The Retina: Vascular Diseases II

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15 The Retina: Vascular Diseases II


Diabetic retinopathy remains the commonest cause of blindness in the working population and is the major cause of legal blindness in this age group in the developed world despite the present techniques of better medical control, ocular screening and photocoagulation. Total blindness due to end-stage proliferative diabetic retinopathy is now much less common but unfortunately increasing numbers of diabetic patients become visually impaired as a result of diabetic maculopathy. The natural history of diabetic retinopathy is now well understood but the sequence of the early biochemical and cellular events in the retina is not.

Diabetes predominantly affects the microvascular circulation of the retina and, apart from minimal venous dilatation in the early stages, no changes are seen in the major retinal vessels. Retinal blood flow is increased in the early stages of retinopathy possibly as an autoregulatory response to tissue hypoxia. The earliest structural changes are found in the retinal capillaries with loss of mural pericytes, thickening of basement membrane, loss of endothelial cells and capillary nonperfusion but the sequence and interrelationship of these changes is uncertain. Capillary basement membrane thickening is a common feature of diabetes in many organs but the full range of microvascular changes is unique to the retina and is not seen elsewhere in the body. The retinal capillaries are supported by a plentiful population of pericytes and a plausible hypothesis is that damage to these cells plays a fundamental role in the genesis of retinopathy. Pericytes support the capillary and also have an inhibitory influence on capillary endothelial cell proliferation through cellular transmitters. Capillary basement membrane thickening may separate pericytes from endothelial cells. Capillary endothelium is lost (some authorities believe this is the fundamental change) and this is followed by nonperfusion of the capillary and loss of the retinal capillary bed. Microaneurysms are the hallmark of diabetic retinopathy; although they are seen in a wide variety of other retinopathies they never occur in the same profusion as in diabetes. Potential causes for their appearance are mechanical weakness of the capillary wall, capillary looping, proliferation of endothelium, changes in haemodynamics or an abortive attempt to perfuse adjacent retina. As the microvascular abnormalities develop there is leakage of plasma, haemorrhage and vascular shunting. Neovascularization seems to be controlled by a complex interaction of many stimulatory and inhibitory factors released from hypoxic retina, vascular endothelium, pericytes and retinal pigment epithelium.

The underlying biochemical processes in diabetic retinopathy are far from being understood. Chronic hyperglycaemia is usually thought to be the underlying defect but the metabolic abnormalities associated with diabetes are diverse. There appear to be three major pathways of importance, these are the glycosylation of proteins, the polyol pathway and the DAG–PKC pathway. The nonenzymatic glycosylation of proteins by raised levels of glucose appears to be of importance in the development of capillary basement membrane thickening. The polyol pathway in which aldose reductase converts intracellular glucose into sorbitol through aldose reductase increases intracellular osmolarity. Clinical studies have, however, cast doubt on the importance of this pathway in human retinopathy. Diacylglycerol (DAG) is produced during glycolysis; its concentration is increased in diabetes and it is a potent activator of protein kinase C (PKC), which regulates vascular permeability and plays a significant role in the regulation of vascular endothelial growth factor (VEGF), the best understood of the neovascular growth factors. Other growth factors such as fibroblast growth factor, pigment epithelium-derived factor and insulin growth factors, also appear to be important in the neovascular response. PKC inhibitors and VEGF modulators are currently under investigation as potential treatments for diabetic retinopathy. Clinical trials have shown that aspirin does not influence diabetic retinopathy, suggesting that platelet aggregation is not an important mechanism.


The initial clinical features of diabetic retinopathy are microaneurysms, small retinal haemorrhages and small areas of capillary closure (Table 15.1). Visual acuity is commonly normal at this stage, although subclinical changes in colour vision and contrast sensitivity might be found. This is followed by vascular leakage, hard exudate and cotton-wool spots. Retinopathy may progress to compromise vision in two ways: (1) maculopathy develops with oedema, lipid exudation or ischaemia, or (2) a proliferative retinopathy occurs, in which retinal hypoxia and neovascularization predominate and reduce vision by vitreous haemorrhage or traction retinal detachment. Not uncommonly, both mechanisms coexist in the same patient. Diabetic retinopathy is staged by its clinical features. Maculopathy is classified by extent as focal or diffuse, and by mechanism as exudative, ischaemic or mixed.

