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Retinal Phlebitis with Chorioretinal Emboli
RETINAL PHLEBITIS WITH CHORIORETINAL EMBOLI JAMES R. PATRINELY, M.D., W. RICHARD GREEN, AND M. ELLIOTT RANDOLPH, M.D.
M.D.,
Baltimore, Maryland
Emboli to the eye may cause retinal vascular occlusive disease with a wide range of clinicopathologic manifestations including arteriolar occlusion, retinal ischemia and infarction, and retinal neovascularization. Clinical observations of a progressive obliterative arteriolitis in patients with systemic embolic disease have led to the speculation that retinal vasculitis may be a feature of ocular embolic disease. A postmortem examination of the enucleated eyes of two elderly female patients disclosed gross and histopathologic features of retinal periphlebitis associated with many chorioretinal calcific emboli. These patients also had premortem and postmortem manifestations of systemic thromboembolic disease originating from the heart and great vessels. One patient had a progressive decrease in visual acuity, paracentral scotoma, and midperipheral perivascular sheathing. These findings suggest that ocular embolism may sometimes be a factor in the development of retinal phlebitis.
Emboli to the retinal circulation usually produce retinal ischemia or infarction distal to the site of vessel occlusion. Clinically this may appear as intravascular plugging, a gray edematous retina, optic disk pallor, cotton-wool spots, intraretinal hemorrhage, 1 or, occasionally, neovascularization. 2,3 Retinal vascular inflammation is an unusual manifestation of chorioretinal emboli. More commonly, retinal vasculitis is idiopathic (as in Eales' disease), but it Accepted for publication March 11, 1982. From the Eye Pathology Laboratory, Wilmer Ophthalmological Institute, and the Department of Ophthalmology, Johns Hopkins Medical Institutions, Baltimore, Maryland. This study was supported in part by research grant ROI-01684 from the National Eye Institute (Dr. Green). This study was presented in part at the Residents Association Meeting, Baltimore, Maryland, May 7, 1981. Reprint requests to W. Richard Green, M. D., Eye Pathology Laboratory, Wilmer Institute, Johns Hopkins Hospital, 600 N. Wolfe Rd., Baltimore, MD 21205.
may also occur in association with uveitis, ocular sarcoidosis, pars planitis, and several systemic diseases.v" Several recent reports, however, have noted a progressive obliterative arteriolitis with peripheral neovascularization ("atypical Eales' disease") in patients who were later found to have embolic retinal disease.I" Thus, cases previously classified as idiopathic retinal vasculitis may actually contain a subgroup with an embolic origin. The association of calcific chorioretinal emboli with retinal phlebitis in two patients with systemic embolic disease is the subject of this report. CASE REPORTS Case i-This woman was first examined at the age of 38 years, at which time mild blurring of the optic disks was noted. Vision was normal in both eves. During the next 20 years, she developed a s~aIl paracentral scotoma of the right eye and changes considered to represent early macular degeneration in both eyes. Her visual acuity was 6/9 (20/30) in both eyes.
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At about the age of 64 years, she had a ten-minute episode of visual blurring that was presumed to have a retinal vascular cause. No ocular laterality or associated neurologic deficits were described. Later that year, she noted the onset of additional small blindspot areas around the fixation point in each eye and the optic disk margins were noted to be irregular, with adjacent areas of retinal pigment epithelial atrophy. Both maculas had a granular "moth-eaten" appearance. The visual fields were full peripherally, but there was slight enlargement of each blind spot. There were also three small isolated paracentral scotomas temporally and below fixation in the right eye (3/1,000, white test object). The following year fluorescein angiography showed drusen around the optic disk and late peripapillary and optic disk leakage. The visual fields were unchanged and she was thought to have a retinal degenerative process. When last examined in May 1979, her visual acuity was 6/12 (20/40) bilaterally, and perivenous sheathing was noted for the first time. Her medical history included migraine headaches and ventricular extrasystoles. There was no history of hypertension, diabetes mellitus, rheumatic fever, cerebrovascular accidents, or tuberculosis. Her family history was noncontributory. In 1979 she was admitted to the hospital with crescendo angina. The patient suffered a massive anteroseptal myocardial infarction and died ten hours later at the age of 70 years.
Postmortem studies-The postmortem findings included ulcerated and calcified atheromatous lesions of the ascending aorta and a left ventricular anteroseptal wall rupture from myocardial infarction. There was no histopathologic evidence of tuberculosis. The eyes were opened horizontally. The right eye had marked vitreous liquefaction and typical peripheral cystoid degeneration. No distinct abnormalities were noted in the macula. There was peripapillary retinal pigment epithelial atrophy. Prominent perivascular sheathing was present throughout the midperiphery (Fig. 1). Examination of the left globe disclosed similar peripapillary retinal pigment epithelial atrophy and peripheral retinal vascular sheathing. Serial sections through the plane of the optic nerve head, macula, and pupil were prepared. Selected areas of retinal vascular sheathing were prepared for routine sectioning, electron microscopy,
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Fig. 1 (Patrinely, Green, and Randolph). Case 1. Gross appearance of perivenous sheathing (arrows) in the midperiphery of the right eye.
