Journal of Neuro-Ophthalmology, March 1989, Volume 9, Issue 1

Posterior ischemic optic neuropathy due to Aspergillus fumigatus.

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.

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. 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