Orbital Apex Syndrome Secondary to Invasive Aspergillus Infection: A Case Series and Literature Review

Invasive fungal sinusitis carries high morbidity and mortality and often poses a diagnostic challenge. Orbital apex syndrome (OAS) is not an uncommon presentation in the setting of invasive fungal sinusitis. Delays in diagnosis and appropriate treatment can result in permanent visual dysfunction and, potentially, death. We present 2 cases of OAS secondary to invasive sinus aspergillosis, detailing the diagnostic process, treatment, and outcome for both patients. Subsequently, we present a review of the literature and combined analysis of our 2 patients plus 71 cases from previously published reports

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Orbital Apex Syndrome Secondary to Invasive Aspergillus Infection: A Case Series and Literature Review Melissa Yuan, BA, Anika Tandon, MD, Anfei Li, PhD, Editha Johnson, DO, Christine Greer, MD, Andrea Tooley, MD, Ann Q. Tran, MD, Kyle J. Godfrey, MD, Marc Dinkin, MD, Cristiano Oliveira, MD Background: Invasive fungal sinusitis carries high morbidity and mortality and often poses a diagnostic challenge. Orbital apex syndrome (OAS) is not an uncommon presentation in the setting of invasive fungal sinusitis. Delays in diagnosis and appropriate treatment can result in permanent visual dysfunction and, potentially, death. We present 2 cases of OAS secondary to invasive sinus aspergillosis, detailing the diagnostic process, treatment, and outcome for both patients. Subsequently, we present a review of the literature and combined analysis of our 2 patients plus 71 cases from previously published reports. Methods: Literature review was performed to identify demographic, diagnostic, clinical, and treatment data of patients with OAS caused by Aspergillus species. Results: The review resulted in 52 included articles with 71 patients, plus our 2 reported patients, leading to a total of 73 subjects included in the analysis. The average age of patients at presentation was 59.9 years. A combination of visual disturbance and pain (headache and/or periocular pain) was the most common presentation reported (46 cases; 63%). Diabetes mellitus was reported in 15 cases (21%), with more than half specifically noted to have poorly controlled diabetes. After diabetes, the second most common cause of immunocompromise was chronic steroid use (n = 13; 18%). Empiric antifungal treatment was started in 10 patients (14%), while 25 patients (34%) were first treated with systemic steroids due to a concern for an inflammatory etiology. Time to diagnosis from initial presentation was on average 7.4 weeks (range of 0.3–40 weeks). Approximately 78% of the cases (57 of 73) had biopsies with histology that confirmed Aspergillus fungal morphology, and 30/73 (41%) had diagnostic fungal cultures. The majority of the cases received monotherapy with intravenous Weill Cornell Medical College (MY, AL), New York, New York; and Department of Ophthalmology (A. Tandon, EJ, CG, A. Tooley, A. Tran, KJG, MD, CO), Weill Cornell Medical College, New York, New York. The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). Address correspondence to Cristiano Oliveira, MD, Department of Ophthalmology, Weill Cornell Medical College, 1305 York Avenue, 11th Floor, New York, NY 10021; E-mail: [e-mail] Yuan et al: J Neuro-Ophthalmol 2021; 41: e631-e638 (IV) amphotericin B (36 patients; 49%) and IV voriconazole (19 patients; 26%), with a combination of the 2 or more antifungal agents being used in 11 patients (15%). Forty patients (55%) showed signs of clinical improvement with treatment, while 33 (45%) patients did not experience any improvement or continued to deteriorate, and 23 (32%) died in the course of their reported follow-up. Conclusions: The present cases illustrate well the challenge in the diagnosis and treatment of OAS due to invasive sinus aspergillosis. Our review and analysis of 73 cases support the notion that a high index of suspicion leading to early biopsy with histology and fungal culture is paramount for diagnosis. Early empiric antifungal treatment and debridement can potentially reduce morbidity and mortality. Journal of Neuro-Ophthalmology 2021;41:e631–e638 doi: 