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Retinopathy, Diabetic, Proliferative
Article Last Updated: Sep 7, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Abdhish R Bhavsar, MD, Adjunct Assistant Professor, Department of Ophthalmology, University of Minnesota; Director of Clinical Research, Retina Center, PA; Past Chair, Consulting Staff, Department of Ophthalmology, Phillips Eye Institute
Abdhish R Bhavsar is a member of the following medical societies: Alpha Omega Alpha, American Academy of Ophthalmology, American Medical Association, American Society of Retina Specialists, Association for Research in Vision and Ophthalmology, and Minnesota Medical Association
Coauthor(s):
Neal H Atebara, MD, Clinical Assistant Professor, Department of Surgery, Division of Ophthalmology, University of Hawaii School of Medicine;
John H Drouilhet, MD, FACS, Clinical Associate Professor, Department of Surgery, Section of Ophthalmology, University of Hawaii, John A Burns School of Medicine
Editors: Vytautas A Pakainis, MD, Chief of Ophthalmology, Dorn Veterans Administration Medical Center, Professor of Ophthalmology, Ophthalmology, University of South Carolina School of Medicine; Simon K Law, MD, PharmD, Assistant Professor of Ophthalmology, Jules Stein Eye Institute; Chief of Section of Ophthalmology Surgical Services, Department of Veterans Affairs Healthcare Center, West Los Angeles; Steve Charles, MD, Director of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine; Lance L Brown, OD, MD, Ophthalmologist, Affiliated With Freeman Hospital and St John's Hospital, Regional Eye Center, Joplin, Missouri; Hampton Roy Sr, MD, Associate Clinical Professor, Department of Ophthalmology, University of Arkansas for Medical Sciences
Author and Editor Disclosure
Synonyms and related keywords:
PDR, proliferative diabetic retinopathy, neovascularization, optic disc, optic disk, NVD, neovascularization elsewhere, NVE, background diabetic retinopathy, nonproliferative diabetic retinopathy, NPDR, diabetes mellitus, DM, diabetes mellitus retinopathy, DM retinopathy, blindness, vision loss, visual acuity loss, visual loss, tractional retinal detachment, vitreous hemorrhage
Background
Diabetes mellitus (DM) is a major medical problem throughout the world. Diabetes causes an array of long-term systemic complications, which have considerable impact on both the patient and the society because it typically affects individuals in their most productive years. Ophthalmic complications of diabetes include corneal abnormalities, glaucoma, iris neovascularization, cataracts, and neuropathies. However, the most common and potentially most blinding of these complications is diabetic retinopathy.
Pathophysiology
The exact mechanism by which diabetes causes retinopathy remains unclear, but several theories have been postulated to explain the typical course and history of the disease.
Growth hormone
Growth hormone appears to play a causative role in the development and progression of diabetic retinopathy. It was noted that diabetic retinopathy was reversed in women who had postpartum hemorrhagic necrosis of the pituitary gland (Sheehan syndrome). This led to the controversial practice of pituitary ablation to treat or prevent diabetic retinopathy in the 1950s. This technique has been abandoned because of numerous systemic complications and the discovery of the effectiveness of laser treatment.
Platelets and blood viscosity
Several hematologic abnormalities in diabetes, such as increased erythrocyte aggregation, decreased RBC deformability, increased platelet aggregation, and adhesion, predispose to sluggish circulation, endothelial damage, and focal capillary occlusion. This leads to retinal ischemia, which, in turn, contributes to the development of diabetic retinopathy.
Aldose reductase and vasoproliferative factors
Fundamentally, DM causes abnormal glucose metabolism as a result of decreased levels or activity of insulin. Increased levels of blood glucose are thought to have a structural and physiologic effect on retinal capillaries causing them to be both functionally and anatomically incompetent.
A persistent increase in blood glucose levels shunts excess glucose into the aldose reductase pathway in certain tissues, which converts sugars into alcohol (eg, glucose into sorbitol, galactose to dulcitol). Intramural pericytes of retinal capillaries seem to be particularly affected by this increased level of glucose because of its high aldose reductase content, eventually leading to the loss of its primary function (ie, autoregulation of retinal capillaries).
