Proliferative diabetic retinopathy

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CHAPTER 61 Proliferative diabetic retinopathy

Management of proliferative diabetic retinopathy is guided by the findings and recommendations of the Diabetic Retinopathy Study (DRS)13, Early Treatment Diabetic Retinopathy Study (ETDRS)4, Diabetic Retinopathy Vitrectomy Study (DRVS)5,6 and the Diabetes Control and Complication Trial (DCCT)7. The combination of successful results achieved with the DRS, ETDRS, DRVS, and DCCT have clearly established the indications, techniques, and benefits of photocoagulation and pars plana vitreous surgery, and intensive control of blood sugars for people with diabetes. Advances in anti-angiogenic therapies have the potential to influence the way we care for patients with proliferative diabetic retinopathy in the future.

Clinical features

The severity of diabetic retinopathy is strongly related to the duration of diabetes: the prevalence of proliferative diabetic retinopathy ranges from 0% in individuals with fewer than 5 years of diabetes to as high as 50% in individuals with 20 or more years of diabetes8. In addition to duration of diabetes, other factors are influential in the development and progression of proliferative diabetic retinopathy. These include puberty, pregnancy, poor metabolic control, hypertension, hypercholesterolemia, renal disease, and intraocular surgery. Recent reports of lower rates of proliferative diabetic retinopathy may reflect improvements in primary care for diabetes and these other systemic associations9,10.

Proliferative diabetic retinopathy is characterized by the presence of newly formed blood vessels arising from the retina or optic disc. The risk of proliferative diabetic retinopathy is related to the extent of ischemia within the retina11,12. As the retina becomes progressively more ischemic, a cascade of events occurs that ultimately results in the proliferation of abnormal blood vessels; vascular endothelial growth factor (VEGF) plays a significant role in this process13. Clinically, the most important findings in predicting progression to proliferative diabetic retinopathy include intraretinal hemorrhages and microaneurysms, venous beading, and intraretinal microvascular abnormalities (IRMA)14. The ‘four-two-one rule’ is helpful in assessing the severity of diabetic retinopathy and predicting the progression to proliferative retinopathy. Severe non-proliferative diabetic retinopathy is defined as the presence of either four quadrants of dot/blot hemorrhages or microaneurysms, two quadrants of venous beading, or one quadrant of IRMA. In eyes with severe non-proliferative diabetic retinopathy, approximately 50% will progress to proliferative diabetic retinopathy within 1 to 3 years.

Most eyes with neovascularization will have neovascularization on the disc itself or within one disc diameter of the disc (NVD). Neovascularization of the disc appears as fine lacy vessels lying on the surface of the disc or bridging the physiologic cup (Fig. 61.1). As the NVD progresses, the vessels become more prominent and extend into the vitreous cavity or along the vascular arcades; the new vessels may be associated with significant fibrous proliferation (Fig. 61.2). Neovascularization elsewhere (NVE) is defined as new vessels located at retinal sites other than on or within one disc diameter of the optic disc. Neovascularization elsewhere is usually associated with the retinal veins and arteriovenous crossing sites between areas of perfused and non-perfused retina (Fig. 61.3).

The vitreous plays a critical role in the development and progression of proliferative diabetic retinopathy15. It appears that the posterior vitreous surface provides a ‘scaffold’ for the progression of neovascularization. As the posterior vitreous detachment progresses, there is increased traction on the fibrovascular tissue. This may result in recurrent preretinal/vitreous hemorrhage or traction retinal detachment, or both.

Iris neovascularization or rubeosis may develop during the course of proliferative diabetic retinopathy. Iris neovascularization is characterized by the proliferation of fine lacy vessels on the iris surface; progressive iris neovascularization may result in angle closure and neovascular glaucoma.

Major diabetic retinopathy studies

The DRS and ETDRS provide clear guidelines for the management of proliferative diabetic retinopathy. Definitions used by the DRS and ETDRS are listed in Table 61.1.

Table 61.1 Diabetic Retinopathy Study (DRS) and Early Treatment Diabetic Retinopathy Study (ETDRS) definitions

Moderate visual loss Loss of 15 or more letters on the ETDRS reading chart (equivalent to a doubling of the initial visual angle, e.g., 20/20 to 20/40 or 20/50 to 20/100)
Severe visual loss Visual acuity less than 5/200 on two consecutive follow-up visits scheduled at 4-month intervals
Severe non-proliferative retinopathy Any one of the following:
Hemorrhages and/or microaneurysms in four quadrants
Venous beading in two quadrants
Intraretinal microvascular abnormalities (IRMA) in one quadrant
Early proliferative retinopathy Proliferative retinopathy without DRS high risk characteristics
Less severe retinopathy Mild or moderate non-proliferative retinopathy
More severe retinopathy Severe non-proliferative or early proliferative retinopathy
High risk proliferative diabetic retinopathy At least three of the following risk factors:
New vessels present
New vessels located on or within 1 disc diameter of the disc (NVD)
Vitreous and/or preretinal hemorrhage
Moderate to severe new vessels
NVD greater than standard photo 10a (image disc area) (Fig. 61.2)
In absence of NVD, neovascularization elsewhere (NVE) greater than image disc area

