Apical Orbital Aspergillosis Complicating Giant Cell Arteritis

Isolated amyloid deposition in an extraocular muscle is a rare event but can be a presenting feature of systemic amyloidosis. A 67-year-old woman with an acquired exotropia and hypertropia was found to have unilateral diffuse extraocular muscle enlargement on magnetic resonance imaging. Owing to the progressive nature of her strabismus and the negative laboratory testing for thyroid disease, she underwent an extraocular muscle biopsy that revealed amyloid deposition. Further workup demonstrated a monoclonal gammopathy consistent with systemic amyloidosis. This case demonstrates the need to consider amyloidosis in the differential diagnosis of patients presenting with an atypical acquired strabismus. We review other reports of isolated amyloid deposition in extraocular muscles and its association with systemic amyloidosis, emphasizing the importance of the ophthalmologist in the early recognition of this disease to prevent irreversible, life-threatening end organ damage.

Clinical Observation Apical Orbital Aspergillosis Complicating Giant Cell Arteritis Yang Zhou, BA, Michael L. Morgan, MD, PhD, Sumayya J. Almarzouqi, Patricia Chevez-Barrios, Andrew G. Lee, MD Abstract: A 75-year-old woman with new onset headaches and left vision loss, temporal scalp tenderness, and jaw claudication was found to have biopsy-proven giant cell arteritis (GCA). Despite treatment and improvement with prednisone, she later developed left orbital apex syndrome, and an orbital biopsy revealed aspergillosis. After antifungal treatment, extraocular motility improved although vision in the left eye remained no light perception. Clinicians should be aware that fungal orbital apex disease may mimic or complicate steroid-treated GCA. Journal of Neuro-Ophthalmology 2016;36:159-163 doi: 10.1097/WNO.0000000000000344 © 2016 by North American Neuro-Ophthalmology Society GCA is high, even before confirmatory temporal artery biopsy (2). However, with the immunosuppression of corticosteroid therapy, suspicion for other etiologies that can mimic GCA symptoms should remain, especially if the presentation or response to steroids is atypical (3). Several case reports have described fungal infections producing symptoms and signs similar to GCA (3-11), and we add to this literature by describing a case of biopsy-proven GCA with delayed development of left orbital apex syndrome, subsequently proven to be due to aspergillosis. CASE REPORT G iant cell arteritis (GCA) classically presents with a constellation of clinical symptoms related to ischemia and inflammation, including headache, scalp tenderness, jaw claudication, proximal myalgias (polymyalgia rheumatica), fever and, at times, profound vision loss (1). Corticosteroid therapy should be started immediately when suspicion for Baylor College of Medicine (YZ, AGL, PCB), Adjunct Professor of Ophthalmology, Houston, Texas; Department of Ophthalmology (MLM, SJA, PCB, AGL), Blanton Eye Institute, Houston Methodist Hospital, Houston, Texas; Department of Pathology and Genomic Medicine, Houston Methodist (PCB), Houston, Texas; Weill Cornell Medical College, Adjunct Professor of Pathology and Laboratory Medicine, MD Anderson Cancer Center, Houston, Texas; and Departments of Ophthalmology, Neurology, and Neurosurgery (AGL), Weill Cornell Medical College, Houston, Texas; Clinical Professor, UTMB Galveston, TX and the UT MD Anderson Cancer Center, Houston, Texas; Adjunct Professor of Ophthalmology, The University of Iowa Hospitals and Clinics, Iowa City, Iowa City. Presented in part at the 2015 Walsh Society Meeting, San Diego, CA on February 21, 2015. This work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc, New York, NY. The authors report no conflicts of interest. Address correspondence to Andrew G. Lee, MD, Department of Ophthalmology, Blanton Eye Institute, Houston Methodist Hospital, 6560 Fannin Street, Scurlock 450, Houston, TX 77030; E-mail: [e-mail] Zhou et al: J Neuro-Ophthalmol 2016; 36: 159-163 A 75-year-old caucasian woman developed new onset headaches, left sided temporal scalp tenderness, and jaw claudication. Medical history was significant for asthma and hypothyroidism. Brain magnetic resonance imaging (MRI) and magnetic resonance angiography revealed no abnormalities. Two months later, the patient's vision in the left eye fell to 