HEMATOGENOUS OCULAR SIDEROSIS O F LOCAL CAUSE H . S A U L SUGAR, M.D., S I D N E Y D. KOBERNICK, M.D., AND JOEL E. W E I N G A R T E N ,
Detroit, Michigan Though ocular siderosis due to iron-con taining foreign bodies is frequently men tioned in ophthalmic literature, the corre sponding ocular siderosis which results from the breakdown of hemoglobin is rela tively rare. Experience with seven such cases, including the histopathologic study of one, has stimulated presentation of this ma terial. Von Hippel, in 1894, distinguished be tween ocular siderosis due to iron foreign bodies (xenogenous) and that which follows intraocular hemorrhages (hematogenous.) 1 Systemic causes for ocular siderosis have since been found, including intravenous in jections of iron, such hematogenous causes as repeated blood transfusions, protracted hemolysis or hypersideremia due to deficient or defective hemoglobin formation (Cibis and associates 2 ), cirrhosis of the liver and hemochromatosis.8'* The cases to be described here all resulted from severe or repeated local hemorrhage within the posterior portion of the globe. They are divided according to clinical cause. Other local causes which are not included are Eales' disease and surgical hemorrhage. C A S E REPORTS
A. Diabetic retinal and vitreous hemorrhages CASE 1
M. C, a 56-year-old Negress, had been treated for diabetes with insulin for six years but was a known diabetic for 15 years. Her visual acuity was light perception and projection in the right eye and light perception temporally in the left. The right lens showed fine posterior subcapsular cataractous changes. Hemorrhage was present in the right vitreous. The left eye showed marked vit reous hemorrhage and anterior subcapsular rust like deposits (fig. 1). The ocular tension was nor mal. A diagnosis of siderosis oculi due to iron pigment from repeated vitreous hemorrhage was made. From the Departments of Ophthalmology and Pathology, the Sinai Hospital of Detroit, and Wayne State University School of Medicine.
Fig. 1 (Sugar, Kobeernick and Weingarten). Case 1. Siderotic subcapsular deposits following repeated diabetic vitreous hemorrhages. CASE 2
T. T., a 37-year-old Caucasian man, had had diabetes since the age of nine years. He noted de creased visual acuity in October, 1965. The left eye became totally blind in January, 1966. The right vision was 20/100 corrected when he was seen in September, 1966, at Detroit General Hos pital. The left eye showed total detachment of the retina. Vitreous hemorrhage was present in both eyes, more on the left. The left iris showed a hyperchromic heterochromia due to rust pigment. The right eye showed marked proliferative retinopathy. The intraocular pressure was normal. B. Central vein occlusion with vitreous hemorrhage CASE 3
C. M., a 63-year-old Caucasian woman, was first seen in September, 1959. She gave a history of a central retinal venous thrombosis one year previ ously. A massive vitreous hemorrhage was present in the left eye. The right eye was normal. Hyper tensive vascular sclerotic changes were present in the otherwise normal right eye. The right visual acuity remained 20/30 (+1.5D sph C +3.5D cyl ax 33°) but the left vision was reduced to no light perception in April, 1963. A mature cataract was present in the left eye, with rust-colored siderotic patches present under the anterior capsule (fig. 2). The ocular tension was normal. In September, 1964, the systemic blood pressure was 210/110 mm Hg. CASE 4
B. S., a 55-year-old Caucasian dentist, was ex amined in January, 1966. He had had a central vein occlusion in his right eye two and a half years previously. Four days before examination he began to have pain in the right eye. The intra ocular pressure at that time was 60 mm Hg (Schätz) and was treated with 4% pilocarpine and Diamox, 250 mg twice daily. On examination his 749
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M. F., an 81-year-old Caucasian man, was first seen in May, 1963. Since 1961 he had been treated with pilocarpine \% twice daily for glaucoma. There was never any subsequent elevation of tension. In April, 1962, the right vision was 20/25 and the left
< " * * * . ' / Fig. 2 (Sugar, Kobernick and Weingarten). Case 3. Siderotic subcapsular deposits following repeated vitreous hemorrhages associated with cen tral vein occlusion. visual acuity was reduced in the right eye to no light perception and was 20/20 in the left. Siderosis lentis and hyperchromic heterochromia were present. The intraocular pressure was 36 mm Hg, R.E., and 18 mm Hg, L.E. A vitreous hemorrhage was present. A diagnosis of hemosiderosis and secondary glaucoma was made.
