>30 yr of age at diagnosis of diabetes and with duration of >20 yr, the prevalence of PDR was ~ 2 5 % in those taking insulin and 5% in those not taking insulin. After 15 yr of diabetes, the prevalence of macular edema was ~12-20%, MATTHEW D. DAVIS, MD with less variation by diabetes type. But diabetes diagnosed after 30 yr of age is the more common type; probably >50% of diabetic individuals with PDR belong After an introductory summary, this review presents a description of the natural to this group, as do —80% of those with course of diabetic retinopathy, then briefly considers selected pathogenetic and macular edema. Evidence from animal models epidemiological concepts, and concludes with a discussion of current treatment. suggests that hyperglycemia per se is the primary cause of diabetic retinopathy, rather than other metabolic abnormaliicroaneurysm formation, exces- into the vitreous from these new vessels sive vascular permeability, and is one of the principal mechanisms of ties of the diabetic state or genetic faccapillary occlusion are funda- visual loss in PDR. Fibrous tissue char- tors. Damage to the pericytes of the retmental pathological processes occurring acteristically accompanies the new ves- inal capillaries mediated by excessive in NPDR, but their interrelationships and sels and precedes vitreous hemorrhage. flux of glucose through the polyol pathcausal mechanisms are poorly under- Contraction of these fibrovascular prolif- way is perhaps the most appealing stood. Fluid leaking from the plasma erations and of the vitreous are the prin- pathogenetic theory currently under through the walls of excessively perme- cipal causes of the distortion and/or de- consideration, but initial attempts to preable microaneurysms and capillaries tachment of the retina that is the other vent or slow the development of galacleads to thickening (edema) of the retina. principal mechanism of visual loss in tosemic and diabetic retinopathy with Edema involving the center of the mac- PDR. ARIs have been disappointing. Increasula is the principal mechanism of visual The prevalence of retinopathy, ingly persuasive evidence linking poorer loss in NPDR. Retinal edema often is and particularly of PDR, is greater in type glycemic control with more prevalent accompanied by hard exudates, which I diabetes and in this group is closely and/or severe retinopathy continues to tend to form partial or complete rings related to the duration of diabetes. In a accumulate. In a recent study, a dosearound zones of thickened retina. Retinal recent population-based study, preva- response relationship appeared to exist ischemia secondary to widespread capil- lence of PDR in insulin-taking individu- between baseline decile of GHb and risk lary loss is probably an important cause als whose age at diagnosis of diabetes of retinopathy progression during the of the new vessels that often develop on was 20 yr. Among individuals severity of retinopathy. However, whether this is a cause-and-effect relationship has not been demonstrated. It is FROM THE DEPARTMENT OF OPHTHALMOLOGY, UNIVERSITY OF WISCONSIN, MADISON, WISCONSIN. hoped that this question will be anADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO MATTHEW D. DAVIS, MD, DEPARTMENT OF swered by the DCCT, and that the risk: OPHTHALMOLOGY, UNIVERSITY OF WISCONSIN, WARF BUILDING, ROOM 417, 610 N. WALNUT STREET, benefit balance of strict control versus a PO Box 5240, MADISON, WI 53705. less demanding regimen mimicking curTHIS ARTICLE APPEARED PREVIOUSLY, IN PART, IN DIABETES METABOLISM REVIEWS, 4 : 2 9 1 - 3 2 2 , 1988. rent widespread practice will be docuN P D R , NONPROLIFERATIVE DIABETIC RETINOPATHY; P D R , PROLIFERATIVE DIABETIC RETINOPATHY; TYPE I mented. DIABETES, INSULIN-DEPENDENT DIABETES MELLITUS; D C C T , DIABETES CONTROL AND COMPLICATIONS In a large long-term randomized TRIAL; IRMA, INTRARETINAL MICROVASCULAR ABNORMALITIES; TYPE II DIABETES, NON-INSULIN-DEPENDENT clinical trial, aspirin was not found to DIABETES MELLITUS; D R S , DlABETIC RETINOPATHY STUDY; E T D R S , EARLY TREATMENT DIABETIC RETINOPATHY STUDY; ALX, ALLOXAN; AR, ALDOSE REDUCTASE; ARI, ALDOSE REDUCTASE INHIBITORS; UGDP, have either beneficial or harmful effects UNIVERSITY GROUP DIABETES PROGRAM; CSII, CONTINUOUS SUBCUTANEOUS INSULIN INFUSION; DAMon the course of diabetic retinopathy. In A D S , DlPYRIDAMOLE ASPIRIN MlCROANGIOPATHY OF DIABETES STUDY; D R V S , DlABETIC RETINOPATHY two smaller shorter trials, aspirin or VlTRECTOMY STUDY. other antiplatelet agents appeared to slow the increase in microaneurysm

