Case Report
Cerebral Aspergillosis in a Diabetic Patient Leading to Cerebral Artery Occlusion and Ischemic Stroke: A Case Report and Literature Review Wentao Li, BA,* Neelofer Shafi, MD,* Ramayee Periakaruppan, MD,† Tibor Valyi-Nagy, MD, PhD,† John Groth, MD,† and Fernando D. Testai, MD, PhD, FAHA*
Cerebral aspergillosis is a rare and highly fatal hematogenous infection most commonly found in immune compromised patients. From the onset of neurologic symptoms, the median reported rate of survival is between 5 and 9 days. Compounded with increased hemorrhagic risks and the lack of specificity in both clinical presentation and traditional imaging, a fast and noninvasive method of definitive diagnosis is necessary if there is to be any hope for positive outcomes. We describe the case of a 50-year-old female diabetic with a history of otitis media, an uncharacterized inflammatory nasopharyngeal process, and prior ischemic strokes who presented with a new cerebral infarction in the setting of an angioinvasive fungal infection of the large cerebral arteries. We also present a literature review of aspergillosis detection and treatment in hopes that future cases will be diagnosed in a timely manner and more patients may be saved. Key Words: Cerebral aspergillosis—stroke—angioinvasive aspergillosis—carotid occlusion. Ó 2015 by National Stroke Association
Cerebral aspergillosis (CA) is a relatively rare form of angioinvasive fungal infection most often seen in immune compromised individuals.1 The angioinvasive nature of Aspergillus greatly increases the risk of intraoperative hemorrhage, rendering biopsy and direct diagnosis risky in many cases.2 Here, we describe a 50-year-old patient with a new cerebral infarction in the setting of an angioinFrom the *Department of Neurology, University of Illinois College of Medicine, Chicago; and †Department of Pathology, University of Illinois College of Medicine, Chicago, Illinois. Received May 6, 2014; revision received August 5, 2014; accepted August 25, 2014. This manuscript was not supported or sponsored by any grants or foundations. Address correspondence to Fernando D. Testai, MD, PhD, FAHA, Department of Neurology and Rehabilitation, University of Illinois at Chicago Medical Center, 912 S Wood Street, Rm 855N NPI (MC 796), Chicago, IL 60612-7330. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.08.025
vasive fungal infection of the large cerebral arteries and a literature review on contemporary diagnostic and treatment approaches.
Case Study A 50-year-old female with a past history of diabetes, hypertension, hyperlipidemia, chronic otomastoiditis, recent left ear infection status after tympanic tube placement, and progressive hearing loss presented to an outside hospital with headache, mild confusion, and slurred speech. Workup revealed an acute left parietooccipital ischemic stroke, and the patient was transferred to our institution for higher level of care. On arrival the patient had normal vital signs. The general examination was unrevealing. Neurologically the patient was fully oriented with normal attention and concentration and had anisocoria (right pupil: 3 mm; left pupil: 5 mm), left VI cranial neuropathy, right homonymous hemianopsia, and dysarthria. Review of magnetic resonance imaging
Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 1 (January), 2015: pp e39-e43
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disclosed the known left hemispheric ischemic stroke along with inflammatory changes at the skull base and mastoid cells with no evidence of extension into the brain parenchyma. Magnetic resonance angiography demonstrated a complete occlusion of the proximal left internal carotid artery (ICA) and left posterior cerebral artery. The left middle cerebral artery showed decreased enhancement and was served by cross flow from the right side via the anterior communicating artery. The right ICA and the rest of the intracranial vessels were intact. Hypercoagulable workup was unrevealing, and transthoracic echocardiogram was negative for vegetations. Glycosylated hemoglobin was 7.7% and low-density lipoprotein (LDL) cholesterol was 59 mg/dL. Further assessment via head and neck computed tomography showed mild ethmoid sinus fullness, opacification of the left mastoid air cells, and nasopharyngeal asymmetry with inflammatory changes extending into the left Eustachian tube. Nasopharyngeal biopsy demonstrated a chronic inflammatory infiltrate and granulomatous reaction without evidence of active infection. A left mastoidectomy was performed; excision contents revealed granulation tissue and normal flora but stained negative for fungal elements. The patient refused additional workup and was released on antibiotic treatment for otitis media and aspirin. She was also offered a close neurologic followup, which was not observed. Two months later the patient presented with new onset of confusion and headache. Blood pressure on arrival was 146/106 mm Hg, pulse 110 bpm, respiration 24, and oral temperature 36.8 C. The general examination was unremarkable with no clinical evidence of systemic embolism or obvious infection. Neurologically, the patient was oriented to place and name, somnolent but arousable to tactile stimuli, and able to follow 1-step commands. She demonstrated paucity of spontaneous speech and had limited participation with the interview. Cranial nerve
