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Show Monocular Vision Loss and Headache in a 60-Year-Old Liver Transplant Patient Collin M. McClelland, MD, Ronald L. Wolf, MD, PhD, Christopher H. Rassekh, MD, Emily A. Blumberg, MD, M. Sean Grady, MD, Virginia A. LiVolsi, MD, Grant T. Liu, MD Dr McClelland: A60-year-old man with a history of a liver transplanta-tion 3 months earlier for hepatitis C-induced cirrhosis was transferred from an outside hospital. He reported 2 weeks of progressive visual decline in the right eye, associ-ated with 2 months of right temporal headaches. The patient denied scalp tenderness, jaw claudication, and mus-cle weakness. Other significant medical history included celiac sprue, well-controlled hypertension, poorly controlled insulin-dependent diabetes mellitus, coronary artery disease, and hypercholesterolemia. The patient admitted confusion regarding his posttransplant medication regimen and re-cently had transferred his outpatient care from another medical facility. These factors contributed to an unintended month of 80 mg of prednisone daily following transplanta-tion and intermittent compliance with his cyclosporine and sulfamethoxazole/trimethoprim posttransplant prophylactic agents. Cyclosporine trough levels ranged from less than 35 to 48 mg/L during the 3 weeks prior to presentation (main-tenance trough levels, 100-150 mg/L). Liver function tests following the transplantation and as recently as 1 week prior to presentation revealed no evidence of rejection. Following transfer, the patient's examination revealed a visual acuity of 20/40, right eye, and 20/15, left eye. Color vision was reduced in the right eye, and there was a right relative afferent pupillary defect. Ocular motility and align-ment, intraocular pressures, and external findings were nor-mal. There was moderate optic disc swelling in the right eye without associated hemorrhage or exudate, and the left fun-dus was normal. Laboratory studies performed upon admission revealed mild normocytic anemia with normal white blood cell and platelet counts. An erythrocyte sedimentation rate (ESR) was 80 mm/h, and a high sensitivity C-reactive protein (CRP) was 9.2 mg/L (normal, 0-7.4 mg/L). CT of the brain was interpreted as showing no abnormal-ities other than mucosal thickening in the sphenoid sinus, and a diagnosis of giant cell arteritis (GCA) was considered likely. Before starting the patient on systemic corticosteroids, it was elected to perform an MRI of the brain. Dr Wolf: MRI of the brain and orbits (Fig. 1A-D) shows an expansile, contrast-enhancing process involving the right cavernous sinus and orbital apex and is contiguous with enhancing tissue along the right superolateral aspect of the sphenoid sinus. There is mass effect on the prechiasmatic optic nerve. The area of enhancement also involves the right optic canal, and there is prominence of the intraorbital optic nerve sheath complex. Finally, there is encasement of the right cavernous internal carotid artery with almost com-plete obliteration of the cavernous segment, confirmed by MRA, which also shows reconstitution of flow in the right internal carotid artery and branches distal to the cavernous segment (Fig. 2). On reviewing the CT, there is a bony defect near the sphenoid sinus abnormality (Fig. 3). In retrospect, subtle asymmetric fullness in the region of the right orbital apex and right cavernous sinus is apparent. Division of Neuro-Ophthalmology, Departments of Neurology and Ophthalmology (CMM, GTL); and Departments of Radiology (RLW); Otorhinolaryngology-Head and Neck Surgery (CHR); Medicine (EAB); Neurosurgery (MSG); and Pathology and Laboratory Medi-cine (VAL), The Perelman/University of Pennsylvania School of Medicine, Philadelphia, PA. The authors report no conflicts of interest. Address correspondence to Grant T. Liu, MD, Division of Neuro- Ophthalmology, Department of Neurology, University of Pennsyl-vania School of Medicine, 3400 Spruce Street, Philadelphia, PA 19104; E-mail: gliu@mail.med.upenn.edu McClelland et al: J Neuro-Ophthalmol 2012; 32: 167-171 167 Clinical-Pathological Case Study Section Editor: Neil R. Miller, MD Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. FIG. 1. Precontrast (A) and postcontrast (B) T1 axial orbital MRI shows an expansile contrast-enhancing process (short thick arrow) involving the sphenoid sinus, right orbital apex, and right cavernous sinus. The right cavernous carotid artery flow void is absent (long thin arrow) with a normal flow void evident on the left (curved arrow). Precontrast (C) and postcontrast (D) T1 coronal MRI demonstrates the expansile process (short, thick arrow) involving the right superolateral aspect of the sphenoid sinus with bony destruction and extension into the right cavernous sinus. Loss of the carotid flow void is demonstrated on the right. The right