Diabetic Relinopalhy

A clinical overview

M

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counts, a finding of uncertain clinical importance. Photocoagulation is well established as an effective treatment for PDR and macular edema, although its mechanisms of action are poorly understood. When edema involves the center of the macula, the 2-yr risk of moderate visual loss (a doubling or more of the visual angle) is —25%, and photocoagulation reduces this risk to — 10%. Because retinal thickening is difficult to detect with conventional direct ophthalmoscopy, patients with any hard exudates in the posterior pole or any decrease in visual acuity should have an ophthalmologicai evaluation. A history or presence of vitreous hemorrhage or the presence of new vessels on the retina or optic disc also mandates prompt ophthalmologicai attention. The 2-yr risk of severe visual loss (visual acuity worse than 5/200) is —25% in eyes with new vessels on the optic disc or vitreous hemorrhage, and photocoagulation reduces this risk to —10%. Vitrectomy techniques have improved considerably in recent years; this procedure has become safer, and its indications have broadened. NATURAL COURSE OF DIABETIC RETINOPATHY— The natural course of diabetic retinopathy is best understood in relationship to five fundamental pathological processes: 1) formation of retinal capillary microaneurysms, 2) excessive vascular permeability, 3) vascular occlusion, 4) proliferation of new blood vessels and accompanying fibrous tissue on the surface of the retina and optic disc, and 5) contraction of these fibrovascular proliferations and the vitreous ( 1 7). Microaneurysms The retinal capillary microaneurysm is the hallmark of diabetic retinopathy and its earliest reliable sign. Histologically, microaneurysms appear initially as hypercellular saccular outpouchings from the capillary wall, seen best with the trypsin digest technique of Kuwabara

DIABETES CARE, VOLUME 15,

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and Cogan (8), in which retinal tissue is digested away from the vascular network, which can then be stained and examined as a flat mount (8). Studies with this technique have shown that loss of the intramural pericytes of the capillaries, development of acellular (nonperfused) capillaries, and microaneurysm formation are the earliest morphological abnormalities (Fig. 1) (9-13). The sequence of these changes is not clear; some observers suggest that pericyte loss occurs first, others that capillary closure may be the earlier event (9,14). Few human autopsy eyes with very early retinopathy have been studied, but in experimental diabetic retinopathy in dogs, it appears that pericyte loss usually precedes the development of microaneurysms and acellular capillaries (13). Angiographically, microaneurysms appear to precede capillary nonperfusion, but the resolution of angiography is probably not sufficient to recognize capillary loss at its earliest stage (15). Mechanisms suggested for microaneurysm formation have included vasoproliferation, weakness of the capillary wall (perhaps from loss of pericytes), abnormalities of the adjacent retina, and increased intraluminal pressure, but no convincing evidence exists for any of these alternatives (9,14,16,17). Early in their evolution, microaneurysms are seen with direct ophthalmoscopy as tiny dots of the same deep red color as the retinal veins. At this stage, the wall of the microaneurysm is completely transparent, and only the blood within its lumen is visible, as is the case for normal retinal vessels. Ophthalmoscopically visible microaneurysms commonly vary in diameter from —15 to 60 jim, i.e., from one-eighth to one-half the diameter of a normal retinal vein at the disc margin, but occasionally may be larger (the dimensions used herein are based on the commonly used clinical convention of considering the diameter of the average optic disc to be 1500 (xm, although 1800-1900 |xm may be a better estimate) (18,19). To determine oph-