Fig. 3 (Sugar, Kobernick and Weingarten). Case 5. Siderotic subcapsular deposits following repeated vitreous hemorrhages associated with central vein occlusion.
Fig. 4 (Sugar, Kobernick and Weingarten). Case 5. Limbus of globe, showing accumulation of lym phocytes and increased density of connective tissue. At upper left there is an elongated deposit of calcium. At the lower left there is a concentration of lymphocytes. (Hematoxylin-eosin, X165.)
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Fig. S (Sugar, Kobernick and Weingarten). Case 5. Ciliary body, showing dense fibrosis, decreased vascularity and atrophy of the processes. There is marked lymphocytic infiltrate throughout. Some of the epithelial cells contain hemosiderin. (See fig. 12.) (Hematoxylin-eosin, X165.)
of 20/50 was suddenly reduced to light perception due to central retinal vein occlusion. When the pa tient was examined a month later, the right vision was 20/25, corrected with +1.75D sph Z +0.25D cyl ax 145° ; there was no light perception, L.E. An incipient cataract was present in the left eye. Vitre ous haze was present, suggesting old hemorrhage. There was no visible heterochromia. The intraocular pressure remained normal. In February, 1966, het erochromia became obvious. The left iris was brown, the right blue. Definite siderosis lentis was present. In July, 1966, an acute glaucomatous episode oc curred in the left eye (fig. 3). This could not be controlled by miotics and Diamox. Because of per sistent pain the eye was enucleated. The pathologic description in this case is en larged from that of Dr. Windsor S. Davies, Kresge Eye Institue. Grossly the eyeball measured 24 mm anteroposteriorly, 23.5 horizontally and 23 mm vertically. The cornea was 11 mm horizontally, 10 mm verti cally. Microscopically the cornea shows peripheral subepithelial calcium deposition (fig. 4) and pe ripheral degenerative pannus with some lympho
cytic infiltration. Hyphema is present in the an terior chamber. The uveal tract is atrophied. A dense periph eral anterior synechia blocks the chamber angles (fig. 14). The iris substance is atrophie. Areas of prolifieration, as well as areas of cystic degenera tion of the iris pigment epithelium, are present. A rather coarse golden-brown pigment which stains positively for iron is deposited in cells in the iris (fig. 14). Similar pigment is present in the nonpigmented and pigmented ciliary epitheli um and interstitially in the ciliary body (figs. 5 and 12). The retina is detached in some areas due to processing procedures. It shows multiple proteinaceous exudates about vessels (fig. 7) and occlu sive disease involving the retinal venous system. In the periphery some vessels show no lumen but contain macrophages laden with pigment gran ules. Pigment is deposited in fibroblasts and mac rophages (fig. 6). The retina is atrophie, with gliosis, pigment migration and fine pigment depo sition in its substance. There is absence of gan glion cells and most of the outer nuclear layer. A preretinal neovascular membrane is present with
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(fig. 15) throughout the circumference of the globe, with some larger granules in macrophages in the nuclear layers of the retina, most marked in the inner (figs. 6 and 15). Scattered pigment cells of the retina also contain iron-positive mate rial which is not evident in the black and white photomicrographs. Diagnosis. Glaucoma, acute angle-closure su-
Fig. 6 (Sugar, Kobernick and Weingarten). Case 5. Section of retina, showing lymphocytic in filtration and preretinal fibrovascular membrane. Virtual disappearance of the ganglion cells and inner nuclear layer, decreased cellularity of the outer nuclear layer with pigmented macrophages just inside the pigment epithelial layer. The macrophages contain hemosiderin. (See fig. IS.) (Hematoxylin-eosin, χ330.) pigment deposits (both melanin and iron) within it (fig. 15). The optic nerve is atrophie and shows glaucomatous excavation of the optic papilla. A neovascular membrane with lymphocytic infiltration is present within the cup (figs. 10 and 16). Some vit reous hemorrhage is present. Macrophages contain ing granular pigment which does not stain positively for iron is present in the vitreous. The lens shows cataractous change, some dim inution of epithelial cells and pigment accumula tion both in macrophages and diffusely under the epithelium (fig. 13). Iron stains show an accumulation of siderotic pigment in coarse granules in the epithelial cells of the ciliary body, particularly the nonpigmented epithelium and pars plana (fig. 11), in the pig ment and muscle (especially the dilator) layers and connective tissue of the iris (fig. 14) and the retina (fig. 15). In the iridocorneal angle the pig ment is in macrophages and fibroblasts in marked amount (fig. 14). A similar picture is present in the fibrovascular membranes in the optic cup and lining the retina (figs. 6, 8 and 9). There is diffuse iron-positive material in the inner retinal layers
Fig. 7 (Sugar, Kobernick and Weingarten). Case 5. Section of retina, showing marked hyaline fibrosis around a vessel in the distorted inner plexiform and nerve-fiber layers. At left of vessel are three hemosiderin-laden macrophages. The inner nuclear layer shows depletion of nuclei with the occasional larger cells, also seen in outer nu clear layer, containing hemosiderin pigment. The scierai layers are relatively undisturbed in this section. (Hematoxylin-eosin, X65.)
