Management Of Diabetic Retinopathy In The New Millennium

K.V. Chalam, M.D., FACS and James Lawler, M.D.
K.V. Chalam, M.D., FACS and James Lawler, M.D. are with the
Department Of Ophthalmology, University Of Florida School Of Medicine.

Epidemiology

Diabetic retinopathy is the leading cause of new cases of legal blindness among working age Americans. Sixteen million Americans have diabetes mellitus, but only one half are aware that they have the disease. Two forms of diabetes are recognized. Type 1, previously called juvenileonset or insulin dependent diabetes, is characterized by betacell destruction and usually leads to absolute insulin deficiency. Type 2, previously called adultonset or noninsulin dependent diabetes, is characterized by insulin resistance with an insulin secretory defect that leads to relative insulin deficiency.^1-2 Ninety percent of patients with diabetes have type 2 diabetes. Because of the disproportionately large number of patients with type 2 diabetes, this group comprises a substantial proportion of patients with visual impairment secondary to diabetic retinopathy, even though type I diabetes is associated with more frequent and more severe ocular complications.

Risk Factors

Duration of diabetes is a major risk factor associated with the development of diabetic retinopathy. After 5 years, approximately 25% of type I patients have retinopathy. After 10 years, almost 60% have retinopathy, and after 15 years, 80% have retinopathy. Proliferative diabetic retinopathy (PDR), the most visionthreatening form of the disease, is present in approximately 25% of type I patients with 15 years' duration of the disease.

Of type 2 patients who have a known duration of diabetes of less than 5 years, 40% of those patients taking insulin and 24% of those not taking insulin have retinopathy. These rates increase to 84% and 53%, respectively, when the duration of diabetes has been documented up to 19 years. Proliferative retinopathy develops in 2% of patients who have diabetes for less than 5 years and in 25% of patients who have diabetes for 25 years or more.

There is general agreement that the duration of diabetes and the severity of hyperglycemia are the major risk factors for developing retinopathy. The severity of hyperglycernia is the key alterable risk factor associated with the development of diabetic retinopathy. Support for this association is found in results of clinical trials and epidemiologic studies.^3-4

After retinopathy is present, duration of diabetes appears to be a less important factor than hyperglycernia for progression from earlier to later stages of retinopathy. There is less agreement between studies concerning the importance of other factors such as age, type of diabetes, blood pressure, clotting factors, renal disease, and use of angiostensinconverting enzyme (ACE) inhibitors. Many of these factors are associated with the significant cardiovascular morbidity and mortality and other complications associated with diabetes.

Natural History

Nearly all patients with diabetes of 20 or more years' duration will develop some degree of retinopathy. Diabetic retinopathy in its earliest stages is characterized by retinal vascular abnormalities including microaneurysms, intraretinal hemorrhages, and cotton wool spots. Increased retinal vascular permeability that occurs at this or later stages of retinopathy results in retinal thickening or edema (Figure 1). It is called clinically significant macular edema if the center of the macula is involved (Figure 2). Signs of increasing ischemia include venous abnormalities (beading, duplication, etc.), IRMA, and more severe and extensive vascular leakage characterized by increasing retinal hemorrhages and exudation.

Diabetic retinopathy is broadly categorized as nonproliferative or proliferative. In the nonproliferative stage, retinopathy is categorized further into four levels of severity: mild, moderate, severe, and very severe. The more advanced stage of diabetic retinopathy is characterized by the onset of retinal neovascularization induced by the retinal ischemia from microangiopathy of the vessels (Figure 3). New vessels at the optic disc and new vessels elsewhere in the retina are prone to bleed, resulting in vitreous hemorrhage (Figure 4). These new vessels may undergo fibrosis and contraction; this and other fibrous proliferation may result in epiretinal membrane formation, vitreoretinal traction bands, retinal tears, and traction or rhegmatogenous retinal detachments. Neovascular glaucoma can result from new vessels extending from the iris to the trabecular meshwork. Medical treatment such as aspirin therapy has been evaluated for the prevention and retardation of diabetic retinopathy. The ETDRS found no evidence that aspirin therapy retards or accelerates the progression of diabetic retinopathy, or that it causes more severe or more longlasting vitreous hemorrhages in patients with proliferative retinopathy.

