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Diabetic Retinopathy

This version was saved 15 years, 6 months ago View current version     Page history
Saved by Robert Rushakoff, MD
on September 9, 2008 at 7:28:32 pm
 

RETINOPATHY

 

Jay M Stewart, MD

Daniel M Schwartz, MD 

 

 


 

INTRODUCTION

Diabetes is a leading cause of blindness in the U.S.[1] The same pathologic mechanisms that damage the kidneys and other organs affect the microcirculation of the eye. Often, by the time many patients seek ophthalmologic examination and treatment, there are significant alterations of the retinal microvasculature. Therefore a fundamental understanding of diabetic eye disease is important for non-ophthalmologists so that appropriate referral to eye-care specialists can be a part of their diabetes management.

 

EPIDEMIOLOGY

The National Society to Prevent Blindness has estimated that 4 to 6 million diabetics in the U.S. have diabetic retinopathy. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), a population-based study, the prevalence of diabetic retinopathy was evaluated in patients diagnosed with diabetes before and after age 30. In the younger group, in which all the patients received insulin therapy, retinopathy was present in 13% of patients whose diabetes had been present for less than 5 years, whereas over 90% of patients with diabetes for 10 to 15 years had retinopathy. In the older group, 40% of patients using insulin and 24% of those not receiving insulin had retinopathy after less than 5 years of diabetes. In older patients with diabetes for 15 or more years, 84% of patients on insulin and 53% of those not using insulin had retinopathy.[2]

The WESDR also showed that the rate of vision loss increased with the severity of retinopathy and with the duration of diabetes.[3] In patients diagnosed before age 30, 3% of those with diabetes for 15 to 19 years were blind, as were 12% of those with diabetes for 30 years or more. In all diabetics aged 65 to 74 years old, 14% of males and 20% of females were legally blind. Over a 10-year period, 9% of the younger-onset patients had doubling of the visual angle (e.g. a drop from 20/40 to 20/80 on Snellen acuity testing), compared with 32% of older patients on insulin and 21% of older patients not on insulin.[4] Another study found that diabetes increased the rate of legal blindness by a factor of 50 to 80.[5]

In caring for diabetic patients, therefore, health care providers must bear in mind the substantial risks of developing visual loss that these patients face. For affected patients, diabetes-related visual loss decreases the quality of life and interferes with the performance of daily activities. On a larger scale, it is estimated to cost the U.S. $500 million per year.[6] An understanding of the factors predisposing to the development and worsening of retinopathy can help practitioners delay or prevent its onset.

 

RISK FACTORS

The principal factor related to the development or worsening of diabetic retinopathy is glucose control. The Diabetes Control and Complications Trial (DCCT), a randomized, controlled study of 1441 patients with type 1 diabetes found that an intensive glucose control regimen reduced the risk of developing retinopathy by 76%.[7] In patients with pre-existing retinopathy, intensive control slowed progression of the condition by 54%. An analysis of HbA1C levels revealed that a 10% decrease in HbA1C resulted in a 35% to 40% reduction in the risk of worsening of retinopathy.[8]

Patients with type 2 diabetes were evaluated in the United Kingdom Prospective Diabetes Study (UKPDS). The study found a 25% reduction in the risk of microvascular endpoints, including the need for diabetic retinal laser treatment, with intensive glucose control.[9] Like the DCCT, the UKPDS also showed that decreasing the HbA1C lowered the risk of microvascular complications substantially. Of note, during 10 years of followup in the UKPDS and 9 years in the DCCT, retinopathy could not be completely prevented, even in the intensive therapy groups.