optic nerve (long thin arrow) is elevated by the mass; more anterior sections (not shown) demonstrate enhancement surrounding the right optic nerve in the optic canal extending into the orbital apex. The right optic nerve is less well seen on postcontrast coronal images partly due to motion artifact. FIG. 2. MRA source image (A) at the level of the cavernous sinus mass and segmented maximum intensity projection image (B) of the right internal carotid distribution confirmed the involvement of the right cavernous internal carotid artery, with narrowing of the cavernous carotid artery resulting in loss of flow-related enhancement on the source image (short, thick arrow) and flow gap on the segmented maximum intensity projection image (long, thin arrow). There is reconstitution of flow in the right internal carotid artery distal to the involved segment. The source image shows normal flow in the left cavernous carotid artery (curved arrow). FIG. 3. Axial CT with soft tissue (A) and bone window (B) settings reveals asymmetric soft tissue prominence of the right cavernous sinus (arrow), with adjacent bony defect of the sphenoid sinus wall (arrowhead). 168 McClelland et al: J Neuro-Ophthalmol 2012; 32: 167-171 Clinical-Pathological Case Study Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Dr McClelland: A lumbar puncture revealed clear cerebrospinal fluid (CSF), with no cells, a normal glucose content, and a mildly elevated protein concentration of 59 mg/dL (normal, 15-45 mg/dL). Gram stain was negative as were bacterial, fungal, and acid-fast bacilli cultures. Polymerase chain reaction was negative for evidence of varicella zoster virus, cytomegalovirus, human her-pes virus-6, and herpes simplex virus. Additional normal serum laboratory studies included galactomannan (Aspergillus antigen), Bartonella henselae IgG/IgM, Mycoplasma IgM, angiotensin-converting enzyme, Lyme antibody, and cryptococcal antigen. Dr Liu: In view of the neuroimaging findings in this immunocom-promised patient, an otolaryngological consultation was requested. Dr Rassekh: The cranial base surgery team discussed the case and reviewed the neuroimaging studies. We agreed that endo-scopic biopsy with limited debridement was appropriate but that the mass in the lateral wall of the sphenoid sinus adjacent to the right optic nerve and cavernous sinus could not be biopsied unless it could be removed with suction. Aggressive debridement would dramatically increase the risk of catastrophic hemorrhage or stroke related to injury to the cavernous internal carotid artery, visual loss due to injury to the optic nerve, and CSF rhinorrhea in the region of the cavernous sinus that could lead to intracranial infection. At surgery, the sphenoid sinus was opened and the bone of the sphenoid rostrum was removed inferiorly to reveal a whitish yellow mass that was removed and sent for pathological and microbiological analyses. In addition, there were areas of white plaque under the mucosa, most prominently found in the superolateral sphenoid sinus in the region of the opticocarotid recess. The sphenoid sinus was irrigated to remove remaining debris. Dr LiVolsi: Multiple biopsies from the sphenoid sinus show inflamed sinonasal mucosa, bone fragments, and associated necrotic material containing abundant fungal organisms (Fig. 4A) with septate hyphae morphologically suggestive of Aspergillus species (Fig. 4B). Fungal cultures of the sphenoid sinus biopsy specimen grew Aspergillus fumigatus. Final Diagnosis Right optic neuropathy due to invasive sinonasal aspergil-losis with cavernous sinus and orbital apex extension. Dr Blumberg: Prior to the biopsy, the patient had been placed on both antibacterial and antiviral agents. In view of the biopsy findings suggestive of Aspergillus species, the patient was started immediately on intravenous amphotericin with cessa-tion of other antimicrobial agents. The clinical picture was further complicated by acute elevation of liver function tests. A transjugular core biopsy of the liver demonstrated acute cellular rejection without evidence of infection. The diagnosis of acute hepatic rejection mandated urgent steroid therapy, placing the patient in a precarious and grave balancing act between suppressing immunity to prevent liver failure and bolstering immunity to prevent progression of Aspergillus. The chronic and serious nature of both issues denoted a very poor prognosis for this patient if treated medically. Given the angioinvasive nature of Aspergillus and the patient's obligatory future immunosuppression, it was thought that the best chance for recovery was aggressive surgical debridement. The neurosurgery and otolaryngology services were asked to consider a right orbital exenteration with extensive debride-ment of the sphenoid sinuses and right orbital apex/cavernous sinus region. FIG. 4. Sphenoid sinus