Review

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iabetic Retinopathy: A General Survey

GEORGE W. BLANKENSHIP AND JAY S. SKYLER

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iabetic retinopathy has become one of the major causes of legal blindness and can cause a degree of visual loss that prevents independent ambulation and even total blindness. It_ is now the second leading cause of new blindness in the United States and the leading cause in adults under age sixty-five.1"2 The tragedy of this is even more greatly magnified when one considers that those blinded by diabetes are often quite young, in their twenties or thirties. Fortunately, most patients with diabetic retinopathy do not have visual impairment. The prevalence of diabetic retinopathy is strongly and positively associated with duration of diabetes.3"5 Retinopathy is seen after a shorter duration of diabetes in older patients than in younger patients, but prevalence figures for all ages seem to merge after ten years duration of diabetes.3 Thus, the overall prevalence of clinically detectable retinopathy in patients under age thirty at diagnosis is less than 10% if the duration of the disease is less than ten years, while the prevalence for patients over age 60 at diagnosis is 35-40% with the same duration.4 After fifteen years duration of diabetes, 60-70% of patients will have retinopathy.3""5 The true prevalence of diabetic retinopathy remains unknown, however, and statistical data are complicated by a variety of factors. Most studies focus on juvenile-onset diabetes, or of diabetes of long duration, and do not include the large numbers of elderly patients with mild diabetes without retinopathy. Studies have usually been done in referral centers for either diabetes or eye disease. Thus, the prevalence of the disease is probably more common than appreciated by most physicians, but not as common as thought by most ophthalmologists who are biased by the type of diabetic patients referred for ophthalmic care. This review will provide a general description of the ophthalmoscopic findings, level of visual function, pathophysiology, and treatment of the various forms of diabetic

retinopathy. For convenience, we have divided diabetic retinopathy into four categories. CLINICAL AND PATHOLOGICAL FEATURES

Background diabetic retinopathy. Probably 80 per cent of eyes

afflicted with diabetic retinopathy have only this mild form of the disease, background or nonproliferative retinopathy, although all diabetic retinopathy starts this way. These eyes will have good visual function unless there is some ophthalmic problem other than the retinopathy. The ophthalmoscopic findings are illustrated in figures 1 and 2, and have been more extensively illustrated elsewhere.5"8 These changes are primarily confined to the posterior portion of the fundus and are easily seen with the direct ophthalmoscope through a dilated pupil. All of these changes are confined to the retina itself. Microaneurysms appear as small, well-defined red dots about the size of smaller retinal vessels. These aneurysms will often appear to have a shiny surface (a light reflex indicating their spherical form), tend to be sharply defined, and are round in shape. They may be associated with a surrounding ring of retinal hemorrhages and hard exudates. Two forms of retinal hemorrhages are found in background diabetic retinopathy. Both are confined to the retina. The characteristic form is the punctate, or dot hemorrhage, which is usually round, although with diffuse borders. These small dot hemorrhages may be difficult to distinguish from microaneurysms. They are located in the deep or inner layers of the retina. Flameshaped (or blot) hemorrhages, located in the superficial or nerve fiber layer of the retina, may be seen as well. These retinal hemorrhages may vary in size, from being barely visible with the ophthalmoscope, to involving an area equivalent to the size of the disc. Hard exudates appear as discrete yellowish-white refractile particles ("white dots")* characteristically seen scattered around microaneurysms, im-

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as it passes through the retinal circulation. Normal retinal vessels prevent extravasation of the fluorescein, but the water-soluble fluorescein will diffuse through damaged vessels, and thus will accumulate at specific sites of leakage. Fluorescein angiography will also outline perfused microaneurysms and allow detection of sites of vascular obstruction. The clinical course of background retinopathy is quite variable. The retinal vascular abnormalities are constantly changing with a reabsorption of the hemorrhages and exudates, while at the same time new abnormalities are developing. There may be almost complete clearing of background changes, or they may progress to the point of causing a loss of visual function. The eyes should be observed on a regular basis so that treatment can be given when indicated. Background diabetic retinopathy with macular edema (maculopFIG. I. Background diabetic retinopathy without macular involvement showing retinal microaneurysms, intraretinal hemorrhages, hard exudates, and soft exudates.

