Diabetic Retinopathy

Practice Essentials

Diabetes mellitus (DM) is a major medical problem throughout the world. Diabetes causes an array of long-term systemic complications that have considerable impact on the patient as well as society, as the disease typically affects individuals in their most productive years.^[1] An increasing prevalence of diabetes is occurring throughout the world.^[2] In addition, this increase appears to be greater in developing countries. The etiology of this increase involves changes in diet, with higher fat intake, sedentary lifestyle changes, and decreased physical activity.^{[3, 4]}

Important aspects of workup regarding diabetic retinopathy include fasting glucose and hemoglobin A1c (HbA1c), fluorescein angiography, optical coherence tomography, and B-scan ultrasonography. Controlling diabetes and maintaining the HbA1c level in the 6-7% range are the goals in the optimal management of diabetes and diabetic retinopathy.

Patients with diabetes often develop ophthalmic complications, such as corneal abnormalities, glaucoma, iris neovascularization, cataracts, and neuropathies. The most common and potentially most blinding of these complications, however, is diabetic retinopathy,^{[5, 6, 7]} which is, in fact, the leading cause of new blindness in persons aged 25-74 years in the United States. Approximately 700,000 persons in the United States have proliferative diabetic retinopathy, with an annual incidence of 65,000. An estimate of the prevalence of diabetic retinopathy in the United States showed a high prevalence of 28.5% among those with diabetes aged 40 years or older.^[8] (See Epidemiology.)

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.^{[9, 10]} See the image below.

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Fundus photograph of early background diabetic retinopathy showing multiple microaneurysms.

In the initial stages of diabetic retinopathy, patients are generally asymptomatic, but in more advanced stages of the disease patients may experience symptoms that include floaters, distortion, and/or blurred vision. Microaneurysms are the earliest clinical sign of diabetic retinopathy. (See Clinical Presentation.)

Renal disease, as evidenced by proteinuria and elevated blood urea nitrogen (BUN)/creatinine levels, is an excellent predictor of retinopathy; both conditions are caused by DM-related microangiopathies, and the presence and severity of one reflects that of the other. Aggressive treatment of the nephropathy may slow progression of diabetic retinopathy and neovascular glaucoma. (See Treatment and Management.)

A study by Ito et al indicated that in patients with type 2 diabetes, the presence of reduced peripheral nerve conduction velocity is associated with the existence of early diabetic retinopathy. The report included 42 patients with type 2 diabetes (42 eyes), who had either no diabetic retinopathy or mild nonproliferative diabetic retinopathy. The investigators found that the latter group had significantly lower sural sensory conduction velocity and tibial motor conduction velocity than did patients with no diabetic retinopathy, with logistic regression analysis showing these velocities to be independent risk factors for the mild nonproliferative eye disease.^[11]

According to The Diabetes Control and Complications Trial controlling diabetes and maintaining the HbA1c level in the 6-7% range can substantially reduce the progression of diabetic retinopathy. (See Treatment and Management.)

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. (See Patient Education.)

For more information, see Type 1 Diabetes Mellitus and Type 2 Diabetes Mellitus.

Signs and symptoms

In the initial stages of diabetic retinopathy, patients are generally asymptomatic; in the more advanced stages of the disease, however, patients may experience symptoms that include floaters, blurred vision, distortion, and progressive visual acuity loss. Signs of diabetic retinopathy include the following:

• Microaneurysms: The earliest clinical sign of diabetic retinopathy; these occur secondary to capillary wall outpouching due to pericyte loss; they appear as small, red dots in the superficial retinal layers
• Dot and blot hemorrhages: Appear similar to microaneurysms if they are small; they occur as microaneurysms rupture in the deeper layers of the retina, such as the inner nuclear and outer plexiform layers
• Flame-shaped hemorrhages: Splinter hemorrhages that occur in the more superficial nerve fiber layer
• Retinal edema and hard exudates: Caused by the breakdown of the blood-retina barrier, allowing leakage of serum proteins, lipids, and protein from the vessels
• Cotton-wool spots: Nerve fiber layer infarctions from occlusion of precapillary arterioles; they are frequently bordered by microaneurysms and vascular hyperpermeability
• Venous loops and venous beading: Frequently occur adjacent to areas of nonperfusion; they reflect increasing retinal ischemia, and their occurrence is the most significant predictor of progression to proliferative diabetic retinopathy (PDR).
• Intraretinal microvascular abnormalities: Remodeled capillary beds without proliferative changes; can usually be found on the borders of the nonperfused retina
• Macular edema: Leading cause of visual impairment in patients with diabetes

Nonproliferative diabetic retinopathy

• Mild: Indicated by the presence of at least 1 microaneurysm
• Moderate: Includes the presence of hemorrhages, microaneurysms, and hard exudates
• Severe (4-2-1): Characterized by hemorrhages and microaneurysms in 4 quadrants, with venous beading in at least 2 quadrants and intraretinal microvascular abnormalities in at least 1 quadrant

Proliferative diabetic retinopathy

• Neovascularization: Hallmark of PDR
• Preretinal hemorrhages: Appear as pockets of blood within the potential space between the retina and the posterior hyaloid face; as blood pools within this space, the hemorrhages 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: Usually seen associated with the neovascular complex; may appear avascular when the vessels have already regressed
• Traction retinal detachments: Usually appear tented up, immobile, and concave
• Macular edema

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies of HbA1c levels are important in the long-term follow-up care of patients with diabetes and diabetic retinopathy.

