Clinical Neurology and Neurosurgery 124 (2014) 179–181
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case Report
Cerebral phaeohyphomycosis in an immunocompetent patient: A case report and literature summary Vlady Litchevski a , Anna Goldschmidt b , Dvora Nass c , Galia Rahav a,e , Zvi R. Cohen d,e,∗ a
Infectious Diseases Unit, Ramat Gan, Israel Clinical Microbiology, Ramat Gan, Israel Neuropathology, Ramat Gan, Israel d Department of Neurosurgery, Ramat Gan, Israel e The Chaim Sheba Medical Center, Tel-Hashomer, and Sackler School of Medicine, Tel Aviv University, Ramat Gan, Israel b c
a r t i c l e
i n f o
Article history: Received 6 January 2014 Received in revised form 9 June 2014 Accepted 5 July 2014 Available online 14 July 2014 Keywords: Phaeohyphomycosis Brain abscess Brain biopsy
1. Introduction Phaeohyphomycosis is an infection caused by a darkly pigmented or ‘dematiaceous’ fungi that derives its coloration from melanin in the cell walls [1,2]. These fungi are typically found in the soil and introduced through inhalation. Infections can occur in various parts of the body, most commonly the skin and soft tissues, sinuses, and the central nervous system (CNS) [1,2]. This infection has been described in both immunocompetent and immunocompromised hosts [3]. Treatment is often challenging, giving phaeohyphomycosis a high rate of mortality, particularly when the CNS is affected. We present an apparently immunocompetent patient who developed a phaeohyphomycotic brain abscess and was successfully treated with voriconazole alone. 2. Case report A 21-year-old healthy soldier was admitted to the emergency room due to new onset generalized seizures which caused lacerations in his face and broken teeth. He denied any history of
∗ Corresponding author at: The Chaim Sheba Medical Center, Tel.:-Hashomer, and Sackler School of Medicine, Tel Aviv University, Israel. Tel.: +97 235302650; fax: +97 235354413. E-mail address: [email protected] (Z.R. Cohen). http://dx.doi.org/10.1016/j.clineuro.2014.07.003 0303-8467/© 2014 Elsevier B.V. All rights reserved.
travel, he was born in Israel to immigrants from Ethiopia. On examination, he was afebrile, alert and oriented. Physical examination was intact except for mild receptive dysphasia. Brain computed tomography scan revealed a left temporo-parietal lesion. Magnetic resonance imaging revealed an enhancing lesion with surrounding edema (Fig. 1), suggestive of a brain neoplasm. The paranasal sinuses showed no significant abnormality. The patient did not have any tuberculosis contact. The results of a complete blood cell count, serum chemistry tests including glucose and liver function tests were normal. Serology for human immunodeficiency virus was negative. A skin test for tuberculosis was non-reactive. Serological tests for toxoplasma revealed positive IgG and negative IgM. Immunoglobulins were normal, CD4 count was 914 cell/mm3 . Phenytoin was administered and stereotactic biopsy was performed. Histopathological findings as well as PAS stain revealed focal white matter necrosis, neutrophilic infiltration, and focal collections of fungal elements, composed of yeast like forms and septate, infrequently branched hyphae. A brown mold grew in Sabouraud Dextrose Agar after 5 days (Fig. 2). The mold was subcultured in potato dextrose agar. The mold was defined microscopically as Bipolaris spicifera due to frequent sporulation, sympodial geniculate conidiophores, enhanced hilum and large three celled condia. Galactomannan was negative. There was no evidence of pulmonary or other clinical sites of fungal disease after thorough evaluation, including chest and abdomen CT. Blood cultures were without growth. Trans-esophageal echocardiogram was
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V. Litchevski et al. / Clinical Neurology and Neurosurgery 124 (2014) 179–181
Fig. 1. T1 weighted axial MR imaging with Gadolonium showing left temporoparietal enhancing lesion.
