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A Cryptic Case: Isolated Cerebral Mucormycosis
DIAGNOSTIC DILEMMA Aimee K. Zaas, MD Thomas J. Marrie, MD, Section Editors
A Cryptic Case: Isolated Cerebral Mucormycosis Monica B. Dhakar, MD, MS,a Mahmoud Rayes, MD,a William Kupsky, MD,b Alexandros Tselis, MD,a Gregory Norris, MDa Departments of aNeurology and bPathology, Wayne State University, Detroit Medical Center, Detroit, Mich.
PRESENTATION A rare infection raging within the brain of a 50-year-old African-American man was impossible to diagnose until after his death. He presented to the emergency department after the acute onset of garbled speech, confusion, right-arm weakness, and right facial droop. His medical history was significant for poorly controlled diabetes mellitus and polysubstance abuse, including intravenous drug abuse. He had never had a stroke, had no sick contacts, and had not traveled recently.
ASSESSMENT On examination, the patient was cachectic and febrile with a temperature of 102.2 F (39 C). General examination showed no lesions of the nose, paranasal sinuses, orbits, or skin. He was drowsy but arousable to verbal stimuli, produced incomprehensible words, and did not follow any commands. Laboratory investigations disclosed hyperglycemia (blood sugar, >600 mg/dL), and a urine drug screen was positive for cocaine, opiates, and methadone. The patient was admitted to the neurointensive care unit and empirically treated with vancomycin and ceftriaxone because of concern for bacterial meningitis. Initial noncontrast computed tomography (CT) of the head showed left basal ganglia hypodensity suggestive of subacute infarction. Brain magnetic resonance imaging (MRI) demonstrated diffusion-restricting lesions within the head of the left caudate nucleus, lentiform nucleus, and internal capsule without surrounding edema. Areas of gradient susceptibility Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data. All the authors declared that they met criteria for authorship including acceptance of responsibility for the scientific content of the manuscript. Disclosures: None. Requests for reprints should be addressed to Monica Dhakar, MD, MS, Yale Neurology, 15 York Street, PO Box 208018, New Haven, CT 065208018 E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.08.033
indicated a hemorrhagic component (Figure 1). Curvilinear enhancement along the ependymal margin of the left frontal ventricle on postcontrast images indicated some degree of damage to the blood-brain barrier. Magnetic resonance angiography of the head and neck did not disclose evidence of stenosis or thrombosis of any major intracranial blood vessel. Cerebrospinal fluid analysis indicated the presence of meningitis with an elevated white blood cell count of 513 103 cells/mm3 (59% neutrophils, 34% lymphocytes, 7% monocytes), a red blood cell count of 1.88 million cells/ mm3, increased protein of 153 mg/dL, and low cerebrospinal fluid glucose of 54 mg/dL (serum glucose was 176 mg/dL). The following investigations were done and were negative: serial blood cultures for bacteria and fungi and serology for human immunodeficiency virus 1, syphilis, Toxoplasma species, and Aspergillus species. Cultures of cerebrospinal fluid were negative for bacteria, viruses, fungi. Cerebrospinal fluid, also analyzed via polymerase chain reaction, proved negative for herpes simplex viruses 1 and 2, varicella zoster virus, and Aspergillus species. Results of a transthoracic echocardiogram were normal, revealing no valvular vegetations or intracardiac masses.
DIAGNOSIS Despite antibiotic treatment, the patient continued to spike fevers for 2 days. Repeat MRI of the brain, obtained 48 hours after the first images, revealed a new diffusionrestricting lesion of the right basal ganglia and right parietal white matter (Figure 2). More evidence of hemorrhage was seen within the previous infarction of the left basal ganglia, and signs of hemorrhage were also seen in the right basal ganglia infarction. Because the patient remained feverish and his condition was worsening, the neurosurgery department was consulted, and a brain biopsy was performed. Histopathology of the left frontal biopsy specimen disclosed small fragments of white matter with scattered noncaseating granulomas. It was negative for any fungal stain. Over the next 3 days, the
2
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2015
Figure 1 Magnetic resonance imaging (MRI) was obtained on the patient’s admission day. (A) Diffusion-weighted MRI showed restricted diffusion in the left basal ganglia and internal capsule. (B) Fluid attenuation inversion recovery (FLAIR) demonstrated minimal edema around the lesion. (C) A gradient echo sequence revealed areas of hemorrhage within the basal ganglia lesion. (D) Post-gadolinium T1-weighted images identified curvilinear enhancement along the ependymal margin of the left frontal ventricle.
