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From: Contemporary Cardiology: Diabetes and Cardiovascular Disease, Second Edition Edited by: M. T. Johnstone and A. Veves © Humana Press Inc., Totowa, NJ
16 Diabetic Retinopathy
Lloyd Paul Aiello,
MD,
PhDand Jerry Cavallerano,
OD,
PhDCONTENTS
INTRODUCTION
PATHOPHYSIOLOGY OF DIABETIC RETINOPATHY AND STRUCTURAL
CHANGES OF RETINAL MICROCIRCULATION
NATURAL HISTORY AND CLINICAL FEATURES OF DIABETIC
RETINOPATHY
CONCLUSIONS
APPENDIX
REFERENCES
INTRODUCTION
Diabetic retinopathy (DR) is a microvascular complication that eventually afflicts virtually all patients with diabetes mellitus (DM) (1). Despite decades of research, there is presently no known cure or means of preventing DR, and DR remains the leading cause of new-onset blindness in working-aged Americans (1). Several nationwide clinical trials have demonstrated that scatter (panretinal) laser photocoagulation reduces the 5-year risk of severe vision loss (i.e., best corrected visual acuity of 5/200 or worse) from prolifera- tive DR from as high as 60% to less than 4%. Additionally, timely and appropriate focal laser photocoagulation for clinically significant diabetic macular edema (DME) reduces the risk of moderate vision loss (i.e., a doubling of the visual angle) from DME from nearly 30% to approx 12%. Vitrectomy surgery, with endolaser photocoagulation as indicated, can frequently prevent further vision loss or restore useful vision in eyes that have nonresolving vitreous hemorrhage or traction retinal detachment threatening cen- tral vision. Although numerous new therapies are under investigation with some already in phase 2 or 3 clinical trials, until a prevention or cure for diabetes is discovered, the keys to preventing vision loss from DR are regular eye examinations to determine the need for timely laser photocoagulation and rigorous control of blood glucose and any accompany- ing systemic medical conditions, such as hypertension, renal disease, and dyslipidemias.
This chapter reviews the current understanding of the etiology and pathophysiology of DR, the clinical manifestations of the disease, and current guidelines for appropriate disease management and treatment strategies.
PATHOPHYSIOLOGY OF DIABETIC RETINOPATHY
AND STRUCTURAL CHANGES OF RETINAL MICROCIRCULATION Early Studies
Diabetic retinopathy (DR) is a highly specific retinal vascular complication of both type 1 and type 2 diabetes. Initial studies (2–4) of DR concentrated on retinal microaneurysms, an early clinical sign of retinal disease. Cogan, Toussaint, and Kuwabara pioneered many of these early investigations to elucidate the pathophysiology of DR (2).
Microaneurysms were shown to develop bordering areas of occluded capillaries with either normal or hyperplastic endothelial linings (4). Additionally, a loss of mural cells in the diabetic vessels resulted in outpouchings of the capillary walls. The retinal microaneurysms appeared to develop from these areas that were deficient in mural cells.
The relative retinal ischemia common to DR and numerous other retinal vascular disorders is thought to underlie the development of retinal neovascularization (NV) and edema (5,6). In 1948, Michaelson postulated that retinal ischemia initiated the release of a vasoproliferative factor (5). This putative vasoproliferative factor resulted in new ves- sel growth at the optic disc and other areas of the retina and iris, and might account for the increased vascular permeability associated with these disorders. As discussed below, recent studies have greatly increased our understanding of these vasoproliferative factors.
Studies using experimentally induced diabetes in dogs demonstrated that hyperglyce- mia, characterized by deficient insulin activity, is capable of eliciting DR, even in animals that do not have hereditary forms of diabetes (7–11). Engerman’s studies of alloxan- induced diabetic dogs showed that progression of DR was related to the level of glycemic control, further underscoring the role of hyperglycemia as the underlying etiology of DR.
Present Understanding
More recent investigations of DR have focused on the biochemical basis of the disease (12,13). Studies of numerous biochemical pathways, including the sorbitol pathway, advanced glycation end-products (AGE), and the protein kinase C (PKC) pathway dem- onstrate that biochemical changes occur in the retina long before clinically evident ab- normalities are observed. These studies suggest that if appropriate novel therapeutic interventions can be identified, early intervention might prevent or reverse the microvas- cular abnormalities associated with DR.
Numerous studies have focused on the polyol pathway resulting from the increased flux through this pathway in the diabetic condition. Aldose reductase is present in the pericytes of the retinal capillaries and because damage to the pericytes occurs early in the evolution of DR, the role of aldose reductase in the pathogenesis of DR has been exten- sively evaluated. Furthermore, aldose reductase is present in nerve tissue and induces depletion of myoinositol, leading to a decrease in nerve conduction velocity in diabetic neuropathy. Inhibitors of aldose reductase have been effective in preventing damage to the lens, in preventing thickening of retinal capillary basement membranes in diabetic animals, and in improving nerve conduction velocity in patients with diabetic neuropa- thy. Thus, it has been postulated that aldose reductase inhibitors may also be able to
prevent, delay, or halt the development or progression of DR. Unfortunately, clinical trials of the aldose reductase inhibitor sorbinil have not proved clinically effective in preventing the progression of DR (14,15).
More recent studies have evaluated AGE. The presence of high concentrations of glucose can result in the glycation of numerous proteins, especially albumin. These glycated proteins adversely affect cellular and capillary function, structure, and metabo- lism. Exposure to glycated proteins induces changes in the glomerulus similar to those observed in diabetes, and changes in the nerves resembling diabetic neuropathy. The effect of AGE in the eye is being actively studied. AGE can affect both the neuronal and vascular components of the eye, and induce numerous growth factors. As such, it may play a role in the progression of DR.
Other studies have concentrated on the hyperglycemia-induced activation of PKC, which can affect a wide range of vascular functions including vascular permeability, contractility, retinal blood flow, and growth factor expression and signal transduction (16,17). Hyperglycemia is known to increase the level of diacyglcerol (DAG), which is the physiological activator of PKC. Much of the vascular dysfunction associated with DM is thought to be mediated through this increased action of PKC. There are numerous isoforms of PKC; however, in the retina, PKCF, -G, and -_ are primarily expressed.