normal. He was started empirically with Amphotericin B 1.5 mg/kg. Following identification of the mold and its antibiotic susceptibility voriconazole was administered at a daily dose of 600 mg, which was reduced to 400 mg/d due to increased liver enzymes. Levetiracetam was administered. Excision of the abscess was less feasible, due to its location. On follow-up clinical visit at 12 weeks post discharge, MRI showed ongoing resolution of the lesion. At his 15month follow-up, a brain MRI showed resolution of the lesion and voriconazole was discontinued. 3. Discussion Phaeohyphomycosis is a rare infection caused by dematiaceous or dark pigmented melanin-containing cell wall fungus. They can cause life-threatening infections mainly in immunocompromised patients; however, infections were noted also in immunocompetent individuals as in our patient [4]. They have worldwide distribution and are mainly found in the soil. Infection most commonly affects the skin and soft tissues from direct inoculation following trauma or the paranasal sinuses from inhalation. Phaeohyphomycosis can invade the CNS through hematogenous spread,
direct invasion from surrounding tissues or direct inoculation through an open cranial wound. However, our patient did not have evidence of sinusitis or an open cranial wound that could be the source of his CNS infection. CNS phaeohyphomycosis manifests as a single brain abscess (87%), meningitis (9%), encephalitis (2%), myelitis (2%), or arachnoiditis (1%). Common presenting symptoms include headache, seizures, fever, neurological deficits and behavioral changes [1,2]. These findings are compatible with our patient that was presented with seizures and a single lesion on MR scan. Phaeohyphomycosis is caused by more than 100 different species; however, the most common species associated with cerebral phaeohyphomycosis are Cladophialophora bantiana (more than half cases), Ramichloridium mackenzei, Exophiala dermatitidis and Ochroconus gallopavum. On the other hand, B. spicifera that was isolated from our patient was isolated in only four cases. Infections related to B. spicifera are frequently associated with sinus pathology, disseminated infections, keratitis, cutaneous infections, peritonitis, meningitis and endarteritis however, our patient did not have evidence of any of these pathologies that could be the source of his CNS infection. Radiographically, cerebral phaeohyphomycosis typically appears as a ring-enhancing lesion as opposed to the imaging of our patient that was more suggestive of a tumor (Fig. 1). Definite diagnosis requires tissue sampling as was performed in our patient using a Radionics® CRWTM frame and localizer with a side-cutting brain biopsy needle. Several therapeutic approaches have been used for these pathogens, with disappointing results. Combined antifungal chemotherapy and surgical debridement are strongly recommended to eradicate these intractable infections [2]. Revanker et al. [1] reviewed 101 cases of culture-proven cerebral phaeohyphomycosis reported in the literature from 1966 to 2002; he found that complete excision of brain lesions may provide better results than simple aspiration or partial excision. However, due to the location of the lesion adjacent to speech areas in our patient, aggressive resection was considered as a high neurological risk procedure. In most cases reported in the literature combination of amphotericin B, flucytosine and azoles were administered. However, resistance to amphotericin B, fluconazole and flucytosine has been reported. Itraconazole posaconazole and voriconazole have comparable minimal inhibitory concentrations (MIC). Voriconazole was administered to six patients with phaeohyphomycosis associated brain abscess, of whom five died and one patient was cured [3]. Echinocandins are at least 10 times less active in vitro than itraconazole and voriconazole [5], as was also demonstrated in B. spicifera isolated from our patient. Outcomes in most cases reported in the literature were poor, with an overall mortality exceeding 70%. Our patient has recovered completely even though we have chosen a less aggressive approach due the location of the lesion.
4. Conclusion
Fig. 2. A brown mold grew in Sabouraud Dextrose Agar after 5 days.
Our case report is important in several respects. First, our patient did not suffer from fever, headaches or any neurological deficit prior the seizures. Second, he was not immunosuppressed nor had he any exposure to the mold following trauma. Third, his imaging was more suggestive of a tumor than an abscess. Fourth, B. spicifera, though reported in isolated cases, is still quite a rare cause of cerebral phaeohyphomycosis. Finally, the patient was completely cured with voriconazole treatment alone, without surgical resection. We assume that the improvement may be a result of the broad spectrum activity of voriconazole together with its better CNS penetration.
V. Litchevski et al. / Clinical Neurology and Neurosurgery 124 (2014) 179–181
Authors’ contributions VL and ZRC wrote the manuscript. GR and VL were the primary care physicians of the patient, ZRC performed the surgical procedures and was part of the decision-making process. DN reviewed all the pathology and wrote the reports. AG performed the fungal cultures, and GR reviewed and edited the manuscript. All authors read and approved the final manuscript. References [1] Revankar SG, Sutton DA, Rinaldi MG. Primary central nervous system phaeohyphomycosis: a review of 101 cases. Clin Infect Dis 2004;38:206–16.
