Development and proliferation of new vessels

Initially, new vessels may be barely visible. Later, their caliber is commonly one-eighth to one-quarter that of a major retinal vein at the disc margin, and occasionally they are as large as such veins (Fig. 48.4). New vessels frequently form networks that often resemble part or all of a carriage wheel. The vessels radiate like spokes from the center of the complex to a circumferential vessel bounding its periphery (see Figs 48.2A and 48.4). New vessel networks may also be irregular in shape, without a distinct radial pattern. New vessel patches often lie over retinal veins and appear to drain into them. The superotemporal vein is involved somewhat more frequently than others.^31,32 In the 1158 DRS control-group eyes that had NVE in at least one of the five photographic fields in which they were graded (fields 3 to 7 in Fig. 48.3), the number of times each field was involved was assessed. In each eye a count of one was divided equally among all fields containing NVE, and the counts for each field were totaled for all eyes. Field 4, which usually includes a major portion of the superotemporal vein, had a score of 308 (27% of 1158), whereas other scores ranged from 194 (17%) for field 5 to 242 (21%) for field 7.²

Fig. 48.4 Proliferation and regression of new vessels elsewhere (NVE). (A) Severe nonproliferative diabetic retinopathy in a patient with newly diagnosed type 2 diabetes (superotemporal quadrant of the right eye). Present were many microaneurysms, hemorrhages, and hard exudates, as well as extensive retinal edema and venous beading. Most of the tortuous small vessels appeared to be within the retina (large intraretinal microvascular abnormalities), but some may have been on its surface (NVE). (B) Eight months later, marked improvement in the intraretinal abnormalities was noted, but a wheel-like network of new vessels had appeared on the surface of the retina. Venous beading had decreased, and venous sheathing had increased. (C) Three months later, the new vessel patch had enlarged, and a second patch had developed above it. During the next 2 years, the new vessels continued to grow slowly at the edges of the patches, while regressing at their centers. (D) Three years after they had appeared, most of the new vessels had regressed, although there was still one dilated loop at the upper edge of the upper patch. No contraction of fibrous proliferation or vitreous had occurred, no vitreous hemorrhage was present, and vision remained good.

At times new vessels grow for several DD across the retina without forming prominent networks. The new vessels appear much like normal retinal vessels but are easily recognized as new vessels because of their unique capability of crossing both arterioles and veins in the underlying retina (Figs 48.5. 48.6). New vessels of this type commonly arise on the disc and are often accompanied during their actively growing phase by mild-to-moderate thickening (presumably edema) of the disc and surrounding retina (Fig. 48.7). This appearance is similar to typical cases of diabetic papillopathy,⁴⁰ in which all or most of the dilated small vessels on and adjacent to the disc are intraretinal and characteristically do not leak on fluorescein angiography.

Fig. 48.5 Rapid development of large-caliber new vessels from the disc. (A) In the left eye of this 21-year-old white woman, whose age at diagnosis of diabetes was 7 years, new vessels arose on the disc and extended across its margins in all quadrants. The disc margins were blurred. There were soft and hard exudates, intraretinal microvascular abnormalities, and hemorrhages in the retina and on its surface. Blood pressure was 126/96 mmHg. (B) Two months later, new vessels had grown remarkably, and preretinal hemorrhage had increased. Arrow indicates large new vessel that crosses the inferotemporal artery and vein. (C) Three months later, one of the new vessels (arrows) had become as large as a major retinal vein and extended nasally beyond the edge of the figure. The new vessels on and adjacent to the disc had regressed partially. Two months later, the patient died suddenly of a myocardial infarction.

Fig. 48.6 New vessels elsewhere (NVE) without prominent network formation. Over much of their course, these new vessels did not form networks. Large aneurysmal dilations were present at the end of a long new-vessel loop (left arrow) and at the circumference of a partial wheel-like network (right arrow).

(Courtesy of Diabetic Retinopathy Study Research Group.)

Fig. 48.7 Optic disc swelling. This 20-year-old man, whose diabetes had been diagnosed at age 14, sought ophthalmologic attention because of the sudden onset of floaters, first in the left eye and several days later in the right eye. (A) The disc was swollen, had blurred margins, and was partially obscured by extensive new vessels arising on it and extending on to the retina in all quadrants. (B) Five months later, disc swelling had resolved, and all new vessels had regressed spontaneously. Vision remained 20/15.

(Courtesy of Diabetic Retinopathy Study Research Group.)

The growth rate of new vessels is extremely variable. In some patients a patch of vessels may show little change over many months, whereas in others a definite increase may be seen in 1–2 weeks. Early in their evolution new vessels appear bare, but later, delicate white fibrous tissue usually becomes visible adjacent to them. The common clinical convention of referring to such tissue as “fibrous” is adhered to in this chapter, even though it has been shown to contain both fibrocytes and glial cells.^41,42 New vessels characteristically follow a cycle of proliferation followed by partial or complete regression.^31,43 Regression of a wheel-shaped net of new vessels typically begins with a decrease in the number and caliber of the vessels at the center of the patch, followed by their partial replacement with fibrous tissue. Simultaneously, the peripheral vessels tend to become more narrow, although they may still be growing in length and the patch may still be enlarging (Fig. 48.4). At times, regressing new vessels appear to become sheathed. The width of the sheath, which presumably represents opacification and thickening of the vessel wall, increases until only a network of white lines without visible blood columns remains (Fig. 48.8). At times certain new vessels seem to become preferential channels, enlarging while adjacent vessels regress and disappear. Fresh, active new vessels are commonly seen emerging from the edges of partially regressed patches, and new vessels are frequently seen at different stages of development in different areas of the same eye. Early in their evolution, the fibrous components of fibrovascular proliferations tend to be translucent and are easily underestimated. Subsequently, with increasing growth, contraction, or separation from the retina, they become more prominent. If contraction of the vitreous and fibrovascular proliferations does not occur, new vessels may pass through all the stages described here without causing any visual symptoms. Concurrently, a decrease in intraretinal lesions and in the caliber of major retinal vessels may occur as retinopathy enters the quiescent stage. Occasionally, new vessels appear to regress completely, leaving no trace of their previous presence.⁴⁴

Fig. 48.8 Dragging of the macula by contraction of fibrovascular proliferations; regression of new vessels. (A) In the right eye of this 21-year-old woman, whose age at diagnosis of diabetes was 10 years, extensive new vessels were present on the surface of the disc and retina, as well as many dilated intraretinal vessels (intraretinal microvascular abnormalities). A soft exudate was noted about 1 disc diameter (DD) superonasally to the disc, and several small preretinal hemorrhages were found (near bottom left). The macula was in its normal position, centered at or just temporal to the left edge of the figure. Fibrous tissue accompanying the new vessels was visible adjacent to the temporal vascular arcades and nasal to the disc. Fibrous proliferations were actually much more extensive but were transparent and difficult to detect. Visual acuity was 20/20. Contraction of the proliferations occurred within the next several months, dragging the retina nasally and superiorly, and new vessels regressed. (B) Four years later, the center of the macula was above the disc and about 1 DD temporal to it. The central dark retinal pigment epithelial pigmentation appeared to coincide with the neurosensory macula. The first major bifurcation of the inferotemporal vein had been pulled upward to the disc margin from its previous position. New vessels had regressed completely, some of them now appearing as networks of white lines. Visual acuity was 20/30.

(Courtesy of Diabetic Retinopathy Vitrectomy Study Research Group.)