evaluation showed partial central left VII palsy and the known left VI cranial neuropathy and homonymous hemianopsia. There were no focal motor or sensory deficits, and the gait was steady. Infectious workup revealed urinary tract infection but negative blood cultures and chest X-ray. Electroencephalogram showed diffuse bifrontal slowing but no epileptiform discharges. Magnetic resonance imaging confirmed paranasal sinus disease and new areas of ischemia within the left posterior cerebral artery vascular territory. Imaging also revealed a new area of flow limiting stenosis at the cervical/petrous junction of the right ICA and abnormal enhancement surrounding the vessel walls of the entirety of the left ICA (Fig 1). Following a 10-minute hypotensive event during the imaging procedure, the patient became unresponsive and an emergent head computed tomography showed early infarction in the region of the left Sylvian fissure. Extensive infarcts in bilateral cerebral hemispheres and deep gray matter led to diffuse left hemispheric edema with subfalcine and transtentorial herniation. Ischemic changes were also visualized in the brain stem; patient was terminally extubated per wishes of family and pronounced dead on hospital day 6.
Pathology Findings An autopsy was performed and showed cerebral edema and subfalcine and transtentorial herniation. Sections from the skull base, including internal carotid canal contents and sphenoid sinus contents demonstrated angioinvasive fungal infection involving large arteries, associated with thrombosis and necrotizing acute and chronic inflammation. The fungal organisms demonstrated septated and homogenous hyphae of uniform width, with parallel contours and dichotomous branches arising at an acute angle. Conidial heads were absent. Sections from the brain demonstrated cerebral arteriosclerosis,
Figure 1. (A) Magnetic resonance (MR) image showing enlargement and abnormal T2 signal along the left internal carotid artery (ICA) suggestive of thrombus within the vessel. (B) MR image demonstrating narrowing and enhancement of the right ICA at the cervical/petrous junction.
CASE REPORT
changes of acute global cerebral ischemia, and focal remote ischemia. These findings suggested that the cause of death was cerebral infarction and herniation due to angioinvasive fungal infection and thrombotic obliteration of large cerebral arteries at the skull base. Although no fungal cultures were performed, the fungal forms detected in histologic sections were most consistent with Aspergillus sp, (Fig 2). No evidence of fungal infection was detected in the lungs or other organs.
Discussion Presentation Angioinvasive CA is typically a manifestation of disseminated aspergillosis in transplant patients and patients with hematologic malignancies, but it has also been reported in diabetic patients.1-6 Besides hematogenous fungal spread from the lungs and infected heart valves, direct fungal invasion of the central nervous system (CNS) from adjacent tissues is also possible. As the evidence in this case was more consistent with an infiltrative process rather than seeding from a primary cardiac or pulmonary source, direct invasion to the large arteries of the skull base was the most likely mechanism of dissemination. Immunosuppression from the patient’s diabetes likely also played a role in the pathogenesis of the detected CA. In addition to nonpyogenic cerebral abscesses, CA also manifests as granulomatous formations, meningitis, aneurysms, and multifocal infarcts; lesion size and number vary from single distinct masses to multiple nonfocal lesions.7,8 Clinical findings are similar to malignant neoplasms in the same anatomic regions, ranging from severe headache and nausea to altered mental status, cranial neuropathies, decreased cognitive function, weakness, seizures, visual changes, and focal neurologic deficits.2,9 In particular, rhinocerebral infections extending into cavernous sinus often result in unilateral or bilateral exophthalmos, ptosis, vision loss, and orbital apex syndrome with cranial nerves III, IV, and VI involvement.10-12 Our patient was unusual in that she lacked obvious immunosuppression besides her diabetes and presented with a negative sinus biopsy. However, the nonspecific
Figure 2. Gomori methenamine silver stain of skull base temporal bone demonstrating septate fungal hyphae with acute angle branching consistent with Aspergillus sp in a background of necrotizing acute inflammation. Magnification: 503 (A); 4003 (B).