patient rapidly deteriorated, becoming deeply comatose. He died from brain herniation 9 days after the onset of symptoms. At autopsy, his brain was swollen without any exudate on the surface. Sections from the deep basal ganglia and thalamus were marked by extensive hemorrhagic necrosis with numerous microabscesses and small granulomas with giant cells. The tissue and giant cells were permeated with fungal hyphae, which were broad but irregular in thickness and frequently branched at right angles (Figure 3). This finding confirmed a diagnosis of mucormycosis. Sections from blood vessels at the base of the brain showed thrombosed vessels with numerous fungal hyphae. General autopsy did not show any evidence of involvement at the paranasal
sinuses, orbits, pharynx, or chest, all sites that are more commonly infected. Mucormycosis is an aggressive fungal infection caused by members of the order Mucorales; most belong to genera in the family Mucoraceae.1 These saprophytic fungi are ubiquitous in the environment, particularly in the soil and decomposing plant matter.2 The organism is pathogenic in people who are immunosuppressed, such as patients with hematologic malignancies, neutropenia, or diabetic ketoacidosis, those who have undergone organ transplantation, and intravenous drug abusers.3,4 The infection usually manifests as rhino-orbitocerebral mucormycosis, in which the organism is inhaled, and infection ascends upwards from the nasal passages or sinuses and spreads intracranially to involve the brain.5,6
Dhakar et al
A Cryptic Case of Isolated Cerebral Mucormycosis
3
Figure 2 MRI of the brain was repeated 48 hours later, (A) A diffusion-weighted imaging sequence showed new areas of restricted diffusion involving the right basal ganglia and the internal capsule. (B) FLAIR indicated minimal edema around the lesion. (C) A hemorrhagic component was noted, as seen on a gradient-recalled echo image.
Typically, as the fungal infection progresses, it leaves a visible trail of tissue necrosis, a telltale sign of mucormycosis. While our patient had 2 risk factors, diabetes mellitus and intravenous drug abuse, he did not have discernable evidence of fungal meningitis, so the disease was not at the top of the
differential diagnosis. He had no evidence of paranasalorbital involvement on clinical examination or on imaging with CT and MRI. Moreover, fungal stains of blood, cerebrospinal fluid, and tissue were all negative. As a result, no antifungal treatment was instituted.
Figure 3 Microphotographs of autopsy sections from the brain are shown. (A) Thrombosed blood vessels in the middle cerebral artery were permeated with fungal hyphae (Luxol fast blue stain/hematoxylin and eosin, 40). (B) The fungal hyphae found in the middle cerebral artery were nonseptate and branched at right angles (Luxol fast blue stain/hematoxylin and eosin, 400). (C) A sample from the middle cerebral artery showed fungal hyphae with similar characteristics as above. (Grocott’s methenamine silver stain, 400). (D) A granuloma with giant cells, polymorphonuclear cells, and fungal hyphae was found in the white matter (Luxol fast blue stain/hematoxylin and eosin, 400).
4 Isolated cerebral mucormycosis, a unique clinical entity, is seldom reported.7 Our patient’s case highlights its distinctiveness. First, isolated cerebral mucormycosis has been consistently associated with intravenous drug abuse.7,8 A possible explanation is that fungal spores are inoculated directly into the bloodstream via contaminated illicit drugs. Some microspores might escape filtering by pulmonary capillaries, subsequently gaining access to the arterial circulation and ultimately, to intracranial structures.8,9 In rodent models, hematogenous inoculation of spores of Absidia ramosa resulted in localized brain lesions.10 Second, while patients with isolated central nervous system involvement can present with headache or rapidly progressive focal neurologic deficits, they may lack visible evidence of the tissue damage ordinarily seen in patients with rhino-orbital-cerebral mucormycosis. Our patient’s cerebrospinal fluid examination indicated the presence of meningitis, but blood cultures, cerebrospinal fluid cultures, and serological tests were negative, and this is often so in patients with isolated cerebral mucormycosis. Prior reports have shown that ante-mortem diagnosis is possible in only 50% of cases.11,12 This poses a diagnostic challenge, and hence, a very high index of suspicion is required based on clinical grounds. Last, isolated cerebral mucormycosis has been shown to have consistent predilection for basal ganglia, a finding that has been reported in previous studies.11,13 Therefore, imaging may be the only clue to the diagnosis. CT without contrast shows hypoattenuation of unilateral basal ganglia, which may rapidly progress to become bilateral. MRI may identify diffusion-restricted lesions with a different pattern of enhancement, along with hemorrhagic products, as seen in our patient. This propensity for destruction of the basal ganglia is explained by the angioinvasive nature of the organism. The hyphae proliferate in the internal elastic lamina, penetrate the endothelium, and eventually occlude the lumen of blood vessels.14 Thrombosis of the blood vessels at the base of the brain appears to cause the stroke-like lesions in the deep nuclei of basal ganglia. Such dramatic changes in basal ganglia are also seen in uremia, hypoglycemia, hypoxic-ischemic injury, vasculitis, and CreutzfeldteJakob disease. But whereas these conditions cause symmetric abnormalities of basal ganglia, mucormycosis usually starts on one side and then spreads to involve the other side. Our patient had extensive necrotizing and hemorrhagic cerebritis with numerous fungal hyphae, similar to findings in prior cases of isolated cerebral disease.
