- Author: Abdhish R Bhavsar, MD; Chief Editor: Romesh Khardori, MD, PhD, FACP more...
Diabetic retinopathy is the leading cause of new blindness in persons aged 25-74 years in the United States. 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.[1, 2] See the image below.
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
See Clinical Presentation for more detail.
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
See Workup for more detail.
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
The Diabetes Control and Complications Trial found that intensive glucose control in patients with insulin-dependent diabetes mellitus (IDDM) decreased the incidence and progression of diabetic retinopathy.[3, 4, 5] It may be logical to assume that the same principles apply in non-insulin-dependent diabetes mellitus (NIDDM).
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.[6, 7] It involves applying laser burns over the entire retina, sparing the central macular area.
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.
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.
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. An increasing prevalence of diabetes is occurring throughout the world. 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.[10, 11]
Diabetic retinopathy is 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. A recent 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 and older. (See Epidemiology.)
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.[13, 14]
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 and blurred vision. Microaneurysms are the earliest clinical sign of diabetic retinopathy. (See Clinical Presentation.)
Workup for diabetic retinopathy includes fasting glucose and hemoglobin A1c measurements. (See Workup.)
Renal disease, as evidenced by proteinuria and elevated 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.)
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.
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.[1, 2]
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.
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.)
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.
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.)
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 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.
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.
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.
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.)
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.
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.
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.
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.
For more information, see Diabetes Mellitus and Pregnancy.
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. 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.
For more information, see Macular Edema.
Prognostic factors that are favorable for visual loss include the following:
Circinate exudates of recent onset
Good perifoveal perfusion
Prognostic factors that are unfavorable for visual loss include the following:
Diffuse edema/multiple leaks
Lipid deposition in the fovea
Cystoid macular edema
Preoperative vision of less than 20/200
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%.[18, 19]
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.
Frank RN. Etiologic mechanisms in diabetic retinopathy. Ryan SJ, ed. Retina. 1994. Vol 2: 1243-76.
Crawford TN, Alfaro DV 3rd, Kerrison JB, Jablon EP. Diabetic retinopathy and angiogenesis. Curr Diabetes Rev. 2009 Feb. 5(1):8-13. [Medline].
Klein R. The Diabetes Control and Complications Trial. Kertes C, ed. Clinical Trials in Ophthalmology: A Summary and Practice Guide. 1998. 49-70.
Rodriguez-Fontal M, Kerrison JB, Alfaro DV, Jablon EP. Metabolic control and diabetic retinopathy. Curr Diabetes Rev. 2009 Feb. 5(1):3-7. [Medline].
Liew G, Mitchell P, Wong TY. Systemic management of diabetic retinopathy. BMJ. 2009 Feb 12. 338:b441. [Medline].
Bhavsar AR. Diabetic retinopathy: the latest in current management. Retina. 2006 Jul-Aug. 26(6 Suppl):S71-9. [Medline].
Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008 Sep. 115(9):1447-9, 1449.e1-10. [Medline]. [Full Text].
Federman JL, Gouras P, Schubert H, et al. Systemic diseases. Podos SM, Yanoff M, eds. Retina and Vitreous: Textbook of Ophthalmology. 1994. Vol 9: 7-24.
Bhavsar AR, Emerson GG, Emerson MV, Browning DJ. Diabetic Retinopathy. Browning DJ. Epidemiology of Diabetic Retinopathy. Springer, New York.: 2010.
Williams R, Airey M, Baxter H, Forrester J, Kennedy-Martin T, Girach A. Epidemiology of diabetic retinopathy and macular oedema: a systematic review. Eye (Lond). 2004 Oct. 18(10):963-83. [Medline].
Gupta R, Kumar P. Global diabetes landscape-type 2 diabetes mellitus in South Asia: epidemiology, risk factors, and control. Insulin; 2008. 3:78-94.
Zhang X, Saaddine JB, Chou CF, Cotch MF, Cheng YJ, Geiss LS, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA. 2010 Aug 11. 304(6):649-56. [Medline]. [Full Text].
Aiello LM, Cavallerano JD, Aiello LP, Bursell SE. Diabetic retinopathy. Guyer DR, Yannuzzi LA, Chang S, et al, eds. Retina Vitreous Macula. 1999. Vol 2: 316-44.