Imaging studies used in the diagnosis of diabetic retinopathy include the following:

• Fluorescein angiography: Microaneurysms appear as pinpoint, hyperfluorescent lesions in early phases of the angiogram and typically leak in the later phases of the test
• Optical coherence tomography scanning: Administered to determine the thickness of the retina and the presence of swelling within the retina, as well as vitreomacular traction
• B-scan ultrasonography

See Workup for more detail.

Management

Pharmacologic therapy

• Triamcinolone: Administered intravitreally; corticosteroid used in the treatment of diabetic macular edema
• Bevacizumab: Administered intravitreally; monoclonal antibody that can help to reduce diabetic macular edema and neovascularization of the disc or retina
• Ranibizumab: Administered intravitreally; monoclonal antibody that can help to reduce diabetic macular edema and neovascularization of the disc or retina

Glucose control

The Diabetes Control and Complications Trial found that intensive glucose control in patients with type 1 diabetes (previously called insulin-dependent diabetes mellitus [IDDM]) decreased the incidence and progression of diabetic retinopathy.^{[12, 13, 14]} It may be logical to assume that the same principles apply in type 2 diabetes (previously called non-insulin-dependent diabetes mellitus [NIDDM]).

Laser photocoagulation

This involves directing a high-focused beam of light energy to create a coagulative response in the target tissue. In nonproliferative diabetic retinopathy (NPDR), laser photocoagulation is indicated in the treatment of clinically significant macular edema.

Panretinal photocoagulation (PRP) is used in the treatment of PDR.^{[15, 16]} It involves applying laser burns over the entire retina, sparing the central macular area.

Vitrectomy

This procedure can be used in PDR 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.

Cryotherapy

When laser photocoagulation in PDR is precluded in the presence of an opaque media, such as in cases of cataracts or vitreous hemorrhage, cryotherapy may be applied instead.

See Treatment and Medication for more detail.

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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.^{[9, 10]}

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Fundus photograph of early background diabetic retinopathy showing multiple microaneurysms.

Growth hormone

Growth hormone appears to play a causative role in the development and progression of diabetic retinopathy. Diabetic retinopathy has been shown to be reversible 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 since been abandoned because of numerous systemic complications and the discovery of the effectiveness of laser treatment. It should be noted that diabetic retinopathy has been reported in parients with hypopituitarism as well.

Platelets and blood viscosity

The variety of hematologic abnormalities seen in diabetes, such as increased erythrocyte aggregation, decreased red blood cell deformability, increased platelet aggregation, and adhesion, predispose the patient 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, diabetes mellitus (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 affected by this increased level of sorbitol, eventually leading to the loss of their primary function (ie, autoregulation of retinal capillaries). This results in weakness and eventual saccular outpouching of capillary walls. These microaneurysms are the earliest detectable signs of DM retinopathy. (See the image below.)

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Fundus photograph of early background diabetic retinopathy showing multiple microaneurysms.

Using nailfold video capillaroscopy, a high prevalence of capillary changes is detected in patients with diabetes, particularly those with retinal damage. This reflects a generalized microvessel involvement in both type 1 and type 2 diabetes.^[17]

Ruptured microaneurysms result in retinal hemorrhages either superficially (flame-shaped hemorrhages) or in deeper layers of the retina (blot and dot hemorrhages). (See the image below.)

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Retinal findings in background diabetic retinopathy, including blot hemorrhages (long arrow), microaneurysms (short arrow), and hard exudates (arrowhe....

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 involve the macula, a diminution in central vision may be experienced.

Macular edema

Macular edema is the most common cause of vision loss in patients with nonproliferative diabetic retinopathy (NPDR). However, it is not exclusively seen in patients with NPDR; it may also complicate cases of proliferative diabetic retinopathy.

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Fluorescein angiogram demonstrating foveal dye leakage caused by macular edema.

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Fundus photograph of clinically significant macular edema demonstrating retinal exudates within the fovea.

Another theory to explain the development of macular edema focuses on the increased levels of diacylglycerol from the shunting of excess glucose. This is thought to activate protein kinase C, which, in turn, affects retinal blood dynamics, especially permeability and flow, leading to fluid leakage and retinal thickening.

Hypoxia

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, with associated stasis in axoplasmic flow.