Numerous recent investigations have suggested that the G isoform of PKC is principally responsible for the pathology associated with the diabetic state (16). In laboratory ani- mals, PKCG selective inhibitors have been shown to ameliorate renal dysfunction, retinal blood-flow abnormalities, vascular permeability (17), and NV associated with DM and diabetes-like models (18). Additionally, activation of PKC is involved in the expression of critical growth factors such as vascular endothelial growth factor (VEGF) (19), which mediates much of the NV and vascular permeability in the eye. Furthermore, activation of the G isoform of PKC is required in order for VEGF to induce its actions within the cell.
Thus, inhibition of PKC (especially the G isoform) is likely to block numerous pathologi- cal processes in the diabetic condition that result in the vascular dysfunction and ocular complications associated with diabetic retinopathy. Because a PKCG-selective inhibitor has been shown to be well tolerated in animals and ameliorates many of the abnormalities associated with diabetes, these molecules are now under evaluation in clinical trial.
NATURAL HISTORY AND CLINICAL FEATURES OF DIABETIC RETINOPATHY
Epidemiology
Duration of diabetes is closely associated with the onset and severity of DR. DR is rare in prepubescent patients with type 1 diabetes, but nearly all patients with type 1 diabetes and more than 60% of patients with type 2 diabetes will develop some degree of retin- opathy after 20 years (1,20,21). In patients with type 2 diabetes, approx 20% will have retinopathy at the time of diabetes diagnosis, and most will develop some degree of retinopathy over subsequent decades. DR is the most frequent cause of new-onset blind- ness among Americans adults aged 20 to 74 years. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy, approx 4% of younger-onset patients (aged <30 years at diabe- tes diagnosis) and nearly 2% of older-onset patients (aged >30 years at diabetes diagno- sis) were legally blind. In the younger-onset group, 86% of blindness was attributable to DR. In the older-onset group, in which other eye diseases were also common, 33% of the cases of legal blindness were a result of DR (20,21).
Level of glycemic control is another significant risk factor for the onset and progres- sion of DR (22–27). The Diabetes Control and Complications Trial (DCCT) demon- strated a clear relationship between hyperglycemia and diabetic microvascular complications in type 1 diabetes, including retinopathy, nephropathy, and neuropathy (22–27). In the DCCT, 1,441 patients with type 1 diabetes who had either no retinopathy at baseline (primary prevention cohort) or minimal to moderate nonproliferative diabetic retinopathy (NPDR) (secondary progression cohort) were treated by either conventional diabetes therapy (i.e., one or two injections of insulin daily) or intensive diabetes man- agement (i.e., three or more daily insulin injections or a continuous subcutaneous insulin infusion). The patients were followed for 4 to 9 years. The DCCT showed that intensive insulin therapy reduced or prevented the development of DR by 27% as compared with conventional therapy. Additionally, intensive therapy reduced the progression of DR by 34% to 76%, and had a substantial beneficial effect over the entire range of retinopathy.
This improvement was achieved with an average 10% reduction in HbA1c from 8% to 7.2%. These results underscore that although intensive therapy does not prevent retinopa- thy completely, it reduces the risk of the development and progression of DR.
The United Kingdom Prospective Diabetes Study (UKPDS) found similar results for patients with type 2 diabetes. In the UKPDS, 4209 patients with newly diagnosed type 2 diabetes who had either no retinopathy at baseline (primary prevention cohort) or minimal to moderate NPDR (secondary progression cohort) were randomly assigned to conventional or intensive blood glucose control, using sulfonylureas and/or insulin. The UKPDS showed that intensive therapy reduced the risk of all microvascular endpoints, including vitreous hemorrhage, retinopathy requiring laser photocoagulation, and renal failure by 25%. Overall, intensive control resulted in a 29% reduction in need for laser photocoagulation, a 17% reduction in a two-step progression of DR, a 24% reduction in the need for cataract extraction, a 23% reduction in vitreous hemorrhage, and a 16%
reduction in legal blindness. This improvement was achieved with an average 10%
reduction in HbA1c from 7.9% to 7% (81).
Renal disease, as manifested by microalbuminuria and proteinuria, is yet another significant risk factor for onset and progression of DR (28,29). Similarly, hypertension is associated with proliferative DR and is an established risk factor for the development of DME (30,82). Both renal retinopathy and hypertensive retinopathy can be superim- posed on DR. Additionally, elevated serum lipid levels are associated with lipid in the retina (hard exudates) and visual loss (31,83,84) Thus, systemic control of blood pres- sure, renal disease, and serum lipids are critically important components in the manage- ment of DR (85). Additionally, several studies suggest that pregnancy in patients with type 1 diabetes patients may aggravate retinopathy (32–34).
Clinical Findings in Diabetic Retinopathy
Clinical findings associated with early and progressing DR include hemorrhages and/
or microaneurysms (H/Ma), cotton wool spots (CWS), hard exudates (HE), intraretinal microvascular abnormalities (IRMA), and venous caliber abnormalities (VCAB), includ- ing venous loops, venous tortuosity, and venous beading. Microaneurysms are saccular outpouchings of the capillary walls. These microaneurysms can leak fluid, causing areas of hyperfluorescence on a fluorescein angiogram. Ruptured microaneurysms, leaking capillaries, and IRMAs result in intraretinal hemorrhages. These intraretinal hemor- rhages can be “flame-shaped” or spot-like in appearance, reflecting the architecture of
layer of the retina in which they occur. Flame-shaped hemorrhages are generally in the nerve fiber layer of the retina, which runs parallel to the retinal surface. Dot or pinpoint hemorrhages are deeper in the retina, reflecting cells that are arranged perpendicular to the retinal surface.
IRMAs are abnormal vessels located within the retina itself. They may represent either localized intraretinal new vessel growth or shunting vessels through areas of poor vas- cular perfusion. It is common for IRMAs to be found adjacent to CWS, which are feathery lesions in the nerve fiber layer of the retina resembling the fluffy appearance of cotton.
CWS are caused by microinfarcts in the nerve fiber layer. CWS in a ring or partial ring surrounding the optic nerve head are frequently signs of severe renal disease or hyper- tension.
VCABs are a sign of severe retinal hypoxia. VCABs can be associated with any of the lesions of NPDR. However, in many cases of severe retinal hypoxia, distal retinal areas may be free of nonproliferative lesions resulting from the extensive vascular loss present.
