Diabetic Eye Disease

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Chapter 26

Diabetic Eye Disease

Diabetes mellitus (DM) affects virtually all structures of the eye and many aspects of visual function. Diabetic retinopathy (DR) remains an important cause of new-onset blindness in the United States and other industrialized nations.1 Additionally, coexisting morbidities of DM, including hypertension, renal disease, and dyslipidemia, are associated risk factors for the progression of DR. Multicenter clinical trials have demonstrated the efficacy of glycemic and blood pressure control in preventing the onset and progression of retinopathy24 and have demonstrated the effectiveness of laser photocoagulation in preserving vision and reducing the risk of vision loss.5,6 Laser photocoagulation, however, is usually reserved for advanced DR, may be associated with side effects and complications, does not prevent loss of visual acuity in all cases, and often does not restore vision. Nevertheless, because laser photocoagulation is the only treatment proven to reduce the risk of visual loss once vision-threatening retinopathy is present, and because a significant number of persons with DM at risk for visual loss from vision-threatening retinopathy do not receive necessary eye care, public health efforts have been directed at earlier detection and timely photocoagulation.711 The purpose of this chapter is to provide a better understanding of the natural history, pathogenesis, epidemiology, detection, and management of DR.


The pathogenesis of DR is not fully understood; however, many mechanisms have been suggested and are summarized in Fig. 26-1.12 The development and progression of DR probably result from a complex interplay of these and other factors, which may vary from person to person. It is likely that the relative contributions of different mechanisms vary in importance at different stages of retinopathy. Glycosylation, protein kinase C and polyol pathways, and changes in retinal blood flow may be particularly important early in the course of the disease, even before the development of microaneurysms or other clinically evident findings. Angiogenesis factors such as vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 are more likely to be important later in the course of the disease, just before and during the development of proliferative retinopathy or diabetic macular edema. In addition, interindividual and intraindividual variations in biochemical or physiologic responses to hyperglycemia (perhaps as a result of differences in genetic susceptibility) may exist among people at different stages of diabetic disease. This variability may explain why a few diabetic patients have minimal retinopathy despite years of severe hyperglycemia, whereas in others severe retinopathy develops in a short period despite relatively good glycemic control. Furthermore, these pathogenetic factors have not often been studied together in a prospective fashion, making it difficult to prove a causal relationship.

Natural History of Diabetic Retinopathy

Nonproliferative Diabetic Retinopathy

The earliest diabetes-induced changes in the retina are biochemical, hemodynamic, and cellular in nature and imperceptible clinically. These include changes in biochemical pathways, enzyme activation, retinal blood flow, and cellular loss, particularly pericytes. The first clinical signs of DR are microaneurysms, which are saccular outpouchings of retinal capillaries.13 These lesions usually appear as round red dots ranging in size from 20 to 200 µm and represent an outpouching of the retinal capillaries. They often appear first in the macular area in areas of capillary closure. It is unusual to detect retinal microaneurysms within 3 years of the diagnosis of type 1 DM; however, they are often present at the time of diagnosis in people with type 2 DM.14 In the United Kingdom Prospective Diabetes Study (UKPDS), where subjects were enrolled at the time of diagnosis of type 2 DM, nearly 40% of the enrollees had some level of DR at entrance into the study.15 Moreover, after 10 years of diabetes, 69% of people with type 1 DM and 55% of people with type 2 DM have microaneurysms present.16,17

Retinal microaneurysms are not pathognomonic of DR, since they also may be associated with essential hypertension, retinal venous stasis caused by atherosclerotic carotid artery disease, AIDS, and other systemic and ocular conditions.18 The appearance of a microaneurysm or two in only one eye of a person with type 2 DM should not be regarded as specific for DR; however, when larger numbers of microaneurysms are present (four or more in an eye or their presence in both eyes), they are more likely due to DM, and the likelihood of progression to more severe nonproliferative DR is greater.19

Microaneurysms have abnormal permeability to fluorescein, red blood cells, and lipoproteins.13 By themselves, microaneurysms are not a threat to vision; however, as the disease progresses, hard exudates and retinal dot or blot hemorrhages appear. Dot hemorrhages are frequently indistinguishable from microaneurysms, and for the purposes of grading the severity of retinopathy, they are frequently grouped with microaneurysm, being referred to as hemorrhages and/or microaneurysms (H/Ma). The blot hemorrhages are round with blurred edges and result from extravasation of blood from retinal capillaries or microaneurysms into the inner nuclear layer of the retina (Fig. 26-2). Retinal blot hemorrhages usually disappear within 3 to 4 months.20 Ruptured microaneurysms, decompensated capillaries, and intraretinal microvascular abnormalities can result in intraretinal hemorrhages. The clinical appearance of these hemorrhages reflects the retinal architecture at the level at which the hemorrhage occurs. Hemorrhages in the nerve-fiber layer assume a more flame-shaped appearance, coinciding with the structure of the nerve-fiber layer that runs parallel to the retinal surface. Hemorrhages deeper in the retina, where the arrangement of cells is more or less perpendicular to the surface of the retina, assume a pinpoint or dot shape.