More extensive retinal hypoxia triggers compensatory mechanisms in 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 represent either new vessel growth or remodeling of preexisting vessels through endothelial cell proliferation within the retinal tissues to act as shunts through areas of nonperfusion.

Neovascularization

Further increases in retinal ischemia trigger the production of vasoproliferative factors 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. (See the images below.)

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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.

In patients with proliferative diabetic retinopathy (PDR), nocturnal intermittent hypoxia/reoxygenation that results from sleep-disordered breathing may be a risk factor for iris and/or angle neovascularization.^[18]

Neovascularization is most commonly observed at the borders of perfused and nonperfused retina and most commonly occurs along the vascular arcades and at the optic nerve head. The 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, but 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 degree of 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.

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Etiology

Duration of 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 is made. After 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. Proliferative diabetic retinopathy (PDR) is rare within the first decade of type I diabetes diagnosis but increases to 14-17% by 15 years, rising steadily thereafter.

In patients with type II diabetes, the incidence of diabetic retinopathy increases with the disease duration. Of patients with type II diabetes, 23% have nonproliferative diabetic retinopathy (NPDR) after 11-13 years, 41% have NPDR after 14-16 years, and 60% have NPDR after 16 years.

Hypertension and hyperlipidemia

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, but the reason behind this is unclear.

Pregnancy

Pregnant women with proliferative diabetic retinopathy do poorly without treatment, but those who have had prior panretinal photocoagulation remain stable throughout pregnancy. Pregnant women without diabetic retinopathy run a 10% risk of developing NPDR during their pregnancy; of those with preexisting NPDR, 4% progress to the proliferative type.^[19]

A study by Toda et al found that among pregnant women with diabetic retinopathy, those who showed progression of the eye disorder tended to have a longer duration of diabetes, to have had diabetic retinopathy prior to pregnancy, and to have higher blood pressure in the second trimester.^[20]

For more information, see Diabetes Mellitus and Pregnancy.

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Epidemiology

Of the approximately 16 million Americans with diabetes, 50% are unaware that they have it. Of those who know they have diabetes, only half receive 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 700,000 Americans have proliferative diabetic retinopathy, with an annual incidence of 65,000. Approximately 500,000 persons have clinically significant macular edema, with an annual incidence of 75,000.

Diabetes is responsible for approximately 8000 eyes becoming blinded each year, meaning that diabetes is responsible for 12% of blindness.^[21] The rate is even higher among certain ethnic groups. An increased risk of diabetic retinopathy appears to exist in patients of Native American, Hispanic, and African American heritage.

With increasing duration of diabetes or with increasing age since its onset, there is a higher risk of developing diabetic retinopathy and its complications, including diabetic macular edema or proliferative diabetic retinopathy.

Nonetheless, a literature review by Sabanayagam et al indicated that although the prevalence of diabetes has increased worldwide, the incidence of diabetic retinopathy–related blindness has fallen, especially in developed nations.^[22]

A retrospective study by Porter et al of patients under age 21 years with type 1 or type 2 diabetes mellitus seen at an urban tertiary eye-care center found the overall incidence of diabetic retinopathy in these individuals to be 3.8%. More specifically, the rates were 3.4% and 6% in patients with type 1 and type 2 diabetes, respectively. Moreover, diabetic retinopathy occurred after a shorter disease duration in patients with type 2 diabetes than in those with type 1. The investigators also found no diabetic retinopathy in patients with an HbA1c level below 8%.^[23]

For more information, see Macular Edema.

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Prognosis

Prognostic factors that are favorable for visual loss include the following:

• Circinate exudates of recent onset
• Well-defined leakage
• Good perifoveal perfusion

Prognostic factors that are unfavorable for visual loss include the following:

• Diffuse edema/multiple leaks
• Lipid deposition in the fovea
• Macular ischemia
• Cystoid macular edema
• Preoperative vision of less than 20/200
• Hypertension

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.

The Early Treatment for Diabetic Retinopathy Study has found that laser surgery for macular edema reduces the incidence of moderate visual loss (doubling of visual angle or roughly a 2-line visual loss) from 30% to 15% over a 3-year period. The Diabetic Retinopathy Study has found that adequate scatter laser panretinal photocoagulation reduces the risk of severe visual loss (< 5/200) by more than 50%.^{[24, 25]}

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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.

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.

The following symptoms and/or health concerns must be addressed in any patient education program for those with diabetic retinopathy:

• Systemic problems (eg, hypertension, renal disease, and hyperlipidemia) may contribute to disease progression.
• Smoking, although not directly proven to affect the course of the retinopathy, may further compromise oxygen delivery to the retina. Therefore, all efforts should be made in the reduction, if not outright cessation, of smoking.
• Visual symptoms (eg, vision changes, floaters, distortion, redness, pain) could be manifestations of disease progression and should be reported immediately.

