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RUBEOSIS IRIDIS AND GLAUCOMA ASSOCIATED WITH SICKLE CELL RETINOPATHY: ALIGHT AND ELECTRON MICROSCOPIC STUDY MORTON

F.

GOLDBERG, MD

MARK O. M. Tso, MD CHICAGO, ILLINOIS

The ultrastructure of rubeosis iridis in sickle cell-hemoglobin C disease is described for the first time. Findings included open interendothelial cell junctions, intraendothelial cytoplasmic attenuations (fenestrations), and pericyte formation. The ultrastructural appearance of rubeosis iridis gives no clue to the underlying etiology and is similar to that reported in rubeosis associated with diabetes mellitus, central retinal vein occlusion, and uveitis. The electron microscopic findings explain the functional incompetence of rubeotic vessels that are manifested by transmural leakage of fluorescein. COMPLICATIONS caused by sickled erythrocytes have been extensively described in the retina l - 4 and have been attributed to ischemia and hypoxia. The anterior segment of the eye may also show sequelae of hypoxia in sickle cell disease. This report documents extensive rubeosis iridis, degeneration of the trabecular meshwork, and absolute glaucoma in a case of sickle cell-hemoglobin C (hemoglobin SC) disease.

Submitted for publication Oct 4, 1977. From the Department of Ophthalmology, Univer· sity of Illinois Eye and Ear Infirmary, Chicago. Presented at the Eighty·second Annual Meeting of the American Academy of Ophthalmology and Otolaryngology, Dallas, Oct 2·6, 1977. Reprint requests to University of Illinois Eye and Ear Infirmary, 1855 W Taylor St, Chicago, IL 60612 (Dr Goldberg).

CASE REPORT A 47-year-old black man with hemoglobin SC disease had unremitting pain in his blind right eye (OD), despite treatment with a retrobulbar injection of alcohol; the eye was enucleated. The patient had nrst been seen about ten months previously with spontaneous hyphema, extensive rubeosis iridis, mature cataract OD, and an intraocular pressure (lOP) of 40 mm Hg. Medical therapy had been ineffective in reducing his lOP, and he had undergone a series of three cyclocryotherapy treatments during the following year. The lOP had remained 24 to 30 mm Hg. The pupil was maximally dilated (10 mm), secondary to extensive ectropion uveae. Gonioscopy had shown complete, permanent closure of the anterior chamber angle with extensive peripheral anterior synechiae for 3600 • Laboratory studies, including a glucose tolerance test, were all normal, except for a borderline serum alkaline phosphatase value. The enucleated eye was bisected equatorially and immediately immersed in 2% buffered glutaraldehyde. Anterior chamber angle structures (including Schlemm's canal), trabecular meshwork, ciliary body, and iris, were dissected from different quadrants of the eye. Some of the tissues were embedded in paraffin; others were postnxed in Dalton's chrome osmium solution for 90 minutes, and, after dehydration in a graded series of alcohol of increasing concentrations and after passage through propylene oxide, were embedded in an araldite-based agent (Durcupan ACM). Specimens were then sectioned III to 21l thick and stained with toluidine blue for light microscopic study. Ultrathin sections were stained with uranyl acetate and lead citrate and examined with a transmission electron microscope. The paraffin-

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embedded tissues were sectioned and stained for the Prussian-blue reaction, for the periodic acid-Schiff reaction, and with hematoxylin-eosin.

GROSS EXAMINATION

The enucleated eye was average in size and transmitted light normally. An exuberant pannus was visible at the limbus. The pupil measured 10 mm. The short and atrophic iris leaflet was displaced forward to form peripheral anterior synechiae circumferentially. The lens was in place but showed cortical opacification. Focal atrophy of the ciliary processes, associated with multiple depigmented patches in the pars plana region, was noted. The vitreous was condensed near the ora serrata. The peripheral retina appeared atrophic and mottled, and the retinal vessels presented as whitish lines. A blacksunburst lesion was distinguishable in the equatorial region. The optic disc was deeply cupped. Choroidal and scleral findings were unremarkable. MICROSCOPIC EXAMINATION