Treatment

In general, laser photocoagulation is advised for patients with highrisk proliferative disease and for patients with CSME. Neovascularization of the anterior chamber angle is also an indication for laser photocoagulation surgery. Argon laser photocoagulation is the standard, most widely used technique for treating diabetic retinopathy. In a randomized, controlled clinical trial of scatter laser photocoagulation with either argon or krypton, there was no statistically significant difference in the clinical effect of these two wavelengths in the rates of regression of highrisk PDR.

Three different methods of laser surgery are used, depending on the pathology being treated. Scatter (panretinal) photocoagulation retards development and facilitates regression of new vessels on the optic nerve head and the retinal surfaces or in the anterior chamber angle. Focal photocoagulation refers to direct laser treatment applied to leaking microaneurysms in the posterior fundus to reduce or eliminate macular edema. Grid photocoagulation is a laser technique in which a grid pattern of burns is applied to the areas of edema apparently arising from abnormalities indicated by leakage or capillary nonperfusion on fluorescein angiography.

High Risk PDR

DRS highrisk characteristics for severe visual loss with highrisk PDR include:

• New vessels within one disc diameter of the optic nerve head that are larger than 1/3 disc area.
• Vitreous or preretinal hemorrhage associated with less extensive new vessels at the optic disc, or with new vessels elsewhere 1/2 disc area or more in size.

Most patients with highrisk PDR should receive laser scatter treatment without delay. The risk of severe visual loss among patients with highrisk PDR can be substantially reduced by means of scatter photocoagulation. Scatter photocoagulation causes regression of neovascularization. Following scatter photocoagulation, additional laser treatment may be required.⁸ Indications for additional treatment may include the following:

• Failure of the neovascularization to regress
• Increasing neovascularization of the retina or iris ⁹
• New vitreous hemorrhage
• New areas of neovascularization

For patients who have CSME in addition to highrisk PDR, focal and panretinal photocoagulation at the first treatment session may be considered. Since panretinal photocoagulation can exacerbate macular edema, the scatter treatment is often divided into two or more treatment sessions. Fluorescein angiography is sometimes helpful in assessing the extent of capillary nonperfusion, identifying subtle areas of neovascularization, and establishing the cause of documented loss of visual acuity.

Early vitrectomy to clear vitreous opacities may be undertaken to permit photocoagulation in some patients who have vitreous opacities and active proliferation of neovascularization. Vitrectomy also may be helpful for selected patients who have extensive active neovascular or fibrovascular proliferation. The value of early vitrectomy tends to increase with the increasing severity of neovascularization.

High Risk PDR Not Amenable To Photocoagulation

Vitreous surgery is frequently indicated in patients with tractionmacular detachment (particularly of recent onset), combined traction-rhegmatogenous retinal detachment, vitreous hemorrhage precluding scatter photocoagulation, severe PDR, and nonclearing vitreous hemorrhage. Patients with vitreous hemorrhages and rubeosis iridis also should be considered for prompt vitrectomy and intraoperative panretinal photocoagulation.

The DRVS showed that early vitrectomy for type I patients with severe vitreous hemorrhage is beneficial. Early vitrectomy for type II diabetic patients with severe nonclearing vitreous hemorrhage should probably be considered, particularly if active neovascularization is present. Rarely, pars plana vitrectomy to manage carefully selected patients with diffuse CSME unresponsive to previous macular laser photocoagulation may improve visual acuity when significant vitreomacular traction is present.

The main causes of visual loss in diabetic retinopathy are the result of complications of the microvascular abnormalities: PDR that results in tractional retinal detachment involving the macula and / or non-clearing vitreous hemorrhage or neovascular glaucoma, and/or macular edema or macular ischemia. Macular edema can occur in the presence of NPDR or PDR.