The American Journal of Medicine, Vol -, No -,
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2015
MANAGEMENT Treatment of cerebral mucormycosis usually consists of intravenous amphotericin B or a less nephrotoxic liposomal formulation of amphotericin. Infrequently, surgical debridement may lead to a better outcome, however it can be difficult to reach deep-seated lesions.15 Even with aggressive medical and surgical intervention, the outcome is generally dismal. Isolated cerebral mucormycosis is extremely uncommon and presents as a distinct entity. Clinicians should have a very high index of suspicion for cerebral mucormycosis in patients who have a history of intravenous drug abuse and present with fever, focal neurological signs, and lesions of the basal ganglia on imaging. Once the diagnosis is suspected, empiric treatment should be instituted immediately to reduce the likelihood of a fatal outcome.
References 1. Baker RD. The phycomycoses. Ann N Y Acad Sci. 1970;174:592-605. 2. Gartenberg G, Bottone EJ, Keusch GT, Weitzman I. Hospital-acquired mucormycosis (Rhizopus rhizopodiformis) of skin and subcutaneous tissue: epidemiology, mycology, and treatment. N Engl J Med. 1978;299:1115-1118. 3. Jeevanan J, Gendeh BS, Faridah HA, Vikneswaran T. Rhino-orbito-cerebral mucormycosis: a treatment dilemma. Med J Malaysia. 2006;61:106-108. 4. Munir N, Jones NS. Rhinocerebral mucormycosis with orbital and intracranial extension: a case report and review of optimum management. J Laryngol Otol. 2007;121:192-195. 5. Martin-Moro JG, Calleja JM, García MB, Carretero JL, Rodríguez JG. Rhinoorbitocerebral mucormycosis: a case report and literature review. Med Oral Patol Oral Cir Bucal. 2008;13:E792-E795. 6. Toumi A, Larbi Ammari F, Loussaief C, et al. Rhino-orbito-cerebral mucormycosis: five cases. Med Mal Infect. 2012;42:591-598. 7. Verma A, Brozman B, Petito CK. Isolated cerebral mucormycosis: report of a case and review of the literature. J Neurol Sci. 2006;240:65-69. 8. Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41:634-653. 9. Bichile LS, Abhyankar SC, Hase NK. Chronic mucormycosis manifesting as hydrocephalus. J Neurol Neurosurg Psychiatry. 1985;48:1188. 10. Smith JM, Jones RH. Localization and fate of Absidia ramosa spores after intravenous inoculation of mice. J Comp Pathol. 1973;83:49-55. 11. Stave GM, Heimberger T, Kerkering TM. Zygomycosis of the basal ganglia in intravenous drug users. Am J Med. 1989;86:115-117. 12. Sundaram C, Mahadevan A, Laxmi V, et al. Cerebral zygomycosis. Mycoses. 2005;48:396-407. 13. Hopkins RJ, Rothman M, Fiore A, Goldblum SE. Cerebral mucormycosis associated with intravenous drug use: three case reports and review. Clin Infect Dis. 1994;19:1133-1137. 14. Weprin BE, Hall WA, Goodman J, Adams GL. Long-term survival in rhinocerebral mucormycosis. Case report. J Neurosurg. 1998;88:570-575. 15. Han SR, Choi CY, Joo M, Whang CJ. Isolated cerebral mucormycosis. J Korean Neurosurg Soc. 2007;42:400-402.