Fig. 8 (Sugar, Kobernick and Weingarten). Case 5. Section through optic nervehead, showing cupping and neovascular membrane in cup. (Hema toxylin-eosin, X48.)
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perimposed on old chronic open-angle type (histo ry), cataract, old occlusion of central retinal vein, siderosis bulbi secondary to vitreous hemorrhage. C. Repeated vitreous hemorrhages due to sickle-cell hemoglobinopathy CASE 6
J. M., a 46-year-old Negro, had had episodic and then persistent loss of vision in both eyes since 19SS. He had been hospitalized and treated unsuc cessfully with steroids, Daraprim and sulfonamides because of a positive toxoplasmin skin test He developed hypertension, a diabetic glucose tol erance curve and glaucoma as a result of the steroid therapy. When he was first seen at Sinai Hospital in SepFig. 11 (Sugar, Kobernick and Weingarten). Case 5. Portion of the pars plana, showing marked iron pigmentation of the cells. All the dark material represents iron. (Prussian blue-eosin, χ165.)
Fig. 9 (Sugar, Kobernick and Weingarten). Case 5. Section adjacent to the one shown in Fig ure 8 at same magnification but stained for iron. The dark streaks show the location of iron de posits at the nervehead and in the retina. (Prus sian blue-eosin, X48.)
Fig. 10 (Sugar, Kobernick and Weingarten). Case 5. Section from left section of optic cup, showing fibrosis on the surface containing marked lymphocytic reaction with marked perivascular fibrosis and hyalinization of the vessel. There is also slight lymphocytic infiltration in the more superficial portions of the nerve but the latter is otherwise unaltered. (For comparison with fig. 16.) (Hematein, phloxine, saffron, χ165.)
tember, 1966, his corrected vision was reduced to hand movements right and 20/200 left. External examination showed a 15-prism diopter right exotropia. The conjunctiva showed no aneurysms. Posterior saucer-shaped cataracts were present in each eye with retractile orange and green opaci ties. The fundus was obscured by old blood in the vitreous except for dense chorioretinal patches in the extreme periphery. The intraocular pressure was normal. Gonioscopy showed no abnormalities. The general physical examination showed a blood pressure of 160/125 mm Hg, bilateral inguinal hernias and radiologie evidence of narrowing of the right hip space and eburnation and thinning of the right acetabulum. An electrocardiogram showed anterior heart-wall ischemia. Fasting blood sugar measured 97 mg%. Blood studies showed the hemoglobin to be 14.4 gm, hematocrit 43, red blood cells 5.50 million, leukocytes 15,000 (2% stab, 61% segmented, 33% lympho cytes, 2% monocytes and 2% eosinophiles), plate lets 99,000. The red blood cells showed marked anisocytosis and poikilocytosis with target cells. Hemoglobin electrophoresis (agar gel) showed S-C hemoglobinopathy. The VDRL test for syphilis was negative. Because of the vitreous clouding a right vitre ous replacement with 2.0 ml of saline through diathermized sciera over the pars plana was done on November 9, 1966. Material obtained at the end of aspiration was rust-colored vitreous. The vision improved to 20/200 but a month later the patient noted a decrease in vision. This was found to be due to further vitreous hemorrhage. D. Traumatic vitreous hemorrhage CASE 7
S. G., a 15-year-old Caucasian girl, was hit in the left eye with a fist while swimming. A
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Fig. 12 (Sugar, Kobernick and Weingarten). Case 5. Ciliary body and adjacent iris, showing the pigmented epithelium on the surface and granular deposits of iron in the subjacent tissues and in microphages. Iron was also present in the pigment layer but is not differentiable from the normal melanin in the black and white print. (Prussian blue-eosin, χ165.)