Despite the well-established benefits of tight glucose control for achieving favorable outcomes with diabetic retinopathy, patients must be advised that an initial worsening of retinopathy can occur when a more intensive glycemic control regimen is implemented. The DCCT and other smaller trials have found that in both type 1 and 2 diabetics, these changes can occur over the first 3 to 12 months after the glucose levels are controlled. For many patients, the changes are not clinically significant, but for patients with mild to moderate levels of retinopathy at baseline, the worsening of the retinopathy potentially can result in a decline in visual acuity, requiring intervention with laser treatment. In the DCCT, 19% of patients with moderate nonproliferative retinopathy experienced this early worsening effect. The reasons for this phenomenon are not understood. Observers agree that although these risks are outweighed by the long-term benefits in preventing severe vision loss from retinopathy, patients with retinopathy at baseline should be observed closely in the initial period following implementation of tighter glucose control

.[10]

Other risk factors for progression of diabetic retinopathy include hypertension, hypercholesterolemia, and pregnancy. Both the WESDR and the UKPDS have established relationships between hypertension and worsening of diabetic retinopathy.[11] Strict blood pressure control with either atenolol or captopril was found to reduce the need for laser treatment by 35% compared to less rigorous control. Elevated cholesterol and triglycerides are also associated with retinopathy progression. Finally, pregnancy is a significant risk factor for worsening; type 1 diabetics are twice as likely to progress to proliferative disease if they are pregnant. Smoking, although a known risk factor for cardiovascular disease, did not correlate with increased likelihood of retinopathy progression in the UKPDS and WESDR.

 

SCREENING

The American Academy of Ophthalmology has recommended screening for diabetic retinopathy 5 years after diagnosis in patients with type 1 diabetes, and at the time of diagnosis in patients with type 2 diabetes. Patients without retinopathy should undergo dilated fundus examination annually. If mild nonproliferative diabetic retinopathy (NPDR) is present, exams should be repeated every 9 months. Patients with moderate NPDR should be examined every 6 months. In severe NPDR, exams should be conducted every 3 months. Patients with proliferative diabetic retinopathy should be examined every 2 to 3 months. During pregnancy, patients should be examined every 3 months, since retinopathy can progress rapidly in this setting.[12]

 

PATHOGENESIS

Various mechanisms account for the features of diabetic retinopathy. Histopathologic analysis shows thickening of capillary basement membranes, microaneurysm formation, loss of pericytes, capillary acellularity, and neovascularization)[13] Microaneurysms, outpouchings of the capillary wall, serve as sites of fluid and lipid leakage, which can lead to the development of diabetic macular edema. Theories on the biochemistry of these end-organ changes include toxic effects from sorbitol accumulation, vascular damage by excessive glycosylation with crosslinking of basement membrane proteins, and activation of protein kinase C-ß2 by vascular endothelial growth factor (VEGF), leading to increased vascular permeability and endothelial cell proliferation. VEGF, produced by the retina in response to hypoxia, is believed to play a central role in the development of neovascularization.[14]

 

 

Figure 1a. Microaneurysms:focal outpouchings of the capillary wall.

 

 

CLINICAL FEATURES: NONPROLIFERATIVE DIABETIC RETINOPATHY (NPDR)

Studies have found that retinopathy in both insulin-dependent and non-insulin-dependent diabetes occurs 3 to 5 years or more after the onset of diabetes. In the WESDR, the prevalence of at least minimal retinopathy was almost 100% after 20 years.[15] A more recent study has confirmed that at least 39% of young diabetics developed retinopathy within the first 10 years.[16] The earliest clinical sign of diabetic retinopathy is the microaneurysm, a red dot seen on ophthalmoscopy that varies from 15 to 60 microns in diameter.

 

 

Figure 1b. Microaneurysms and intraretinal hemorrhages in nonproliferative retinopathy. (UCSF Department of Ophthalmology)

 

 

The lesions can be difficult to distinguish from intraretinal hemorrhages on examination, but with fluorescein angiography microaneurysms can be identified easily as punctate spots of hyperfluorescence. By contrast, hemorrhages block the background fluorescence and therefore appear dark.