Benson WE, Tasman W, Duane TD. Diabetes mellitus and the eye. Duane's Clinical Ophthalmology. 1994. Vol 3:
Barchetta I, Riccieri V, Vasile M, et al. High prevalence of capillary abnormalities in patients with diabetes and association with retinopathy. Diabet Med. 2011 Sep. 28(9):1039-44. [Medline].
Shiba T, Takahashi M, Hori Y, Saishin Y, Sato Y, Maeno T. Relationship between sleep-disordered breathing and iris and/or angle neovascularization in proliferative diabetic retinopathy cases. Am J Ophthalmol. 2011 Apr. 151(4):604-9. [Medline].
Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXIII: the twenty-five-year incidence of macular edema in persons with type 1 diabetes. Ophthalmology. 2009 Mar. 116(3):497-503. [Medline].
Akduman L, Olk RJ. The early treatment for diabetic retinopathy study. Kertes C, ed. Clinical Trials in Ophthalmology: A Summary and Practice Guide. 1998. 15-36.
Quillen DA, Gardner TW, Blankenship GW. Clinical Trials in Ophthalmology: A Summary and Practice Guide. Kertes C, ed. diabetic retinopathy study. 1998. 1-14.
Bragge P, Gruen RL, Chau M, Forbes A, Taylor HR. Screening for Presence or Absence of Diabetic Retinopathy: A Meta-analysis. Arch Ophthalmol. 2011 Apr. 129(4):435-44. [Medline].
Genuth S. The UKPDS and its global impact. Diabet Med. 2008 Aug. 25 Suppl 2:57-62. [Medline].
Massin P, Lange C, Tichet J, Vol S, Erginay A, Cailleau M, et al. Hemoglobin A1c and fasting plasma glucose levels as predictors of retinopathy at 10 years: the French DESIR study. Arch Ophthalmol. 2011 Feb. 129(2):188-95. [Medline].
Elman MJ, Aiello LP, Beck RW, Bressler NM, Bressler SB, Edwards AR, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010 Jun. 117(6):1064-1077.e35. [Medline]. [Full Text].
Bhavsar AR, Grillone LR, McNamara TR, Gow JA, Hochberg AM, Pearson RK. Predicting response of vitreous hemorrhage after intravitreous injection of highly purified ovine hyaluronidase (Vitrase) in patients with diabetes. Invest Ophthalmol Vis Sci. 2008 Oct. 49(10):4219-25. [Medline].
Wells JA, Glassman AR, Ayala AR, et al. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015 Mar 26. 372(13):1193-203. [Medline].
Brown DM, Nguyen QD, Marcus DM, Boyer DS, Patel S, Feiner L, et al. Long-term outcomes of ranibizumab therapy for diabetic macular edema: the 36-month results from two phase III trials: RISE and RIDE. Ophthalmology. 2013 Oct. 120(10):2013-22. [Medline]. [Full Text].
Korobelnik JF, Do DV, Schmidt-Erfurth U, Boyer DS, Holz FG, Heier JS, et al. Intravitreal aflibercept for diabetic macular edema. Ophthalmology. 2014 Nov. 121(11):2247-54. [Medline].
Arevalo JF, Garcia-Amaris RA. Intravitreal bevacizumab for diabetic retinopathy. Curr Diabetes Rev. 2009 Feb. 5(1):39-46. [Medline].
Rodriguez-Fontal M, Alfaro V, Kerrison JB, Jablon EP. Ranibizumab for diabetic retinopathy. Curr Diabetes Rev. 2009 Feb. 5(1):47-51. [Medline].
FDA Drug and Safety Alerts. FDA Alerts Health Care Professionals of Infection Risk from Repackaged Avastin Intravitreal Injections. August 30, 2011. Available at http://www.fda.gov/drugs/drugsafety/ucm270296.htm.
Meredith TA. Clinical Trials in Ophthalmology-A Summary and Practice Guide. Kertes C, ed. The diabetic vitrectomy study. 1998. 37-48.
Harrison P. Monthly Ranibizumab Improves Diabetic Retinopathy. Medscape Medical News. Sep 5 2013. Available at http://www.medscape.com/viewarticle/810491. Accessed: September 17, 2013.