Graefe's Archive' Ophthalmology for Clinical and Experimeiltal

Laboratory investigations

© Springer-Verlag 1990 Graefe's Arch Clin Exp Ophthalmol (1990) 228 : 12(~t23

Oxygen and diabetic eye disease* Einar Stefansson Department of Ophthalmology, Duke University Medical Center, Durham, NC, USA Abstract. In 1956, Wise suggested that retinal hypoxia stimulated retinal neovascularization in the ischemic proliferative retinopathies. Although not directly proven, this theory is strongly supported by a wealth of circumstantial information. Two treatment modalities, vitrectomy and panretinal photocoagulation, have been shown to be effective against retinal neovascularization in diabetics. Both of these treatment modalities improve retinal oxygenation, and we propose that this is the mechanism through which they halt retinal neovascularization. The mechanism for improving retinal oxygenation is different for the two treatment modalities. In the case of panretinal photocoagulation, the new oxygen supply comes from the choroid through the laser scar in the outer retina. In the case of vitrectomy, it comes from the vitreous cavity itself, but the end result is the same. We have expanded Wise's hypothesis to include these two treatment modalities, which were not known at the time of Wise's original paper.

Introduction The theory that retinal tissue hypoxia plays a role in proliferative diabetic and other neovascular retinopathies was formulated by Wise [24] in 1956. This author reviewed the clinical features of many of the proliferative retinopathies, such as diabetic retinopathy and branch retinal vein occlusion, and proposed a unifying theory. He suggested that retinal hypoxia was a common feature of the proliferative retinopathies and that it stimulated retinal neovascularization through an unknown factor that he termed factor X. Great interest has been shown in the chemical intermediary, factor X, and several laboratories have studied retina-derived growth factors. More recently, renewed attention has been paid to the retinal tissue hypoxia that Wise proposed as the trigger and common stimulator of retinal neovascularization. We review the evidence for the thesis that tissue hypoxia stimulates neovascularization in the proliferative retinopathies in general and in diabetic retinopathy and branch retinal vein occlusion in particular. * Presented at the 8th International Congress of Eye Research Symposium on Retinal Oxygenation, San Francisco, September 1988. Supported by Research to Prevent Blindness, The National Eye Institut (R01-7001) and the Veterans Administration Present address and address for offprint requests: University of Ice-

land, Landakotsspitali, Reykjavik, Iceland

Clinical evidence for retinal hypoxia in proliferative retinopathies There is no direct evidence confirming the presence of retinal hypoxia in proliferative retinopathies such as diabetic or branch retinal vein occlusion. However, strong circumstantial evidence showing a disturbance or lack of blood flow in the retina in these disorders suggests but does not prove the existence of retinal hypoxia. Cogan et al. [3] used the trypsin digestion technique to examine the retinal vasculature in patients with diabetic retinopathy. These authors demonstrated patches of nonperfused (ghost) capillaries in the retina of diabetics. They also noted proliferative changes, microaneurysms and endothelial hyperplasia in retinal vessels adjacent to these areas of nonperfused capillaries. Fluorescein angiography has confirmed the presence of nonperfused areas in the retina in diabetic retinopathy [16], branch retinal vein occlusion and other proliferative retinopathies. The finding of capillary nonperfusion or retinal ischemia suggests that retinal hypoxia may be present. However, the tissue compensates for ischemia through increased blood flow in adjacent blood vessels as well as atrophy of the ischemic tissue to reduce its oxygen consumption, and this may partially or completely relieve the hypoxic state. The retinal blood flow in diabetic retinopathy is increased in the early stage and decreased in late proliferative retinopathy [7, 8]. Blood flow studies have also shown decreased autoregulation of the retinal circulation in severe diabetic retinopathy [7]. These findings are certainly consistent with the presence of retinal hypoxia. However, it is difficult to relate the blood flow studies directly to the presence or absence of retinal hypoxia. For example, the decreased retinal blood flow might be primary and cause retinal hypoxia, or it could be an autoregulatory reaction to a hyperoxic state resulting, for instance, from decreased oxygen consumption by the tissue. A similar argument can be made about increased retinal blood flow.