A vascular pannus was present at the limbus. There was advanced ectropion uveae and the iris leaflet, which was folded anteriorly, was adherent to the posterior surface of the cornea in the form of peripheral anterior synechiae (Fig 1). New vessels grew along the superficial layer of the disfigured iris leaflet, and the corneal endothelial cells extended posteriorly to cover the anterior surface of the iris. Mod~r­ ate disruption of the iris musculature and pigment epithelium was exhibited. The trabecular meshwork was totally covered by the anterior synechiae, and the trabe-

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cular beams appeared sclerotic (Fig 2). The ciliary processes were atrophic and moderately hyalinized, and the ciliary muscle lacked most of the circular and oblique bundles. There were focal disruptions of the ciliary pigmented and nonpigmented epithelium at the pars plana and pars plicata regions. Posterior migration of the lens epithelium at the equatorial region and abundant Morgagni's globules in the cortex were visible. The nucleus of the lens stained homogeneously and showed sclerotic changes. Ganglion cells were absent from the entire retina, and there was moderate gliosis of the nerve fiber layer of the retina (Fig 3, top). The retinal blood vessels had thickened walls with some vessels demonstrating occluded lumens. In most of the retina at the posterior pole, there was also loss of the inner plexiform layer and reduction of cells in the inner nuclear layer. Other areas exhibited additional focal loss of the outer nuclear layer with mild swelling of the retinal pigment epithelium (Fig 3, bottom). At the equator and periphery of the retina were focal areas showing necrosis of pigment epithelium and scattered pigment-laden macrophages in the subretinal regions, but the outer nuclear layer remained intact (Fig 4, top). In other areas, reduction of the retina to a thin glial membrane was observed (Fig 4, bottom). Focal disruptions of the internal limiting membrane, associated with extension of glial tissue into the vitreous cavity, were also noted (Fig 5). Bruch's membrane was intact. While the choriocapillaries and choroidal stroma appeared unremarkable at the posterior pole by light microscopy, the choriocapillaries were severely attenuated and focally absent in the equatorial and peripheral fundus. Some sickled

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Fig 1.-Top, Advanced ectropion uveae (arrows) in iris. Mesodennalleaflet of iris is folded anteriorly and is adherent to posterior surface of cornea forming peripheral anterior synechiae (toluidine blue, X40). Bottom, New vessels (long arrows) grow from native iris blood vessels (B) toward anterior surface of disfigured iris leaflet. Corneal endothelial cells (arrowheads) extend posteriorly to cover anterior surface of iris (toluidine blue, X300).

erythrocytes were observed within the blood vessels of the iris and ciliary body. There was mild staining in macrophages in the iris and ciliary body, in the nonpigmented ciliary epithelium, and in astrocytes

in the nerve fiber layer of the retina with the Prussian-blue reaction. There was, however, no positive staining reaction in the subretinal pigment-laden macrophages and the retinal pigment epithelium.

Fig 2.-Top, Trabecular meshwork (between arrowheads) is totally covered by anterior synechiae. Long arrow indicates canal of Schlemm; scleral spur (sp) (toluidine blue, greatly reduced from x 350). Middle, Trabecular beams (long arrows) are mostly devoid of endothelial cells. Occasional endothelial cells (arrowheads) can still be seen (greatly reduced from X5,300). Bottom, Cells with phagocytosed pigment granules (long arrows) are observed in region of trabe· cular meshwork (greatly reduced from X5,300).

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Fig 3.-Top, Retina from posterior pole of eye demonstrates loss of ganglion cells, moderate gliosis of nerve fiber layer of retina. Retinal blood vessel (B) has thickened walls, occluded lumen (hematoxylineosin, X260). Bottom, Retina, detailing focal loss of outer nuclear layer (arrows), mild swelling of retinal pigment epithelium (hematoxylin-eosin, Xl90).

Fig 4.-Top, Retina, exhibiting focal necrosis of retinal pigment epithelium, scattered pigment·laden macrophages (white arrows) in subretinal region. Note preservation of outer nuclear layer, but thinning of inner nuclear layer (hematoxylin-eosin, X180). Bottom, Whole retina is reduced to glial membrane. Pigment-laden macrophages (arrows) are seen in subretinal space. Note condensation and adherence of vitreous to internal limiting membrane (hematoxylin-eosin, X180).

