heat generated when light was absorbed by the RPE or by hemorrhage within the retina or on its surface (68). These intense burns usually involved the full thickness of the retina and often led to nerve fiber bundle field defects, particularly if hemorrhages were present in or on the retina. When new vessels were located some distance from the RPE, either in the vitreous or on the optic disc, they could not be treated directly with the xenon arc photocoagulator because it was not possible to concentrate enough energy in a short enough time to coagulate the rapidly flowing blood within them. The possibility of a much more exciting effect of extensive photocoagulation began to emerge with the observation that regression of new vessels and diminution of retinal edema and vascular congestion at some distance from the areas of retina directly treated could occur (67, 69, 70). Beetham et al. (69) and Aiello et al. (71) began a study in which ruby laser burns were scattered across the retina from the posterior pole to the midperiphery. The long wavelength and very brief exposure time of the ruby laser limited burns mainly to the outer layers of the retina, without immediately visible effects in new vessels on its surface. The rationale initially proposed for regression of new vessels after this indirect treatment was that ischemic retina, which was postulated to be producing a vasoformative factor, was destroyed; hence the term retinal ablation, paralleling pituitary ablation. Indeed this mechanism has been proven by the discovery that the powerful angiogenic protein VEGF is found in high levels in the vitreous of patients with active, but not inactive, PDR (72). Hypoxia upregulates the production of VEGF (73), VEGF levels are associated with intraocular neovascularization in animal models (74), and its inhibition causes the regression of neovascularization in animal models (75). VEGF appears to be a major mediator of the hypoxic neovascular response in PDR.

Photocoagulation may improve oxygenation of the ischemic inner retinal layers by destroying some of the metabolically highly active photoreceptor cells and allowing the oxygen normally diffusing from the choriocapillaris to supply these cells to continue into the inner layers of the retina, relieving hypoxia and removing the stimulus for expression of angiogenic factors such as VEGF (76–79). This theory fails to explain why stronger burns sometimes seem more effective clinically. Retinal blood flow decreases and the autoregulatory response to breathing pure oxygen improves following scatter photocoagulation, as might be expected if more oxygen were reaching the inner retina from the choroid (80, 81). However, the choriocapillaris, which presumably is an important source of the oxygen postulated to be relieving inner retinal ischemia, has been found to be destroyed beneath at least some scatter burns (82). The cells of the RPE produce growth-stimulating and growth-inhibiting factors and the response of these cells to photocoagulation injury may change the balance of these factors (7, 83, 84).

Randomized Clinical Trials of Laser Photocoagulation

THE DIABETIC RETINOPATHY STUDY

The early reports concerning treatment of PDR with photocoagulation suffered from small numbers of patients, brief periods of follow-up, or lack of a randomly selected control group (85). Two collaborative randomized trials were initiated in

Table 2

Diabetic Retinopathy Study Risk Characteristics

• Any new vessels

• New vessels on or within 1,500 m (1 standard disc diameter) from the disc

•New vessels on the disc ≥ standard photograph 10A (Fig. 7)

•If no disc new vessels, a patch of new vessels on the retina ≥ ½ disc area

•Vitreous or preretinal hemorrhage

3 or more is high-risk PDR

hemorrhage (or both) present (Table 2). In counting the risk factors, the presence and severity of NVE were considered only in eyes without NVD because a subgroup analysis indicated that in eyes with NVD the presence of moderate or severe NVE did not further increase the risk of severe visual loss.

The DRS investigators concluded in 1976 that prompt photocoagulation treatment usually was desirable for eyes with high-risk characteristics. The protocol was therefore modified to allow treatment of eyes originally assigned to the untreated control group, if they had high-risk characteristics then or developed them in the future (8).

Some smaller reports support the results of the DRS. The British multicenter trial, a small randomized study of xenon photocoagulation, reported that of 77 patients observed at the 5-year follow-up visit, 27 untreated eyes (35%) were blind (visual acuity, 6/60 or less), compared with 8 treated eyes (10%) (86, 87). About 2,700 eyes treated for PDR with xenon arc photocoagulation were reported by Okun et al. (68), with about 1,200 eyes observed at the 4-year follow-up visit. Cumulative rates of severe visual loss were almost identical to those observed in DRS-treated eyes, both in eyes with high-risk characteristics and in those with less severe PDR. Decreases in visual acuity of one to four lines were similar to those observed with DRS xenon treatment. Little (88) reported results in 457 eyes with NVD exceeding one-fourth disc area treated with 2,000–4,000, 500- m argon laser burns. New vessels regressed completely in 50% of eyes and showed some decrease in nearly all the remainder. Last recorded visual acuity was <20/200 in about 18% of 241 eyes followed for 5 or more years, an outcome similar to that observed in the DRS.

RISKS AND BENEFITS PHOTOCOAGULATION IN THE DRS

A temporary decrease in visual acuity is frequently noted after extensive scatter photocoagulation, with recovery to the pretreatment level in most cases within several weeks. In the DRS, visual acuity decreases of one or more lines from which recovery did not occur were attributed to treatment in 14% of argon-treated and 30% of xenon-treated eyes. Visual field losses also were more common in the xenon group (Table 3) (89). In a small subgroup of eyes with severe fibrous proliferations or localized traction retinal detachment, or both, visual acuity decreases of five lines or more were attributed to xenon treatment in 18% of eyes but were not significantly more frequent in argon-treated than in control eyes (89). Because the harmful effects of the DRS argon treatment were less than