Journal of Neuro-Ophthalmology, December 1997, Volume 17, Issue 4

Orbital Aspergillosis

Ocular manifestations of aspergillosis are emerging as increasingly more atypical, with a wide spectrum of presentations. The classic teaching is that this fungus presents as an endogenous endophthalmitis in immunocompromised hosts. In most other ocular conditions, the index of suspicion for this infection has typically been low, especially in apparently immunocompetent individuals. However, reports continue to appear that confirm involvement of Aspergillus species in a wide variety of primary ocular and orbital conditions characterized by rapid, uncontrollable progression and, not uncommonly, death. This report highlights a case of autopsy-proven orbital aspergillosis that masqueraded as temporal arteritis in terms of initial clinical presentation and response to standard therapy. Any ocular condition that manifests even subtle atypical features, including temporal arteritis, should be regarded as suspect, and an aggressive approach to secure a biopsy of any involved sites should follow.

Journal of Neuro- Ophthalmology 17( 4): 257- 261, 1997. © 1997 Lippincott- Raven Publishers, Philadelphia Orbital Aspergillosis A Fatal Masquerader Cindy M. L. Hutnik, B. SC. ( Hon.), Ph. D., M. D., David A. Nicolle, M. B., ch. B., F. R. C. S. C, F. R. C. S. E, F. R. c. Ophth, and David G. Munoz, M. D., F. R. C. P. C. Ocular manifestations of aspergillosis are emerging as increas­ingly more atypical, with a wide spectrum of presentations. The classic teaching is that this fungus presents as an endogenous endophthalmitis in immunocompromised hosts. In most other ocular conditions, the index of suspicion for this infection has typically been low, especially in apparently immunocompetent individuals. However, reports continue to appear that confirm involvement of Aspergillus species in a wide variety of primary ocular and orbital conditions characterized by rapid, uncontrol­lable progression and, not uncommonly, death. This report highlights a case of autopsy- proven orbital aspergillosis that masqueraded as temporal arteritis in terms of initial clinical presentation and response to standard therapy. Any ocular con­dition that manifests even subtle atypical features, including temporal arteritis, should be regarded as suspect, and an ag­gressive approach to secure a biopsy of any involved sites should follow. Key Words: Aspergillosis, atypical- Ocular disease- Masquerader. CASE REPORT A 75- year- old white man was referred with a 1- week history of rapidly declining vision in his right eye. He denied any pain or tenderness in his head, jaw, or scalp. One week before presentation, he had been hospitalized and treated for pneumonia with intravenous erythromy­cin followed by oral ciprofloxacin. Eight months previ­ously, he had a limited episode of right herpes zoster ophthalmicus. Best- corrected visual acuity was no light perception in the right eye and 20/ 25 in the left eye. The right pupil did not react to light. Extraocular motility, optokinetic nys­tagmus, and saccadic eye movements were within nor­mal limits. Anterior segment examination and intraocular pressures were normal. The right temporal artery was Manuscript received November 12, 1996; accepted March 26, 1997. From the Departments of Ophthalmology ( C. M. L. H., D. A. N.) and Pathology ( D. G. M.), University of Western Ontario, London, Ontario, Canada. Address correspondence and reprint requests to Dr. David A. Nicolle, Department of Ophthalmology, London Health Sciences Cen­ter, University Hospital Campus, 339 Windermere Road, London, On­tario, Canada N6A 5A5. prominent and tender to palpation ( Fig. 1). There was pallid edema of the entire right optic disc, compared with a normal- appearing left disc. The retinal vessels and macular regions were unremarkable in both eyes. Gold-mann perimetry was not possible on the right but re­vealed a full field on the left. The Wintrobe erythrocyte sedimentation rate ( ESR) was 34 ( reference range, 0- 7 mm/ hour). Unlike the Westergren scale, age dependence is usually not specified with the Wintrobe scale. The hematocrit was 40% ( reference range, 40- 50%). An 80- mg daily dose of oral prednisone was started in view of the presumptive diagnosis of right anterior ischemic op­tic neuropathy secondary to temporal arteritis. A right temporal artery biopsy performed 48 hours later revealed ' ' no evidence of inflammation to support a diagnosis of temporal arteritis." Because the patient felt systemically better, the oral steroids were continued. Nine days later, the ocular examination demonstrated no worsening and the ESR was down to 10 mm/ hour. A slow taper of prednisone by 5 mg/ week was initiated. The patient remained stable until 6 weeks later, when he returned with increasing pain in the right forehead. The ESR was 21 and a computed tomography ( CT) scan revealed a homogeneous right orbital apex mass extend- FIG. 1. Prominent, nodular, tender right temporal artery. 