and trypsin digestion. Stains included hematoxylin-eosin, von Kossa, PAS, and Verhoeff-Van Gieson. A flat preparation of the retinal vessels in the right inferior cap, using trypsin digestion, was also performed. Light microscopy of the right eye showed focal lymphocytic choroidal infiltrates that did not invade the choriocapillaris or disturb Bruch's membrane or the retinal pigment epithelium. Choroidal neovascularization was observed in one area of the peripapillary zone. These peripapillary retinal pigment epithelial changes were associated with photoreceptor cell loss and some deep intraretinal gliosis. A thin hypocellular preretinal membrane containing some lymphocytes extended from the optic nerve head to the equator on both sides. The retinal vessels, especially the larger veins in the midperiphery and equatorial areas, showed a marked inflammatory cell infiltration in their walls and the surrounding area. These infiltrates consisted mostly of lymphocytes with some plasma cells. In many areas the lymphocytes were interspersed in a fibrocellular membrane that extended from the vessel area into the vitreous cavity for a short distance (Fig. 2). In the temporal peripapillary area a
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Fig. 2 (Patrinely, Green, and Randolph). Case 1. Intense retinal phlebitis with extension of inflammatory cells into the vitreous (hematoxylin and eosin, x 325).
choroidal vessel was occluded by a laminated calcific embolus with an adjacent foreign-body giant-cell reaction (Fig. 3). Also, posterior to the equator in the inferior cap, there was one retinal arteriole with its lumen partially occluded by a
Fig. 3 (Patrinely, Green, and Randolph). Case 1. Foreign-body giant cell (arrow) adjacent to choroidal calcific embolus (arrowhead). There is a round-cell infiltrate in the choroid (hematoxylin and eosin, x 300).
calcific embolus (Fig. 4). The macular area showed no evidence of inner ischemic or descending atrophy. Longitudinal and cross sections of the optic nerve were normal. Special sections through the perivascular sheathing disclosed an intense area of mononuclear cell infiltration in the wall and surrounding area of the vessels. The vessel wall was thickened by intralamellar PAS-positive material, edema, and mononuclear cells. Examination of the trypsin-digested retinal Hat preparations of the inferior cap
Fig. 4 (Patrinely, Green, and Randolph). Case 1. Partial occlusion of a retinal arteriole by a calcific embolus (arrow) (hematoxylin and eosin, x 625).
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Fig. 5 (Patrinely, Green, and Randolph). Case I. Retinal phlebitis and periphlebitis shown by the trypsin-digestion technique (PAS and hematoxylin and eosin, x 60).
disclosed a marked phlebitis with lymphocytes in the wall and surrounding area of veins (Fig. 5). The larger retinal veins were surrounded by large numbers of lymphocytes, monocytes, and occasional plasma cells (Fig. 6). The walls and surrounding areas of the retinal arteries, precapillary arterioles, and postcapillary venules were also infiltrated with similar inflammatory cells, but to a lesser degree. No capillary microaneurysms were seen. Transmission electron microscopy of one area of retinal phlebitis disclosed an
Fig. 6 (Patrinely, Green, and Randolph). Case l. Vein wall infiltrated by lymphocytes (PAS and hematoxylin and eosin, x 250).
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intact endothelium, normal-appearing pericytes with multilaminated basement membrane, and lymphocytes outside the basement membrane of the pericytes (Fig. 7). Cellular proliferation consisting of fibrocytes and fibrous astrocytes, along with lymphocytes and plasma cells, extended into the vitreous (Fig. 8), adjacent to a large retinal vein. The astrocytes were identified by the presence of basement membrane and intermediate cytoplasmic filaments (Fig. 8, inset). Fibrocytes were identified by their spindle shape, lack of polarity and basement membrane, and the presence of conspicuous cytoplasmic organelles. Microscopic examination of the left eye disclosed features similar to those found in the right eye, including two calcific emboli in choroidal arteries (Fig. 9). No retinal emboli were identified in the prepared sections. Case 2-An 82-year-old woman was admitted to the hospital on April 28, 1979, because of hallucinations, headaches, and irritability. The next day the patient died of a right intracerebral hemorrhage. No previous ophthalmic examinations or ocular history had been documented. Her medical history included adult-onset diabetes mellitus, hypertension, and atrial fibrillation.