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1992

thalmoscopically whether a given red spot is a microaneurysm or a punctate hemorrhage is often difficult. Most round red dots with smooth edges fill during fluorescein angiography, proving that they are microaneurysms; some that do not fill can be shown to be microaneurysms packed with erythrocytes by clinicohistopathological correlation (20). When only occasional microaneurysms are present, they may be overlooked easily. Clinically, little or no harm is done by such an error, because follow-up of patients with only occasional microaneurysms differs little from that of patients free of any retinal abnormality (a careful ophthalmoscopic examination every year or so). For this same reason, it seems pointless to use fluorescein angiography clinically for early detection of retinopathy in patients who have been shown to be free of it by an ophthalmoscopic examination. When angiography demonstrates microaneurysms in such patients, their number is usually limited to one or two, a clinically unimportant finding (15). Microaneurysms may show little change over periods of several years, or their walls may become thickened, sometimes sufficiently to occlude their lumens (20). As the wall of a microaneurysm thickens, it becomes less transparent, and its color changes from the bluish-red of venous blood through shades of orange, which offers little contrast with the fundus background, to the yellowish-white color of hard exudate. During the reddish-orange stage, the wall of the microaneurysm, seen on edge, may be visible as a white ring surrounding the blood in its lumen (Fig. 2). Excessive vascular permeability When the number of microaneurysms in an eye exceeds 10, fluorescein angiography usually demonstrates retinal capillary abnormalities, consisting of capillary dilation, capillary nonperfusion (capillary dropout), and/or focal fluorescein leakage from microaneurysms or more diffuse leakage from capillaries (15).

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Diabetic retinopathy: a clinical overview

t \

/

I \

Figure 1—Saccular capillary microaneurysm in a trypsin digest preparation of dog retinal vessels after 60 mo of ALK-induced diabetes. Most capillaries are hypocellular and some are acellular. Vertical arrow indicates pericyte nucleus, oblique arrow a degenerating pericyte on the way to becoming a ghost. Oval nuclei are those of endothelial cells. Courtesy ofR.L. Engerman.

With ophthalmoscopy, such eyes usually can be seen to have progressed beyond the microaneurysm-only stage, with development of retinal hemorrhages and/or hard exudates, or more advanced lesions (see below). Hard exudates are composed mainly of lipid, most of which presumably has leaked from the plasma across the excessively permeable walls of microaneurysms and adjacent leaky capillaries. Hard exudates may be sprinkled across the fundus in no particular pattern, but more often are arranged in partial or complete rings, each ring marking the circumference of a roughly circular zone of thickened (edematous) retina that surrounds one or more microaneurysms (Fig. 2). The lipid presumably re-

1846

mains dispersed within the retina in the edematous zones and becomes deposited at their edges as water and other small molecules are resorbed across the walls of surrounding, more normal capillaries. The posterior pole is the most common location of retinal edema and hard exudates, and when the retina within a disc diameter of the center of the macula is involved (macular edema), visual acuity is threatened. However, it does not actually become impaired until the center of the macula is involved. If the center is not involved by a plaque of hard exudate and if thickening here is mild, visual loss may be slight and may go unnoticed by the patient for a long time, especially if vision in the fellow eye is good.

Retinal edema is not easy to recognize with direct ophthalmoscopy because the thickened retina maintains normal or near-normal transparency, and its increased thickness is difficult to appreciate without a stereoscopic examining method, such as slit-lamp biomicroscopy or stereoscopic fundus photography. Patients with hard exudates or other obvious retinal lesions in the posterior pole should be referred for ophthalmological consultation, as should patients with any impairment of visual acuity uncorrected by glasses. Photocoagulation has been found capable of reducing macular edema and slowing or preventing visual loss, but is not very effective in restoring visual acuity that is

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aretinal lesions tend to disappear, leading to a featureless appearance (Fig. 5B).