plying that there is a leakage of extracellular fluid from the aneurysms. These are true exudative deposits, resulting from extravasation of cellular breakdown products, plasma proteins, and lipids. They will sometimes become confluent to form rings of exudates called circinate complexes. Soft exudates or "cotton wool patches" are seen less frequently, appearing as soft grey-white areas with ill-defined borders ("white blots"), and are caused by retinal infarction secondary to small vessel occlusions. The retinal veins often show generalized dilatation, but may also have segmental dilatations giving the involved vein the appearance of link sausages. These dilated veins will often be associated with perivascular retinal hemorrhages which often extend out into the midperipheral fundus. Probably the most frequent retinal vascular abnormalities are the intraretinal microvascular abnormalities (IRMA), 6 which represent dilated capillary shunt vessels. Microscopic examination of retinas with background retinopathy reveals obliteration and occlusions of retinal capillaries,9"11 surrounding areas of dilated capillary shunt vessels,12 generalized loss of supportive mural cells (pericytes),13"14 microaneurysms occurring primarily on the venous side of the capillary circulation early in the disease,9'n'13~15 increased thickness of the capillary endothelial cell basement membrane,16"18 and an unusual amount of arteriosclerotic disease.9'15 The retinal vascular changes of background diabetic retinopathy can be easily seen with direct ophthalmoscopy, but become even more apparent with fluorescein angiography.10*11'19 This procedure is performed by an injection of 10 per cent sodium flourescein into the antecubital vein of the arm, while the fundus is observed through a monochromatic filter transmitting only the wavelengths of the fluorescein dye 128

athy). Probably five per cent of diabetic eyes will at some time have macular involvement with background diabetic retinopathy, which some authors have called diabetic maculopathy.20"23 When the macula becomes involved, there is a loss of central visual activity. This usually results in impaired vision (in the range of 20/30 to 20/200), but can progress to legal blindness. Indeed, macular complications account for the majority of cases of visual impairment of this degree. Fortunately, the peripheral retina is usually not involved and maintains sufficient peripheral vision to permit independent ambulation. The typical retinal changes of background diabetic retinopathy are generally (but not invariably) present, with involvement of the macula as well as the rest of the posterior fundus, as shown in figure 2. The macular area becomes thickened due to the edema and loses its transparency. Frequently, hard exudates are deposited in the center of the macula, and occasionally cystic spaces develop in this area. The ophthalmoscopic findings are subtle and may be easily

FIG. 2. Background diabetic retinopathy with macular involvement showing microaneurysms, intraretinal hemorrhages, and hard exudates.

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missed. Sometimes decrease in visual acuity may be the only demonstrable feature on routine examination. Slit-lamp contact lens examination may be required to demonstrate the macular edema. This type of involvement is most common in maturity onset diabetes. It is usually not accompanied by proliferative retinopathy. Fluorescein angiography is particularly useful in this stage of retinopathy. Most patients will demonstrate areas of nonperfused capillary beds with profuse leakage of fluorescein, which is indicative of leakage of serum.24""25 Rarely, maculopathy and profuse fluorescein leakage may occur with good capillary perfusion.26 Visual acuity and prognosis is often poorest in those who have few ophthalmoscopically visible lesions but who show widespread and severe leakage on fluorescein angiography.

proliferative" lesions indicating non-perfused retina, which when present imply an increased likelihood of neovascularization.30 These include: multiple cotton-wool spots in the absence of hypertension; large sheets of multiple hemorrhages (both dot and blots) usually in clusters; venous loops and beading; white lines replacing peripheral retinal vasculature (arterioles and venules); and a featureless, atrophic retina darker in appearance than normal.