Postmortem studies-An autopsy disclosed a massive intracerebral hemorrhage and many recent cerebral, cerebellar, and brain-stem infarctions. The heart contained a mural thrombus in the left atrium, and also calcified mitral stenosis. Plaque ulceration of the aorta and organizing thromboemboli in the lungs were present. Several old calcified granulomas were noted in the lungs, but there was no evidence of active tuberculosis. The eyes were processed similarly to those of Patient 1. Gross internal examination of both eyes disclosed occasional retinal hemorrhages in the posterior pole and prominent sheathing of retinal veins in the midperiphery. Light microscopy of the right eye dis-
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Fig. 7 (Patrinely, Green, and Randolph). Case 1. Electron micrograph shows a retinal vein (V)with an intact endothelium, an incomplete layer of pericytes (asterisk), and lymphocytes (arrowheads) external to the multilaminated basement membrane (arrows) (x 5,000).
closed mild cystoid macular edema and extensive inner retinal ischemic atrophy. Most of the grossly observed retinal hemorrhages were located within the inner retinal layers. There were several areas of moderate lymphocytic infiltrates of the larger retinal veins. Cross sections of the optic nerve showed an axial area of partial atrophy. Microscopic examination of the left eye disclosed similar features and a lamellar macular hole. Nasally, there were numerous retinal hemorrhages and serous exudates in the outer retinal layers. Trypsin digestion preparation of the inferior cap of the left eye showed a retinal vasculature with many localized areas of endothelial cell and pericyte loss in the capillaries, veins, and arteries, most evident posteriorly. Capillary microaneurysms were also found in the margins of some of these areas of capillary "dropout." The larger veins had prominent lymphocytic infiltrates in their walls (Fig. 10, top). When stained with the von
Kossa technique, the trypsin-digestion preparation of the superior cap of the left eye disclosed a retinal vessel that contained an occlusive calcific embolus (Fig. 10, bottom). DISCUSSION
Idiopathic retinal perivasculitis, or Eales' disease, does not quite reflect the original description of "repeated peripheral retinal haemorrhages. . . full and tortuous retinal vessels, especially the veins" in young men by Eales in 1880. 9 He attributed the disorder to "sluggish bowels" that caused a portal hypertension leading to epistaxis and retinal hemorrhages. Females were thought to be "saved from the retinal haemorrhage by their menstruation." It was not until 30 years later that Axenfeld and Stock" described the associated retinal periphlebitis and possible etiologic significance of tuberculosis. Eales' disease is now considered to be a primary bilateral perivasculitis of the retina, more commonly in-
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Fig. 8 (Patrinely, Green, and Randolph). Case 1. Ultrastructural appearance of area showing extension of fibrocytes (arrow), fibrous astrocytes (arrowhead), lymphocytes (asterisks), and plasma cells (P) into the vitreous cavity (x 4,200). Inset, Higher-power view of an astrocyte shows basement membrane (circle) and cytoplasmic filaments (brackets) that measure 8 to IO nm in diameter (x 55,000).
volving the peripheral retinal veins. There is usually perivascular sheathing with vitreous exudation of inflammatory debris. As the disease progresses, there
may be retinal and vitreous hemorrhages, neovascularization, and tractional retinal detachment. 11,12 Atypical forms of Eales' disease primarily involve the retinal arte-
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Fig. 9 (Patrinely, Green, and Randolph). Case l. Multilaminated calcific emboli (arrows) in a nasal midperipheral choroidal artery of the left eye (top, von Kossa, x 375; bottom, hematoxylin and eosin, x 5(0).
Fig. 10 (Patrinely, Green, and Randolph). Case 2. Trypsin-digestion preparation of retina showing marked lymphocytic infiltrate in wall of, and around, a retinal vein (top) and a calcific embolus (bottom, area between arrows) in a retinal artery (top, PAS and hematoxylin and eosin, x 210; bottom, von Kossa, x 215).
rioles and may lead to arteriole occlusion and extensive neovascularization.W There have been three recent case reports describing progressive obliterative retinal arteriolitis with peripheral neovascularization associated with retinal emboli. Kelley and Randall! described a Ifi-year-old boy with rheumatic heart disease who developed signs of cerebral embolism, followed by retinal vasculitis and peripheral neovascularization. Fluorescein angiography demonstrated a peripheral area of non perfusion consistent with embolic occlusion. Both the neurologic and ophthalmic signs were lateralized, and they implicated embolization through the left carotid artery. Caltrider and associates? described a 14-year-old girl with a progressive occlusive retinal arteriolitis and neovascularization. The
patient had documented mitral-valve prolapse (Barlow's syndrome), which is sometimes associated with systemic embolic phenomena.P The retinal features were thought to be secondary to recurrent small fibrin emboli from the abnormal mitral apparatus. [ampol, Isenberg, and Coldberg" described a 34-year-old woman who had used oral contraceptive for a prolonged time and who developed a progressive bilateral occlusive retinal arteriolitis, with neovascularization associated with transient central nervous system dysfunction. They suggested that the patient's retinal disease was possibly caused by recurrent emboli. It is known that the use of birth-control pills increases the risk of thromboembolic phenomena.P:" Our two elderly female patients had