Proliferation of new vessels and fibrous tissue

Figure 2—A hard exudate ring ~1.5-disc diameters in diameter is centered —1.0-disc diameter superotemporal to the center of the macula in this right eye. Part of the ring is a plaque of hard exudate just above the center of the macula. Within the ring many large microaneurysms can be seen, some with visible walls (arrows). They are slightly out of focus because the retina here is thickened (edematous) and the camera is focused on the surrounding retina. With stereoscopic viewing retinal thickening was obvious and could be seen to extend into the center of the macula. Courtesy of the ETDRS Research Group.

already lost (21). Thus, it is important to recognize macular edema early so that treatment can be initiated while vision is still reasonably good.

Vaso - obliteration In the earliest stages of diabetic retinopathy, individual closed capillaries can be seen histologically, but not ophthalmoscopically. As retinopathy becomes more severe, larger patches of capillary closure appear, each typically supplied by an occluded terminal arteriole. Such patches are often marked initially by overlying cotton-wool spots (soft exudates), which tend to fade over periods of many months (Figs. 3 and 4). Adjacent to patches of capillary closure, microaneurysms and tiny tortuous vessels are frequently seen. It is difficult to determine

DIABETES CARE, VOLUME 15,

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whether these vessels are dilated preexisting capillaries or intraretinal new vessels, and the term IRMA is used to include both possibilities (22; Fig. 3). Histologically, these vessels are hypercellular, and most observers agree that the stimulus for them and new vessels on the surface of the retina is probably partial ischemia of the inner retinal layers caused by capillary closure. In its early stages, capillary closure is most easily seen on fluorescein angiography (Fig. 5C). As capillary closure becomes extensive, dark-red blot hemorrhages often appear (Fig. 4), as does segmental dilation of retinal veins (venous beading, Figs. 3, 4, and 5A). When these lesions are prominent, NPDR is considered severe (preproliferative). When capillary closure becomes extensive, these intr-

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When new vessels appear on the surface of the retina or optic disc, diabetic retinopathy is said to have entered the proliferative stage. New vessels arise most frequently posteriorly, within 45° of the optic disc, and are particularly common on the disc itself (4,23). Eyes with new vessels on the disc are at greater risk of visual loss, and new vessels here (on or within 1-disc diameter of the disc, or in the vitreous cavity anterior to this area) are commonly designated NVD and considered separately from new vessels elsewhere (22,24-29). New vessels on the optic disc begin typically as fine loops or networks lying on the surface of the disc or adjacent retina, or bridging across the physiological cup (Fig. 5B). In their earliest stages, they may easily be mistaken for normal vessels during direct ophthalmoscopy, but when well established, are easily identified (Fig. 6). On fluorescein angiography, new vessels usually leak profusely (Fig. 5C). Early new vessels elsewhere are easily overlooked and may be difficult to distinguish from IRMA (Fig. 4). As they become larger, new vessels elsewhere are easily identified, either by their tendency to form networks or by their course across both arterial and venous branches of the underlying retinal vessels, a pattern never occurring in the normal vasculature. The most striking networks are roughly circular patches resembling carriage wheels, with vessels radiating like spokes from the center of the patch to a circumferential vessel bounding its periphery (Figs. 5A and 7). The centers of such patches often lie over retinal veins, from which the vessels appear to arise. The rate of growth of new vessels is extremely variable. In some patients, a patch of vessels may remain essentially unchanged for many months, whereas in others, a definite increase may be seen in as little as 1-2 wk. New vessels charac-