Based on the findings of the DRS, the development of PDR with high-risk characteristics places the patient at an increased risk for visual loss and generally requires prompt laser treatment. PDR with high-risk characteristics is defined by one or more of the following lesions: (1) NVD that is approximately one-quarter to one-third disc area or more in size (i.e., greater than or equal to NVD in standard photograph 10A); (2) any amount of NVD if fresh vitreous or preretinal hemorrhage is present; or (3) NVE greater than or equal to one-half disc area in size if fresh vitreous or preretinal hemorrhage is present Therefore, attention must be paid to the presence, location, and severity of new vessels, as well as the presence or absence of preretinal or vitreous hemorrhages.²

Contraction of the vitreous and fibrovascular proliferation

Before the onset of posterior vitreous detachment, neovascular networks appear to propagate primarily on or slightly anterior to the retina. At this stage, slit-lamp examination of new vessel patches that appear to be slightly elevated shows no change in the vitreous adjacent to them nor any separation between them and the retina. This finding suggests that mild thickening of the retina may be responsible for the slightly elevated appearance of the new vessels. Typically, the edges of such a new vessel patch are tightly apposed to the retina, and its center appears slightly elevated, giving the patch as a whole a mildly convex curvature. Nearly all new vessel patches are adherent to the posterior vitreous surface. This adhesion becomes apparent when posterior vitreous detachment occurs adjacent to the patch, pulling its edge forward. If vitreous detachment surrounds the patch, all its edges become more elevated than its center, giving its anterior surface a concave appearance.

Before the beginning of posterior vitreous detachment, new vessels are usually asymptomatic.^31,43 Small hemorrhages in the posterior vitreous are occasionally seen near the growing ends of the new vessels, but they usually remain subhyaloid or hang suspended in the most posterior portion of the vitreous without becoming apparent to the patient. When symptomatic vitreous hemorrhages occur, some evidence of localized posterior vitreous detachment can usually be found. When only a small area of the posterior vitreous surface is detached, it appears flat and very close to the retina, but as detachment becomes more extensive, this surface moves forward and assumes a curved contour more or less parallel to the retina and about 0.5–2 DD anterior to it. This otherwise smoothly curved surface is held posteriorly by vitreoretinal adhesions at the sites of new vessels. The new vessels in turn tend to be pulled forward in these same areas. Vitreous strands and opacities can usually be seen anterior to the posterior vitreous surface, whereas posteriorly the vitreous cavity is optically empty or contains red blood cells.^31,45 The principal force pulling the posterior vitreous surface forward usually appears to be the forward vector resulting from contraction of this surface and the fibrovascular proliferation growing along it. In explaining this process to students and patients, it helps to use the analogy of a bowl lined with a piece of cloth attached to the rim of the bowl: if the cloth shrinks, it eventually becomes tightly stretched across the top of the bowl.

The thickness of the posterior vitreous surface varies, as indicated by three different appearances. Immediately adjacent to the site of new vessels, the surface is often thick enough to be seen easily with the ophthalmoscope. Presumably this increased opacity is due to proliferation of fibrous tissue along the posterior vitreous surface. In other areas some distance from any visible new vessels, the surface is also sometimes thick enough to be detected ophthalmoscopically or in stereoscopic fundus photographs. In these areas the surface is usually somewhat shiny, with thinner and thicker areas alternating to give a “Swiss cheese” effect but without actual holes; presumably a thin layer of fibrous tissue is also present here. In still other areas the posterior vitreous surface is so thin that it can be appreciated only by mentally integrating many separate slit-lamp sections. Only the portion directly illuminated by the slit beam is visible, and the impression of a continuous surface is gained by watching the slit beam glide along smoothly over the surface as the slit lamp is moved. Frequently in the same eye all these various appearances can be seen in different areas of the same surface, the general course of the surface continuing without change as its thickness varies (Fig. 48.9).

Fig. 48.9 The posterior vitreous surface. In this left eye fibrovascular proliferations were present at the disc and above the superotemporal vascular arcade. The posterior vitreous surface was adherent to these proliferations but was detached elsewhere. In the center of the figure the posterior vitreous surface was thin (visible only with slit illumination), but its position is marked by fine dots of hemorrhage deposited on it. Temporal to this area, the posterior vitreous surface has the typical “Swiss cheese” appearance; that is, the surface can be seen as a semiopaque sheet in which there are round and oval clear areas. This same appearance is present 1 to 2 disc diameters above the disc, near the left edge of the figure. The retina was attached but is blurred, in part because the camera was focused on the elevated proliferations and also because of blood present in the posterior fluid vitreous.

(Courtesy of Diabetic Retinopathy Vitrectomy Study Research Group.)

Posterior vitreous detachment usually begins near the posterior pole, the most common locations being the region of the superotemporal vessels, temporal to the macula, and above or below the disc.³¹ Detachment often spreads fairly rapidly (within hours, days, or weeks) to the periphery of the quadrant in which it begins, unless such spread is impeded by vitreoretinal adhesions associated with patches of new vessels. Extension circumferentially into other quadrants of the fundus tends to be slower, sometimes requiring months or years to reach completion. Detachment of the vitreous from the disc is usually prevented by adhesions between the vitreous and fibrovascular proliferations arising there. Vitreous detachment is not a smoothly progressive process. It occurs in abrupt steps, usually halting whenever its advancing edge meets a patch of active or regressed new vessels. If contraction continues, the patch is pulled forward, with or without the underlying retina, and vitreous detachment spreads beyond it. At times the peripheral spread of posterior vitreous detachment is halted temporarily by invisible adhesions to the retina in areas where no new vessels are present. These adhesions are indicated by a subtle linear elevation of the inner surface of the retina at the junction of posteriorly detached and anteriorly attached vitreous. After several weeks or months, vitreous detachment usually spreads farther peripherally, and the subtle retinal fold flattens.

Traction exerted on the new vessels appears to be a factor contributing to the recurrent vitreous hemorrhages that often coincide with extension of vitreous detachment. Hemorrhages also occur independently, sometimes apparently in relation to bouts of severe coughing or vomiting and occasionally at the time of insulin reactions. More often they occur during sleep and are unrelated to any obvious factor.^46,47 Blood in the fluid vitreous posterior to the detached vitreous framework usually absorbs within weeks or several months, retaining its red color until absorbed. Hemorrhage in the formed vitreous tends to lose its red color and become white before absorption is complete. Absorption of a large hemorrhage from the formed vitreous is usually slow, requiring many months.

The arrangement and movement of blood in the posterior fluid vitreous often make it possible to define the limits of posterior vitreous detachment ophthalmoscopically.^31,48 In areas of vitreous detachment, the presence of fresh blood in the posterior fluid vitreous obscures fundus details, distinguishing these areas from adjacent areas in which the vitreous remains attached and details of the retina are clear. In the upper quadrants of the fundus, blood tends to become deposited in thin meridional streaks on the detached posterior vitreous surface, identifying its position. Inferiorly, blood pools between the detached vitreous and attached retina, outlining the inferior extent of vitreous detachment and often forming a fluid-level or “boat-shaped” hemorrhage. At times, even when posterior vitreous detachment cannot definitely be identified with slit lamp and contact lens, a thin, curving line of subhyaloid hemorrhage parallel to and behind the inferior equator can be seen, presumably marking the lower edge of an area of vitreous detachment. Occasionally the posterior vitreous surface can be traced across the macula on slit-lamp examination, but usually its continuity is lost in this region. In some of these cases a round or oval hole with sharp edges can be detected in the posterior vitreous surface, occupying an area 2–4 DD wide in the posterior pole. The posterior vitreous surface in this area appears broken, with solid vitreous protruding back through the hole and coming into contact with the retina. At times the surface of a bulging mushroom of vitreous can be seen extending posteriorly through such a hole, occasionally with hemorrhage suspended within its lower part (Fig. 48.10).

Fig. 48.10 Vitreous detachment in proliferative diabetic retinopathy. (A) Blood deposited on the detached posterior surface of the formed vitreous after hemorrhage into the posterior fluid vitreous. (B) Neovascular and fibrous proliferations creating a tight vitreoretinal adhesion, which pulls the retina forward and holds the formed vitreous posteriorly. (C) Localized collection of subretinal fluid. (D) Curved upper surface of a “mushroom” of formed vitreous extending posteriorly to reach the retina through a “hole” in the posterior vitreous surface. (E) Hole in the posterior vitreous surface. (F) Blood collected in the dependent portion of the mushroom of vitreous after hemorrhage into the formed vitreous. (G) Posterior vitreous surface. (H) A single new vessel stretching between the retina and proliferations on the detached posterior vitreous surface without traction retinal detachment. (I) Blood with fluid level pooling between the retina and the posterior vitreous surface above the inferior limit of vitreous detachment after hemorrhage into the posterior fluid vitreous. (J) Blood settled out in the inferior part of the formed vitreous.

