2 Proliferative Diabetic Retinopathy

Ronald P. Danis and Matthew D. Davis

CONTENTS

DEVELOPMENT AND NATURAL HISTORY

SYSTEMIC ASSOCIATIONS

OTHER TYPES OF INTRAOCULAR NEOVASCULAR

PROLIFERATION IN DIABETES

MANAGEMENT OF PROLIFERATIVE DIABETIC RETINOPATHY

REFERENCES

ABSTRACT

Proliferative diabetic retinopathy continues to be a major cause of blindness throughout the world. The natural history demonstrates that its development is primarily related to progressive retinal ischemia from diabetic retinopathy. The primary complications leading to vision loss, tractional retinal detachment and vitreous hemorrhage, are dependent upon the relationship between the neovascular tissue and the vitreous. The major risk factors are duration of diabetes and the level of glycemic control of the patient, with glycemic control being the modifiable risk factor as demonstrated in the DCCT/EDIC and UKPDS trials. Timely treatment with laser photocoagulation has been demonstrated to be of immense value for the preservation of vision, as reported by the DRS, ETDRS, and other studies. Pars plana vitrectomy is indicated for some patients with vitreous hemorrhage, retinal detachment, and other complications. With growing understanding of the cell biology of diabetes complications, pharmacologic therapies are emerging as promising treatment options.

Key Words: Diabetes mellitus; Diabetic retinopathy; Neovascularization; Laser photocoagulation Vitrectomy.

DEVELOPMENT AND NATURAL HISTORY

Histopathology and Early Development

Endothelial proliferation and new vessel formation in the retina are stimulated by ischemia of its inner layers secondary to regional closure of the retinal capillary bed

From: Contemporary Diabetes: Diabetic Retinopathy

Edited by: E. Duh © Humana Press, Totowa, NJ

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(1–4). Retinal hypoxia induces upregulation of genes such as hypoxia inducible factor that in turn stimulate the production of a variety of endothelial mitogens, most notably vascular endothelial growth factor (VEGF). Chronic ischemia also produces a localized low-grade inflammatory response within the vessels, with the subsequent migration and stimulation of immunogenic cells in the tissue, which also produce a variety of mitogenic cytokines. These growth factors promote a neovascular (NV) response locally and by diffusing through the vitreous to other areas of the retina, to the optic disc, and into the anterior chamber (5–7).

The background of intraretinal lesions against which preretinal new vessels arise is variable. The risk of proliferative diabetic retinopathy (PDR) is greatest in eyes with severe NPDR (nonproliferative diabetic retinopathy, also called preproliferative retinopathy), characterized by the presence of soft exudates (cotton-wool patches), intraretinal microvascular abnormalities (IRMAs, a term chosen so as to be neutral about whether these abnormal vessels represent intraretinal new vessels or dilated preexisting vessels), venous beading, and extensive retinal hemorrhage or microaneurysms (Fig. 1). In the Diabetic Retinopathy Study (DRS) severe NPDR was basically defined as the presence of at least three of the four above-mentioned characteristics, each generally involving at least two quadrants of the fundus. About 50% of such eyes assigned to the untreated control group had developed PDR within 15 months (8). The presence and extent of retinal and optic nerve head NV in the diabetic retina are roughly correlated with the extent of capillary loss on fluorescein angiography (1).

Although there is little doubt that the presence of severe NPDR is predictive of subsequent NV, the characteristic intraretinal lesions are not always present when preretinal

Fig. 1. Severe nonproliferative diabetic retinopathy. Two prominent cotton-wool spots (soft exudates) are noted on the left side with a large blot hemorrhage between them. Venous beading is present where the superior branch of the superotemporal vein passes by the upper exudate. On the right are two faint soft exudates (arrows) and many intraretinal microvascular abnormalities. (Courtesy Early Treatment Diabetic Retinopathy Study Research Group.)

new vessels are first recognized. A possible explanation for this is the relatively transient nature of some of these lesions. Soft exudates usually disappear within 6–12 months. Blot hemorrhages and IRMA tend to disappear after extensive capillary closure, when the number of small vascular branches decreases and some small arterioles become white threads, producing a picture aptly described as featureless retina (Fig. 2).

