Overview
Diabetic retinopathy remains a major cause of morbidity in diabetic patients. To date, the retinopathy has been defined based on lesions that are clinically demonstrable, and all of those have been vascular in nature, including degeneration or nonperfusion of the vasculature, and excessive leakage of the vasculature (retinal edema, cottonwool spots, hemorrhage, hard exudates). Available clinical evidence strongly suggests that the late, clinically meaningful stages of the retinopathy are a direct consequence of the earlier changes. This chapter is an overview of the vascular changes associated with diabetic retinopathy. Macular edema is the specific focus of Chapter 67 and neovascularization of Chapter 66 .
Clinical background
Clinical findings in nonproliferative diabetic retinopathy (NPDR) arise from progressive capillary cell damage, loss of blood–retina barrier integrity, and leakage of vascular components into adjacent retinal tissue. Clinical signs of microaneurysms, retinal edema, retinal exudate, and retinal hemorrhage are all associated with increased capillary permeability and worsening vasculopathy. Yellow-white precipitates (hard exudates) may accompany leaking microaneurysms. Increased permeability of the blood–retinal barrier is known to occur in patients with diabetes, and this defect contributes to retinal edema and visual impairment in diabetic patients. Macular edema is the most common cause of visual loss in diabetic retinopathy ( Figure 65.1A ).
Larger microaneurysms and diffuse microvascular damage result in retinal hemorrhage. Focal areas of ischemia further damage the inner retina. Cottonwool spots describe opaque yellow-white lesions and represent areas of inner retinal infarction. The term soft exudate is now seldom used but describes the soft, ill-defined borders of these lesions. Retinal fluorescein angiography reveals progressive enlargement of areas of nonperfusion in diabetic retinopathy ( Figure 65.1B ).
Proliferative diabetic retinopathy (PDR) occurs when progressive cell dysfunction, vascular nonperfusion, and/or ischemia stimulate the development of retinal neovascularization. Progressive growth of abnormal vessels may lead to vitreous hemorrhage, preretinal hemorrhage, and iris neovascularization. Neovascular glaucoma is painful and arises as neovascular iris vessels block aqueous outflow. Contraction of fibrovascular proliferation may lead to retinal tears, vitreous hemorrhage, and traction retinal detachment.
It has long been appreciated that vascular permeability is increased in diabetic retinopathy. In early NPDR, hyperpermeability arises primarily from well-defined microaneurysms and results in focal areas of edema. Capillary fenestration and gaps in the vascular wall allow egress of serum, serum proteins, lipoproteins, and cellular components of peripheral blood. Macular edema is defined as retinal edema involving or threatening the macula. Distortion of normal macular architecture results in visual symptoms of blurring. Moderate leakage is often accompanied by the presence of yellow-white intraretinal deposits – hard exudates. Exudate results from precipitation of soluble lipoproteins at the junction of edematous and nonedematous retina. This is discussed further in Chapter 67 .
The prevalence of diabetic retinopathy varies widely depending on the population studied, but data from about 20 years ago indicate that nonproliferative stages of the retinopathy were almost universal after 20 years of diabetes, and PDR affected about half of the people with type 1 diabetes after 30 years’ duration. More recent assessments suggest that this may be changing. The retinopathies of type 1 and type 2 diabetes are fundamentally similar ( Box 65.1 ).
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Diabetic retinopathy seems not to be different in type 1 and type 2 diabetes
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The severity of lesions seems directly related to the severity of hyperglycemia, but the type of lesions that develop are not different between type 1 and type 2 diabetes
Studies have shown that familial predispositions to diabetic retinopathy can be detected, and there has been appreciable effort to identify the genetic component. Current knowledge on the genetics of diabetic retinopathy has come from family studies, population studies, or studies using candidate genes focused primarily on genes related to vascular complications. There are problems with many of the studies reported, however, because many use small sample sizes that are often limited to specific ethnic groups, or have detected only weak associations.