Retinal hard exudates are sharply defined, yellow, and variable in size; they may be aggregated or scattered and partially or fully circinate in their distribution (see Fig. 26-2). A ring of hard exudates generally reflects the border of an area of retinal leakage. Hard exudates result from leakage of lipoprotein material from retinal microaneurysms or capillaries into the outer retinal layer, and they may persist for months to years.20 They are usually found in the posterior layer of the retina, and if they extend into the foveal area, they may reduce visual acuity.

With closure of the retinal capillaries and arterioles, whitish or grayish swellings appear in the nerve-fiber layer of the retina. These changes, termed “cotton-wool spots” or “soft exudates,” are microinfarcts of the nerve-fiber layer (see Fig. 26-2). They may remain only a few weeks to months. After they disappear, the retina may appear normal on ophthalmoscopy, but fluorescein angiography reveals a corresponding area of nonperfusion of the retinal arterioles.

Dilated capillaries called intraretinal microvascular abnormalities (IRMA) are another manifestation of focal retinal ischemia. They are found in areas of capillary nonperfusion and may be abnormally permeable to plasma proteins. IRMA represent either new vessel growth within the retina or preexisting vessels that have developed abnormal morphology thought to include endothelial cell proliferation. IRMA may be seen adjacent to cotton-wool spots. Multiple IRMA identify a severe stage of NPDR.

Venous caliber abnormalities are indicators of severe retinal hypoxia. These abnormalities can take the form of venous dilatation, beading, or loop formation. There are often large areas of nonperfusion adjacent to these abnormalities. Treatment with scatter (panretinal) photocoagulation (PRP) may cause these abnormal veins to become less dilated and more regular. IRMA, intraretinal hemorrhages, and venous beading (VB) represent significant retinal ischemia. These changes were referred to as “preproliferative” retinopathy under previous classification systems and are clearly associated with more severe stages of NPDR, being a warning sign of the impending retinal neovascularization. Late in the course of the disease, thinly sheathed sclerotic “white, threadlike” arterioles may be present.

Proliferative Diabetic Retinopathy

Proliferative diabetic retinopathy is characterized by proliferating retinal vessels, the growth of which is variable. They are commonly identified according to their retinal location: at or near the optic disc (neovascularization of the disc [NVD], Fig. 26-3) or elsewhere in the retina (neovascularization elsewhere [NVE], see Fig. 26-2). Retinal neovascularization may be difficult to detect when the vessels first appear as fine tufts of “naked” vessels on the surface of the retina or optic nerve head.21 They are prone to proliferate on the posterior surface of the vitreous and hemorrhage into the vitreous. With time, the new vessels often fibrose, and if this fibrovascular tissue contracts, traction detachment of the retina may result. Once regression of new vessels occurs as a result of photocoagulation or the natural course of the disease, fibrous tissue may remain.

PDR poses a significant risk for vision loss. Patients with high-risk PDR generally require prompt PRP. High-risk PDR is characterized by one or more of the following lesions: (1) NVD that is approximately one quarter to one third the disc area or more in size (i.e., greater than or equal to NVD in standard photograph No. 10A); (2) any amount of NVD if fresh vitreous or preretinal hemorrhage is present; or (3) NVE greater than or equal to one half the disc area in size if fresh vitreous or preretinal hemorrhage is present Therefore, attention must be paid to the presence, location, and severity of new vessels, as well as the presence or absence of preretinal or vitreous hemorrhages.22

Diabetic Macular Edema, Ischemia, and Traction

DM affects the macula in a number of ways. First, increased permeability of retinal capillaries and microaneurysms may result in the accumulation of extracellular fluid and thickening of the normally compact macular tissue, with or without the development of cystoid spaces. The edema may be easily missed, especially if not evaluated with appropriate equipment and by an experienced examiner. The edema is often associated with hard exudates distributed in rings, clumps, or large deposits. Accumulation of exudate is often gradual, and spontaneous resolution may occur. Involvement of the foveal area can be associated with a profound drop in visual acuity.

