10/2/13 www.medscape.com/viewarticle/760431_print www.medscape.com Diabetic Retinopathy A Team Approach to Screening, Referral, and Treatment Charles C. Wykoff, MD, PhD, David M. Brown, MD Mar 20, 2012 The Scope of Diabetic Retinopathy An estimated 6.3% of the US population and 4% of the world's population has diabetes mellitus.[1] Diabetic retinopathy affects about one half of all people with diabetes mellitus and is the leading cause of vision loss and new onset blindness in Americans 2064 years of age.[2] Fortunately, several prospective clinical trials provide excellent data on the natural course of diabetic retinopathy and treatment strategies that are 90% effective in preventing severe vision loss.[3,4] In its earliest clinical stage, diabetic retinopathy is called "nonproliferative diabetic retinopathy" and is characterized by retinal vascular abnormalities, such as microaneurysms, intraretinal hemorrhages, and cottonwool spots (Figure 1). As diabetic retinopathy progresses, the closure of retinal vessels results in ischemia (impaired perfusion of retinal tissue). This ischemia is believed to stimulate the production of vascular endothelial growth factor (VEGF) and other cytokine mediators that can result in a transition to proliferative diabetic retinopathy (PDR). Proliferative diabetic retinopathy develops when new and abnormal blood vessels grow on the inner surface of the retina (Figure 2). With sufficient duration of diabetes, approximately 60% of patients will develop PDR; without intervention, nearly one half of eyes with PDR will progress to profound vision loss.[5] Increased retinal vascular permeability may result in retinal thickening (edema) and lipid deposits (hard exudates). Known as "diabetic macular edema" (DME), this can occur at any stage of diabetic retinopathy. The term "clinically significant macular edema" is reserved for DME involving the center of the macula or threatening to spread into this area. Who Is at Risk for Diabetic Retinopathy? Duration of diabetes and severity of hyperglycemia are the 2 major risk factors for diabetic retinopathy. After 5 years, approximately 25% of patients with type 1 diabetes have diabetic retinopathy; this increases to 80% after 15 years.[6] Of patients with type 2 diabetes with a known duration of disease shorter than 5 years, 24%40% have diabetic retinopathy. The prevalence increases to 53%84% after 19 years of diabetes.[7] Severity of hyperglycemia is the key modifiable risk factor associated with the development and progression of diabetic retinopathy, as shown in the prospective landmark studies Diabetes Control and Complications Trial (DCCT) [8] and the United Kingdom Prospective Diabetes Study (UKPDS). [9] Once diabetic retinopathy is present, duration of diabetes is a less important factor than hyperglycemia for progression of diabetic retinopathy from early to more advanced stages.[10] Intensive management of elevated blood glucose levels and hypertension can significantly slow the progression of diabetic retinopathy.[8,9,11] Elevated serum lipid levels also have been associated with the development of diabetic retinopathy.[12] The effects of many other clinical factors (age, type of diabetes, renal disease, physical inactivity, and use of angiotensinconverting enzyme inhibitors) on the development and progression of diabetic retinopathy have been studied, with less definitive findings.[4] Screening and Referring Patients With Diabetes In many cases, the complications of diabetes that cause blindness can be mitigated with treatments that are highly effective in preventing severe vision loss.[3,4] Despite the availability of these treatments, many fewer patients with diabetes are referred by primary care physicians than expected according to guidelines from the American Diabetes www.medscape.com/viewarticle/760431_print 1/7 10/2/13 www.medscape.com/viewarticle/760431_print Association and the American Academy of Ophthalmology.[13] The Los Angeles Latino Eye Study found that 65% of patients with type 2 diabetes had not received a dilated eye examination in the previous year.[14] The Table summarizes the recommended timing of comprehensive eye evaluations, including dilated fundus examinations, for patients with diabetes. Table. Recommended Eye Examination Schedule for Patients With Diabetes Diabetes Type Recommended Time of First Examination Recommended Followup Type 1 35 years after diagnosis Yearly (abnormal findings may necessitate more frequent examinations) Type 2 At time of diagnosis with diabetes Yearly (abnormal findings may necessitate more frequent examinations) Before pregnancy for type 1 or type 2 Before conception and early in first trimester At direction of eye doctor Numerous ancillary tests can be performed to define the extent of diabetic retinopathy, to direct management, and to optimize outcomes: Fundus photography: documents extent and severity of