257 258 C. M. L. HUTNIKETAL. FIG. 2. Axial computed tomography scan of head showing right posterior orbital apical lesion with involvement of the adjacent ethmoid sinus. ing into the posterior ethmoid sinus ( Fig. 2). Magnetic resonance imaging ( MRI) confirmed the mass involved the right optic canal and superior orbital fissure. There was no change in the ocular examination compared with presentation. We sought the opinion of an otolaryngolo­gist, who stated the lesion was too close to the optic nerve to sample for biopsy and appeared inflammatory, thus recommending close observation. The oral steroids were rapidly tapered off. One week later, 2 mm of right proptosis and a 20% limitation of right extraocular motility in all fields of gaze developed in the patient. Oral cephalexin was started with the suspicion that this could be an extended paranasal infectious process. Over the next 2 weeks, the patient's condition continued to deteriorate rapidly, with the development of a right ptosis and complete ophthal­moplegia ( Fig. 3). This was accompanied by increasing weakness and weight loss. A malignancy screen, which included chest radiography, CT of abdomen, and gastro­intestinal endoscopy, was negative. Within a period of days, the patient manifested left- sided hemiparesis, ataxia, and decreased vision in his left eye to hand mo­tion. A repeat MRI revealed a large, right temporal he­matoma with associated mass effect and hemorrhage in the lateral ventricle. The meninges were diffusely en­hancing, especially around the right cavernous sinus. Two small, ring- enhancing lesions were noted in the right inferior frontal lobe ( Fig. 4). The right orbital apex mass was extending into the cavernous sinus and signifi­cant mucosal changes were apparent in the ethmoid and sphenoid sinuses. In consultation with the infectious dis­eases service, the patient was started on daily intravenous doses of 200 mg fluconazole and 50 mg amphotericin B. Despite broad antibacterial and antifungal coverage, the patient died 1 week after admission. The cause of death was found to be a massive right inferior intraparen-chymal cerebral and subarachnoid hemorrhage second­ary to rupture of the right internal carotid artery weak­ened by invasion with Aspergillus fumigatus ( Fig. 5). Numerous septate, branching hyphae were noted in the connective tissue, muscles, and cranial nerves in the right orbit ( Fig. 5). No fungal elements were noted in the lungs FIG. 3. Right blepharoptosis and ophthalmoplegia demonstrated in various positions of gaze. J Neuro- Ophthalmol, Vol. 17, No. 4, 1997 ORBITAL ASPERGILLOSIS 259 FIG. 4. A: Fat- suppressed, T1- weighted, coronal magnetic reso­nance images ( MRI) of head demonstrating ring- enhancing le­sions ( arrow) in the right inferior frontal lobe. The pregadolinium and postgadolinium images are depicted from left to right. B: T2- weighted axial MRIs of head showing massive hematomas ( arrows) with a mass effect in the right cerebral hemisphere. The pregadolinium and postgadolinium images are depicted from left to right. or any other extracranial location. The findings were consistent with a fungal vasculitis presenting clinically in the right orbit and with involvement of the paranasal sinuses, neighboring dura, and right cavernous sinus, as confirmed pathologically. DISCUSSION Aspergillus is a saprophytic fungus with a particularly ominous status in terms of ocular disease. It is a ubiqui­tous organism that typically colonizes the respiratory and gastrointestinal tracts and rarely causes infection in the immunocompetent host. The most common ocular infection caused by this fun­gus is endogenous endophthalmitis ( 1), which has been reported in immunocompetent hosts with no predispos­ing factors ( 2). Orbital involvement is much less fre­quent, and most often presents in an immunocompro­mised patient with a fulminant sinusitis and necrotizing vasculitis of the sinus and nasal mucosa, orbit, and cra­nium with typical dissemination involving the lung, liver, and spleen ( 3). In the minority of patients, it has a more insidious onset with a slow erosion through the bones of the orbit and skull, with headache and neuro­logic and orbital signs and symptoms being the more usual presentation. In healthy, immunocompetent people, an Aspergillus infection is most commonly associated with a chronic sinusitis ( 4). However, orbital