10.1097/WNO.0000000000001105 © 2020 by North American Neuro-Ophthalmology Society A spergillus species are ubiquitous fungi found in soil that rarely causes lung and paranasal sinus infection (1). Orbital extension is reported in 60%–90% of patients with primary invasive fungal sinusitis (IFS) and can manifest as diffuse orbital inflammation or produce an orbital apex syndrome (OAS) with ophthalmoplegia and optic neuropathy (2–4). Although the incidence of OAS from fungal infection is low, the risk of vision and life-threatening sequelae is high (2,4–6). In these cases, diagnosis is often delayed because of unfamiliarity of care providers with this rare manifestation, nonspecific examination findings, and unrevealing initial diagnostic studies (1). Delays in diagnosis and treatment can lead to significant morbidity and mortality, with reported mortality rates between 70% and 90% (2,7,8). IFS can also be caused by Mucor, which carries an even higher mortality rate (2,8,9). We describe 2 cases of OAS secondary to invasive sinus aspergillosis, emphasizing the diagnostic process, treatment, and outcomes, and present a literature review of published reports of invasive Aspergillus sinusitis causing OAS. e631 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Case 1 A 78-year-old woman with a history of poorly controlled diabetes mellitus (DM) was admitted to an outside hospital for 3 months of diplopia, right eye pain, and temporal headaches. With the findings of a right abducens palsy, an elevated erythrocyte sedimentation rate (77 mm/h), and an allegedly unrevealing noncontrast head computed tomography (images unavailable to our team), she was started on oral prednisone 60 mg daily for presumed temporal arteritis. A temporal artery biopsy 3 weeks later was negative, but prednisone could not be tapered by her neurologist without worsening of her pain. One month later, she developed right upper eyelid ptosis, and contrast-enhanced MRI brain/ orbits demonstrated new right sphenoid sinusitis. Within a week, she progressed to complete right eye ophthalmoplegia, with repeat neuroimaging concerning for worsening sinus disease and extension to the right cavernous sinus; magnetic resonance angiogram of the head was normal. Lumbar puncture showed a normal white blood cell count and elevated protein and glucose. Empiric treatment with vancomycin, ceftriaxone, and metronidazole was started, and she was transferred to our institution. Inpatient neuro-ophthalmic examination demonstrated a visual acuity of 20/200, dyschromatopsia and a relative afferent pupillary defect (by reverse) in the right eye with no funduscopic abnormalities. There was complete ophthalmoplegia of the right eye with ptosis and mydriasis. Visual function was normal in the left eye. A contrast-enhanced MRI brain/orbits revealed inflammatory changes in the right orbit consistent with OAS (Fig. 1A, B). Endoscopic right sphenoidotomy with biopsy was performed, with fungal and bacterial cultures sent. Broad spectrum antibiotics were continued, and amphotericin B 5 mg/kg daily was added. Oral prednisone was quickly tapered. Fungal beta-D glucan was positive at 377, and on hospital day 4, nasal sinus cultures grew Aspergillus fumigatus complex. She was discharged on hospital day 14 on voriconazole 400 mg twice daily with vision 20/400 in the right eye and stable efferent dysfunction. Two weeks after discharge, her vision decreased to light perception. After 3 months of treatment with oral voriconazole, the neuro-ophthalmic examination showed partial improvement of the ophthalmoplegia with resolved right ptosis, unchanged no light perception vision in the right eye, and mild temporal optic disc pallor, while MRI brain/orbits showed only partial improvement of the right orbital apex and cavernous sinus inflammation. The examination was largely unchanged at 10 months after her hospitalization, except with more diffuse right optic disc pallor. Case 2 A 64-year-old man with poorly controlled DM, systemic hypertension, and macular scar of unknown etiology in the left eye causing longstanding poor vision, developed acute, e632 painless vision loss in his right eye; at that time, an evaluation by a local specialist in Bangladesh was