Proliferative diabetic retinopathy. Only 3 — 10 per cent of

diabetic patients will develop proliferative retinopathy. The disease differs from background retinopathy in that the process almost invariably extends from the retina into the vitreous cavity, although occasional patients have only proliferation on the retinal surface. Ophthalmoscopically, the eyes will continue to show the changes characteristic of background diabetic retinopathy. The hallmark of proliferative diabetic retinopathy, however, is the presence of neovascularization on the inner retinal surface or on the back of the formed vitreous, as illustrated in figure 3. The neovascularization will appear as a network of tortuous vessels that may vary in size from being barely visible with the ophthalmoscope to being as large as the larger retinal vessels. These vessels are usually located in the posterior fundus in the vicinity of the disc or over the major vascular arcades. The vessels need a supportive framework upon which to develop, and initially proliferate in the space between the formed vitreous and the inner retina. As the vitreous detaches and separates from the retina, the vessels are usually pulled into the vitreous cavity, and this traction on these fragile vessels often results in a hemorrhage located in the preretinal space created between the retina and vitreous (and limited by the retrovitreal or subhyaloid membrane), or into the vitreous itself. The increased traction on these vessels can also elevate and detach the retina in the area surrounding the origin of the neo| vascularization. | Pathologically, the progression from background to proliferative retinopathy is characterized by proliferation of endothelial cells from the diseased retinal vessels through the inner retinal layers into the vitreous cavity.13"14'27 The supportive framework of glial cells also proliferate with the endothelial cells into the vitreous cavity, and gives the proliferation a fibrotic appearance. Neovascular formations always are associated with large areas of non-perfusion, and profusely leak fluorescein dye.28"29 Kohner notes that there are a number of "pre-

FIG. 3. Proliferative diabetic retinopathy showing surface retinal neovascularization over the superior portion of the disc with preretinal and vitreous hemorrhage.

Visual function in proliferative diabetic retinopathy remains good, unless there is coexistent disease, macular edema, involvement of the macular area by vitreous hemorrhage, or detachment of the macula—the complications of proliferative retinopathy that can result in a marked loss of vision. Central visual acuity is affected when the involvement is in the macular area, while peripheral vision is affected when the complications involve the more peripheral retina. Prognosis is thus considerably better when there is only peripheral neovascularization. In contrast, when neovascularization involves the disc, there is usually relentless progression to visual impairment, although this progression is generally slow (i.e. perhaps a 40 per cent chance of visual loss in one year, and a 60—70 per cent chance of visual loss in five years, if untreated). A very small group of patients will have a rapidly progressive form of proliferative retinopathy ("florid" retinopathy), which is bloody and blinding, usually within one year.31"32 These patients are usually less than thirty years of age and have very poor diabetic control. They have rapid development of multiple areas of capillary nonperfusion, sudden appearance of multiple cotton-wool spots (indicating arterial occlusion), dilated veins with reduplication, and rapidly progressing proliferative changes. An example is illustrated in figure 4.

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Proliferative diabetic retinopathy with severe vitreous involve' ment (advanced diabetic eye disease). Probably only 1-3 per

cent of diabetic eyes will have a progression of their proliferative retinopathy to the point of developing dense vitreous hemorrhages or large traction retinal detachments. These severe complications are associated with profound loss of vision, usually to the point of preventing independent ambulation. The ophthalmoscopic examination of the fundus is prevented when a dense vitreous hemorrhage is present (figure 5). When a retinal detachment is present, it is observed as an elevated vascularized membrane positioned in the vitreous cavity. PATHOGENESIS

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he exact etiology and pathogenesis of diabetic retinopathy has yet to be defined. A number of potential contributing factors have been identified, but their relative importance and sequence of interaction are unclear. A comprehensive review of these potential pathogenetic mechanisms is beyond the scope of this article. Rather, we will provide one formulation that appears logical to us and is not inconsistent with available data. It has been proposed that the development of an hypoxic retina is the primary factor leading to diabetic