Retinal distortion and tractional detachment

With contraction of an extensive sheet of fibrovascular proliferations, distortion or displacement (“dragging”) of the macula may occur.⁴⁹ In some cases the central, more intensely pigmented area of the retinal pigment epithelium (RPE) appears to be dragged with the neurosensory macula toward the major focus of contracted tissue, whereas in other cases only the neurosensory macula appears displaced. Since the most common site of extensive fibrovascular proliferations is on and near the disc, the macula is usually dragged nasally and often also somewhat vertically (Figs 48.11, 48.12).

Fig. 48.11 Dragging of the macula. (A) In the left eye of this 39-year-old white woman, whose age at diagnosis of diabetes was 10 years, extensive fibrovascular proliferations were present on and adjacent to the disc, centered superotemporally. The temporal edge of the patch of proliferations was tightly apposed to the retina, and the nasal edge was elevated about one-third of a disc diameter by localized posterior vitreous detachment, the lower edge of which was marked by a preretinal hemorrhage. Visual acuity was 20/60. Scatter photocoagulation was initiated. (B) Three weeks after photocoagulation, the patient noted a marked decrease in visual acuity and returned for examination. There had been marked regression of the new vessels. Contraction of the proliferations had pulled the neurosensory macula (but not the corresponding, more deeply pigmented retinal pigment epithelium) up and nasally. Vitrectomy was carried out. (C) Two months later, visual acuity had improved to 20/30, and the neurosensory macula had returned to near-normal position. There appeared to be a rather large, full-thickness retinal break (near upper right corner), but this did not lead to retinal detachment during the remaining 3 years of follow-up. At 4-year follow-up, vision had improved to 20/20.

(Courtesy of Diabetic Retinopathy Vitrectomy Study Research Group.)

Fig. 48.12 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 of Diabetic Retinopathy Vitrectomy Study Research Group.)

Contraction of vitreous or areas of fibrovascular proliferation may also lead to retinal detachment. This retinal detachment may be limited to avulsion of a retinal vessel, usually a vein, sometimes accompanied by vitreous hemorrhage. Alternatively, a relatively thin fold of retina may become elevated, with only a narrow zone of retinal detachment adjacent to its base, sometimes outlined by a pigmented demarcation line. In other cases retinal detachment may be more extensive, but the concave shape that is typical of traction detachment is generally maintained. At times, small, apparently full-thickness retinal holes may be seen near the proliferation; these sometimes, but not always, lead to rhegmatogenous detachment. When such detachment does occur, it tends to have a flat or convex anterior surface and be more extensive, often reaching the ora serrata. The occurrence and severity of retinal detachment are influenced by the timing and degree of shrinkage of the vitreous and fibrovascular proliferations and by the type, extent, and location of the new vessels responsible for vitreoretinal adhesions. Extensive nets of large-caliber new vessels accompanied by heavy fibrous tissue produce broad, tight vitreoretinal adhesions. Contraction of such proliferations is often followed by extensive retinal detachment (Fig. 48.12). New vessels with little accompanying fibrous tissue tend to produce less extensive vitreoretinal adhesions and less risk of retinal detachment, particularly when posterior vitreous detachment begins soon after the onset of neovascularization (Fig. 48.13). At times, new vessels that extend for a considerable distance along the surface of the retina appear to be adherent to the retina only at their sites of origin and to the vitreous only near their distal ends. In this case, the posterior vitreous surface can pull away from the retina by a distance equal to the length of the vessels before exerting traction on the retina. When new vessels are confined to the surface of the disc, vitreous detachment can reach completion without producing traction on the retina, since there are no vitreoretinal adhesions. Retinal detachment does not occur in such eyes, but recurrent vitreous hemorrhage from the new vessels is common.

Fig. 48.13 Contraction of fibrovascular proliferations with limited vitreoretinal adhesions, leading to pulled-up retinal vessels and localized retinal detachment, and spontaneous regression of new vessels. (A) In the superotemporal quadrant of the right eye of this 25-year-old man, whose age at diagnosis of diabetes was 8 years, several small, wheel-shaped networks of new vessels on the surface of the retina, venous beading, intraretinal microvascular abnormalities, and localized hemorrhage far anterior to the retina in the formed vitreous were noted. Several small, white, threadlike arterioles were present superiorly, where the retina appeared featureless, indicating loss of much of the retinal capillary bed. (B) The disc and new vessels nasal to it are blurred by vitreous hemorrhage. The macula is visible in its normal position at the left edge of the figure. (C) New vessels along the inferior temporal vein were in focus inferiorly, where they were on the surface of the retina, but were out of focus above the vein, where they were about a half-disc diameter (DD) anterior to the retina, growing along the detached posterior vitreous surface. (D) New vessels and thin fibrous proliferations inferonasal to the disc. Inferiorly, the new vessels were flat on the surface of the retina; superiorly, they were elevated about a half-DD in front of the retina, on the detached posterior vitreous surface. Preretinal hemorrhages marked the inferior extent of posterior vitreous detachment. Visual acuity was 20/20. (E) One year later, following spontaneous regression of the new vessels and completion of posterior vitreous detachment, most of the proliferations were far anterior to the retina and out of focus. The inferonasal vein had been pulled upward to the horizontal meridian, and a loop of it had been pulled forward (lower arrow) without adjacent retinal detachment. The superonasal vein was also pulled forward, together with a narrow fold of retina (upper arrow). Tension lines ran through the macula, which had been displaced somewhat downward. (F) The inferotemporal vein had been pulled forward, together with a narrow fold of retina, but the adjacent retina was flat. Visual acuity was 20/30. (G) (focused on the elevated inferotemporal vein) Three years later, a small oval retinal hole (arrow) could be seen just below the point where the inferotemporal vein was most highly elevated. Retinal detachment extended inferotemporally past the edge of the figure. (H) (focused on the attached posterior retina) The retina above the superotemporal vein remained flat, and visual acuity had improved to 20/20. Panels (G) and (H) may be viewed stereoscopically by relaxing convergence (or using a base-out prism).

(Courtesy of Diabetic Retinopathy Vitrectomy Study Research Group.)

Involutional or “Quiescent” Proliferative Diabetic Retinopathy

DR ultimately reaches an involutional stage wherein the retinopathy has “burned-out” and is termed “quiescent.” At this stage vitreous contraction has reached completion and the vitreous is detached from all areas of the retina except where vitreoretinal adhesions associated with new vessels prevent such detachment.^31,43,50,51 Vitreous hemorrhages decrease in frequency and severity and may stop entirely, although many months may elapse before substantial vitreous clearing occurs. Some degree of retinal detachment may be present at this stage. If the detachment is localized and the macula remains intact, visual acuity may be good. However, dragging or distortion of the macula or long-standing macular edema can lead to substantial reduction in vision. In some cases, retinal detachment involves the entire posterior pole, with resultant severe loss of vision. Although spontaneous partial reattachment occasionally occurs, if the macula has been detached for months or years, usually little significant return of vision occurs.

A marked reduction in the caliber of retinal vessels is characteristic of this stage. Previously dilated or beaded veins return to normal caliber or become narrower and often appear sheathed. Fewer small venous branches are visible. Changes in the arterioles are often even more striking, with decreased caliber and reduction of the number of visible branches. Some small arterioles can appear to be white threads without visible blood columns. Characteristically, only occasional retinal hemorrhages and microaneurysms are present. New vessels are usually reduced in caliber and number and at times no patent new vessels can be seen. Fibrous tissue may become thinner and more transparent, allowing the retina to be observed more clearly. Vision loss at this stage is related to macular detachment, macular ischemia, chronic macular edema, optic nerve disease or media opacity. Marked vision loss is likely due to severe retinal ischemia.