e41
findings of mild confusion and cranial neuropathies do concur with published symptoms. In future cases of ischemic stroke with large artery occlusive disease in the setting of skull base inflammation and negative routine workup, we hope this patient’s presentation will help form the clinical suspicion of CA and lead to timely employment of specific detection methods.
Detection As seen in the case of our patient, Aspergillus can invade into major blood vessels resulting in aneurysms and thrombosis. Furthermore, due to species’ capacity to disrupt the blood vessel’s internal elastic lamina, up to 25% of acute infarctions also result in hemorrhage.3 Such hematologic cases often render biopsies infeasible; to make diagnosis even more difficult, lumbar punctures are typically inconclusive as well. Routine cerebrospinal fluid (CSF) analysis may show mild to moderate elevations of white blood cell counts and protein concentrations with normal or decreased glucose content, but it is generally unreliable and in most cases fail to grow Aspergillus in culture. Currently, culture remains the gold standard for the definitive identification of fungal organisms, with histologic evaluation able to correctly identify fungal organisms in 79% of cases.13 Recently, a new approach using the galactomannan (GM) test is demonstrating some success in indirectly determining the presence of the fungus. This sandwich enzyme-linked immunosorbent assay detects aspergillum GM antigen in CSF, serum, plasma, and bronchoalveolar lavage fluid with high specificity.4,14 However, the sensitivity of this test has not been established in cases with CNS involvement. One study by Viscoli et al15 demonstrated the inability of GM testing to differentiate between CNS and pulmonary forms of infection. Moreover, it has been postulated that the presence of antiAspergillus antibodies in chronic infection may interfere with the detection of serum antigens, resulting in negative GM assays when CNS involvement is secondary to the initial Aspergillus infection.16 Since its inclusion as a probable indicator of Aspergillus infection by the 2008 Consensus Group, positive GM results in 2 of 4 confirmed CA cases has led to timely intervention with voriconazole and remission in this usually fatal disease (Table 1).
W. LI ET AL.
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Table 1. Reported CA cases using GM tests since incorporation by the EORTC/MSG Consensus Group in 2008* Reference
Age, y
Sex
Affected locations
Saito et al16
63 (Deceased)
F
Miki et al17
76 (Deceased)
M
Cerebrovascular, disseminated from pulmonary aspergillosis. Granulomatous lesions on optic chiasm and nerves, thickened frontal base dural mater, middle cerebral artery. Right frontal lobe (12 mm), nodular lesions on left cerebellum and cingulate gyrus. Paraventricular, adjacent to left ventricular wall and choroid plexus.
Sav et al18
F 4
Soeffker et al19
M 51
GM result Serum GM: ,.2 ng/mL (negative) Serum GM: negative in 9 consecutive tests Serum GM: 3.39 ng/mL (positive), .72 ng/mL (positive) CSF GM (ratio):8.8 (positive)
Abbreviations: CA, cerebral aspergillosis; CSF, cerebrospinal fluid; EORTC/MSG, European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group; GM, galactomannan. *Case studies including patients from before 2008 were omitted.
