10 Diabetic Retinopathy
10.1 Introduction
Due largely to numerous well-designed landmark clinical trials performed over the past half century, the methods by which diabetic retinopathy is diagnosed, classified, and treated have evolved enormously since Jaegar first described direct evidence of alterations in the macula of patients with glycosuria in 1856. 1 Although diabetic retinopathy is still the leading cause of vision loss in the working age population of many developed countries such as the United States, visual outcomes in diabetic patients continue to improve with substantial advancements in systemic diabetes control and more effective retinopathy therapy.
In 1952, Luft and associates 2 performed a hypophysectomy in the hope of ameliorating the vascular complications of diabetes, and in 1960, photocoagulation for the treatment of diabetic retinopathy was first reported by Meyer-Schwickerath, 3 who used a xenon arc photocoagulator to directly treat new vessels on the surface of the retina. Despite these efforts, by 1967 there were still no effective treatments available, prompting Duke-Elder to describe the visual complications of diabetes mellitus as “not preventable” and “relatively untreatable.”
Treatments developed in the early 1970s, such as argon laser photocoagulation as proposed by Beetham et al 4 and pars plana vitrectomy, were put to the test during the ensuing years in several landmark clinical trials that ultimately proved their remarkable effectiveness in preserving vision in patients with diabetes mellitus. The first of such trials was the Diabetic Retinopathy Study (DRS) of 1976, which showed that the rate of severe visual loss (SVL) in high-risk proliferative diabetic retinopathy (PDR) could be reduced by as much as 60% following the timely application of panretinal photocoagulation (PRP). 5 In the mid-1980s, results from the Early Treatment Diabetic Retinopathy Study (ETDRS) and the Diabetic Retinopathy Vitrectomy Study (DRVS) become available. The ETDRS demonstrated that providing PRP at or as an eye-approached high-risk PDR could reduce the risk of SVL by 96%. The ETDRS also demonstrated that focal laser photocoagulation treatment to the macula could substantially reduce the risk of moderate visual acuity loss in patients with diabetic macular edema. 6 The Diabetic Retinopathy Vitrectomy Study (DRVS) showed that in eyes with severe vitreous hemorrhage, early intervention with pars plana vitrectomy resulted in better visual outcomes than deferral of surgery in patients with type I diabetes mellitus. 7
The past decade has witnessed the advent of anti-vascular endothelial growth factor (anti-VEGF) agents for diabetic eye disease. Major phase 3 clinical trials including the Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol I, 8 RIDE/RISE, 9 and VISTA/VIVID 10 studies have demonstrated that these medications are highly effective and superior to macular laser photocoagulation in improving visual acuity outcomes in eyes with diabetic macular edema. The formation of the National Institutes of Health–sponsored DRCR.net, the nation’s largest collaborative network of academic and community sites dedicated to research in diabetic retinopathy, was another recent landmark in the field of clinical research for diabetic retinopathy. Since its inception in 2002, the DRCR.net has designed, implemented, and reported on more than 20 clinical studies that have informed the current standard of care for diabetic eye disease on diverse topics including imaging of the diabetic retina, optimal protocols for macular laser photocoagulation, and the safety and efficacy of intravitreal anti-VEGF and steroid treatment for diabetic macular edema.
Clinical trials have better defined those eyes at greatest risk, the appropriate times to intervene, and the therapeutic modalities that are most effective in preserving vision in patients with diabetes. This chapter reviews the clinical manifestations and pathophysiologic mechanisms underlying the visual complications of diabetes mellitus, as well as the current appropriate management of diabetic retinopathy based on the results of major clinical studies.
10.2 Epidemiology
Despite treatment advances, and overall improvements in glycemic and hypertensive control over the past few decades, diabetic retinopathy remains a leading cause of new-onset blindness in working age adults in the United States. It is estimated that approximately 7.7 million Americans had diabetic retinopathy in 2010, but this number will nearly double to 14.6 million by the year 2050. 11 The strongest risk factors for development of diabetic retinopathy are longer duration of diabetes and worse glycemic control. The prevalence of all types of retinopathy increases with the duration of diabetes, probably reflecting the consequences of prolonged hyperglycemia. Early reports suggested that, after 15 years of diabetes duration, nearly all patients (98%) with type 1 diabetes and more than 78% of patients with type 2 diabetes have some degree of retinopathy. 12 , 13 Uncontrolled hypertension and cholesterol have also been related to worse outcomes in diabetic retinopathy. Young persons with type 1 diabetes are more likely to suffer severe visual complications from PDR during their lifetime, whereas a greater total number of older patients with type 2 diabetes mellitus experience visual loss from macular edema.
