Original Report

Phaeohyphomycosis of the central nervous system in immunocompetent hosts: report of a case and review of the literature

Marcel0 J. Filizzola,(l) Fernando Martinez@ and Shariq J. Rauf(l)

Background: Phaeohyphomycosis refers to infections caused by phaeoid fungi that can have an aggressive course in normal hosts. Involvement of the central nervous system may occur with a generally poor outcome.

Clinical report and literature review: We report a case of Bipolaris sp. brain abscess in an immunologically competent host. We also review all previous cases of cerebral phaeohyphomycosis in normal hosts reported in the literature to date.

Conclusions: Central nervous system phaeohyphomycosis remains an unusual disease; however, its incidence has been increasing in recent years. The prognosis of this condition is still poor, despite medical and surgical interventions. Aggressive diagnostic approaches and careful interpretation of cultures might modify the natural history of this disease.

Int J Infect Dis 2003; 7:282-286

INTRODUCTION

Phaeohyphomycosis refers to soft tissue and systemic infections caused by phaeoid fungi. These are unusual pathogens that can affect the central nervous system (CNS). These ubiquitous organisms have been isolated from soil, water, and air, and as plant parasites or saprophytic fungi.l” Several cases of phaeohypho- mycosis have been reported in the past, and its incidence may be increasing, particularly in immunocompromised patients;4 however, cases have also been reported in immunocompetent hosts. 5,6 We report a case of phaeo- hyphomycosis in an immunologically competent host whose lesion was a primary brain abscess caused by Bipolaris sp. We also review all previous cases of cerebral phaeohyphomycosis in normal hosts reported in the literature to date.

REPORT OF CASE

A previously healthy 2%year-old African-American male presented to John Sealy Hospital in Galveston on 23 December 2001 with a 3-month history of progressive diplopia and right-eye ptosis. He visited several optometrists and tried different prescription glasses, with no improvement of symptoms. Two months prior to

(‘)Department of Internal Medicine, Division of Infectious Diseases, (*)Department of Pathology, The University of Texas Medical Branch (UTMB), Galveston, Texas, USA.

Address correspondence to: Marcel0 J. Filizzola, MD, 1515 West Fir, Portales, NM 88130, USA.

E-mail: filizzola@aol.com

Corresponding Editor: Jonathan Cohen, Brighton, UK

admission, he also started complaining of left-sided tongue and lip numbness. He denied a history of trauma and fever. The patient was a Galveston resident, who worked at a local bank as a purchasing manager. He denied any history of travel or soil exposure. He reported no allergies and no history of sinus infection.

On initial physical examination, the pupils were found to be anisocoric (right > left), but reactive to light. Despite the complaint of binocular diplopia, the extraocular muscles were intact; however, there was a mild ptosis on the right eye. No other cranial nerve abnormalities were noted, and results of sensory and motor examinations were unremarkable. The results of a complete blood cell count, serum chemistry tests and liver function tests were normal. Serology for human immunodeficiency virus was negative. A skin test for tuberculosis was non-reactive.

The patient’s initial evaluation included magnetic resonance imaging (MRI) of the brain, which showed a 5.5 cm by 4 cm mass located in the region of the posterior right basal ganglia and posterior temporal lobe with additional extension into the brainstem (Figure 1). The optic tracts were also involved. A computed tomography scan of the brain obtained at the same time showed enhancement of the mass after the adminis- tration of contrast material. Both studies included sinus windows that showed no evidence of acute or chronic sinus infection. Our initial impression according to this finding was an aggressive primary brain neoplastic lesion. The patient underwent a stereotactic brain biopsy, and the pathology was reported as negative for malignancy, with some inflammation and reactive gliosis. Cultures were not sent at that time. The procedure was complicated by an intracranial hemorrhage leading to an increase in the intracranial pressure and a significant

Phaeohyphomycosis of the central nervous system in immunocompetent hosts I Filizzola et al 283

Figure 1. MRI of the brain (TZ-weighted), showing the 5.5 cm by 4 cm mass located in the region of the posterior right basal ganglia and posterior temporal lobe with surrounding edema.

deterioration in mental status. The patient became unresponsive and required mechanical ventilation.

A second stereotactic brain biopsy was performed; the pathology report described fungal hyphae and necrotizing granulomatous inflammation with severe vascular wall necrosis. Hyphae were seen with variable diameters, often wide with right-angle branching, occasionally septated, and they were well observed with hematoxylin-eosin and melanin-specific Fontana-Mason stains (Figure 2). Tissue submitted for culture was sliced and placed in plates of inhibitory mold agar and brain heart infusion agar and incubated at 30°C. A brown mold grew in the plates after 5 days. The mold was then subcultured in potato dextrose agar and forced to sporulate. Occasional geniculate conidiophores with dark macroconidia produced in a sympodial pattern were observed microscopically, indicating that the organism was a Bipolaris sp. Species identification was not possible, due to the scarcity of the macroconidia. Curiously, a sputum culture done immediately after the first biopsy also grew a Bipolaris sp., which was initially thought to be a contaminant. The patient was treated with itraconazole and amphotericin B; this was later changed to liposomal amphotericin B, due to nephro- toxicity. Voriconazole was tried but discontinued, secondary to hepatotoxicity, and itraconazole was resumed. Excision of the abscess was not feasible, due to its location. The patient’s response to therapy was poor, and after prolonged hospitalization complicated by ventilator-associated pneumonia and catheter-related infections, the patient died. An autopsy was not performed.

