Diabetic Retinopathy A Team Approach to Screening, Referral, and Treatment The Scope of Diabetic Retinopathy

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
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
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
Recommended Follow­up
Type 1
3­5 years after diagnosis
Yearly (abnormal findings may necessitate more
frequent examinations)
Type 2
At time of diagnosis with
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.
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.
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
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
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 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
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.
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.
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
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.