 

 

Figure 2. Microaneurysms: hyperfluorescent dots in early phase of fluorescein angiogram (arrows). (San Francisco General Hospital, Dept. of Ophthalmology)

 

Figure 3. Two minutes later, fluorescein leakage from the microaneurysms gives them a hazy appearance. (San Francisco General Hospital, Dept. of Ophthalmology)

 

 

The severity of NPDR can be graded as mild, moderate, severe, or very severe. In mild disease, microaneurysms are present with hemorrhage or hard exudates (lipid transudates). In moderate NPDR, these findings are associated with cotton-wool spots (focal infarcts of the retinal nerve fiber layer or areas of axoplasmic stasis) or intraretinal microvascular abnormalities (vessels that may be either abnormally dilated and tortuous retinal vessels, or intraretinal neovascularization). The "4-2-1 rule" is used to diagnose severe NPDR: criteria are met if hemorrhages and microaneurysms are present in 4 quadrants, or venous beading is present in 2 quadrants, or moderate intraretinal microvascular abnormalities are present in 1 quadrant. In very severe NPDR, two of these features are present.

The correct evaluation and staging of NPDR is important as a means of assessing the risk of progression. In the ETDRS, eyes with very severe NPDR had a 60-fold increased risk of developing high-risk proliferative retinopathy after 1 year compared with eyes with mild NPDR.[17] For eyes with mild or moderate NPDR, early treatment with laser was not warranted, as the benefits in preventing vision loss did not outweigh the side effects. By contrast, in very severe NPDR, early laser treatment was often helpful.

 

 

Figure 4. Venous beading (arrows) in a case of proliferative diabetic retinopathy. (UCSF Department of Ophthalmology)

 

 

Vision loss in nonproliferative diabetic retinopathy is most commonly caused by macular edema. Because of the increased vascular permeability and breakdown of the blood-retinal barrier, fluid and lipids leak into the retina and cause it to swell. This causes photoreceptor dysfunction, leading to vision loss when the center of the macula, the fovea, is affected. In the ETDRS, macular edema was characterized as "clinically significant" if any of the following were noted: retinal thickening within 500 microns of the fovea, hard exudates within 500 microns of the fovea if associated with adjacent retinal thickening, or an area of retinal thickening 1 disc diameter or larger if any part of it is located within 1 disc diameter of the fovea.[18]

 

 

Figure 5. Clinically significant macular edema with hard exudates in the fovea. Cotton-wool spots are present near the major retinal vessels (arrows). (UCSF Dept. of Ophthalmology)

 

 

Capillary closure can also result in macular ischemia, another cause of vision loss in NPDR. This can be identified clinically as an enlargement of the normal foveal avascular zone on fluorescein angiography.

 

 

Figure 6. Capillary dropout around the fovea (white arrow) and in the temporal macula (black arrow). (San Francisco General Hospital, Dept. of Ophthalmology)

 

 

CLINICAL FEATURES: PROLIFERATIVE DIABETIC RETINOPATHY (PDR)

In proliferative diabetic retinopathy, many of the changes seen in NPDR are present in addition to neovascularization that extends along the surface of the retina or into the vitreous cavity. These vessels are in loops that may form a network of radiating spokes or may appear disorganized. In many cases the vessels are first noted on the surface of the optic disc, although they can be easily missed due to their fine calibur.[19][20] Close inspection often reveals that these new vessels cross over both the normal arteries and the normal veins of the retina, a sign of their unregulated growth.

 

 

Figure 7. Active neovascularization in PDR. Fibrovascular proliferation overlies the optic disc (white arrow). Loops of new vessels are especially prominent superior to the disc and extending into the macula, where leakage of fluid has led to deposition of a ring of hard exudate around the neovascular net (black arrow). (UCSF Department of Ophthalmology)

 

 

New vessels can also appear on the iris, a condition known as rubeosis iridis. When this occurs, careful inspection of the anterior chamber angle is essential, as growth of neovascularization in this location can obstruct aqueous fluid outflow and cause neovascular glaucoma.