Experimental studies Diabetic animals

Ernest et al. [5] measured retinal oxygen tension in alloxandiabetic dogs and found no difference in retinal oxygen tension between normal and diabetic dogs. Stefansson and associates [19, 21] have also measured the preretinal oxygen tension in alloxan-diabetic dogs and pancreatectomized,

121 diabetic cats. All of the studies have shown that the retinal oxygen tension is similar in both diabetic and normal animals. However, dogs and cats do not develop diabetic retinopathy to the same degree as people, and these studies in relatively short-term diabetic animals do not definitely rule out retinal hypoxia in the human disease. Branch retinal vein occlusion Branch retinal vein occlusion is more easily simulated in the animal model than is diabetic retinopathy. Pournaras and associates [15] found retinal hypoxia in miniature pigs with experimental branch retinal vein occlusion. We have created branch retinal vein occlusion in the cat [20], which resulted in a sharp drop in preretinal oxygen tension from 20 _ 7 to 6 _ 5 torr (mean_+ SD, n = 10). The retinal hypoxia was sustained for at least 1 week, after which collateral formation and tortuosity similar to that observed in human branch retinal vein occlusion was seen in the area of the occluded venule.

Treatment mechanisms

Wise's theory is that retinal hypoxia leads to neovascularization in the retina, and it follows logically that relief of the retinal hypoxia should stop the neovascular stimulation. Two treatment modalities, panretinal laser photocoagulation and vitrectomy, stop retinal neovascularization. Although both procedures were developed empirically, recent studies have shown that both relieve retinal hypoxia. This strongly supports Wise's hypothesis that retinal hypoxia is important in the proliferative retinopathies and that relief of the hypoxia stops the neovascularization. Panretinal laser photocoaguIation Panretinal laser photocoagulation was initially applied to diabetic retinopathy in an effort to coagulate the new blood vessels in the eye [26]. Scattered photocoagulation of the retina itself was later found to suppress retinal neovascularization [4] ; the mechanism of this effect remained unknown. Early researchers suggested that panretinal photocoagulation worked through "ablating sick and hypoxic" retinal tissue to prevent it from producing a vasoproliferative factor, in accordance with Wise's theory. However, this explanation did not fit well with the histologic finding that retinal photocoagulation primarily destroyed the outer retina [26], whereas the inner retina, which is the site of proliferation in diabetic retinopathy, was left intact after mild or moderate photocoagulation. The search was on for mechanisms by which photocoagulation could indirectly affect the inner retina. In the mid-1970s, Snyder and associates [17] first suggested the possibility that retinal photocoagulation could change inner retinal metabolism. These authors applied scattered photocoagulation to the retina in rabbits and looked at the ATP/ADP ratio in the inner retina. This ratio was increased following panretinal photocoagulation, indicating that the oxidative state of the retina was improved. A few years later, Wolbarscht and Landers [25] and Weiter and Zuckerman [22] suggested on theoretical grounds that panretinal photocoagulation improves the oxygenation of the inner retina.

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Fig. 1. Schematic drawing that demonstrates oxygen fluxes to the inner retina. After laser photocoagulation, the flux comes through the photocoagulation scars from the choroid. Following vitrectomy, dissolved oxygen is transported in fluid in the vitreous cavity and can be transported from oxygen-rich areas to oxygen-poor, ischemic retinal areas. RPE, Retinal pigment epithelium In 1981, we showed experimentally that panretinal photocoagulation improves the oxygen supply to the inner retina in rhesus monkeys [18]. Similarly, in normal and diabetic cats [19], panretinal photocoagulation was found to improve the oxygen supply to the inner retina. In monkeys and cats, autoregulation of the retinal circulation decreases the blood flow in response to improved oxygen supply. Because of this, the improved oxygenation resulted in only a slightly increased oxygen tension when the animals were breathing 21% oxygen. However, the photocoagulation resulted in much higher oxygen tension over the treated retina when the animals were breathing 100% oxygen, which maximally constricts the blood vessels and neutralizes autoregulatory vasoconstriction in the retina, enabling the full effect of the choroidal oxygen flux to be seen. In the miniature pig, panretinal photocoagulation raises the preretinal oxygen tension even when the animal is breathing 21% oxygen [12]. Similarly, in the avascular rabbit retina, panretinal photocoagulation raises the preretinal oxygen tension when the rabbit breathes 21%-32% oxygen [13]. The physiologic finding of improved oxygenation of the retina after scattered laser photocoagulation correlates well with the histologic appearance of the retina, on the one hand, and the clinically apparent vasoconstriction, decreased blood flow and regression of neovascularization, on the other. Laser photocoagulation of the retina predominantly affects the retinal pigment epithelium and the outer retina [26]. It destroys the photoreceptors, which are replaced by a glial scar. The inner segments of the photoreceptors normally have a high concentration of mitochondria and a high oxygen consumption. Normally, oxygen diffuses from the choroid to the inner segments of the photoreceptots, where it is consumed. The laser scar represents a window in the photoreceptor layer, through which choroidal oxygen can diffuse without being consumed, thus reaching the inner retina (Fig. 1). The morphologic appearance of retinal photocoagulation is consistent with the physiologic data. Increased oxygen supply to the retina results in autoregulatory vasoconstriction and decreased blood flow [10]. The choroidal oxygen flux to the inner retina after panretinal photocoagulation also results in retinal vasoconstriction and decreased blood flow [6, 9]. The degree of vasoconstriction is closely associated with the regression of neovas-

122 cularization on the disc in diabetic retinopathy [23]. This suggests a direct relationship between the physiologic effect of improved oxygenation and vasoconstriction and the clinical effect of regression of new vessels.