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the clinical and postmortem signs of arterial thromboembolic disease. One patient had had transient ischemic attacks and at autopsy was found to have ulcerated calcified atheromatous lesions of the ascending aorta. The other patient had had many intracerebral hemorrhages and infarcts, atrial fibrillation with a left atrial mural thrombus, and calcific mitral stenosis. Patient 1 had decreased visual acuity and paracentral scotomas, and developed bilateral perivascular sheathing in the midperiphery. On histopathologic study, however, there was evidence of calcific emboli and intense phlebitis and periphlebitis of the retina and choroid in both cases. Patient 1 also had fibroglial proliferation with inflammation that extended into the vitreous along the major veins. Neither patient had clinical or bacteriologic evidence of sepsis, systemic vasculitis, or active tuberculosis. Emboli from eroded atheromatous plaques usually consist of cholesterol crystals, hyalin debris, and occasional bits of calcified material. The effects of such emboli are chiefly attributable to the mechanical obstruction and the reparative process within the vessel--eausing progressive stenosis, spasm, or occlusion. The distal tissue then becomes ischemic, resulting in impaired function, atrophy, or necrosis. 17 Overt vasculitis is an unusual response to non septic emboli, although there are reports of a foreign-body reaction (granulomatous endarteritis) and intimal fibrosis in response to emboli in medium-sized and small arteries. 18 The usually high incidence of positive tuberculin skin-tests in patients with Eales' disease suggests that the perivasculitis may be an antigenic response to the tubercular protein. 19 Perhaps certain emboli can elicit a similar ocular allergic mechanism in some patients. In our patients and those described by others, the calcific or fibrinous emboli seemed to
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originate from the heart or great vessels. Why these patients developed retinal vasculitis in response to substances that are usually nonantigenic is not clear. A search for predisposing factors to thromboembolism-such as birth-control pills, cardiac valvular disease, cardiac dysrhythmias, and ulcerated atheromatous disease of the great vessels-may be indicated in patients with signs of retinal phlebitis. REFERENCES 1. Duke-Elder, S., and Dobree, J. H.: Diseases of the Retina. In Duke-Elder, S. (ed.): System of Ophthalmology, vol. 10. St. Louis, C. V. Mosby, 1967, pp. 82-87. 2. Brucker, A. J.: Disk and peripheral retinal neovascularization secondary to talc and cornstarch emboli. Am. J. Ophthalmol. 88:864, 1979. 3. Kresca, L. J., Goldberg, M. F., and [ampol, L. M.: Talc emboli and retinal neovascularization in a drug abuser. Am. J. Ophthalmol. 87:334, 1979. 4. Duke-Elder, S., and Dobree, J. H.: Diseases of the Retina. In Duke-Elder; S. (ed.): System of Ophthalmology, vol. 10. St. Louis, C. V. Mosby, 1967, pp. 218-233. 5. Wise, G. N., Dollery, C. T., and Henkind, P.: The Retinal Circulation. New York, Harper & Row, 1971, pp. 380--381. 6. Kelley, J. S., and Randall, H. G.: Peripheral retinal neovascularization in rheumatic fever. Arch. Ophthalmol. 97:81, 1979. 7. Caltrider, N. D., Irvine, A. R., Kline, H. J., and Rosenblatt, A.: Retinal emboli in patients with mitral valve prolapse. Am. J. Ophthalmol. 90:534, 1980. 8. Jampol, L. M., Isenberg, S. J., and Goldberg, M. F.: Occlusive retinal arteriolitis with neovascularization. Am. J. Ophthalmol. 81:583, 1976. 9. Eales, H.: Cases of retinal haemorrhage, associated with epistaxis and constipation. Birmingham Med. Rev. 3:262, 1880. 10. Axenfeld, T., and Stock, W.: Uber die Bedeutung der Tuberkulose in der Aetiologie der intraoKulare Hamorrhagien und der proliferierenden Veranderungen in der Netzhaut, besonders tiber Periphlebitis retinalis bei Tuberkulosen. Klin. Monatsbl. Augenheilkd. 49:28, 1911. ll. Elliot, A.: Periphlebitis retinae. In Duane, T. (ed.): Clinical Ophthalmology. New York, Harper & Row, 1979, vol. 3, ch. 16. 12. - - : 3D-year observation of patients with Eales's disease. Am. J. Ophthalmol. 80:404, 1975. 13. Delaney, W. V., Jr., and Torrisi, P. F.: Occlusive retinal vascular disease and deafness. Am. J. Ophthalmol. 82:232, 1976. 14. Barnett, H. J. M., Boughner, D. R., Taylor, D. W., Cooper, P. E., Kostuk, W. J., and Nichol,
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P. M.: Further evidence relating mitral-valve prolapse to cerebral ischemic events. N. Engl. J. Med. 302:139, 1980. 15. Stadel, B. V.: Oral contraceptives and cardiovascular disease. Part I. N. Eng!. J. Med. 305:612, 198!. 16. - - - ; Oral contraceptives and cardiovascular disease. Part II. N. Engl. J. Med. 305:672, 198!. 17. Anderson, W. A. D., and Kissane, J. M.: Pa-
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thology, 7th ed. St. Louis, C. V. Mosby, 1977, pp. 176-189. 18. Handler, F. P.: Clinical and pathologic significance of atheromatous embolization, with emphasis on an etiology of renal hypertension. Am. J. Med. 20;366, 1956. 19. Ashton, :\.: Pathogenesis and aetiology of Eales's disease. In XIX Concilium Ophthalmologicum, New Delhi, India, 1962. Bombay, Pandit, 1963, vol. 2, pp. 828-840.