 

 

Figure 8. Rubeosis iridis in a case of PDR. Abnormal new vessels are growing along the surface of the iris (arrows). (UCSF Dept. of Ophthalmology)

 

 

Neovascularization can remain relatively stable or it can grow rapidly; progression can be noted ophthalmoscopically over a period of weeks. The vessels often develop an associated white, fibrous tissue component that can increase in size as the vessels regress. The resulting fibrovascular membrane may then develop new vessels at its edges. This cycle of growth and fibrous transformation of diabetic neovascularization is typical.[21] The proliferation occurs on the anterior surface of the retina, and the vessels extend along the posterior surface of the vitreous body. Fibrous proliferation takes place on the posterior vitreous surface; when the vitreous detaches, the vessels can be pulled forward and the thickened posterior vitreous surface can be seen ophthalmoscopically, highlighted areas of fibrovascular proliferation.

The severity of PDR can be classified as to the presence or absence of high-risk characteristics. As determined in the Diabetic Retinopathy Study, eyes are classified as high-risk if they have 3 of the following 4 characteristics: the presence of any neovascularization; neovascularization on or within 1 disc diameter of the optic disc; a moderate to severe amount of neovascularization (greater than 1/3 disc area neovascularization of the disc, or greater than 1/2 disc area if elsewhere), or vitreous hemorrhage.[22]

Vision loss in proliferative diabetic retinopathy results from three main causes. First, vitreous hemorrhage occurs because the neovascular tissue is subject to vitreous traction. Coughing or vomiting may also trigger a hemorrhage. Hemorrhage may remain in the preretinal space between the retina and the posterior vitreous surface, in which case it may not cause much vision loss if located away from the macula. In other cases, though, hemorrhage can spread throughout the entire vitreous cavity, causing a diffuse opacification of the visual media with marked vision loss.

 

 

Figure 9. Preretinal hemorrhage: blood trapped between the retina and the vitreous in a case of incomplete vitreous detachment. Visual acuity is unaffected. (UCSF Department of Ophthalmology)

 

Figure 10. Above: moderate vitreous hemorrhage; vision = 20/150. Below: 1 year later after spontaneous clearing of the hemorrhage; vision = 20/30. (San Francisco General Hospital, Dept. of Opthalmology)

 

Figure 11. Dense vitreous hemorrhage almost completely obscuring the view of the fundus. (San Francisco General Hospital, Dept. of Ophthalmology)

 

 

Another cause of severe vision loss in PDR is retinal detachment. As the fibrovascular membranes and vitreous contract, their attachments to the retina can cause focal elevations of the retina, resulting in a traction retinal detachment. In other cases the retinal vessels can be avulsed or retinal holes may be created by this traction, leading to a combined traction-rhegmatogenous retinal detachment.

 

 

Figure 12. Marked fibrosis with traction exerted on the retina outside the macula (arrows). The macula does not appear to be elevated. (UCSF Dept. of Ophthalmology)

 

Figure 13. Traction retinal detachment outside the macula. Note elevation of retinal vessel out of the plane of focus (white arrow). Scatter photocoagulation scars are seen peripherally (black arrow). (UCSF Dept. of Ophthalmology)

 

 

Finally, patients with PDR may have macular nonperfusion or coexisting diabetic macular edema that causes vision loss through photoreceptor dysfunction.

 

 

TREATMENT: LASER PHOTOCOAGULATION FOR NPDR

Tight glucose and blood pressure control are critical systemic factors in controlling the progression of diabetic retinopathy. Ocular complications of diabetes are addressed directly through treatment with laser photocoagulation or surgery.