The projected rapid rise in diabetes over the next few decades will place approximately 592 million individuals at risk for vision complications from diabetes worldwide by the year 2035. 14 Major challenges will be the timely evaluation and triage of these patients in order to provide access to expert care across potential socioeconomic and geographic barriers. In this era, a critical role for the ophthalmologist is to identify accurately the stages of retinopathy at which patients are most amenable to treatment, as ocular interventions such as intravitreal anti-VEGF injections, laser photocoagulation, and surgery are most effective in preserving vision when initiated before vision is lost from macular edema or the complications of proliferative retinopathy.
10.3 Preclinical Molecular and Pathophysiologic Changes in the Diabetic Retina
Diverse molecular pathways have been implicated in the mechanisms that underlie the development of diabetic retinopathy. Eyes with active neovascularization from diabetes or with diabetic macular edema have been shown to have increased levels of VEGF, 15 which is a potent enhancer of both ocular angiogenesis and retinal vascular permeability. Currently, the most effective clinical interventions for diabetic macular edema target the VEGF molecule to block its activity. Such approaches are currently being studied to determine their efficacy in the treatment of PDR. Multiple earlier stage pathways may play key roles in the onset or worsening of diabetic eye disease, including increased oxidative stress, activation of protein kinase C, and the presence of advanced glycation end products. The sorbitol pathway has also been a subject of investigation because under hyperglycemic conditions, aldose reductase reduces many aldose sugars (glucose, galactose) to their respective sugar alcohols (sorbitol, galactitol), which can subsequently accumulate to high levels in cells. Animal studies have demonstrated increased pericyte dropout, formation of microaneurysms, and capillary acellularity in nondiabetic dogs fed a diet enriched with galactose. 16 However, the role of aldose reductase inhibitors (sorbinil) in preventing these microvascular changes in animal models has been controversial, and their efficacy in slowing down the progression of diabetic retinopathy in humans has not been demonstrated. 17
Although there is increasing evidence that abnormalities of the neural retina such as thinning of the inner retinal layers are present in early diabetes, 18 the fundus changes observed in diabetic retinopathy are primarily the result of pathologic changes within the retinal blood vessels. One of the earliest findings in the diabetic retina is loss of pericytes, the supporting mural cells of the retinal capillaries. In the normal retinal vasculature, endothelial cells and intramural pericytes are distributed in equal numbers in a ratio of approximately 1:1. Trypsin-digest preparations have shown that eyes with diabetic retinopathy demonstrate a preferential loss of microvascular pericytes. 19 Diabetic retinal capillaries can also become acellular, and studies correlating fluorescein angiograms with trypsin-digest preparations provide direct evidence that acellular ghost capillaries are usually nonperfused. 20 Perhaps as a response to retinal hypoxia, the adjacent capillary bed becomes dilated and hypercellular. Intraluminal factors that contribute to abnormalities in the retinal vasculature even before clinically observable signs of retinal vasculopathy include slowing of retinal blood flow and blood viscosity abnormalities due to elevated plasma fibrinogen, increased platelet adhesiveness, and abnormal aggregation properties of erythrocytes. Thickening of endothelial basement membranes also occurs, which can cause luminal narrowing and potentially lead to retinal capillary closure.
The endothelial cell is the principal site of breakdown in the inner blood–retinal barrier that leads to abnormal vascular permeability in the diabetic eye. Defects in the tight junctions between endothelial cells may arise secondary to obstruction of adjacent vessels, or from the well-documented dropout of capillary pericytes. 21 Even before any retinopathy is demonstrable clinically, evidence of abnormal vascular permeability may be seen on fluorescein angiography as focal staining of the arteriole wall. As the leakage becomes more widespread, accumulation of fluid and plasma constituents in the surrounding retina can lead to marked retinal thickening, cystoid changes in the fovea, and the formation of hard exudates (composed of plasma lipoprotein).
10.4 Clinical Features
Diabetic retinopathy is broadly classified as either nonproliferative diabetic retinopathy (NPDR) or PDR. The microvascular changes that occur in NPDR are limited to the confines of the retina and do not include the growth of new vessels from the existing retinal vasculature. In contrast, PDR is characterized by the growth and possible extension of retinal neovascularization beyond the internal limiting membrane. Diabetic macular edema, the most common cause of decreased central vision in patients with diabetes, can occur in either NPDR or PDR. Each of these manifestations of diabetic retinal vascular pathology is associated with hallmark lesions that are described in this section.