When macular edema threatens or involves the center of the macula, the edema is considered clinically significant macular edema (CSME). CSME can be present with any level of NPDR or PDR but is more common with more severe DR. The Early Treatment Diabetic Retinopathy Study (ETDRS) found that CSME is associated with a 30% risk of visual loss over a 3- to 5-year period if left untreated with focal photocoagulation. This risk is reduced by 50% or more with appropriate focal laser photocoagulation. CSME is defined as the presence of any of the following: thickening of the retina at or within 500 µm of the center of the macula, hard exudates at or within 500 µm of the center of the macula with thickening of the adjacent retina, or a zone or zones of retinal thickening one disc area or larger in size, any part of which is within one disc diameter of the center of the macula (see Fig. 26-2). The vast majority of vision loss occurs only once macular edema involves the center of the macula.

The underlying cause of macular edema is not known. It may be a result of both increased leakage and impaired removal. Breakdown of the blood-retinal barrier has been postulated as an important cause of fluid accumulation in the macula.13 Reduced osmotic pressure resulting from decreased serum albumin levels, increased intravascular fluid load, increased arterial perfusion pressure, and tissue hypoxia, have been postulated to lead to breakdown of the blood-retinal barrier. The retinal pigment epithelium normally serves to “pump” fluid out of the sensory retina, and this function is postulated to be impaired in patients with hyperglycemia. Recently, key growth factors involved in the progression of DR, such as VEGF, have been shown to be potent permeability factors and probably contribute significantly to this problem. Early clinical trials have shown that compounds which inhibit VEGF appear to rapidly induce regression of retinal neovascularization and may have an ameliorative effect on macular edema.

In addition to macular edema, DM may cause macular capillary nonperfusion, retinal or preretinal hemorrhage, lamellar or full-thickness hole formation, or dragging or detachment of the macula due to contraction of fibrovascular tissue. These changes may occur in isolation or in combination and generally result in the loss of central vision if the fovea is involved.

Clinical Classification of Diabetic Retinopathy Severity

To recap, DR can be broadly classified as nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). Lesions of NPDR include hemorrhages and/or microaneurysms (H/Ma), dot and blot hemorrhages, cotton wool spots (CWS), hard exudates (HE), venous caliber abnormalities (VCAB), and intraretinal microvascular abnormalities (IRMA). Based on the presence and degree of retinal lesions, NPDR is clinically classified as mild, moderate, severe, or very severe NPDR. PDR is marked by new vessels on the optic disc (NVD), new vessels elsewhere on the retina (NVE), preretinal hemorrhage (PRH), vitreous hemorrhage (VH), or fibrous tissue proliferation (FP). Diabetic macular edema (DME) can be present with any level of DR. DME that involves or threatens the center of the macula is classified as clinically significant macular edema (CSME). Accurate diagnosis of the severity of DR is essential, since the risk of progression to PDR and high-risk PDR is closely correlated with each specific NPDR level. Proper diagnosis of DR severity establishes the risk of progression to sight-threatening retinopathy and appropriate clinical management both in terms of follow-up schedule and therapeutic options. For example, it is important to consider PRP as DR reaches severe NPDR, early PDR, or high-risk PDR.

Nonproliferative Diabetic Retinopathy Levels

Mild NPDR is marked by at least one retinal microaneurysm, but hemorrhages and microaneurysms are less than those in ETDRS standard photograph No. 2A, and no other retinal lesion or abnormality associated with DM is present. Those with mild NPDR have a 5% risk of progression to PDR within 1 year and a 15% risk of progression to high-risk PDR within 5 years.23,24 Moderate NPDR is characterized by H/Ma greater than those pictured in ETDRS standard photograph No. 2A. Soft exudates, VB, and IRMA are definitely present to a mild degree. The risk of progression to PDR within 1 year is 12% to 27%, and the risk of progression to high-risk PDR within 5 years is 33%. These risks are based on estimates from a clinical trial done in the 1980s, the ETDRS, and may be lower now based on changes in management of diabetes resulting in generally improved glycemic and blood pressure control.25 Patients with mild or moderate NPDR generally are not candidates for PRP and can be followed safely at 6- to 12-month intervals. The presence of macular edema, even with mild or moderate degrees of NPDR, requires follow-up in a shorter period, and if CSME is present, focal laser treatment is to be considered. Coincident medical problems or pregnancy will reduce the period until reevaluation. Severe NPDR, based on the severity of H/Ma, IRMA, and VB, is characterized by any one of the following lesions: H/Ma > standard photograph No. 2A in four quadrants or venous beading in two or more quadrants or IRMA > standard photograph No. 8A in at least one quadrant. Clinically, severe NPDR is diagnosed by applying the “4-2-1- rule” reflected in the previous definition. Eyes with severe NPDR have a 52% risk of developing PDR within 1 year and a 60% risk of developing high-risk PDR within 5 years. These patients require follow-up evaluation in 2 to 4 months. Treatment of CSME is strongly indicated in these patients because of the high risk of the development of PDR requiring PRP.