retinopathy.33 A variety of metabolic factors may contribute to hypoxia. In vitro studies have demonstrated lactic acid accumulation in diabetic retinas, particularly in the presence of high ambient glucose concentrations.34 Decreased erythro cyte 2,3-diphosphoglyceric acid (2,3-DPG) levels are seen in poorly controlled diabetes, as are increased concentrations of hemoglobin AjC. 35 " 37 Both of these changes result in increased hemoglobin affinity for oxygen, which could produce tissue hypoxia,36'38 although it is not clear that this mechanism is responsible for the development of hypoxia. Nevertheless, most investigators accept that hypoxia ultimately does develop and plays a central role in the further pathogenesis of diabetic retinopathy. One consequence of hypoxia is microvascular dilatation, presumably resulting from local autoregulatory mechanisms.39 With capillary dilatation, there is a decrease in retinal transit time40"41 with an increase in blood flow.40"43 The role of the mural cells (pericytes) in the pathogenesis of early retinopathy is unclear. There is no question that selective loss of these cells is an early pathologic feature of retinopathy.13"14 Their speculated function is the regulation of tone and luminal size of retinal capillaries. Their loss may thus contribute to the microvascular dilatation.12 The mechanism by which these cells are damaged may be related to their ability to accumulate sorbitol when grown in culture.44 Sorbitol accumulation clearly can account for damage in other tissues45 and may thus lead to mural cell death.

FIG. 4- "Florid" diabetic retinopathy in a 21-year-old girl, which had rapid progression from essentially no retinopathy to blindness over a fivemonth period.

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becomes thick-walled, finally hyalinized, and eventually completely obliterated. Whether endothelial cell proliferation is initiated by a hypoxic stimulus is unknown. It is generally accepted that neovascularization develops as a consequence of retinal hypoxia.60 Clearly, all disorders in which neovascularization is seen, are associated with retinal hypoxia.61 In retinal branch vein occlusion62 and in diabetic experimental animals,40'63 it has been demonstrated that the non-perfused retina is responsible for stimulating neovascularization. Further support for the role of retinal hypoxia in triggering neovascularization is the regression of central neovascularization following peripheral panretinal photocoagulation.64"66 This retinal ablation presumably converts the hypoxic retina to an anoxic retina, thus reducing vascular demand. How the hypoxic stimulus for neovascularization is mediated is unclear. It has been suggested that there may be a FIG. 5. Advanced proliferative diabetic retinopathy with neovasculari' lation over the disc and dense preretinal and vitreous hemorrhage vasoproliferative substance or angiogenesis factor liberated by which obscures most of the posterior fundus. ischemic retina.67"68 Preliminary evidence also reveals that there may be specific inhibitors of vasoproliferation produced by the vitreous.67 It is thus possible that neovascularization Another early feature of diabetic retinopathy is increased may result from an imbalance between vasoproliferative capillary permeability. This appears to be secondary to the substances and their inhibitors. opening of the intercellular tight junctions present in Thus, our current formulation of diabetic retinopathy endothelial cells. Normally these tight junctions form an ef- assigns the development of retinal hypoxia the central role fective "blood-retinal barrier" that prevents capillary leakage. in the pathogenetic sequence. A variety of factors may The breakdown of this blood-retinal barrier has been demon- contribute to the development of hypoxia—metabolic strated both pathologically46 and clinically by use of fluores- factors, increased platelet aggregation, increased blood cein dye,47 although the mechanism responsible for the viscosity. Some of these latter factors lead to capillary breakdown is unknown. closure and obliteration of retinal vessels. Retinal hypoxia is Thickening of capillary basement membranes is another thus aggravated. Hypoxia itself leads to cellular dysearly finding in diabetic microangiopathy.16"18 It has been function of both endothelial cells (manifested by increased suggested that such thickening may be a result of increased permeability and leakage) and of mural cells (eventuating in capillary permeability, by allowing leakage of macromole- mural cell loss). Compensatory mechanisms of endothelial cules that interfere with basement membrane degradation.48 cell proliferation ensue, resulting in microaneurysm formaRetinal capillary occlusion is another important feature of tion and later in neovascularization. The hypoxic stimulus diabetic retinopathy.8"12 A number of abnormalities have for such compensatory mechanisms may be mediated by been demonstrated in individuals with diabetic retinopathy, an imbalance between vasoproliferative stimulatory and inwhich may contribute to capillary closure. These include hibitory factors. Fibrous tissue proliferation accompanies neoincreased platelet aggregation .49-51 increased plasma vascular proliferation. Ultimately, there may be fibrous tisviscosity52 54 with elevation of a number of acute phase sue contraction, with concomitant contraction of the plasma proteins, including fibrinogen;54 decreased fibrinolytic vitreous to which it is related. 55 56 58 activity; and increased erythrocyte aggregation. " With capillary occlusion, hypoxia is probably aggravated further. Three mechanisms have been suggested for the development of capillary microaneurysms. They may result from TREATMENT i of vascular tone due to mural cell loss, with subrophylaxis. A subject of continuing debate is the Kquent outpouching of the capillaries.12 Alternatively, question of the relationship of blood glucose tfiey may occur in response to hypoxia, representing an control to the development of retinopathy. This abortive attempt at neovascularization.59 The most recent subject has been recently reviewed,69"72 and the Studies suggest that there may be an evolutionary cycle American Diabetes Association has issued a policy statement of microaneurysm formation.19 These studies show that the advocating careful control of blood glucose.73 The various initial stage results from proliferation of endothelial cells, studies find a correlation between good diabetic control and with development of a thin-walled aneurysm. This eventually less frequency, severity, and/or rate of progression of