Fig. 13 (Sugar, Kobernick and Weingarten). Case 5. Surface layer of the lens. The black ma terial is an intense accumulation of iron pigment representative of the whole surface of the lens. The diminution of the cells is not observable with this stain. Cataractous changes were also present throughout the lens. (Prussian blue-eosin, xS40.) marked vitreous hemorrhage occurred without any hyphema. The blood did not clear rapidly. Three months later the vision was light perception and projection with this eye. Iris hyperchromia and liquefaction of the anterior vitreous with rustcovered vitreous membranes and strands de veloped. No increase in intraocular pressure was found at any time.
ternal nuclear layers and proliferation of the pigment epithelium. A microscopic pic ture resembling retinitis pigmentosa occurs. Ultimately complete retinal degeneration, optic atrophy and gliosis may occur. The hyaluronic acid of the vitreous is similarly bound by the iron, leading to vitreous con traction bands and, possibly, retinal detach ment.4 Duke was unable to find evidence of reti nal changes due to siderosis in 40 patients with systemic siderosis; in 21 of the 40 si derosis was present in the sciera and choroid.8 Glaucoma is a frequent complication, probably a result of the toxic effects on the trabecular meshwork. However, other types of glaucoma may occur. In Case 5 the
The histologie study in Case S indicates the widespread deposition of iron through out the globe. The iris, ciliary body and lens epithelium, the dilator muscle, retina and retinal pigment epithelium show the greatest amount of siderosis, but the corneal endothelial cells, the trabecular meshwork and uveal stroma may become involved. The ret ina shows iron especially in its external lim iting membrane and in the perivascular tis sue. The iron is evidently bound by the acid mucopolysaccharide in the perivascular tis sue and results in narrowing of the retinal vessels, degeneration of the internal and ex-
Fig. 14 (Sugar, Kobernick and Weingarten). Case 5. Iridocorneal angle, showing obliteration of the angle. The pigment layers contain some hemosiderin pigment. Iron pigment can also be seen in the substance of the iris, at the synechia and in the adjacent cornea. (Prussian blue-eosin, X16S.)
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patient had been treated for glaucoma for five years with pilocarpine drops. He showed no evidence of angle closure until the episode resulting in enucleation of his blind eye. Histologically the glaucoma ap pears to be acute primary angle-closure in type. In other cases the glaucoma may be associated with the ischémie rubeosis iridis related to the causative central venous occlu sion. Clinical diagnosis of siderosis in eyes with repeated vitreous hemorrhages depends on the appearance of iron-rust pigment
Fig. 15 (Sugar, Kobernick and Weingarten). Case 5. Retina stained for iron, showing the pig ment in a preretinal fibrovascular membrane. The larger agglomerations are in macrophages. In the inner retinal layers there are also diffuse, finely granular iron deposits. Some of the pigment in the pigment epithelium of the choroid is iron. Nor mal melanin is reduced in this layer. The two pig ments are not recognizable separately in the choroid in the black and white print. (Prussian blue-eosin, x50.)