Treatment Currently, voriconazole is the most effective pharmacologic treatment against CA.20,21 Compared with 100% morality in 17 patients treated with amphotericin-B alone or with itraconazole, 25 of 95 patients treated with voriconazole were not known to have died.20,22,23 Of these, 15 reported a median survival length of 237 days after termination of therapy.20 Moreover, patients unresponsive to initial amphotericin or itraconazole treatments have demonstrated noticeable improvement on switching to voriconazole.12 In all studies, neurosurgical management via abscess resection or drainage in conjunction with antifungal therapy resulted in greater survival rates compared with pharmacologic treatment alone.2,9,20,24 Of 123 confirmed CA cases from the past decade, 28.6% of patients who underwent neurosurgery died compared with 67.5% of patients who did not.9 Nevertheless, the optimal neurosurgical approach has yet to be defined, and the effectiveness of direct administration of antifungals via reservoirs or lavages is mixed.25-27 As in the case of biopsies, risk of hemorrhage during surgery is increased because of the angioinvasive nature of CA. In cases where total resection of the abscess is not feasible and intradural invasion has been confirmed, intensive postoperative systemic antifungal therapy must be continued to prevent the development of lethal vasculitis or meningoencephalitis.28
Conclusion Despite the recent advances in the detection of Aspergillus, the diagnosis of angioinvasive CA continues to be challenging. The CSF analysis is generally unreliable and the recovery of Aspergillus in culture is in most cases unsuccessful. In some cases like ours, an unusual clinical presentation such as the absence of obvious immunosuppression and local rather than hematogenous fungal
spread can further complicate the diagnostic process. Clinical suspicion therefore remains crucial for establishing a timely diagnosis, a fact further highlighted by the negative sinus biopsy in our patient. Recent reports suggest that the measurement of GM in CSF is superior to routine CSF analysis, particularly for angioinvasive forms.4 Physicians should keep in mind, however, that the sensitivity and specificity of this test for diagnosing CA is still to be established.
References 1. Dubey A, Patwardhan RV, Sampath S, et al. Intracranial fungal granuloma: analysis of 40 patients and review of the literature. Surg Neurol 2005;63:254-260. discussion 260. 2. Schwartz S. Cerebral aspergillus infections and meningitis. In: Pasqualotto AC, ed. Aspergillosis: From Diagnosis to Prevention. Netherlands: Springer 2010:835-852. 3. Almutairi BM, Nguyen TB, Jansen GH, et al. Invasive aspergillosis of the brain: radiologic-pathologic correlation. Radiographics 2009;29:375-379. 4. De Pauw B, Walsh TJ, Donnelly JP, et al, European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group; National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46:1813-1821. 5. Norlinah MI, Ngow HA, Hamidon BB. Angioinvasive cerebral aspergillosis presenting as acute ischemic stroke in a patient with diabetes mellitus. Singapore Med J 2007; 48:e1-e4. 6. Popalzai MJ, Kushawaha A, Mobarakai N, et al. Chronic fungal sinusitis leading to disastrous cerebral aspergillosis: a case report. Cases Journal 2009;2:9406. 7. DeLone DR, Goldstein RA, Petermann G, et al. Disseminated aspergillosis involving the brain: distribution and imaging characteristics. AJNR Am J Neuroradiol 1999; 20:1597-1604.
CASE REPORT 8. Alsultan A, Williams MS, Lubner S, et al. Chronic granulomatous disease presenting with disseminated intracranial aspergillosis. Pediatr Blood Cancer 2006;47:107-110. 9. Kourkoumpetis TK, Desalermos A, Muhammed M, et al. Central nervous system aspergillosis: a series of 14 cases from a general hospital and review of 123 cases from the literature. Medicine (Baltimore) 2012;91:328-336. 10. Yip CM, Hsu SS, Liao WC, et al. Orbital apex syndrome due to aspergillosis with subsequent fatal subarachnoid hemorrhage. Surg Neurol Int 2012;3:124. 11. Jayashree P, Puranik R, Kulkarni MH. Cerebral aspergilloma presenting as atypical meningioma in an immunologically competent patient: a case report. Indian J Pathol Microbiol 2007;50:367-369. 12. Lee GJ, Jung TY, Choi SM, et al. Cerebral aspergillosis with multiple enhancing nodules in the right cerebral hemisphere in the immune-competent patient. J Korean Neurosurg Soc 2013;53:312-315. 13. Sangoi AR, Rogers WM, Longacre TA, et al. Challenges and pitfalls of morphologic identification of fungal infections in histologic and cytologic specimens: a ten-year retrospective review at a single institution. Am J Clin Pathol 2009;131:364-375. 14. Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a metaanalysis. Clin Infect Dis 2006;42:1417-1427. 15. Viscoli C, Machetti M, Gazzola P, et al. Aspergillus galactomannan antigen in the cerebrospinal fluid of bone marrow transplant recipients with probable cerebral aspergillosis. J Clin Microbiol 2002;40:1496-1499. 16. Saito T, Shime N, Itoh K, et al. Disseminated aspergillosis following resolution of pneumocystis pneumonia with sustained elevation of beta-glucan in an intensive care unit: a case report. Infection 2009;37:547-550. 17. Miki Y, Tomiyama M, Haga R, et al. Fatal subarachnoid hemorrhage caused by Aspergillus arteritis without angiographic abnormalities. Neuropathology 2012;32: 566-569. 18. Sav H, Atalay MA, Demir G, et al. Early diagnosis of cerebral aspergillosis with various methods: a case report. Infez Med 2013;21:134-138.