Pituitary ablation

Building on the fundamental discovery of Biasotti and Houssay⁹⁸ and that hypophysectomy reduced the severity of diabetes in pancreatectomized dogs, Luft and corworkers⁹⁹ carried out hypophysectomy in the hope of ameliorating the vascular complications of diabetes. Further impetus was provided by Poulsen’s report^100,101 of remission of DR in a woman with postpartum anterior pituitary insufficiency (Sheehan syndrome). Over the next 25 years, various types of pituitary suppression were used, ranging from external irradiation to transfrontal hypophysectomy, and consensus developed among advocates of these procedures that complete or nearly complete suppression of anterior pituitary function (pituitary ablation) produced rapid improvement in eyes with the intraretinal lesions characteristic of severe NPDR and actively growing new vessels not yet accompanied by extensive fibrous proliferations. Although only two randomized trials have been reported,¹⁰² both small and neither in itself compelling, the weight of evidence supports the strongly held opinion of those most experienced with this procedure that it was beneficial. Particularly persuasive are comparisons between patients in whom transsphenoidal implantation of radioactive yttrium was followed by complete or nearly complete anterior pituitary suppression and similar patients in whom little or no suppression was achieved. Substantially better outcome was observed in the former group.¹⁰³ Additional support is provided by a nonrandomized comparison of eyes with very extensive new vessels and IRMA, in which outcome was better in the eyes of patients undergoing pituitary ablation than in similar eyes receiving photocoagulation or no treatment.¹⁰⁴ Pituitary ablation is now primarily of historical interest because photocoagulation is more effective and is free of the many substantial disadvantages of inducing and living in the hypopituitary state with concomitant diabetes (e.g., operative and immediate postoperative risks, increased susceptibility to severe insulin reactions, need for continuing replacement of adrenal corticosteroids, sterility).

The favorable effect of pituitary ablation on retinopathy is thought to be mediated by suppression of growth hormone activity and effects on insulin-like growth factor 1 (IGF-1).¹⁰⁵ Daily subcutaneous injections of a genetically engineered growth hormone receptor antagonist, pegvisomant, have been given for 3 months in 25 patients with non-high-risk PDR. Regression of new vessels did not occur in any patient, although the serum level of insulin-like growth factor 1 (IGF-1), a growth factor whose secretion is stimulated by growth hormone, did decrease an average of 55% compared to baseline levels.¹⁰⁶ In a small randomized clinical trial, multiple daily subcutaneous injections of octreotide, a somatostatin analog that inhibits both growth hormone and insulin-like growth factor, were given to 11 patients with severe NPDR or non-high-risk PDR. During 15 months’ follow-up, 1 out of 22 of these patients’ eyes required scatter laser photocoagulation compared to 9 out of 24 eyes of 12 patients randomly assigned to an untreated control group.¹⁰⁷ Unfortunately, larger clinical trials of somatostatin analogs were not found to be effective.

Early laser trials

Early observations noted that certain ocular conditions seemed to prevent severe diabetic retinopathy. In addition, as many as 10% of patients experienced spontaneous resolution of PDR.⁵¹ In these eyes the retinopathy becomes stable, the hemorrhages resolve, the retinal vasculature becomes quiescent, the proliferating tissue thins, the retinal veins lose their distended appearance, the retinal arteries become small and attenuated and many obliterated vessel branches are observed. This appearance of the retina is strikingly similar to eyes that have undergone chorioretinal scarring, optic atrophy, high myopia, retinitis pigmentosa, and the end stage of the desired outcome following pituitary ablation.^108,109 The initial use of the xenon arc photocoagulator developed by Meyer–Schwickerath¹¹⁰ in the treatment of PDR involved direct treatment of new vessels on the surface of the retina, particularly those that appeared to be the source of vitreous hemorrhage.^111–113 Large, slow, moderately intense burns were used, turning the retina white adjacent to the new vessels and sometimes causing them to narrow and the flow within them to slow. These effects were the result of heat generated when light was absorbed by the retinal pigment epithelium (RPE) or by hemorrhage within the retina or on its surface. Direct destruction of new vessels required heavy burns, which 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 hope that this effect would be possible with the narrow, intense, blue–green beam of the argon laser was part of the rationale for its development.

Before the argon laser became widely available, and before recognition of the tendency for NVD and elevated NVE to regrow after apparently successful direct treatment, the novel concept of panretinal treatment described above began to evolve. Based on observations of remarkable asymmetry of retinopathy favoring the involved eye in diabetic patients who had unilateral disseminated chorioretinal scarring, high myopia, or optic atrophy, Beetham and Aiello began a study in which ruby laser burns were scattered across the retina from the posterior pole to the midperiphery.^109,114,115 The hope was that the induced scarring might have a distant effect across the retina and promote regression of new vessels and diminution of retinal edema and vascular congestion.^109,116,117 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 mechanisms by which panretinal photocoagulation mediates its remarkable benefit are not fully understood. Several mechanisms have been proposed and all may contribute toward the beneficial effect. Ischemic retina, which produces growth factors, is destroyed, thus reducing the angiogenic stimulus. Another possibility is that retinal cells may produce growth-inhibiting factors or reduce production of growth-promoting factors in response to photocoagulation injury. Such factors have not been shown to be of importance in vivo to date.^118,119 It is thought that the primary mediating factor is an increase in oxygenation from the choroid to the inner retina that occurs through the laser scars due to the thinning of the retina in the treated area.^120–124 Indeed, retinal blood flow decreases and the autoregulatory response to breathing pure oxygen improves following scatter photocoagulation, as might be expected if more oxygen reached the inner retina from the choroid.^125,126 Furthermore, direct measurements of increased vitreous oxygen have been made using intraocular microelectrodes.¹²⁷The oxygen concentration of the vitreous is much higher overlying the areas of laser burns than over the untreated retina. Regardless of the relative contributions of these mechanisms, the remarkable efficacy of panretinal photocoagulation in the treatment of PDR has been thoroughly documented in multiple randomized clinical trials.

Panretinal photocoagulation

The initial reports concerning photocoagulation suffered from small numbers of patients, brief periods of follow-up, or lack of a randomly selected control group.¹¹⁹ Randomized clinical trials were needed to evaluate the possible benefits and risks of this treatment objectively. Two collaborative studies were initiated in the early 1970s: the British multicenter trial using xenon arc photocoagulation¹²⁸ and the National Eye Institute’s Diabetic Retinopathy Study (DRS), which compared xenon arc and argon laser photocoagulation to no photocoagulation in patients with PDR.¹²⁹ The DRS provided the initial evidence to establish the safety and efficacy of modern panretinal (scatter) photocoagulation (PRP).

The DRS conclusively demonstrated that PRP significantly reduces the risk of severe visual loss (SVL) from PDR, particularly when high-risk PDR is present.^1,26,130 Patients entering the DRS had PDR in at least one eye or severe NPDR in both eyes. Visual acuity of 20/100 or better was present in each eye. Each patient was randomly assigned to either the argon or xenon treatment group. One eye was randomly assigned to photocoagulation treatment and the other to indefinite deferral of treatment (i.e., no treatment ever), unless evidence that treatment was beneficial resulted in a change of study protocol. Patients were followed at 4-month intervals according to a protocol that provided for measurement of best-corrected visual acuity under standard lighting conditions, with separate charts for each eye. The visual acuity examiners did not know the identity of the treated eye or type of treatment and attempted to reduce patient bias by urging the patient to read as far down the chart as possible with each eye, guessing at letters until more than one in a line was missed.¹

DRS treatment techniques are summarized in Table 48.2. Both techniques included scatter treatment with burns spaced about one-half to one burn-width apart, extending from the posterior pole to the equator and often completed in a single sitting. The argon treatment technique specified 800–1600 500 µm scatter burns of 0.1 second duration and direct treatment of new vessels on the disc and elsewhere, whether flat or elevated. Direct treatment was also applied to microaneurysms or other lesions thought to be causing macular edema. Follow-up treatment was applied as needed at 4-month intervals. The xenon technique was similar, but burns were fewer, of longer duration, and stronger. Direct treatment was not applied to elevated new vessels or those on the surface of the disc in the xenon treated group.