The natural history and progression of NPDR and PDR, as well as visual outcomes and treatment efficacy for the complications of diabetic retinopathy, were addressed in four major clinical trials: the Diabetes Control and Complications Trial (DCCT), the Diabetic Retinopathy Study (DRS), the Early Treatment Diabetic Retinopathy Study (ETDRS), and the Diabetic Retinopathy Vitrectomy Study (DRVS). The outcomes of these trials guide current management of diabetic retinopathy.^5-6

Prevention And Early Detection

Although diabetes itself cannot be prevented currently, in many cases its blinding complications can be moderated markedly. Treatment can yield significant savings compared to the direct costs for those disabled by vision loss. Analyses from two clinical trials show that the treatment for diabetic retinopathy may be 90% effective in eradicating severe vision loss (visual acuity less than 5/200) with present treatment strategies. Although effective treatment is available, the number of patients with diabetes referred by their primary care physicians for ophthalmic care is far below the guidelines of the American Diabetes Association and the American Academy of Ophthalmology (Table 1). Ophthalmologists, physicians who care for diabetic patients, and patients themselves, need to be educated about indications for referral.

The results of the DCCT showed that the development and the progression of diabetic retinopathy in patients with type 1 diabetes can be delayed if glucose concentrations are maintained in the nearnormal range. After 3 years of intensive treatment to reduce glucose levels, the DCCT showed that among patients without retinopathy, the development of any retinopathy could be reduced significantly (by 75%) but not prevented completely over the 9year course of the study. The benefit of strict glucose control also was evident in patients with existing retinopathy (50% reduction in the rate of progression of retinopathy compared to controls). Beyond 3.5 years of followup, the risk of progression was five times lower with intensive insulin treatment than with conventional treatment.

Vitreous surgery has the potential for serious complications, including severe visual loss and eye pain. it should not be undertaken without careful consideration of the potential risks and benefits. For example, if the risk of the spread of extramacular traction retinal detachment into the macula is low, it is best to defer vitreous surgery unless definite progression threatening the vascular center is documented or the patient has another indication for vitreous surgery. Deferral is particularly appropriate when new vessels have regressed substantially and retinopathy appears to be inactive.

Counseling / Referral

While it is clearly the responsibility of the ophthalmologist to manage eye disease, it is the realm of the patient, family physician, internist, or endocrinologist to manage the systemic condition of the patient with diabetes. The ophthalmologist should communicate with the attending physician. Where appropriate, diabetic patients should be under the care of an ophthalmologist experienced in the management of diabetic retinopathy. Ophthalmologists with specialized knowledge and experience in managing the disease are best able to detect and treat serious disease.

Some patients with diabetic retinopathy will lose substantial vision despite being treated according to the recommendations in this document. Those that fail to respond to surgery and those for whom further treatment is unavailable should be provided with proper professional support, counseling, rehabilitative, or social services. Referral to an individual experienced in lowvision rehabilitation care with the ability to provide lowvision aids can also be useful. It is important for ophthalmologists to be sensitive to and assist in addressing implications of visual impairment in patients with diabetes.

REFERENCES

1. American Academy of Ophthalmology. Diabetic Retinopathy. Preferred Practice Pattern. San Francisco: American Academy of Ophthalmology, 1998
2. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care. 1998; 21(Supp): S5SI9.
3. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulindependent diabetes mellitus. New Engl J Med. 1993; 329: 97786.
4. Davis MD, Fisher MR, Gangnon RE, et al, for the Early Treatment Diabetic Retinopathy Study Research Group. Risk factors for highrisk proliferative diabetic retinopathy and severe visual loss. ETDRS Report #18. Invest Ophthalmol Vis Sci. 1998; 39:23252.
5. The Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. ETDRS Report No. 2. Ophthalmology. 1987; 94:76174.
6. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Fouryear results of a randomized trial. DRVS Report No. 5. Arch Ophthalmol. 1990; 108: 95864.
7. Ferris F. Early photocoagulation in patients with either type I or type 11 diabetes. Trans Am Ophthalmol Soc. 1996; 94:50537.
8. Jacobson DR, Murphy RP, Rosenthal AR. The treatment of angle neovascularization with panretinal photocoagulation. Ophthalmology. 1979; 86:12705.

September, 2000/ Jacksonville Medicine

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