Table 15.1 Classification of diabetic retinopathy

Descriptive term Features
No diabetic retinopathy (DR)  
Mild or moderate nonproliferative DR Microaneurysms, retinal haemorrhages and exudate
Severe nonproliferative DR Deep retinal haemorrhages in four quadrants, or venous beading or loops in two quadrants, or the presence of IRMAs
Proliferative DR without high-risk characteristics New vessels on the disc smaller than one-third of a disc diameter without vitreous or preretinal haemorrhages or new vessel elsewhere only
Proliferative DR with high-risk characteristics New vessels on the disc larger than one-third of a disc diameter or any new vessel with vitreous or preretinal haemorrhages
Advanced proliferative DR Tractional retinal detachment, unresolved vitreous haemorrhage, rubeotic glaucoma


Visual loss is a late event in diabetic retinopathy. Retinopathy normally develops many years after the onset of diabetes, although in some adults it may be the first presenting sign of the disease. About 25 per cent of type I diabetics have some retinopathy after 10 years of disease, whereas type II diabetics seem to develop retinopathy earlier with significant numbers being affected by 5 years after diagnosis and 50 per cent by 10 years. Diabetics lose vision as a result of either maculopathy or proliferative retinopathy. In general, type I diabetics are more likely to have proliferative retinopathy whereas type II diabetics are more likely to have maculopathy. More than 80 per cent of visual loss in diabetics is due to maculopathy, due in part to the 10-fold greater number of type II patients. These patients lose central vision but retain navigating sight. Proliferative retinopathy is much more serious as about 70 per cent of these eyes would be totally blind within 5 years from vitreous haemorrhage and retinal traction detachment if left untreated.

Risk factors for the progression of retinopathy are the duration of diabetes and the type (type I is worse than type II). Recent clinical trials have shown that meticulous long-term glycaemic and blood pressure control retards the onset and progression of diabetic retinopathy. Tightening poor glycaemic control may, however, initially markedly worsen retinopathy and cause neovascularization, possibly because initiating good control lowers retinal blood flow and exacerbates ischaemia. Careful monitoring of diabetic retinopathy when altering glycaemic control is therefore critical. Pregnancy, renal disease and cataract surgery may worsen the retinopathy whereas high myopia, optic atrophy, glaucoma, central retinal artery occlusion and carotid artery stenosis appear to protect, possibly by reducing retinal metabolic demand (Table 15.2). Diabetic retinopathy is not seen before puberty.

Table 15.2 Risk and protective factors for progression of retinopathy

Risk factors Protective factors
Duration of diabetes High myopia
Poor long-term control Optic atrophy
Tightening of poor control Glaucoma
Hypertension Carotid stenosis
Pregnancy Retinal artery occlusion
Renal failure  


Previously termed ‘background’, this is the commonest form of diabetic retinopathy. Microaneurysms, dot haemorrhages (indistinguishable from microaneurysms without fluorescein angiography) and small, deep, blotchy haemorrhages are seen in the posterior pole and become more numerous as the retinopathy progresses. Initially, NPDR tends to be most prominent in the retina temporal to the macula, possibly because this is a watershed area in the retinal circulation. Splinter haemorrhages are a feature of combined hypertensive–diabetic retinopathy. Small focal areas of closure in the capillary bed are common. Hard exudates appear in relationship to focal vascular leakage, and the occasional cotton-wool spot may be seen. Fluorescein angiography shows more extensive changes than can be seen ophthalmoscopically.


Previously the stage between background and proliferative retinopathy was called ‘preproliferative diabetic retinopathy’, but is now termed severe or very severe nonproliferative diabetic retinopathy. These patients have a substantial risk of progressing to proliferative diabetic retinopathy (PDR). Severe or very severe NPDR is characterized by signs of marked retinal hypoxia such as cotton-wool spots, capillary nonperfusion, numerous intraretinal haemorrhages, venous beading and loops, and intraretinal microvascular abnormalities (IRMAs). Cotton-wool spots have often been considered the hallmark of preproliferative diabetic retinopathy, but the Early Treatment Diabetic Retinopathy Study (ETDRS) found that IRMAs, venous changes and many deep haemorrhages were more predictive of imminent PDR. The retinopathy is defined as severe when one of the following signs is present and as very severe when two of the signs are present: (1) deep haemorrhages in four quadrants, (2) venous abnormalities in two or more quadrants, and (3) IRMAs in one or more quadrants.


This tends to occur in diabetics who have evidence of other diabetic complications with renal, vascular and neurological complications. The prognosis of these patients has improved considerably in recent years with better medical management.

The stimulus for neovascularization, as in other neovascular retinopathies, appears to be retinal hypoxia from extensive areas of retinal capillary closure. This leads to a reduction of the increased retinal blood flow which is a feature of nonproliferative retinopathy. Neovascularization starts to appear from the capillaries on the venous side of the circulation on either the optic disc or retina, usually at the junction of normal and hypoxic retina. At first the new vessels lie as vascular membranes flat on the retinal surface, but induced changes in the vitreous gel cause the gel to collapse and detach from the retina. New vessels that have penetrated the internal limiting membrane are dragged forwards on the posterior hyaloid face which acts as a scaffold for further proliferation. The neovascular tissue proliferates on the posterior hyaloid face but does not penetrate the vitreous gel.

In common with neovascularization elsewhere in the eye these vessels have fenestrated endothelial cell junctions and tend to leak, while minor trauma and vitreous traction causes them to tear and bleed to cloud the ocular media. Subsequent formation of fibrous tissue produces traction bands between the retina and posterior vitreous face; these eventually contract and detach the retina (see Ch. 12).

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