Diabetes mellitus, in general, and diabetic retinopathy, in particular, are progressive conditions, and regular follow-up care with a physician is crucial for detection of any changes that may benefit from treatment.

For excellent patient education resources, see eMedicineHealth's Diabetes Center. Also, visit eMedicineHealth's patient education article Diabetic Eye Disease.

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History

In the initial stages of diabetic retinopathy, patients are generally asymptomatic; in the more advanced stages of the disease, however, patients may experience symptoms that include floaters, blurred vision, distortion, and progressive visual acuity loss.

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Physical Examination

The mainstay of diagnosing diabetic retinopathy is a complete ophthalmic examination and dilated retinal examination by an ophthalmologist or retina specialist or retina surgeon.

Outreach screening has the potential to increase screening coverage of high-risk patients with diabetic retinopathy in remote and resource-poor settings or in areas in which no ophthalmologist or retina specialist is available, without the risk of missing diabetic retinopathy and the opportunity to prevent vision loss.^[26]

Microaneurysms

Microaneurysms are the earliest clinical sign of diabetic retinopathy and occur secondary to capillary wall outpouching due to pericyte loss. They appear as small red dots in the superficial retinal layers, and there is fibrin and red blood cell accumulation in the microaneurysm lumen. A rupture produces blot/flame hemorrhages. Affected areas may appear yellowish in time, as endothelial cells proliferate and produce basement membrane.

Dot and blot hemorrhages

Dot and blot hemorrhages occur as microaneurysms rupture in the deeper layers of the retina, such as the inner nuclear and outer plexiform layers. These appear similar to microaneurysms if they are small; fluorescein angiography may be needed to distinguish between the two.

Flame-shaped hemorrhages

Flame-shaped hemorrhages are splinter hemorrhages that occur in the more superficial nerve fiber layer.

Retinal edema and hard exudates

Retinal edema and hard exudates are caused by the breakdown of the blood-retina barrier, allowing leakage of serum proteins, lipids, and protein from the vessels.

Cotton-wool spots

Cotton-wool spots are nerve fiber layer infarctions from occlusion of precapillary arterioles. With the use of fluorescein angiography, there is no capillary perfusion. These are frequently bordered by microaneurysms and vascular hyperpermeability.

Venous loops and venous beading

Venous loops and venous beading frequently occur adjacent to areas of nonperfusion and reflect increasing retinal ischemia. Their occurrence is the most significant predictor of progression to proliferative diabetic retinopathy.

Intraretinal microvascular abnormalities

Intraretinal microvascular abnormalities are remodeled capillary beds without proliferative changes. These collateral vessels do not leak on fluorescein angiography and can usually be found on the borders of the nonperfused retina.

Macular edema

Macular edema is the leading cause of visual impairment in patients with diabetes. A reported 75,000 new cases of macular edema are diagnosed annually. This may be due to functional damage and necrosis of retinal capillaries.

Clinically significant macular edema 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

Nonproliferative diabetic retinopathy

Mild nonproliferative diabetic retinopathy (NPDR) is indicated by the presence of at least 1 microaneurysm. Mild NPDR reflects structural changes in the retina caused by the physiological and anatomical effects of diabetes.

More advanced stages of NPDR reflect the increasing retinal ischemia, setting the stage for proliferative changes.

Moderate nonproliferative diabetic retinopathy includes the presence of hemorrhages, microaneurysms, and hard exudates. With this condition, soft exudates, venous beading, and intraretinal microvascular abnormalities (IRMA) occur less frequently than with severe NPDR.

Severe NPDR (4-2-1) is characterized by hemorrhages and microaneurysms in 4 quadrants, with venous beading in at least 2 quadrants and IRMA in at least 1 quadrant.

Proliferative diabetic retinopathy

Neovascularization is the hallmark of PDR. It 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]). (See the image below.)

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New vessel formation on the surface of the retina (neovascularization elsewhere)

Preretinal hemorrhages appear as pockets of blood within the potential space between the retina and the posterior hyaloid face. As blood pools within this space, they may appear boat shaped. (See the image below.)

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Boat-shaped preretinal hemorrhage associated with neovascularization elsewhere.

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. (See the images below.)

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Fibrovascular proliferations within the vitreous cavity

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Extensive fibrovascular proliferations within and around the optic disc

Traction retinal detachments usually appear tented up, immobile, and concave, as compared to rhegmatogenous retinal detachments, which are bullous, mobile, and convex. A combination of both mechanisms is not an uncommon finding, however.

Macular edema is the leading cause of visual impairment in patients with diabetes. It may result from 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.

Proliferative diabetic retinopathy is classified as early or high risk.^[27] In early PDR, new vessels are present, but they do not meet the criteria for high-risk PDR. In high-risk PDR, NVD is one-third to one-half, or greater, of the disc area (DA); there may be any amount of NVD with vitreous or preretinal hemorrhage; and NVE is one-half or greater of the DA, with preretinal or vitreous hemorrhage.