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We have already indicated that enhanced platelet agretinopathy.4'74 83 Unfortunately, all of the available studies suffer flaws in design, most being either retrospective or gregation has been demonstrated in diabetic patients, particnonrandomized. One recent, much heralded study82 also suf- ularly in the presence of microangiopathy.49"51'92 Aspirin fered from a high cross-over rate among subjects, and from is a potent inhibitor of platelet aggregation.49'93 Because of what we believe to be a very poor end point, i.e. number of this and the observation that patients chronically treated microaneurysms. We have already discussed the life cycle with aspirin have a decreased frequency of retinopathy,94 it of microaneurysms19 and have indicated that these may wax has been suggested that aspirin might be beneficial in the and wane in a constantly changing pattern. Nevertheless, prevention of progression of diabetic retinopathy.92>95~96 the bulk of studies do find the correlations indicated. Therefore, aspirin will be evaluated in a controlled clinical Further, a recently reported study examining retinopathy in trial, in the National Eye Institute's Diabetic Retinopathy dogs with alloxan diabetes, prospectively followed for five Study, Phase II. years, demonstrated a clear increase in retinopathy in poorly The Diabetic Retinopathy Study, Phase II, will also controlled dogs and protection from retinopathy in well evaluate the role of photocoagulation as therapy of backcontrolled dogs.84 ground diabetic retinopathy. Background diabetic retinopathy with macular edema The totality of studies leads us to believe that control likely has an important relationship to retinopathy, but that (maculopathy). Both laser and light (xenon arc) photoconvincing evidence of a cause and effect relationship is coagulation have been used to create retinal scars which, lacking. Further, there are clearly exceptions in both di- when located around areas of vascular leakage, will somerections— i.e., well controlled patients with severe times reduce the amount of leakage.21~26'97 The aim of such retinopathy and poorly controlled patients who escape any treatment is to slow or stop further visual loss. Two of the significant retinopathy. Two clinical points emerge from this. studies have used a randomized design for symmetric First, we believe that it is beneficial to strive to achieve the maculopathy, treating one eye and not treating the fellow best control possible in any given patient, recognizing that eye.24*97 These did demonstrate some improvement in visual there is individual variation in what degree of control is acuity. Marked improvement or complete resolution of edema readily attainable. Second, we believe that patients with is a common morphologic observation. The degree of funcretinopathy must not be made to feel guilty about their tional improvement, however, is not as striking and may be earlier control, whatever it has been. This is extremely disappointing. The lack of success is usually related to the important in a patient with threatened visual loss. Thus, extent of vessel disease. Thus, when there is generalized we accept the conclusions of the available data in our involvement, particularly within one disc diameter of the approach to diabetic control (particularly in juvenile macula, or if there is cystoid accumulation of fluorescein diabetes), while acknowledging the imperfection of that same dye, treatment is not likely to be beneficial.25"26 Prognosis data in our approach to patients with impending blindness. is probably best when areas of fluorescein leakage are disAnother factor that must be considered is the control of crete and capillary loss is not severe, particularly if located coexisting hypertension. Some authors have suggested that temporal to the macula. To provide more definitive answers diabetic patients who have concomitant hypertension have with regard to the efficacy, timing, and extent of treatment a greater frequency of diabetic retinopathy81'85 or of severe with laser and light photocoagulation for maculopathy, a diabetic retinopathy.78'86 The association in the Pima Indians controlled prospective trial will soon be instituted by the is particularly striking.85 Others have felt that the associ- National Eye Institute as Phase II of the Diabetic ation may only be with linear hemorrhages.87 Although a Retinopathy Study, which includes the investigation of the definite association remains to be proven, we believe that role of aspirin therapy. Proliferative diabetic retinopathy. The major treatment there is sufficient suggestive evidence to advocate that coexistent hypertension be carefully controlled in diabetic pa- modality in use today for proliferative diabetic retinopathy is photocoagulation. Such therapy involves the destruction tients. Background diabetic retinopathy. No treatment has been of retinal tissue and/or blood vessels by either the focused shown to be clearly beneficial for background retinopathy. light from a xenon arc or a laser beam (figure 6). In the It should be noted, however, that this type of retinopathy latter circumstance, the argon laser is most commonly used, does not generally effect vision, so that treatment would because the absorption by hemoglobin is approximately 70 per only be aimed at preventing further progression of cent in the argon wavelengths; thus, vascular obliteration is possible. Such is not the case with the ruby laser, because retinopathy. One agent that has undergone clinical trials is calcium there is virtually no absorption of its red color by hemoglobin. dobesilate, an agent which decreases capillary fragility.88~91 The argon laser differs from the xenon arc in that the laser Although some investigators have claimed that this agent beam is much smaller in size, and has the potential, therefore, may have beneficial effects for retinopathy, the data are of being used closer to the macula and disc than the wider beamed xenon arc can be used.98"101unimpressive in our view. 132