e43 19. Soeffker G, Wichmann D, Loderstaedt U, et al. Aspergillus galactomannan antigen for diagnosis and treatment monitoring in cerebral aspergillosis. Prog Transplant 2013;23:71-74. 20. Schwartz S, Ruhnke M, Ribaud P, et al. Improved outcome in central nervous system aspergillosis, using voriconazole treatment. Blood 2005;106:2641-2645. 21. Gallien S, Fournier S, Porcher R, et al. Therapeutic outcome and prognostic factors of invasive aspergillosis in an infectious disease department: a review of 34 cases. Infection 2008;36:533-538. 22. Herbrecht R, Denning DW, Patterson TF, et al. Invasive Fungal Infections Group of the European Organisation for Research and Treatment of Cancer and the Global Aspergillus Study Group: voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408-415. 23. Schwartz S, Ruhnke M, Ribaud P, et al. Poor efficacy of amphotericin B-based therapy in CNS aspergillosis. Mycoses 2007;50:196-200. 24. Coleman JM, Hogg GG, Rosenfeld JV, et al. Invasive central nervous system aspergillosis: cure with liposomal amphotericin B, itraconazole, and radical surgery: case report and review of the literature. Neurosurgery 1995; 36:858-863. 25. Nabika S, Kiya K, Satoh H, et al. Local administration of amphotericin B against aspergilloma in the prepontine cistern–case report. Neurol Med Chir (Tokyo) 2007; 47:89-92. 26. Mylonakis E, Paliou M, Sax PE, et al. Central nervous system aspergillosis in patients with human immunodeficiency virus infection: report of 6 cases and review. Medicine (Baltimore) 2000;79:269-280. 27. Peregud-Pogorzelski J, Wawrykow P, Wozniak S, et al. Highly effective unconventional management of aspergillosis of the left maxillary sinus in an 11-year-old girl with rhabdomyosarcoma embryonale of the frontal sinus. J Med Microbiol 2013;62(Pt 4):652-654. 28. Lee JC, Lim DJ, Ha SK, et al. Fatal case of cerebral aspergillosis: a case report and literature review. J Korean Neurosurg Soc 2012;52:420-422.
Cerebral Aspergillosis in a Diabetic Patient Leading to Cerebral Artery Occlusion and Ischemic Stroke: A Case Report and Literature Review Wentao Li, BA,* Neelofer Shafi, MD,* Ramayee Periakaruppan, MD,† Tibor Valyi-Nagy, MD, PhD,† John Groth, MD,† and Fernando D. Testai, MD, PhD, FAHA*
Cerebral aspergillosis is a rare and highly fatal hematogenous infection most commonly found in immune compromised patients. From the onset of neurologic symptoms, the median reported rate of survival is between 5 and 9 days. Compounded with increased hemorrhagic risks and the lack of specificity in both clinical presentation and traditional imaging, a fast and noninvasive method of definitive diagnosis is necessary if there is to be any hope for positive outcomes. We describe the case of a 50-year-old female diabetic with a history of otitis media, an uncharacterized inflammatory nasopharyngeal process, and prior ischemic strokes who presented with a new cerebral infarction in the setting of an angioinvasive fungal infection of the large cerebral arteries. We also present a literature review of aspergillosis detection and treatment in hopes that future cases will be diagnosed in a timely manner and more patients may be saved. Key Words: Cerebral aspergillosis—stroke—angioinvasive aspergillosis—carotid occlusion. Ó 2015 by National Stroke Association
Cerebral aspergillosis (CA) is a relatively rare form of angioinvasive fungal infection most often seen in immune compromised individuals.1 The angioinvasive nature of Aspergillus greatly increases the risk of intraoperative hemorrhage, rendering biopsy and direct diagnosis risky in many cases.2 Here, we describe a 50-year-old patient with a new cerebral infarction in the setting of an angioinFrom the *Department of Neurology, University of Illinois College of Medicine, Chicago; and †Department of Pathology, University of Illinois College of Medicine, Chicago, Illinois. Received May 6, 2014; revision received August 5, 2014; accepted August 25, 2014. This manuscript was not supported or sponsored by any grants or foundations. Address correspondence to Fernando D. Testai, MD, PhD, FAHA, Department of Neurology and Rehabilitation, University of Illinois at Chicago Medical Center, 912 S Wood Street, Rm 855N NPI (MC 796), Chicago, IL 60612-7330. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.08.025
vasive fungal infection of the large cerebral arteries and a literature review on contemporary diagnostic and treatment approaches.