DISCUSSION

Phaeohyphomycosis is caused by several species of fungi (more than 100) that have in common the morphologic characteristic of a darkly pigmented melanin-containing cell wall that can be seen in unstained tissue or with routine hematoxylin-eosin stain.4%5 They have distinctive branched septated hyphae, but the definitive identific- ation is based on culture and characteristic microscopic features. Melanin has been implicated as an important factor in the pathogenesis of these infections, due to the protection it confers against phagocytosis4 Reports of these infections are complicated by several previous changes in taxonomy;5 nevertheless, we have attempted to use the most recent nomenclature available.

We searched the MEDLINE database from 1966 through April 2002, using the following terms: phaeo- hyphomycosis, brain abscess, CNS abscess, and immuno- competent. Additional cases were obtained from the bibliographies of these articles. In addition to our case, we found 20 cases of CNS involvement in immuno- competent hosts (Table 1). In these cases, diagnosis was confirmed by histopathology and cultures of tissue sample obtained by biopsy, excision of tissue or post- mortem examination (from brain tissue or, in cases of disseminated disease, from the major organ affected). The agents of phaeohyphomycosis have a worldwide distribution, and cases of CNS involvement have been reported in North America,r South America6 and Asia.3,5,7-9 Some species, such as Ramichloridium mackenziei, appear to be geographically restricted.7 Most cases have been reported during the past 20 years (16 of 21 cases), and the most frequent causative agents were Cladophialophora bantiana (six cases), Bipolaris spicifera (three cases), Ramichloridium mackenziei (three cases), Curvularia lunata (two cases) and Wangiella dermatitides (two cases). The higher incidence of CNS involvement in some species might be related to differences in neurotrophism. This fact has been corroborated in mice animal models showing that species such as Cladophialophora bantiana are highly neurotropic1,3~6 and others, such as Bipolaris spicifera, are not.2

In our review, most cases occurred in young people under the age of 35 years (12 cases), and there was a predilection for the male sex (12 cases). While it is well known for these fungi to cause disseminated disease in immunocompromised hosts, most of our cases had only CNS involvement (13 cases). This can be a distinctive feature of patients with apparently normal immunity.

The varied presentations were single or multiple, uniloculated or multiloculated brain abscesses and diffuse granulomatous encephalitis (21 cases). Isolated meningeal involvement was not seen in these cases, but it has been reported before in immunocompromised patients.lO The histopathology usually showed granulo- matous inflammation around characteristic fungal elements (chlamydospores and/or septated hyphae).2

284 International Journal of Infectious Diseases i Volume 7, Number 4,2003

Figure 2. Hematoxylin-eosin stain of brain tissue showing hyphae with occasional swollen walls and branching (A). Multinucleated giant cells and polymorphonuclear cells as well as nuclear debris in association with the hyphae were prominent in some areas (B). Fontana-Mason staining revealed that the hyphae had melanin (C). Brown hyphae with conidia originating from geniculate conidiophore (D),

Vascular wall necrosis can be a prominent feature and makes the prognosis very unfavorable, as for the patient reported here.

The mechanism of CNS involvement has been proposed to be direct extension from a sinus infection or by fungemia.ll The fact that many of these patients have multiple brain abscesses and disseminated disease supports a hematogenous route of spread as being most common. The paranasal sinuses or the lung are the probable sources of fungemia.3J1 It is interesting to note that, from our review, only one patient had evidence of sinusitis, and three patients had concomitant lung involvement at the time of diagnosis. It is also relevant that, in the case we report today, the fungus was recovered from the sputum, despite a negative chest X- ray at the time of culture. These facts suggest that the initial phase of sinus and lung involvement is usually asymptomatic and clinically silent. Other sources of

fungemia might also be related to trauma,ll cutaneous infection3 or illicit intravenous drug use.‘j

Several therapeutic approaches have been used for these pathogens, with disappointing results. In our review, six patients survived after treatment, and in five of these, treatment included amphotericin B alone or in combination with flucytosine, different azoles and surgery. Resistance of these organisms to amphotericin B and different azoles has been reported, and is almost universal to flucytosine.ll-l3 Azoles as monotherapy have been rarely used (two cases in this review), but previous reports suggest that itraconazole and the new azoles such as voriconazole might have good activity even as single agents.4 In vitro data have shown that the recently FDA-approved voriconazole and other related drugs such as pozaconazole have comparable geometric mean MICs to itraconazole and amphotericin B.14 In contrast to itraconazole, voriconazole has excellent oral