Table 48.2 Diabetic retinopathy study photocoagulation techniques

^* NVE, new vessels elsewhere (more than 1 disc diameter [DD] from the disc); NVD, new vessels on or within 1 DD of the disc.

(Reproduced with permission from 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. Copyright © 1981 American Academy of Ophthalmology.)

The principal outcome of the DRS was visual acuity of <5/200 at each of two consecutively completed follow-up visits, scheduled at least 4-months apart (termed severe visual loss). Visual acuity of <5/200 was chosen as the level at which vision becomes too poor to be useful for walking about or for other self-care activities. The requirement of two consecutive visits was included because the rate of recovery to better visual acuity after a single visit at the <5/200 level was 29% in the control group and 49% in the treated group whereas after two visits it was 12% and 29%, respectively, and after three visits, 8% and 21%.¹ Because recovery was somewhat more common in treated eyes, the chosen endpoint tends to underestimate the treatment benefit.

Table 48.3 presents 2-year cumulative rates of severe visual loss in eyes grouped by baseline retinopathy severity and treatment assignment.² For severe visual loss to be present at the 2-year visit, visual acuity had to be <5/200 no later than the 20-month visit. For all eyes in the untreated control group, the risk of severe visual loss within 2 years was 15.9%, and this risk was reduced to 6.4% by treatment. The risk was greatest in group J (36.9% in the control group). These eyes had preretinal or vitreous hemorrhage and NVD exceeding those in standard photograph 10A of the modified Airlie House classification (Fig. 48.15). The risk appeared somewhat lower for eyes with NVD of this severity without hemorrhage (group I, 26.2% in the control group). Similar risks (25.6 and 29.7%, respectively) were observed for untreated eyes in groups H and F, eyes with vitreous or preretinal hemorrhage, and less severe new vessels. Eyes in these four groups were referred to in the DRS as eyes with high-risk characteristics or, alternatively, eyes with three or four new vessel-vitreous hemorrhage (NV-VH) risk factors, these factors being: (1) new vessels present; (2) new vessels located on or within 1 DD of the disc (NVD); (3) new vessels moderate to severe (NVD equaling or exceeding those in standard photograph 10A or, for eyes without NVD, NVE equaling or exceeding one-half disc area in at least one photographic field); and (4) vitreous or preretinal hemorrhage (or both) present. In counting 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.² In the remaining groups (A through E and G), the risk without treatment varied from 3.6 to 10.5%. Treatment reduced the rate of severe visual loss in each group, most impressively in groups F through J. Since it appeared that a small permanent reduction in visual acuity might occur in 10–20% of treated eyes, the DRS investigators concluded in 1976 that prompt photocoagulation treatment was usually 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 at the time or developed them subsequently.¹

Fig. 48.15 Standard photograph 10A of the modified Airlie House classification, defining the lower limit of moderate new vessels on or within 1 disc diameter of the disc.

(Reproduced with permission from Diabetic Retinopathy Study Research Group. A modification of the Airlie House classification of diabetic retinopathy. DRS report number 7. Invest Ophthalmol Vis Sci 1981;21:210–26.)

In Table 48.4 the retinopathy severity groups presented in Table 48.3 have been combined, and observations from follow-up visits completed after the 1976 protocol change have been included.¹ Forty-three percent of the 2-year visits and all the 4-year visits included in this analysis were carried out after the 1976 protocol change. At the 2-year visit, 12% of control-group eyes had been treated, and by the 4-year visit 35% had been treated. All eyes were classified in the group to which they were originally randomly assigned, without reference to treatment of control-group eyes. In the control group the 2-year risk of severe visual loss increased from 3.2% in eyes with NPDR to 7% in eyes with PDR without high-risk characteristics, and to 26.2% in eyes with high-risk characteristics. The 4-year rates in these groups were, respectively, 12.8, 20.9, and 44.0%. Treatment reduced the risk of severe visual loss by 50% to 65% in all three groups at both 2 and 4 years, except for the NPDR group at 2 years.

Figure 48.16 depicts cumulative rates of severe visual loss by treatment assignment (argon and xenon groups combined) for up to 6 years. Two separate analyses are summarized, one excluding and the other including visits made after the 1976 protocol change. The curves for control-group eyes are very similar over the first 20 months of follow-up, and those for treated eyes are similar over at least the first 28 months. The difference between the two control-group curves is probably due, at least in part, to the beneficial effect of treatment experienced by some of these eyes after the protocol change, and the long-term analysis probably underestimates treatment effect. In each of these analyses, treatment reduced the risk of severe visual loss by 50% or more at and after the 16-month visit.¹³⁰ In Fig. 48.17, the plots from Fig. 48.16, including all visits, are presented separately for the argon and xenon groups. The treatment effect (i.e., the difference between treatment and control groups) appeared somewhat greater in the xenon group, but this difference was small, its statistical significance was borderline, and its clinical importance was outweighed by the greater harmful effects of DRS xenon treatment.

Fig. 48.16 Cumulative rates of severe visual loss, including and excluding observations made after the 1976 protocol change, for argon and xenon groups combined.

(Reproduced with permission from 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. Copyright © 1981 American Academy of Ophthalmology.)

Fig. 48.17 Cumulative rates of severe visual loss by treatment group.

(Reproduced with permission from 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. Copyright © 1981 American Academy of Ophthalmology.)

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 were also more common in the xenon group^130,131 (Table 48.4). In a small subgroup of eyes with severe fibrous proliferations or localized traction retinal detachment, or both, visual acuity decreases of 5 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.¹³¹

In Fig. 48.18, the Fig. 48.16 plots including all visits are presented separately for the three subgroups shown in Table 48.4. In each subgroup treatment reduced the risk of severe visual loss to about one-half of that observed in control-group eyes, but this effect became apparent later, and the percentage of eyes treated that benefited (the arithmetic difference between treated and control groups) was smaller as retinopathy severity decreased. On the basis of this analysis and the estimates of the harmful effects of treatment summarized in Table 48.5, the DRS confirmed its previous conclusion that, for eyes with high-risk characteristics, the chance of benefit from treatment clearly outweighed its risk and recommended prompt photocoagulation for most such eyes.¹³⁰

Fig. 48.18 Cumulative rates of severe visual loss for eyes classified by the presence of proliferative retinopathy (PDR) and high-risk characteristics (HRC) in baseline fundus photographs, argon, and xenon groups combined. NPDR, Nonproliferative diabetic retinopathy.

(Reproduced with permission from 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. Copyright © 1981 American Academy of Ophthalmology.)

Table 48.5 Estimated percentages of eyes with harmful effects attributable to diabetic retinopathy study treatment

(Reproduced with permission from 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. Copyright © 1981 American Academy of Ophthalmology.)

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 high-risk characteristics developed was satisfactory and that DRS results were not helpful in choosing between these strategies. In unadjusted 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 IRMA – were also risk factors for visual loss in control-group eyes with NPDR.³³ 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.¹³² 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.