1847

Diabetic retinopathy: a clinical overview

tient is in the sitting position, the detached, more solid part of the vitreous falls downward and forward to occupy the anterior and inferior part of the vitreous cavity, with fluid vitreous filling the remainder of this cavity. This condition is termed posterior vitreous detach-

ment with collapse and can be detected with the slit-lamp biomicroscope. Posterior vitreous detachment tends to occur at an earlier age in patients with PDR. In areas free of fibrovascular proliferations, the posterior vitreous surface pulls away from the retina. Where proliferations are present, they are pulled forward, and with them the retina from which they arise, often resulting in localized areas of tractional retinal detachment (Fig. 8). The fibrovascular proliferations themselves also play an important part in the contraction process, particularly when they are extensive. In addition to producing a vector of Figure 3—Severe NPDR (superior temporal quadrant of a right eye). On the left side of the figureforce that tends to pull the retina forward are two prominent cotton-wool spots (soft exudates) with a large blot hemorrhage between them.away from the retinal pigment epitheVenous beading is present where the superior branch of the superior temporal vein passes by the upper lium and choroid, contraction of a sheet exudate. On the right side of thefigureis a faint soft exudate (arrow) with many prominent IRMA of fibrous tissue also tends to pull the near it. Courtesy of the ETDRS Research Group. surrounding retina toward the center of the sheet (tangential traction). Because fibrovascular membranes usually are centered on or near the optic disc, tangential traction often leads to displaceteristically follow a cycle of prolifera- Contraction of vitreous and ment (dragging) of the macula nasally tion and regression (3,4). Early in their fibrovascular proliferations evolution, new vessels appear bare, but Posterior vitreous detachment is a pro- toward the disc (Fig. 9) (30). later, translucent fibrous tissue often ap- cess occurring in most normal eyes durAs contraction begins, traction is pears adjacent to them and becomes in- ing or after the sixth or seventh decade. exerted on the new vessels (4,5). Preretcreasingly opaque as regression of the Its mechanism, apparently, is shrinkage inal and/or vitreous hemorrhage often new vessels occurs (Fig. 7). Usually re- of the posterior surface of the vitreous, a occurs concomitantly, probably in part gression is incomplete, but occasionally zone that has more collagen fibers than because of the traction (Fig. 5D). The blood-filled new vessels may disappear the central part of the vitreous does. severity of visual symptoms varies with altogether, being replaced by tufts of Shrinkage in the plane of the posterior the extent of the hemorrhage, from a few white tissue or networks of white lines, vitreous surface produces a vector of floating specks lasting only 1-2 h (until or occasionally leaving no trace at all. force forward away from the retina (con- the blood disperses or settles inferiorly) These fibrovascular proliferations char- veniently explained to patients and stu- to loss of all but hand movement or light acteristically become adherent to the dents by comparison with a bowl lined perception vision. It is unusual for the vitreous framework, and such adhe- with a piece of cloth that is adherent to first vitreous hemorrhage that occurs in sions remain even after the new vessels the edges of the bowl; shrinkage of the an eye to be massive, but a large hemorregress. So long as neither vitreous hem- cloth will lead it to move upward toward rhage often follows an initial small one orrhage nor contraction of the vitreous the top of the bowl). Normally the vitre- within a few days or weeks. Thus, even and/or fibrovascular proliferations oc- ous is not adherent to the retina, so that an extremely small vitreous hemorrhage curs, the new vessels remain asymptom- its posterior surface can pull away with- is an urgent indication for prompt ophatic. out causing retinal tears. When the pa- thalmological attention. The rate at