Case Study A 50-year-old female with a past history of diabetes, hypertension, hyperlipidemia, chronic otomastoiditis, recent left ear infection status after tympanic tube placement, and progressive hearing loss presented to an outside hospital with headache, mild confusion, and slurred speech. Workup revealed an acute left parietooccipital ischemic stroke, and the patient was transferred to our institution for higher level of care. On arrival the patient had normal vital signs. The general examination was unrevealing. Neurologically the patient was fully oriented with normal attention and concentration and had anisocoria (right pupil: 3 mm; left pupil: 5 mm), left VI cranial neuropathy, right homonymous hemianopsia, and dysarthria. Review of magnetic resonance imaging
Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 1 (January), 2015: pp e39-e43
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W. LI ET AL.
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disclosed the known left hemispheric ischemic stroke along with inflammatory changes at the skull base and mastoid cells with no evidence of extension into the brain parenchyma. Magnetic resonance angiography demonstrated a complete occlusion of the proximal left internal carotid artery (ICA) and left posterior cerebral artery. The left middle cerebral artery showed decreased enhancement and was served by cross flow from the right side via the anterior communicating artery. The right ICA and the rest of the intracranial vessels were intact. Hypercoagulable workup was unrevealing, and transthoracic echocardiogram was negative for vegetations. Glycosylated hemoglobin was 7.7% and low-density lipoprotein (LDL) cholesterol was 59 mg/dL. Further assessment via head and neck computed tomography showed mild ethmoid sinus fullness, opacification of the left mastoid air cells, and nasopharyngeal asymmetry with inflammatory changes extending into the left Eustachian tube. Nasopharyngeal biopsy demonstrated a chronic inflammatory infiltrate and granulomatous reaction without evidence of active infection. A left mastoidectomy was performed; excision contents revealed granulation tissue and normal flora but stained negative for fungal elements. The patient refused additional workup and was released on antibiotic treatment for otitis media and aspirin. She was also offered a close neurologic followup, which was not observed. Two months later the patient presented with new onset of confusion and headache. Blood pressure on arrival was 146/106 mm Hg, pulse 110 bpm, respiration 24, and oral temperature 36.8 C. The general examination was unremarkable with no clinical evidence of systemic embolism or obvious infection. Neurologically, the patient was oriented to place and name, somnolent but arousable to tactile stimuli, and able to follow 1-step commands. She demonstrated paucity of spontaneous speech and had limited participation with the interview. Cranial nerve
evaluation showed partial central left VII palsy and the known left VI cranial neuropathy and homonymous hemianopsia. There were no focal motor or sensory deficits, and the gait was steady. Infectious workup revealed urinary tract infection but negative blood cultures and chest X-ray. Electroencephalogram showed diffuse bifrontal slowing but no epileptiform discharges. Magnetic resonance imaging confirmed paranasal sinus disease and new areas of ischemia within the left posterior cerebral artery vascular territory. Imaging also revealed a new area of flow limiting stenosis at the cervical/petrous junction of the right ICA and abnormal enhancement surrounding the vessel walls of the entirety of the left ICA (Fig 1). Following a 10-minute hypotensive event during the imaging procedure, the patient became unresponsive and an emergent head computed tomography showed early infarction in the region of the left Sylvian fissure. Extensive infarcts in bilateral cerebral hemispheres and deep gray matter led to diffuse left hemispheric edema with subfalcine and transtentorial herniation. Ischemic changes were also visualized in the brain stem; patient was terminally extubated per wishes of family and pronounced dead on hospital day 6.