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Approach Considerations

Important aspects of workup regarding diabetic retinopathy include fasting glucose and hemoglobin A1c, fluorescein angiography, optical coherence tomography, and B-scan ultrasonography.

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Fasting Glucose and Hemoglobin A1c

Fasting glucose and hemoglobin A1c (HbA1c) are important laboratory tests that are performed to help diagnose diabetes. The HbA1c level is also important in the long-term follow-up care of patients with diabetes and diabetic retinopathy.

The Data From an Epidemiological Study on the Insulin Resistance Syndrome (DESIR) Study evaluated diabetic retinopathy in 235 individuals with diabetes and 227 individuals with impaired fasting plasma glucose levels.^[28] The study found that the risk of developing diabetic retinopathy at 10 years was higher in individuals with a fasting plasma glucose level of more than 108 mg/dL and HbA1c level of more than 6%. Controlling diabetes and maintaining the HbA1c level in the 6-7% range are the goals in the optimal management of diabetes and diabetic retinopathy. If the levels are maintained, then the progression of diabetic retinopathy is reduced substantially, according to The Diabetes Control and Complications Trial.

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Fluorescein Angiography

Fluorescein angiography is an invaluable adjunct in the diagnosis and management of diabetic retinopathy. Microaneurysms appear as pinpoint hyperfluorescent lesions in early phases of the angiogram and typically leak in the later phases of the test.

Blot and dot hemorrhages can be distinguished from microaneurysms as hypofluorescent rather than hyperfluorescent. Areas of nonperfusion appear as homogeneous hypofluorescent or dark patches bordered by occluded blood vessels.

Intraretinal microvascular abnormalities are evidenced by collateral vessels that do not leak, usually found in the borders of the nonperfused retina. 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. (See the images below.)

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Fluorescein angiogram demonstrating an area of capillary nonperfusion (arrow).

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Fluorescein angiogram demonstrating foveal dye leakage caused by macular edema.

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An area of neovascularization that leaks fluorescein on angiography.

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Optical Coherence Tomography

Optical coherence tomography (OCT) uses light to generate a cross-sectional image of the retina. This is used to determine the thickness of the retina and the presence of swelling within the retina as well as vitreomacular traction. This test is particularly used for the diagnosis and management of diabetic macular edema or clinically significant macular edema.

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B-scan Ultrasonography

B-scan ultrasonography can be used to evaluate the status of the retina if the media is obstructed by vitreous hemorrhage.

• References

Approach Considerations

Controlling diabetes and maintaining the HbA1c level in the 6-7% range are the goals in the optimal management of diabetes and diabetic retinopathy. If the levels are maintained, then the progression of diabetic retinopathy is reduced substantially, according to The Diabetes Control and Complications Trial.^[12]

The Early Treatment for Diabetic Retinopathy Study^[24] has found that laser surgery for macular edema reduces the incidence of moderate visual loss (doubling of visual angle or roughly a 2-line visual loss) from 30% to 15% over a 3-year period.

Two-year results from the Diabetic Retinopathy Clinical Research network (DRCR.net) Randomized Trial Evaluating Ranibizumab Plus Prompt or Deferred Laser or Triamcinolone Plus Prompt Laser for Diabetic Macular Edema, known as the Laser-Ranibizumab-Triamcinolone for DME Study, demonstrated that ranibizumab paired with prompt or deferred focal/grid laser treatment achieved superior visual acuity and optical coherence tomography (OCT) outcomes compared with focal/grid laser treatment alone. In the ranibizumab groups, approximately 50% of eyes had substantial improvement (10 or more letters) and 30% gained 15 or more letters. Intravitreal triamcinolone combined with focal/grid laser did not result in superior visual acuity outcomes compared with laser alone, but did appear to have a visual acuity benefit similar to ranibizumab in pseudophakic eyes.^[29]

The Diabetic Retinopathy Study has found that adequate scatter laser panretinal photocoagulation reduces the risk of severe visual loss (< 5/200) by more than 50%.^[25]

• References

Glucose Control

The Diabetes Control and Complications Trial has found that intensive glucose control in patients with type 1 diabetes decreases the incidence and progression of diabetic retinopathy.^{[12, 13, 14]}

The United Kingdom Prospective Diabetes Study (UKPDS), which involved newly diagnosed patients with type 2 diabetes mellitus, revealed that the risk of retinopathy was reduced through both improved glycemic control and improved blood pressure control. A 1% reduction in HbA1c reduced the risk for retinopathy by 31%, and a 10 mm Hg reduction in systolic blood pressure reduced photocoagulation or vitreous haemorrhage by 11%.^[30] The ADA recommends that all patients with diabetes (type 2 and type 1) strive to maintain glycated hemoglobin levels of less than 7% (reflecting long-term glucose levels) to prevent or at least minimize the long-term complications of diabetes mellitus, including retinopathy.