unrevealing. One month later, he traveled to the United States and sought medical attention for persistent poor vision and right periorbital and face pain. Inpatient neuro-ophthalmic examination revealed no light perception vision in the right eye and 20/200 vision in the left eye with a right amaurotic pupil and full ocular motility; dilated funduscopic examination was significant only for background diabetic retinopathy in both eyes and a macular scar in the left eye. Contrast-enhanced MRI brain/orbits revealed a nonspecific enhancing soft-tissue mass in the right sphenoid sinus with extension to the orbital apex. He was started on boardspectrum antibiotics. Blood cultures, lumbar puncture, and laboratory testing including QuantiFERON gold were normal. Biopsy of the right sphenoid sinus showed nonspecific chronic inflammation with mixed lymphoplasmacytic infiltrates, and cultures were negative; therefore, antibiotics were discontinued by the primary team and he was discharged, with a working diagnosis of a nonspecified inflammatory or malignant process. Unfortunately, there was a delay in his outpatient neuroophthalmological follow-up, which took place 4 weeks after his hospital discharge and showed stable afferent function, new complete right eye ophthalmoplegia (no eye movement, fixed mydriasis, and ptosis), and unchanged dilated funduscopic examination in both eyes. MRI brain/orbits revealed progression of the enhancing soft-tissue mass within the right sphenoid sinus and right orbital apex (Fig. 1C, D). He was readmitted and treated with vancomycin, metronidazole, and amphotericin B. Repeat endoscopic right sphenoid sinus biopsy was again unrevealing, but 2 weeks later, internal transcribed spacer (ITS) sequencing on the same specimen confirmed the diagnosis of A. fumigatus. His ophthalmic examination remained stable throughout his month-long hospitalization, and he was discharged on isavuconazole. On subsequent outpatient follow-up, he demonstrated improvement in his extraocular motility. The recommended surveillance MRI was not obtained because of patient nonadherence. Six months later, he became somnolent, and repeat neuroimaging revealed multifocal intracranial abscesses and a new subacute infarction in the right middle cerebral artery watershed territory with occlusion of the right internal carotid artery, attributable to angioinvasive fungus. A multidisciplinary care team of ophthalmology, rhinology, and neurosurgery discussed all surgical options with the patient including endoscopic, transorbital, and transcranial debridement and resection of the sinusoidal mass, but the patient elected to decline surgery and return to his home country on oral voriconazole. METHODS A literature search of published cases of OAS secondary to Aspergillus species was performed on April 7, 2020, by Yuan et al: J Neuro-Ophthalmol 2021; 41: e631-e638 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Postcontrast sequences with fat saturation of the MRI brain and orbits for both cases, demonstrating the orbital apex enhancement (white arrows) and paranasal sinus involvement (stars). A and B. From case 1, coronal and axial sequences, respectively; (C and D) from case 2, coronal and axial sequences, respectively. searching PubMed and Google Scholar with the terms: “orbit* apex syndrome,” “invasive sino-orbital Aspergillus,” “orbital Aspergillus infection,” “invasive fungal orbit* infect*,” “invasive aspergillosis,” and “orbital Aspergillus.” The inclusion criteria were full length articles (with data available regarding presentation, diagnosis, and/or treatment), in English, sole infection with Aspergillus, patients 18 years or older, and evidence of OAS, defined as a syndrome of orbital inflammation with ophthalmoplegia and optic neuropathy (63). A standardized table was used to collect data including patient demographics, comorbidities, presentation, diagnostic testing, treatment, and outcomes (see Supplemental Digital Content 1, Table E1, http:// links.lww.com/WNO/A441). RESULTS Our search yielded 107 articles, of which 54 were excluded (17 for insufficient data, 3 for coinfection with other fungal species, 6 for no infection with Aspergillus, 4 had no full text, 11 were not in English, 12 did