Loss of function of pericytes results in weakness and eventual saccular outpouching of capillary walls. These microaneurysms are the earliest detectable signs of DM retinopathy.
Ruptured microaneurysms (MA) result in retinal hemorrhages either superficially (flame-shaped hemorrhages) or in deeper layers of the retina (blot and dot hemorrhages).
Increased permeability of these vessels results in leakage of fluid and proteinaceous material, which clinically appears as retinal thickening and exudates. If the swelling and exudation would happen to involve the macula, a diminution in central vision may be experienced. Macular edema is the most common cause of vision loss in patients with nonproliferative diabetic retinopathy (NPDR). However, it is not exclusively seen only in patients with NPDR, but it also may complicate cases of proliferative diabetic retinopathy (PDR).
As the disease progresses, eventual closure of the retinal capillaries occurs, leading to hypoxia. Infarction of the nerve fiber layer leads to the formation of cotton-wool spots (CWS) with associated stasis in axoplasmic flow.
More extensive retinal hypoxia triggers compensatory mechanisms within the eye to provide enough oxygen to tissues. Venous caliber abnormalities, such as venous beading, loops, and dilation, signify increasing hypoxia and almost always are seen bordering the areas of capillary nonperfusion.
Intraretinal microvascular abnormalities (IRMA) represent either new vessel growth or remodeling of preexisting vessels through endothelial cell proliferation within the retinal tissues that act as shunts through areas of nonperfusion.
Further increases in retinal ischemia trigger the production of vasoproliferative factors, such as vascular endothelial growth factor (VEGF), that stimulate new vessel formation. The extracellular matrix is broken down first by proteases, and new vessels arising mainly from the retinal venules penetrate the internal limiting membrane and form capillary networks between the inner surface of the retina and the posterior hyaloid face.
Neovascularization most commonly is observed at the borders of perfused and nonperfused retina and most commonly occur along the vascular arcades and at the optic nerve head. New vessels break through and grow along the surface of the retina and into the scaffold of the posterior hyaloid face. By themselves, these vessels rarely cause visual compromise. However, they are fragile and highly permeable. These delicate vessels are disrupted easily by vitreous traction, which leads to hemorrhage into the vitreous cavity or the preretinal space.
These new blood vessels initially are associated with a small amount of fibroglial tissue formation. However, as the density of the neovascular frond increases, so does the fibrous tissue formation. In later stages, the vessels may regress leaving only networks of avascular fibrous tissue adherent to both the retina and the posterior hyaloid face. As the vitreous contracts, it may exert tractional forces on the retina via these fibroglial connections. Traction may cause retinal edema, retinal heterotropia, and both tractional retinal detachments and retinal tear formation with subsequent detachment.
Frequency
United States
Approximately 700,000 Americans have PDR with an annual incidence of 65,000. Approximately 500,000 persons have clinically significant macular edema (CSME) with an annual incidence of 75,000.
Mortality/Morbidity
Approximately 16 million Americans have diabetes, with 50% of them not even aware that they have it. Of these, only one half receives appropriate eye care. Thus, it is not surprising that diabetic retinopathy is the leading cause of new blindness in persons aged 25-74 years in the United States.
Approximately 8,000 eyes become blind yearly because of diabetes. The treatment of diabetic retinopathy entails tremendous costs, but it has been estimated that this represents only one eighth of the costs of social security payments for vision loss. This cost does not compare to the cost in terms of loss of productivity and quality of life.
History
In the initial stages, patients are generally asymptomatic; however, in the advanced stages of the disease, patients may experience floaters, blurred vision, or progressive visual acuity loss.
Physical
These findings occur in addition to all the findings that can be seen in nonproliferative or background diabetic retinopathy. See Retinopathy, Diabetic, Background.
- Neovascularization
- Hallmark of PDR
- Most often occurs near the optic disc (neovascularization of the disc [NVD]) or within 3 disc diameters of the major retinal vessels (neovascularization elsewhere [NVE])
- Preretinal or vitreous hemorrhage
- Preretinal hemorrhages appear as pockets of blood within the potential space between the retina and the posterior hyaloid face. As the blood pools within this space, they may appear boat shaped.