Diabetic macular edema is believed to result from fluid and lipid transudation from microaneurysms and telangiectatic capillaries. Focal laser photocoagulation is used to heat and close the microaneurysms, causing them to stop leaking. Macular edema often improves following this form of treatment. Some clinicians apply laser burns in a grid pattern overlying areas of retinal edema without directing treatment to specific microaneurysms; this method can also be effective in reducing retinal thickening. The mechanism by which grid laser treatment achieves these results is not known.[23]

The ETDRS found that the risk of moderate visual loss in eyes with diabetic macular edema was reduced by 50% by photocoagulation. At 3 years, 24% of untreated eyes experienced a 3-line decrease in vision compared with 12% of treated eyes[24] Only a very small percentage of eyes improved with treatment, highlighting the fact that the goal of treatment is not to improve vision, but rather to stabilize it and prevent worsening. Eyes meeting the criteria for clinically significant macular edema in which the edema was closest to the center were most likely to benefit from treatment. Side effects of laser treatment include scotomas, noticeable immediately after the procedure; late enlargement of laser scars can also occur, causing delayed visual loss. Inadvertent photocoagulation of the fovea is a risk of the procedure.[25] Since the amount of energy used is minimal, the treatment is performed under topical anesthesia.

 

 

TREATMENT: LASER PHOTOCOAGULATION FOR PDR

Figure 14. Focal laser scars in the macula following treatment for macular edema (arrow). Edema has resolved. (San Francisco General Hospital, Dept. of Ophthalmology)

 

Scatter laser photocoagulation, also known as panretinal photocoagulation (PRP), is an important treatment modality for PDR and severe NPDR. Laser spots are placed from outside the major vascular arcades to the equator of the eye, with burns spaced approximately 1/2 to 1 burn width apart. Although the treatment destroys normal retina, the central vision is unaffected since all spots are placed outside the macula. The theory underlying this treatment is that photocoagulation of the ischemic peripheral retina decreases the elaboration of vasoproliferative factors contributing to PDR. Indeed, VEGF levels in the vitreous are increased in eyes with neovascularization, and they are lower after scatter photocoagulation.([26] Other factors such as insulin-like growth factor-1 are similarly elevated in the vitreous of eyes with PDR.[27]

Side effects of scatter photocoagulation include decreased night vision and dark adaptation, and visual field loss. The procedure can be painful, so treatment may be divided into several sessions, and either topical or retrobulbar anesthesia may be used.

 

 

Figure 15. Scatter photocoagulation scars in an eye with active PDR. Note that all scatter laser scars are located outside the macula. (UCSF Department of Ophthalmology)

 

Figure 16. View of laser scars superior to the macula in the same eye. Spots are approximately one-half burn width apart. In the treated area, the retinal vessels are sclerotic (arrows). (UCSF Department of Ophthalmology)

 

 

The Diabetic Retinopathy Study evaluated the effects of scatter photocoagulation in over 1700 patients with PDR or severe NPDR. Patients had one eye randomized to treatment and one eye to observation. Treatment was shown to reduce severe visual loss by 50%. The ETDRS also found a positive risk-benefit ratio for early scatter treatment in patients with severe NPDR or early PDR.[28]

 

 

TREATMENT: SURGERY FOR PDR

Surgery may be necessary for eyes in advanced PDR with either vitreous hemorrhage or retinal detachment. In the case of vitreous hemorrhage, many cases will clear spontaneously. For this reason, clinicians often wait 3 to 6 months or more before performing vitrectomy surgery. If surgery is indicated because of persistent nonclearing hemorrhage, retinal detachment involving the macula, or vitreous hemorrhage with neovascularization of the anterior chamber angle (a precursor of neovascular glaucoma), then vitrectomy is performed via a pars plana approach. The vitreous is removed, fibrovascular membranes are dissected away from the retina, retinal detachment is repaired, and scatter laser treatment is applied at the time of surgery via direct intraocular application.

 

The Diabetic Retinopathy Vitrectomy Study assessed the value of early vitrectomy in patients with severe PDR. The study found that early intervention increased the likelihood of obtaining 20/40 vision or better in eyes with recent severe vitreous hemorrhage or severe PDR. Compared with 15% of control eyes, 25% of treated eyes achieved this level of vision at 2 years.

[29] In type 1 diabetes, the benefit of early surgery was even more pronounced, with 36% of treated eyes achieving 20/40 vision compared to 12% of control eyes. The importance of this study, performed between 1976 and 1983 when vitrectomy techniques were much less advanced than they are today, was that it showed conventional "watch and wait" management will not necessarily lead to the best visual outcomes in cases of severe PDR. In practice, clinicians evaluate the risks and benefits of each option before proceeding with scatter photocoagulation, vitrectomy, or observation in such cases.