not fit clinical criteria for OAS, and 1 due to age). Seventy-one patients from 52 articles were included (see Supplemental Digital Content 1, Table E1, http://links.lww.com/WNO/A441); those combined with the presented 2 cases provided a total of 73 subjects analyzed. Yuan et al: J Neuro-Ophthalmol 2021; 41: e631-e638 Patient Characteristics Patient characteristics are shown in Table 1. The average age at presentation was 59.9 years (range 20–83). Thirtynine (53%) patients were male. Thirty-nine patients (53%) had only right-side involvement, and 5 (7%) presented with bilateral disease. A combination of visual disturbance and pain (headache and/or periocular) was the most common presenting symptom (46 cases; 63%). Painless vision loss was seen in 13 (18%), and isolated pain with no loss of vision was the first symptom in 7 (10%). Other presenting symptoms included seizure, back pain, eye discharge, and hemiparesis. The average duration of symptoms before initial presentation was 9.4 weeks (range 1–72). Comorbidities and immunocompromising conditions are detailed in Table 2. Twenty-eight patients (38%) were immunocompromised. DM was reported in 15 cases (21%), with 8 noted to be poorly controlled, and chronic steroid use was reported in 13 (18%). Empiric antifungal treatment was started in only 10 patients (14%), while 25 patients (34%) were initially treated with systemic steroids. Diagnostics Time to diagnosis from the initial presentation to the treating team was specified only in 27 cases, with a mean of 7.4 weeks (range 0.3–40 weeks; Table 1). Biopsy confirmed e633 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Patient characteristics Characteristic Age (y) (n = 73) Gender (n = 73) Laterality (n = 73) Presenting symptoms (n = 73) Visual acuity at presentation (n = 55) Duration of symptoms before presentation (wk) (n = 64) Empiric antifungals before diagnosis (n = 73) Empiric steroids before diagnosis (n = 73) Imaging (n = 60) Time from presentation to diagnosis (wk) (n = 27) Clinical improvement with treatment (n = 73) Length of follow-up (wk) (n = 33) Death (n = 73) Categories Number (%) Mean Range Male Female Left Right Bilateral Visual disturbance Pain (headache or periocular) Both visual disturbance and pain Other No light perception Light perception, hand motion, or count fingers Other Mean Range Yes No Yes No CT only MRI only CT and MRI Mean Range Yes No Mean Range Yes No 59.9 20–80 39 (53) 34 (47) 29 (39) 39 (53) 5 (7) 13 (18) 7 (10) 46 (63) 7 (10) 16 (29) 12 (22) 27 (49) 9.4 1–72 10 (14) 63 (86) 25 (34) 48 (66) 19 (32) 13 (22) 28 (47) 7.4 0.3–40 40 (55) 33 (45) 45.2 1–192 23 (32) 50 (68) CT, computed tomography Aspergillus fungal morphology in 57/73 (78%) of cases (Table 3). Thirty patients (41%) also had diagnostic fungal cultures performed on vitrectomy fluid, pus aspirate, soft tissue, and bone specimens. Twenty-five patients (34%) had definitive diagnosis from both histology and fungal cultures, while 5 had initially nondiagnostic biopsies. Two patients had positive Polymerase chain reaction (PCR) of the blood for Aspergillus in addition to positive fungal cultures, 1 patient had diagnostic blood PCR in addition to a biopsy with characteristic histology, and 1 had diagnostic PCR alone. Four patients had positive Aspergillus blood antigen. Treatment The initial antifungal treatment regimen was specified in 58 patients (Table 4), of whom the majority received monotherapy with intravenous (IV) amphotericin B (36 patients; 49%) or IV voriconazole (19 patients; 26%), with a combination of $2 antifungal agents in 11 patients (15%). Six patients received no antifungal treatment, 2 received unspecified “intense” or “IV” antifungal treatment, and no information on treatment was available in 15 (Table 4). e634 Outcomes The length of follow-up was documented in 33 cases, with mean length of follow-up of 45.2 weeks (range 1–192). Forty patients (55%) improved clinically with treatment, reporting decreased pain, improved extraocular movements, decreased proptosis, and improved vision, while 33 (45%) patients did not experience any improvement or showed further deterioration. Twenty-three patients (32%) died in the course of their reported follow-up (Table 1). DISCUSSION