and intracerebral findings may be the initial presentation of a fungal infection in people with few obvious predisposing factors. Heier and coworkers reported four cases of fungal sinusitis in immunocompe­tent young adults who presented with proptosis ( 5). Su­zuki et al. ( 6) described the rare case of an 83- year- old woman who suffered a fatal massive subarachnoid hem­orrhage due to rupture of an Aspergillus infection of the middle cerebral artery. The infection was believed to have extended from the paranasal sinuses, even though visual disturbance and headache were the main present­ing symptoms. The only predisposing factor in this pa­tient was age. Mauriello et al. ( 7) described five case series of patients with invasive rhino- orbital aspergillosis who presented with the acute onset of profound visual loss, ophthalmoplegia, blepharoptosis, proptosis, and pe­riorbital pain or headache. They described how the in­fection in this location can be fatal despite early ex­enteration. Wiggins ( 8) reported the case of an 80- year-old woman with biopsy- proven temporal arteritis who died of disseminated aspergillosis 6 weeks after initiation of corticosteroid therapy. Similar to the patient described in this report, his patient initially improved, only to suc­cumb to a relentless deterioration marked by ring-enhancing cerebral abscesses. Wiggins attributed the death of this patient to a rare complication of the corti­costeroid immunosuppressive therapy of temporal arteri­tis. Her only other predisposing factor was advanced age. The current report demonstrates yet another rare pre­sentation of ocular aspergillosis. The symptoms of pro­found, unilateral visual loss and a tender, nodular tem­poral artery closely mimicked temporal arteritis. Because the temporal artery biopsy was shown to be negative in multiple sections, it is likely that the Aspergillus infec­tion was the primary event in this patient's demise. The visual compromise was secondary to the orbital involve­ment. The optic nerve was not invaded by the organism. Although not causative, the corticosteroid therapy likely contributed to the precipitous course of the disease. It is likely the infection arose from the paranasal sinuses based on the known disease patterns of this organism; however, the possibility of primary orbital involvement cannot be excluded based on the investigations reported here. The major predisposing factors in this patient were age, recent bacterial pneumonia, and possibly the previ­ous herpes zoster infection. Each of these factors may have created a state of relative immunodeficiency. At autopsy, no evidence of fungal elements was identified in the lungs or any other extracranial organ. A recent review describes the case of a 74- year- old man with optic nerve aspergillosis who presented with headache, amaurosis fugax, diplopia, and a negative tem­poral artery biopsy ( 9). Over a period of 6 days, he underwent rapid development of no light perception vi- J Neuro- Ophthalmol, Vol. 17, No. 4, 1997 260 C. M. L. HUTNIK ET AL. FIG. 5. A: Gross pathology of brain showing massive right hemispheric hemorrhage ( arrow). B: Microscopic pathology of ruptured wall of right internal carotid artery ( arrow). C: Higher magnification of the wall of the right internal carotid artery shown in ( B) with multiple branching septate hyphae ( arrow) of Aspergillus fumigatus visible. D: High- magnification view of the right orbital tissue displaying numerous branching septate hyphae ( arrow) of A. fumigatus within areas of collagen necrosis. sion, at which time an orbital apex mass was discovered. Orbital biopsy provided optic nerve dural tissue that was positive for Aspergillus species. Despite treatment with amphotericin B, the patient died 2- 3 months later sec­ondary to pneumococcal pneumonia and sepsis. At the time of diagnosis, radical debridement of the orbital apex tissue was deferred secondary to the tenuous medical status of the patient. Possible iatrogenic potentiation of the infectious process was raised because the patient had been treated with intravenous heparin and methylpred-nisolone on presentation, despite a negative temporal ar­tery biopsy. The review highlighted that corticosteroids may contribute to the pathogenicity of aspergillosis by a combination of suppression of the host immune response as well as by increasing the actual growth rate of the organism ( 9). It is now clear that orbital aspergillosis should be in­cluded in the differential diagnosis of infectious, neo­plastic, and granulomatous orbital conditions, as well as certain neuro- ophthalmologic and even adnexal condi­tions. Although Aspergillus species are the most com­mon fungal contaminants