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Fig 5.-Disruption of internal limiting membrane (between arrowheads), growth of preretinal membrane from nerve fiber layer into vitreous cavity anterior to internal limiting membrane (toluidine blue, X300).

ELECTRON MICROSCOPIC STUDIES

were distinguished in new and native blood vessels of the iris.

The new vessels on the anterior surface of the iris were variable in appearance. In some areas, the endothelial cells showed focal attenuation (fenestration) of their cytoplasm, simulating the choriocapillaries (Fig 6 and 7). These focal attenuations were exposed directly to the iris stroma or were adjacent to a pericyte. In other areas, the endothelial cells appeared cuboidal with bilobed nuclei. Some of the cell junctions of the endotheial cells in these new vessels appeared to be open and did not form tight junctions (Fig 8). The basement membrane of the endothelial cells was thin and in some places multilaminar. The lumens of these new vessels were large and irregular or slit-like. In contrast, the endothelial cells of the native blood vessels of the iris had thick cytoplasm and had produced multiple layers of basement membrane (Fig 6). Abundant collagenous fibers were arranged concentrically around these native blood vessels. The lumens were always regular and oval when observed in cross section. Pericytes

Macrophages were frequently observed in the neighborhood of the new iris vessels (Fig 6). On one occasion, many cells were completely surrounded by basement membrane, had fine cytoplasmic filaments, an active rough-surfaced endoplasmic reticulum, and were visible in the neighborhood of the new vessels in large numbers (Fig 9). One of these cells, which appeared to be a pericyte, seemed to share a basement membrane and had a specialized contact area with one of the endothelial cells of the new blood vessels. Although the trabecular beams were mostly devoid of endothelial cells (Fig 2), pigment-laden macrophages and some remaining endothelial cells were observed. Filamentous material filled the intertrabecular spaces. The pathologic diagnoses of this case were ischemic sickle cell retinopathy secondary to central retinal artery occlusion and multiple focal areas of choroidal ischemia, rubeo-

Fig 6.-Top, New vessels on anterior superficial layer of iris. Note large, irregular capillary lumen, presence of pericytes (P). Endothelial cells (E) vary in appearance; in most regions they are cuboidal in shape with bilobed nucleus, abundant cytoplasmic organelles; in other areas, they have markedly attenuated cytoplasm (black arrows). Multiple layers of basement membrane have been laid down by endothelial cells. Few macrophages carrying phagocytosed melanin granules (M) are observed in neighborhood of new blood vessels. Endothelial cells of cornea (EN) have extended to line anterior surface of iris (greatly reduced from X3,600). Bottom, Native blood vessel of iris showing endothelial cells without focal attenuations, pericytes, and continuous basement membrane investing both pericyte and endothelial cells. Note, multiple layers of basement membrane have been laid down in perivascular space (arrows). Sickled cells of irregular shapes are visible within lumen of capillary (S) (greatly reduced from X5,lOO).

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Fig 7.-New vessels on superficial iris stroma exhibiting focal attenuations of endothelial cells directly opposed to adjacent pericyte (long arrow) and directly exposed to iris stroma (arrowhead). Multiple layers of basement membrane are evident in perivascular space (X13,OOO).

sis iridis and ectropion uveae, peripheral anterior synechiae and secondary angle-closure glaucoma, cataractous changes of the lens, focal atrophy of the ciliary body secondary to cryotherapy, and optic atrophy. DISCUSSION

Rubeosis iridis occurs following a variety of pathologic entities characterized by ocular ischemia, including central retinal vein occlusion, central retinal artery occlusion, diabetes mellitus, Eales' disease, cranial arteritis, aortic arch syndromes, carotid insufficiency, and more. 5 It is thus likely that rubeosis iridis is a relatively nonspecific response to ocular ischemia

caused by a variety of disease processes, including those affecting either the arteriolar or venular side of the vascular tree. 6 Similarly, "hemorrhagic glaucoma," caused by the rubeosis, is also nonspecific and its presence gives no precise clue to the underlying ocular or systemic disorder. 7 Other than hemoglobin se disease, there was no known predisposing factor that might have contributed to the formation of the rubeosis iridis in the present case. As a complication of sickle cell hemoglobinopathies, rubeosis iridis has been reported previously in only a small number of cases, none of which has included results of electron microscopic study. Galinos et al 8 described the angiographic