- Hemorrhage into the vitreous may appear as a diffuse haze or as clumps of blood clots within the gel.
- Fibrovascular tissue proliferation is usually seen associated with the neovascular complex and also may appear avascular when the vessels have already regressed.
- Traction retinal detachments usually appear tented up, immobile, and concave compared to rhegmatogenous retinal detachments, which are bullous, mobile, and convex. However, a combination of both mechanisms is not an uncommon finding.
- Macular edema
- Leading cause of visual impairment in patients with diabetes
- Possibly due to functional damage and necrosis of retinal capillaries
- In cases of PDR, edema also may be caused by retinal traction if the retina is sufficiently elevated away from the retinal pigment epithelium (RPE).
- CSME is defined as any of the following:
- Retinal thickening located 500 µm or less from the center of the foveal avascular zone (FAZ)
- Hard exudates with retinal thickening 500 µm or less from the center of the FAZ
- Retinal thickening 1 disc area or larger in size located within 1 disc diameter of the FAZ
- Classification of proliferative diabetic retinopathy
- Early proliferative diabetic retinopathy - Presence of new vessels but not meeting the criteria for high-risk PDR
- High-risk proliferative diabetic retinopathy
- NVD greater than or equal to one-third to one-half disc area (DA)
- Any amount of NVD with vitreous or preretinal hemorrhage
- NVE greater than or equal to one-half DA with preretinal or vitreous hemorrhage
Causes
Risk factors
- Duration of the diabetes
- In patients with type I diabetes, no clinically significant retinopathy can be seen in the first 5 years after the initial diagnosis of diabetes. In 10-15 years, 25-50% of patients show some signs of retinopathy. This prevalence increases to 75-95% after 15 years and approaches 100% after 30 years of diabetes. PDR is rare within the first decade of diagnosis but increases to 14-17% by 15 years, rising steadily thereafter.
- In patients with type II diabetes, the incidence of diabetic retinopathy likewise increases with the duration of the disease. Of patients with type II diabetes, 23% have NPDR after 11-13 years, 41% have NPDR after 14-16 years, and 60% have NPDR after 16 years. PDR was found in 3% of patients 11 or more years after the diagnosis.
- Renal disease, as evidenced by proteinuria and elevated BUN/creatinine levels, is an excellent predictor of the presence of retinopathy. This is probably because of the fact that both conditions are caused by DM-related microangiopathies such that the presence and severity of one reflects that of the other. Evidence suggests that aggressive treatment of the nephropathy may have a beneficial effect on the progression of diabetic retinopathy and neovascular glaucoma.
- Systemic hypertension, in the setting of diabetic nephropathy, correlates well with the presence of retinopathy. Independently, hypertension also may complicate diabetes in that it may result in hypertensive retinal vascular changes superimposed on the preexisting diabetic retinopathy, further compromising retinal blood flow.
- Proper management of hyperlipidemia (elevated serum lipids) may result in less retinal vessel leakage and hard exudate formation. The reason behind this is unclear.
- Pregnant women without any diabetic retinopathy run a 10% risk of developing NPDR during their pregnancy. Of those with preexisting NPDR, 4% progress to the proliferative type. Those with proliferative retinopathy do poorly without treatment, but those who have had prior panretinal photocoagulation (PRP) remain stable throughout their pregnancy.
Branch Retinal Vein Occlusion
Central Retinal Vein Occlusion
Macroaneurysm
Macular Edema, Diabetic
Retinopathy, Diabetic, Background
Retinopathy, Hemoglobinopathies
Retinopathy, Valsalva
Terson Syndrome
Other Problems to be Considered
Retinopathy, radiation
Lab Studies
- The fasting glucose level and the hemoglobin A1c (HbA1c) level are important to control. If the HbA1c level is maintained in the 6-7% range for several years, then the progression of diabetic retinopathy is reduced substantially, according to the DCCT.
Imaging Studies
- Fluorescein angiography is an invaluable adjunct in the diagnosis and treatment of diabetic retinopathy.