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Aspirin Therapy

The Early Treatment for Diabetic Retinopathy Study found that 650 mg of aspirin daily did not offer any benefit in preventing the progression of diabetes mellitus retinopathy. Additionally, aspirin was not observed to influence the incidence of vitreous hemorrhage in patients who required it for cardiovascular disease or other conditions.^{[24, 15]}

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Ovine Hyaluronidase Therapy

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.^[31]

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VEGF Inhibitors

In a DRCR.net clinical trial comparing Eylea (aflibercept), Lucentis (ranibizumab), and Avastin (bevacizumab) for diabetic macular edema (DME), aflibercept provided greater visual improvement, on average, than did the other 2 drugs for vision of 20/50 or worse at the start of the trial. The 3 drugs achieved similar average improvement for vision of 20/40 to 20/32. No major differences in safety were found for the 3 drugs.^[32]

Investigators included 660 people with macular edema at 88 clinical trial sites across the US. Only people with vision of 20/32 or worse were eligible. About half the participants had 20/32 or 20/40 vision at time of enrollment, and the other half had vision of 20/50 or worse.

Participants were randomly assigned to receive aflibercept (2.0 mg/0.05 mL), bevacizumab (1.25 mg/0.05 mL), or ranibizumab (0.3 mg/0.05 mL) and were evaluated monthly. The drug was injected into the eye until the DME resolved or stabilized. Laser treatment was used if DME persisted without continual improvement after 6 months of injections.

Vision substantially improved for most participants at one year after the trial began. For people whose vision was 20/32 or 20/40 at the start of the trial, vision improved almost two lines on an eye chart in those receiving each of the 3 drugs. However, for those whose vision was 20/50 or worse at the start of the trial, aflibercept improved vision on average almost four lines, bevacizumab improved vision on average almost 2.5 lines, and ranibizumab improved vision on average almost 3 lines.

Aflibercept and ranibizumab reduced the swelling of the macula more than bevacizumab. Also, a smaller percentage of participants on aflibercept (36%) had laser treatment for persistent edema that did not resolve with anti–vascular endothelial growth factor (anti-VEGF) treatment alone, compared with participants on bevacizumab (56%) or ranibizumab (46%).^[32]

Aflibercept gained US Food and Drug Administration (FDA) approval for all stages of diabetic retinopathy (NPDR) in May 2019. Approval was based on the 1-year data from the PANORAMA trial (n=402). The study enrolled patients with moderately severe to severe NPDR without DME. At week 52, 80% of patients receiving aflibercept every 8 weeks and 65% of those receiving the drug every 16 weeks improved by two or more steps from baseline on the Early Treatment Diabetic Retinopathy Study Diabetic Retinopathy Severity Scale (ETDRS-DRSS), compared with 15% of placebo patients.^{[33, 34]}

Ranibizumab intravitreal injection was initially approved for diabetic retinopathy in patients with DME. Approval was based on the RISE and RIDE studies (n = 759). The trials measured the proportions of patients who gained 15 letters or more from baseline at month 36 in the sham/0.5 mg, 0.3 mg, and 0.5 mg ranibizumab groups. Results in each group were 19.2%, 36.8%, and 40.2%, respectively, in RIDE and 22.0%, 51.2%, and 41.6%, in RISE.

In the ranibizumab arms, reductions in central foveal thickness (CFT) seen at 24 months were, on average, sustained through month 36. Visual acuity (VA) gains and improvement in retinal anatomy achieved with ranibizumab at month 24 were sustained through month 36. In the third year, sham patients, while still masked, were eligible to cross over to monthly 0.5 mg ranibizumab. After crossover to 1 year of treatment with ranibizumab, average VA gains in the sham/0.5 mg group were lower compared with gains seen in the ranibizumab patients after 1 year of treatment (2.8 vs. 10.6 and 11.1 letters).^[35]

Subsequent studies have also pointed to ranibizumab's efficacy in diabetic retinopathy. A literature review by Stewart found that in a large minority of eyes, regular injections of ranibizumab resulted in improved diabetic retinopathy severity scores. In proliferative diabetic retinopathy, patients experienced less visual field loss with the drug than with laser photocoagulation. The literature also indicated that ranibizumab is superior to laser photocoagulation for the treatment of diabetic macular edema.^[36]

Similarly, a literature review by Vergmann and Grausland indicated that in the treatment of proliferative diabetic retinopathy, VEGF inhibitors are less damaging to visual fields than is conventional panretinal photocoagulation (PRP).^[37]

A 4-year study by Epstein and Amrén found that after receiving a loading dose of ranibizumab (three monthly injections of 0.5 mg), best-corrected visual acuity in patients could be maintained with the drug administered on an as-needed basis. The number of required injections was low, the mean numbers during the first through fourth years being 4.7, 1.4, 0.7, and 0.9, respectively.^[38]