Vitrectomy Vitreous surgery was invented for the purpose of removing opacified vitreous gel, particularly vitreous hemorrhages in diabetic patients. Gradually, it became apparent that vitreous surgery affects neovascularization in the eye. Neovascularization of the retina stops after vitrectomy, whereas iris neovascularization is stimulated. In a 10-year follow-up of diabetic patients after vitrectomy, Blankenship and Machemer [1] showed that neovascularization of the retina stopped. Although retinal neovascularization does not progress in the posterior portion of the retina, where the vitreous gel has been removed, it may proceed under the remaining vitreous, left-over parts of the peripheral retina [11]. Blankenship et al. [2] have also shown that the risk of iris neovascularization increases substantially following vitrectomy in diabetes, especially if the crystalline lens is also removed. Two main theories have been proposed to explain the effect of vitreous surgery on ocular neovascularization. The earlier theory [14] suggested that removal of the vitreous gel and lens facilitated the diffusion of a retina-derived vasoproliferative factor from the retina to the iris, where it stimulated iris neovascularization. However, if the retinaderived growth factor is produced in the retina and diffuses to the iris, it should occur at a higher concentration at the retina than at the iris. This theory does not explain why the low concentration of the factor at the iris stimulates neovascularization, whereas the higher concentration at the retina does not. More recently, we [18, 20] attempted to correlate the effect of vitreous surgery on ocular neovascularization with its effect on ocular oxygenation. After vitrectomy and lens extraction, the anterior segment of the eye gives up oxygen to the retina. The anterior segment becomes relatively hypoxic and neovascularization develops, whereas the retinal oxygenation improves and neovascularization is halted. We measured the oxygen tension in the anterior chamber of cats following removal of the vitreous and/or crystalline lens. The anterior-chamber oxygen tension averages 34 +_7 torr and drops to 22_+ 6 torr if the vitreous and lens are removed. If the retinal circulation is compromised by occlusion of the retinal vessels, the oxygen tension falls further to 17_+4 torr [18]. In the one-chamber eye, fluid currents transport oxygen from the relatively oxygen-rich anterior segment to the vitreous cavity, which normally has a lower oxygen tension. The oxygen supply of the retina is improved while oxygen is being "stolen" from the anterior segment, This corresponds nicely with the suppression of neovascularization at the retina and its development at the iris in vitrectomized diabetic patients. When the vitreous gel is removed and the vitreous cavity is filled with fluid, the occurrence of fluid currents in the vitreous cavity becomes possible. Oxygen and other nutrients can diffuse into the fluid from the ciliary body as well as from well-perfused areas of the retina (Fig. 1). Oxygen can be given up from this fluid to ischemic areas of the retina to improve its oxygenation and reduce retinal hypoxia in these nonperfused areas. In this way, vitrectomy

can improve the oxygenation of ischemic retina and reduce the hypoxic effect of nonperfusion, such as that seen in diabetic retinopathy or in branch retinal vein occlusion. Branch retinal vein occlusion in nonvitrectomized cats leads to significant retinal hypoxia, where the oxygen tension drops from 21 tort to an average of 6 tort. If the cat has previously undergone vitrectomy, the induction of branch retinal vein occlusion does not lead to significant retinal hypoxia and the preretinal oxygen tension drops insignificantly, from 19 to 16 torr, when branch retinal vein occlusion is induced. Vitrectomy prevents retinal hypoxia due to branch retinal vein occlusion in the cat [20]. It is reasonable to assume that vitrectomy can similarly reduce or prevent retinal hypoxia in people with branch retinal vein occlusion or patchy retinal ischemia due to diabetic retinopathy. The reduction of retinal hypoxia would be expected to reduce the neovascular stimulation according to Wise's original hypothesis.