Pearls
Macular edema is the most common cause of decreased visual acuity in patients with diabetes mellitus. Although more common with more advanced disease, it can be present at any stage of diabetic retinopathy.
One of the earliest and most common clinically observable lesions in diabetic retinopathy is the microaneurysm, a saccular outpouching of the retinal capillary (Fig. 10-1). Initially detectable only on fluorescein angiography as small hyperfluorescent foci that may or may not leak fluorescein in the late phase of the angiogram, they subsequently enlarge and appear as scattered, red dots on ophthalmoscopic examination. Two hypotheses that have been proposed for microaneurysm formation are as follows: (1) saccular outpouchings occur at the sites of pericyte degeneration and (2) microaneurysm formation involves a proliferative cellular response to focal retinal hypoxia. Microaneurysms tend to cluster at the margins of capillary nonperfusion and follow a typical life cycle of gradual enlargement, thickening, and hyalinization of the wall, and eventual auto-occlusion by encroachment of the thickened wall into the lumen. It has been suggested that the rate of formation and turnover appears to be correlated with the level and severity of diabetic retinopathy. 22
With progression of NPDR, intraretinal hemorrhages resulting from ruptured microaneurysms and decompensated capillaries become visible, with superficial flame-shaped hemorrhages being located in the nerve fiber layer and dot-shaped hemorrhages within the deeper retina (Fig. 10-2). Occasionally, retinal hemorrhages in diabetes may demonstrate a white center, reflecting either their fibrin component or their origin from a hyalinized microaneurysm.
Another important fundus sign of retinal ischemia is the development of intraretinal microvascular abnormalities (IRMAs), a descriptive term for irregular, segmental dilations and vascular looping of the retinal capillary bed (Fig. 10-3b). IRMAs are thought to represent either a compensatory dilation of preexisting vascular channels (shunt vessels) or a form of intraretinal neovascularization. In longitudinal fluorescein angiographic studies, IRMAs have been shown to develop slowly within the focal areas of arteriolar nonperfusion over the course of months. 23 The network of dilated capillaries appears to originate from the venous side of the circulation and also drains into the retinal veins, with a direct connection to a retinal arteriole being a rare finding. IRMAs are distinguishable from preretinal neovascularization in that they remain within the confines of the retina and do not leak fluorescein. An additional hallmark finding in diabetic retinopathy is venous caliber abnormalities, or venous beading, consisting of alternating areas of dilation and constriction of the retinal venules (Fig. 10-3a). “Reduplication” of venous segments and abnormal venous “loop” formation are also common in the diabetic retina.
Increased vascular permeability of the diabetic retina is manifested by the exudation of fluid, lipoproteins, and various other plasma constituents into the retinal neural tissue. The leakage stems from microaneurysms and defective small retinal vessels and can result in the formation of intraretinal cysts and/or accumulation of subretinal fluid (Fig. 10-4). Hard exudates are commonly seen along the borders of zones of current or previous retinal thickening and consist of intraretinal yellow cholesterol deposits that are hyperreflective on imaging with optical coherence tomography (OCT).
Retinal capillary abnormalities can affect adjacent arterioles, resulting in arteriolar closure and discrete areas of capillary dropout or nonperfusion. Clinically, the most obvious manifestation of such arteriolar ischemia is the cotton-wool spot (Fig. 10-5), a localized infarct of the nerve fiber layer that results from occlusion of the terminal arteriole (precapillary arteriole). Cotton-wool spots in diabetic eyes tend to persist for extended periods; their mean half-life is approximately 8 months in diabetic patients younger than 40 years and 17 months in those older than 40 years, compared with about 6 weeks in hypertensive retinopathy. 24 Once the cotton-wool spot resolves, the inner retina layers may become atrophic, with the site becoming ophthalmoscopically visible as a focal, depressed area. Data from the ETDRS suggest that isolated cotton-wool spots represent a common but nonprognostic sign of diabetic retinopathy and do not necessarily correlate with either the angiographic evidence of retinal ischemia or a high likelihood of progression to proliferative retinopathy. 25
In performing fundus examinations, it is important to keep in mind that the characteristic intraretinal lesions of diabetic retinopathy may be absent in the severely ischemic stages of NPDR. Cotton-wool spots and retinal exudates tend to resolve with time, and blot hemorrhages and IRMAs may also disappear following extensive capillary nonperfusion. With a reduction in the normal vascularity of the retina, fewer hemorrhages and microaneurysms may be apparent and some arterioles may become thin, white threads, producing a fundus appearance that has been described as “featureless” retina. On a cursory inspection, such an absence of lesions can mislead the examiner into substantially underestimating the severity of the retinopathy.