Ranibizumab’s indication for diabetic retinopathy was expanded in 2017 to include all forms (ie, patients who have been diagnosed either with or without DME). Approval for treatment of diabetic retinopathy without DME followed an evaluation of the Diabetic Retinopathy Clinical Research Network's (DRCR.net) Protocol S study (n=305). The study assessed ranibizumab therapy in comparison with panretinal laser treatment in diabetic retinopathy patients with or without DME, with the analysis finding that retinopathy improved in patients in the ranibizumab group, either with or without DME.^[39]

Bevacizumab has been used off-label to treat vitreous hemorrhage. In addition, this agent has been used to treat optic nerve or retinal neovascularization as well as rubeosis.^{[40, 41]} In August, 2011, FDA announced a warning regarding several cases of intravitreal infections associated with repackaged bevacizumab that was potentially due to poor aseptic compounding technique.^[42] Bevacizumab is commonly used to treat DME throughout the world and is a much lower cost alternative.

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Laser Photocoagulation

The advent of laser photocoagulation in the 1960s and early 1970s provided a noninvasive treatment modality that has a relatively low complication rate and a significant degree of success. This involves directing a high-focused beam of light energy to create a coagulative response in the target tissue. In nonproliferative diabetic retinopathy, laser treatment is indicated in the treatment of clinically significant macular edema. The strategy for treating macular edema depends on the type and extent of vessel leakage.

If the edema is due to leakage of specific microaneurysms, the leaking vessels are treated directly with focal laser photocoagulation.^[16] In cases where the foci of leakage are nonspecific, a grid pattern of laser burns is applied. Medium intensity burns (100-200 µm) are placed 1 burn-size apart, covering the affected area. Other off-label potential treatments of diabetic macular edema include intravitreal triamcinolone acetonide (Kenalog) and bevacizumab; these medications can result in a substantial reduction or resolution of macular edema.

• References

level of Activity

Maintaining a healthful lifestyle with regular exercise is important, especially for individuals with diabetes. Exercise can assist in maintaining optimal weight and with peripheral glucose absorption. This can help with improved diabetes control, which, in turn, can help reduce the complications of diabetes and diabetic retinopathy.

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Treatment of Proliferative Diabetic Retinopathy

Panretinal photocoagulation

Panretinal photocoagulation (PRP) is the preferred form of treatment of proliferative diabetic retinopathy (PDR).^{[15, 16]} It involves applying laser burns over the entire retina, sparing the central macular area, and 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 if DRS criteria are used, but most specialists today avoid directly treating neovascularization. This procedure is continued peripherally to achieve a total of 1200-1600 applications in 2 to 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, laser treatment is used for the macular edema; then for PDR, the PRP is spread over 3 to 4 sessions. If it is necessary to complete the 2 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 decreases the production of vasoproliferative factors, such as VEGF, thus reducing 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.

According to The Diabetic Retinopathy Vitrectomy Study, vitrectomy is advisable for eyes with vitreous hemorrhage that fails to resolve spontaneously within 6 months.^[43] 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 are 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.

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Prevention of Diabetic Retinopathy

The Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study were large randomized clinical trials that demonstrated the importance of tight glucose control with respect to reducing the incidence and progression of diabetes complications, including diabetic retinopathy for both type I and type II diabetes.

All individuals with diabetes should be aware of the importance of regular dilated retinal examinations. Early diagnosis and treatment of diabetic retinopathy can help prevent blindness in more than 90% of cases. In spite of treatment, however, individuals can sometimes still lose vision.

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Consultations

The patient, ophthalmologist or retina specialist, and internist or endocrinologist must work together as a team to optimize the diabetes control and help to reduce the risk of blindness.

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Long-Term Monitoring

The frequency of follow-up care is dictated primarily by the baseline stage of the retinopathy and its rate of progression to proliferative diabetic retinopathy (PDR). Only 5% of patients with mild nonproliferative diabetic retinopathy (NPDR) would progress to PDR in 1 year without follow-up care, and thus, monitoring these patients every 6-12 months is appropriate. As many as 27% of patients with moderate NPDR would progress to PDR in 1 year; therefore, they should be seen every 4 to 8 months.

More than 50% of patients with severe NPDR (preproliferative stage) would progress to PDR in a year without follow-up care and 75% would develop high-risk characteristics within 5 years; thus, follow-up care as frequently as every 2 to 3 months is mandated to ensure prompt recognition and treatment.

Any stage associated with clinically significant macular edema should be treated promptly with laser panretinal photocoagulation and observed closely (every 1-2 mo) to monitor the status of the macula and decrease the chance of severe visual loss.

Diabetes mellitus, in general, and diabetic retinopathy, in particular, are progressive conditions, and regular follow-up care with a physician is crucial for detection of any changes that may benefit from treatment.

