OCR Text |
Show JOUrtUll of Clinical Neuro- ophthalmology 9( 1): 7- 13, 1989. © 1989 Raven Press, Ltd., New York Posterior Ischemic Optic Neuropathy due to Aspergillus fumigatus Joel M. Weinstein, M. D., George L. Morris, M. D., Gabriele M. ZuRhein, M. D., and Lindell R. Gentry, M. D. A 35- year- old woman with metastatic breast cancer experienced acute monocular visual loss. Her fundus examination was normal. The patient died 48 h later, and autopsy demonstrated hematogenously disseminated aspergillosis. The retrobulbar optic nerve of the affected eye showed infarction due to massive embolization with Aspergillus fumigatus. Although the retrobulbar optic nerve is relatively resistant to ischemia, its meningeal derived blood supply may be occluded by massive showers of emboli. Key Words: Aspergillus- Ischemic optic neuropathyImmunosuppression. From the Departments of Ophthalmology a. M. W) and Neurology a. M. W. and G. L. M.), the Division of Neurosurgery and the Departments of Pathology ( G. M. Z.) and Radiology ( L. R. G.), Clinical Science Center, University of Wisconsin, Madison, Wisconsin, U. S. A. Address correspondence and reprint requests to Dr. J. M. Weinstein, Department of Ophthalmology, Clinical Science Center, 600 Highland Ave., Madison, WI 53792, U. S. A. This study was presented at the Frank Walsh Society Meeting, May 7, 1988, Vancouver, British Columbia, Canada. 7 Posterior ischemic optic neuropathy is a rare disorder caused by infarction of the retrobulbar portion of the optic nerve. This clinical syndrome consists of acute, usually monocular, visual loss with optic nerve- related field defects, an afferent pupil defect, and a normal- appearing optic disc and retina ( 1- 7). The presence of a normal disc distinguishes this entity from the more common syndrome of anterior ischemic optic neuropathy, in which the optic disc is swollen, often in a segmental fashion ( 8,9). Pallor of all or part of the swollen disc may be present in anterior ischemic optic neuropathy, especially in patients with temporal arteritis. Prior reports of posterior ischemic optic neuropathy have detailed cases of this disorder due to systemic vasculitides, including systemic lUpus erythematosus ( 1, 10) and temporal arteritis ( 1,9,11); massive thromboembolism ( 3); herpes zoster vasculitis ( 12); systemic hypotension, usually associated with anemia ( 4- 7) or as a complication of surgery and general anesthesia, often with associated hypotension ( 2,13,14); and unknown causes, presumably arteriosclerosis ( 15,16). Only two prior reports have included histopathologic correlation ( 4,6). We report the clinical and histopathologic findings in a patient who suffered ischemia of the posterior optic nerve dUring a fatal episode of hematogenously disseminated aspergillosis. Our observations demonstrate that the retrobulbar optic nerve may suffer ischemic damage as a result of massive embolization of its meningeal derived blood supply. CASE REPORT A 34- year- old woman had been in good health until a small right axillary mass was noted. She was found to have infiltrative intraductal carci- 8 J. M. WEINSTEIN ET AL. noma and was treated with a modified radical mastectomy and chemotherapy. Fourteen months later, she was noted to have metastases to the thoracolumbar part of the spine, and 15 months ~ fter her mastectomy, she was admitted to the Uruversity of Wisconsin Hospital to evaluate complaints of severe back pain. Myelography was normal, as were the cerebrospinal fluid ( CSF) examination results, including cytologic findings. Thirty- six hours after the myelography, she complained of diminished vision in both eyes. Neurologic and neuro- ophthalmologic examinations at that time revealed light perception vision in each eye with normal pupillary reactions. There was a limitation of upgaze that improved with vestibulo- ocular stimulation. Horizontal eye movements, ophthalmoscopy, and the remainder of the neurologic and neuro- ophthalmologic examination results was normal. The magnetic resonance ( MR) examination revealed a small, well- circumscribed right frontal lesion with surrounding edema most consistent with a metastatic lesion ( Fig. 1). Magnetic resonance also detected several other abnormalities that were atypical for metastatic disease. There was evidence of abnormal blood flow in the left sigmoid sinus with areas suggestive of partial thrombosis. In addition, there were multiple bilateral cortical and subcortical