of the sinuses, other fungal elements can produce a similar clinical picture, espe­cially in endemic areas. When a patient presents with optic nerve signs or symptoms, especially with concomi­tant ophthalmoplegia, the possibility of aspergillosis should be considered before instituting steroid therapy. This can be aided by recognition of certain risk factors such as neutropenia, hematologic malignancies, diabetes mellitus, endemic exposure, and perhaps even advanced age ( 9). Both CT and MRI play key roles in the diagnosis. Studies have demonstrated that radiodense concretions may be present in up to 56% of patients with aspergillo­sis of the sinus ( 10), especially if the radiodensity is greater than 2000 Hounsfield units ( 11). Ideally, most sources recommend biopsy of the involved area with extensive surgical debridement and antifungal therapy once the diagnosis is confirmed ( 12). In the case pre­sented in this report, the unfortunate posterior location of the abscess in the orbital apex, the atypical clinical pre­sentation, and the low index of suspicion reduced the aggressiveness to secure the biopsy. Reports have de­scribed the utility of fine- needle aspiration biopsy ( 13) and CT- guided transorbital needle biopsy ( 14) in the di­agnosis of orbital lesions, including aspergillosis. How­ever, because a definitive diagnosis is not always pos­sible owing to small specimen size, the more standard neurosurgical or orbital approaches of biopsy are still preferred if the patient can withstand the process. We support the recommendations of Wiggins ( 8) that all patients with suspected temporal arteritis have a tem- J Neuro- Ophthalmol, Vol. 17, No. 4, 1997 ORBITAL ASPERGILLOSIS 261 poral artery biopsy. We further recommend that those patients who, after initiation of treatment, continue to deteriorate or manifest other unexplained findings, be further investigated based on an increased index of sus­picion for aspergillosis. A number of risk factors, includ­ing advanced age alone, should alert the clinician to the possibility of orbital aspergillosis. Biopsy of any sus­pected areas should be aggressively pursued early in the management of these conditions, even by needle, if a posterior orbital location, or poor general medical status, precludes a standard surgical approach. If repeat tempo­ral artery biopsy is negative, steroid therapy should be discontinued, unless laboratory evidence exists for a definite inflammatory condition that may benefit from such therapy. REFERENCES 1. McDonnell PJ, McDonnell, JM, Brown RH, Green WR. Ocular involvement in patients with fungal infections. Ophthalmology 1985; 92: 706- 9. 2. Valluri S, Moorthy RS, Liggett PE, Rao NA. Endogenous As­pergillus endophthalmitis in an immunocompetent individual. Int Ophthalmol 1993; 17: 131- 5. 3. Maniglia AJ, Goodwin WJ, Arnold JE, Ganz E. Intracranial ab­scesses secondary to nasal, sinus, and orbital infections in adults and children. Arch Otolaryngol Head Neck Surg 1989; 115: 1424- 9. 4. Washburn RG, Kennedy DW, Begley MG, et al. Chronic fungal sinusitis in apparently normal hosts. Medicine 1988; 67: 231- 47. 5. Heier JS, Gardner TA, Hawes MJ, McGuire KA, Walton WT, Stock J. Proptosis as the initial presentation of fungal sinusitis in immunocompetent patients. Ophthalmology 1995; 102: 713- 17. 6. Suzuki K, Iwabuchi N, Kuramochi S, et al. Aspergillus aneurysm of the middle cerebral artery causing a fatal subarachnoid hemor­rhage. Int Med 1995; 34: 550- 3. 7. Mauriello JA Jr, Yepez N, Mostafavi R, et al. Invasive rhinosino-orbital aspergillosis with precipitous visual loss. Can J Ophthalmol 1995; 30: 124- 30. 8. Wiggins RE Jr. Invasive aspergillosis. A complication of treatment of temporal arteritis. Journal of Clinical Neuro- Ophthalmology 1995; 15: 36- 8. 9. Levin LA, Avery R, Shore JW, et al. The spectrum of orbital aspergillosis: a clinicopathological review. Surv Ophthalmol 1996; 41: 142- 54. 10. Kopp W, Fotter R, Steiner H, et al. Aspergillosis of the paranasal sinuses. Radiology 1985; 156: 715- 6. 11. Krennmair G, Lenglinger F, Muller- Schelken HP. Computed to­mography ( CT) in the diagnosis of sinus aspergillosis. J Craniom-axillofac Surg 1994; 22: 120- 5. 12. Harris GJ, Will BR. Orbital aspergillosis: conservative debride­ment and local amphotericin irrigation. Ophthal Plast Reconstr Surg 1989; 5: 207- 11. 13. Austin P, Dekker A, Kennerdell JS. Orbital aspergillosis: report of a case diagnosed by fine needle aspiration biopsy. Acta Cytol 1983; 27: 166- 9. 14. Rowed DW, Kassel EE, Lewis AJ. Transorbital intracavernous needle biopsy in painful ophthalmoplegia. J Neurosurg 1985; 62: 776- 80. J Neuro- Ophthalmol, Vol. 17, No. 4, 1997 [CLorbitalinfections]