When the DRS first reported evidence of a beneficial treatment effect and modified its protocol to encourage treatment of control-group eyes with high-risk characteristics, it also modified its treatment protocol. Because the harmful effects of the DRS argon treatment were less than 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. However, because the beneficial treatment effect in the xenon group, in which no focal treatment had been applied to NVD or elevated NVE, had been at least as great as that in the argon group, these technically difficult parts of the argon protocol were dropped. Two large case series^133,134 and two smaller randomized trials reported beneficial treatment effects similar to those found in the DRS.^135,136

Early treatment diabetic retinopathy study and the timing of treatment

As mentioned previously 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 Early Treatment Diabetic Retinopathy Study (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.¹³⁷ Other goals were to evaluate photocoagulation for diabetic macular edema¹³⁸ and to determine the possible effects of aspirin on DR.¹³⁹ Between 1980 and 1985, 3711 patients were enrolled and assigned randomly to aspirin 650 mg/day or placebo. 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 µm, 0.1 sec argon blue–green or green laser burns of moderate intensity, placed one-half burn apart, extending from the posterior pole to the equator. Between 1200 and 1600 burns were applied, divided between two or more sittings. The mild scatter protocol was the same, except that 400–650 more widely spaced burns were applied to the same area in a single sitting. Direct (local) treatment was specified for patches of flat surface NVE that were two disc areas or less in extent (the area of a circle about 1.4 times the diameter of the disc), using confluent, moderately intense burns that extended 500 µm beyond the edges of the patch. For larger patches or several small ones close together, full scatter alone to this area was an acceptable alternative. No direct treatment was carried out for NVD.¹⁴⁰

One important outcome measure used in the ETDRS was the first occurrence of either severe visual loss, as defined in the DRS, or vitrectomy.¹³⁷ These events were combined because progression to a stage requiring vitrectomy may rightly be considered an undesirable outcome for ETDRS-eligible eyes and since 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 performed. Five-year life-table rates of severe visual loss or vitrectomy, and relative risks for early photocoagulation compared to deferral over the entire follow-up period, are shown in Table 48.6. The first two rows include eyes with macular edema, subdivided by retinopathy severity. As anticipated, the poor outcome was more frequent in eyes with more severe retinopathy (in the deferral group, 10% in eyes with severe NPDR or early PDR versus 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%. The third row of the table includes all eyes without macular edema regardless of retinopathy severity (eyes with mild NPDR were not eligible unless macular edema was present), and outcome here was intermediate between that in rows 1 and 2. Some harmful effects of scatter photocoagulation were also observed in the ETDRS, including an early decrease in visual acuity (a doubling or more of the visual angle at the 4-month visit in about 10% of eyes assigned to early full scatter, compared to about 5% of eyes assigned to deferral) and some decrease in visual field. Both beneficial and harmful effects were somewhat greater with full than with mild scatter.

Figure 48.19 presents cumulative incidence rates of high-risk PDR in ETDRS eyes assigned to deferral of photocoagulation, by severity of retinopathy at baseline. It is of interest that high-risk PDR developed at about equal rates in eyes with moderate PDR or very severe NPDR, with rates of about 50% after 18 months. Figures 48.15, 48.20, and 48.21 present the standard photographs used in the definitions of high-risk PDR and very severe NPDR, the most important severity levels for application to clinical practice. It is convenient to express the approximate definitions of severe and very severe NPDR with the 4–2–1 rule described earlier (see Box 48.1).

Fig. 48.19 Cumulative incidence of high-risk proliferative diabetic retinopathy in the eyes of Early Treatment Diabetic Retinopathy Study (ETDRS) patients assigned to deferral of photocoagulation. The 5-year rate for eyes with mild nonproliferative diabetic retinopathy (NPDR: level 35) was 15%. For eyes with very severe NPDR (level 53E) or moderate PDR (level 65), the 5-year rate was about 75% and the 1-year rate was almost 50%. Levels 43 and 47 represent moderate NPDR; level 53A–D, severe NPDR; and level 61, mild PDR (nVE less than half disc area or fibrous proliferation only).

(Reproduced with permission from Early Treatment of Diabetic Retinopathy Study Group. Early photocoagulation for diabetic retinopathy. ETDRS report no. 9. Ophthalmology 1991;98:766–85. Copyright © 1991 American Academy of Ophthalmology.)

Fig. 48.20 Standard photograph 2A of the modified Airlie House classification, defining lower margin of the “severe” category for retinal hemorrhages and microaneurysms.

(Reproduced with permission from Diabetic Retinopathy Study Research Group. A modification of the Airlie House classification of diabetic retinopathy. DRS report number 7. Invest Ophthalmol Vis Sci 1981;21:210–26. Copyright © 1981 American Academy of Ophthalmology.)

Fig. 48.21 Standard photograph 8A of the modified Airlie House classification, defining the lower margin of the “moderate” category for intraretinal microvascular abnormalities (IRMA) (and for soft exudates, indicated by arrows). IRMA are prominent in three areas, two of which are shown in insets. Additional IRMA can be seen when the color transparencies used in grading are viewed stereoscopically with ∞5 magnification.

(Reproduced with permission from Diabetic Retinopathy Study Research Group. A modification of the Airlie House classification of diabetic retinopathy. DRS report number 7. Invest Ophthalmol Vis Sci 1981;21:210–26. Copyright © 1981 American Academy of Ophthalmology.)

The ETDRS recommended that scatter treatment not be used in eyes with mild to moderate NPDR but that it be considered for eyes approaching the high-risk stage (i.e., eyes with very severe NPDR or moderate PDR) and that it usually should not be delayed when the high-risk stage is present. The recommendation to consider photocoagulation for eyes approaching the high-risk stage was made because, although both the benefits and risks of treatment were small and roughly in balance, the risk–benefit ratio was approaching a clearly favorable range. A policy of continued observation would be expected to spare only a minority of eyes from the risks of treatment, while increasing the risk that rapid progression might occur between follow-up visits and that entry into the high-risk stage might be marked by occurrence of a large vitreous hemorrhage, making satisfactory treatment difficult. In choosing between prompt treatment and deferral, the commitment of the patient to careful follow-up and the state of the fellow eye were important factors. If visual function decreased in the fellow eye after scatter photocoagulation, deferral of treatment in the second eye may be desirable. On the other hand, in a patient whose first eye had an unfortunate outcome without photocoagulation or one with photocoagulation only after PDR was advanced, prompt treatment may be preferable, particularly if close follow-up will be difficult.

These initial ETDRS recommendations were made without regard to patient age or type of diabetes. Subsequent analyses of ETDRS data suggest that, among patients whose retinopathy is in the severe NPDR to non-high-risk PDR range, the benefit of prompt treatment is greater in those who have type 2 diabetes or are older than 40 years of age (these characteristics are highly correlated, and analyses using either gave almost identical results)¹⁴¹ (Fig. 48.22). In the type 2 group, the 5-year rate of severe visual loss or vitrectomy was about 5% in eyes assigned to early photocoagulation versus 13% in eyes assigned to deferral, whereas in the type 1 group the rates were about 8% in both treatment groups (Fig. 48.19). 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 2 diabetes resulted mainly from greater responsiveness to early treatment. The DRS also found greater photocoagulation treatment benefit in patients with type 2 diabetes.¹⁴¹ Greater responsiveness to photocoagulation in older versus younger patients has also been observed in other studies.^142,143 These studies are consistent with the clinical impression that, in patients with type 2 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 1 diabetes, NVD is more often the first sign of high-risk PDR, an occurrence more easily managed with photocoagulation.

Fig. 48.22 Development of severe visual loss or vitrectomy in eyes with severe nonproliferative or early proliferative retinopathy at baseline. Early treated eyes compared with deferred eyes, for those with type 1 (P = 0.43) and type 2 (P = 0.0001) diabetes. Test for interaction of treatment and type (P = 0.0002).

(Reproduced with permission from Ferris F. Early photocoagulation in patients with either type 1 or type 2 diabetes. Trans Am Ophthalmol Soc 1996;94:505–37.)

Thus, in older patients with type 2 diabetes who have very severe NPDR or early PDR, ETDRS results and clinical impression suggest that prompt photocoagulation is probably safer than deferral. In younger patients with type 1 diabetes, ETDRS results suggest that there is little to lose from deferring scatter photocoagulation until high-risk PDR develops assuming appropriate compliance with follow-up. However, even in younger patients, when early NVD (less than shown in Fig. 48.15) is accompanied by the intraretinal signs of severe or very severe NPDR (see Fig. 48.2), prompt treatment is generally recommended. On the other hand, when younger patients have only mild intraretinal lesions and NVE (only) that appear stable, an initial period of observation is generally recommended. If new vessels are demonstrated to be growing, photocoagulation is usually recommended. However, these eyes often remain asymptomatic for many years, with little new vessel growth and often demonstrate spontaneous regression of the new vessels. In such eyes vitreoretinal adhesions tend to be delicate, and when posterior vitreous detachment occurs, there is less tendency for traction retinal detachment. When the process of posterior vitreous detachment has reached completion in such an eye, new vessels are likely to be few, narrow, elevated, and partially replaced by fibrous proliferations, and there may be little to be gained from photocoagulation at this stage unless vitreous hemorrhages are occurring. Presumably the reduced aggressiveness of new vessels in the setting of posterior vitreous detachment results from the lack of the posterior vitreous face scaffold for proliferation and less possibility for retinal traction. These findings support studies regarding the therapeutic usefulness of pharmacologic vitreolysis described later in this chapter.

