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Retinal Findings of Diabetic Retinopathy
Jeremy Chess, MD
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Examination of the ocular fundus can provide valuable information for the physician.
Examination of the retina may disclose a previously unrecognized condition as well as
confirm evidence for a specific diagnosis. Retinal findings may be pathognomonic for
unsuspected systemic disorders or may characterize the severity of previously detected
conditions.
From time to time, Dr Chess and Dr Fischer will describe ophthalmoscopic abnormalities
that characterize certain degenerative, vascular, immunologic, infectious, and hereditary
diseases.
Diabetic retinopathy has become a major cause of blindness in the United States, accounting for approximately 10% of new cases of legal blindness each year. Since early detection and intervention can reduce the morbidity of this condition, yearly ocular examination (with pupillary dilation) is mandatory. The risk of retinopathy increases the longer a patient has had diabetes. For example, retinopathy develops in one third of patients who have had diabetes for 10 years. This number increases to 70% after 20 years and 90% after 30 years. Of the 90%, proliferative diabetic retinopathy will develop in 30% and may lead to complete visual loss. Approximately 5 % of diabetics will lose vision after 30 years. Many theories have been proposed to explain the retinal changes observed in patients with diabetes mellitus. Although the fundamental pathogenetic mechanisms remain obscure, retinal hypoxia appears to play a central role. The ophthalmoscopic abnormalities seen are categorized by several stages, which represent a continuum of diabetic retinopathy from the mildest to most severe form.
Retinal vascular dilation without noticeable signs of retinopathy may be the earliest sign of diabetic retinopathy. Other findings include breakdown of the blood retina barrier, which can be demonstrated by specialized tests such as vitreous fluorophotometry, and markedly increased blood flow, as shown by laser Doppler techniques. Retinal micro circulatory changes as well as systemic factors contribute to retinal hypoxia, which itself may be the stimulus for this chronic vasodilation and subsequent increase in blood flow. Hemoglobin Alc has been implicated in the development of retinal hypoxia. In normoglycemic individuals, hemoglobin Alc levels are approximately 50%; in diabetics the levels often range between 10% and 20%. The significance of these elevated levels relates to their effect on oxygen diffusion. With an increase in the affinity of oxygen for hemoglobin, the oxygen-releasing properties of 2,3-diphosphoglyceric are minimized; thus, tissue oxygenation is lowered at any given oxygen pressure. This hypoxia may stimulate retinal autoregulatory mechanisms, causing vasodilation. Changes in both blood and vessel walls may exacerbate the situation. The basement membrane in diabetic capillaries is abnormal, characterized by progressive thickening and hyalination over the course of the disease. Function of the small blood vessels is further compromised by the loss of capillary pericyte cells, a well-documented feature of diabetic retinopathy believed to be a precursor of abnormal endothelial cell proliferation. These alterations in the vasculature in diabetic patients apparently contribute to the hypoxic stimulus. The normal retinal vasculature is shown in Fig1 |
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| Fig 1. Retinal vasculature (red-free photograph) |
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Additional circulatory findings in diabetes mellitus include increased levels of fibrinogen, -2 macro globulin, and thromboxane A2. The resultant increased blood viscosity and coagulability may
predispose to vascular occlusion, particularly in vessels that are already damaged.
Chronic elevation of blood glucose levels is also damaging to normal capillary function. High intra cellular levels of sorbitol are produced when glucose metabolism is shunted to the polyol pathway. This causes an osmotic gradient that leads to intracellular edema and impairs function of capillary endothelium and pericytes. Reduced diffusion of nutrients and oxygen further contributes to retinal hypoxia. Prolonged damage to vessels leads to hyperpermeability, hemorrhage, and formation of exudate. A remarkable feature of the ophthalmoscopic examination at the earliest stage of diabetic retinopathy may be the absence of any visual abnormality. Subtle dilation of the retinal arterioles and venules may be the only suggestion of abnormality despite the microscopic changes in blood vessel structure. The characteristic features of diabetic retinopathy do not become apparent for some time.
Persistent vasodilation leads to permanent damage to blood vessel walls and advancing signs of retinopathy. This stage of disease is characterized by continual loss of capillary pericytes and endothelial damage. The ensuing vascular incompetence allows extravasation of blood and fluid. Clinically, small focal hemorrhages, microaneurysms, hard exudates, and retinal edema may be observed. Microaneurysms are 15- to 50-Am diameter dilations in capillary walls and consist of focal proliferations of endothelial cells. Clinically, they appear as well-circumscribed red dots. Fluorescein angiography may be of help in making the difficult distinction between microaneurysms and small hemorrhages (Fig 2). |
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| Fig 2. (A) Fundus in early phase of background diabetic retinopathy with posterior microaneurysms and exudates. (B) Fluorescein angiogram of A. |
| Intraretinal hemorrhage is a prominent feature of diabetic retinopathy (Fig 3). The so-called dot-and-blot type of hemorrhage is classically associated with diabetes. These hemorrhages vary in size but are usually less than one half of the diameter of the optic disk; the margins tend to be less well defined than are those of microaneurysms. Dot-and-blot hemorrhages are found in the middle retinal layers. The vertical orientation of cells in these layers restricts the diffusion of the hemorrhage to small pockets, causing a "blotchy" ophthalmoscopic appearance. |
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| Fig 3. Prominent features of diabetic retinopathy: intraretinal hemorrhages, exudated, and cytoid bodies. The dot-and-blot type of hemorrhage is classically associated with diabetes. |
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In contrast, flame-shaped hemorrhages are found in the innermost retina. Because they are located in the nerve fiber layer, these hemorrhages have feathery margins and a radial configuration and
obscure underlying retinal detail.