Pearls
In some cases, as the NPDR progresses and the retina becomes severely ischemic, the usual characteristics of nonproliferative retinopathy may actually become less apparent. This presentation is often referred to as a “featureless” fundus, and with a cursory retinal examination, the severity of the retinopathy may be underestimated.
In response to retinal ischemia resulting from retinal capillary nonperfusion, vasoproliferative factors such as VEGF are released from the retina and induce the development of neovascularization on the retina, optic nerve head, and/or iris. Preretinal neovascular networks have a propensity to bleed into the vitreous cavity and obscure vision. They also retain the potential for differentiation into fibroblasts, and this fibrous component contributes to the formation of firm adhesions at the interface between the retina and vitreous body. As the fibrovascular tissue contracts, these vitreoretinal adhesions may lead to complications involving the underlying retina, such as traction retinal detachment, focal areas of retinoschisis, and retinal breaks. When neovascularization occurs in the anterior chamber angle and iris (rubeosis iridis), increased intraocular pressure from neovascular glaucoma can result.
A presumably distinct type of optic nerve head swelling with a relatively benign clinical course, termed diabetic papillopathy, is occasionally seen in patients with various degrees of diabetic retinopathy (Fig. 10-6). This entity was originally reported in young patients with type 1 diabetes mellitus, but it can also occur in older individuals with type 2 diabetes. 26 It is more likely to occur in patients with worse glycemic control. The visual prognosis is usually good and the optic disc edema is often self-limited. As a cause of disc edema, diabetic papillopathy is considered a diagnosis of exclusion but can be differentiated by the following constellation of features: common bilateral (simultaneous or sequential) presentation, minimal or no signs or symptoms of significant optic nerve dysfunction, hyperemic disc swelling (with prominent, telangiectatic disc vessels), and resolution occurring during a period of months without the appearance of optic atrophy. Clinically, it is important to distinguish the radially oriented, telangiectatic vessels of diabetic papillopathy from disc neovascularization, which is more randomly oriented and typically elevated above the plane of the disc and retina. An association between diabetic papillopathy and widespread retinal capillary disease has been found in a large series, supporting the suspicion that diabetes-related microangiopathy is related pathogenetically to the disc swelling in some way. 26
Controversial Points
Diabetic papillopathy is a transient swelling of the optic nerve head in the setting of diabetic retinopathy. Clinically, it is differentiated from an ischemic optic neuropathy by the lack of significant, permanent optic nerve dysfunction. Whether these cases represent mild ischemic events or vascular incompetence of the optic nerve head remains controversial.
Although a history of systemic hyperglycemia and the bilateral, generally rather symmetric presentation of diabetic retinopathy makes the diagnosis obvious in most cases, other entities that may present with similar microangiopathic changes in the posterior pole should be considered in the differential diagnosis for diabetic retinopathy. The most common ocular diseases that may mimic diabetic retinopathy are other retinal vascular disorders, including central and branch retinal vein occlusion (CRVO, BRVO), hypertensive retinopathy, ocular ischemic syndrome (OIS), radiation retinopathy, human immunodeficiency virus (HIV) retinopathy, and idiopathic juxtafoveal telangiectasis. The fundus appearance, accompanying systemic history, and asymmetry of presentation are useful in ruling out the majority of these conditions. A recent CRVO may closely resemble the fundus findings of diabetic retinopathy, and typically presents with venous dilation, cotton-wool spots, and a distribution of retinal hemorrhages involving all four quadrants. These two conditions also affect similar populations, and CRVOs are thought to occur with a higher frequency in diabetic patients, particularly in the younger age groups. However, the symptoms associated with a CRVO tend to be more acute, and there is typically more asymmetry between the eyes. Finally, it should be kept in mind that patients sometimes present with two different retinal diseases simultaneously (i.e., BRVO or HIV retinopathy and NPDR).