Systemic factors should also be considered when deciding whether to initiate treatment in patients with very severe NPDR or moderate PDR. The progression of retinopathy may accelerate during pregnancy,^144,145 development of renal failure,¹⁴⁶ extreme illness, and poor glycemic control. If photocoagulation is deferred until high-risk characteristics develop in these situations, these more pressing problems may make it difficult to provide prompt and complete photocoagulation.

Scatter photocoagulation and macular edema

Macular edema sometimes increases, at least temporarily, after scatter photocoagulation, and this edema may be followed by transient or persistent reduction of visual acuity.^147–149 In the ETDRS, 18% of eyes had center-involved DME and less severe retinopathy without center involvement at baseline at 4 months.¹³⁷ The DRS also found early harmful effects, which were greater in the xenon group.¹³¹ At the 6-week post-treatment visit, 21% of argon-treated and 46% of xenon-treated eyes that had DME and were free of high-risk characteristics at baseline had a decrease in visual acuity of two or more lines, compared with 9% of untreated eyes. Comparable percentages for eyes with neither DME nor high-risk characteristics were 9% argon, 18% xenon, and 3% untreated. After one year of follow-up in the group with DME at baseline, the greater progression of retinopathy in untreated eyes had led them to catch up with treated eyes; the percentages with a decrease in visual acuity of 2 or more lines were 32% argon, 33% xenon, and 34% untreated.^130,150 Both the ETDRS and the DRS support the clinical impression that eyes with DME requiring scatter treatment are at less risk of visual acuity loss when focal or grid treatment to reduce the DME precedes scatter photocoagulation. If a delay of scatter treatment seems undesirable, the ETDRS protocol can be used, combining focal/grid treatment for macular edema with scatter treatment during the first photocoagulation sitting.^140,151 VEGF inhibitors combined with either immediate or deferred macular laser have been shown to be more effective at reducing visual loss than laser alone.^152–154 In eyes with DME and PDR, VEGF inhibitors used to treat the edema may have a temporary beneficial effect on the retinal neovascularization until PRP can be performed. Certainly, scatter treatment should not be delayed when the risks of vitreous hemorrhage or neovascular glaucoma seem high, regardless of the status of the macula.

The Diabetic Retinopathy Clinical Research Network (DRCR.net) evaluated 364 eyes with center-involved ME to evaluate the short-term effects of intravitreal ranibizumab or intravitreal triamcinolone on preexisting ME in eyes receiving both PRP for severe NPDR (or non-high risk PDR) and focal/grid laser for concurrent ME.¹⁵⁵ Mean change in visual acuity from baseline was significantly better in the ranibizumab (+1 letters; P <0.001) and triamcinolone (+2 letters; P < 0.001) groups compared with the sham group (−4 letters) at the 14-week visit. The effect on retinal thickness mirrored these results. These differences were not maintained when study participants were followed for 56 weeks for safety outcomes. These data suggested that at least in the short term, exacerbation of DME and visual acuity loss following PRP in eyes also receiving focal/grid laser for ME can be reduced by intravitreal triamcinolone or ranibizumab. Whether continued long-term intravitreal treatment is beneficial cannot be determined from this study.

As noted above, the ETDRS divided PRP into two or more sittings in an effort to reduce side effects, including exacerbation of ME. Utilizing optical coherence tomography (OCT), studies have evaluated the effect of PRP on macular thickness. Alterations in OCT measured macular thickening during and after PRP in patients with severe DR and good vision were evaluated in a study comparing weekly versus biweekly spacing between episodes of PRP.¹⁵⁶ Thirty-six patients with severe nonproliferative or early proliferative retinopathy and 20/20 vision in each eye at baseline received scatter photocoagulation in the following manner: in one eye, one quadrant was treated every week for 4 weeks and in the other eye, one quadrant was treated every other week for 8 weeks. OCT assessment of macular thickness was performed at baseline, before each session of photocoagulation, and at 16 weeks, the end of the follow-up period. Four of 36 eyes in the weekly treatment group and 3 of 36 in the biweekly group developed center-involved DME with decreased visual acuity (from 20/40 to 20/200), which was treated with photocoagulation. Additional photocoagulation for residual neovascularization was carried out in 35–40% of eyes in each group. The response of the remaining eyes is shown in Fig. 48.23. At baseline, mean retinal thickness was 191 µm in the central zone of the macular grid (1000 µm in diameter) in both groups. Thickness increased progressively after each weekly treatment to a maximum of 275 µm at week 4 and then decreased to 225 µm at 16 weeks. The increase was less after the biweekly treatments and at 16 weeks was closer to, but had not reached, the baseline value. There was little change in retinal thickness outside the central zone with either treatment technique.

Fig. 48.23 Comparison of retinal thickness in the central zone between the weekly treated eyes and biweekly treated eyes. Each point and vertical bar indicates mean retinal thickness ± standard error of the mean. Arrows indicate each session of weekly treatment at 0-, 1-, 2-, and 3-week time points and biweekly treatment at 0-, 2-, 4-, and 6-week time points.

(Reproduced with permission from Shimura M, Yasuda K, Nakazawa T, et al. Quantifying alterations of macular thickness before and after panretinal photocoagulation in patients with severe diabetic retinopathy and good vision. Ophthalmology 2003;110:2386–94. Copyright © 2003 American Academy of Ophthalmology.)

The DRCR.net conducted an observational study to compare the effects of 1-sitting vs 4-sitting PRP on DME in subjects with severe nonproliferative or early proliferative diabetic retinopathy with relatively good visual acuity and no or mild center-involved macular edema.¹⁵⁷ Patients enrolled in the study were treated with 1 sitting or 4 sittings of PRP in a nonrandomized, prospective, multicenter clinical trial. The median change in central subfield thickness was slightly greater in the 1-sitting group (n = 84) than in the 4-sitting group (n = 71) at the 3-day (+9 µm vs +5 µm, P = 0.01) and 4-week visits (+ 13 µm vs +5 µm, P = 0.003). At the 34-week primary outcome visit, the slight differences had reversed, with the thickness being slightly greater in the 4-sitting group than in the 1-sitting group (+14 µm vs +22 µm, P = 0.06). Visual acuity changes paralleled OCT changes: 1 vs 4 sittings at 3 days (−3 vs −1 letters, P = 0.005), 4 weeks (−1 vs −1 letters, P = 0.37) and 34 weeks (0 vs −2 letters, P = 0.006). The results of the study suggest that clinically meaningful differences are unlikely in OCT thickness or visual acuity following application of PRP in a single sitting compared with 4 sittings in patients without center-involved macular edema and good vision.

Panretinal photocoagulation and advanced proliferative diabetic retinopathy

There is widespread agreement that PRP should be performed promptly in most eyes with PDR and high-risk characteristics. However, progressive contraction of fibrous proliferations leading to displacement or detachment of the macula sometimes follows PRP in eyes with extensive fibrous proliferations (see Fig. 48.11). Such cases have led to some reluctance to advise photocoagulation in this situation. Few such eyes were included in the DRS, but analyses of such cases indicated that outcome was better with photocoagulation than without it and suggested that it is only excessively heavy treatment that should be avoided. The adverse treatment effect was only evident in the xenon group, and even there the benefit of treatment outweighed its risks.¹³¹ When high-risk characteristics are definitely present, PRP should usually be carried out, despite the presence of fibrous proliferation or localized traction retinal detachment. Treatment directly over areas of fibrous proliferation and retinal detachment should be avoided, and treatment strength should be mild to moderate.