Pathology Findings An autopsy was performed and showed cerebral edema and subfalcine and transtentorial herniation. Sections from the skull base, including internal carotid canal contents and sphenoid sinus contents demonstrated angioinvasive fungal infection involving large arteries, associated with thrombosis and necrotizing acute and chronic inflammation. The fungal organisms demonstrated septated and homogenous hyphae of uniform width, with parallel contours and dichotomous branches arising at an acute angle. Conidial heads were absent. Sections from the brain demonstrated cerebral arteriosclerosis,
Figure 1. (A) Magnetic resonance (MR) image showing enlargement and abnormal T2 signal along the left internal carotid artery (ICA) suggestive of thrombus within the vessel. (B) MR image demonstrating narrowing and enhancement of the right ICA at the cervical/petrous junction.
CASE REPORT
changes of acute global cerebral ischemia, and focal remote ischemia. These findings suggested that the cause of death was cerebral infarction and herniation due to angioinvasive fungal infection and thrombotic obliteration of large cerebral arteries at the skull base. Although no fungal cultures were performed, the fungal forms detected in histologic sections were most consistent with Aspergillus sp, (Fig 2). No evidence of fungal infection was detected in the lungs or other organs.
Discussion Presentation Angioinvasive CA is typically a manifestation of disseminated aspergillosis in transplant patients and patients with hematologic malignancies, but it has also been reported in diabetic patients.1-6 Besides hematogenous fungal spread from the lungs and infected heart valves, direct fungal invasion of the central nervous system (CNS) from adjacent tissues is also possible. As the evidence in this case was more consistent with an infiltrative process rather than seeding from a primary cardiac or pulmonary source, direct invasion to the large arteries of the skull base was the most likely mechanism of dissemination. Immunosuppression from the patient’s diabetes likely also played a role in the pathogenesis of the detected CA. In addition to nonpyogenic cerebral abscesses, CA also manifests as granulomatous formations, meningitis, aneurysms, and multifocal infarcts; lesion size and number vary from single distinct masses to multiple nonfocal lesions.7,8 Clinical findings are similar to malignant neoplasms in the same anatomic regions, ranging from severe headache and nausea to altered mental status, cranial neuropathies, decreased cognitive function, weakness, seizures, visual changes, and focal neurologic deficits.2,9 In particular, rhinocerebral infections extending into cavernous sinus often result in unilateral or bilateral exophthalmos, ptosis, vision loss, and orbital apex syndrome with cranial nerves III, IV, and VI involvement.10-12 Our patient was unusual in that she lacked obvious immunosuppression besides her diabetes and presented with a negative sinus biopsy. However, the nonspecific
Figure 2. Gomori methenamine silver stain of skull base temporal bone demonstrating septate fungal hyphae with acute angle branching consistent with Aspergillus sp in a background of necrotizing acute inflammation. Magnification: 503 (A); 4003 (B).
e41
findings of mild confusion and cranial neuropathies do concur with published symptoms. In future cases of ischemic stroke with large artery occlusive disease in the setting of skull base inflammation and negative routine workup, we hope this patient’s presentation will help form the clinical suspicion of CA and lead to timely employment of specific detection methods.