10.5 Nonproliferative Diabetic Retinopathy
10.5.1 Diagnosis and Staging
The ETDRS validated a classification system for diabetic retinopathy severity grading that has been utilized thereafter in numerous epidemiologic and interventional clinical studies that have set the current gold standards for the diagnosis and management of diabetic retinopathy. This system relies on grading of diabetic retinopathy findings in comparison to standard photographs. NPDR is divided into severity levels (Table 10-1) that predict the risk for retinopathy progression over time. The risk of diabetic retinopathy progression for an individual eye is strongly related to the presence and extent of the following clinical findings: increasing severity of intraretinal hemorrhages and microaneurysms, venous beading, and IRMAs. Conversely, hard exudate deposits have not been found to be a significant risk factor for diabetic retinopathy progression (although they are associated with visual loss from diabetic macular edema), and the presence of cotton-wool spots is only weakly correlated with subsequent progression to PDR. With stratification into three general groups based on these intraretinal findings, the ETDRS found a substantial difference in the 1-year risk for development of proliferative retinopathy between the mildest and most severe levels of NPDR. 27
Mild NPDR is defined as the presence of at least one retinal microaneurysm and a minimal number of intraretinal hemorrhages. Patients with mild NPDR have a 4% risk for progression to PDR within 1 year and a 15% risk for progression to high-risk PDR within 5 years. Moderate NPDR is characterized by more extensive hemorrhages and microaneurysms (more than on standard photograph 2A, Fig. 10-2). Cotton-wool spots and a limited amount of venous beading can also be seen in this stage. With moderate NPDR, the risk for progression to PDR within 1 year is 8 to 18%, and the risk for progression to high-risk PDR within 5 years is 24 to 39%.
Severe NPDR (formerly known as preproliferative retinopathy) is characterized by any one of the following (“four-two-one rule”):
Numerous hemorrhages and microaneurysms (greater than or equal to standard photograph 2A) in four quadrants
Definite venous beading in two or more quadrants
IRMA (greater than or equal to standard photograph 8A) in one or more quadrants
The intraretinal findings of severe NPDR reflect widespread arteriolar closure, and angiographic studies of patients with severe NPDR demonstrate extensive zones of capillary nonperfusion (Fig. 10-7). Eyes with severe NPDR have a 33% risk for development of PDR within 1 year and a 58% risk for development of high-risk PDR within 5 years. In certain situations, patients with severe NPDR may be candidates for scatter (panretinal) laser photocoagulation. Because progression to proliferative stages of retinopathy is often rapid in eyes with severe NPDR, frequent surveillance is important, and evaluation at 2- to 4-month intervals is recommended (Table 10-1).
Pearls
Eyes meeting the criteria for severe NPDR must be followed up closely, as the risk for progression to PDR is high. If close follow-up is not possible, scatter (panretinal) laser treatment should be considered to reduce the risk of vision loss from progression to PDR and PDR-related complications.
Analysis of angiographic characteristics from the ETDRS untreated (deferred) eyes indicates that fluorescein leakage, capillary loss and dilation, and various other arteriolar abnormalities are associated with the likelihood of progression to PDR. 28 Widespread capillary nonperfusion is a particularly significant risk factor for progression to PDR (Fig. 10-7); the extent of capillary closure seen on angiography appears to be correlated with the severity of new vessels involving the retina, optic disc, and anterior chamber angle. 29 Despite this correlation and the additional risk factors provided by fluorescein angiography, clinical examinations and/or color fundus photographs appear to give the same prognostic information. Therefore, the increase in power to predict progression to PDR provided by fluorescein angiography is not of enough clinical importance to warrant routine ordering of angiograms for patients with NPDR. 28 Ophthalmoscopic examination supplemented by color photography remains the mainstay of staging diabetic retinopathy severity levels, and periodic follow-up of all patients with diabetic retinopathy continues to be of fundamental importance to document progression.
The recent availability of instruments that can provide ultrawide field imaging of the retina, obtaining fields of up to 200 degrees with a single image, has sparked renewed interest in whether careful documentation of the retinal periphery outside the standard ETDRS 7 fields allows the detection of more retinal pathology and a more accurate assessment of risk for future worsening in eyes with diabetic retinopathy. Multiple studies have demonstrated that peripheral pathology is common in eyes of patients with diabetes and that this pathology suggests a more severe level of diabetic retinopathy than that documented within the ETDRS fields approximately 9 to 10% of the time (Fig. 10-8). 30 Studies have also found that eyes in which diabetic lesions are greater in extent or severity in the periphery as compared to within the ETDRS fields at baseline have a threefold higher risk of diabetic retinopathy worsening and a nearly fivefold higher risk of new-onset PDR over the subsequent 4 years. 31 If these results are confirmed in currently ongoing large, multicenter studies, these findings may substantively impact the manner in which we determine diabetic retinopathy severity and necessitate revision of the current standard severity grading guidelines.