Current means of inhibiting development or progression of diabetic retinopathy
Clinical studies of diabetic retinopathy have primarily focused on sequelae of vascular lesions (microaneurysms, capillary nonperfusion, vascular leakage, and hemorrhage) to date ( Table 65.1 ), although attention has also been paid to function of the neural retina. There have been fewer attempts to inhibit the retinopathy in diabetic patients than there have been in diabetic animals, undoubtedly due to the long durations and significant costs required to demonstrate any effect, and those attempts have been far less successful compared to the animal studies (described below). Pharmacologic studies of histopathology lasting about 3 years or less have not been successful (whether this is due to a faulty hypothesis or insufficient study duration is not clear) to date. The Diabetes Control and Complications Trial (DCCT) did demonstrate efficacy of insulin therapy on development or progression of histopathology after about 5 years, suggesting that 5 or more years may be required for an objective test of drug therapies in clinical studies for these parameters. Effects on retinal edema (secondary to vascular leakage) and retinal function have required lesser durations of study.
| Therapy | Effect of therapy | Reference |
|---|---|---|
| Insulin | Significant inhibition of capillary lesions | |
| Laser photocoagulation | Significant inhibition of retinopathy progression | |
| Aldose reductase inhibitor | No beneficial effect | |
| Aspirin | No beneficial effect | |
| Protein kinase C inhibitor | Preserved vision, but no effect on vascular lesions | |
| Antivascular endothelial growth factor therapy | Significant correction of retinal edema | |
| Steroids | Significant correction of retinal edema | |
| Calcium dobesilate | Corrected permeability defect | |
| Fibrates | Reduced need for retinal photocoagulation | |
| Blood pressure medication | Inhibition of retinopathy progression |
Advanced retinopathy can currently be treated by laser photocoagulation or intravitreal steroids. Panretinal (scatter) photocoagulation, which is performed using a relatively high-energy laser, ablates relatively large areas of retina, presumably to reduce the hypoxia of the remaining retina. It results in a decrease in the formation of proliferative vessels, intravitreal hemorrhage, and retinal detachment, and can significantly reduce the risk for severe vision loss. Focal/grid laser photocoagulation to the retina can reduce the risk of loss of vision by nearly 50% in patients with clinically significant diabetic macular edema. Intravitreal steroids likewise are having dramatic effects on visual impairments due to macular edema. Nevertheless, vision loss continues in some patients, and these approaches do not address the underlying etiology of the retinopathy.
Intensive insulin therapy has been shown to inhibit development of vascular lesions of diabetic retinopathy in patients, dogs, and rats transplanted with exogenous islets. DCCT showed that intensive control of blood glucose inhibited the progression of existing retinopathy by 54% in patients with type 1 diabetes. Likewise, both the UK Prospective Diabetes Study (UKPDS) and the Kumomoto study demonstrated a protective effect of glycemic control on the development of retinopathy in type 2 diabetes. Nevertheless, the DCCT and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) studies have shown that instituting tight glycemic control in diabetic patients does not immediately inhibit the progression of retinopathy ( Box 65.2 ). Adverse effects of prior poor glycemic control continue to progress even if hyperglycemia is reduced or eliminated in diabetic patients, in diabetic dogs and rats, and the benefits of good control persist even if the good glycemic control is not maintained: benefits of a few years of modestly improved glycemic control continued to be apparent for the decade after the glycemic control was relaxed. This phenomenon, commonly referred to as “metabolic memory,” has also been observed in diabetic dogs and rats. The molecular basis of this memory is not yet known, but it is initiated early in the course of diabetes. Apparently, the level of glycemia results in a long-term imprinting on the cell.
