visually debilitating persistent vitreous blood.

2. Advancing neovascularization despite maximum photocoagulation.

3. Significant and severe vascular proliferation.

4. Severe fibrous proliferation.

5. Severe proliferation in which vitreous hemorrhage precludes photocoagulation.

6. Bridging premacular fibrosis.

7. Progressive macular distortion resulting from fibrosis.

8. Severe posterior pole hemorrhage without significant vitreous detachment.

Because diabetic retinal disease presents a significant morbidity problem to the patient, prompt identification and early ophthalmological referral is important in not only prevention but also treatment.

The prevention and/or treatment of diabetic retinopathy involves the following:

1. Controlling blood glucose.

2. Controlling blood pressure.

3. Retinal laser photocoagulation, including panretinal scatter photocoagulation for pro-liferative retinopathy or neovascular glaucoma, or focal photocoagulation for macular edema.

4. Vitrectomy for nonclearing vitreous hemorrhage or traction detachment of the retina.

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