Some, but probably a minority, of the IRMAs eventually develop into neovascular tissue (9). IRMAs feature endothelial proliferation and vascular caliber larger than retinal capillaries with loose adventitia, similar to NV lesions. A critical distinction is that IRMAs lie exclusively below the level of the internal limiting membrane (ILM) of the retina, whereas NV lies above the ILM, growing along the interface between the retina and posterior vitreous face, where they can become elevated as vitreous detachment occurs.

Although new vessels may arise anywhere in the retina, they are most frequently seen within 10–15 mm of the optic disc, and on the disc itself (Davis (10): 69% of 155 eyes with PDR; Taylor and Dobree (11): 73% of 86 eyes). In the DRS, among 1,377 control group eyes with new vessels present in baseline photographs, 15% had new vessels only on or within 1 disc diameter (DD) of the disc, 40% had new vessels only outside this zone, and 45% had new vessels in both zones (12).

Neovascularization of the optic disc (NVD) begins as fine loops or networks of vessels lying on the surface of the disc or bridging across the physiologic cup. The most satisfactory examining methods are those that provide a magnified stereoscopic view, either biomicroscopy with contact or precorneal lens or stereoscopic 30-deg photography. If any doubt remains, it can usually be resolved by fluorescein angiography, which demonstrates the profuse leakiness characteristic of preretinal new vessels. Wide-angle angiography can be helpful in identifying ischemia and NV, particularly when NV

Fig. 2. Early proliferative diabetic retinopathy. New vessels form a small wheel-like network (arrow) in the superotemporal quadrant of an eye with venous beading, cotton-wool spots (soft exudates), intraretinal microvascular abnormalities, and blot hemorrhages. (Courtesy Early Treatment Diabetic Retinopathy Study Research Group.)

lesions are suspected (e.g., due to recent vitreous hemorrhage) but are not found on clinical examination. The possibility that the vitreous hemorrhage may come from a peripheral retinal tear, unrelated to diabetic retinopathy, should be kept in mind, and a careful examination of the peripheral fundus with scleral depression should be performed.

Early new vessels elsewhere (NVE) may be difficult to distinguish from IRMA, particularly if the IRMA are extensive and NVE do not yet show any of their unique features, such as formation of wheel-like networks, extension across both arterial and venous branches of the underlying retinal vascular network, accompanying fibrous proliferations, or elevation. The true nature of such borderline lesions soon becomes clear with careful follow-up.

NV requires a scaffold or matrix in which to grow (13); therefore, NV does not typically occur in areas where the vitreous has detached or has been surgically removed (14). In fact, in an eye with complete posterior vitreous detachment with severe NPDR, the clinical concern should be more for the possibility of the development of rubeosis iridis, NV of the iris, than of PDR. In some instances, small buds or “popcorn kernels” of NV may appear in eyes with vitreous separation, but such lesions rarely progress or lead to complication. Some investigators have suggested that iatrogenic induction of posterior vitreous detachment in eyes with NPDR, or drug treatment to prevent vitreous senescence and detachment, would be beneficial, since it would prevent the development and complications of PDR (15).

Proliferation and Regression of New Vessels

Initially, new vessels may be very subtle on clinical examination. Their caliber may eventually range up to that of a major retinal vein at the disc margin (Fig. 3). New vessels frequently form wheel-like networks (see Fig. 2). NV networks also may be irregular in

Fig. 3. New vessels elsewhere without prominent network formation. Over much of their course, these new vessels did not form networks. Large aneurysmal dilations were present at the end of a long new vessel loop (left arrow) and at the circumference of a partial wheel-like network (right arrow). (Courtesy Diabetic Retinopathy Study Research Group.)