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wo major approaches to photocoagulation treatment have been used: focal treatment and panretinal photocoagulation. Focal treatment involves the direct coagulation of neovascular foci. A variant of focal treatment involves identification of the feeder vessel of a frond of neovascularization, and coagulation of the feeder vessel first, and then the frond. This reduces the risk of hemorrhage from the vessels at the site of photocoagulation.102 Panretinal photocoagulation involves widespread ablation of peripheral retina, except in the region of the macula and disc (figure 7). Although the mechanism by which panretinal photocoagulation exerts its effects is unknown, current theory is that such widespread destruction of retinal tissue converts an ischemic hypoxic retina into anoxic scar tissue, thus reducing the hypoxic stimulus for neovascularization. Whether this is through reduction of production of vasoproliferative stimulatory factors,67"68 or some other mechanism, is not known. Nevertheless, such peripheral panretinal ablation often does lead to regression of central neovascularization. It should be noted, however, that such peripheral retinal destruction obviously carries with it attendant side effects, including peripheral field loss.103 Although photocoagulation therapy for proliferative diabetic retinopathy has been the subject of a variety of reports, we will discuss only the results of two controlled clinical trials, the National Eye Institute's Diabetic Retinopathy Study64"65 and the British Multicentre Randomised Controlled Trial.66 In these prospective studies, one eye was randomly selected to receive treatment, with the other eye being followed as a control. In the American study, masked techniques were used to evaluate the level of visual function in each eye, and the anatomical changes which took place after one eye was treated. In the British

FIG. 6. The argon instrument system.

in use with the slit lamp delivery

FIG. 7. Proliferative diabetic retinopathy after pan retinal laser photocoagulation therapy, as recommended by the Diabetic Retinopathy Study.

study, xenon arc photocoagulation was used, using a focal approach, with some patients receiving panretinal ablation as well. In the American study, one of two treatment modalities, xenon arc or argon laser, was assigned randomly. With both treatment modalities, panretinal photocoagulation was used in conjunction with focal treatment of surface neovascularization. Additionally, in the argontreated eyes, there was focal treatment of neovascularization on the optic disc. The results of the Diabetic Retinopathy Study revealed that treatment was beneficial in all stages of the disease in reducing the occurrence of severe visual loss and in reducing progression to more severe stages of proliferative retinopathy as judged by fundus photographs. Occurrence of "severe visual loss" (defined as visual acuity less than 5/200 at two or more consecutively completed four-month follow-up visits) 36 months after entry into the study was found to be 26.4 per cent for untreated eyes and 10.5 per cent for treated eyes. There was a slightly lower incidence of such severe visual loss in xenon-treated eyes than in argon-treated eyes. The xenon-treated eyes, however, had a greater degree of visual field loss and of treatment-induced decrease in visual acuity, than did the argontreated eyes. Thus, follow-up will continue to determine if there are significant differences between these treatment modalities. A very significant level of benefit was seen in subcategories of eyes with three "high-risk characteristics." These characteristics are: (1) neovascularization on or within one disc diameter of the optic disc, in which the area of neovascularization is equal to or exceeds one-fourth disc diameter in size; (2) any eye with neovascularization on or within one disc diameter of the optic disc that has had a recent preretinal or vitreous hemorrhage; and (3) any