diabetic retinopathy (Figures 1 and 2); Fluorescein angiography: a physiologic study that defines the retinal vasculature, identifying areas of poor perfusion (ischemia), macular edema or neovascularization (Figure 3); and Ocular coherence tomography: a highresolution anatomical study invaluable in clinical practice for quantifying macular edema and after response to treatments. www.medscape.com/viewarticle/760431_print 2/7 10/2/13 www.medscape.com/viewarticle/760431_print Figure 1. Fundus photographs of the right and left eyes of a patient with bilateral nonproliferative diabetic retinopathy. Scattered intraretinal hemorrhages and hard exudates are visible. Figure 2. Fundus photograph of proliferative diabetic retinopathy, demonstrating a large preretinal hemorrhage involving the macula. www.medscape.com/viewarticle/760431_print 3/7 10/2/13 www.medscape.com/viewarticle/760431_print Figure 3. Fluorescein angiogram of proliferative diabetic retinopathy, demonstrating extensive retinal capillary nonperfusion (ischemia), leaking neovascular vessels, and blockage of underlying fluorescence due to the preretinal hemorrhage shown in Figure 2. Treatments and Prognosis The management of diabetic retinopathy requires an understanding of the importance of general medical management and when to consider laser therapies, intravitreal injection of medications, and vitrectomy. Medical Management of Diabetic Retinopathy Control of cardiovascular risk factors is central to slowing the progression of diabetic retinopathy. Maintaining near normal glucose levels and blood pressure reduces the risk for development and progression of diabetic retinopathy. The DCCT showed that development and progression of diabetic retinopathy in patients with type 1 diabetes can be delayed by maintaining glucose concentrations in the nearnormal range.[8] After 3 years of intensive treatments to reduce glucose levels in patients without retinopathy, the development of any diabetic retinopathy was reduced by 75% over the 9year duration of the study. Strict glucose control also resulted in a 50% reduction in the rate of progression of retinopathy in patients with existing diabetic retinopathy. Similar data indicating a reduction in risk for progression of diabetic retinopathy in type 2 diabetes was demonstrated in the UKPDS.[9] Furthermore, improved www.medscape.com/viewarticle/760431_print 4/7 10/2/13 www.medscape.com/viewarticle/760431_print control of hypertension in the UKPDS reduced progression of diabetic retinopathy by 34%. Some medications may contribute to DME. In particular, glitazone antihyperglycemic agents have been associated with DME.[15] If a patient with DME is taking a glitazone antihyperglycemic agent, the eye doctor and the doctor prescribing the glitazone agent should consider alternative medications if possible. LaserBased Therapies Laser photocoagulation (panretinal or focal) has been a standard technique for treating diabetic retinopathy since 2 landmark prospective trials: the Diabetic Retinopathy Study and Early Treatment of Diabetic Retinopathy Study (ETDRS). Panretinal photocoagulation is used to treat PDR, and it indirectly treats neovascularization of the optic nerve, retinal surface, or anterior chamber angle by placing burns throughout the peripheral fundus. Appropriate panretinal photocoagulation reduces the risk for severe vision loss (tripling of the visual angle eg, a decrease of visual acuity from 20/40 to 20/120) by 50%.[16] Focal photocoagulation is used to treat DME and involves applying light, smallsized burns to areas of leaking microaneurysms in the macula. The ETDRS demonstrated that moderate vision loss (doubling of the visual angle eg, a decrease of visual acuity from 20/50 to 20/100) can be reduced by more than 50% by performing appropriate focal laser photocoagulation.[17] The primary goal of treatment is to stabilize visual acuity, because vision improves for only a minority of patients. Intravitreal Injections More recent research has identified VEGF as a key player in the pathogenesis of DME by mediating vascular permeability and accumulation of intracellular and extracellular fluid. Because DME is the major cause of visual impairment in patients with diabetes, VEGFs are appealing as a target of therapy for the treatment of DME. Multiple antiVEGF drugs, including pegaptanib, ranibizumab, bevacizumab, and aflibercept, are currently available for routine clinical use. Two recent phase 3 randomized controlled trials (the RISE and RIDE studies) demonstrated good efficacy of ranibizumab in the treatment of DME. These studies randomly assigned patients with DME to undergo standard focal photocoagulation or receive monthly intravitreal injections of ranibizumab. The primary endpoint was the percentage of patients with substantial improvement of vision (able to read at least 15 additional letters [3 lines] on the eye chart). After 24 months, 33.6%45.7% of patients treated with ranibizumab met the primary endpoint, compared with 12.3%18.1% of patients treated with standard photocoagulation alone.