- Microaneurysms would appear as pinpoint hyperfluorescence that does not enlarge but rather fades in the later phases of the test.
- Blot and dot hemorrhages can be distinguished from microaneurysms in that they appear as hypofluorescent rather than hyperfluorescent.
- Areas of nonperfusion appear as homogenous dark patches bordered by occluded blood vessels.
- IRMA is evidenced by collateral vessels that do not leak, usually found in the borders of the nonperfused retina.
- Neovascularization: Neovascular tufts leak dye because of their high permeability; they start as hyperfluorescent areas that increase in size and intensity in the later phases of the test.
Other Tests
- B-scan ultrasonography can be used to evaluate the status of the retina if the media is obstructed by vitreous hemorrhage.
Medical Care
- Glucose control: The DCCT has found that intensive glucose control in patients with insulin-dependent diabetes mellitus (IDDM) has decreased the incidence and progression of diabetic retinopathy. Although no similar clinical trials for patients with non–insulin-dependent diabetes mellitus (NIDDM) exist, it may be logical to assume that the same principles also apply. In fact, the American Diabetes Association (ADA) has suggested that all diabetics (NIDDM and IDDM) should strive to maintain glycosylated hemoglobin levels of less than 7% to prevent or at the very least to minimize the long-term complications of DM, including DM retinopathy.
- The Early Treatment for Diabetic Retinopathy Study (ETDRS) found that 650 mg of aspirin daily did not offer any benefit in preventing the progression of DM retinopathy. Additionally, aspirin was not observed to influence the incidence of vitreous hemorrhage in patients who required it for cardiovascular disease (CVD) or other conditions.
- Recently, in large phase III clinical trials, intravitreal injections of ovine hyaluronidase (Vitrase) have been shown to be safe and to have modest efficacy for the clearance of severe vitreous hemorrhage. More than 70% of subjects in these studies had diabetes, and the most frequent etiology of the vitreous hemorrhage was proliferative diabetic retinopathy.
- More recently, bevacizumab (Avastin) has been used to treat vitreous hemorrhage. In addition, this medicine has been used to treat optic nerve or retinal neovascularization as well as rubeosis.
Surgical Care
The advent of laser photocoagulation in the 1960s and early 1970s provided a noninvasive treatment modality, which has a relatively low complication rate and a significant degree of success.
- PRP is the preferred form of treatment of PDR. This involves applying laser burns over the entire retina sparing the central macular area. This may be performed using a variety of delivery systems, including the slit lamp, an indirect ophthalmoscope, and the EndoProbe.
- Application starts in a circumference of 500 µm from the disc and 2 disc diameters from the fovea to wall off the central retina. Moderate intensity burns of 200-500 µm (gray-white burns) are placed 1 spot size apart, except in areas of neovascularization where the entire frond is treated. This procedure is continued peripherally to achieve a total of 1200-1600 applications over 2-3 sessions.
- The presence of high-risk PDR is an indication for immediate treatment.
- In cases where macular edema and PDR coexist, laser treatments are performed, first for the macular edema, and then the PRP is spread over 3-4 sessions. If it is necessary to complete both procedures at the same time, the PRP is applied initially to the nasal third of the retina.
- The strategy for treating macular edema depends on the type and extent of vessel leakage. If the edema is due to focal leakage, microaneurysms are treated directly with laser photocoagulation. In cases where the foci of leakage are nonspecific, a grid pattern of laser burns is applied. Burns (100-200 µm) are placed 1 burn size apart covering the affected area.
- The exact mechanism by which PRP works is not entirely understood. One theory is that destroying the hypoxic retina presumably decreases the production of vasoproliferative factors, such as VEGF, which, in turn, reduces the rate of neovascularization. Another theory is that PRP allows increased diffusion of oxygen from the choroid, supplementing retinal circulation. The enhanced oxygen delivery also down-regulates vasoproliferative factor production and subsequent neovascularization.
- Vitrectomy
- Vitrectomy may be necessary in cases of long-standing vitreous hemorrhage (where visualization of the status of the posterior pole is too difficult), tractional retinal detachment, and combined tractional and rhegmatogenous retinal detachment. More uncommon indications include epiretinal membrane formation and macular dragging.