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Fig S.-Cell junctions (arrows) between endothelial cells of new iris vessels appear to be open; there is no fusion of outer leaflets of plasma membranes between endothelial cells (x17,OOO).

appearance of iris neovascularization in two cases of hemoglobin SC disease. Iris atrophy and occluded iris vessels were observed by slitlamp biomicroscopy. Profound ischemic iris atrophy and angiographic leakage of fluorescein were clinically documented in another hemoglobin SC case by Chambers et al. 9 Yanoff and Fine10 described the light microscopic appearance of rubeosis iridis in a patient with sickle cell trait who also had central retinal vein thrombosis. Vogel l l also presented light· microscopic findings of rubeosis iridis in a patient with hemoglobin SC disease and marked retinal atrophy. Boniuk and Burton 12 reported absolute glaucoma and rubeosis iridis in two pa-

tients whose eyes were enucleated (one with hemoglobin SC disease and one with sickle cell trait). Both patients also had diabetes mellitus and one had a central retinal vein occlusion. Any or all of these factors may have played a role in the pathogenesis of neovascular membranes in these irides. Boniuk and Burton 12 also attributed a causative role to the severe vaso-occlusive disease in their patients' retinas, drawing an analogy between their cases and those of "idiopathic" (that is, non sickle cell) central retinal artery occlusion contributed by Perraut and Zimmerman,13 which were also characterized by rubeosis iridis. Interestingly, it has been estimated that rubeosis iridis and

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neovascular glaucoma developed after occlusion of the central retinal artery in 1% to 5% of the cases. 14 .15 The explanation for the severe glaucoma in our patient was clearly provided by the rubeosis iridis and synechial closure of the anterior chamber angle. Extensive degeneration was documented in the trabecular meshwork by means of electron microscopy (Fig 2). The pathogenesis of the rubeosis iridis in this case appears to be similar to that reported in other occlusive vascular diseases of the eye. 5-7 Considerable morphologic evidence was present for vaso-occlusions in both the retina and the choroid (Fig 3). Severe retinal ischemia in sickle cell disease (including central retinal artery occlusion 16 ) has been previously documented by both clinical and histologic studies. Evidence for choroidal ischemia has been sparse,2-4.16-24 possibly because the rich blood supply of the choroid minimizes or nullifies many potential embolic or thrombotic events. Choroidal ischemia is unusual, regardless of the underlying systemic or ocular disease, but occasionally occurs in such disorders as severe systemic hypertension 25 (eg, Elschnig spots), amyloidosis,26 and others. The patient's eye showed definite histologic evidence of both retinal and focal choroidal ischemia. Figure 3 shows the spectrum of retinal and choroidal atrophy as a result of both acute and chronic ischemia. Loss of the ganglion cells, atrophy of the nerve fiber layer, and partial loss of the inner nuclear layer are attributable to occlusion of the central retinal artery (Fig 3, top). Focal absence of the photoreceptor cell nuclei with intact retinal pigment

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epithelium (RPE) suggests chronic hypoxia of the outer layers of the sensory retina caused by choroidal insufficiency (Fig 3, bottom). Since both the photoreceptor cells and the RPE are believed to be nourished by the choroidal circulation, and since the photoreceptor cells are farther away from the choroidal circulation than the RPE, it is expected that the photoreceptor cells die before the RPE in the face of choroidal ischemia. More difficult to explain are the focal areas in the equatorial and peripheral retina, where necrosis of the RPE and accumulation of pigment-laden macrophages in the subretinal space exist, but a relatively intact outer nuclear layer is present (Fig 4, top). Klien 26 observed focal necrosis of the RPE with retinal detachment in acute choroidal ischemia associated with malignant hypertension. The photoreceptor cells in the detached retina, shown in one of her cases, appear intact, possibly protected in some way by the serous retinal detachment. Is it possible, in analogy with Klien's findings, that the occlusion of the choriocapillaris in our case of sickle cell disease is focal and acute, resulting in necrosis of the RPE but survival of some of the photoreceptor nuclei? It is ironic that rubeosis iridis was once considered a rarity.7.27-29 Considering the current importance of rubeosis as a major cause of ocular disability,29-31 it is also surprising that so few ultrastructural studies of this disease have been reported. Electron microscopic studies of normal iris capillaries have shown the following structural features: (1) the endothelium is of the continuous