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type II diabetes) and in the non-insulintaking (type II diabetes) group. Prevalence of PDR (Fig. 11) in the younger-onset group was 0 when duration of diabetes was 50% in individuals with >20 yr duration of diabetes. In the older-onset insulin-taking group, prevalence rose fairly steadily from 2% in individuals with < 5 yr of diabetes to >25% in those with >20 yr duration of diabetes. In the non-insulin-taking group, prevalence remained —2-5%, regardless of duration. Among individuals with PDR, its severity did not appear to differ between the younger-onset and the combined older-onset groups; in each case, in the worse eye, —25% of individuals had DRS high-risk PDR, and 15% had advanced PDR (Table 1). Prevalence of macular edema did not vary as widely by diabetes type (Fig. Figure 4—Transition from severe NPDR to PDR (superior temporal quadrant of a right eye). 12), but PDR was significantly more Extensive retinal hemorrhages, venous beading, and several large faint soft exudates (just to the left common in younger-onset individuals of the center of the figure) are present. Arrows indicate tortuous small vessels that could be either with macular edema (65 vs. 36 and 19% IRMA or early new vessels on the surface of the retina. Courtesy of the ETDRS Research Group. in the younger-onset, older-onset insulin-taking, and older-onset non-insulintaking groups, respectively), and moderately extensive hard exudate was which hemorrhages clear is highly vari- rize the prevalence of any degree of retsignificantly less common (2, 9, and able, from a few weeks when they are inopathy and PDR, respectively, in a 18%, in the younger-onset, older-onset small to months, years, or never when population-based sample of diabetic ininsulin-taking, and older-onset non— they are large. Hemorrhages tend to re- dividuals in southwestern Wisconsin. insulin-taking groups, respectively). cur periodically, usually without any ob- Retinopathy severity was assessed in stevious precipitating event and often dur- reoscopic color fundus photographs Diabetes with onset after 30 yr of ing sleep (31,32). age is more common than the youngergraded according to the Modified Airlie onset type; however, in the population House classification (28,29). In the PREVALENCE, SEVERITY, AND from which Klein et al. (33) drew their younger-onset group, which was made PROGRESSION OF sample, these older-onset individuals up of individuals whose age at diagnosis RETINOPATHY comprised most of the total number with of diabetes was 2 LINES

duced the risk of severe visual loss to —50% of that observed in control group eyes; but this effect became apparent later, and the percentage of eyes treated that benefitted (the arithmetic treatment difference) became smaller as retinopathy severity decreased. On the basis of this analysis and the harmful effects of treatment summarized in Table 6, the DRS confirmed its earlier conclusion that for eyes with high-risk characteristics (high-risk PDR), the chance of benefit from treatment (e.g., reduction of the 2-yr risk of severe visual loss from ~26 to 11%) clearly outweighed its risks of harm and recommended prompt photocoagulation for most such eyes. When the DRS first reported strong evidence of a beneficial treatment effect and modified its protocol to en-

courage treatment of those control group eyes that were then at the high-risk stage, it also modified its treatment protocol. Because the harmful effects of argon treatment were less, it was given preference, and, in the hope of further reducing these effects, treatment was more often divided between two or more episodes several days apart (41). However, because the beneficial effect observed with the xenon protocol, in which focal treatment of new vessels on the optic disc and elevated new vessels elsewhere was not used, had been the same or greater than that with the argon protocol, these technically difficult parts of the argon protocol were dropped. This modified technique was much like the argon laser panretinal photocoagulation advocated by Little et al. (117) and similar to the extensive milder xenon treatment advocated by Meyer-Schwickerath et al. (128) and Okun et al. (129). A similar technique was specified for the ETDRS: 1200-1600 500-jim 0.1-s argon laser burns placed about one-half bum diameter apart, extending from the posterior pole to or beyond the equator, and applied in two or more episodes (Fig. 5E). In the ETDRS, this scatter treatment is combined with moderate direct treatment of new vessels on the surface of the retina (105), but many experienced observers use scatter treatment alone. New vessels usually regress sub-