A Cryptic Case: Isolated Cerebral Mucormycosis Monica B. Dhakar, MD, MS,a Mahmoud Rayes, MD,a William Kupsky, MD,b Alexandros Tselis, MD,a Gregory Norris, MDa Departments of aNeurology and bPathology, Wayne State University, Detroit Medical Center, Detroit, Mich.
PRESENTATION A rare infection raging within the brain of a 50-year-old African-American man was impossible to diagnose until after his death. He presented to the emergency department after the acute onset of garbled speech, confusion, right-arm weakness, and right facial droop. His medical history was significant for poorly controlled diabetes mellitus and polysubstance abuse, including intravenous drug abuse. He had never had a stroke, had no sick contacts, and had not traveled recently.
ASSESSMENT On examination, the patient was cachectic and febrile with a temperature of 102.2 F (39 C). General examination showed no lesions of the nose, paranasal sinuses, orbits, or skin. He was drowsy but arousable to verbal stimuli, produced incomprehensible words, and did not follow any commands. Laboratory investigations disclosed hyperglycemia (blood sugar, >600 mg/dL), and a urine drug screen was positive for cocaine, opiates, and methadone. The patient was admitted to the neurointensive care unit and empirically treated with vancomycin and ceftriaxone because of concern for bacterial meningitis. Initial noncontrast computed tomography (CT) of the head showed left basal ganglia hypodensity suggestive of subacute infarction. Brain magnetic resonance imaging (MRI) demonstrated diffusion-restricting lesions within the head of the left caudate nucleus, lentiform nucleus, and internal capsule without surrounding edema. Areas of gradient susceptibility Funding: None. Conflict of Interest: None. Authorship: All authors had access to the data. All the authors declared that they met criteria for authorship including acceptance of responsibility for the scientific content of the manuscript. Disclosures: None. Requests for reprints should be addressed to Monica Dhakar, MD, MS, Yale Neurology, 15 York Street, PO Box 208018, New Haven, CT 065208018 E-mail address: [email protected] 0002-9343/$ -see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2015.08.033
indicated a hemorrhagic component (Figure 1). Curvilinear enhancement along the ependymal margin of the left frontal ventricle on postcontrast images indicated some degree of damage to the blood-brain barrier. Magnetic resonance angiography of the head and neck did not disclose evidence of stenosis or thrombosis of any major intracranial blood vessel. Cerebrospinal fluid analysis indicated the presence of meningitis with an elevated white blood cell count of 513 103 cells/mm3 (59% neutrophils, 34% lymphocytes, 7% monocytes), a red blood cell count of 1.88 million cells/ mm3, increased protein of 153 mg/dL, and low cerebrospinal fluid glucose of 54 mg/dL (serum glucose was 176 mg/dL). The following investigations were done and were negative: serial blood cultures for bacteria and fungi and serology for human immunodeficiency virus 1, syphilis, Toxoplasma species, and Aspergillus species. Cultures of cerebrospinal fluid were negative for bacteria, viruses, fungi. Cerebrospinal fluid, also analyzed via polymerase chain reaction, proved negative for herpes simplex viruses 1 and 2, varicella zoster virus, and Aspergillus species. Results of a transthoracic echocardiogram were normal, revealing no valvular vegetations or intracardiac masses.
DIAGNOSIS Despite antibiotic treatment, the patient continued to spike fevers for 2 days. Repeat MRI of the brain, obtained 48 hours after the first images, revealed a new diffusionrestricting lesion of the right basal ganglia and right parietal white matter (Figure 2). More evidence of hemorrhage was seen within the previous infarction of the left basal ganglia, and signs of hemorrhage were also seen in the right basal ganglia infarction. Because the patient remained feverish and his condition was worsening, the neurosurgery department was consulted, and a brain biopsy was performed. Histopathology of the left frontal biopsy specimen disclosed small fragments of white matter with scattered noncaseating granulomas. It was negative for any fungal stain. Over the next 3 days, the
2
The American Journal of Medicine, Vol -, No -,
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2015
Figure 1 Magnetic resonance imaging (MRI) was obtained on the patient’s admission day. (A) Diffusion-weighted MRI showed restricted diffusion in the left basal ganglia and internal capsule. (B) Fluid attenuation inversion recovery (FLAIR) demonstrated minimal edema around the lesion. (C) A gradient echo sequence revealed areas of hemorrhage within the basal ganglia lesion. (D) Post-gadolinium T1-weighted images identified curvilinear enhancement along the ependymal margin of the left frontal ventricle.