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type 32-34 with endothelial cells in betic proliferative retinopathy, Tancontinuity with their neighbors, (2) iguchi45 suggested the possibility of pericytes are present,35 and (3) a pericytes arising from endothelial basement membrane completely in- cells. Our observations of intimate vests both pericytes and endothelial contact of pericytes and endothecells. Cytoplasmic attenuations (fen- lial cells suggest such a possibility. estrations) in normal iris endothelial cells are absent. 35 -38 Although Previous electron microscopic studthere is some evidence to suggest ies on rubeotic iris vessels are limthat normal interendothelial junc- ited in number,36.46-48 and none has tional complexes in iris capillaries appeared in the American literature. are in the shape of maculae occlu- These reports, dealing with rubeodentes,34.37.39-4o most investigators sis in association with diabetes, have shown complete, barrier-type central retinal vein occlusion, and zonulae occludentes. 38.41-44 uveitis, showed several ultrastructural findings in common; namely, It is well known that new blood interendothelial gaps, widened luvessels in rubeosis iridis leak flu- mens, intraendothelial cytoplasmic orescein profusely.5 Our observa- attenuations (fenestrations), abuntions of focal attenuations of the dant cytoplasmic organelles, and cytoplasm of the endothelium and pericyte formation. These reports, open cell junctions between the en- coupled with our similar findings dothelial cells provide an explana- in sickle cell disease, suggest that tion for the functional incompetence the ultrastructural appearance of of these blood vessels. rubeosis iridis is nonspecific and not diagnostic of an underlying One interesting observation in ocular or systemic cause. In fact, this study was the presence of four the ultrastructural features of rubeto five cells in the immediate vicinotic vessels are similar to those of ity of some new blood vessels. These newly formed capillaries elsewhere cells, which were completely sur- in the body.33.47 rounded by basement membrane, showed fine intracytoplasmic filaSUMMARY ments and abundant cytoplasmic organelles. Yet, they were not arRubeosis iridis and severe glauranged in a cord-like fashion and did not surround a lumen. They coma occurred in a patient with were interspersed among the stro- sickle cell-hemoglobin C disease. mal cells of the iris and interpreted Evidence of central retinal artery to be proliferating pericytes, but the occlusion and focal choroidal inpossibility that they may be pro- farctions was found histologically. liferating endothelial cells cannot Electron microscopy of the rubeosis be ruled out. One of the cells iridis showed open interendothelial seemed to be in contact with an cell junctions, intraendothelial cyendothelial cell (Fig 9), a most toplasmic attenuations (fenestraunusual finding. Vegge 38 reported tions), and pericyte formation. These specialized contact areas between findings are similar to those reported endothelial cells and pericytes in in rubeosis iridis associated with normal iris vessels and attributed diabetes mellitus, central retinal electrical and contractile properties vein occlusion, and uveitis. Rubeoto these areas. In his study of dia- sis iridis appears to be a nonspecific

Fig 9.-New vessels on superficial layer of iris showing large lumen, focal attenuations of endothelial cytoplasm, and presence of sickle cells (S) within lumen of capillaries. Five pericytes (PI to P5) are noted in vicinity of new vessels. These cells do not arrange in cord·like fashion or surround lumen. PI appears to have arisen from endothelial cell EI (moderately reduced from X6,400). Insert shows presence of basement membrane surrounding these cells (PI, P2), which have fine intracytoplasmic filaments (arrows) and abundant cytoplasmic organelles (moderately reduced from X9,600).

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response in the iris to ocular ischemia and hypoxia. The ultrastructural appearance gives no clue to the underlying ocular or systemic cause, but explains the functional incompetence of rubeotic vessels that is manifested by transmural leakage of intravascular fluorescein.

