Optic Neuropathy and Stroke Secondary to Invasive Aspergillus in an Immunocompetent Patient

Angioinvasive aspergillosis is an aggressive fungal infection that is potentially life threatening without prompt treatment. Optic nerve involvement of Aspergillus can mimic optic neuritis commonly seen in demyelinating and other inflammatory conditions. Treatment of Aspergillus infection with steroids may worsen the clinical course. We describe a unique case of disseminated central nervous system aspergillosis, initially presenting as an optic neuropathy, with subsequent stroke in multiple vascular territories.

Clinical Observation Optic Neuropathy and Stroke Secondary to Invasive Aspergillus in an Immunocompetent Patient Carrie M. Hersh, DO, MS, Seby John, MD, Adnan Subei, DO, Mary A. Willis, MD, Gregory S. Kosmorsky, DO, Richard A. Prayson, MD, MEd, Adarsh Bhimraj, MD Abstract: Angioinvasive aspergillosis is an aggressive fungal infection that is potentially life threatening without prompt treatment. Optic nerve involvement of Aspergillus can mimic optic neuritis commonly seen in demyelinating and other inflammatory conditions. Treatment of Aspergillus infection with steroids may worsen the clinical course. We describe a unique case of disseminated central nervous system aspergillosis, initially presenting as an optic neuropathy, with subsequent stroke in multiple vascular territories. Journal of Neuro-Ophthalmology 2016;36:404-407 doi: 10.1097/WNO.0000000000000361 © 2016 by North American Neuro-Ophthalmology Society A ngioinvasive aspergillosis of the optic nerve is a rare and potentially fatal condition if not treated early and aggressively. Clinical presentation of this fungal infection can mimic optic neuritis caused by demyelinating conditions, such as multiple sclerosis and neuromyelitis optica (NMO), and other inflammatory and vasculitic conditions. The diagnosis of optic nerve aspergillosis is often difficult because neuroimaging, hematologic, and cerebrospinal fluid (CSF) findings are usually nonspecific. Dissemination of Aspergillus to the central nerve system usually occurs in patients who are immunocompromised, but a few cases have been described in immunocompetent patients. Tissue diagnosis is therefore warranted for expedient diagnosis and targeted treatment. Lou Ruvo Center for Brain Health (CMH), Cleveland Clinic, Las Vegas, Nevada; Cerebrovascular Center (SJ), Cleveland Clinic, Cleveland, Ohio; Neuroscience Institute (AS), Memorial Healthcare System, Hollywood, Florida; Mellen Center of Multiple Sclerosis Treatment and Research (MAW), Cleveland Clinic; Department of Neuro-Ophthalmology (GSK), Cleveland Clinic Cole Eye Institute; Department of Anatomic Pathology (RAP); and Section of Neurologic Infectious Disease (AB), Cleveland Clinic, Cleveland, Ohio. The authors report no conflicts of interest. Address correspondence to Carrie M. Hersh, DO, MS, Lou Ruvo Center for Brain Health, Cleveland Clinic, 888 W Bonneville Avenue, Las Vegas, NV 89106; E-mail: [e-mail] 404 CASE REPORT A 55-year-old woman with a history of hypertension and heavy alcohol use initially presented with constant left-sided headaches with mixed autonomic and migrainous features, including nausea, photophobia, and phonophobia. Six months before initial consultation, her headaches were episodic but gradually became constant, mainly affecting the left side of her head and neck. During this time, she also developed gradual vision loss in her left eye, describing a central gray scotoma and associated eye pain. Her mother recently died of diffuse T-cell lymphoma. The patient's medications included tramadol for headache and amlodipine-benazepril for hypertension. Visual acuity was 20/20, right eye, and hand motions, left eye. There was a left relative afferent pupillary defect. Visual field testing was normal in the right eye and revealed superior and inferior arcuate defects in the left eye. The right fundus was normal while the left showed optic disc pallor. On neurological examination, the patient was cognitively intact. Upper and lower extremity strength was normal. Reflexes also were normal in the upper and lower extremities with flexor plantar responses. Perception of light touch and superficial pain was normal in the upper and lower extremities, but she had marked vibratory sensation loss in both distal lower extremities up to the knees, affecting the right foot more than the left. Her gait was mildly wide-based. Erythrocyte sedimentation rate (ESR), C-reactive protein, noncontrast brain computed tomography (CT), and temporal artery biopsy were normal. Routine blood and metabolic laboratory studies were unremarkable. Other than mildly positive antinuclear antibodies with 1:160 with a homogeneous pattern, studies for autoimmune conditions were negative. Lyme disease antibody with Western Blot, rapid plasma regain, NMO antibody, and HIV screen also were negative. Magnetic resonance imaging (MRI) of the Hersh et al: J Neuro-Ophthalmol 2016; 36: 404-407 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation brain and orbits revealed thickening and enhancement of the left optic nerve, involvement of the left cavernous sinus, and evidence of right maxillary sinusitis (Fig. 1). Lumbar puncture showed pleocytosis of 253 white blood cells (WBCs)/mL with lymphocytic predominance (70%). CSF glucose and protein levels were within normal