biopsy. A. There is inflamed mucosa (straight arrow) adjacent to a cluster of fungal organisms consistent with an aspergilloma (bent arrow) (hematoxylin and eosin, ·10). B. Abundant septate hyphae with a 45° branching pattern (red arrows) are present consistent with Aspergillus (Grocott methenamine silver stain, ·40). McClelland et al: J Neuro-Ophthalmol 2012; 32: 167-171 169 Clinical-Pathological Case Study Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Dr Grady: The surgical treatment for this patient's infection would require a radical resection, including right orbital exenteration, resection of the right cavernous sinus and its contents, and occlusion of the right carotid artery. A tissue graft then would be required to fill the defect and close off the communication between the CSF-filled intracranial cavity and the paranasal sinuses. Given the region of pathology in the cavernous sinus and orbital apex, the angioinvasive tendencies of Aspergillus, and the coagulopathy inherent with liver failure, the risk of stroke and life-threatening hemorrhage in this patient was thought to be considerable. In addition, surgical debridement would be incomplete, given the extensive nature of fungal invasion. Based on these factors, the neurosurgical service declined to perform surgery and instead recommended con-tinuation of medical management. The patient's medication was subsequently changed from amphotericin to voriconazole and caspofungin. Six months following presentation, the patient remains alive on long-term caspofungin and voriconazole, although his condition has progressively worsened. Vision in the right eye declined to no light perception. His last MRI showed mild interval progression in the size of the right orbital apex and cavernous sinus mass. Despite immunosuppression with tacrolimus, his liver continues to fail, leading to massive ascites. The patient has sought second opinions from 4 other academic centers, and all have declined additional surgery due to a consensus that his disease is inoperable. Dr McClelland and Dr Liu: Giant cell arteritis is a relatively common cause of acute-onset catastrophic vision loss in the elderly (1). Prevention of pro-gression to bilateral blindness from GCA relies on clinicians maintaining a high-index of suspicion and initiating early steroid therapy. This case highlights that caution must be exercised when considering steroid therapy for possible giant cell arteritis, particularly in patients with known immunosup-pression, and that an elevated ESR and CRP, although con-sistent with GCA, also occur in patients with other infectious disorders, including fungal infections. Seton et al (2) reported a similar case of invasive sinonasal Aspergillus mimicking GCA in an immunosuppressed 68-year-old man, 3.5 months after a liver transplant for liver failure from hepatitis C. Their patient presented with vision loss in the right eye, fundus findings "consistent with anterior ischemic optic neuropa-thy," new right temporal headaches with scalp tenderness, and jaw fatigue. He was placed on high-dose prednisone for 3 weeks before the infection progressed, ultimately suc-cumbing to a ruptured mycotic basilar artery aneurysm. The rheumatologic literature reports a 93.5% sensitivity and 91.2% specificity for GCA when 3 of the following 5 criteria are met: age being 50 years or older, new onset of localized headache, temporal artery tenderness or decreased temporal artery pulse, elevated ESR $50 mm/h, and a temporal artery biopsy indicative of GCA (3). Cases such as ours suggest that these guidelines may not apply to immunocompromised patients in whom GCA is exceedingly rare and elevated acute phase reactants, such as ESR and CRP, are more likely to reflect an underlying infectious process. Aspergillus fumigatus, along with other less common Aspergillus species, are molds that are ubiquitous in the environment (4). Fungal spores are typically inhaled by humans into the sinonasal and pulmonary airways but rarely cause symptomatic infection in immunocompetent individ-uals. When disease occurs, it can affect virtually any organ system, although the lungs, sinuses, brain, and skin are the most commonly involved (4). Sinonasal involvement by Aspergillus may result in diverse and overlapping clinical find-ings, including benign colonization, allergic fungal sinusitis (AFS), sinus mycetoma (or "fungus ball"), chronic invasive fungal sinusitis, and acute fulminant invasive sinusitis. These disease patterns are not specific to Aspergillus and are seen with numerous other fungi (5). The form and severity of pathology in any given case likely reflects the effectiveness of the host immune response. AFS is the most common form of fungal rhinosinusitis constituting approx-imately 7% of all chronic rhinosinusitis requiring surgery (6,7). AFS is characterized by noninvasive