Fig. 16 (Sugar, Kobernick and Weingarten). Case 5. Section of the lateral portion of the optic cup corresponds to section in Figure 10. All the dark, stippled material is hemosiderin pigment dif fusely deposited in the connective tissue and in macrophages. (Prussian blue-eosin, χ165.)
within the iris and under the lens capsule, producing the clinical picture of heterochromia iridis (at least in unilateral cases) and of siderosis lentis which was present in four of the six cases presented here. In addition to heterochromia, there is decreased pupil lary activity due to precipitation of iron in the sphincter and dilator muscles. Siderosis lentis may cause a decrease in lens fluorescence in ultraviolet light due to diffusion of iron molecules into the lens tissue.6 When a lens is made siderotic in vitro by immersion in ferric compounds and then soaked in EDTA solution to form a metal chelate compound in the medium, its fluorescence completely returns in a day or two. In an in vivo siderotic lens, the use of a chelating agent results in very slight re covery because the iron is bound as insoluble protein salts within the cells. The characteristic clinical picture of sider osis lentis, first described by Kipp in 1906,7 consists of yellow-brown, less often greenish-brown, dots arranged in the form of a wreath under the anterior capsule. The dots are usually round, less than half a mm in diameter and appear at fairly regular in tervals of a mm or two. They are usually seen after dilatation of the pupil and may be present when the lens is still transparent. However, when an iron particle has pene-
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trated the lens, a similar yellowish-brown pigment also develops in the nieghborhood of the particle. Koby8 has described biomicroscopically visible fine dots beneath the anterior cap sule, each being a discolored epithelial cell. The wreath of pigment dots described here in appeared to be formed by an accumula tion and fusion of the tiny brown dots. Velhagen9 found them in a 13-month-old child with vitreous hemorrhage and glioma. Kipp 7 noted them following intraocular hemorrhage. The reason for the location and form of the subcapsular siderotic spots is not known. Mielke10 showed that the iron granules are deposited at border surfaces, thus in the lens epithelium. In the absence of clinical evidence, only the Desferal test for increased sideruria after injection of desferrioxamine B or his tologie examination of the globe or of tissue from the vitreous make the diagnosis possi ble. From a functional viewpoint the diag nosis in suspected cases may be aided by electroretinography.12'18 Karpe reported early evidence of stimulated responses before the condition is clinically recognizable. Later the electroretinogram becomes nega tive and finally extinct, even when the retina may be functioning reasonably well.12 Treatment with desferrioxamine B intra muscularly may be useful in preventing glaucoma due to ferrotoxic effects on the corneoscleral meshwork or secondary ferro toxic glaucoma associated with rubeosis iridis.
Seven cases of ocular siderosis resulting from breakdown of hemoglobin are present ed. The histologie findings in one case, fol lowing occlusion of the central retinal vein, indicate that hematogenous siderosis is dis tributed in the same pattern as xenogenous siderosis. 18140 San Juan (21) REFERENCES
1. von Hippel, E. : Ueber Siderosis bulbi und die Beziehungen zwischen siderotischer und hämatogener Pigmentierung. Graefes Arch. Ophth. 40:123,1894. 2. Cibis, P. A., Yamashita, T. and Rodriguez F. : Clinical aspects of ocular siderosis and hemosiderosis. Arch. Ophth. 62:180, 1959. 3. Duke, J. R. : Ocular effects of systemic si derosis in the human. Am. J. Ophth. 48:628, 1959. 4. Cibis, P. A., Brown, E. B. and Hong, SM. : Ocular effects of systemic siderosis. Am. J. Ophth. 44:158, 1957. 5. Winter, F. C. : Ocular hemosiderosis. Tr. Am. Acad. Ophth. 71: 1967, in press. 6. Haruta, C. : A diagnostic method for ocular siderosis with ultraviolet light. Folia Ophth. Jap. 14:246, 1963. 7. Kipp, J. : Concerning siderosis bulbi. Am. J. Ophth. (Series 2). 23:225,1906. 8. Koby, F. E. : Slit-lamp Microscopy of the Living Eye. Blakiston, London, 1930, ed. 2. 9. Velhagen cited by Mielke." 10. Mielke, S. : Die rolle elektrochemischer Vorgänge bei der Entstehung der Linsen und Hornhautverkupferung. Graefes Arch. Ophth. 141 : 644, 1940. 11. Valvo, A. : Desferrioxamine B in ophthal mology: applications and therapeutic possibili ties. Am. J. Ophth., 63:98, 1967. 12. Karpe, G. : Early diagnosis of siderosis retinae by the use of electroretinography. Doc. Ophth. 2:277, 1948. 13. Burian, H. M. : Clinical electroretinog raphy. Internat Ophth. Clin. 2:21, 1962.