M.D.,
Baltimore, Maryland
Emboli to the eye may cause retinal vascular occlusive disease with a wide range of clinicopathologic manifestations including arteriolar occlusion, retinal ischemia and infarction, and retinal neovascularization. Clinical observations of a progressive obliterative arteriolitis in patients with systemic embolic disease have led to the speculation that retinal vasculitis may be a feature of ocular embolic disease. A postmortem examination of the enucleated eyes of two elderly female patients disclosed gross and histopathologic features of retinal periphlebitis associated with many chorioretinal calcific emboli. These patients also had premortem and postmortem manifestations of systemic thromboembolic disease originating from the heart and great vessels. One patient had a progressive decrease in visual acuity, paracentral scotoma, and midperipheral perivascular sheathing. These findings suggest that ocular embolism may sometimes be a factor in the development of retinal phlebitis.
Emboli to the retinal circulation usually produce retinal ischemia or infarction distal to the site of vessel occlusion. Clinically this may appear as intravascular plugging, a gray edematous retina, optic disk pallor, cotton-wool spots, intraretinal hemorrhage, 1 or, occasionally, neovascularization. 2,3 Retinal vascular inflammation is an unusual manifestation of chorioretinal emboli. More commonly, retinal vasculitis is idiopathic (as in Eales' disease), but it Accepted for publication March 11, 1982. From the Eye Pathology Laboratory, Wilmer Ophthalmological Institute, and the Department of Ophthalmology, Johns Hopkins Medical Institutions, Baltimore, Maryland. This study was supported in part by research grant ROI-01684 from the National Eye Institute (Dr. Green). This study was presented in part at the Residents Association Meeting, Baltimore, Maryland, May 7, 1981. Reprint requests to W. Richard Green, M. D., Eye Pathology Laboratory, Wilmer Institute, Johns Hopkins Hospital, 600 N. Wolfe Rd., Baltimore, MD 21205.
may also occur in association with uveitis, ocular sarcoidosis, pars planitis, and several systemic diseases.v" Several recent reports, however, have noted a progressive obliterative arteriolitis with peripheral neovascularization ("atypical Eales' disease") in patients who were later found to have embolic retinal disease.I" Thus, cases previously classified as idiopathic retinal vasculitis may actually contain a subgroup with an embolic origin. The association of calcific chorioretinal emboli with retinal phlebitis in two patients with systemic embolic disease is the subject of this report. CASE REPORTS Case i-This woman was first examined at the age of 38 years, at which time mild blurring of the optic disks was noted. Vision was normal in both eves. During the next 20 years, she developed a s~aIl paracentral scotoma of the right eye and changes considered to represent early macular degeneration in both eyes. Her visual acuity was 6/9 (20/30) in both eyes.
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At about the age of 64 years, she had a ten-minute episode of visual blurring that was presumed to have a retinal vascular cause. No ocular laterality or associated neurologic deficits were described. Later that year, she noted the onset of additional small blindspot areas around the fixation point in each eye and the optic disk margins were noted to be irregular, with adjacent areas of retinal pigment epithelial atrophy. Both maculas had a granular "moth-eaten" appearance. The visual fields were full peripherally, but there was slight enlargement of each blind spot. There were also three small isolated paracentral scotomas temporally and below fixation in the right eye (3/1,000, white test object). The following year fluorescein angiography showed drusen around the optic disk and late peripapillary and optic disk leakage. The visual fields were unchanged and she was thought to have a retinal degenerative process. When last examined in May 1979, her visual acuity was 6/12 (20/40) bilaterally, and perivenous sheathing was noted for the first time. Her medical history included migraine headaches and ventricular extrasystoles. There was no history of hypertension, diabetes mellitus, rheumatic fever, cerebrovascular accidents, or tuberculosis. Her family history was noncontributory. In 1979 she was admitted to the hospital with crescendo angina. The patient suffered a massive anteroseptal myocardial infarction and died ten hours later at the age of 70 years.
Postmortem studies-The postmortem findings included ulcerated and calcified atheromatous lesions of the ascending aorta and a left ventricular anteroseptal wall rupture from myocardial infarction. There was no histopathologic evidence of tuberculosis. The eyes were opened horizontally. The right eye had marked vitreous liquefaction and typical peripheral cystoid degeneration. No distinct abnormalities were noted in the macula. There was peripapillary retinal pigment epithelial atrophy. Prominent perivascular sheathing was present throughout the midperiphery (Fig. 1). Examination of the left globe disclosed similar peripapillary retinal pigment epithelial atrophy and peripheral retinal vascular sheathing. Serial sections through the plane of the optic nerve head, macula, and pupil were prepared. Selected areas of retinal vascular sheathing were prepared for routine sectioning, electron microscopy,
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Fig. 1 (Patrinely, Green, and Randolph). Case 1. Gross appearance of perivenous sheathing (arrows) in the midperiphery of the right eye.