Such “lesion-free” areas are termed “featureless retina,” and are a sign of severe retinal hypoxia.
Vision loss from DR generally results from persistent, nonclearing vitreous hemor- rhage, traction retinal detachment, and/or DME. NV and contraction of the accompany- ing fibrous tissues can distort the retina and lead to traction retinal detachment. If a traction retinal detachment involves or threatens the macula, irreversible severe vision loss may result. Also, the new vessels may bleed, causing preretinal or vitreous hemor- rhage. Pars plana vitrectomy can relieve the traction in cases in which vision is threatened and can remove persistent vitreous hemorrhage, often restoring useful vision. The most common cause of vision loss from diabetes, however, is macular disease and macular edema. Macular edema is more likely to occur in patients with type 2 diabetes, which represents 90% of the diabetic population. In diabetic macular disease, macular edema or nonperfusion of the capillaries in the macular area results in the loss of central vision.
Classification of Diabetic Retinopathy
Generally, DR progresses from mild nonproliferative disease, through moderate and severe nonproliferative disease, to proliferative diabetic retinopathy. Mild NPDR is characterized by microvascular abnormalities such as H/Ma, CWS, and increased vascu- lar permeability. Moderate and severe NPDR are characterized by VCABs, IRMAs, and vascular closure. Proliferative diabetic retinopathy (PDR) is characterized by vasoproliferation on the retina and posterior surface of the vitreous. In elucidating the natural history of DR, the Early Treatment Diabetic Retinopathy Study (ETDRS) evalu- ated the risks of progression from no or minimal retinopathy to sight-threatening PDR.
The ETDRS was a muilticentered, randomized clinical study designed to test (a) whether 650 mg of aspirin per day had any effect on the progression of DR, (b) whether focal laser photocoagulation for macular edema reduced the risk of moderate vision loss (i.e., a doubling of the visual angle; e.g., 20/20 reduced to 20/40), and (c) whether scatter laser photocoagulation was more beneficial in reducing the risk of severe vision loss (i.e., best corrected visual acuity of 5/200 or worse) when applied prior to the development of high- risk PDR, as defined below. The EDTSR enrolled 1377 patients at 22 centers nationwide and in Puerto Rico.
Major conclusions of the ETDRS are as follow: (a) a daily dose of 650 mg of aspirin did not prevent or retard the progression of DR and did not result in an increased risk of
vitreous hemorrhage or greater need for cataract surgery, (b) focal laser photocoagulation for DME reduced the risk of moderate visual loss by at least 50%, and (c) both early scatter laser photocoagulation and photocoagulation at the time of reaching high-risk PDR resulted in significant reduction in the risk of severe visual loss, although some groups, including those with type 2 diabetes or type 1 diabetes of long duration, had a greater benefit of early treatment (74). Importantly, the ETDRS showed that certain nonproliferative lesions, particularly venous beading, IRMAs, and H/Mas were signifi- cant prognosticators for the development of proliferative disease within a 12-month period. Pregnancy, puberty, and cataract surgery can accelerate these changes.
DR is broadly classified as NPDR and PDR. As described above, the lesions of NPDR include dot and blot H/Mas, CWS, HEs, VCABs, and IRMAs. Based on the presence and extent of these retinal lesions, NPDR is further classified as mild, moderate, severe, or very severe NPDR (Table 1). PDR is characterized by new vessels on the optic disc (NVD), new vessels elsewhere on the retina (NVE), preretinal hemorrhage (PRH), vit- reous hemorrhage (VH), and/or fibrous tissue proliferation (FP). Based on the presence or absence of proliferative lesions, their severity, and their location, PDR is classified as early PDR or high-risk PDR (Table 1). DME can be present with any level of DR and needs to be evaluated in addition to the level of DR. DME that involves or threatens the center of the macula is termed clinically significant macular edema (CSME) (Table 1).
The level of NPDR establishes the risk of progression to sight-threatening retinopathy and appropriate clinical management as specifically detailed in Table 2.
In an effort to standardized classification of DR across international borders and among different health care providers, leaders from various groups and nations (the Global Diabetic Retinopathy Project Group) established and promulgated the Proposed International Classification of Diabetic Retinopathy (86) (Table 3). This classification identifies three levels of NPDR and one level of PDR. In regard to macular edema, two major categories—macular edema present and macular edema absent—are identified. If macular edema is present, three categories are defined: macular edema not threatening the center of the macula, macula edema threatening the center of the macula, and macula edema involving the center of the macula.
Treatment of Diabetic Retinopathy OVERVIEW
Appropriate clinical management of DR has been defined by five major, randomized, multicentered clinical trials: the Diabetic Retinopathy Study (DRS) (35–48), the ETDRS (49–68), the Diabetic Retinopathy Vitrectomy Study (DRVS) (69–73), the DCCT (22–
27), and the UKPDS (81). These studies have elucidated delivery and proper timing for laser photocoagulation surgery for the treatment of both DR and DME. They have also established guidelines for vitrectomy surgery. The DRS demonstrated that scatter (panretinal) laser photocoagulation was effective in reducing the risk of severe vision loss from PDR by 50% or more.