Eyes with very severe NPDR have two or more lesions of severe NPDR but no frank neovascularization. There is a 75% risk of developing PDR within 1 year. Patients with very severe NPDR may be candidates for PRP, and macular edema, if present, generally should be treated. Follow-up evaluation at 2- to 3-month intervals is important. For patients with type 2 DM, early PRP may be considered for patients with severe or very severe NPDR.26

Proliferative Diabetic Retinopathy Levels

DR with new vessel growth on the optic disc (NVD) or elsewhere (NVE) on the retina or with fibrous tissue proliferation is designated PDR. Early PDR does not meet the definition of high-risk PDR. Eyes with early PDR have a 75% risk of developing high-risk PDR within 5 years. Patients with severe or very severe NPDR or early PDR may be considered for early PRP. In the presence of macular edema, patients with severe NPDR or worse DR should be considered for early focal treatment of macular edema in preparation for the probable need of scatter laser photocoagulation.

The ETDRS severity scale was based on the modified Airlie House classification of DR and is a recognized standard for grading severity of DR. Its use in everyday clinical practice, however, poses difficulty, both in its complexity and difficulty, since definitions of the levels are detailed, require comparison with standard photographs, and are complex to remember and apply in a clinical setting. A DR severity scale was developed by the Global Diabetic Retinopathy Group at the International Congress of Ophthalmology in Sydney in April 2002.27

This International Classification scale defines five levels of DR. The first level is “no apparent retinopathy” and the second level is “mild NPDR,” corresponding to ETDRS stage 20 (microaneurysms only). The risk of significant progression over several years is very low in both groups. The third level, “moderate NPDR,” includes eyes with ETDRS levels 35 to 47, and the risk of progression increases significantly by level 47. Still, the 4th level, “severe NPDR” (ETDRS stage 53), carries with it the most ominous prognosis for progression to PDR. The fifth level, “PDR,” includes all eyes with definite neovascularization or vitreous/preretinal hemorrhage (Table 26-1). There was no attempt to subdivide this level as a function of ETDRS “high-risk characteristics,” because significant rates of progression are expected to occur in all cases.

The Diabetic Macular Edema Disease Severity Scale separates eyes with apparent DME from those with no apparent thickening or lipid in the macula. For eyes with apparent DME, three categories classify DME as not threatening the center of the macula (mild), threatening the center of the macula (moderate), or involving the center of the macula (severe) (Table 26-2). The clinical disease severity scale is intended to be a practical and valid method of grading severity of DR and DME.

Table 26-2

International Clinical Diabetic Retinopathy and Diabetic Macular Edema Disease Severity Scales27

DME Disease Severity Findings on Ophthalmoscopy
DME apparently absent No apparent retinal thickening or HE in posterior pole
DME apparently present Some apparent retinal thickening or HE in posterior pole
Mild DME Some retinal thickening or HE in posterior pole but distant from center of the macula
Moderate DME Retinal thickening or HE approaching the center of the macula but not involving the center
Severe DME Retinal thickening or HE involving the center of the macular edema


Epidemiologic studies of DR are useful in developing public health strategies to prevent or reduce the occurrence or progression of this complication. In addition, epidemiologic data concerning DR, visual loss, and associated risk factors may be used in projecting costs, developing etiologic insight, designing future studies such as controlled clinical trials of treatment or prevention, and estimating the need for rehabilitative services.

One epidemiologic study that has provided data on DR, visual loss, and associated risk factors is the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR). This population-based study has been described in detail.14,16,22,23 Data from other epidemiologic studies are also cited. Standardized examination protocols and questionnaires, photographic documentation, photographic standards for grading the severity of retinal lesions, and standardized retinopathy severity scales have permitted, in some cases, comparisons among studies.28,29