and trypsin digestion. Stains included hematoxylin-eosin, von Kossa, PAS, and Verhoeff-Van Gieson. A flat preparation of the retinal vessels in the right inferior cap, using trypsin digestion, was also performed. Light microscopy of the right eye showed focal lymphocytic choroidal infiltrates that did not invade the choriocapillaris or disturb Bruch's membrane or the retinal pigment epithelium. Choroidal neovascularization was observed in one area of the peripapillary zone. These peripapillary retinal pigment epithelial changes were associated with photoreceptor cell loss and some deep intraretinal gliosis. A thin hypocellular preretinal membrane containing some lymphocytes extended from the optic nerve head to the equator on both sides. The retinal vessels, especially the larger veins in the midperiphery and equatorial areas, showed a marked inflammatory cell infiltration in their walls and the surrounding area. These infiltrates consisted mostly of lymphocytes with some plasma cells. In many areas the lymphocytes were interspersed in a fibrocellular membrane that extended from the vessel area into the vitreous cavity for a short distance (Fig. 2). In the temporal peripapillary area a
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Fig. 2 (Patrinely, Green, and Randolph). Case 1. Intense retinal phlebitis with extension of inflammatory cells into the vitreous (hematoxylin and eosin, x 325).
choroidal vessel was occluded by a laminated calcific embolus with an adjacent foreign-body giant-cell reaction (Fig. 3). Also, posterior to the equator in the inferior cap, there was one retinal arteriole with its lumen partially occluded by a
Fig. 3 (Patrinely, Green, and Randolph). Case 1. Foreign-body giant cell (arrow) adjacent to choroidal calcific embolus (arrowhead). There is a round-cell infiltrate in the choroid (hematoxylin and eosin, x 300).
calcific embolus (Fig. 4). The macular area showed no evidence of inner ischemic or descending atrophy. Longitudinal and cross sections of the optic nerve were normal. Special sections through the perivascular sheathing disclosed an intense area of mononuclear cell infiltration in the wall and surrounding area of the vessels. The vessel wall was thickened by intralamellar PAS-positive material, edema, and mononuclear cells. Examination of the trypsin-digested retinal Hat preparations of the inferior cap
Fig. 4 (Patrinely, Green, and Randolph). Case 1. Partial occlusion of a retinal arteriole by a calcific embolus (arrow) (hematoxylin and eosin, x 625).
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Fig. 5 (Patrinely, Green, and Randolph). Case I. Retinal phlebitis and periphlebitis shown by the trypsin-digestion technique (PAS and hematoxylin and eosin, x 60).
disclosed a marked phlebitis with lymphocytes in the wall and surrounding area of veins (Fig. 5). The larger retinal veins were surrounded by large numbers of lymphocytes, monocytes, and occasional plasma cells (Fig. 6). The walls and surrounding areas of the retinal arteries, precapillary arterioles, and postcapillary venules were also infiltrated with similar inflammatory cells, but to a lesser degree. No capillary microaneurysms were seen. Transmission electron microscopy of one area of retinal phlebitis disclosed an
Fig. 6 (Patrinely, Green, and Randolph). Case l. Vein wall infiltrated by lymphocytes (PAS and hematoxylin and eosin, x 250).
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intact endothelium, normal-appearing pericytes with multilaminated basement membrane, and lymphocytes outside the basement membrane of the pericytes (Fig. 7). Cellular proliferation consisting of fibrocytes and fibrous astrocytes, along with lymphocytes and plasma cells, extended into the vitreous (Fig. 8), adjacent to a large retinal vein. The astrocytes were identified by the presence of basement membrane and intermediate cytoplasmic filaments (Fig. 8, inset). Fibrocytes were identified by their spindle shape, lack of polarity and basement membrane, and the presence of conspicuous cytoplasmic organelles. Microscopic examination of the left eye disclosed features similar to those found in the right eye, including two calcific emboli in choroidal arteries (Fig. 9). No retinal emboli were identified in the prepared sections. Case 2-An 82-year-old woman was admitted to the hospital on April 28, 1979, because of hallucinations, headaches, and irritability. The next day the patient died of a right intracerebral hemorrhage. No previous ophthalmic examinations or ocular history had been documented. Her medical history included adult-onset diabetes mellitus, hypertension, and atrial fibrillation.
Postmortem studies-An autopsy disclosed a massive intracerebral hemorrhage and many recent cerebral, cerebellar, and brain-stem infarctions. The heart contained a mural thrombus in the left atrium, and also calcified mitral stenosis. Plaque ulceration of the aorta and organizing thromboemboli in the lungs were present. Several old calcified granulomas were noted in the lungs, but there was no evidence of active tuberculosis. The eyes were processed similarly to those of Patient 1. Gross internal examination of both eyes disclosed occasional retinal hemorrhages in the posterior pole and prominent sheathing of retinal veins in the midperiphery. Light microscopy of the right eye dis-
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Fig. 7 (Patrinely, Green, and Randolph). Case 1. Electron micrograph shows a retinal vein (V)with an intact endothelium, an incomplete layer of pericytes (asterisk), and lymphocytes (arrowheads) external to the multilaminated basement membrane (arrows) (x 5,000).