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eye with neovascularization peripheral to the disc of greater than one-half disc diameter in area, where there is also recent preretinal or vitreous hemorrhage. The benefit in these groups of eyes was such that the protocol was changed to require consideration of photocoagulation for initially untreated eyes with those high-risk characteristics.64"65 The British study also found significant benefit of treatment of eyes with neovascularization on the optic disc.66 The American study did not have sufficient evidence to support a recommendation for treatment for eyes without high-risk characteristics. Such is the subject of continuing investigation. Pituitary ablation has been advocated in the past for the treatment of proliferative diabetic retinopathy.104 Only two controlled studies have been carried out, and these do indeed show some benefit from treatment.105"106 In our opinion, however, the benefit is outweighed by the side effects of hypopituitarism. The only possible exception is in the treatment of rapidly progressive florid retinopathy, where one study has shown pituitary ablation to be the only treatment modality with benefit.31 Proliferative diabetic retinopathy with severe vitreous involvement (advanced diabetic eye disease). In the past, there was little

treatment for eyes that had progressed to this extensive involvement. In the early 1970s, however, Machemer and associates developed an operative procedure that allows removal of the vitreous hemorrhage and the traction which produces the hemorrhage and retinal detachments. 107~108 The pars plana vitrectomy procedure consists of inserting a small cutting instrument through the ciliary body into the vitreous cavity (figure 8). The vitreous infusion suction cutter (VISC) cuts and aspirates from the eye small pieces of vitreous along with hemorrhage and traction-producing neovascular proliferations. The eye is refilled with a salinelike solution and when successful, creates a transparent vitreous cavity and removes the traction-producing proliferation. This then results in improved visual function for the eye. In our series of one hundred consecutive patients, major visual improvement was achieved in 49 per cent of eyes, and there was an overall success rate of 53 per cent. 109 Eyes with only vitreous hemorrhages did better (71 per cent) than eyes with posterior retinal detachments. There was no new tissue proliferation in any operated eye.109 Peyman and coworkers have reported similar results,110 using a similar instrument developed by them. n 0 The National Eye Institute has initiated a prospective, randomized, controlled clinical trial of vitrectomy in the treatment of diabetic retinopathy.111 This Diabetic Retinopathy Vitrectomy Study is comparing early (within one to six months after onset of vitreous hemorrhage) and late (deferred for one year) vitrectomy. This multicentered controlled trial is also examining the effects of vitrectomy as a prophylactic procedure in proliferative diabetic retinopathy with good visual function. Although our report of ten such patients showed improvement in 134

FIG. 8. The vitreous infusion suction cutter (VISC) inserted through the pars plana into the vitreous cavity for removal of vitreous /lemorrhage and traction secondary to advanced proliferative diabetic retinopathy.

visual acuity and limitation of progression in nine of the patients,112 we would await the results of the controlled trial before reaching definitive conclusions about the role of vitrectomy in these early cases. CONCLUSIONS

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or the diabetic population at large, diabetic retinopathy poses the threat of blindness. It is now the leading cause of new blindness among young adults in the United States. Yet, for the individual patient with diabetic retinopathy, progress has been made in developing treatment modalities that can arrest the disease process in a substantial proportion of patients, if identified early and used properly. For the physician caring for diabetic patients, diabetic retinopathy must be regularly sought by periodic funduscopic examinations through dilated pupils. Specialized ophthalmic advice should be sought when diabetic retinopathy is identified. For the ophthalmologist, subcategories of disease that have been shown to benefit from photocoagulation or vitrectomy should be identified, and such treatment implemented by an experienced operator. Patients with other subcategories of retinopathy should be considered for enrollment in the multicentered cooperative clinical trials. The real challenge of diabetic retinopathy, however, is for the basic investigators—biochemists, ophthalmologists, and internists. The challenge is to better understand the fundamental mecha-