10.5.2 Management and Course
The management of NPDR is based on the optimal medical control of diabetes, as patients with NPDR generally do not require PRP, nor are they treated with anti-VEGF therapy in the absence of diabetic macular edema. These eyes can be followed up safely at 2- to 12-month intervals as determined by the severity of retinopathy (Table 10-1). The most important systemic factor affecting the course of retinopathy appears to be blood glucose levels, although blood pressure and lipids play a role as well.
The Diabetes Control and Complications Trial (DCCT) evaluated the role of intensive diabetic management on the course of retinopathy in patients with insulin-dependent diabetes mellitus (IDDM). The DCCT showed that intensive glucose control with three or more daily injections of insulin delayed the onset and decreased the progression of all levels of retinopathy (beginning after 3 years of therapy) in comparison with treatment with conventional insulin dosing in the control group. 32 Intensive control also reduced the likelihood of requiring laser treatment (for proliferative retinopathy) by almost 60%. Careful monitoring is recommended for patients with significant eye disease who are starting on intensive control regimens, as a minority of patients may experience an initial worsening of retinopathy. However, long-term, intensive therapy still results in better outcomes. Although all levels of retinopathy included in the DCCT appeared to benefit from intensive glucose control, intensive therapy was more effective in preventing progression when initiated early in the course of IDDM. Additionally, the Epidemiology of Diabetes Interventions and Complications (EDIC) study conclusively showed that the benefits of early glycemic control in the DCCT intensive control group as compared to the conventional control group persisted for decades even after subsequent glycemic control in these two groups became equivalent. 33 All microvascular complications and the need for retinopathy treatment were dramatically reduced in the intensive versus conventional control group for nearly two decades after the DCCT ended. The rate of ocular surgery was reduced in the intensive control group as compared to the conventional control group by approximately 50% over a median follow-up of 23 years. 34 Therefore, the importance of early optimal control of blood glucose levels should be reinforced to patients as highly significant in reducing the risk for visual complications. Other systemic factors, such as hypertension, hyperlipidemia, and renal failure, can also contribute to the further progression of retinopathy and should be managed appropriately.
One of the aims of the ETDRS was to test the efficacy of systemic aspirin therapy in influencing the course of diabetic retinopathy. 35 In patients with NPDR or early PDR, taking two aspirin tablets a day (650 mg/d) did not produce any demonstrable effects on the progression of NPDR, rates of development of PDR, or visual acuity outcomes. Aspirin therapy also did not increase the risk for vitreous hemorrhage. Although these data do not support a therapeutic role for aspirin to affect diabetic retinopathy favorably, the results indicate that there are no ocular contraindications to aspirin at this dose if required for other medical issues.
Special Considerations
Although the regular use of aspirin does not favorably affect the course of diabetic retinopathy, its use for other indications, such as to reduce the risk of cardiovascular or cerebrovascular mortality, does not have adverse ocular effects in patients with any degree of diabetic retinopathy.
The potential accelerating effects of pregnancy on the natural course of diabetic retinopathy have long been acknowledged, and prospective studies have confirmed a strong association between the onset of pregnancy and worsening of retinopathy severity. 36 , 37 Those pregnant patients at highest risk for progression typically have had diabetes for an extended period and possess significant degrees of retinopathy at conception, whereas women who begin pregnancy with no retinopathy or mild background retinopathy, are unlikely to develop vision-threatening complications during pregnancy. 37 In the counseling of diabetic women who are pregnant or considering pregnancy, their baseline severity of retinopathy should be considered the most important prognostic factor for possible visual complications. Frequent retinal examinations are currently recommended for all pregnant women with diabetes (at least once per trimester), and earlier laser photocoagulation may be prudent in eyes with severe NPDR or early PDR in the setting of pregnancy.