closed mild cystoid macular edema and extensive inner retinal ischemic atrophy. Most of the grossly observed retinal hemorrhages were located within the inner retinal layers. There were several areas of moderate lymphocytic infiltrates of the larger retinal veins. Cross sections of the optic nerve showed an axial area of partial atrophy. Microscopic examination of the left eye disclosed similar features and a lamellar macular hole. Nasally, there were numerous retinal hemorrhages and serous exudates in the outer retinal layers. Trypsin digestion preparation of the inferior cap of the left eye showed a retinal vasculature with many localized areas of endothelial cell and pericyte loss in the capillaries, veins, and arteries, most evident posteriorly. Capillary microaneurysms were also found in the margins of some of these areas of capillary "dropout." The larger veins had prominent lymphocytic infiltrates in their walls (Fig. 10, top). When stained with the von
Kossa technique, the trypsin-digestion preparation of the superior cap of the left eye disclosed a retinal vessel that contained an occlusive calcific embolus (Fig. 10, bottom). DISCUSSION
Idiopathic retinal perivasculitis, or Eales' disease, does not quite reflect the original description of "repeated peripheral retinal haemorrhages. . . full and tortuous retinal vessels, especially the veins" in young men by Eales in 1880. 9 He attributed the disorder to "sluggish bowels" that caused a portal hypertension leading to epistaxis and retinal hemorrhages. Females were thought to be "saved from the retinal haemorrhage by their menstruation." It was not until 30 years later that Axenfeld and Stock" described the associated retinal periphlebitis and possible etiologic significance of tuberculosis. Eales' disease is now considered to be a primary bilateral perivasculitis of the retina, more commonly in-
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Fig. 8 (Patrinely, Green, and Randolph). Case 1. Ultrastructural appearance of area showing extension of fibrocytes (arrow), fibrous astrocytes (arrowhead), lymphocytes (asterisks), and plasma cells (P) into the vitreous cavity (x 4,200). Inset, Higher-power view of an astrocyte shows basement membrane (circle) and cytoplasmic filaments (brackets) that measure 8 to IO nm in diameter (x 55,000).
volving the peripheral retinal veins. There is usually perivascular sheathing with vitreous exudation of inflammatory debris. As the disease progresses, there
may be retinal and vitreous hemorrhages, neovascularization, and tractional retinal detachment. 11,12 Atypical forms of Eales' disease primarily involve the retinal arte-
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Fig. 9 (Patrinely, Green, and Randolph). Case l. Multilaminated calcific emboli (arrows) in a nasal midperipheral choroidal artery of the left eye (top, von Kossa, x 375; bottom, hematoxylin and eosin, x 5(0).
Fig. 10 (Patrinely, Green, and Randolph). Case 2. Trypsin-digestion preparation of retina showing marked lymphocytic infiltrate in wall of, and around, a retinal vein (top) and a calcific embolus (bottom, area between arrows) in a retinal artery (top, PAS and hematoxylin and eosin, x 210; bottom, von Kossa, x 215).
rioles and may lead to arteriole occlusion and extensive neovascularization.W There have been three recent case reports describing progressive obliterative retinal arteriolitis with peripheral neovascularization associated with retinal emboli. Kelley and Randall! described a Ifi-year-old boy with rheumatic heart disease who developed signs of cerebral embolism, followed by retinal vasculitis and peripheral neovascularization. Fluorescein angiography demonstrated a peripheral area of non perfusion consistent with embolic occlusion. Both the neurologic and ophthalmic signs were lateralized, and they implicated embolization through the left carotid artery. Caltrider and associates? described a 14-year-old girl with a progressive occlusive retinal arteriolitis and neovascularization. The
patient had documented mitral-valve prolapse (Barlow's syndrome), which is sometimes associated with systemic embolic phenomena.P The retinal features were thought to be secondary to recurrent small fibrin emboli from the abnormal mitral apparatus. [ampol, Isenberg, and Coldberg" described a 34-year-old woman who had used oral contraceptive for a prolonged time and who developed a progressive bilateral occlusive retinal arteriolitis, with neovascularization associated with transient central nervous system dysfunction. They suggested that the patient's retinal disease was possibly caused by recurrent emboli. It is known that the use of birth-control pills increases the risk of thromboembolic phenomena.P:" Our two elderly female patients had
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AMERICAN JOURNAL OF OPHTHALMOLOGY
