1 Nonproliferative Diabetic Retinopathy
Catherine B. Meyerle, Emily Y. Chew, and Frederick L. Ferris III
CONTENTS
NONPROLIFERATIVE DIABETIC RETINOPATHY
PATHOPHYSIOLOGY OF NONPROLIFERATIVE
DIABETIC RETINOPATHY
CLASSIFICATION OF NONPROLIFERATIVE RETINOPATHY
MACULAR EDEMA
RISK FACTORS FOR PROGRESSION OF RETINOPATHY
MANAGEMENT OF NONPROLIFERATIVE DIABETIC
RETINOPATHY
SUMMARY
REFERENCES
ABSTRACT
Nonproliferative diabetic retinopathy (NPDR) is a microvascular complication of diabetes mellitus that can lead to irreversible visual loss. Intraretinal microvascular changes, such as altered retinal vascular permeability and eventual retinal vessel and capillary closure, characterize NPDR. Macular edema, the most frequent cause of visual loss in NPDR, may result from increased vascular leakage. Retinal hypoxia, secondary to chronic hyperglycemia, triggers the pathologic processes of NPDR. Additionally, there is increasing evidence that inflammatory mechanisms may play a role in the pathogenesis. Systemic factors such as glycemic control, hypertension, and serum lipid level also contribute to the development and progression of NPDR. Prompt and appropriate initiation of laser photocoagulation for macular edema or severe retinal nonperfusion, along with optimal control of systemic factors, can prevent visual loss.
Key Words: Diabetes mellitus; Diabetic retinopathy; Macular edema; Laser photocoagulation.
From: Contemporary Diabetes: Diabetic Retinopathy
Edited by: E. Duh © Humana Press, Totowa, NJ
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NONPROLIFERATIVE DIABETIC RETINOPATHY
Diabetes is an epidemic affecting more than 18 million people in the United States
(1). Chronic hyperglycemia triggers a cascade of molecular events that leads to microvascular damage. Diabetic retinopathy is the most prevalent microvascular complication and can lead to irreversible visual loss. Epidemiologic studies show that diabetic retinopathy is a leading cause of acquired blindness in people aged 20–74 years in the United States, with 12,000–24,000 new cases of legal blindness each year (1–3). The retinal manifestations of diabetes mellitus are broadly classified as either nonproliferative diabetic retinopathy (NPDR) or proliferative diabetic retinopathy (PDR).
Nonproliferative diabetic retinopathy occurs when there are only intraretinal microvascular changes, such as altered retinal vascular permeability and eventual retinal vessel closure. Clinically, the hallmark of the nonproliferative phase is microaneurysms and intraretinal abnormalities. Neovascularization is not a component of the nonproliferative phase. However, in advanced NPDR, nonperfusion of the retina may develop and lead to the proliferative phase. Proliferative diabetic retinopathy is characterized by new vessels and sometimes fibrous bands proliferating on the retinal surface. In both nonproliferative and proliferative diabetic retinopathy, macular edema can occur as increased retinal vascular permeability leads to accumulation of fluid in the retinal area serving central vision. This chapter focuses on the clinical aspects of NPDR.
PATHOPHYSIOLOGY OF NONPROLIFERATIVE DIABETIC
RETINOPATHY
Effective and appropriate management of NPDR is dependent on a clear understanding of the disease course. Chronic hyperglycemia in poorly controlled diabetes results in biochemical alterations and altered hemodynamics of the retinal vasculature, which lead to chronic hypoxia (4, 5). Since the retina is a highly metabolic tissue dependent on optimal oxygenation, compensatory pathways, such as upregulation of vascular endothelial growth factor (VEGF) protein, are targeted against this retinal hypoxia. These efforts are futile, however, and ultimately result in the pathologic processes of NPDR: retinal capillary microaneurysms, vascular permeability, and eventual vascular occlusion, or capillary closure.
Inflammatory Mechanisms
Increasing evidence suggests that inflammation may play a role in the pathogenesis of diabetic retinopathy. Multiple animal and human tissue studies have indicated that chronic inflammation contributes to diabetic vascular damage.
Intercellular adhesion molecule 1 (ICAM-1), a member of the immunoglobulin superfamily involved in immune activation and inflammation, and its counter-receptor CD18 are thought to play a pivotal role (6, 7). ICAM-1 mediates leukocyte migration into inflammatory sites via its interaction with different cytokines. Increased leukocyte adhesion to the diabetic vascular endothelium can promote endothelial apoptosis, resulting in vascular permeability and capillary nonperfusion (7, 8). In the rat model of strepto- zotocin-induced diabetes (9), retinal leukostasis increased within days of developing diabetes and correlated with the increased expression of retinal ICAM-1. Additionally,
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ICAM-1 blockade in this rat model prevented diabetic retinal leukostasis and vascular leakage by 48.5 and 85.6%, respectively. Other rat models have shown that antibodybased inhibition of ICAM-1 and CD18 may prevent acellular capillary formation via the suppression of endothelial cell injury and death (10).
Studies of human tissue have also suggested an inflammatory role in the pathogenesis of diabetic retinopathy. Immunoassays for the quantitative determination of soluble ICAM-1 in the vitreous of PDR patients undergoing vitrectomy showed elevated ICAM-1 levels when compared with that in the control group (6). In another study (11), frozen sections of a donor eye obtained at autopsy from a patient with documented severe NPDR and diabetic macular edema were compared with a normal nondiabetic eye. Immunoperoxidase staining was positive for inflammatory chemokines such as monocyte chemoattractant protein, RANTES (Regulated on Activation Normal T Cell Expressed and Secreted), and ICAM-1 in the retina of the diabetic eye, while the nondiabetic eye showed little reactivity. Serum levels of inflammatory mediators also appear to correlate with increasing diabetic retinopathy severity. In one study of 93 participants, the serum levels of proinflammatory RANTES and stromal cell-derived factor were significantly elevated in patients with at least severe NPDR, compared with those in patients with less severe diabetic retinopathy (11). Similar to the animal studies, these human studies suggest that inflammation may play a central role in the development of diabetic retinopathy.