- The Diabetic Retinopathy Vitrectomy Study (DRVS) has recommended that vitrectomy be advised for eyes with vitreous hemorrhage that fails to resolve spontaneously within 6 months. Early vitrectomy ( <6 mo, mean of 4 mo) may result in a slightly greater recovery of vision in patients with type I diabetes.
- When treatment is delayed, monitoring the status of the posterior segment by ultrasound is mandatory to watch for signs of macular detachment.
- The purpose of surgery is to remove the blood to permit evaluation and possible treatment of the posterior pole, to release tractional forces that pull on the retina, to repair a retinal detachment, and to remove the scaffolding into which the neovascular complexes may grow. Laser photocoagulation through indirect delivery systems or through the EndoProbe can be performed as an adjunctive procedure during surgery to initiate or continue laser treatment.
- Cryotherapy
- When laser photocoagulation is precluded in the presence of an opaque media, such as in cases of cataracts and vitreous hemorrhage, cryotherapy may be applied instead.
- The principles behind the treatment is basically the same, that is, to ablate retinal tissue for oxygen demand to be decreased and to induce a chorioretinal adhesion, which could increase oxygen supply to the retina in the hope of preventing or down-regulating the vasoproliferative response.
Further Outpatient Care
- The follow-up regimen of patients with early PDR is dictated by its risk of developing high-risk characteristics. Of patients with early PDR, 75% develop high-risk characteristics within 5 years; therefore, they need to be monitored every 2-3 months for progression. Once high-risk characteristics are observed, promptly institute laser photocoagulation to decrease the chance of severe visual loss.
- Promptly treat eyes with high-risk PDR with laser PRP to decrease the risk of severe visual loss. Monitor patients every 1-2 months until the retinopathy has stabilized.
- Eyes with CSME, no matter what stage of retinopathy, should be treated promptly and monitored every 2-4 months thereafter to assess the efficacy of treatment and to watch for future incidences of edema.
Complications
- Complications of PRP include the following:
- Visual field constriction
- Night blindness
- Foveal burns
- Macular edema
- Serous and/or choroidal detachment
- Pain
- Anterior segment complications, such as corneal and lenticular burns
Prognosis
- The Diabetic Retinopathy Study (DRS) has found that adequate scatter PRP reduces the risk of severe visual loss ( <5/200) by more than 50%.
Patient Education
- One of the most important aspects in the management of diabetic retinopathy is patient education. Inform patients that they play an integral role in their own eye care. Emphasize the following facts:
- Excellent glucose control is beneficial in any stage of diabetic retinopathy. It delays the onset and slows down the progression of the diabetic complications in the eye.
- Other systemic problems, such as hypertension, renal disease, and hyperlipidemia, may contribute to the progression of the retinopathy and should be addressed promptly.
- Smoking, although not directly proven to affect the course of the retinopathy, also may play a role in further compromising oxygen delivery to the retina. Therefore, all efforts should be made in the reduction, if not outright cessation, of smoking.
- Visual symptoms (eg, changes in vision, redness, pain) could be manifestations of disease progression and should be reported immediately.
- DM in general and diabetic retinopathy in particular are progressive conditions such that regular follow-up care with a physician is crucial to detect any changes that may benefit from treatment.
- For excellent patient education resources, see eMedicine's Diabetes Center. Also, visit eMedicine's patient education article Diabetic Eye Disease.
Medical/Legal Pitfalls
- Failure to emphasize to the patient that all efforts in the treatment of diabetic retinopathy are mainly aimed at reducing the risk of visual loss and not at improving vision.
The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Sherman O Valero, MD, to the development and writing of this article.
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New vessel formation on the surface of the retina (neovascularization elsewhere). |
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An area of neovascularization that leaks fluorescein on angiography. |
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Boat-shaped preretinal hemorrhage associated with neovascularization elsewhere. |
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Fibrovascular proliferations within the vitreous cavity. |
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Extensive fibrovascular proliferations within and around the optic disc. |
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Retinopathy, Diabetic, Proliferative excerpt Article Last Updated: Sep 7, 2006
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