limits. An immunoglobulin (Ig) panel was negative for intrathecal antibody synthesis, although oligoclonal bands were present in the CSF. A paraneoplastic antibody panel of the CSF was negative. The patient was treated with intravenous (IV) methylprednisolone 1,000 mg · 3 days and prednisone taper for presumed inflammatory optic neuropathy. She reported complete relief from headache but no change in vision. While still on a tapering dose of oral steroids, she presented to the emergency department with acute onset of fluctuating dysarthria and right-sided weakness. Although a noncontrast brain CT was unremarkable, MRI findings were consistent with a left pontine infarction (Fig. 2A). CT angiography showed moderate stenosis of the ophthalmic and cavernous segments of the left internal carotid artery, which was confirmed on cerebral angiography that also demonstrated severe stenosis of the left ophthalmic artery. Lipid and glycated hemoglobin profiles were normal as was a hypercoagulation panel and blood cultures (bacterial, fungal). Transthoracic and transesophageal echocardiograms, CT of the chest and abdomen, and positron emission tomography of the brain and full body were unremarkable. Serial CSF studies showed persistent pleocytosis (second: WBC 753/mL, third: WBC 144/mL, fourth: WBC 141/mL) with neutrophilic predominance (second: 72%, third: 66%, fourth: 70%). Although the initial CSF protein was normal, by the fourth lumbar puncture, it was elevated at 71 mg/dL (normal: 15-45 mg/dL). Repeat paraneoplastic autoantibodies, angiotensin-converting enzyme, venereal diseases research laboratory, varicella zoster virus IgG and polymerase chain reaction, and cytology were negative in the CSF. A left optic nerve biopsy was recommended, but the patient acutely developed respiratory failure requiring ventilator assistance. Pupillary responses, oculocephalic reflexes, and cough with suction were absent, although corneal reflexes were preserved bilaterally. There were no volitional movements. The patient's condition continued to deteriorate. Follow-up MRI showed large infarcts in the pons bilaterally, extending to the midbrain, left dorsal medial cerebellum, and left temporal pole (Figs. 2B, 2C). In addition, there were new areas of restricted diffusion in the right thalamus and deep white matter of the bilateral fronal lobes. On hospital day 9, the patient died. An autopsy was conducted, for which postmortem histologic sections identified a left optic nerve abscess with angioinvasive, acute angle branching fungal hyphae. Morphological appearance of this organism was consistent with Aspergillus species (Fig. 3) (1). DISCUSSION Our patient's clinical course of progressive monocular vision loss and headaches, followed by acute cerebral infarcts in multiple vascular territories, illustrates the complexity of targeting treatment for an optic neuropathy of uncertain cause. It is likely that the optic neuropathy, CSF pleocytosis, and stroke were related to the same pathologic process. Initial clinical and neuroimaging findings were strongly suggestive of a demyelinating or inflammatory condition. However, development of new neurological symptoms while on steroids, and a shift from a lymphocytic to FIG. 1. A. Postcontrast axial T1 magnetic resonance imaging shows thickening and enhancement (arrow) of the posterior portion of the left optic nerve. B. Postcontrast coronal T1 scan confirms left optic nerve involvement and increased enhancement of the left cavernous sinus. C. Axial T2 image reveals mucosal thickening in both maxillary sinuses and an airfluid level in the right maxillary sinus. Hersh et al: J Neuro-Ophthalmol 2016; 36: 404-407 405 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 2. A. Diffusion-weighted imaging is consistent with a left pontine infarction. Follow-up scans show extension of pontine infarction with involvement of the left cerebellar hemisphere (B), and left temporal lobe (C). neutrophilic CSF profile would have been unusual for a primary inflammatory process, and more in keeping with an infectious etiology. Mucosal hypertrophy of the maxillary sinuses with airfluid levels more prominent on the right side were noted on initial brain MRI. This may have been the source of Aspergillus infection, although the mechanism of central nervous system (CNS) invasion remains unclear since the patient had no identifiable risk factors for an immunocompromised state. Although a single course of IV methylprednisolone plus prednisone taper could have worsened fungal extension, the course was not chronic enough to cause an immunosuppressed state. Furthermore, our patient presented with symptoms before steroid treatment, thereby leaving the mechanism of invasive fungal CNS disease unknown. Aspergillus species are angioinvasive, leading to occlusive thrombosis, embolism, and infarction. Aspergillosis has a predilection for perforating arteries that can cause sterile infarction. Breakdown of brain parenchyma at sites of infarction can lead to direct fungal extension into the surrounding brain with associated cerebritis and abscess formation. High viscosity and cellularity of Aspergillus, along with associated infarcted tissue, can lead to restricted diffusion on brain MRI. When present, ring enhancement can correlate with capsule formation from chronic inflammation and production of granulation tissue. Serum