- •
Diabetic retinopathy develops slowly, and resists arrest after the process has begun
- •
“Metabolic memory” describes a poorly understood process by which cells are changed as a function of their previous exposure to hyperglycemia. In the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications trial, beneficial effects of previous good glycemic control are maintained for many years (even if glycemia is no longer as good), but, likewise, adverse effects of previous poor glycemic control continue even after re-establishing relatively normal glycemia
Studies have also demonstrated that blood pressure medications, notably ß-blockers and inhibitors of angiotensin-converting enzyme, slow the development of capillary degeneration in diabetic animals, and the progression of advanced stages of diabetic retinopathy in diabetic patients. In the UKPDS type 2 diabetics allocated to tight control of blood pressure had a 34% reduction in risk in the proportion of patients with deterioration of diabetic retinopathy by two steps, and a 47% reduced risk of deterioration in visual acuity. Likewise, lipid levels have been shown to influence the development or progression of the retinopathy in diabetic animals. Lipid-lowering therapy using fenofibrate reduced the need for laser treatment for diabetic retinopathy, although the mechanism of this effect was not regarded as secondary to plasma concentrations of lipids.
Current means of inhibiting development or progression of diabetic retinopathy
Clinical studies of diabetic retinopathy have primarily focused on sequelae of vascular lesions (microaneurysms, capillary nonperfusion, vascular leakage, and hemorrhage) to date ( Table 65.1 ), although attention has also been paid to function of the neural retina. There have been fewer attempts to inhibit the retinopathy in diabetic patients than there have been in diabetic animals, undoubtedly due to the long durations and significant costs required to demonstrate any effect, and those attempts have been far less successful compared to the animal studies (described below). Pharmacologic studies of histopathology lasting about 3 years or less have not been successful (whether this is due to a faulty hypothesis or insufficient study duration is not clear) to date. The Diabetes Control and Complications Trial (DCCT) did demonstrate efficacy of insulin therapy on development or progression of histopathology after about 5 years, suggesting that 5 or more years may be required for an objective test of drug therapies in clinical studies for these parameters. Effects on retinal edema (secondary to vascular leakage) and retinal function have required lesser durations of study.
| Therapy | Effect of therapy | Reference |
|---|---|---|
| Insulin | Significant inhibition of capillary lesions | |
| Laser photocoagulation | Significant inhibition of retinopathy progression | |
| Aldose reductase inhibitor | No beneficial effect | |
| Aspirin | No beneficial effect | |
| Protein kinase C inhibitor | Preserved vision, but no effect on vascular lesions | |
| Antivascular endothelial growth factor therapy | Significant correction of retinal edema | |
| Steroids | Significant correction of retinal edema | |
| Calcium dobesilate | Corrected permeability defect | |
| Fibrates | Reduced need for retinal photocoagulation | |
| Blood pressure medication | Inhibition of retinopathy progression |
Advanced retinopathy can currently be treated by laser photocoagulation or intravitreal steroids. Panretinal (scatter) photocoagulation, which is performed using a relatively high-energy laser, ablates relatively large areas of retina, presumably to reduce the hypoxia of the remaining retina. It results in a decrease in the formation of proliferative vessels, intravitreal hemorrhage, and retinal detachment, and can significantly reduce the risk for severe vision loss. Focal/grid laser photocoagulation to the retina can reduce the risk of loss of vision by nearly 50% in patients with clinically significant diabetic macular edema. Intravitreal steroids likewise are having dramatic effects on visual impairments due to macular edema. Nevertheless, vision loss continues in some patients, and these approaches do not address the underlying etiology of the retinopathy.