patient rapidly deteriorated, becoming deeply comatose. He died from brain herniation 9 days after the onset of symptoms. At autopsy, his brain was swollen without any exudate on the surface. Sections from the deep basal ganglia and thalamus were marked by extensive hemorrhagic necrosis with numerous microabscesses and small granulomas with giant cells. The tissue and giant cells were permeated with fungal hyphae, which were broad but irregular in thickness and frequently branched at right angles (Figure 3). This finding confirmed a diagnosis of mucormycosis. Sections from blood vessels at the base of the brain showed thrombosed vessels with numerous fungal hyphae. General autopsy did not show any evidence of involvement at the paranasal
sinuses, orbits, pharynx, or chest, all sites that are more commonly infected. Mucormycosis is an aggressive fungal infection caused by members of the order Mucorales; most belong to genera in the family Mucoraceae.1 These saprophytic fungi are ubiquitous in the environment, particularly in the soil and decomposing plant matter.2 The organism is pathogenic in people who are immunosuppressed, such as patients with hematologic malignancies, neutropenia, or diabetic ketoacidosis, those who have undergone organ transplantation, and intravenous drug abusers.3,4 The infection usually manifests as rhino-orbitocerebral mucormycosis, in which the organism is inhaled, and infection ascends upwards from the nasal passages or sinuses and spreads intracranially to involve the brain.5,6
Dhakar et al
A Cryptic Case of Isolated Cerebral Mucormycosis
3
Figure 2 MRI of the brain was repeated 48 hours later, (A) A diffusion-weighted imaging sequence showed new areas of restricted diffusion involving the right basal ganglia and the internal capsule. (B) FLAIR indicated minimal edema around the lesion. (C) A hemorrhagic component was noted, as seen on a gradient-recalled echo image.
Typically, as the fungal infection progresses, it leaves a visible trail of tissue necrosis, a telltale sign of mucormycosis. While our patient had 2 risk factors, diabetes mellitus and intravenous drug abuse, he did not have discernable evidence of fungal meningitis, so the disease was not at the top of the
differential diagnosis. He had no evidence of paranasalorbital involvement on clinical examination or on imaging with CT and MRI. Moreover, fungal stains of blood, cerebrospinal fluid, and tissue were all negative. As a result, no antifungal treatment was instituted.
Figure 3 Microphotographs of autopsy sections from the brain are shown. (A) Thrombosed blood vessels in the middle cerebral artery were permeated with fungal hyphae (Luxol fast blue stain/hematoxylin and eosin, 40). (B) The fungal hyphae found in the middle cerebral artery were nonseptate and branched at right angles (Luxol fast blue stain/hematoxylin and eosin, 400). (C) A sample from the middle cerebral artery showed fungal hyphae with similar characteristics as above. (Grocott’s methenamine silver stain, 400). (D) A granuloma with giant cells, polymorphonuclear cells, and fungal hyphae was found in the white matter (Luxol fast blue stain/hematoxylin and eosin, 400).
4 Isolated cerebral mucormycosis, a unique clinical entity, is seldom reported.7 Our patient’s case highlights its distinctiveness. First, isolated cerebral mucormycosis has been consistently associated with intravenous drug abuse.7,8 A possible explanation is that fungal spores are inoculated directly into the bloodstream via contaminated illicit drugs. Some microspores might escape filtering by pulmonary capillaries, subsequently gaining access to the arterial circulation and ultimately, to intracranial structures.8,9 In rodent models, hematogenous inoculation of spores of Absidia ramosa resulted in localized brain lesions.10 Second, while patients with isolated central nervous system involvement can present with headache or rapidly progressive focal neurologic deficits, they may lack visible evidence of the tissue damage ordinarily seen in patients with rhino-orbital-cerebral mucormycosis. Our patient’s cerebrospinal fluid examination indicated the presence of meningitis, but blood cultures, cerebrospinal fluid cultures, and serological tests were negative, and this is often so in patients with isolated cerebral mucormycosis. Prior reports have shown that ante-mortem diagnosis is possible in only 50% of cases.11,12 This poses a diagnostic challenge, and hence, a very high index of suspicion is required based on clinical grounds. Last, isolated cerebral mucormycosis has been shown to have consistent predilection for basal ganglia, a finding that has been reported in previous studies.11,13 Therefore, imaging may be the only clue to the diagnosis. CT without contrast shows hypoattenuation of unilateral basal ganglia, which may rapidly progress to become bilateral. MRI may identify diffusion-restricted lesions with a different pattern of enhancement, along with hemorrhagic products, as seen in our patient. This propensity for destruction of the basal ganglia is explained by the angioinvasive nature of the organism. The hyphae proliferate in the internal elastic lamina, penetrate the endothelium, and eventually occlude the lumen of blood vessels.14 Thrombosis of the blood vessels at the base of the brain appears to cause the stroke-like lesions in the deep nuclei of basal ganglia. Such dramatic changes in basal ganglia are also seen in uremia, hypoglycemia, hypoxic-ischemic injury, vasculitis, and CreutzfeldteJakob disease. But whereas these conditions cause symmetric abnormalities of basal ganglia, mucormycosis usually starts on one side and then spreads to involve the other side. Our patient had extensive necrotizing and hemorrhagic cerebritis with numerous fungal hyphae, similar to findings in prior cases of isolated cerebral disease.