The ETDRS demonstrated that focal laser photocoagulation for clinically significant macular edema reduced the 5-year risk of moderate vision loss from nearly 30% to less than 15%. The study also demonstrated that scatter laser photocoagulation applied when an eye approaches or just reaches high-risk PDR reduces the risk of severe vision loss to less than 4%. The ETDRS also specifically evaluated the use of 650 mg of aspirin in patients with diabetes. The study conclusively demonstrated that the use of aspirin did not
Table 1
Levels of Diabetic Retinopathya Nonproliferative diabetic
retinopathy (NPDR) Characteristics
Mild NPDR At least one microaneurysm
Characteristics not met for more severe diabetic retinopathy (DR) Moderate NPDR Hemorrhages and/or microaneurysms (H/ma) of a moderate degree
(i.e.,ⱖ Standard Photograph 2Ab) and/or
Soft exudates (cotton wool spots), venous beading (VB), or intraretinal microvascular abnormalities (IRMAs) definitely present
and
Characteristics not met for more severe DR Severe NPDR One of the following:
H/Maⱖ standard 2A in four retinal quadrants
Venous beading in more than two retinal quadrants (see standard photo 6B)
IRMA in more than one retinal quadrant more than standard photo 8A
Characteristics not met for more severe DR Very severe NPDR Two or more lesions of severe NPDR
No retinal NV
Proliferative diabetic retinopathy (PDR) Characteristics Early PDR New vessels definitely present
Characteristics not met for more severe DR High-risk PDR One or more of the following:
NV on the optic disc (NVD) greater than standard photo 10 A (i.e., ⱖ1/3 disc area)
Any NVD with vitreous or preretinal hemorrhage NV elsewhere on the retina (NVE) greater than
1/2 disc area with vitreous or preretinal hemorrhage Clinically Significant Macular Edema (CSME)
Any one of the following lesions:
Retinal thickening at or within 500 μ (1/3 disc diameter) from the center of the macula Hard exudates at or within 500 μfrom the center of the macula with thickening of the adjacent
retina
A zone or zones of retinal thickening greater than 1 disc area in size, any portion of which is at or within1 disc diameter from the center of the macula
aBased on Early Treatment Diabetic Retinopathy Study definitions (57).
bStandard photographs refer to the Modified Airlee House Classification of Diabetic Retinopathy (see ref. 61).
Table 2
Recommended General Management of Diabetic Retinopathy Risk of progression to Evaluation Laser treatment
High risk Color Scatter laser Focal
Level of DR PDR 1 yr PDR-5 years photo F.A. (PRP) laser Follow-up (months)
Mild NPDR 5% 15%
• No ME No No No No 12
• ME Yes Occ No No 4–6
• CSME Yes Yes No Yes 2–4
Moderate NPDR 12-27% 33%
• No ME Yes No No No 6–8
• ME Yes Occ No Occ 4–6
• CSME Yes Yes No Yes 2–4
Severe NPDR 52% 60%
• No ME Yes No Rarely No 3–4
• ME Yes Occ OccAF Occ 2–3
• CSME Yes Yes OccAF Yes 2–3
Very Severe NPDR 75% 75%
• No ME Yes No Occ No 2–3
• ME Yes Occ OccAF Occ 2–3
• CSME Yes Yes OccAF Yes 2–3
PDR less than high risk 75%
• No ME Yes No Occ No 2–3
• ME Yes Occ OccAF Occ 2–3
• CSME Yes Yes OccAF Yes 2–3
High-risk PDR
• No ME Yes No Yes No 2–3
• ME Yes Yes Yes Usually 1–2
• CSME Yes Yes Yes Yes 1–2
NPDR, Nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy; ME, macular edema;
CSME, clinically significant macular edema; Occ, occasionally; OccAF, ocasionally after focal. (Copyright Lloyd M. Aiello, MD; used with permission.)
alter the course of DR and determined that aspirin use was not associated with increased risk of VH or PRH or stroke. Thus, patients who require the use of aspirin for optimum medical care should not be discontinued from treatment as a result of the presence of DR alone. The ETDRS has also clarified the natural history of DR and the risk of progression of retinopathy based on the baseline level of retinopathy (59–62) (Table 1). Finally, the ETDRS identified specific lesions that placed an eye at high-risk for visual loss (61).
These lesions include H/Ma, VCABs, and IRMAs as detailed in Table 1 and discussed above. Consequently, proper diagnosis of the level of retinopathy (Table 2) determines appropriate timing of follow-up evaluation and when to initiate laser photocoagulation.
The DRVS demonstrated that early pars plana vitrectomy (PPV) was useful in restor- ing vision for some persons who have severe vision loss as a result of VH. Additionally, the DRVS demonstrated that persons with severe FP were more likely to obtain better vision, and less likely to have poor vision, when PPV was performed early. The DRVS demonstrated the value of PPV in restoring useful vision, particularly in patients with type 1 diabetes. The treatment benefits demonstrated in the DRVS, which was completed in 1989, are not totally applicable today as a result of dramatic advances in surgical
techniques and the advent of laser endophotocoagulation that have occurred in the inter- vening years.
DR and DME are usually most amenable to laser surgery before any vision has been lost. Consequently, it is imperative that health care providers educate their patients re- garding the natural course and effectiveness of treatment so as to motivate patients to seek regular eye examinations even in the absences of symptoms.
Scatter (Panretinal) Laser Photocoagulation for Proliferative Diabetic Retinopathy
Both the DRS and the ETDRS demonstrated the value of scatter (panretinal) laser photocoagulation for treating PDR. In scatter laser photocoagulation, 1200 to 1800 laser burns are applied to the peripheral retinal tissue, focused at the level of the retinal pigment epithelium. Large vessels are avoided, as are areas of PRH. The total treatment is usually applied in two or three sessions, spaced 1 to 2 weeks apart. Follow-up evaluation usually occurs at 3 months.
The response to scatter laser photocoagulation varies. The most desirable effect is to see a regression of the new vessels. In some cases, there may be a stabilization of the NV, with no further growth. This response may be acceptable, with careful clinical monitor- ing. In some cases, new vessels continue to proliferate, requiring additional scatter laser photocoagulation. In cases in which NV continues and does not respond to further laser photocoagulation, vitreous hemorrhage and/or traction retinal detachment may occur,
Table 3
Proposed International Clinical Diabetic Retinopathy (DR) and Diabetic Macular Edema (DME) Disease Severity Scales
Diabetic retinopathy disease severity No apparent DR No abnormalities
Mild NPDR Ma only
Moderate NPDR More than Ma only but less than severe NPDR Severe NPDR Any of the following and no PDR:
a. More than 20 intraretinal hemorrhages in each four quadrants b. Definite VB in two or more quadrants
c. Prominent IRMA in one quadrant
PDR One or more of NV, VH, PRH
Diabetic macular edema disease severity
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 macula
NPDR, nonproliferative diabetic retinopathy; ma, microaneurysm; VB, venous beading; IRMA, intraretinal microvascular abnormalities; PDR, proliferative diabetic retinopathy; NV, neovascularization;
PRH, preretinal hemorrhage: HE, hard exudates. (Data from ref. 86.)
possibly requiring surgical intervention with pars plana vitrectomy if vision is threatened.