 

TREATMENT: NOVEL THERAPIES FOR DIABETIC RETINOPATHY

Current therapies are limited in their ability to reverse vision loss in diabetic retinopathy. For example, although focal laser photocoagulation can help stabilize vision by reducing macular edema, it rarely improves vision. The development of new treatment modalities is being guided by an understanding of the mechanisms of the disease. Research on the inflammatory response in diabetic macular edema has led to studies evaluating the use of intravitreal corticosteroid injection, a promising treatment option in patients who do not benefit from laser.(13) Protein kinase C-ß inhibitors and antiangiogenic therapies targeted toward VEGF and other growth factors are the focus of study in animal models and early clinical trials.[30]

 

CONCLUSION

Retinopathy remains a challenging complication of diabetes that can adversely affect a patient's quality of life. Although ophthalmologists can often stabilize the condition or reduce vision loss, prevention and early detection remain the most effective ways to preserve good vision in patients with diabetes. Ensuring tight glucose and blood pressure control and referring patients for ophthalmologic examination are important ways in which internists and other clinicians can help to maximize their patients' vision and therefore their quality of life.

 

Footnotes

  1. Chew EY, Ferris III FL. "Nonproliferative diabetic retinopathy," in Ryan SJ, ed., Retina. St. Louis: Mosby, 2001. pp. 1295-1308.
  2. Chew EY, Ferris III FL. "Nonproliferative diabetic retinopathy," in Ryan SJ, ed., Retina. St. Louis: Mosby, 2001. pp. 1295-1308.
  3. Klein R and Klein BEK. "Epidemiology of eye disease in diabetes," in Flynn HW and Smiddy WE, eds., Diabetes and Ocular Disease: Past, Present, and Future Therapies. American Academy of Ophthalmology, 2000. pp.19-61.
  4. Moss SE, Klein R, Klein BEK. Ten-year incidence of visual loss in a diabetic population. Ophthalmology 1994;101:1061-1070
  5. Kostraba NJ, Klein R, Dorman JS, et al. The epidemiology of diabetes complications study, IV: correlates of diabetic background and proliferative retinopathy. Am J Epidemiol 1991;133:381-391.
  6. Chiang YP, Bassi LJ, Javitt JC. Federal budgetary costs of blindness. Milbank Q 1992;70:319-340.
  7. Ferris III FL, Davis MD, Aiello LM, Chew EY. "Clinical studies on treatment for diabetic retinopathy," in Flynn HW and Smiddy WE, eds., Diabetes and Ocular Disease: Past, Present and Future Therapies. American Academy of Ophthalmology, 2000. pp. 81-99.
  8. Chew EY, Ferris III FL. "Nonproliferative diabetic retinopathy," in Ryan SJ, ed., Retina. St. Louis: Mosby, 2001. pp. 1295-1308.
  9. Chew EY, Ferris III FL. "Nonproliferative diabetic retinopathy," in Ryan SJ, ed., Retina. St. Louis: Mosby, 2001. pp. 1295-1308.
  10. Davis MD, Blodi BA. "Proliferative diabetic retinopathy," in Ryan SJ, ed., Retina. St. Louis: Mosby, 2001. pp. 1309-1349.
  11. Klein R and Klein BEK. "Epidemiology of eye disease in diabetes," in Flynn HW and Smiddy WE, eds., Diabetes and Ocular Disease: Past, Present, and Future Therapies. American Academy of Ophthalmology, 2000. pp.19-61.
  12. Preferred Practice Patterns Committee, Retina Panel. Diabetic Retinopathy. American Academy of Ophthalmology, 1998