The American Journal of Medicine, Vol -, No -,
-
2015
MANAGEMENT Treatment of cerebral mucormycosis usually consists of intravenous amphotericin B or a less nephrotoxic liposomal formulation of amphotericin. Infrequently, surgical debridement may lead to a better outcome, however it can be difficult to reach deep-seated lesions.15 Even with aggressive medical and surgical intervention, the outcome is generally dismal. Isolated cerebral mucormycosis is extremely uncommon and presents as a distinct entity. Clinicians should have a very high index of suspicion for cerebral mucormycosis in patients who have a history of intravenous drug abuse and present with fever, focal neurological signs, and lesions of the basal ganglia on imaging. Once the diagnosis is suspected, empiric treatment should be instituted immediately to reduce the likelihood of a fatal outcome.
References 1. Baker RD. The phycomycoses. Ann N Y Acad Sci. 1970;174:592-605. 2. Gartenberg G, Bottone EJ, Keusch GT, Weitzman I. Hospital-acquired mucormycosis (Rhizopus rhizopodiformis) of skin and subcutaneous tissue: epidemiology, mycology, and treatment. N Engl J Med. 1978;299:1115-1118. 3. Jeevanan J, Gendeh BS, Faridah HA, Vikneswaran T. Rhino-orbito-cerebral mucormycosis: a treatment dilemma. Med J Malaysia. 2006;61:106-108. 4. Munir N, Jones NS. Rhinocerebral mucormycosis with orbital and intracranial extension: a case report and review of optimum management. J Laryngol Otol. 2007;121:192-195. 5. Martin-Moro JG, Calleja JM, García MB, Carretero JL, Rodríguez JG. Rhinoorbitocerebral mucormycosis: a case report and literature review. Med Oral Patol Oral Cir Bucal. 2008;13:E792-E795. 6. Toumi A, Larbi Ammari F, Loussaief C, et al. Rhino-orbito-cerebral mucormycosis: five cases. Med Mal Infect. 2012;42:591-598. 7. Verma A, Brozman B, Petito CK. Isolated cerebral mucormycosis: report of a case and review of the literature. J Neurol Sci. 2006;240:65-69. 8. Roden MM, Zaoutis TE, Buchanan WL, et al. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41:634-653. 9. Bichile LS, Abhyankar SC, Hase NK. Chronic mucormycosis manifesting as hydrocephalus. J Neurol Neurosurg Psychiatry. 1985;48:1188. 10. Smith JM, Jones RH. Localization and fate of Absidia ramosa spores after intravenous inoculation of mice. J Comp Pathol. 1973;83:49-55. 11. Stave GM, Heimberger T, Kerkering TM. Zygomycosis of the basal ganglia in intravenous drug users. Am J Med. 1989;86:115-117. 12. Sundaram C, Mahadevan A, Laxmi V, et al. Cerebral zygomycosis. Mycoses. 2005;48:396-407. 13. Hopkins RJ, Rothman M, Fiore A, Goldblum SE. Cerebral mucormycosis associated with intravenous drug use: three case reports and review. Clin Infect Dis. 1994;19:1133-1137. 14. Weprin BE, Hall WA, Goodman J, Adams GL. Long-term survival in rhinocerebral mucormycosis. Case report. J Neurosurg. 1998;88:570-575. 15. Han SR, Choi CY, Joo M, Whang CJ. Isolated cerebral mucormycosis. J Korean Neurosurg Soc. 2007;42:400-402.