9. Chambers J, Puglisi J, Kernitsky R, et al: Iris atrophy in hemoglobin SC disease. Am J Ophthalmol 77:247-249, 1974.

ACKNOWLEDGMENT

12. Boniuk M, Burton GL: Unilateral glaucoma associated with sickle-cell retinopathy. Trans Am Acad Ophthalmol Oto· laryngol 68:316-328, 1964.

This study was supported in part by an unrestricted research grant from Research to Prevent Blindness, Inc, New York City; a research grant from the Illinois Society for the Prevention of Blindness, Chicago; grant iP 18HL 15168 from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda; and Public Health Service grant No. 1903 from the National Eye Institute.

Key Words: Sickle cell disease; rubeosis iridis; glaucoma; diabetes; electron microscopy; central retinal artery occlusion; choroidal infarcts; ischemia; hypoxia; endothelium; pericytes.

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10. Yanoff M, Fine BS: Ocular Pathology: A Text and Atlas. Hagerstown, Md, Harper & Row, 1975, pp 340-341. 11. Vogel M: Sickle cell disease: A clinic· opathologic case report. Ophthalmologica 175:171-174, 1977.

13. Perraut LE, Zimmerman LE: The occurrence of glaucoma following occlusion of the central retinal artery: A clinicopath· ologic report of six new cases with a review of the literature. Arch Ophthalmol 61:845· 865, 1959. 14. Gold D: Retinal arterial occlusion, in Symposium: Retinal Vascular Disease. Trans Am Acad Ophthalmol Otolaryngol 38:0P· 392-0P·408, 1977. 15. Karjalainen K: Occlusion of the cen· tral retinal artery and retinal branch arteri· oles. Acta Ophthalmol, sup pI 109, 1971, pp 1·96. 16. Eagle RC Jr, Yanoff M, Fine BS: He· moglobin SC retinopathy and fat emboli to the eye: A light and electron microscopical study. Arch Ophthalmol 92:28-32, 1974. 17. Eagle RC Jr, Yanoff M, Morse PH: Anterior segment necrosis following scleral buckling in hemoglobin SC disease. Am J Ophthalmol 75:426-433, 1973. 18. Geeraets WJ, Guerry D III: Angioid streaks and sickle-cell disease. Am J Oph· thalmol 49:450-470, 1960. 19. Goodman G, von Sallmann L, Holland MG: Ocular manifestations of sickle-cell disease. Arch Ophthalmol 58:655-682, 1957. 20. Lieb WA, Geeraets WJ, Guerry DIll: Sickle·cell retinopathy: Ocular and systemic manifestations of sickle cell disease. Acta Ophthalmol, suppl 58, 1959, pp 5-45.

7. Madsen PH: Hemorrhagic glaucoma: Comparative study in diabetic and nondia· betic patients. Br J Ophthalmol 55:444-450, 1971.

21. Condon PI, Serjeant GR, Ikeda H: Unusual chorioretinal degeneration in sickle cell disease: Possible sequelae of posterior ciliary vessel occlusion. Br J Ophthalmol 57:81-88, 1973.

8. Galinos S, Rabb MF, Goldberg MF, et al: Hemoglobin SC disease and iris atrophy. Am J Ophthalmol 75:421-425, 1973.

22. Stein MR, Gay AJ: Acute chorioretinal infarction in sickle cell trait: Report of a case. Arch Ophthalmol 84:485-490, 1970.

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23. Ryan SJ, Goldberg MF: Anterior segment ischemia following scleral buckling in sickle cell hemoglobinopathy. Am J Ophthalmol 72:35-50, 1971.

36. Mukuno K, Witmer R, Gruber P: Electron-microscopic analysis of iris vessels in two cases of uveitis. Albrecht von Graefes Arch Klin Ophthalmol 202:245-257, 1957.

24. Romayananda N, Goldberg MF, Green WR: Histopathology of sickle cell retinopathy. Trans Am Acad Ophthalmol Oto· laryngol 77:0P-652-0P-676, 1973.