20/40. Erythrocyte sedimentation rate (ESR) was 23 mm/h and C-reactive protein (CRP) was 1.41 mg/dL (normal: 0.00-0.50 mg/dL). Temporal artery biopsy was consistent with GCA (Fig. 1A, B) and the patient was prescribed prednisone, 60 mg/d. One month later, the patient was hospitalized for worsening, recurrent headaches. Computed tomography (CT) of the brain was unremarkable, and prednisone dosage was increased to 160 mg/d. Two weeks later, vision decreased further to 20/ 200, left eye, after tapering of corticosteroids. ESR and CRP were 32 mm/h and 4.50 mg/dL, respectively. MRI showed enhancement within the left orbit. Dural biopsy at the left orbital apex through a frontotemporal craniotomy was nondiagnostic (Fig. 2). Repeat temporal artery biopsy was consistent with treated GCA (Fig. 1C, D). The patient was referred to our institution for neuroophthalmic assessment. Although vision had recovered to 20/40, left eye, the left pupil was dilated, reacted poorly to light with a left relative afferent defect. The optic discs each 159 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 1. Temporal artery biopsies. A. Initial specimen shows narrowing of vessel lumen and inflammation within the vessel wall (hematoxylin and eosin, ·2). B. Circled area in (A) shows inflammation to be granulomatous (hematoxylin and eosin, ·20). C. Second biopsy shows narrowed vascular lumen because of intimal hyperplasia and thinning of the muscular layer, replaced by fibrosis (hematoxylin and eosin, ·2). D. Second biopsy reveals disruption of internal elastic lamina with surrounding macrophages (brown cells) (immunostain with CD 68 antibody and 3, 39 diaminobenzidine [DAB] chromogen, ·40). had a cup-to-disc ratio of 0.5 and the left disc was pale temporally. Prednisone dosage was 50 mg/d. One month later, the patient's vision in the left eye fell to no light perception (NLP) when prednisone was tapered to 20 mg daily. ESR and CRP were 15 mm/h and 1.02 mg/dL, respectively. Methotrexate was initiated as a steroid-sparing agent, and prednisone was maintained at 20 mg/d. One month later, the patient developed limited movements of her left eye in all directions. The left pupil was fixed and dilated and the left eyelid was ptotic. Ophthalmoscopy showed diffuse left optic disc pallor. ESR and CRP were 14 mm/h and 1.03 mg/dL, respectively, MRI revealed enhancement of the left orbital apex and CT showed FIG. 2. Dural biopsy is unremarkable (hematoxylin & eosin, ·20). 160 erosion of the medial orbital wall (Fig. 3). Using an orbital approach, biopsy of the left orbital apex showed hyphae infiltration consistent with aspergillus involving viable and necrotic tissue and partially necrotic bone (Fig. 4). Treatment with voriconazole and amphotericin B was initiated. Over the ensuing 9 months, vision in the left eye remained NLP but left ocular motility and lid position returned to normal. DISCUSSION Our patient with biopsy-proven GCA also had a superimposed orbital apex aspergillus infection. Although she initially responded to steroid treatment, she ultimately lost all sight in her left eye and palsies of the left third, fourth, and sixth cranial nerves. She might have had preexisting asymptomatic fungal sinus disease exacerbated by corticosteroid and methotreaxate treatment. Antifungal treatment led to improvement in ocular motility and ptosis despite vision remaining NLP in her left eye. Aspergillus infections have been reported to mimic GCA, often with poor outcomes after corticosteroid treatment (3-9). In each case, steroid therapy was initiated for suspected GCA, and a negative temporal artery biopsy followed. There was progression to vision loss and to varying combinations of ocular motor cranial nerve palsies. In most cases, systemic spread of infection led to the death of the patient. Disseminated aspergillus infections also have Zhou et al: J Neuro-Ophthalmol 2016; 36: 159-163 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 3. Precontrast (A) and postcontrast axial magnetic resonance imaging with fat suppression (B) shows enhancement of the left orbital apex extending intracranially. Diffusion-weighted imaging (C) with accompanying apparent diffusion coefficient map (D) confirms restricted diffusion within the area of enhancement. Axial (E) and coronal (F) computed tomography demonstrates erosion of the medial orbital wall posteriorly (arrows). FIG. 4. Orbitral apex biopsy. A. Necrotic tissue is infiltrated with numerous fungal hyphae (arrows) along with areas of chronic inflammation (hematoxylin and eosin, ·10). B. Higher magnification reveals septate hyphae with 45° angle branching (Periodic acid-Schiff, ·40). C. Partially necrotic bone also is infiltrated by fungal hyphae (hematoxylin and eosin, ·10). Zhou et al: J Neuro-Ophthalmol 2016; 36: 159-163 161 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. 