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nisms responsible for diabetic retinopathy, so that specific preventive measures can be introduced, and the threat of diabetic retinopathy removed. From the Departments of Ophthalmology, Medicine, and Pediatrics, the Bascom Palmer Eye Institute, and the Diabetes Research Unit, University of Miami School of Medicine, Miami, Florida. Address reprint requests to George W. Blankenship, Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami School of Medicine, 900 N.W. 17th Street, Miami, Florida 33136. REFERENCES 1 Kahn, H. A., and Moorhead, H. B.: Statistics on Blindness in the Model Reporting Area 1969-1970. (DHEW Publication N o . NIH 73-427). Washington, D. C , Government Printing Office, 1973. 2 Kahn, H. A . , and Miller, R.; Blindness caused by diabetic retinopathy. A m . J. Ophthalmol. 78: 5 8 - 6 7 , 1974. 3 Kahn, H. A . , and Bradley, R. F.: Prevalence of diabetic retinopathy. Brit. J. Ophthal. 59: 3 4 5 - 4 9 , 1975. 4 Burditt, A. F., Caird, F. I., and Draper, G. J.: T h e natural history of diabetic retinopathy. Q. J. Med. 37: 3 0 3 - 1 7 , 1968. 5 Caird, F. I., Pirie, A . , and Ramsell, T. G.: Diabetes and the Eye. Oxford, Blackwell Scientific Publications, 1968. 6 Goldberg, M. R., and Fine, S. L., Eds.: Symposium on the Treatment of Diabetic Retinopathy. (DHEW Publication No. PHS 1890) Washington, D. C., Government Printing Office, 1968. ' Duke-Elder, S., and Dobree, J. H.: System of Ophthalmology, Volume X. Diseases of the Retina. St. Louis, C. V. Mosby, 1967, pp. 4 0 8 - 4 5 . 8 Lynn, J. R., Snyder, W. B., and Vaiser, A . : Diabetic Retinopathy. New York, Grune and Stratton, 1974. 9 Ashton, N . : Arteriolar involvement in diabetic retinopathy. Br. J. Ophthalmol. 37: 2 8 2 - 9 2 , 1953. 10 Scott, D. J., Dollery, C. T., Hill, D. W., et al.: Fluorescein studies of diabetic retinopathy. Br. Med. J. J: 8 1 1 14, 1964. 11 Kohner, E. M., Dollery, C. T . , Patterson, J. W . , et al.: Arterial fluorescein studies in diabetic retinopathy. Diabetes 16: 1-10, 1967. 12 Cogan, D. G., and Kuwabara, T.: Capillary shunts in the pathogenesis of diabetic retinopathy. Diabetes 12: 2 9 3 - 3 0 0 , 1963. 13 Cogan, D. G., Toussaint, D., and Kuwabara, T.: Retinal vascular patterns. IV. Diabetic retinopathy. Arch. Ophthalmol. 66: 3 6 6 - 7 8 , 1961. 14 Yanoff, M.: Ocular pathology of diabetes mellitus. A m . J. Ophthalmol. 67: 2 1 - 3 8 , 1969. 15 Ballantyne, A. J., and Loewenstein, A . : Diseases of the retina. ;I. The pathology of diabetic retinopathy. Trans. Ophthalmol. iSoc. U. K. 63: 9 5 - 1 1 5 , 1943. 16 Yamashita, T., and Becker, B.: Basement membrane in hui man diabetic eye. Diabetes 10: 167-74, 1961. 17 Toussaint, D., and Dustin, P.: Electron microscopy of normal [and diabetic capillaries. Arch. Ophthalmol. 70: 9 6 - 1 0 8 , 1963. 18 Bloodworth, J. M. B.: Diabetic microangiopathy. Diabetes 12: |99-114, 1963. 19 DeVenecia, G., Davis, M., and Engerman, R.: Clinical

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