Eyes with high-risk PDR should receive prompt scatter laser photocoagulation. Eyes approaching high risk (i.e., eyes with PDR less than high risk, and eyes with severe or very severe NPDR) may also be candidates for scatter laser photocoagulation. Recent progres- sion of the eye disease, status of the fellow eye, compliance with follow-up, concurrent health concerns such as hypertension or kidney disease, and other factors must be con- sidered in determining if laser surgery should be performed in these patients. In particu- lar, patients with type 2 diabetes should be considered for laser surgery of DR prior to the development of high-risk PDR because the risk of severe visual loss and the need for PPV can be reduced by 50% in these patients by early scatter treatment, especially when macular edema is present (74).
Focal Laser Photocoagulation for Clinically Significant Macular Edema Focal laser for CSME is effective in reducing the risk of moderate visual loss, as defined above. In focal laser photocoagulation, lesions from 300 μ to 3000 μfrom the center of the macula that are contributing to thickening of the macula area are directly photocoagulated. These lesions are generally identified by fluorescein angiography and consist primarily of leaking microaneurysms. Although fluorescein angiography is gen- erally used to identify treatable lesions for focal laser photocoagulation, fluorescein angiography is not necessary for the diagnosis of clinically significant macular edema.
Also, fluorescein angiography is generally not needed to identify lesions of PDR because these findings should be clinically evident in most cases.
Follow-up evaluation following focal laser surgery generally occurs after 3 months.
In the cases in which macular edema persists, further treatment may be necessary. In the presence of macular edema, patients with severe or very severe NPDR should be consid- ered for focal treatment of macular edema whether or not the macular edema is clinically significant because they are likely to require scatter laser photocoagulation in the near future and because scatter photocoagulation may exacerbate existing macular edema.
Vitrectomy for Advanced Proliferative Diabetic Retinopathy
As discussed earlier, in cases of advance PDR, or in cases that do not respond to scatter laser photocoagulation, PPV may be indicated to allow intraocular application of laser photocoagulation (endolaser), to remove nonclearing VH, or to relieve traction that involves or threatens the center of the macula.
Novel Treatments
Numerous recent advances in our understanding of the basic mechanisms underlying the progression of DR have raised the possibility of novel therapies against the progres- sion of NPDR, PDR, and DME. Because the mainstay of DR treatment is laser photoco- agulation surgery, which is an inherently destructive technique resulting in focal destruction of areas of the retina, a noninvasive and nondestructive therapy would be of great clinical importance. Significant advances have been made regarding the role of oxidative stress in the eye and the role of VEGF and PKC as discussed earlier. Increases in oxidative stress induced by the diabetic state are thought to promote ocular and other systemic abnormalities (75). Thus, antioxidants such as vitamin E are being evaluated for their potential ameliorative effect on the progression of DR. Studies utilizing high-dose
vitamin E in diabetic animals have demonstrated a normalization of retinal blood flow and amelioration of excessive PKC activity (76). Furthermore, initial studies utilizing high-dose vitamin E treatment in patients with recent-onset diabetes have demonstrated an amelioration of diabetes-associated retinal blood-flow abnormalities. Further studies will be necessary to determine if vitamin E might be able to slow the progression of diabetic retinopathy.
In the ETDRS, 650 mg of aspirin daily were compared to placebo to evaluate the effect of aspirin on progression of DR. In the ETDRS, there was no difference between the aspirin group and the placebo group on progression of retinopathy, risk of VH, or rate of cataract extraction (57). Although there was no measured beneficial effect of aspirin on progression of retinopathy at levels of disease enrolled in the ETDRS, studies of the effects of higher dose aspirin or other anti-inflammatory agents such as cyclooxygenase- 2 (COX-2) inhibitors on early stages of disease have suggested possible benefit (87,88).
Early clinical studies are currently underway to address the effect of COX-2 inhibitors on DME.
Numerous advances have been made in understanding the role of growth factors in DR. Growth factors mediate both the NV of PDR and the increased permeability asso- ciated with DME. One of the critical growth factors involved in these mechanisms is VEGF. Inhibitors of VEGF have been evaluated in animal models and shown to prevent ischemia-induced NV of the retina and iris (77–79). Furthermore, it has been demon- strated that PKCG activation is essential for VEGF activity (19). PKC activation also increases the expression of VEGF. Finally, PKC activation itself also increases retinal vascular permeability (17). Thus, it would be predicted that an inhibitor of the G isoform of PKC would interrupt numerous diabetes-associated pathological processes that, if left unopposed, result in the complications of DR. PKCG selective inhibitors have amelio- rated the renal and retinal blood flow, retinal permeability, and retinal NV associated with diabetes and diabetes-like processes in animals (16,17). These results suggest that if such a molecule can be well tolerated in humans, an orally administered nondestructive novel therapy for DR would be available. PKCG-selective inhibitor has been and continues to be evaluated in phase 3 clinical trials. Initial results suggest that this orally administered compound is well tolerated and has few side effects. The drug may have beneficial effects on DME in patients with mild to moderate NPDR especially when glycemic control is not poor at baseline. It also may reduce vision loss in patients with moderate to severe NPDR, but the results are not conclusive at this time and await findings from ongoing phase 3 clinical trials specifically addressing these endpoints.
The great need for rigorous and rapid evaluation of new treatment modalities for DR has prompted the formation of the Diabetic Retinopathy Clinical Research Network (DRCR.net), a National Eye Institute (NEI)-sponsored cooperative agreement dedicated to multicenter clinical trial research of DR, macular edema, and associated disorders. The network consist of numerous investigators across the country in both academic and community practices who all use the same certified procedures for patient evaluation and computer-assisted information recording. The DRCR.net is supported by a dedicated coordinating center, fundus photograph reading center and network chair office. This group has designed and implemented protocols evaluating less intense laser photocoagu- lation techniques and intravitreal steroid injections for DME. Additionally, surgical inter- vention trials and trials of novel biochemical agents are planned for future investigation.