Detection As seen in the case of our patient, Aspergillus can invade into major blood vessels resulting in aneurysms and thrombosis. Furthermore, due to species’ capacity to disrupt the blood vessel’s internal elastic lamina, up to 25% of acute infarctions also result in hemorrhage.3 Such hematologic cases often render biopsies infeasible; to make diagnosis even more difficult, lumbar punctures are typically inconclusive as well. Routine cerebrospinal fluid (CSF) analysis may show mild to moderate elevations of white blood cell counts and protein concentrations with normal or decreased glucose content, but it is generally unreliable and in most cases fail to grow Aspergillus in culture. Currently, culture remains the gold standard for the definitive identification of fungal organisms, with histologic evaluation able to correctly identify fungal organisms in 79% of cases.13 Recently, a new approach using the galactomannan (GM) test is demonstrating some success in indirectly determining the presence of the fungus. This sandwich enzyme-linked immunosorbent assay detects aspergillum GM antigen in CSF, serum, plasma, and bronchoalveolar lavage fluid with high specificity.4,14 However, the sensitivity of this test has not been established in cases with CNS involvement. One study by Viscoli et al15 demonstrated the inability of GM testing to differentiate between CNS and pulmonary forms of infection. Moreover, it has been postulated that the presence of antiAspergillus antibodies in chronic infection may interfere with the detection of serum antigens, resulting in negative GM assays when CNS involvement is secondary to the initial Aspergillus infection.16 Since its inclusion as a probable indicator of Aspergillus infection by the 2008 Consensus Group, positive GM results in 2 of 4 confirmed CA cases has led to timely intervention with voriconazole and remission in this usually fatal disease (Table 1).
W. LI ET AL.
e42
Table 1. Reported CA cases using GM tests since incorporation by the EORTC/MSG Consensus Group in 2008* Reference
Age, y
Sex
Affected locations
Saito et al16
63 (Deceased)
F
Miki et al17
76 (Deceased)
M
Cerebrovascular, disseminated from pulmonary aspergillosis. Granulomatous lesions on optic chiasm and nerves, thickened frontal base dural mater, middle cerebral artery. Right frontal lobe (12 mm), nodular lesions on left cerebellum and cingulate gyrus. Paraventricular, adjacent to left ventricular wall and choroid plexus.
Sav et al18
F 4
Soeffker et al19
M 51
GM result Serum GM: ,.2 ng/mL (negative) Serum GM: negative in 9 consecutive tests Serum GM: 3.39 ng/mL (positive), .72 ng/mL (positive) CSF GM (ratio):8.8 (positive)
Abbreviations: CA, cerebral aspergillosis; CSF, cerebrospinal fluid; EORTC/MSG, European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group; GM, galactomannan. *Case studies including patients from before 2008 were omitted.
Treatment Currently, voriconazole is the most effective pharmacologic treatment against CA.20,21 Compared with 100% morality in 17 patients treated with amphotericin-B alone or with itraconazole, 25 of 95 patients treated with voriconazole were not known to have died.20,22,23 Of these, 15 reported a median survival length of 237 days after termination of therapy.20 Moreover, patients unresponsive to initial amphotericin or itraconazole treatments have demonstrated noticeable improvement on switching to voriconazole.12 In all studies, neurosurgical management via abscess resection or drainage in conjunction with antifungal therapy resulted in greater survival rates compared with pharmacologic treatment alone.2,9,20,24 Of 123 confirmed CA cases from the past decade, 28.6% of patients who underwent neurosurgery died compared with 67.5% of patients who did not.9 Nevertheless, the optimal neurosurgical approach has yet to be defined, and the effectiveness of direct administration of antifungals via reservoirs or lavages is mixed.25-27 As in the case of biopsies, risk of hemorrhage during surgery is increased because of the angioinvasive nature of CA. In cases where total resection of the abscess is not feasible and intradural invasion has been confirmed, intensive postoperative systemic antifungal therapy must be continued to prevent the development of lethal vasculitis or meningoencephalitis.28
Conclusion Despite the recent advances in the detection of Aspergillus, the diagnosis of angioinvasive CA continues to be challenging. The CSF analysis is generally unreliable and the recovery of Aspergillus in culture is in most cases unsuccessful. In some cases like ours, an unusual clinical presentation such as the absence of obvious immunosuppression and local rather than hematogenous fungal
spread can further complicate the diagnostic process. Clinical suspicion therefore remains crucial for establishing a timely diagnosis, a fact further highlighted by the negative sinus biopsy in our patient. Recent reports suggest that the measurement of GM in CSF is superior to routine CSF analysis, particularly for angioinvasive forms.4 Physicians should keep in mind, however, that the sensitivity and specificity of this test for diagnosing CA is still to be established.
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