Diabetic retinopathy study

Does photocoagulation surgery reduce the risk of severe visual loss in diabetic retinopathy? The DRS evaluated individuals with proliferative diabetic retinopathy in at least one eye or severe non-proliferative diabetic retinopathy in both eyes1,2. One eye was randomly selected for photocoagulation, while the other eye was observed. Extensive scatter panretinal photocoagulation (PRP) and focal laser of new vessels on the surface of the retina was performed using either argon laser or xenon arc. Typical argon laser parameters included: 800–1600 burns, 500 μm spot size, 0.1 second duration, and intensity to obtain definite whitening.

The DRS identified four retinopathy risk factors for severe visual loss in diabetic retinopathy: new vessels present, new vessels located on or within one disc diameter of the disc, vitreous or preretinal hemorrhage, and moderate to severe new vessels (NVD greater than one-third disc area or, in the absence of NVD, NVE greater than one half the disc area)3. The risk of severe visual loss increased progressively as more risk factors were added: the risk of severe visual loss remained relatively low with two or fewer risk factors (roughly 5% at 2 years) but increased considerably with three or more risk factors (roughly 25% at 2 years). Therefore, the presence of three or four of these retinopathy risk factors indicates ‘high risk’ for severe visual loss.

Extensive PRP reduced the risk of severe visual loss by greater than 50% regardless of the baseline severity of retinopathy (Fig. 61.4). After 2 years, severe visual loss occurred in 16.3% of all untreated eyes compared to only 5.3% of eyes that received xenon arc and 7.4% of eyes treated with argon laser.


Fig. 61.4 Severe visual loss. Cumulative rates of severe visual loss, including and excluding observations made after the 1976 Diabetic Retinopathy Study protocol change, argon and xenon groups combined. Extensive scatter photocoagulation reduces the risk of severe visual loss by 50% or more.

From The Diabetic Retinopathy Study Research Group: Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study [DRS] findings. DRS Report Number 8. Ophthalmology 1981;88:583–600.

Although xenon arc was slightly more effective than argon laser in reducing the risk of severe visual loss, this advantage was outweighed by the greater adverse effects of xenon arc. Visual field constriction attributable to PRP occurred in 10% of argon-treated eyes compared with 35% of xenon arc-treated eyes. Persistent decreases of one or more lines of vision occurred in approximately 10% of argon-treated eyes compared with 20% of xenon arc-treated eyes.

The DRS findings strongly indicate that prompt panretinal laser PRP should be performed in eyes with high risk proliferative diabetic retinopathy. In these eyes, the risk of severe visual loss is high. Laser surgery effectively reduces the risk of severe visual loss by greater than 50%. In high risk proliferative retinopathy, the beneficial effects of PRP clearly outweigh the adverse effects. In eyes with severe non-proliferative or proliferative diabetic retinopathy without high risk characteristics, the DRS does not provide a clear choice between prompt treatment and careful follow-up with deferral of PRP until high risk characteristics develop. The risk of severe visual loss in these eyes is relatively low. Although laser surgery reduces the risk of severe visual loss, the beneficial effects of PRP must be weighed against the adverse effects.

Early treatment diabetic retinopathy study

When, during the course of diabetic retinopathy, is it most appropriate to initiate photocoagulation therapy? The ETDRS enrolled patients with mild to severe non-proliferative diabetic retinopathy or early proliferative retinopathy without high risk characteristics in both eyes4. One eye of each patient was assigned randomly to early full or mild PRP and the other to deferral. For eyes assigned to deferral, full PRP was performed immediately if high risk proliferative diabetic retinopathy developed. Eyes with macular edema were also randomized to immediate or delayed focal laser surgery.

The ETDRS provided very important information on the natural history of diabetic retinopathy. For eyes with mild or moderate non-proliferative retinopathy, the risk of progression to high risk proliferative diabetic retinopathy was low: approximately 10% over 3 years. For eyes with more severe retinopathy, the risk of progression to high risk proliferative retinopathy increased to about 50% over 3 years. Early PRP effectively reduced the rate of developing high risk proliferative retinopathy by over 50% regardless of baseline severity of retinopathy.

The development of severe visual loss for all baseline categories of retinopathy was low for both the treatment and the deferral groups (2.6% vs. 3.7%, respectively).

Adverse effects of PRP on visual acuity and visual field were observed. Eyes assigned to immediate full PRP had significantly greater loss of visual field as measured by the Goldmann 1/4e test object than those eyes assigned to deferral. Treated eyes were more likely to have early moderate visual loss than untreated eyes, particularly when early PRP was applied in eyes with pre-existing macular edema. In eyes with macular edema, immediate focal photocoagulation with delayed PRP – added only if more severe retinopathy developed – was the most effective strategy for reducing the risk of moderate visual loss.

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