10.5.3 Regression of NPDR with Intravitreal Anti-VEGF Therapy
The widespread use of anti-VEGF therapy as first-line treatment for center-involved diabetic macular edema has provided additional insight into the response of nonproliferative diabetic pathology to anti-VEGF. Clinical trials of the anti-VEGF agents, aflibercept and ranibizumab which are used to treat diabetic macular edema, have consistently demonstrated significantly reduced rates of two- and three-step worsening and increasing rates of two- and three-step improvement on the ETDRS diabetic retinopathy severity scale in eyes that are treated with these agents as compared with eyes that receive macular laser photocoagulation alone. 10 , 38 Substantial improvements in diabetic retinopathy severity level have been documented in eyes receiving treatment on an as needed basis for diabetic macular edema as well as in eyes receiving monthly anti-VEGF therapy. 39 These improvements can occur early in the course of therapy. Two-step and even three-step improvement in diabetic retinopathy severity was documented by 3-month follow-up in some eyes treated with monthly ranibizumab in the RIDE/RISE trials. A substantial proportion of eyes receiving anti-VEGF will eventually experience improvement. By 36 months of follow-up, 39 and 15% of the cohort of eyes that had received continuous monthly therapy with 0.3 mg ranibizumab in the RIDE/RISE studies had two- and three-step improvements, respectively. 38
Although these results are promising, treatment with anti-VEGF agents for NPDR in the absence of center-involved macular edema is not currently considered standard care. Phase 3 clinical trials of anti-VEGF for this indication are still pending. One consideration that may limit the use of current formulations of anti-VEGF for NPDR alone is that it is yet unclear how durable the effects of anti-VEGF are on retinopathy regression. In the RIDE/RISE open-label extension phase, eyes that initially received 36 months of continuous, monthly anti-VEGF treatment were transitioned to as needed dosing based solely on macular edema status. Although many of these eyes remained stable or improved in retinopathy severity level as compared to the start of the open-label extension, there were some eyes that worsened over time with this reduced frequency of anti-VEGF dosing. 40 Fortunately, there did not appear to be dramatic rebound rates of diabetic retinopathy worsening even in eyes receiving no anti-VEGF during the open-label extension. The majority of eyes remained stable or improved as compared to the start of the RIDE/RISE trials.
10.6 Proliferative Diabetic Retinopathy
The proliferative stage of diabetic retinopathy (PDR) is characterized by extraretinal neovascular proliferation that is thought to result from a compensatory response to widespread retinal ischemia. In addition to worse glycemic control, the factor most closely related to increased risk of PDR is longer duration of diabetes. In population-based studies, the prevalence of PDR in patients with diabetes onset at age younger than 30 years is near zero when diabetes has been present for less than 10 years, but then it rises rapidly to about 50% when the duration of diabetes reaches 20 years or longer. 12 , 13
10.6.1 Diagnosis
The diagnosis of PDR involves the observation of preretinal new vessels and/or fibrous tissue arising from the optic disc or elsewhere on the retina. These proliferative, immature vessels extend along the inner surface of the retina or into the vitreous cavity and are abnormal in their propensity to bleed into the vitreous cavity, thus obscuring vision. Furthermore, they can result in firm adhesions between the retina and vitreous body, and with contracture or attempted separation of the vitreous gel, they may give rise to the development of traction retinal detachments. Vitreous hemorrhage and traction retinal detachments involving the macula are two of the most common causes of SVL in eyes with PDR (Fig. 10-9).
Although new vessels may arise anywhere in the retina, they are most frequently observed in the posterior aspect of the fundus (within 45 degrees of the optic nerve), and are particularly common on the disc itself (Fig. 10-10 and Fig. 10-11). Among 1,377 control group eyes in the DRS with new vessels present in baseline photographs, 60% demonstrated neovascularization within 1 disc diameter of the optic disc (NVD). 41 NVD is usually readily identified as fine loops of vessels lying on the surface of the disc or bridging across the physiologic cup. New vessels arising from elsewhere on the retina (neovascularization of the retina elsewhere [NVE]) often form wheel-like networks, with vessels radiating like spokes from the center of the patch and a circumferential vessel bounding the periphery. NVE complexes may also be irregular in shape without a distinct radial pattern, or lie over retinal veins and appear to drain into them. A review of DRS baseline photographs demonstrated that 59% of eyes with NVE had their most advanced lesions in the temporal quadrants, suggesting that this is a common area for nonperfusion. 42
It is often difficult to distinguish between IRMAs and nonelevated NVE. A magnified stereoscopic view, obtained with either contact lens biomicroscopy or stereoscopic 30-degree photographs, may aid in the differentiation of early neovascularization by demonstrating its extraretinal nature and more superficial location. OCT can also aid in determining the preretinal location of retinal neovascularization. Preretinal new vessels can also be distinguished by their unique ability to cross both arterioles and veins in the underlying retina. In particularly difficult cases, fluorescein angiography can be used to demonstrate the profuse dye leakage, characteristic of true neovascularization. Routine examination for early NVE should include both slit-lamp biomicroscopy of the posterior pole and examination for preretinal or vitreous hemorrhages in the periphery with indirect ophthalmoscopy.
