Table 3

Estimated Percentages of Wyes with Harmful Effects Attributable to Diabetic Retinopathy Study Treatment

From (143), copyright Elsevier

those observed with the xenon treatment used in the DRS, argon was given preference, and in the hope of further reducing harmful side effects, scatter treatment was more often divided between two or more episodes several days apart.

For eyes with severe NPDR or PDR without high-risk characteristics, the DRS concluded that either prompt treatment or careful follow-up with prompt treatment if highrisk characteristics developed was satisfactory and that DRS results were not helpful in choosing between these strategies. In univariate analyses of DRS control group eyes that had PDR without high-risk characteristics, the severity of each of three retinopathy characteristics was associated with risk of visual loss: retinal hemorrhages or microaneurysms, arteriolar abnormalities, and venous caliber abnormalities. These lesions – and soft exudates and IRMAs – also were risk factors for visual loss in control group eyes with NPDR (90). A multivariable analysis that included all DRS control group eyes found baseline visual acuity; extent of NVD; elevation of NVD (a measure of contraction of vitreous and fibrous proliferations); and severity of hemorrhages or microaneurysms, arteriolar abnormalities, venous caliber abnormalities, and vitreous or preretinal hemorrhage all to be risk factors for visual loss. Neither in this analysis nor in a similar one confined to DRS control group eyes that were free of NVD was the extent of NVE found to be a risk factor (91). These findings support clinical impressions that NVE on the surface of the retina often proliferate and regress over a period of years, remaining asymptomatic unless contraction of vitreous and fibrous proliferations begins, and that the severity of intraretinal lesions may be of greater prognostic importance than the extent of NVE.

THE EARLY TREATMENT DIABETIC RETINOPATHY STUDY

For eyes with severe NPDR or early (not high-risk) PDR, DRS results were not helpful in determining which of two treatment strategies would be attended by a more favorable visual outcome: (1) immediate photocoagulation or (2) frequent follow-up and prompt initiation of photocoagulation only if high-risk PDR developed. One of the goals of the ETDRS, a randomized clinical trial sponsored by the National Eye Institute, was to compare these alternatives (designated “early photocoagulation” and “deferral of

photocoagulation,” respectively) in patients with mild-to-severe NPDR or early PDR, with or without macular edema (92). Other goals were to evaluate photocoagulation for diabetic macular edema and to determine the possible effects of aspirin on diabetic retinopathy. Between 1980 and 1985, 3,711 patients were enrolled. One eye of each patient was randomly assigned to early photocoagulation and the other to deferral. Follow-up ranged from 3 to 8 years. Eyes assigned to early photocoagulation were randomly assigned to either of two scatter treatment protocols, full or mild. The full scatter protocol called for 500- m, 0.1-s argon blue-green or green laser burns of moderate intensity, placed one-half burn apart, extending from the posterior pole to the equator. Between 1,200 and 1,600 burns were applied, divided between two or more episodes. The mild scatter protocol was the same, except that 400–650 more widely spaced burns were applied to the same area in a single episode. Direct (local) treatment was specified for patches of surface NVE that were two disc areas or less in extent using confluent, moderately intense burns that extended 500 m beyond the edges of the patch (93).

One important outcome measure used in the ETDRS was the first occurrence of either severe visual loss, as defined in the DRS, or vitrectomy (92). These events were combined because progression to a stage requiring vitrectomy may rightly be considered a bad outcome for ETDRS-eligible eyes and because presumably most eyes selected for vitrectomy before the occurrence of severe visual loss (68% of the 243 ETDRS eyes undergoing vitrectomy) would have developed severe visual loss within several months if vitrectomy had not been done.