Large hemorrhages in diabetic retinopathy are usually indicative of neovascularization, a phenomenon associated with the most advanced stage of disease (Fig 4). Because new vessels grow on the surface of the retina, these hemorrhages occur either between the retina and vitreous (the so-called preretinal or subhyaloid space) or in the vitreous cavity itself. Unrestricted by any significant anatomic obstacle, preretinal hemorrhages may be large and often assume a boat shape because of gravitational forces (Fig 5). Hemorrhages into the vitreous cavity may be localized but commonly cause a diffuse, reddish haze that prevents adequate visualization of the fundus. |
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| Fig 4. Early proliferative diabetic retinopathy with retinal neovascularization. | Fig 5. Proliferative diabetic retinopathy with preretinal hemorrhage. |
| Areas of hard exudate are frequently associated with advanced retinopathy (Fig 6). These hpoprotein accumulations are located in the outer plexiform layer and result from selective resorption of fluid that leaks from damaged blood vessels or microaneurysms. On ophthalmoscopic examination, the hard exudates appear as discrete, waxy, yellow-white deposits within the retina. They may form clusters or rings when surrounding a damaged, leaking blood vessel or microaneurysm, or they may occasionally form large plaques. When located within the macula, the deposits typically form a ring around the fovea and, by disrupting normal photoreceptor function, may threaten vision. |
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| Fig 6. Extensive retinal exudation in background diabetic retinopathy |
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Retinal edema, another prominent feature of advanced retinopathy, is often found in close association with areas of hard exudate or microaneurysms. Once again, blood vessel damage and
subsequent fluid leakage are causative. When located within the macula, chronic accumulations of fluid reduce central visual function.
Fluorescein angiography may be required to detect early macular edema. In this procedure, the patient is given a 5-mL injection of 1007o fluorescein dye. A fundus camera equipped with the appropriate filters is then used to photograph sequentially the retinal vasculature as it is being traversed by fluorescein. The normal blood retina barrier prevents passage of fluorescein into the surrounding retina. However, alterations in the diabetic vasculature permit identification of pathologic changes, including increased vascular permeability, capillary closure, microaneurysm formation, intraretinal edema, and neovascularization.
As blood vessel abnormalities worsen, retinal hypoxia continues to increase. Occlusion of terminal arterioles and capillaries produces localized ischemic infarctions (cytoid bodies or cotton-wool spots) in the nerve fiber layer. These lesions appear as white to gray-white areas with fluffy indistinct borders and, like the flame-shaped hemorrhages located in this layer, obscure underlying retinal details. When seen in large numbers, cytoid bodies are an ominous prognostic sign, indicating large regions of capillary nonperfusion and worsening hypoxia. They may also indicate the presence of associated systemic hypertension. Another common finding in the preproliferative phase is a change in the appearance of the retinal veins. The caliber of the venules greatly increases. These vessels also assume a "beaded" or "sausage-string" appearance and become tortuous (Fig 7). |
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| Fig 7. Retinal nonperfusion and disk neovascularization. Tortuous and beaded vessels. |
The precursor to the formation of new retinal vessels is the development of intraretinal microvascular abnormalities-small buds of new vessel growth that remain on the retinal surface.
Clinically, these abnormalities appear as tufts of fine-caliber vessels and may be confused with dot hemorrhages. Additional vascular proliferation on the retinal surface or on the posterior vit¬
reous body represents the most advanced stage of the disease, proliferative retinopathy.When seen in large numbers, cytoid bodies are an ominous prognostic sign.
The interval between the development of nonperfusion (with cotton-wool spots and venous abnormalities) and neovascularization may be as brief as several weeks but is more often months to years. Initially, a fine network or frond at the optic disk may be difficult to identify. Additional vessel growth and the use of fluorescein angiography will facilitate diagnosis. Treatment at an early stage is more likely to lead to regression. As the disease process continues, the caliber of the new vessels increases; vessels then grow from the retinal surface toward the vitreous cavity. Increased fibrous proliferation ig associated with the neovascul ar tissue at this stage. If vascular regression occurs, the fibrous bands will remain. The appearance of neovascularization at the interface between perfused and nonperfused retina and the growth of new vessels toward ischemic areas provide strong evidence that the hypoxic retina releases a vasogenic factor. Further support for the existence of such a factor is provided by the observation that removal of the vitreous cavity or the lens (cataract extraction) increases the incidence of new vessel formation on the iris (rubeosis iridis). Presumably, increased diffusion of a vasoproliferative factor toward the anterior segment causes the more distant proliferation on the iris. The role of the vitreous in the neovascular process remains speculative. The posterior hyaloid (vitreous) surface appears to act as a scaffold for the development of new vessels, which leak fibrin and blood products into the vitreous. Collapse of the vitreous cavity may then exert traction on the attached new vessels. Delicate new vessels tend to bleed into either the preretinal space of the vitreous cavity itself, with obvious visual consequences. Furthermore, vitreous hemorrhage hampers laser photocoagulation, necessitating the use of higher risk procedures such as cryotherapy or surgical vitrectomy. Finally, the traction exerted by neovascular membranes can lead to progressive retinal detachment (Fig 8) and the need for a vitrectomy. |
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| Fig 8. Retinal traction detachment in proliferative diabetic retinopathy. |
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