lesions involving the frontal, parietal, and occipital lobes ( Fig. 2). These lesions were interpreted as multiple ischemic areas, most likely arterial but possibly venous in origin. Although the optic chiasm and nerves were normal, there were bilateral ischemic areas in the calcarine cortex. A contrast enhanced computed tomography ( CT) scan 8 h later confirmed the right frontal metastatic focus and revealed multiple areas of vague hypodensity consistent with multiple infarcts. The patient's vision began to improve 24 h after the acute onset of visual loss. Forty- eight hours after the episode began, her vision was 20/ 20 in each eye, and visual fields were normal. Echocardiography, noninvasive carotid investigation, and coagulation studies failed to disclose a cause for the presumed transient cerebral ischemia. She received chemotherapy and returned 6 weeks later complaining of blurred vision in her left eye. At 9 a. m., a neurologic consultant found a visual acuity of 20/ 20 OD and 20/ 25 OS ( near equivalent), and a small paracentral scotoma OS to red confrontation testing. Her pupils and fundus were normal, as was the remainder of the neurologic and general physical examination results, except for a rectal temperature of lOO° F. The neuroophthalmologic examination at 4 p. m. revealed a / ( lin Neuro- ophlhalmol, Vol 9. No. 1. 1989 FIG. 1. An axial T2- weighted magnetic resonance ( MR) scan ( pulse repetition rate/ echo delay time = 2,000/ 90) reveals a small mass consistent with a metastatic lesion ( arrow) in the gyrus rectus of the right frontal lobe surrounded by a circumferential zone of edema ( arrowhead). Also noted is an area of MR signal hyperintensity in the proximal left sigmoid sinus ( curved arrow). Persistence of this abnormal signal on different MR pulse sequences, imaging planes, and data acquisition parameters suggested the possibility of partial sigmoid sinus thrombosis. visual acuity of 20/ 20 OD and hand motions OS. Goldmann fields revealed a large central scotoma OS. A 4+ left afferent pupil defect was present. Ophthalmoscopic findings were entirely normal in both eyes, as was the remainder of the neuroophthalmologic examination results. An unenhanced CT scan of the head that evening demonstrated new hypodensities adjacent to the atrium of the right lateral ventricle. The CSF studies were normal, including routine study results, cytologic findings, and stains for bacteria, fungus, and acidfast bacilli. The peripheral neutrophil count was zero, and broad- spectrum antibiotic therapy was begun. On the evening of her visual loss, acute pulmonary insufficiency developed. A chest roentgenogram demonstrated an extensive nonspecific bilateral infiltrative process. Blood and sputum cultures were negative. The next morning, she lapsed OPTIC NEUROPATHY DUE TO ASPERGILLUS FUMIGATUS 9 I FiG. 2. An aXial' rZ- welgntea' magnell'c resonance scan ( pulse repetition rate/ echo delay time = 2,000/ 90) reveals bilateral areas of signal hyperintensity in the calcarine cortex of the occipital lobes ( arrows). Similar lesions were present more superiorly in both frontal and parietal lobes. The location, shape, and character of the lesions are most consistent with multiple areas of ischemia. into a coma and died 48 h later of cardiopulmonary insufficiency. After death, a culture of skin lesions taken premortem yielded growth of Aspergillus fumigatus. All other cultures for bacteria, fungi, and acid- fast bacilli were negative. HISTOPATHOLOGIC FINDINGS General Autopsy General autopsy disclosed gross tumor metastases to the thoracic vertebrae and microscopic metastases to the spleen and uterus. Multiple nonneoplastic lesions were found in both lungs, both kidneys, the liver, the skin, and the brain. These were found to contain Aspergillus- type organisms on microscopic sections. The endocardium and myocardium were seen to be invaded by Aspergillus organisms on microscopic section and were believed to be the sites from which disseminated aspergillosis originated. CNS A single metastatic carcinoma, 10 mm in diameter, was present in the right gyrus rectus. The brainstem and both cerebral hemispheres, including the left calcarine cortex and the cerebellum, were extensively involved by necrotizing fungal vasculitis and encephalitis. The right calcarine cortex and subcortex showed cortical congestion, edema, and early tissue necrosis, but only a few fungal hyphae were seen. One lesion each was found in the