Pulmonary and sinus aspergillosis occur after inhalation of airborne spores (10) and result from either local, allergic inflammation response (more frequent in immunocompetent hosts) or as a destructive direct fungal invasion (2,4,5,10). OAS most frequently develops due to IFS (often sphenoid sinus involvement) after direct bony invasion (1,3,5,10–21). The location of the paranasal sinuses also allows for invasion of vital intracranial structures, with potentially life-threatening complications including artery Yuan et al: J Neuro-Ophthalmol 2021; 41: e631-e638 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Patient comorbidities and immunocompromising conditions TABLE 3. Method of definitive diagnosis Method of Diagnosis Number (%) Comorbidities Hypertension Liver disease Chronic kidney disease Coronary artery disease Hematologic cancer Solid tumor cancer Asthma Giant cell arteritis Hyperthyroidism Hypothyroidism Tuberculosis infection Immunocompromising conditions Diabetes mellitus Chronic steroid use Immunosuppressive medication other than steroids HIV Cirrhosis 7 5 4 4 3 3 2 1 1 1 1 (10) (7) (5) (5) (4) (4) (3) (1) (1) (1) (1) 15 (21) 13 (18) 4 (5) 2 (3) 1 (1) Several patients had greater than 1 immunocompromising condition, such as diabetes with chronic steroid use. occlusions and cerebral ischemia. More disseminated infection can occur through hematogenous spread (5,10,22,23). Immunocompromised patients are at higher risk of IFS. In our review, only 28 patients (38%) were immunocompromised, most frequently from DM (15 patients), of which 8 were specifically noted to be poorly controlled, and iatrogenic causes, including chronic corticosteroid use and systemic chemotherapy (together comprising 23% of the cohort). Previous reports have suggested that aspergillosis may be more common in immunocompetent patients residing in warmer climates (4). Many immunocompetent patients were reported by authors from warmer climates, including Aggarwal and Pushker’s entirely immunocompetent cohorts from South Asia (4,5). In addition, the absence of complete clinical information regarding comorbid conditions in many of the reports may have led to an underestimation of the prevalence of immune compromise in our cohort. OAS secondary to IFS is often a diagnostic conundrum as presenting symptoms and examination findings are largely nonspecific. In our analysis, the majority of patients (57%) presented with vague, generalized pain and visual disturbances. Visual acuity was reported in 55 patients, of which 51% presented with markedly poor vision. The majority of patients had unilateral presentation, with no significant difference between right and left, with bilateral disease in 5 patients (7%). Neuroimaging provided confirmation of OAS (Fig. 1A– D), with evidence of enhancement of the perioptic orbital tissues including muscles, optic nerve sheath, and fat. In general, Yuan et al: J Neuro-Ophthalmol 2021; 41: e631-e638 Histopathologic diagnosis Soft-tissue biopsy Bone biopsy Tissue from sinus debridement Tissue from exenteration Fungal culture Fungal PCR Serum antigen Postmortem Number (%) 57 40 2 13 2 30 4 4 3 (78) (55) (3) (18) (3) (41) (5) (5) (4) however, radiographic findings of IFS are nonspecific and difficult to recognize; usually a heterogeneously enhancing mass with involvement of the ipsilateral paranasal sinuses and orbit is seen. Although neuroimaging is nonspecific, it is crucial to help identify the extent of infection and follow response to therapy. Diagnosing fungal disease solely based on clinical presentation and neuroimaging is challenging and a high index of suspicion is critical, especially if risk factors such as poorly controlled DM or chronic steroid use are present. Even without these risk factors, a fungal etiology should be considered, given that more than half of the reported patients did not have classic immunocompromising risk factors. Only 14% of patients were started on empiric antifungal therapy, while 34% received systemic steroids as the initial treatment, potentially promoting the progression of the fungal infection. TABLE 4. Types of antifungal treatment initially administered after diagnosis Initial Antifungal Treatment Intravenous Amphotericin B