162 Death Unknown Normal Unknown Ptosis + CN3 palsy Death Normal Death Partial ptosis Stable at 1 y been documented after biopsy-proven GCA treated with corticosteroids. These cases also were characterized by a high mortality rate (Table 1). Typically, aspergillus sinus infections are noninvasive and benign, but invasive aspergillosis has been documented in immunocompromised (7,12) and, rarely, immunocompetent (12) patients. High-dose systemic corticosteroid treatment (defined as prednisone equivalent of 20 mg/d for 3 weeks) also is a recognized risk factor for invasive aspergillosis (13). The clinical manifestations of invasive aspergillosis are variable, but may mimic GCA, with a persistent unilateral headache followed by ophthalmic symptoms and signs, which can improve transiently after corticosteroid treatment, further delaying diagnosis (3,5,7,8,12). With the location of the invasive aspergillus infections within the orbit, most of these cases develop vision loss and varying degrees of ophthalmoplegia, consistent with orbital apex syndrome (14,15). When an infectious process at the orbital aspex such as aspergillus is suspected, neuroimaging is mandatory. MRI is favored for visualization of soft tissues, whereas CT is preferable to evaluate the paranasal sinuses and bony structures (12,16). Biopsy provides definitive diagnosis, with repeat biopsy a consideration if clinical suspicion is high (9,14). Invasion of bone, mucosa, and other tissue by fungal hyphae is considered the hallmark of invasive aspergillosis (17). Primary therapy with voriconazole has been shown to be superior to amphotericin B, with some studies also supporting combination therapy for an echinocandin combined with voriconazole, although further trials are needed to verify this approach (18-20). 80/M 68/M 76/F Murosaki et al (7) Dinowitz et al (8) Ali et al (9) CN3, third nerve; CN6, sixth nerve; F, female; M, male. Yes-positive Yes-positive Normal Partial ptosis Normal Unknown 68/M 82/M Staud and Williams (5) Samy and Chronister (6) Wiggins (10) Chmelewski et al (11) 68/M Seton et al (4) 80/M Vision loss, temporal pain Unknown Unknown 3rd and 6th nerve palsies Normal 3rd and 6th nerve palsies Fever, temporal pain Vision loss Headache, blurred vision IV micafungin Amphotericin B Amphotericin B + voriconazole Amphotericin B Unknown Death Death Yes-negative Inadequate biopsy -negative Yes-negative No Yes-negative 3rd and 6th nerve palsies Normal Headache Headache Ampicillin + metronidazole Amphotericin B "Antifungal therapy" Headache, vision loss No CN 3 + 6 palsy Normal Death Death Ptosis + complete opthalmoplegia CN 6 palsy Cephalexin Yes-negative Ptosis and complete ophthalmyplegia 6th nerve palsy 75/M Hutnik et al (3) Declining vision Ocular Motility Initial Complaint Age, y/ Gender Report TABLE 1. Cases of giant cell arteritis associated with aspergillus infection Temporal Artery Biopsy? Treatment in Addition to Corticosteroids? Motility? Outcome Clinical Observation STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: Y. Zhou, M. L. Morgan, S. J. Almarzouqi, P. Chevez-Barrios, A. G. Lee; b. Acquisition of data: Y. Zhou, M. L. Morgan, S. J. Almarzouqi, P. Chevez-Barrios, A. G. Lee; c. Analysis and interpretation of data: Y. Zhou, M. L. Morgan, S. J. Almarzouqi, P. Chevez-Barrios, A. G. Lee. Category 2: a. Drafting the article: Y. Zhou, M. L. Morgan; b. Revising it for intellectual content: P. Chevez-Barrios, A. G. Lee. Category 3: a. Final approval of the completed article: P. Chevez-Barrios, A. G. Lee. REFERENCES 1. Chew SSL, Kerr NM, Danesh-Meyer HV. Giant cell arteritis. J Clin Neurosci. 2009;16:1263-1268. 2. Aiello PD, Trautmann JC, McPhee TJ, Kunselman AR, Hunder GG. Visual prognosis in giant cell arteritis. Ophthalmology. 1993;100:550-555. 3. Hutnik CM, Nicolle DA, Munoz DG. Orbital aspergillosis. A fatal masquerader. 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