enzyme-linked immunosorbent assay (ELISA) for galactomannan and beta-glucan is 60%-80% sensitive and about 90% specific for the diagnosis (2-4). CSF ELISA has a slightly higher sensitivity but lower specificity. Select cases of invasive optic nerve aspergillosis in immunocompetent patients have been described (5-7). Subramanian et al (5) reported a 40-year-old patient with painless proptosis of the left eye, diplopia, and swelling of the left cheek for 2 years with preservation of vision. MRI revealed a left intraconal mass involving the extraocular muscles with encasement and displacement of the left optic nerve. Biopsy findings were consistent with Aspergillus, and the patient was treated with an eight-week course of amphotericin B and surgical debridement. Leyngold et al (6) described a healthy 61-year-old man with 10-month history of progressive, painful vision loss in his left eye. MRI showed an enhancing soft tissue mass infiltrating the left FIG. 3. Left optic nerve pathology. A. There is an organizing abscess with focal, acute inflammation surrounded by areas of chronic inflammation and occasional giant cells (hematoxylin & eosin, ·200). B. Within the abscess, there are acute angle branching hyphae, morphologically consistent with Aspergillus (Gomori methenamine silver stain, ·400). 406 Hersh et al: J Neuro-Ophthalmol 2016; 36: 404-407 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation optic nerve with extension toward the left aspect of the chiasm. During evaluation, the patient developed a contrast-enhancing mass involving the right optic nerve. Microscopic analysis and fungal culture showed Aspergillus fumigatus, for which the patient was treated with IV voriconazole and micafungin for 2 weeks with subsequent resolution of the right optic nerve and chiasmal enhancement (8). Sivak-Callcott et al (7) reported a 69-year-old man with bilateral vision loss and headaches, previously treated with a short course of high-dose prednisone for presumed giant cell arteritis, despite a normal ESR. MRI revealed enhancement of the ethmoid sinus mucosa, extension into the left cavernous sinus, and invasion into the left vidian canal. Medial orbital biopsy showed fungal organisms consistent with A. fumigatus, but despite multiple courses of IV antifungal therapy and surgical debridement, the patient developed an enlarging mass lesion, brain abscess, and middle cerebral artery stroke. He died 9 months after initial presentation. The differential diagnosis of disseminated aspergillosis is broad and includes demyelination (multiple sclerosis, NMO) and inflammatory (sarcoidosis, Tolosa-Hunt, IgG4) disorders. Neoplastic processes such as lymphomatous and carcinomatosis meningitis are also possibilities. Given the involvement of multiple vascular territories, meningitis causing perivasculitis by extension of inflammation into the Virchow Robin spaces or a primary vasculitic process (CNS vasculitis) are other considerations. Infections include mycobacterial, spirochetal, and dimorphic fungi (histoplasmosis, blastomycosis, cryptococcosis, coccidioidomycosis) are all possibilities. Treatment of CNS aspergillosis in an otherwise healthy patient is controversial with various therapeutic modalities described, but presently there are no universal guidelines for treatment. Medical management with antifungal therapies includes voriconazole, itroconazole, amphotericin B, or micafungin (8). Voriconazole may be a more suitable option for angioinvasive aspergillosis because of better tolerance and lower toxicity compared with amphotericin B (9). Surgery with adjuvant chemotherapy and combination antifungal therapy with surgical debridement for invasive sino-orbital aspergillosis has also been described, although morbidity and mortality are quite high with radical surgical approaches (8). The diagnosis of optic nerve aspergillosis in an immunocompetent patient should be considered when the clinical presentation is characterized by an optic neuropathy and stroke. This is particularly true in the context of brain MRI findings of paranasal sinus disease, and a CSF profile consistent with an infectious process. Tissue biopsy should Hersh et al: J Neuro-Ophthalmol 2016; 36: 404-407 be considered before empiric steroids when the index of suspicion is high for an atypical infection. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: C. M. Hersh; b. Acquisition of data: C. M. Hersh and M. A. Willis; c. Analysis and interpretation of data: C. M. Hersh, M. A. Willis, G. Kosmorsky, R. A. Prayson, A. Bhimraj, S. John, and A. Subei. Category 2: a. Drafting the article: C. M. Hersh, M. A. Willis, G. Kosmorsky, R. A. Prayson, A. Bhimraj, S. John, and A. Subei; b. Revising it for intellectual content: C. M. Hersh, M. A. Willis, G. Kosmorsky, R. A. Prayson, A. Bhimraj, S. John, and A. Subei. Category 3: a. Final approval of the completed article: C. M. Hersh, M. A. Willis, G. Kosmorsky, R. A. Prayson, A. Bhimraj, S. John, and A. Subei. ACKNOWLEDGMENTS We thank Dr. Joao Gomes, Dr. Michael Gostkowski, and the Cleveland Clinic house staff for their excellent clinical care in the treatment of our patient. REFERENCES 1. Yuan L, Prayson RA. Optic nerve aspergillosis. J Clin Neurosci. 2015;22:1191-1193. 2. 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N Engl J Med. 2002;347:408-415. 407 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.