CONCLUSIONS
Appropriate management of DR and diabetic eye disease requires a thorough knowl- edge of both DM and the findings of the key multicentered, randomized clinical trials such as the DRS, ETDRS, DRVS, DCCT, and UKPDS. Accurate diagnosis of retinopa- thy level is essential to determine appropriate follow-up schedules and to assess the need for timely laser photocoagulation for PDR and CSME. Because DR usually causes no symptoms when it is most amenable to treatment, strategies to reduce the risk of vision loss must stress the need for regular eye examination, even in patients with no ocular complaints (80) (Table 4). Currently, patients with type 1 diabetes 10 years of age and older are encouraged to have a comprehensive, dilated retinal eye examination within 3 to 5 years of diagnosis, and at least annually thereafter. Patients with type 2 diabetes are encouraged to have a comprehensive, dilated eye examination at the time of diagnosis, and at least annually thereafter. Patients contemplating pregnancy should have their eyes examined prior to conception whenever possible, and pregnant women should have their eyes examined early in the first trimester and each trimester thereafter. In all cases, abnormal findings may require accelerated examination schedules, and the presence of concurrent medical conditions such as hypertension and renal disease may also require more frequent ocular examination and should be aggressively controlled in conjunction with the patient’s internist or diabetologist.
Our understanding of DR has expanded dramatically in the past 30 years. Treatment modalities that can substantially reduce visual loss have been developed and extensively validated. However, these therapies are not yet ideal and active research is continuing into methods of curing or preventing DR. Until these milestones are reached, current strate- gies must continue to address the critical need for regular eye examination and prompt, appropriate laser photocoagulation when indicated.
APPENDIX
American Diabetes Association Guidelines (80)
1. Patients less than 10 years of age with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 3 to 5 years after the onset of diabetes. In general, screening for diabetic eye disease is not necessary before 10 years of age. Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist shortly after the diagnosis of diabetes is made.
2. Subsequent examinations for both type 1 and type 2 diabetic patients should be repeated annually by an ophthalmologist or optometrist who is knowledgeable and experienced in diagnosing the presence of diabetic retinopathy and is aware of its management.
Examinations will be required more frequently if retinopathy is progressing.
3. When planning pregnancy, women with pre-existing diabetes should have a comprehen- sive eye examination and should be counseled on the risk of development and/or progres- sion of diabetic retinopathy. Women with diabetes who become pregnant should have a comprehensive eye examination in the first trimester and close follow-up throughout pregnancy. This guideline does not apply to women who develop gestational diabetes because such individuals are not at increased risk for diabetic retinopathy.
4. Patients with any level of macular edema, severe NPDR, or any PDR require the prompt care of an ophthalmologist who is knowledgeable and experienced in the management and treatment of diabetic retinopathy. Referral to an ophthalmologist should not be delayed
until PDR has developed in patients who are known to have severe nonproliferative or more advanced retinopathy. Early referral to an ophthalmologist is particularly important for patients with type 2 diabetes and severe NPDR, because laser treatment at this stage is associated with a 50% reduction in the risk of severe visual loss and vitrectomy.
5. Patients who experience vision loss from diabetes should be encouraged to pursue visual rehabilitation with an ophthalmologist or optometrist who is trained or experienced in low-vision care.
REFERENCES
1. Klein R, Klein BEK. Vision disorders in diabetes. National Institutes of Health: National Institute of Diabetes and Digestive and Kidney Diseases. NIH Publication No. 95–1468, 1995, p. 293.
2. Cogan DG, Toussaint D, Kuwabara T. Retinal vascular patterns: IV. Diabetic Retinopathy. Arch Ophthalmol 1961;66:366.
3. Cogan DG, Kuwabara T. Capillary shunts in the pathogenesis of diabetic retinopathy. Diabetes 1963;12:293.
4. Cogan DG, Kuwabara T. The mural cells in perspective. Arch Ophthalmol 1967;78:137.
5. Michaelson IC. The mode of development of the vascular system of the retina, with some observations on its significance for certain retinal diseases. Trans Ophthalmol Soc UK 1948;68:137–180.
6. Ashton N, Ward B, Supell G. Effect of oxygen on developing retinal vessels with particular reference to the problem of retrolental fibroplasia. Br J Ophthalmol 1954;38:397–432.
7. Engerman RI, Kern TS. Experimental galactosemia produces diabetic-like retinopathy. Diabetes 1984;33:97.
8. Engerman RI. Pathogenesis of diabetic retinopathy. Diabetes 1989;38:1203.
9. Engerman RI, Kern TS. Progression of incipient diabetic retinopathy during good glycemic control.
Diabetes 1987;36:808.
10. Engerman RL, Kern TS. Is diabetic retinopathy preventable? International Ophthalmology Clinics 1987:27:225–229.
11. Engerman RI, Kern TS. Aldose reductase inhibition fails to prevent retinopathy in diabetic and galac- tosemic dogs. Diabetes 1993;42:820.
12. Kikkawa U, Nishizuka Y. The role of protein kinase C in transmembrane signaling. Ann Rev Cell Biol 1986;2:149.
13. Pu X, Aiello LP, Ishii H, et al. Characterization of vascular endothelial growth factor’s effect on the activation of protein kinase C, its isoforms and endothelial growth. J Clin Invest 1996;98:2018–2026.
14. The Sorbinil Retinopathy Trial Research Group. A Randomized trial of sorbinil, an aldose reductase inhibitor in diabetic retinopathy. Arch Ophthalmol 1990;108:1234–1244.
15. The Sorbinil Retinopathy Trial Research Group. The sorbinil retinopathy trial: Neurology results. Neu- rology 1993;43:1141–1149.
16. Ishii H, Jirousek MR, Koya D, et al. Amelioration of vascular dysfunctions in diabetic rats by an oral PKC beta inhibitor. Science 1996;272:728–731.
Table 4
Suggested Frequency of Eye Examination Type of
diabetes mellitus (DM) Recommended first examination Routine minimal follow-up Type 1 DM Older than 10 years: 3–5 years after Yearly
onset of diabetes or at puberty
Type 2 DM Upon diagnosis of diabetes Yearly
During Pregnancy • Prior to conception for counseling • Each trimester
• Early in first trimester • More frequently as indicated
• 3–6 months postpartum
17. Aiello LP, Bursell SE, Clermont A, et al. Vascular endothelial growth factor-induced retinal permeabil- ity is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. Diabetes 1997;46:1473–1480.
18. Danis Rp, Bingaman DP, Jirousek M, Yang Y. Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKC beta inhibition with LY333531. Invest Ophthalmol Vis Sci 1998;39:171–179.