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[2] Li DM, de Hoog GS. Cerebral phaeohyphomycosis – a cure at what lengths? Lancet Infect Dis 2009;9:376–83. [3] Rosow L, Jiang JX, Deuel T, Lechpammer M, Zamani AA, Milner DA, et al. Cerebral phaeohyphomycosis caused by Bipolaris spicifera after heart transplantation. Transpl Infect Dis 2011;13:419–23. [4] Chowdhary A, Meis JF, Guarro J, de Hoog GS, Kathuria S, Arendrup MC, et al. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of systemic phaeohyphomycosis: diseases caused by black fungi. Clin Microbiol Infect 2014;20(Suppl. 3):47–75. [5] Espinel-Ingroff A. Comparison of in vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743, 872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts. J Clin Microbiol 1998;36: 2950–6.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case Report
Cerebral phaeohyphomycosis in an immunocompetent patient: A case report and literature summary Vlady Litchevski a , Anna Goldschmidt b , Dvora Nass c , Galia Rahav a,e , Zvi R. Cohen d,e,∗ a
Infectious Diseases Unit, Ramat Gan, Israel Clinical Microbiology, Ramat Gan, Israel Neuropathology, Ramat Gan, Israel d Department of Neurosurgery, Ramat Gan, Israel e The Chaim Sheba Medical Center, Tel-Hashomer, and Sackler School of Medicine, Tel Aviv University, Ramat Gan, Israel b c
a r t i c l e
i n f o
Article history: Received 6 January 2014 Received in revised form 9 June 2014 Accepted 5 July 2014 Available online 14 July 2014 Keywords: Phaeohyphomycosis Brain abscess Brain biopsy
1. Introduction Phaeohyphomycosis is an infection caused by a darkly pigmented or ‘dematiaceous’ fungi that derives its coloration from melanin in the cell walls [1,2]. These fungi are typically found in the soil and introduced through inhalation. Infections can occur in various parts of the body, most commonly the skin and soft tissues, sinuses, and the central nervous system (CNS) [1,2]. This infection has been described in both immunocompetent and immunocompromised hosts [3]. Treatment is often challenging, giving phaeohyphomycosis a high rate of mortality, particularly when the CNS is affected. We present an apparently immunocompetent patient who developed a phaeohyphomycotic brain abscess and was successfully treated with voriconazole alone. 2. Case report A 21-year-old healthy soldier was admitted to the emergency room due to new onset generalized seizures which caused lacerations in his face and broken teeth. He denied any history of
∗ Corresponding author at: The Chaim Sheba Medical Center, Tel.:-Hashomer, and Sackler School of Medicine, Tel Aviv University, Israel. Tel.: +97 235302650; fax: +97 235354413. E-mail address: [email protected] (Z.R. Cohen). http://dx.doi.org/10.1016/j.clineuro.2014.07.003 0303-8467/© 2014 Elsevier B.V. All rights reserved.
travel, he was born in Israel to immigrants from Ethiopia. On examination, he was afebrile, alert and oriented. Physical examination was intact except for mild receptive dysphasia. Brain computed tomography scan revealed a left temporo-parietal lesion. Magnetic resonance imaging revealed an enhancing lesion with surrounding edema (Fig. 1), suggestive of a brain neoplasm. The paranasal sinuses showed no significant abnormality. The patient did not have any tuberculosis contact. The results of a complete blood cell count, serum chemistry tests including glucose and liver function tests were normal. Serology for human immunodeficiency virus was negative. A skin test for tuberculosis was non-reactive. Serological tests for toxoplasma revealed positive IgG and negative IgM. Immunoglobulins were normal, CD4 count was 914 cell/mm3 . Phenytoin was administered and stereotactic biopsy was performed. Histopathological findings as well as PAS stain revealed focal white matter necrosis, neutrophilic infiltration, and focal collections of fungal elements, composed of yeast like forms and septate, infrequently branched hyphae. A brown mold grew in Sabouraud Dextrose Agar after 5 days (Fig. 2). The mold was subcultured in potato dextrose agar. The mold was defined microscopically as Bipolaris spicifera due to frequent sporulation, sympodial geniculate conidiophores, enhanced hilum and large three celled condia. Galactomannan was negative. There was no evidence of pulmonary or other clinical sites of fungal disease after thorough evaluation, including chest and abdomen CT. Blood cultures were without growth. Trans-esophageal echocardiogram was
180
V. Litchevski et al. / Clinical Neurology and Neurosurgery 124 (2014) 179–181
Fig. 1. T1 weighted axial MR imaging with Gadolonium showing left temporoparietal enhancing lesion.