tantially within a few weeks after photocoagulation. When they do not, or when they recur after initial regression, there is generally ample room between the scars of the initial treatment to add more (Fig. 8), and this is usually effective (128, 130-134). Eyes with small patches of residual new vessels often do well without additional treatment, remaining free of serious vitreous hemorrhage for many years. For eyes with severe NPDR or early (non- high-risk) PDR, the DRS concluded that either of two approaches was satisfactory, and that DRS results were not helpful in choosing between them: prompt photocoagulation or careful follow-up with prompt photocoagulation if high-risk PDR developed. In the ETDRS, these alternatives (designated early photocoagulation and deferral of photocoagulation, respectively) were compared in eyes with mild to severe NPDR or early PDR. One important outcome measure used in the ETDRS was the first occurrence of either severe visual loss, as defined in the DRS, or vitrectomy. These events were combined because progression to a stage requiring vitrectomy may be considered a bad outcome for ETDRSeligible eyes, and because presumably many or most eyes selected for vitrectomy before the occurrence of severe visual loss (68% of the 243 ETDRS eyes

Table 7—Cumulative 5-yr rates of severe visual loss or vitrectomy, and relative risks for the entire period of follow-up, by baseline retinopathy status and treatment group TREATMENT GROUP DEFERRAL

EARLY PHOTOCOAGULATION

RELATIVE RISK

BASELINE RETINOPATHY MILD TO MODERATE NPDR WITH MACULAR EDEMA SEVERE NPDR OR EARLY PDR WITH MACULAR EDEMA MODERATE TO SEVERE NPDR OR EARLY PDR

N AT

5-YR

N AT

5-YR

BASELINE

RATE ( % )

BASELINE

RATE ( % )

INTERVAL)

1448 1090 1173

2 6 4

1429 1103 1179

4 10 5

0.55 (0.33-0.94) 0.68 (0.47-0.99) 0.78 (0.47-1.29)

(99%

CONFIDENCE

WITHOUT MACULAR EDEMA

Data from ETDRS 1991 (42).

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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 the early photocoagulation groups compared with the deferral groups over the entire follow-up period, are shown in Table 7. The first two rows include eyes with macular edema, subdivided by retinopathy severity. As would be anticipated, 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 groups, early treatment reduced the event rate by —50%, but the percentage of eyes treated that benefitted (the arithmetic treatment difference) was only 2-4%. The third row of the table includes all eyes without macular edema regardless of retinopathy severity (eyes with mild NPDR, i.e., level 31 in Table 1, were not eligible unless macular edema was present), and, as might be expected, outcome here was intermediate between that in rows 1 and 2. Some harmful effects of scatter photocoagulation were observed in the ETDRS, an early decrease in visual acuity (a doubling or more of the visual angle at the 4-mo visit in about 10% of eyes assigned to early photocoagulation, compared with —5% of eyes assigned to deferral) and some decrease in visual field. It was 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 (levels 53E and 65 in Fig. 15, in which 50% of deferral group eyes developed high-risk PDR within 12-18 mo), and that it usually should not be delayed when the high-risk stage is present (42). In its early stages, before the anterior chamber angle is completely closed, neovascular glaucoma can be arrested by scatter photocoagulation, or by

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peripheral retinal cryocoagulation, if the media are too cloudy for photocoagulation, and this is an urgent indication for such treatment, regardless of the severity of retinopathy (135,136). Photocoagulation for diabetic macular edema In the ETDRS, 50% of the eyes that had mild to moderate NPDR and macular edema at baseline and were assigned to early photocoagulation were assigned to immediate treatment with a combination of focal and grid photocoagulation for the macular edema, and scatter treatment was withheld unless severe NPDR or PDR developed. This group of eyes was compared with eyes within the same retinopathy category assigned to deferral. An important outcome measure used in this comparison was a decrease of three or more lines on a specially designed eye chart, on which a three-line decrease in any part of the chart amounts to a doubling of the visual angle, e.g., a change from 20/20 to 20/40 or from 20/50 to 20/100. After 3 yr of follow-up, 24% of the 526 deferral-group eyes had experienced a three or more line loss compared with 12% of the 268 eyes assigned to immediate focal/grid photocoagulation. Among eyes in these groups with visual acuity of worse than 20/40 at baseline, —40% of eyes assigned to early photocoagulation showed improvement of one line or more compared with 20% of eyes assigned to deferral, but few eyes in either group improved by as much as three lines (21). No adverse effects of focal/grid photocoagulation on visual acuity, visual field, or color vision were detected. Figure 23 shows the percentages of treated- and control-group eyes with a visual acuity decrease of three or more lines at each follow-up visit for three subgroups defined by macular edema severity in baseline stereoscopic fundus photographs (110). In the mildest subgroup, eyes with macular edema that was not clinically significant, i.e., eyes in which neither retinal thickening nor hard exudates involved or threatened the