chronic infection of the paranasal sinuses in immunocompetent patients associated with copious allergic mucin (5). Sinus mycetoma is another noninvasive form of fungal rhinosinusitis gener-ally involving one sinus and characterized histopathologi-cally by a matted "ball" of inflammation and fungal hyphae (8). In both forms of noninvasive fungal sinonasal infection (AFS and mycetoma), the related symptoms are typical of chronic rhinosinusitis (e.g., nasal obstruction, purulent dis-charge, facial pain), but neuro-ophthalmic complications are rare. Our patient's subacute onset, progressive optic neuropathy, and neuroimaging evidence of invasion into the cavernous sinus through the wall of the sphenoid sinus made the diagnosis of invasive fungal rhinosinusitis evident. Invasive fungal rhinosinusitis can present in a fulminant or insidious fashion and is usually associated with aspergillosis or mucormycosis (5). Invasive Aspergillus can infect any paranasal sinus although the maxillary, ethmoid, and sphenoid sinuses are the most commonly affected (9). Cerebral aspergillosis occurs in 10%-20% of all invasive aspergillosis cases and may arise hematogenously or extend directly from the para-nasal sinuses as in our case (9). Initially, invasive sinonasal and cerebral aspergillosis were documented in immunocompro-mised patients, but reports among immunocompetent patients are becoming more common (10,11). Definitive diagnosis of sinonasal and cerebral aspergillosis can be chal-lenging. CSF examination is rarely helpful in diagnosis (4). Serum Aspergillus antigen (galactomannan) may be suggestive of the diagnosis, with an estimated sensitivity and specificity of 71% and 89%, respectively (12). Considering false-negative galactomannan results in biopsy-proven invasive aspergillosis, 170 McClelland et al: J Neuro-Ophthalmol 2012; 32: 167-171 Clinical-Pathological Case Study Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. as occurred in our case, and false-positive results from cross-reactivity with other fungi or beta-lactam antibiotics (4), definitive diagnosis requires biopsy and/or culture of affected tissue (13). Optimal treatment for invasive sinonasal and cerebral Aspergillus remains controversial and is limited by a lack of prospective trials comparing treatment options. Historically, treatment consists of antifungal pharmacotherapy with aggressive surgical debridement of affected tissue (13-16). Pro-ponents of extensive debridement consider Aspergillus an "infectious cancer" that must be excised (14). Some theorize that hypoxic tissue necrosis surrounding the angioinvasive Aspergillus promotes further growth of the fungus and prevents effective tissue penetration by antifungal agents. The risk and morbidity associated with surgical debridement has been justi-fied by the grim prognosis in these cases. In the literature published prior to the development and widespread utilization of newer antifungal agents, invasive sinonasal aspergillosis with-out intracranial involvement had a 66% mortality rate (17) and cerebral aspergillosis an 88%-100% mortality rate (17-19). Since the advent of alternative antifungal agents to amphoter-icin (e.g., voriconazole, caspofungin, itraconazole), some clini-cians have reported improved outcomes with medical management of invasive Aspergillus although early recognition of the infection is critical for treatment success (15,20-22). Panda et al (15) reported a 100% survival rate with 20-47 months of follow-up in a series of 6 immunocompetent patients with invasive aspergillosis, resulting in orbital and/or intracranial extension. All patients were treated medically with a combination of itraconazole and amphotericin B. Surgical intervention was required in only one patient; an orbital mass excision with paranasal sinus debridement was curative. It remains unclear which patients may be successfully managed by a medical approach alone and whether combination antifungal therapy may be beneficial in patients with invasive sinonasal and cerebral Aspergillus. The low prevalence of the disease hinders quality prospec-tive trials while the wide variability of infection location, treatment regimens, and patients' immune status make ret-rospective studies difficult to interpret. Scarce existing data on the use of combination antifungal therapy reveal con-flicting results, and there is no clear guidance regarding the use of combination therapy for solid organ transplant recip-ients with invasive rhinocerebral aspergillosis (23). ACKNOWLEDGMENTS The authors thank Roger Selouan, MD, for his assistance with radiographic interpretation and Kenneth S. Shindler, MD, PhD, for his assistance with photographing biopsy specimens. REFERENCES 1. Liu GT, Volpe NJ, Galetta S. Neuro-Ophthalmology: Diagnosis and Management, 2nd edition. 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