the clinical and postmortem signs of arterial thromboembolic disease. One patient had had transient ischemic attacks and at autopsy was found to have ulcerated calcified atheromatous lesions of the ascending aorta. The other patient had had many intracerebral hemorrhages and infarcts, atrial fibrillation with a left atrial mural thrombus, and calcific mitral stenosis. Patient 1 had decreased visual acuity and paracentral scotomas, and developed bilateral perivascular sheathing in the midperiphery. On histopathologic study, however, there was evidence of calcific emboli and intense phlebitis and periphlebitis of the retina and choroid in both cases. Patient 1 also had fibroglial proliferation with inflammation that extended into the vitreous along the major veins. Neither patient had clinical or bacteriologic evidence of sepsis, systemic vasculitis, or active tuberculosis. Emboli from eroded atheromatous plaques usually consist of cholesterol crystals, hyalin debris, and occasional bits of calcified material. The effects of such emboli are chiefly attributable to the mechanical obstruction and the reparative process within the vessel--eausing progressive stenosis, spasm, or occlusion. The distal tissue then becomes ischemic, resulting in impaired function, atrophy, or necrosis. 17 Overt vasculitis is an unusual response to non septic emboli, although there are reports of a foreign-body reaction (granulomatous endarteritis) and intimal fibrosis in response to emboli in medium-sized and small arteries. 18 The usually high incidence of positive tuberculin skin-tests in patients with Eales' disease suggests that the perivasculitis may be an antigenic response to the tubercular protein. 19 Perhaps certain emboli can elicit a similar ocular allergic mechanism in some patients. In our patients and those described by others, the calcific or fibrinous emboli seemed to
JULY, 1982
originate from the heart or great vessels. Why these patients developed retinal vasculitis in response to substances that are usually nonantigenic is not clear. A search for predisposing factors to thromboembolism-such as birth-control pills, cardiac valvular disease, cardiac dysrhythmias, and ulcerated atheromatous disease of the great vessels-may be indicated in patients with signs of retinal phlebitis. REFERENCES 1. Duke-Elder, S., and Dobree, J. H.: Diseases of the Retina. In Duke-Elder, S. (ed.): System of Ophthalmology, vol. 10. St. Louis, C. V. Mosby, 1967, pp. 82-87. 2. Brucker, A. J.: Disk and peripheral retinal neovascularization secondary to talc and cornstarch emboli. Am. J. Ophthalmol. 88:864, 1979. 3. Kresca, L. J., Goldberg, M. F., and [ampol, L. M.: Talc emboli and retinal neovascularization in a drug abuser. Am. J. Ophthalmol. 87:334, 1979. 4. Duke-Elder, S., and Dobree, J. H.: Diseases of the Retina. In Duke-Elder; S. (ed.): System of Ophthalmology, vol. 10. St. Louis, C. V. Mosby, 1967, pp. 218-233. 5. Wise, G. N., Dollery, C. T., and Henkind, P.: The Retinal Circulation. New York, Harper & Row, 1971, pp. 380--381. 6. Kelley, J. S., and Randall, H. G.: Peripheral retinal neovascularization in rheumatic fever. Arch. Ophthalmol. 97:81, 1979. 7. Caltrider, N. D., Irvine, A. R., Kline, H. J., and Rosenblatt, A.: Retinal emboli in patients with mitral valve prolapse. Am. J. Ophthalmol. 90:534, 1980. 8. Jampol, L. M., Isenberg, S. J., and Goldberg, M. F.: Occlusive retinal arteriolitis with neovascularization. Am. J. Ophthalmol. 81:583, 1976. 9. Eales, H.: Cases of retinal haemorrhage, associated with epistaxis and constipation. Birmingham Med. Rev. 3:262, 1880. 10. Axenfeld, T., and Stock, W.: Uber die Bedeutung der Tuberkulose in der Aetiologie der intraoKulare Hamorrhagien und der proliferierenden Veranderungen in der Netzhaut, besonders tiber Periphlebitis retinalis bei Tuberkulosen. Klin. Monatsbl. Augenheilkd. 49:28, 1911. ll. Elliot, A.: Periphlebitis retinae. In Duane, T. (ed.): Clinical Ophthalmology. New York, Harper & Row, 1979, vol. 3, ch. 16. 12. - - : 3D-year observation of patients with Eales's disease. Am. J. Ophthalmol. 80:404, 1975. 13. Delaney, W. V., Jr., and Torrisi, P. F.: Occlusive retinal vascular disease and deafness. Am. J. Ophthalmol. 82:232, 1976. 14. Barnett, H. J. M., Boughner, D. R., Taylor, D. W., Cooper, P. E., Kostuk, W. J., and Nichol,
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P. M.: Further evidence relating mitral-valve prolapse to cerebral ischemic events. N. Engl. J. Med. 302:139, 1980. 15. Stadel, B. V.: Oral contraceptives and cardiovascular disease. Part I. N. Eng!. J. Med. 305:612, 198!. 16. - - - ; Oral contraceptives and cardiovascular disease. Part II. N. Engl. J. Med. 305:672, 198!. 17. Anderson, W. A. D., and Kissane, J. M.: Pa-
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thology, 7th ed. St. Louis, C. V. Mosby, 1977, pp. 176-189. 18. Handler, F. P.: Clinical and pathologic significance of atheromatous embolization, with emphasis on an etiology of renal hypertension. Am. J. Med. 20;366, 1956. 19. Ashton, :\.: Pathogenesis and aetiology of Eales's disease. In XIX Concilium Ophthalmologicum, New Delhi, India, 1962. Bombay, Pandit, 1963, vol. 2, pp. 828-840.