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Guidelines Summary

The American Diabetes Association’s “Standards of Medical Care in Diabetes-2018” include the following recommendations regarding diabetic retinopathy^[44] :

• Optimize glycemic control to reduce the risk or slow the progression of diabetic retinopathy
• Optimize blood pressure and serum lipid control to reduce the risk or slow the progression of diabetic retinopathy
• Adults with type 1 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years after the onset of diabetes
• Patients with type 2 diabetes should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist at the time of the diabetes diagnosis
• If there is no evidence of retinopathy for one or more annual eye exams and glycemia is well controlled, then exams every 1-2 years may be considered; if any level of diabetic retinopathy is present, subsequent dilated retinal examinations should be repeated at least annually by an ophthalmologist or optometrist; if retinopathy is progressing or sight-threatening, then examinations will be required more frequently
• While retinal photography may serve as a screening tool for retinopathy, it is not a substitute for a comprehensive eye exam
• Women with preexisting type 1 or type 2 diabetes who are planning pregnancy or who are pregnant should be counseled on the risk of development and/or progression of diabetic retinopathy
• Eye examinations should occur before pregnancy or in the first trimester in patients with preexisting type 1 or type 2 diabetes, and then patients should be monitored every trimester and for 1 year postpartum as indicated by the degree of retinopathy
• Promptly refer patients with any level of macular edema, severe nonproliferative diabetic retinopathy (a precursor of proliferative diabetic retinopathy), or any proliferative diabetic retinopathy to an ophthalmologist who is knowledgeable and experienced in the management of diabetic retinopathy
• The traditional standard treatment, panretinal laser photocoagulation therapy, is indicated to reduce the risk of vision loss in patients with high-risk proliferative diabetic retinopathy and, in some cases, severe nonproliferative diabetic retinopathy
• Intravitreous injections of the vascular endothelial growth factor inhibitor ranibizumab are not inferior to traditional panretinal laser photocoagulation and are also indicated to reduce the risk of vision loss in patients with proliferative diabetic retinopathy
• Intravitreous injections of vascular endothelial growth factor inhibitor are indicated for central-involved diabetic macular edema, which occurs beneath the foveal center and may threaten reading vision
• The presence of retinopathy is not a contraindication to aspirin therapy for cardioprotection, as aspirin does not increase the risk of retinal hemorrhage

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Medication Summary

Several medications are indicated for treatment of diabetic retinopathy. At present, these medications are administered into the eye by intravitreal injection.^{[45, 46]}

Intravitreal triamcinolone is being used in the treatment of diabetic retinopathy and diabetic macular edema. A recent Diabetic Retinopathy Clinical Research Network (DRCR.net) clinical trial demonstrated that although some reduction in macular edema occurred after intravitreal triamcinolone, this effect was not as robust as that achieved with focal laser treatment at the primary endpoint of 2 years.^[16] In addition, intravitreal triamcinolone can have some adverse effects, including steroid response with intraocular pressure increase and cataracts.

Other medications used in clinical practice and in clinical trials include intravitreal aflibercept (Eylea) and ranibizumab (Lucentis). These medications are VEGF antibodies and antibody fragments, respectively. They can help reduce diabetic macular edema and neovascularization of the disc or retina. Combinations of some of these medications with focal laser treatment have been investigated in the DRCR.net clinical trials and have proven efficacy, as described above.

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Triamcinolone acetonide (Triesence)

• Dosing, Interactions, etc.

Clinical Context:  Triamcinolone is a synthetic corticosteroid with anti-inflammatory effects. It is indicated for several ophthalmic diseases such as ocular inflammatory conditions and visualization during vitrectomy. Intravitreal triamcinolone is also being used in the treatment of diabetic macular edema.

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Class Summary

Corticosteroids inhibit inflammatory responses. They inhibit processes associated with inflammation such as edema, fibrin deposition, capillary dilation, deposition of collagen, leukocyte migration, and fibroblast and capillary proliferation.

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Ranibizumab (Lucentis)

• Dosing, Interactions, etc.

Clinical Context:  Ranibizumab is a recombinant humanized monoclonal antibody indicated for all forms of diabetic retinopathy (ie, with or without diabetic macular edema). It is also indicated for neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion, myopic choroidal neovascularization, and diabetic macular edema. It prevents the interaction of VEGF-A with its receptors (VEGFR1 and VEGFR2), thereby suppressing neovascularization, endothelial cell proliferation, and vascular leakage.

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Aflibercept intravitreal (Eylea)

• Dosing, Interactions, etc.

Clinical Context:  Aflibercept is a recombinant decoy VEGF receptor that competes for ligand binding with the endogenous VEGFR 1 and 2 receptors to prevent angiogenesis. It is indicated for all stages of diabetic retinopathy. It is also indicated for neovascular (wet) age-related macular degeneration (AMD), macular edema following retinal vein occlusion, and diabetic macular edema.

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Class Summary

These agents can help reduce diabetic macular edema and neovascularization of the disc or retina.

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