Intensive insulin therapy has been shown to inhibit development of vascular lesions of diabetic retinopathy in patients, dogs, and rats transplanted with exogenous islets. DCCT showed that intensive control of blood glucose inhibited the progression of existing retinopathy by 54% in patients with type 1 diabetes. Likewise, both the UK Prospective Diabetes Study (UKPDS) and the Kumomoto study demonstrated a protective effect of glycemic control on the development of retinopathy in type 2 diabetes. Nevertheless, the DCCT and the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) studies have shown that instituting tight glycemic control in diabetic patients does not immediately inhibit the progression of retinopathy ( Box 65.2 ). Adverse effects of prior poor glycemic control continue to progress even if hyperglycemia is reduced or eliminated in diabetic patients, in diabetic dogs and rats, and the benefits of good control persist even if the good glycemic control is not maintained: benefits of a few years of modestly improved glycemic control continued to be apparent for the decade after the glycemic control was relaxed. This phenomenon, commonly referred to as “metabolic memory,” has also been observed in diabetic dogs and rats. The molecular basis of this memory is not yet known, but it is initiated early in the course of diabetes. Apparently, the level of glycemia results in a long-term imprinting on the cell.
- •
Diabetic retinopathy develops slowly, and resists arrest after the process has begun
- •
“Metabolic memory” describes a poorly understood process by which cells are changed as a function of their previous exposure to hyperglycemia. In the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications trial, beneficial effects of previous good glycemic control are maintained for many years (even if glycemia is no longer as good), but, likewise, adverse effects of previous poor glycemic control continue even after re-establishing relatively normal glycemia
Studies have also demonstrated that blood pressure medications, notably ß-blockers and inhibitors of angiotensin-converting enzyme, slow the development of capillary degeneration in diabetic animals, and the progression of advanced stages of diabetic retinopathy in diabetic patients. In the UKPDS type 2 diabetics allocated to tight control of blood pressure had a 34% reduction in risk in the proportion of patients with deterioration of diabetic retinopathy by two steps, and a 47% reduced risk of deterioration in visual acuity. Likewise, lipid levels have been shown to influence the development or progression of the retinopathy in diabetic animals. Lipid-lowering therapy using fenofibrate reduced the need for laser treatment for diabetic retinopathy, although the mechanism of this effect was not regarded as secondary to plasma concentrations of lipids.
Pathology
Histologically, vascular lesions in the early stages of diabetic retinopathy in humans and animals are characterized by the presence of saccular capillary microaneurysms, pericyte-deficient capillaries, and obliterated and degenerate capillaries. These degenerate capillaries are not perfused, and so increases in their frequency represent reductions in retinal perfusion. Capillary occlusion and degeneration initially occur in single, isolated capillaries, and have no clinical importance when only few capillaries have become nonperfused. As more and more capillaries become occluded, however, retinal perfusion likely decreases, at least locally ( Figure 65.2 ). No one of these lesions is totally specific for diabetic retinopathy, but in combination, they are quite unique.
The clinically demonstrable changes to the retinal vasculature in diabetes have led to the general assumption that the retinopathy is solely a microvascular disease. Nevertheless, diabetes can also damage nonvascular cells of the retina, resulting in alterations in function, loss of ganglion cells, horizontal cells, amacrine cells, and photoreceptors, and activation or death of Müller glial cells in some, but not all, studies. Findings in diabetic mice have not necessarily been in agreement with findings in rats. These important topics exceed the breadth of the present review, and are covered elsewhere.
Pathophysiology
Diabetic retinopathy is an important cause of visual impairment in diabetes, but the pathogenesis of the condition remains unclear. A current working model of diabetic retinopathy is that the clinically significant (proliferative) phase of the retinopathy is a direct consequence of earlier changes, especially increased leakage and degeneration of retinal capillaries ( Figure 65.3 ). Efforts to inhibit the development of the early stages of diabetic retinopathy have focused to a great extent on histologic endpoints (degeneration of retinal capillaries and neurons), and these studies have provided considerable insight into the pathogenesis of the retinopathy. Table 65.2 summarizes a number of therapies reported to inhibit retinal vascular histopathology in diabetes, grouped by their presumed mode of action. Most of the research focus to date has been on the role of hyperglycemia and its sequelae in the pathogenesis of the retinopathy. Also, most of these studies have been conducted in rodents, and accordingly, the histologic parameters of diabetic retinopathy that develop in those species (degeneration of retinal capillaries and pericyte loss) are the endpoints for most of these studies.