References 1. Blankenship GW, Machemer R (1985) Long-term diabetic vitrectomy results: report of 10 years follow-up. Ophthalmology 92: 503-506 2. Blankenship G, Cortez R, Machemer R (1979) The lens and pars plana vitrectomy for diabetic retinopathy complications. Arch Ophthalmol 97:1263-1267 3. Cogan DG, Toussaint D, Kuwabara T (1961) Retinal vascular patterns: IV. Diabetic retinopathy. Arch Ophthalmol 66:100-112 4. Diabetic Retinopathy Study Research Group (1978) Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Trans Am Acad Ophthalmol 85:82-106 5. Ernest JT, Goldstick TK, Engerman RL (1983) Hyperglycemia impairs retinal oxygen autoregulation in normal and diabetic dogs. Invest Ophthalmol Vis Sci 24:985-989 6. Feke GT, Green GJ, Goger DG, McMeel JW (1982) Laser Doppler measurements of the effect of panretinal photocoagulation on retinal blood flow. Ophthalmology 89 : 757-762 7. Feke GT, Tagawa H, Yoshida A, Goger DG, Welter JJ, Buzney SM, McMeel JW (1985) Retinal circulatory changes related to retinopathy progression in insulin-dependent diabetes mellitus. Ophthalmology 92:151~1522 8. Grunwald JE, Riva CE, Sinclair SH, Brucker AJ, Petrig BL (1986) Laser Doppler velocimetry study of retinal circulation in diabetes mellitns. Arch Ophthalmol 104:991-996 9. Grunwald JE, Riva CE, Brucker AJ, Sinclair SH, Petrig BL (1986) Effects of panretinal photocoagulation on retinal blood flow in proliferative diabetic retinopathy. Ophthalmology 93 : 590-595 10. Hiekam JB, Frayser R (1966) Studies of the retinal circulation in man. Circulation 33 : 302-316 11. Lewis H, Abrams GW, Foos RY (1987) Clinicopathologic findings in anterior hyaloidal fibrovascnlar proliferation after diabetic vitrectomy. Am J Ophthalmol 104 :614-618 12. Molnar I, Poitry S, Tsacopoulos M, Gilodi N, Leuenberger PM (1985) Effect of laser photocoagulation on oxygenation of the retina in miniature pigs. Invest Ophthalmol Vis Sci 26:1410-1414 13. Novack R, Stefansson E, Hatchell DL (1989) Photocoagulation of avascular retina: oxygenation and ultrastructure. Invest Ophthalmol Vis Sci 30 [Suppl 3]:273 14. Patz A (1980) Studies on retinal neovascularization. Friedenwald lecture. Invest Ophthalmol Vis Sci 19:1133-1138 15. Pournaras CJ, Ilic J, Tsacopoulos M, Leuenberger PM, Gilodi N (1985) Experimental branch vein occlusion: modifications of preretinal PO2, in the affected territory. Invest Ophthalmol Vis Sci 26[Suppl 3]:246

123 16. Shimuzu K, Kobayashi Y, Muraokaa K (1981) Mid-peripheral fundus involvement in diabetic retinopathy. Ophthalmology 88 : 601-612 17. Snyder DA, Miech RP, Tamura H, Geltzer AI (1976) Effects of laser photocoagulation on adenine nucleotides in rabbit retinas. Arch Ophthalmol 94:1004~1008 18. Stefansson E, Landers MB III, Wolbarsht MI (1981) Increased retinal oxygen supply following pan retinal photocoagulation, vitrectomy and lensectomy. Trans Am Ophthalmol Soc 79 : 307-334 19. Stefansson R, Hatchell DL, Fisher BL, Sutherland FS, Machemer R (1986) Panretinal photocoagulation and retinal oxygenation in normal and diabetic cats. Am J Ophthalmol 101:657-664 20. Stefansson E, Novack RL, Hatchell DL (1988) Hypoxia in branch retinal vein occlusion is prevented by vitrectomy. Invest Ophthalmol Vis Sci 29 :220 21. Stefansson E, Peterson JI, Wang YH (1989) Intraocular oxygen tension measured with a fiberoptic sensor in normal and diabetic dogs. Am J Physiol 256:H11271133

22. Weiter JJ, Zuckerman R (1980) The influence of the photoreceptor-RPE complex on the inner retina. Ophthalmology 87:1133-1139 23. Wilson CA, Stefansson E, Klombers L, Hubbard LD, Kaufman SC, Ferris FL III (1988) Optic disk neovascularization and retinal vessel diameter in diabetic retinopathy. Am J Ophthalmol 106:131-134 24. Wise GN (1956) Retinal neovascularization. Trans Am Ophthalmol Soc 54 : 729-826 25. Wolbarsht ML, Landers MB III (1980) The rationale of photocoagulation therapy for proliferative diabetic retinopathy: a review and a model. Ophthalmic Surg 11:235-245 26. Zweng HC, Little HL, Peabody RR (1969) Laser photocoagulation and retinal angiography. Mosby, Philadelphia, pp 25, 29

Received May 24, 1989 / Accepted November 3, 1989

Oxygen and diabetic eye disease.

In 1956, Wise suggested that retinal hypoxia stimulated retinal neovascularization in the ischemic proliferative retinopathies. Although not directly ...
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