When a patient presents with a fresh vitreous hemorrhage in the absence of any detectable neovascularization, examination of the more peripheral retina with the Goldmann three-mirror lens or fluorescein angioscopy using the indirect ophthalmoscope may be helpful. When new vessels still cannot be found, one should remember that a vitreous hemorrhage may also arise from a peripheral retinal tear, a partially avulsed retinal vessel, or the complete avulsion of a small neovascular patch from its connections to the disc or retina.
10.6.2 Pathophysiology
A generally accepted explanation for the pathogenesis of endothelial cell proliferation and new vessel formation is ischemia of the inner retinal layers leading to the release of “vasoproliferative factors” from the ischemic retina, such as VEGF. Such vessel-stimulating growth factors act locally and also diffuse through the vitreous to other areas of the retina, the optic disc, and the anterior chamber, causing neovascularization at these sites. Preretinal new vessels characteristically evolve through a cycle of proliferation followed by partial or complete regression. Their initial appearance is that of fine new vessels accompanied by minimal fibrous tissue that grow along the anterior surface of the retina. As the abnormal vessels increase in size and extent, the accompanying fibrous component, composed of both fibrocytes and glial cells, also undergoes a comparable rate of growth. A period of regression ensues, characterized by a decrease in the number and caliber of the vessels at the center of the patch, followed by their partial replacement with fibrous tissue. Fresh, active vessels are commonly seen emerging from the edges of partially regressed patches, and patches of neovascularization at different stages of development may be seen in the same eye.
Neovascular complexes may cycle through all these stages without causing any visual sequelae. Most of the visual complications of PDR can be attributed to the contraction of fibrovascular tissue growing along the posterior hyaloid face, which leads to the onset of posterior vitreous detachment (PVD). Like the age-related PVD that occurs secondary to vitreous syneresis, vitreous detachment in diabetic eyes usually begins in the posterior pole, most frequently near the superotemporal vessels, temporal to the macula, and above or below the disc. 43 However, PVD in diabetic eyes with PDR is not a smoothly progressive process and often spreads in an asymmetric, abrupt fashion, its advancing edge impeded by vitreoretinal adhesions associated with patches of neovascularization. The posterior vitreous surface also tends to vary in thickness, with alternating thin and thicker areas imparting a “Swiss cheese” appearance, but without actual hole formation. 43 Traction exerted by the shrinking vitreous body on fragile fibrovascular proliferations contributes to the recurrent vitreous hemorrhages that coincide with the progression of a PVD, and symptomatic vitreous hemorrhages are typically accompanied by some clinical evidence of localized PVD.
In addition to vitreous hemorrhage, vitreous contraction can also lead to complications involving the underlying retina, such as avulsion of retinal vessels, distortion or dragging of the macula, formation of retinal breaks, and traction retinal detachments. Tractional detachments in the setting of PDR are usually confined to the posterior fundus, most commonly along the temporal arcades, with possible extension into the macula. Continued vitreoretinal traction can also lead to the formation of retinal breaks and the development of a combined traction–rhegmatogenous retinal detachment. Retinal breaks in PDR are typically small, difficult to identify, and located adjacent to areas of fibrovascular proliferations. Traction on the retina can also cause focal areas of retinoschisis that may be difficult to distinguish from full-thickness retinal detachment.
When a PVD has reached completion or is no longer progressing, proliferative retinopathy tends to enter the burned-out or “involutional” stage. Vitreous hemorrhages decrease in frequency as well as severity, although many months may elapse before there is substantial vitreous clearing from previous hemorrhages. A marked reduction in the caliber and number of retinal vessels is also characteristic. Loss of central vision experienced at this quiescent stage is best explained by severe macular ischemia, central vitreous hemorrhage, or involvement of the macula by traction retinal detachment.
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