| Presumed action | Therapy | Defect corrected by therapy | Species | Reference |
|---|---|---|---|---|
| Blood pressure | Captopril | Capillary degeneration | Rat | |
| Inflammation | CD-18 −/− | Capillary degeneration, pericyte loss, permeability | Mouse | |
| Inflammation | ICAM-1 −/− | Capillary degeneration, permeability | Mouse | |
| Inflammation | IL-1β receptor −/− | Capillary degeneration | Mouse | |
| Inflammation | Minocycline | Capillary degeneration, permeability, neurodegeneration | Mouse | |
| Inflammation | Nepafenac | Capillary degeneration, pericyte loss | Rat | |
| Inflammation | PARP inhibitor | Capillary degeneration, pericyte loss | Rat | |
| Iinflammation | Salicylates | Capillary degeneration, pericyte loss, neurodegeneration | Rat, dog | |
| Metabolic abnormality | sRAGE | Capillary degeneration, retinal function | Mouse | |
| Metabolic abnormality | Aldose reductase inhibitor | Capillary degeneration, neurodegeneration | Rat but not dog | |
| Metabolic abnormality | Benfotiamine | Capillary degeneration | Rat | |
| Metabolic abnormality | Pyridoxamine | Capillary degeneration | Rat | |
| Metabolic abnormality, inflammation | Aminoguanidine | Capillary degeneration, pericyte loss | Rat, dog | |
| Metabolic abnormality, inflammation | iNOS −/− | Capillary degeneration | Mouse | |
| Metabolic abnormality, inflammation | 5-Lipoxygenase −/− | Capillary degeneration | Mouse | |
| Metabolic abnormality | Tenilsetam | Capillary degeneration but not pericyte loss | Rat | |
| Oxidative stress | Antioxidants | Capillary degeneration, pericyte loss | Rat | |
| Oxidative stress | Mn superoxide dismutase | Capillary degeneration, pericyte loss | Mouse | |
| Oxidative stress, neuroprotection, | Nerve growth factor | Capillary degeneration, neurodegeneration | Rat, mouse | , Kern, unpublished |
Other biochemical or metabolic abnormalities, including impaired insulin signaling, have been postulated to contribute to the retinopathy, but effects of correcting these abnormalities have not been demonstrated histologically to date.
Hyperglycemia is strongly associated with development of diabetic retinopathy, and this has been strongly supported by clinical and animal studies showing that reduction in the severity of hyperglycemia significantly inhibited development of the retinopathy. Nevertheless, this evidence does not prove that hyperglycemia per se is the critical abnormality, because intensive insulin therapy can normalize defects also related to lipids and proteins in diabetes. The strongest evidence that hyperglycemia is sufficient to initiate the vascular lesions of diabetic retinopathy is the evidence that lesions that are morphologically identical to those of diabetic retinopathy also develop in nondiabetic animals made experimentally hyperglycemic by feeding a galactose-rich diet.
Although one would assume that all vascular cells should be exposed to the same concentration of blood glucose in a given individual, there is unexplained regional variability in susceptibility to diabetes-induced microvascular disease even within the same retina. Microaneurysms and acellular capillaries have been found to develop in a nonuniform distribution even within the same retina in diabetic patients and in experimentally diabetic or galactosemic dogs. In both species, lesions were most common in the superior and temporal portions of the retina. Likewise, neovascularization in diabetic patients has been noted to be more common in the superior and temporal portions of the retina than in other regions.
Diabetic retinopathy is not made up of a single lesion ( Box 65.3 ). It is a spectrum of abnormalities, none of which is totally unique to diabetic retinopathy, but which in combination offer a clinical picture that is relatively unique to diabetes. Whether or not these individual lesions share a common pathogenesis or differ in aspects remains to be determined. Thus, the individual lesions of early diabetic vascular disease in the retina are discussed individually below.