  13. Frank RN, "Etiologic mechanisms in diabetic retinopathy," in Ryan SJ, ed., Retina. St. Louis: Mosby, 2001. pp. 1259-1294.
  14. Gardner TW, Aiello LP. "Pathogenesis of diabetic retinopathy," in Flynn HW and Smiddy WE, eds., Diabetes and Ocular Disease: Past, Present and Future Therapies. American Academy of Ophthalmology, 2000. pp. 1-17.
  15. Frank RN, "Etiologic mechanisms in diabetic retinopathy," in Ryan SJ, ed., Retina. St. Louis: Mosby, 2001. pp. 1259-1294.
  16. Henricsson M, Nystrom L, Blohme G, et al. The incidence of retinopathy 10 years after diagnosis in young adult people with diabetes: results from the nationwide population-based Diabetes Incidence Study in Sweden (DISS). Diabetes Care 2003;26(2):349-354.
  17. Chew EY, Ferris III FL. "Nonproliferative diabetic retinopathy," in Ryan SJ, ed., Retina. St. Louis: Mosby, 2001. pp. 1295-1308.
  18. Chew EY, Ferris III FL. "Nonproliferative diabetic retinopathy," in Ryan SJ, ed., Retina. St. Louis: Mosby, 2001. pp. 1295-1308.
  19. Folk JC and Oh KT. "Photocoagulation for diabetic macular edema and diabetic retinopathy," in Flynn HW and Smiddy WE, eds., Diabetes and Ocular Disease: Past, Present and Future Therapies. American Academy of Ophthalmology, 2000. pp. 115-153.
  20. Folk JC and Oh KT. "Photocoagulation for diabetic macular edema and diabetic retinopathy," in Flynn HW and Smiddy WE, eds., Diabetes and Ocular Disease: Past, Present and Future Therapies. American Academy of Ophthalmology, 2000. pp. 115-153.
  21. Davis MD, Blodi BA. "Proliferative diabetic retinopathy," in Ryan SJ, ed., Retina. St. Louis: Mosby, 2001. pp. 1309-1349.
  22. Davis MD, Blodi BA. "Proliferative diabetic retinopathy," in Ryan SJ, ed., Retina. St. Louis: Mosby, 2001. pp. 1309-1349.
  23. Folk JC and Oh KT. "Photocoagulation for diabetic macular edema and diabetic retinopathy," in Flynn HW and Smiddy WE, eds., Diabetes and Ocular Disease: Past, Present and Future Therapies. American Academy of Ophthalmology, 2000. pp. 115-153.
  24. Chew EY, Ferris III FL. "Nonproliferative diabetic retinopathy," in Ryan SJ, ed., Retina. St. Louis: Mosby, 2001. pp. 1295-1308.
  25. Chew EY, Ferris III FL. "Nonproliferative diabetic retinopathy," in Ryan SJ, ed., Retina. St. Louis: Mosby, 2001. pp. 1295-1308.
  26. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med 1994;331:1480-1487.
  27. Simo R, Lecube A, Segura RM, et al. Free insulin growth factor-1 and vascular endothelial growth factor in the vitreous fluid of patients with proliferative diabetic retinopathy. Am J Ophthalmol 2002;134(3):376-382.
  28. Ferris III FL, Davis MD, Aiello LM, Chew EY. "Clinical studies on treatment for diabetic retinopathy," in Flynn HW and Smiddy WE, eds., Diabetes and Ocular Disease: Past, Present and Future Therapies. American Academy of Ophthalmology, 2000. pp. 81-99.
  29. Ferris III FL, Davis MD, Aiello LM, Chew EY. "Clinical studies on treatment for diabetic retinopathy," in Flynn HW and Smiddy WE, eds., Diabetes and Ocular Disease: Past, Present and Future Therapies. American Academy of Ophthalmology, 2000. pp. 81-99.
  30. Aiello LP, Gardner TW. "Future therapies for diabetic retinopathy," in Flynn HW and Smiddy WE, eds., Diabetes and Ocular Disease: Past, Present and Future Therapies. American Academy of Ophthalmology, 2000. pp. 239-273.

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