19. Xia P, Aiello LP, Ishii H, et al. Characterization of vascular endothelial growth factor’s effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest 1996;98:2018–
2026.
20. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemilogic Study of Diabetic Retinopathy. II.
Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 1984;102:520–526.
21. Klein R, Klein BEK, Moss SE, et al. The Wisconsin Epidemilogic Study of Diabetic Retinopathy. III.
Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 1984;102:527–532.
22. Diabetes Control and Complications Trial Research Group. Are continuing studies of metabolic control and microvascular complications in insulin-dependent diabetes mellitus justified? N Engl J Med 1988;318:246–250.
23. The Diabetes Control and Complications Trial Research Group. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Com- plications Trial. Diabetes 1995;44:968–983.
24. The Diabetes Control and Complications Trial Research Group. Progression of retinopathy with inten- sive versus conventional treatment in the Diabetes Control and Complications Trial. Ophthalmology 1995;102:647–661.
25. The Diabetes Control and Complications Trial Research Group. Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes 1997;46:271–286.
26. The Diabetes Control and Complications Trial Research Group. Lifetime benefits and costs of intensive therapy as practiced in the Diabetes Control and Complications Trial. JAMA 1996;276:1409–1415.
27. The Diabetes Control and Complications Trial Research Group The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin dependent diabetes mellitus. N Engl J Med 1993;329:977–986.
28. Chase HP, Jackson WE, Hoops SL et al. Glucose control in the renal and retinal complications of insulin- dependent diabetes. JAMA 1989;261:1155–1160.
29. The Kroc Collaborative Study Group. Blood glucose control and the evolution of diabetic retinopathy and albuminuria. N Engl J Med 1984;311:365–372.
30. Krowlewski AS, Canessa M, Warram JH et al. Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus: N Engl J Med 1988;318:140–145.
31. Stern MP, Patterson JK, Haffner SM et al. Lack of awareness and treatment of hyperlipidemia in Type II diabetes in a community survey. JAMA 1989;262:360–364.
32. Moloney JEM, Drury MI. The effect of pregnancy on the natural course of diabetic retinopathy. Am J Ophthalmol 1982;93:745–756.
33. Serup L. Influence of pregnancy on diabetic retinopathy. Acta Endocrinol 1986; 277:122–124.
34. Phelps RL, Sakol P, Metzger BE et al. Changes in diabetic retinopathy during pregnancy: Correlations with regulation of hyperglycemia. Arch Ophthalmol 1986;104:1806–1810.
35. Diabetic Retinopathy Study Research Group. Preliminary report on effects of photocoagulation therapy.
DRS Report No. 1. Am J Ophthalmol 1976;81:1–14.
36. Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic re- tinopathy. DRS Report No. 2. Ophthalmology 1978;85:82–106.
37. Diabetic Retinopathy Study Research Group. Four risk factors for severe visual loss in diabetic retin- opathy. DRS Report No. 3. Arch Ophthalmol 1979;97:654–655.
38. Diabetic Retinopathy Study Research Group. A short report of long-term results. DRS Report No. 4.
Proc 10th Congr Int Diabetes Fed. Vienna, September 9–14, 1979. North Holland: Excerpta Medica, 1980, pp. 789–794.
39. Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic re- tinopathy: relationship of adverse treatment effects to retinopathy severity. DRS Report No. 5. Dev Ophthalmol 1981;2:248–261.
40. Diabetic Retinopathy Study Research Group. Design methods and baseline results. DRS Report No. 6.
Invest Ophthalmol 1981;21(1, Pt 2):149–209.
41. Diabetic Retinopathy Study Research Group. A modification of the Airlie House classification of diabetic retinopathy. DRS Report No. 7. Invest Ophthalmol 1981;21(1, Pt 2):210–226.
42. Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic re- tinopathy. Clinical applications of Diabetic Retinopathy Study (DRS) findings. DRS Report No. 8.
Ophthalmology 1981;88:583–600.
43. Ederer F, Podgor MJ, DRS Research Group. Assessing possible late treatment effects in stopping a clinical trial early: a case study. DRS Report No. 9. Cont Clin Trials 1984;5:373–381.
44. Rand LI, Prud’homme GJ, Ederer F, Canner PL, DRS Research Group. Factors influencing the devel- opment of visual loss in advanced diabetic retinopathy. DRS Report No. 10. Invest Ophthalmol 1985;26:983–991.
45. Kaufman SC, Ferris F, Swartz M, DRS Research Group. Intraocular pressure following panretinal photocoagulation for diabetic retinopathy. DRS Report No. 11. Arch Ophthalmol 1987;102:807–809.
46. Diabetic Retinopathy Study Research Group. Macular edema in diabetic retinopathy study patients.
DRS Report No. 12. Ophthalmology 1987;94:754–760.
47. Diabetic Retinopathy Study Report Number 13: Factors associated with visual outcome after photoco- agulation for diabetic retinopathy. Invest Ophthalmol 1989;30:23–28.
48. Diabetic Retinopathy Study Research Group. Indications for photocoagulation treatment of diabetic retinopathy. DRS Report No. 14. Int Ophthalmol Clin 1987;27:239–253.
49. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. ETDRS Report No. 1. Arch Ophthalmol 1985;103:1796–1806.
50. Early Treatment Diabetic Retinopathy Study Research Group. Treatment techniques and clinical guide- lines for photocoagulation of diabetic macular edema. ETDRS Report No. 2. Ophthalmology 1987;96:761–774.
51. Early Treatment Diabetic Retinopathy Study Research Group. Techniques for scatter and local photoco- agulation treatment of diabetic retinopathy. ETDRS Report No. 3. Int Ophthalmol Clin 1987;27:254–264.
52. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. ETDRS Report No. 4. Int Ophthalmol Clin 1987;27:265–272.
53. Early Treatment Diabetic Retinopathy Study Research Group. Case reports to accompany early treat- ment diabetic retinopathy study reports Nos. 3 and 4. Int Ophthalmol Clin 1987;27:273–333.
54. Early Treatment Diabetic Retinopathy Study Research Group. Detection of diabetic macular edema:
Ophthalmoscopy versus photography. ETDRS Report No. 5. Ophthalmology 1989;96:746–751.