[18] The use of antiVEGF medications for the longterm management of DME holds great promise. Vitrectomy Vitrectomy plays an important role in the management of patients with diabetic retinopathy and has been shown to increase visionrelated quality of life in specific patients.[19] In PDR, the neovascular vessels are fragile and often accompanied by damaging scar tissue. These vessels can bleed into the vitreous cavity of the eye, causing vitreous hemorrhage and obscuring the visual axis. Alternatively, the associated scar tissues can distort and detach the retina, causing tractional retinal detachment. These are the primary indications for surgical intervention. A Team Approach Management of diabetic retinopathy requires a team approach. Primary care physicians play a critical role in patients' eye health in the setting of diabetes mellitus. Both the development and progression of diabetic retinopathy can be slowed by optimizing patients' cardiovascular risk factors. Patients with diabetes should obtain yearly comprehensive eye examinations, including detailed macula and peripheral evaluations. Timely diagnosis and appropriate www.medscape.com/viewarticle/760431_print 5/7 10/2/13 www.medscape.com/viewarticle/760431_print management can be 90% effective in preventing severe vision loss from diabetic retinopathy. Together, we can reduce the burden of visual impairment due to diabetes. References 1. Scott I, Flynn HW, Smiddy WE. Diabetes and Ocular Disease: Past, Present, and Future Therapies. American Academy of Ophthalmology Monograph 14. New York: Oxford University Press; 2009. 2. Kempen JH, O'Colmain BJ, Leske MC, et al. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol. 2004;122:552563. Abstract 3. Ferris FL 3rd. How effective are treatments for diabetic retinopathy? JAMA. 1993;269:12901291. 4. American Academy of Ophthalmology. Diabetic Retinopathy. Preferred Practice Pattern Guidelines. 2008. http://one.aao.org/CE/PracticeGuidelines/PPP_Content.aspx?cid=d0c853d3219f487ba524326ab3cecd9a Accessed February 14, 2012. 5. Preliminary report on effects of photocoagulation therapy. The Diabetic Retinopathy Study Research Group. Am J Ophthalmol. 1976;81:383396. Abstract 6. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol. 1984;102:520526. Abstract 7. Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol. 1984;102:527532. Abstract 8. Progression of retinopathy with intensive versus conventional treatment in the Diabetes Control and Complications Trial. Diabetes Control and Complications Trial Research Group. Ophthalmology. 1995;102:647 661. Abstract 9. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837853. Abstract 10. Davis MD, Fisher MR, Gangnon RE, et al. Risk factors for highrisk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic Retinopathy Study report #18. Invest Ophthalmol Vis Sci. 1998;39:233252. Abstract 11. Snow V, Weiss KB, MotturPilson C; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. The evidence base for tight blood pressure control in the management of type 2 diabetes mellitus. Ann Intern Med. 2003;138:587592. Abstract 12. Lyons TJ, Jenkins AJ, Zheng D, et al. Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthalmol Vis Sci. 2004;45:910918. Abstract 13. Kraft SK, Marrero DG, Lazaridis EN, Fineberg N, Qiu C, Clark CM Jr. Primary care physicians' practice patterns and diabetic retinopathy. Current levels of care. Arch Fam Med. 1997;6:2937. Abstract 14. Paz SH, Varma R, Klein R, Wu J, Azen SP, Los Angeles Latino Eye Study Group. Noncompliance with vision care guidelines in Latinos with type 2 diabetes mellitus: the Los Angeles Latino Eye Study. Ophthalmology. 2006;113:13721377. Abstract www.medscape.com/viewarticle/760431_print 6/7 10/2/13 www.medscape.com/viewarticle/760431_print 15. Colucciello M. Vision loss due to macular edema induced by rosiglitazone treatment of diabetic mellitus. Arch Ophthalmol. 2005;123:12731275. Abstract 16. Ferris F. Early photocoagulation in patients with either type I or type II diabetes. Trans Am Ophthalmol Soc. 1996;94:505537. Abstract 17. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985;103:17961806. Abstract 18. Nguyen QD, Brown DM, Marcus DM, et al; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Ophthalmology. 2012 Feb 11. [Epub ahead of print]. 19. Okamoto F, Okamoto Y, Fukuda S, Hiraoka T, Oshika T. Visionrelated quality of life and visual function following vitrectomy for proliferative diabetic retinopathy. Am J Ophthalmol. 2008;145:10311036. Abstract Medscape Ophthalmology © 2012 WebMD, LLC Cite this article: Charles C. Wykoff, David M. Brown. Diabetic Retinopathy. Medscape. Mar 20, 2012. www.medscape.com/viewarticle/760431_print 7/7
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