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center of the macula (upper panel), little difference was noted between treated and control groups, but in the other two subgroups treatment reduced visual loss by >50% at most visits. The risk of visual loss in untreated eyes was greater when the center of the macula was involved (lower panel). Prompt photocoagulation is usually indicated for such eyes. When the center is threatened, but not yet involved, visual acuity is usually good and either prompt treatment or deferral of treatment with careful follow-up may be appropriate. If major leakage sites are close to the center, increasing the risk that it may be damaged directly during treatment or indirectly by the spread of retinal pigment epithelial degeneration into it from nearby scars some years later, deferral may be preferable. If a large plaque of hard exudate threatens the center by its close proximity, prompt treatment may be the wiser course, particularly if the principal leakage sites are >500 |im from the center. Such decisions may be difficult, and it is helpful if the ophthalmologist who will be responsible for treatment, when and if it is conducted, has been able to follow the patient for some time before a decision is necessary. Vitrectomy In pars plana vitrectomy, small instruments inserted into the eye —3-4 mm behind the comeoscleral limbus are used to cut and remove the vitreous, vitreous hemorrhage, and fibrovascular membranes that are distorting or detaching the retina or threatening to do so. When initially developed by Machemer in 1970, the principal indication for this procedure was long-standing vitreous hemorrhage (137). In the two decades that have elapsed since its introduction, the operation has undergone many improvements, and indications have expanded (138). Improvements include better instrumentation (e.g., smaller instruments, more versatile scissors for cutting membranes, and adaptation of the argon laser to allow photocoagula-

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Diabetic retinopathy: a clinical overview

Macular Edema— Not Clinically Significant

30

O

1.96* Z< 2.58

A

2.58 i Z< 3.29

*

Z 2 3.29

20 10 n 12

24

36

Macular Edema—Clinically Significant without Center Involvement

12

24

36

Macular Edema—Clinically Significant with Center Involvement 30 20 10

12 24 Months of Follow-up

36

Figure 23—Comparison of percentages of eyes that experienced visual loss of three or more lines (equivalent to at least doubling of the initial visual angle) in eyes classified by seventy of macular edema in baselinefundus photographs and assigned to either immediate photocoagulationfor macular edema (broken line) or deferral of photocoagulation unless high-risk characteristics develop (solid line). From ETDRS Research Group (110).

tion during surgery) and more advanced techniques (e.g., multiple incisions to allow use of two instruments simultaneously, use of intravitreal air or other fluid to push detached retina back into place, and improvement of irrigating so-

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lutions so that they do not cause clouding of the lens necessitating its removal during the procedure). The risks of serious complications (chiefly retinal detachment secondary to retinal breaks occurring during surgery and postoperative

neovascular glaucoma) have been reduced from >20% to - 1 0 % (139,140). Traditionally, extensive vitreous hemorrhage that fails to clear spontaneously after >6 mo and retinal detachment involving the center of the macula have been the two principal indications for vitrectomy in diabetic retinopathy. More recently, vitrectomy is sometimes advised within 1-2 mo after the occurrence of severe hemorrhage, particularly when new vessels and fibrous proliferations behind the hemorrhage are known from a previous examination to be extensive or are considered likely to be so on the basis of type and duration of diabetes. The DRVS, a randomized clinical trial sponsored by the National Eye Institute, found that for patients with type I diabetes (

Diabetic retinopathy. A clinical overview.

After an introductory summary, this review presents a description of the natural course of diabetic retinopathy, then briefly considers selected patho...
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