pons, midmedulla, and the periaqueductal gray matter. The dural venous sinuses were unobstructed. Optic Nerves Both optic nerves were examined from the globe to the chiasm. The right optic nerve and its dural sheath were grossly and microscopically normal. Gross examination of the dural ensheathed left optic nerve revealed an area of vascular injection that began immediately behind the globe and extended for a distance of 15 mm ( Fig. 3). The outer diameter of the left optic nerve and dura was 2 mm wider than the comparable area on the right side. On microscopic examination, the dura was markedly thickened, and the subarachnoid space was narrowed and collapsed ( Fig. 4A and B). The anterior 15 mm of the optic nerve showed marked swelling. Transverse sections throughout this portion of the nerve showed early ischemic necrosis involving the entire cross section of the nerve ( Fig. 5) with pyknosis and karyorrhexis of glial nuclei ( Fig. 4A). FIG. 3. Optic nerves with dural sheaths and orbital tissues. There is marked distension of dural vessels of t~ e left optic nerve ( left optic nerve, left; anterior portion of nerves, top). I Clin Neuro- ophthalmol, Vol. 9, No. 1. 1989 10 J. M. WEINSTEIN ET AL. FIG. 4. A: Compressed pia- arachnoid ( arrows) between the dura with vascular thrombosis ( curved arrow) and the acutely necrotic optic nerve with pyknosis of glial nuclei. B: Noncompressed pia- arachnoid of the same nerve from a segment without inflammation or necrosis for comparison with A. A and B: hematoxylin- eosin. x82. A section of the optic nerve located more posteriorly ( 17 mm behind the globe) showed only patchy necrosis most prominent centrally ( Fig. 6). The intracranial optic nerves and chiasm were microscopically normal. Prominent vascular changes were present in the diseased portion of the left nerve. The vessels of the dura and epidura were involved by an inflammatory process manifested by vascular distension, vasculitis with inflammatory infiltrates ( Fig. 7A), and focal fibrinoid necrosis. Within these vessels, a methanamine silver stain revealed septate filamentous fungi of rather uniform width ( 4- 6 f. 1m) exhibiting sharp angle dichotomous branching ( Fig. 78). The vascular inflammatory process extended in some areas to involve vessels of the pia ( Fig. 8), but extensive fungal involvement with thrombosis was seen in many vessels even without inflammation ( Fig. 9A and B). Inflammatory cells were seen neither in the optic nerve parenchyma nor in the vascular walls within the nerve. FIG. 5. A transverse section of the optic nerve with acute necrosis. Note the tissue pallor and focal dissociation. Hematoxylin- eosin. x18. The majority of septal vessels also contained numerous fungi. Fungi were frequently seen outside of vessel lumina but usually only in close proximity to vessels. A central vessel also contained fresh thrombotic material and numerous fungi. This vessel had no intraneural branches except in one area, FIG. 6. A transverse section of the optic nerve obtained more posteriorly. The darker peripheral areas are the surviving nerve tissue, and the patchy pale areas are necrotic tissue. The central artery is unremarkable. Hematoxylin- eosin. x16. OPTIC NEUROPATHY DUE TO ASPERGILLUS FUMIGATUS 11 FIG. 7. A: An epidural artery with inflammatory infiltrates and early thrombosis hematoxylin- eosin. x 130. B: The same artery stained with methenamine silver. There is extensive fungal invasion of the wall and into the neighboring fat tissue. x82. where it may have anastomosed with a pial artery. An elastica van Gieson stain demonstrated this central vessel to be an artery, and it was presumed to be the central retinal artery. A transverse section FIG. 8. A small pial artery with inflammation of its wall and surrouding connective tissue. The optic nerve is on the left ( hematoxylin- eosin, x320). FIG. 9. A: A pial vessel filled with filamentous fungi. Some organisms are also seen in septal vessels ( arrows), in their vicinity, and in the dura. Methenamine silver. x82. B: A pial vessel and a presumably connected septal vessel with extensive recent thrombosis. There is no vasculitis. Hematoxylin- eosin. x82. through the optic nerve 17 mm behind the globe demonstrated patency of this artery with early ischemic necrosis of the central portion of the nerve and relative peripheral sparing ( Fig. 6). No fungi or inflammatory cells were seen at this level. The intracranial optic nerves and the chiasm were grossly and microscopically normal. The portion of the left optic nerve from 18 mm behind the globe to the optic canal was grossly normal and was not examined microscopically. DISCUSSION Our patient first came to us with an episode of transient cerebral ischemia consisting of cortical blindness and upgaze paresis. Although the appearance of her initial MR imaging was consistent with ischemia, no predisposing risk factors for cerebrovascular disease were found. At postmortem examination, an extensive fungal vasculitis in- I eli" Neuro- ophlhalmol. Vol. 9. No. 1. 