Nonproliferative Diabetic Retinopathy
Retinal microvascular changes that occur in NPDR are limited to the retina and do not extend beyond the internal limiting membrane (ILM). Characteristic findings in NPDR include intraretinal hemorrhages, microaneurysms, cotton-wool spots, intraretinal microvascular abnormalities (IRMAs), and dilation and beading of retinal veins. The NPDR severity level (mild, moderate, severe) is graded based on the extent and severity of these findings as compared to standard photographs from the Early Treatment Diabetic Retinopathy Study (ETDRS). Rates of progression to more advanced disease are higher with increased baseline ETDRS retinopathy severity levels.
To help clinicians identify those patients at greatest risk of progression to PDR and high-risk PDR, the ETDRS investigators developed the 4:2:1 rule, which is largely based on results from the ETDRS Report Number 9 (Clinical Trial 5-3). A case of severe NPDR was defined as having any 1 of the following features:
severe intraretinal hemorrhages and microaneurysms in 4 quadrants (Fig 5-2)
definite venous beading in 2 or more quadrants (Fig 5-3)
moderate IRMA in 1 or more quadrants (Fig 5-4)
Figure 5-2 Fundus photograph shows diffuse intraretinal hemorrhages (arrow) and microaneurysms in an eye with NPDR.
(Standard photograph 2A, courtesy of the Early Treatment Diabetic Study [ETDRS].)
Figure 5-3 Fundus photograph shows venous beading in an eye with NPDR (arrows).
(Standard photograph 6B, courtesy of the ETDRS.)
Figure 5-4 Fundus photograph shows intraretinal microvascular abnormalities (IRMAs) (arrows) in an eye with NPDR.
(Courtesy of Jennifer K. Sun, MD, MPH.)
In the ETDRS, patients with severe NPDR were found to have a 15% and 60% chance of progression to high-risk PDR within 1 and 3 years, respectively. Very severe NPDR, which was defined as having 2 or more of the features in the preceding list, increased the chance of progression to high-risk PDR within 1 year to 45%.
The ETDRS scale for classification of diabetic retinopathy severity level has been considered the gold-standard method for several decades. To employ it, clinicians need to acquire and interpret standardized photographic fields that cover approximately 90° of the posterior retina. With ultra-wide-field imaging, over 80% of the retina can now be visualized in a single 200° image. Peripheral diabetic retinopathy lesions are often present outside of the standard ETDRS fields; these suggest greater diabetic retinopathy severity in nearly 10% of eyes. Preliminary studies suggest that predominantly peripheral diabetic retinopathy lesions may be associated with greater risk of subsequent diabetic retinopathy progression. This association is being evaluated in the ongoing Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol AA.
Retinal capillary nonperfusion is a common finding in diabetic retinopathy, especially in more advanced levels of severity. Closure of retinal arterioles may result in larger areas of nonperfusion and progressive ischemia. The foveal avascular zone may appear increasingly irregular on fluorescein angiography (FA) or OCTA and enlarged as the innermost capillaries become nonperfused. Peripheral nonperfusion is frequently seen on ultra-wide-field FA, even in eyes with mild NPDR.
Patients with NPDR can lose visual function through 2 mechanisms: (1) increased intraretinal vascular permeability, resulting in macular edema (see the section Diabetic Macular Edema, later in this chapter), and (2) variable degrees of intraretinal capillary closure, resulting in macular ischemia.
Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Ophthalmology. 1991;98(5 suppl): 766–785.
Early Treatment Diabetic Retinopathy Study Research Group. Grading diabetic retinopathy from stereoscopic color fundus photographs—an extension of the modified Airlie House classification. ETDRS report number 10. Ophthalmology. 1991;98(5 Suppl): 786–806.
Silva PS, Cavallerano JD, Haddad NM, et al. Peripheral lesions identified on ultrawide field imaging predict increased risk of diabetic retinopathy progression over 4 years. Ophthalmology. 2015;122(5):949–956.
Treatment of Nonproliferative Diabetic Retinopathy
Aside from systemic control of blood glucose, lipids, and hypertension, there is no clear treatment mandate for eyes with NPDR without DME. Early treatment with panretinal photocoagulation should be considered for patients with severe NPDR or worse, especially if the patient has type 2 diabetes or is likely to be nonadherent to recommendations for follow-up or systemic control. In addition, anti-VEGF therapy given for DME has been shown to substantially improve diabetic retinopathy severity in eyes at all severity levels of NPDR. After 2 years of continuous, monthly treatment with an anti-VEGF drug, nearly 40% of eyes will improve by 2 or more levels on the ETDRS diabetic retinopathy severity scale. Although ranibizumab is FDA-approved for use in diabetic retinopathy, including NPDR without DME, large-scale randomized controlled trials to evaluate the efficacy and safety of anti-VEGF treatments in eyes with moderate to severe NPDR without DME are currently ongoing.
Intravitreal steroid therapy for DME has also been shown to improve diabetic retinopathy severity level. The ACCORD and Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) studies demonstrated reductions in diabetic retinopathy progression after fenofibrate treatment in patients with type 2 diabetes through mechanisms that are likely independent of fenofibrate’s effects on blood lipid levels. Finally, it has been hypothesized that creation of a posterior vitreous detachment might improve outcomes in diabetic eyes at risk of developing PDR because the vitreous scaffolding that enables extraretinal neovascular proliferation is removed. However, currently there is no role for surgery in the management of NPDR.
ACCORD Study Group; ACCORD Eye Study Group, Chew EY, Ambrosius WT, Davis MD, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med. 2010;363(3):233–244.
Bressler SB, Qin H, Melia M, et al; Diabetic Retinopathy Clinical Research Network. Exploratory analysis of the effect of intravitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial. JAMA Ophthalmol. 2013;131(8):1033–1040.
Ferris F. Early photocoagulation in patients with either type I or type II diabetes. Trans Am Ophthalmol Soc. 1996;94:505–537.
Ip MS, Domalpally A, Sun JK, Ehrlich JS. Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy. Ophthalmology. 2015;122(2):367–374.
Excerpted from BCSC 2020-2021 series: Section 10 - Glaucoma. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.