normal. He was started empirically with Amphotericin B 1.5 mg/kg. Following identification of the mold and its antibiotic susceptibility voriconazole was administered at a daily dose of 600 mg, which was reduced to 400 mg/d due to increased liver enzymes. Levetiracetam was administered. Excision of the abscess was less feasible, due to its location. On follow-up clinical visit at 12 weeks post discharge, MRI showed ongoing resolution of the lesion. At his 15month follow-up, a brain MRI showed resolution of the lesion and voriconazole was discontinued. 3. Discussion Phaeohyphomycosis is a rare infection caused by dematiaceous or dark pigmented melanin-containing cell wall fungus. They can cause life-threatening infections mainly in immunocompromised patients; however, infections were noted also in immunocompetent individuals as in our patient [4]. They have worldwide distribution and are mainly found in the soil. Infection most commonly affects the skin and soft tissues from direct inoculation following trauma or the paranasal sinuses from inhalation. Phaeohyphomycosis can invade the CNS through hematogenous spread,
direct invasion from surrounding tissues or direct inoculation through an open cranial wound. However, our patient did not have evidence of sinusitis or an open cranial wound that could be the source of his CNS infection. CNS phaeohyphomycosis manifests as a single brain abscess (87%), meningitis (9%), encephalitis (2%), myelitis (2%), or arachnoiditis (1%). Common presenting symptoms include headache, seizures, fever, neurological deficits and behavioral changes [1,2]. These findings are compatible with our patient that was presented with seizures and a single lesion on MR scan. Phaeohyphomycosis is caused by more than 100 different species; however, the most common species associated with cerebral phaeohyphomycosis are Cladophialophora bantiana (more than half cases), Ramichloridium mackenzei, Exophiala dermatitidis and Ochroconus gallopavum. On the other hand, B. spicifera that was isolated from our patient was isolated in only four cases. Infections related to B. spicifera are frequently associated with sinus pathology, disseminated infections, keratitis, cutaneous infections, peritonitis, meningitis and endarteritis however, our patient did not have evidence of any of these pathologies that could be the source of his CNS infection. Radiographically, cerebral phaeohyphomycosis typically appears as a ring-enhancing lesion as opposed to the imaging of our patient that was more suggestive of a tumor (Fig. 1). Definite diagnosis requires tissue sampling as was performed in our patient using a Radionics® CRWTM frame and localizer with a side-cutting brain biopsy needle. Several therapeutic approaches have been used for these pathogens, with disappointing results. Combined antifungal chemotherapy and surgical debridement are strongly recommended to eradicate these intractable infections [2]. Revanker et al. [1] reviewed 101 cases of culture-proven cerebral phaeohyphomycosis reported in the literature from 1966 to 2002; he found that complete excision of brain lesions may provide better results than simple aspiration or partial excision. However, due to the location of the lesion adjacent to speech areas in our patient, aggressive resection was considered as a high neurological risk procedure. In most cases reported in the literature combination of amphotericin B, flucytosine and azoles were administered. However, resistance to amphotericin B, fluconazole and flucytosine has been reported. Itraconazole posaconazole and voriconazole have comparable minimal inhibitory concentrations (MIC). Voriconazole was administered to six patients with phaeohyphomycosis associated brain abscess, of whom five died and one patient was cured [3]. Echinocandins are at least 10 times less active in vitro than itraconazole and voriconazole [5], as was also demonstrated in B. spicifera isolated from our patient. Outcomes in most cases reported in the literature were poor, with an overall mortality exceeding 70%. Our patient has recovered completely even though we have chosen a less aggressive approach due the location of the lesion.
4. Conclusion
Fig. 2. A brown mold grew in Sabouraud Dextrose Agar after 5 days.
Our case report is important in several respects. First, our patient did not suffer from fever, headaches or any neurological deficit prior the seizures. Second, he was not immunosuppressed nor had he any exposure to the mold following trauma. Third, his imaging was more suggestive of a tumor than an abscess. Fourth, B. spicifera, though reported in isolated cases, is still quite a rare cause of cerebral phaeohyphomycosis. Finally, the patient was completely cured with voriconazole treatment alone, without surgical resection. We assume that the improvement may be a result of the broad spectrum activity of voriconazole together with its better CNS penetration.
V. Litchevski et al. / Clinical Neurology and Neurosurgery 124 (2014) 179–181
Authors’ contributions VL and ZRC wrote the manuscript. GR and VL were the primary care physicians of the patient, ZRC performed the surgical procedures and was part of the decision-making process. DN reviewed all the pathology and wrote the reports. AG performed the fungal cultures, and GR reviewed and edited the manuscript. All authors read and approved the final manuscript. References [1] Revankar SG, Sutton DA, Rinaldi MG. Primary central nervous system phaeohyphomycosis: a review of 101 cases. Clin Infect Dis 2004;38:206–16.
181
[2] Li DM, de Hoog GS. Cerebral phaeohyphomycosis – a cure at what lengths? Lancet Infect Dis 2009;9:376–83. [3] Rosow L, Jiang JX, Deuel T, Lechpammer M, Zamani AA, Milner DA, et al. Cerebral phaeohyphomycosis caused by Bipolaris spicifera after heart transplantation. Transpl Infect Dis 2011;13:419–23. [4] Chowdhary A, Meis JF, Guarro J, de Hoog GS, Kathuria S, Arendrup MC, et al. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of systemic phaeohyphomycosis: diseases caused by black fungi. Clin Microbiol Infect 2014;20(Suppl. 3):47–75. [5] Espinel-Ingroff A. Comparison of in vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743, 872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts. J Clin Microbiol 1998;36: 2950–6.