1989 12 J. M. WEINSTEIN ET AL. volved both calcarine cortices and presumably developed from fungal emboli originating in the heart. We presume that the transient cerebral ischemia was due to fungal embolization of the posterior circulation and that the initial MR imaging reflected a vascular occlusive process rather than fungal invasion of brain parenchyma. It seems unlikely that the myelography was directly related to the cerebrovascular event. Infection of the eNS by Aspergillus species usually occurs in the setting of hematogenous dissemination from a pulmonary or cardiac focus, most often in an immunosuppressed host or an individual involved in i. v. drug abuse ( 17). Signs and symptoms may result from a mass lesion due to granulomatous abscess formation, thrombosis of large arteries traversing the infected subarachnoid space at the base of the brain, or distal propagation of septic thrombus or showers of septic emboli leading to a necrotizing angiitis of small vessels, as was present in our patient ( 17). An indolent or stuttering course over weeks to months, as occurred in our patient, is not uncommon ( 17,18). The pattern of optic nerve involvement in our patient is consistent with the diagnosis of posterior ischemic optic neuropathy due to involvement of small meningeal perforating vessels with fungal embolization and thrombosis. The necrosis of the nerve appeared to be ischemic in nature, with no inflammation of the parenchyma of the nerve. Although the central retinal artery appeared to be involved at autopsy, occlusion of this artery could not have been the cause of acute visual loss in view of the normal fundus examination at the time of acute visual loss. The arterial blood supply to the anterior intraorbital segment of the optic nerve has been extensively reviewed by Singh and Dass ( 19) and by Hayreh ( 20) and consists of two components: an axial centrifugal system derived from the intraneural portion of the central retinal artery, and a peripheral centripetal system derived from the pial arterioles. The axial centrifugal system was present in 75% of specimens examined by Singh and Dass and Hayreh and was absent in 25% ( 19,20). It was entirely absent in our patient, in whom the central retinal artery made no contribution to the blood supply of the retrobulbar optic nerve ( except for a single possible pial anastomosis). A central artery of the optic nerve has been postulated by some authors ( 21) but has not been found either histologically ( 19,20) or in vascular cast studies ( 22) by other investigators ( 19,20). The peripheral pial centripetal system is derived from several sources. Recurrent pial branches, derived from the peripap- I Clin Neuro- ophthalmol, Vol. 9, No. 1, 1989 illary choroid and the circle of Zinn or its substitute, contribute to the immediately retrolaminar portion of the optic nerve. Pial branches may also be derived from the central retinal artery in its intravaginal or intraneural segment. Finally, ophthalmic artery collaterals, such as the muscular branches, may give rise to multiple pial branches that contribute to the peripheral centripetal system. When the centrifugal system is absent or poorly developed, as in our patient, the centripetal system is the major blood supply for the anterior intraorbital optic nerve. In view of the absence of an axial centrifugal vascular system in our patient, we conclude that the ischemic necrosis of her anterior intraorbital nerve was due to infarction of the pial derived centripetal vascular supply ( Fig. 9B). The severe dural inflammation with collapse of the subarachnoid space may have contributed to the ischemic process by compression of the pial vasculature ( Fig. 4A). The patient described by Rootman and Butler had infarction of the entire orbital optic nerve ( 6), unlike our patient and the patient described by Johnson et a1. ( 4). The pathophysiologic