The outcome was more frequent in eyes with more severe retinopathy (in the deferral group, 10% in eyes with severe NPDR or early PDR vs. 4% in eyes with mild-to-moderate NPDR). In both of these retinopathy subgroups, early treatment reduced the event rate to about one half that of the deferral group, but the percentage of eyes treated that benefited was only 2–4% (Table 4). Some harmful effects of scatter photocoagulation also were

Table 4

Cumulative 5-year Rates of Severe Visual Loss or Vitrectomy, and Relative Risks For the Entire Period of Follow-Up, by Baseline rRetinopathy Status and Treatment Group

From (93), copyright Elsevier

NPDR nonproliferative diabetic retinopathy, PDR proliferative diabetic retinopathy a Values in parentheses are 99% confidence interval

Table 5

Characteristics of severe and very severe NPDR (4–2–1 rule)

Severe NPDR (any one of the following)

•H/MA ≥ Fig. 68–21 in four quadrants

•VB definitely present in ≥ two quadrants

•IRMA ≥ Fig. 68–22 in ≥ one quadrant

Very severe NPDR (two or more of the above characteristics)

NPDR nonproliferative diabetic retinopathy, H/MA hemorrhage/microaneurysms, VB venous bleeding, IRMA intraretinal microvascular abnormalities

assigned to deferral, whereas in the type I group the rates were about 8% in both treatment groups. In eyes assigned to deferral, severe visual loss or vitrectomy developed over the first 3 years at about the same rate in both diabetes types; apparently, the greater treatment effect in type II diabetes resulted mainly from greater responsiveness to early treatment. The DRS also found greater photocoagulation treatment benefit in patients with type II diabetes (94). These studies are consistent with the clinical impression that in patients with type II diabetes high-risk PDR is often first detected on the basis of a symptomatic vitreous hemorrhage in an eye in which new vessels had not been observed on previous visits, whereas in patients with type I diabetes, NVD is more often the first sign of high-risk PDR, an occurrence more easily managed with photocoagulation.

INDICATIONS FOR PHOTOCOAGULATION OF PDR

Treatment should be carried out promptly in most eyes with PDR that have wellestablished NVD or vitreous or preretinal hemorrhage. Treatment is particularly urgent when localized fresh vitreous or preretinal hemorrhage is present because of the risk that dispersion of the hemorrhage throughout the vitreous or recurrent bleeding may soon make laser treatment more difficult or impossible. In the great majority of such eyes, new vessels of sufficient extent to fulfill the definition of DRS high-risk characteristics can either be seen ophthalmoscopically or be presumed to be present behind the hemorrhage. When visible or suspected new vessels seem insufficient to explain the hemorrhage, special consideration should be given to other possible causes, such as fresh retinal tears, partially avulsed retinal veins, or small patches of new vessels that have been completely avulsed from the disc or retina. Complete avulsion of a small new vessel patch from its connections to the disc or retina should be considered as a possible explanation of a recent vitreous hemorrhage when the detached posterior vitreous surface can be seen anterior to the disc or retina and contains a subtle opacity, suggesting a small patch of empty new vessels (95).

Progressive contraction of fibrous proliferations leading to displacement or detachment of the macula sometimes follows scatter photocoagulation for high-risk characteristics in eyes with extensive fibrous proliferations (Fig. 11). Experience with such cases has led to some reluctance to advise photocoagulation in this situation and to proceed with vitrectomy as a first line management option or to schedule surgery soon after PRP.

Fig. 11. Contraction of fibrovascular proliferations leading to extensive retinal detachment. (a) In the left eye of this 35-year-old man, whose age at diagnosis of diabetes was 14 years, networks of new vessels extended over the surface of the retina along the superotemporal vein. Scars were typical of initial scatter photocoagulation, with space between scars available for additional treatment. (b) Four months later, new vessels had increased, and dense fibrous tissue had appeared. (c) Seven months later, fibrous proliferations had contracted. Broad adhesions prevented them from pulling away from the retina. Instead, the retina was pulled forward (detached) throughout the area shown in the figure. The photocoagulation scars were blurred by the overlying detached retina (and are out of focus). (Courtesy Diabetic Retinopathy Vitrectomy Study Research Group).

Few such eyes were included in the DRS, but analyses of them indicated that outcome was better with photocoagulation than without it; however, vitrectomy instrumentation and procedures in the current era carry a lower risk of intraoperative and postoperative complications, and the risk/benefit ratio may favor surgery in some situations. When high-risk characteristics are definitely present, scatter photocoagulation usually should be carried out, despite the presence of fibrous proliferations or localized traction retinal detachment. Areas of fibrous proliferations and retinal detachment should be avoided, and treatment strength should be mild to moderate. It may be desirable to divide treatment between several episodes. Of course, photocoagulation is not indicated when PDR