Extensive neovascularization in the anterior chamber angle is a strong indication for PRP regardless of the presence of high-risk characteristics as regression of these new vessels before extensive closure of the angle has occurred can prevent neovascular glaucoma.^133,158

Direct (local) treatment of NVE

In the ETDRS, investigators had the option of applying direct photocoagulation (referred to as “local treatment”) to flat new vessels on the retina. Confluent argon laser burns of 200–1000 µm spot size and a 0.1–0.5 second duration were specified with a resulting appearance (Fig. 48.24A) very similar to that obtained with mild xenon arc photocoagulation. Local treatment was limited to patches of NVE <2 disc areas in size in order to avoid large scotomas or nerve fiber bundle field defects. Although most retina specialists today do not perform local treatment, the efficacy of PRP without it, although clearly good, is not precisely known.

Fig. 48.24 (A) Immediate post-treatment photograph illustrating Early Treatment Diabetic Retinopathy Study full-scatter treatment and local confluent treatment of a patch of new vessels everywhere (NVE). (B) Appearance of pattern scanning laser burns 1 week after treatment.

(Panel (A) reproduced with permission from Early Treatment of Diabetic Retinopathy Study Research Group. Techniques for scatter and local photocoagulation treatment of diabetic retinopathy: the ETDRS report no. 3. Int Ophthalmol Clin 1987;27:254–64; panel (B) Courtesy of the Beetham Eye Institute Library.)

Distribution and strength of panretinal photocoagulation

A common feature of most scatter laser treatment protocols is the location of burns beginning about 2–3 DD from the center of the macula and extending peripherally to the equator. It is important to realize that the size of the burn produced depends not only on the spot-size setting used, but also on power and duration, so it is difficult to compare techniques precisely, even those using the same wavelength and spot-size setting, on the basis of number and theoretical size of burns. It is also difficult to describe burn strength. Reporting power level is not particularly helpful, since the required power for a burn of given strength, even if spot-size setting and duration are kept constant, depends on the clarity of the media and the pigmentation of the fundus. The ETDRS protocol for full scatter treatment provides useful guidelines for initial treatment,¹⁴⁰ calling for a total of 1200–1600 500 µm 0.1 s argon laser burns of moderate intensity placed one-half to one burn apart and divided between two or more sittings (at least 2 weeks apart if two sittings and at least 4 days apart if three or more sittings). Burns appear to enlarge slightly within several minutes after their application, resulting in the closer spacing of the scatter burns shown in Fig. 48.24A.

Pattern scanning laser delivery systems

The development of scanning laser delivery systems (PASCAL®, OptiMedica, Inc., Santa Clara, CA and Zeiss VITE, Carl Zeiss Meditec, Dublin, CA) has given ophthalmologists the ability to deliver various semi-automated operator-selected burn patterns. These systems utilize a 532 nm frequency-doubled neodymium-doped yttrium aluminum garnet (Nd : YAG) solid-state laser and typically have a 20 ms pulse duration for each laser burn that is 5–10 times shorter as compared with conventional lasers. This allows defined multispot patterns to be delivered nearly simultaneously with a single application of the foot pedal. The shorter duration results in less thermal damage, less burn spread, and potentially improves patient comfort and safety without apparently compromising efficacy.

Preclinical animal experiments on the effects of various pulse durations demonstrated that laser burns of pulse durations greater than 20 ms resulted in significant diffusion of heat with a less homogeneous lesion on histological examination.¹⁵⁹ Pulse durations of approximately 20 ms have been shown to represent an optimal compromise between the favorable impact of speed, spatial localization, and reduced collateral damage with a sufficient therapeutic window.¹⁶⁰ The 10–30 ms pulse of the pattern laser systems is associated clinically with a more uniform and predictable burn dimension with minimal thermal spread compared with conventional photocoagulation.^159,161,162 Clinically, pattern scanning laser burns are typically lighter in intensity and more uniform, as confirmed by clinical retinal morphologic studies that demonstrated pattern scanning laser burns to be nearly identical in size and sharply delineated from the surrounding untreated retina.¹⁶³ Furthermore, the area of tissue destruction was confined to the outer retinal layers, from the outer nuclear layer to the RPE, reflecting less energy spread and less damage to the inner retinal layers and choriod¹⁶³ (Fig. 48.24).

Number of episodes used for scatter treatment

The effect of single and multiple laser sittings on DME has been discussed earlier in this chapter, noting that complete application within a single sitting did not appear to be detrimental as compared with dividing treatment over multiple sittings. Among the techniques in use for PDR alone, the number of sittings in which initial scatter treatment is carried out varies from one to four or more. Those techniques using a smaller number of larger burns tend toward a single sitting, sometimes with retrobulbar anesthesia, whereas those using a larger number of smaller burns have generally been divided into two or more sittings. In general, multiple sittings may reduce discomfort, but may cause delays and inconvenience for patients. Angle-closure glaucoma secondary to serous detachment of the peripheral choroid and ciliary body is reportedly less common when treatment is carried out in two or more sessions over a period of 1 or 2 weeks.¹⁶⁴

Doft and Blankenship¹⁶⁵ addressed this question in a small randomized trial. They randomly assigned one eye from each of 50 patients with DRS high-risk characteristics to scatter photocoagulation with 1200, 500 µm, 0.1 s argon laser burns of moderate intensity applied in either of two ways: (1) at a single sitting or (2) in three sittings at 1-week intervals. Retrobulbar anesthesia was used in the single-sitting group and for the first of the multiple-sitting group. In this latter group at the first episode, several rows of burns were placed surrounding the posterior pole, and treatment was extended temporally and nasally to the periphery, leaving the remainder of the upper quadrants (from the 10 o’clock to the 2 o’clock position) for the second episode and the remainder of the lower quadrants (from the 4 o’clock to the 8 o’clock position) for the third. Surrounding the posterior pole with treatment at the initial sitting is different from most protocols, where posterior burns are usually divided between multiple sittings.

Patients were examined 3, 7, 14, 21, 60, and 180 days after completion of the initial treatment episode. Peripheral choroidal detachment was noted more frequently at the 3-day visit in the single than in the multiple-sitting group (17 of 25 and 10 of 25 eyes, respectively), and three eyes in the single-sitting group developed angle closure which resolved spontaneously without any adverse effect. Transient (present at the 3-day and 7-day visit but not at the 14-day visit) exudative retinal detachment involving the macula was noted in 7 of 25 (28%) eyes treated in a single sitting and in 2 of 25 (8%) eyes treated in three sittings. Eyes with exudative macular detachment had, on average, a visual acuity decrease of about 5 lines at the 3-day visit, but at the 6-month visit they had recovered to approximately the same level as eyes without transient detachments. At the 6-month visit the numbers of eyes with a decrease in visual acuity of 1 line, 2–4 lines, and 5 or more lines from the baseline visit were 3, 6, and 1 in the single-sitting group, compared with 4, 4, and 1 in the multiple-sitting group. These differences were not statistically significant in this small low-power study.

Wavelength

The Krypton-Argon Regression of Neovascularization Study (KARNS) randomly assigned 907 eyes (of 696 patients) that had NVD equaling or exceeding those in Fig. 48.15 to scatter photocoagulation (1600–2000 moderate-intensity 500 mm burns) with either blue–green argon or red krypton wavelengths.¹⁴² If, after the initial treatment, NVD increased by more than 0.5 disc area, retreatment was recommended (and could also be applied for other reasons, such as increasing NVE or vitreous hemorrhage). Retreatment was carried out in 36% and 33%, respectively, of the argon and krypton groups. Worsening NVD was the reason for the retreatment in ~40% of retreated eyes in each group. Regression of NVD to less than that shown in Fig. 48.15 was observed in almost identical proportions of the two groups (41.4% and 41.8%, respectively, at 3 months and 55.0% and 52.8%, respectively, at 1 year). No differences were found in the effectiveness of argon versus krypton treatment, although retrobulbar anesthesia was used more frequently with krypton treatment. In two small randomized trials, diode (810 nm) and double-frequency Nd : YAG (532 nm) lasers gave results similar to those of the argon green laser.^166,167