Fluconazole Voriconazole Caspofungin Micafungin 5-Fluorocytosine Oral Itraconazole Voriconazole Retrobulbar Amphotericin B Intravitreal Amphotericin B Local irrigation Amphotericin B Number (%) 36 2 19 2 1 3 (49) (3) (26) (3) (1) (4) 2 (3) 5 (7) 1 (1) 1 (1) 2 (3) Numbers of patients treated with each medication do not add up to total number of patients with treatment information (58) because of combinations of antifungal treatments. Six patients did not receive any antifungal treatment. Two patients had unspecified antifungal treatment. No information was provided on treatment for 15 patients. e635 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution In patients with suspected OAS secondary to IFS, we advocate beginning empiric antifungal therapy and pursuing tissue biopsy as soon as possible, in line with the 2016 Infectious Diseases Society of America guidelines for management of aspergillosis (24). Fifty-seven patients underwent a tissue biopsy that was positive for Aspergillus species; 5 patients required repeat biopsies. Importantly, biopsy with histopathology has been shown to have a diagnostic accuracy of only 78% based on morphology alone, emphasizing the role of culture for accurate speciation (25). The sensitivity of biopsy with histology is also limited, with 1 study showing a sensitivity of 75% (26). The possibility for false-negative results is supported by the 5 patients in this group who initially had nondiagnostic biopsies. We also recommend the use of additional confirmatory testing including PCR for ITS sequences. ITS sequencing is the molecular characterization of fungi using PCR to amplify specific regions of the nuclear ribosomal repeat unit of the rRNA gene, otherwise known as the ITS region (27). The ITS region is a genetic marker for molecular identification of fungi and an increasingly useful diagnostic tool (28). Importantly, ITS sequencing can be performed on formalin fixed tissue; thus, even if fungal cultures were not sent at the time of initial biopsy, the test can be performed secondarily if suspicion for fungal infection arises at a later point (29). Another serologic test to consider is b-d glucan, as was performed in our first patient, which is a sensitive marker of invasive fungal infection (30,31). Current guidelines recommend treatment with either systemic voriconazole or amphotericin B for IFS caused by Aspergillus in addition to consideration of surgical debridement (24). These were the most commonly used antifungal agents in our review. Although it is clear that patients with invasive fungal infection require long-term antifungal maintenance therapy, there is no consensus regarding the optimal treatment duration. This disease can be very difficult to control, even with a multidisciplinary approach, regular follow-up, and adherence to antifungal treatment. A multitude of complications including ischemic stroke, intracranial hemorrhage and cerebral abscess can occur. OAS may be an important early warning sign of imminent intracranial spreading of the fungal infection. Future research should focus on creating a riskstratification scoring system to determine high suspicion cases of IFS when patients present with OAS. This may be performed in combination with analysis of cases of other invasive fungal infections involving the orbital apex. CONCLUSION The present cases illustrate the diagnostic and management challenges associated with OAS due to invasive sinus aspergillosis. Our review and analysis of 73 cases support the notion that a high index of suspicion leading to early biopsy with histology and fungal culture is essential for e636 diagnosis of OAS due to IFS. Early empiric antifungal treatment and debridement can potentially reduce morbidity and mortality. REFERENCES 1. Milroy CM, Blanshard JD, Lucas S, Michaels L. Aspergillosis of the nose and paranasal sinuses. J Clin Pathol. 1989;42:123– 127. 2. Lee AS, Lee PWY, Allworth A, Smith T, Sullivan TJ. Orbital mycoses in an adult subtropical population. Eye. 2020;34:1640–1647. 3. Kang H, Takahashi Y, Nishimura K, Yamagishi Y, Mikamo H, Kakizaki H. Invasive fungal sinusitis involving the orbital apex in a patient with chronic renal failure. 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