37. Saari M: Ultrastructure of the microvessels of the iris in mammals with special reference to their permeability. Albrecht von Graefes Arch Klin Ophthalmol 194:87-93, 1975.

25. Klien BA: Ischemic infarcts of the choroid (Elschnig spots): A cause of retinal separation in hypertensive disease with renal insufficiency: A clinical and histopathologic study. Am J Ophthalmol 66: 1069-1074, 1968. 26. Ts'o MOM, Bettman JW Jr: Occlusion of choriocapillaris in primary nonfamilial amyloidosis. Arch Ophthalmol 86:281-286, 1971. 27. Lisman JV: Rubeosis iridis diabetica. Am J Ophthalmol 31:989-994, 1948. 28. Madsen PH: Rubeosis of the iris and haemorrhagic glaucoma in patients with proliferative diabetic retinopathy. Br J Ophthalmol 55:368-371, 1971. 29. Ohrt V: The frequency of rubeosis iridis in diabetic patients. Acta Ophthalmol 49:301-307, 1971. 30. Wilensky JT, Goldberg MF, Alward P: Glaucoma after pars plana vitrectomy. Trans Am Acad Ophthalmol Otolaryngol 83:0P114-0P-121, 1977. 31. May DR, Klein ML, Peyman GA: A prospective study of xenon arc photocoagulation for central retinal vein occlusion. Br J Ophthalmol 60:816-818, 1976. 32. Simon G: Ultrastructure des capillaries. Angiologica 2:370-434, 1965. 33. Majno G: Ultrastructure of the vascular membrane, in Hamilton WF, Dow P (eds): Handbook of Physiology. Washington, DC, American Physiological Society, 1965, vol 3, chap 64. 34. Shakib M, Cunha-Vaz JG: Studies on the permeability of the blood-retinal barrier: IV. Junctional complexes of the retinal vessels and their role in the permeability of the blood-retinal barrier. Exp Eye Res 5:229234, 1966. 35. Ikui H, Mimatsu T, Maeda J, et al: Fine structure of the blood vessels of the iris: Light and electron microscopic studies (preliminary report). Kyushu J Med Sci 11:113124, 1960.

38. Vegge T: A study of the ultrastructure of the small iris vessels in the vervet monkey (Cercopithecus aethiops). Z Zellforsch Mikrosk Anat 123:195-208, 1972. 39. Saari M: Fine structure of the microcirculatory bed of the pig iris. Ann Med Exp Bioi Fenn 50:12-23, 1972. 40. Saari M, Huhtala A, Johansson G: Ultrastructural changes of the capillaries of the cat iris in experimental neuroparalytic keratitis. Albrecht von Graefes Arch Klin Ophthalmol 194:199-207, 1975. 41. Ringvold A: Electron microscopy of the wall of iris vessels in eye with and without exfoliation syndrome (pseudoexfoliation of the lens capsule). Virchows Arch (Pathol Anat) 348:328-341, 1969. 42. Smith RS: Ultrastructural studies of the blood-aqueous barrier: I. Transport of an electron-dense tracer in the iris and ciliary body of the mouse. Am J Ophthalmol 71: 1066-1077, 1971. 43. Vegge T: An electron-microscopic study of the permeability of iris capillaries to horseradish peroxidase in the vervet monkey (Cercopithecus aethiops). Z Zellforsch Mikrosk Anat 121:74-81, 1971. 44. Vegge T, Ringvold A: Ultrastructure of the wall of human iris vessels. Z Zellforsch Mikrosk Anat 94:19-31, 1969. 45. Taniguchi Y: Ultrastructure of newly formed blood vessels in diabetic retinopathy. Jpn J Ophthalmol 20:19-31, 1976. 46. Okamura R, Rohen JW: Elektronenmikroskopische untersuchungen uber die rubeosis iridis. Albrecht von Graefes Arch Klin Ophthalmol 182:53-75, 1971. 47. Tamura T: Electron microscopic study on the small blood vessels in rubeosis iridis diabetica. Jpn J Ophthalmol 13:1-14, 1969. 48. Taniguchi Y, Sameshima M: Fine structure of small blood vessels in the iris of human diabetics. Acta Soc Ophthalmol Jpn 75:1685-1697, 1971.