findings of the posterior optic nerve infarction in the case of Rootman and Butler were quite different, however, in that their patient had both severe ketoacidosis due to diabetes and giant cell arteritis involving the ophthalmic arteries. The pattern of infarction in our patient is in many ways similar to that reported by Johnson et a1. in a patient with hypotension and anemia ( 4). In both patients, there was severe involvement of the core of the intraorbital nerve with relative sparing of the periphery at the posterior border of the infarcted zone. The patient of Johnson et a1. also had peripheral sparing at the anterior border of the infarct. The selective vulnerability of the central portion of the nerve may be due to its somewhat tenuous blood supply, which is derived from the fine septal branches that constitute an end arterial zone of the centripetal vascular system. Although not specifically mentioned by Johnson et aI., it appears that their patient, like ours, lacked a supplementary centrifugal supply from the central retinal artery. Further histopathologic studies may help to determine whether the absence of a centrifugal system is an important predisposing factor for retrobulbar optic nerve ischemia. In summary, our observations confirm the importance of the meningeal derived centripetal blood supply of the anterior intraorbital optic nerve and demonstrate that infarction of the nerve may occur with massive embolization of this vascular system. OPTIC NEUROPATHY DUE TO ASPERGILLUS FUMIGATUS 13 REFERENCES 1. Hayreh 55. Posterior ischemic optic neuropathy. Ophthalmologica 1981; 182: 2~ 1. 2. Rizzo JF, Lessell S. Posterior ischemic optic neuropathy during general surgery. Am I OphthalmoI1987; 103: 808- 11. 3. Lieberman MF, Shahi A, Green WR. Embolic ischemic optic neuropathy. Am I Ophthalmol 1978; 86: 206-- 10. 4. Johnson MW, Kincaid MC, Trobe JD. Bilateral retrobulbar optic nerve infarctions after blood loss and hypotension. A clinicopathologic case study. Ophthalmology 1987; 94: 157784. 5. Chisholm JA. Optic neuropathy of recurrent blood loss. Br I Ophthalmol 1969; 53: 289- 95. 6. Rootrnan J, Butler D. Ischemic optic neuropathy- a combined mechanism. Br I OphthalmoI1980; 64: 826-- 31. 7. Mazzia VDB, Mark LC, Schner RL, et al. Blindness after hemorrhage. NY State I Med 1962; 62: 2549- 50. 8. Hayreh 55. Anterior ischemic optic neuropathy. I. Terminology and pathogenesis. Br I Ophthalmol 1974; 58: 955-{, 3. 9. Boghen DR, Glaser JS. Ischemic optic neuropathy: the clinical profile and natural history. Brain 1975; 98: 689- 708. 10. Hackett ER, Martinez RD, Larson PF, Paddison RM. Optic neuritis in systemic lupus erythematosus. Arch Neurol 1974; 31 : 9- 11. 11. Hollenhorst RW. Effect of posture on retinal ischemia from temporal arteritis. Arch Ophthalmol 1967; 78: 569- 77. 12. Hedges III TR, Albert DM. The progression of the ocular abnormalities of Herpes Zoster. Histopathologic observations of nine cases. Ophthalmology 1982; 89: 165- 77. 13. Jaben SL, Glaser JS, Daily M. Ischemic optic neuropathy following general surgical procedures. I Clin Neuro Ophthalmol 1983; 3: 239- 44. 14. Sweeney PJ, Breuer AC, Selhorst JB, et al. Ischemic optic neuropathy. A complication of cardiopulmonary by- pass surgery. Neurology 1982; 32: 56G- 2. 15. Hilton GF, Hoyt WF. An arteriosclerotic chiasmal syndrome. lAMA 1966; 196: 1018- 20. 16. Miller NR. Retrobulbar ischemic optic neuropathies. In: Miller NR. Walsh and Hoyt's clinical neuro- ophthalmology. Vol. 1. 4th ed. Baltimore: Williams & Wilkins, 1982: 279-- S3. 17. Young RC, Bennett JE, Vogel CL, Carbone PP, DeVita Yr. Aspergillosis. The spectrum of the disease in 98 patients. Medicine 1970; 49: 147- 63. 18. Weinstein JM, Sattler F, Sassani JW, Towfighi J, Page RB. Optic neuropathy and paratrigeminal syndrome due to Aspergillus fumigatus. Arch Neurol 1982; 39( 9): 582- 5. 19. Singh 5, Dass R. The central artery of the retina. II. A study of its distribution and anastomoses. Br I Ophthalmol 1960; 44: 280- 99. 20. Hayreh 55. The central artery of the retina- its role in the blood supply of the optic nerve. Br I Ophthalmol 1963; 47: 651-{ j3. 21. Francois J, Neetens A. Vascularization of the optic pathway. I. Lamina cribrosa and optic nerve. Br I Ophthalmol 1954; 38: 472-- S8. 22. Fryczkowski A. Branches of the extravaginal, intervaginal and intraneural parts of the central retinal artery of man. Pol Med I 1972; 11: 1305- 10. I Gin Neuro- ophthalmol, Vol. 9, No. 1. 191N |