While the precise components of the inflammatory pathways in the pathogenesis of diabetic retinopathy are still being investigated, the recognition of the role of inflammation in this retinal disease suggests the potential utility of using anti-inflammatory therapies. Further research is required to translate these scientific findings into clinical care.
Microaneurysms
The retinal capillary microaneurysm usually is the first visible sign of diabetic retinopathy. Microaneurysms, identified clinically by ophthalmoscopy as deep-red dots varying from 15 to 60 m in diameter, are most common in the posterior pole. Although microaneurysms can be associated with other retinal vascular diseases, particularly those associated with vascular occlusion such as branch and central vein occlusions, they are the hallmark of NPDR.
Histologically, microaneurysms are hypercellular saccular outpouchings of the capillary wall, as demonstrated by trypsin digest retinal mounts (12). Experimental models of diabetic retinopathy in dogs and rats and studies of human autopsy eyes indicate that the initial step in the pathogenesis of diabetic retinopathy is the loss of intramural capillary pericytes. Subsequently, microaneurysms form and capillary closure ensues, leading to the development of acellular capillaries. Another early morphologic finding in diabetic retinopathy is the thickening of the basement membrane of the retinal capillaries. The importance of this thickening in the pathogenesis of diabetic retinopathy is unknown
(13–15).
The mechanism for the formation of microaneurysms is also unknown. Possible mechanisms include release of a vasoproliferative factor with endothelial cell proliferation, weakness of the capillary wall (from loss of pericytes), abnormalities of the adjacent retina, and increased intraluminal pressure (16–18).
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Microaneurysms may be difficult to differentiate from punctate hemorrhages seen in diabetic retinopathy. However, on the early frames of a fluorescein angiogram, microaneurysms are easily distinguished from intraretinal hemorrhages because they exhibit bright hyperfluorescence against the darker choroidal background, whereas retinal hemorrhages block fluorescence (Figs. 1 and 2). Microaneurysms may show little change over many years, but the lumens can occlude, as demonstrated by hyperfluorescence on fluorescein angiography, and after recanalization the microaneurysms can disappear (19). It is typical for individual microaneurysms to appear and disappear with time. Without the other components of diabetic retinopathy, microaneurysms alone have no apparent clinical significance. However, an increase in the number of microaneurysms in the retina is associated with progression of retinopathy (20–22). When the number of microaneurysms increases, there is an increased likelihood that the other microvascular changes of diabetic retinopathy may also be present.
Vascular Permeability
As microvascular damage increases in the presence of excessive blood glucose, increased vascular permeability occurs through multiple pathways. Vascular endothelial growth factor (VEGF) protein is thought to play a pivotal role. A healthy human retina contains little VEGF, but its level is increased in response to hypoxia that can occur in states such as diabetic retinopathy. Originally described as vascular permeability factor, VEGF is not only a mediator of new blood vessel formation seen in PDR, but also an inducer of vascular permeability, which can lead to retinal edema seen in both nonproliferative and proliferative diabetic retinopathy (23–25). The molecular pathway for this
Fig. 1. The right eye of a 55-year-old woman with mild macular edema. (A) Color photograph shows circinate ring of lipid and microaneurysms. Best-corrected vision is 20/25. (B) Optical coherence tomography shows mild macular edema with preservation of the foveal contour. (C) Early phase of fluorescein angiogram highlights the multiple microaneurysms. (D) Late phase of fluorescein angiogram shows patchy areas of leakage.
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Fig. 2. The right eye of a 68-year-old man with chronic macular edema. (A) Red-free photograph shows multiple microaneurysms in this patient with type 2 diabetes for 45 years. Best-corrected visual acuity was 20/63 despite multiple treatments over many years, including focal laser, subtenon triamcinolone, and intravitreal bevacizumab. (B) Optical coherence tomography shows large intraretinal cysts and foveal distortion. (C) Early fluorescein angiogram highlights the multiple microaneurysms. (D) Late fluorescein angiogram shows petalloid edema.
pro-angiogenic factor involves VEGF tyrosine kinase receptors located on endothelial cells. This homodimeric protein promotes endothelial cell proliferation, migration, apoptosis, and vascular tube formation. On a molecular level, VEGF induces vessel permeability by causing conformational changes in the tight junctions of the retinal vascular endothelial cells (26). Additionally, some animal studies suggest that VEGF contributes to the inflammatory component of diabetic retinopathy by upregulating ICAM-1 (7). Other molecules suspected to be involved in vascular permeability include protein kinase C-beta (PKC-beta) (27, 28). In addition to vessel permeability changes, PKC-beta is associated with other classic pathological changes seen in diabetes, such as basement membrane thickening and prolonged retinal circulation time (29–32).
Retinal edema resulting from increased vascular permeability is particularly significant if it occurs in the macula. Macular edema is defined clinically as retinal thickening from accumulation of fluid within 1 disc diameter of the macula (24, 33, 34). As the fluid disrupts the architecture of the macular region serving central visual acuity, macular edema can cause significant visual loss. Fluorescein angiography can be used to identify excessive permeability and may demonstrate the classic petalloid leakage pattern that occurs as fluid accumulates in the radially oriented layer of Henle (Fig. 2). While fluorescein angiography may be useful to guide focal laser treatment of macular edema and to identify macular nonperfusion contributing to visual loss, it is not required to make the diagnosis of macular edema. Macular edema is best detected with a combination of