55. Early Treatment Diabetic Retinopathy Study Research Group. C-peptide and the classification of dia- betes patients in the Early Treatment Diabetic Retinopathy Study. ETDRS Report No. 6. Ann Epidemiol 1993;3:9–17.
56. Early Treatment Diabetic Retinopathy Study Research Group. Design and baseline patient characteris- tics. ETDRS Report No. 7. Ophthalmology 1991;98:741–756.
57. Early Treatment Diabetic Retinopathy Study Research Group. Effects of aspirin treatment on diabetic retinopathy. ETDRS Report No. 8. Ophthalmology 1991; 98:757–765.
58. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy. ETDRS Report No. 9. Ophthalmology 1991;98:766–785.
59. Early Treatment Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from ste- reoscopic color fundus photographs: an extension of the modified Airlie House classification. ETDRS Report No. 10. Ophthalmology 1991;98:786–806.
60. Early Treatment Diabetic Retinopathy Study Research Group. Classification of diabetic retinopathy from fluorescein angiograms. ETDRS Report No. 11. Ophthalmology 1991;98:807–822.
61. Early Treatment Diabetic Retinopathy Study Research Group. Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS Report No. 12. Ophthalmology 1991;98:823–833.
62. Early Treatment Diabetic Retinopathy Study Research Group. Fluorescein angiographic risk factors for progression of diabetic retinopathy. ETDRS Report No. 13. Ophthalmology 1991;98:834–840.
63. Early Treatment Diabetic Retinopathy Study Research Group. Aspirin effects on mortality and morbid- ity in patients with diabetes mellitus. ETDRS Report No. 14. JAMA 1992;268:1292–1300.
64. Early Treatment Diabetic Retinopathy Study Research Group. Aspirin effects on the development of cataracts in patients with diabetes mellitus. ETDRS Report No. 16. Arch Ophthalmol 1992;110:339–342.
65. Early Treatment Diabetic Retinopathy Study Research Group. Pars plana vitrectomy in the early treat- ment diabetic retinopathy study. ETDRS Report No. 17. Ophthalmology 1992;99:1351–1357.
66. Early Treatment Diabetic Retinopathy Study Report Number 19. Focal photocoagulation treatment of diabetic macular edema: Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline. Arch Ophthalmol 1995;113:1144–1155.
67. Chew EY, Klein ML, Murphy RP, Remaley NA, Ferris FL III, ETDRS Research Group. Early Treatment Diabetic Retinopathy Study Report Number 20. Effects of aspirin on vitreous/preretinal hemorrhage in patients with diabetes mellitus. Arch Ophthalmol 1995;13:52–55.
68. Chew EY, Klein ML, Ferris FL III, Remaley NA, Murphy RP, Chantry K, Hoogwerf BJ, Miller D, ETDRS Research Group. Early Treatment Diabetic Retinopathy Study Report Number 22. Association of elevated serum lipid levels with retinal hard exudates in diabetic retinopathy. Arch Ophthalmol 1996;114:1079–1084.
69. Diabetic Retinopathy Vitrectomy Study Research Group. Two-year course of visual acuity in severe proliferative diabetic retinopathy with conventional management. DRVS Report No. 1. Ophthalmology 1985;92:492–502.
70. Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemor- rhage in diabetic retinopathy. Two year results of a randomized trial. DRVS Report No. 2. Arch Ophthalmol 1985;103:1644–1652.
71. Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Results of a randomized trial. DRVS Report No. 3.
Ophthalmology 1988;95:1307–1320.
72. Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. DRVS Report No. 4. Ophthalmology 1988;95:1321–
1334.
73. Diabetic Retinopathy Vitrectomy Study Report Number 5: Early vitrectomy for severe vitreous hem- orrhage in diabetic retinopathy. Four-year results of a randomized trial. Arch Ophthalmol 1990;108:958–
964.
74. Ferris FL III. Early photocoagulation in patients with either Type I or Type II diabetes. Tr AM Ophth Soc 1996;94:505–537.
75. Baynes JW, Thorpe SR. Role of oxidative stress in diabetic complications. A new perspective on an old paradigm. Diabetes 1999;48:1–9.
76. Kunisaki M, Bursell SE, Clermont AC, Ishii H, Ballas LM, Jirousek MR et al. Vitamin E prevents diabetes-induced abnormal retinal blood flow via the diacylglycerol-protein kinase C pathway. Am J Physiol 1995;269:E239–E246.
77. Aiello LP, Pierce EA, Foley ED, Takagi H, Chen H, Riddle L et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-recptor chimeric proteins. Proc Natl Acad Sci U S A 1995;92:10,457–10,461.
78. Robinson GS, Pierce EA, Rook SL, Foley E, Webb R, Smith LE. Oligodeoxynucleotides inhibit retinal neovascularization in a murine model of proliferative retinopathy. Proc Natl Acad Sci USA 1996;93:4851–4856.
79. Adamis AP, Shima DT, Tolentino MJ, Gragoudas ES, Ferrara N, Folkman J et al. Inhibition of vascular endothelial growth factor prevents retinal ischemia-assoociated iris neovasculrization in a nonhuman primate. Arch Ophthalmol 1996;114:66–71.
80. Position Statement: American Diabetes Association. Diabetic Retinopathy. Diabetes Care 2004;27:
584–587.
81. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352(9131):837–853 (Erratum in: Lancet 1999;354(9178):602).
82. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 1998;317(7160):713–720.
83. Chew EY, Klein ML, Ferris FL 3rd, et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Arch Ophthalmol 1996;114(9):1079–1084.
84. Davis MD, Fisher MR, Gangnon RE, et al. Risk factors for high-risk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic Retinopathy Study Report #18. Invest Ophthalmol Vis Sci 1998;39(2):233–252.
85. Aiello LP, Cahill MT, Wong JS. Systemic considerations in the management of diabetic retinopathy. Am J Ophthalmol 2001;132(5):760–776.
86. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales.
Ophthalmology 2003;110:1677–1682.
87. Kern TS, Engerman RL. Pharmacological inhibition of diabetic retinopathy: aminoguanidine and aspi- rin. Diabetes 2001;50:1636–1642.
88. Joussen AM, Poulaki V, Mitsiades N, Kirchhof B, Koizumi K, Dohmen S, Adamis AP. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J 2002;16(3):438–440.