Prevalence and Incidence of Retinopathy

The prevalence of DR and CSME by age, gender, and diabetes group in the WESDR is presented in Table 26-3. The highest frequencies of DR and PDR were found in the younger-onset group using insulin; the lowest frequencies were in the older-onset group not using insulin. CSME was most frequent in the younger-onset group using insulin. The prevalence of DR has been reported in other selected population-based studies.2849 Pooled data from eight studies, including the WESDR, estimate that among persons 40 years of age and older, the crude prevalence of DR was 40%, and the crude prevalence of severe retinopathy (severe-very severe NPDR and PDR or macular edema) was 8%. Projection of these rates to the diabetic population 40 years of age or older in the United States resulted in an estimate of 4 million persons with DR, of whom 900,000 have signs of vision-threatening retinopathy.1

In the WESDR, the highest incidence and rate of progression of DR were found in the younger-onset group using insulin; the lowest incidence and rate of progression were found in the older-onset group not using insulin.50,51 Based on the WESDR data, it is estimated that approximately 63,000 new cases of PDR occur annually nationwide, 29,000 of which have proliferative retinopathy with DRS high-risk characteristics. In addition, approximately 50,000 new cases of diabetic macular edema occur each year in the United States. It should be noted that these rates may currently be different owing to the increasing frequency of type 2 diabetes and decreasing incidence of PDR and CSME.52,53

Risk Factors for Diabetic Retinopathy

Gender, Race, Genetics, and Age

Few differences are found in the risk of development and progression of DR in men and women with DM. However, differences among race/ethnic groups have been reported. Results from the study of Pima Indians with type 2 DM suggest that they are at increased risk for PDR in comparison to whites with type 2 DM.48 After controlling for all measured risk factors, diabetic Mexican Americans in San Antonio had a 2.4 times higher frequency of DR than diabetic non-Hispanic whites studied in the WESDR.28 Similarly, Mexican Americans with type 2 DM participating in the National Health and Nutrition Examination Survey III (NHANES III) had an 84% higher frequency of DR than non-Hispanic whites.49 The higher frequency of DR in Mexican Americans than whites remained after controlling for the duration of DM, hemoglobin A1c level, insulin and oral agent use, and hypertension in that study. However, Hamman et al. failed to find a difference in the frequency of DR between Hispanics and non-Hispanic whites examined in the San Luis Valley Study.29 West et al. also reported a similar prevalence of retinopathy in Mexican Americans with type 2 DM living in Arizona, of whom 48% had any retinopathy; 6% had proliferative retinopathy, and 5% had clinically significant macular edema.54 A higher prevalence of proliferative retinopathy and macular edema was found in Mexican Americans living in Los Angeles than in Caucasians living in Beaver Dam.54 It has been suggested that blacks with type 2 DM may have more severe DR and loss of vision than whites with type 2 DM.55 In the NHANES III, the prevalence of DR in people with type 2 DM was 46% higher in non-Hispanic blacks than non-Hispanic whites.49 However, after adjustment for glycosylated hemoglobin, the duration of DM, insulin and oral agent use, and hypertension, the rates for DR were similar between whites and blacks in that study.

Reports of a relationship between genetic factors and the prevalence of DR have been inconsistent.26,5659 Supporting such a relationship has been the observation that the severity and onset of DR are similar among concordant identical twins, which suggests that the tendency for the development of DR and possibly its progression are influenced by genetic factors.60 In addition, Hanis demonstrated an 8.3-fold increased risk of DR in 46 Mexican American siblings of probands who had DR when compared with the siblings of those who did not.61 A high degree of familial aggregation and concordance in the development of PDR and end-stage renal disease in diabetic patients implies that common genetic factors may be important in susceptibility or resistance to these complications.62 Case-controlled studies have examined various candidate gene single nucleotide polymorphisms (SNP) and suggested that chromosome locus 7q21 is a modifier for the risk of nephropathy in diabetes.6366 Recent work has identified a specific SNP at the promoter of the erythropoietin gene, located at 7q21, associated with higher rates of development of severe diabetic eye and kidney complications.67

It is uncommon to find clinical evidence of DR in children younger than 10 years, regardless of the duration of type 1 DM; the frequency of any DR or more severe DR increases after age 13.68-71 This age effect has been postulated to result from a protective effect lost after the start of puberty. In the WESDR, menarchal status at the time of the baseline examination was associated with the prevalence of DR.72 After controlling for other factors such as diastolic blood pressure and duration of type 1 DM, those who were postmenarchal in the WESDR were 3.2 times more likely to have DR than those who were premenarchal.

A number of changes occurring at puberty have been thought to explain the higher risk for DR. These changes include increases in insulin-like growth factor 1, growth hormone, sex hormones, and blood pressure and poorer glycemic control. Increased insulin resistance, inadequate insulin dosage, and poorer compliance in attempts to control blood sugar may result in poorer glycemic control in postpubertal teenagers.73-78

Diabetes-Related Risk Factors

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