Phaeohyphomycosis of the central nervous system in immunocompetent hosts I Filizzola et al 285

Table 1. Cases of phaeohycomycosis of the central nervous system in normal hosts reported from 1966 to 2002

Reference Year Species isolated Age Sex Site of disease Therapy Outcome

2002 Bipolar-is sp. 28 M 7 1998 Ramichloridium mackenziei 70 M 7 1998 Ramichloridium mackenziei 70 M 7 1998 Ramichloridium mackenziei 55 F 6 1997 Cladophialophora bantiana 33 M

15 1995 Cladophialophora bantiana” NR NR 5 1993 Cladophialophora bantianaa 14 F

11 1992 Bipolaris spicifera 26 F 1 1992 Cladophialophora bantianaa 76 M 8 1989 Cladophialophora bantianab 28 M 9 1988 Fonsecaea predosoi 70 M

10 1987 Cladophialophora ~pp.~ 55 F

12 1986 17 1985 13 1984

4 1983

2 1981 Bipolaris spiciferad 21 F 3 1980 Cladophialophora bantiana’ 17 F

17 1979 Curvularia luna ta 25 M

4 1977

4 1966

Bipolaris hawaiiensis Curvularia lunata Bipolaris spicifera

Wangiella dermatitidis

Curvularia pallescens

Wangiella dermatitidis

18 M 41 M NR NR

24 M

13 M

19 F

Brain, sputum AMB, Lipid AMB ,Itra, Vori Brain AMB, 5-FC Brain AMB Brain AMB, 5-FC, Ket Brain AMB, Flu, 5-FC, Mic Brain 5-FC, Itra, surgery Brain Flu, surgery

Died Unknown Died Died Died Survived Partial response,

died Survived Died Survived No response Partial response,

died Survived Survived

Brain, sinuses Brain Brain Brain Brain, lung

Brain Brain, lung Brain,

osteomyelitis Brain, LN, bile

Brain Brain Brain, spine,

pleura, skin

Brain,lung

Brain, LN, liver, pancreas

AMB, Ket AMB, 5-FC, surgery AMB AMB, 5-FC AMB, 5-FC, Ket, surgery

AMB, 5-FC, surgery AMB

NR AMB, Flu, 5-FC, Mic

AMB, 5-FC AMB, surgery

NR Partial response,

died Survived Died

AMB, 5-FC, Mic

Mic

Partial response (relapse)

Partial response, died

AMB Died

AMB, amphotericin; Lipid AMB, lipid formulation of amphotericin B; Itra, itraconazole; Vori, voriconazole; 5-FC, flucytosine; Flu, fluconazole; Mic, miconazole; Ket, ketoconazole; NR, no record available; CSF, cerebrospinal fluid; LN, lymph node.

“Reported as Xylohypha bantiana. bReported as Cladosporium trichoides. CReported as Cladosporium sp. dReported as Drechslera spicifera. ‘Reported as Cladosporium bantianum.

bioavailability and could be a good therapeutic alter- native for the treatment of this fungus, which usually requires prolonged therapy. Caspofungin and the related drug anidulafungin are at least 10 times less active in vitro than itraconazole and voriconazole against this mold.14 The clinical efficacies of all these new therapeutic agents will most likely be determined case by case in the future, due to the extremely low incidence of this fungal infection. To our knowledge, the patient we reported in this article was the first one treated with voriconazole for this condition. Unfortunately, therapy had to be discontinued early in the course of treatment, due to liver toxicity. It was proposed that the most effective treatment is complete or partial removal of the abscess by surgery;12J-l7 however, in our review, of six craniotomies that were performed, only two patients had good responses.

The prognosis of this disease is poor, and the out- come in most cases is death.3 Among these 21 patients, the overall mortality was very high (11 cases). This number may be even higher, since four patients did not have adequate follow-up (two of them with initial incomplete response). Some patients had an initial partial response with subsequent progression or relapse

of disease. It has been reported that the overall mortality of patients with phaeohyphomycosis is 79%, with a non- statistically significant difference between immuno- compromised and immunocompetent hosts.4 This might be explained by the fact that some of these isolates are resistant to amphotericin B, which has long been con- sidered the gold standard for empirical and definitive therapy.4 Furthermore, some of these competent patients might also have unrecognized immune dysfunction.3J1

The incidence of phaeohyphomycosis appears to be increasing over time. This is understandable in the immunocompromised population, and may be due to the increasing number of transplant patients, more aggressive chemotherapies and the AIDS epidemic.4 However, as we have shown in this review, this trend is also true for immunocompetent patients with CNS involvement. Increased awareness of this disease and improved isolation and identification techniques of laboratories may partly explain this.

Because of the aggressive nature of this disease and the increased number of cases being reported, this review emphasizes that, although the majority of isolates from clinical laboratories reflect surface contamination or colonization,13 no isolate should be dismissed as such

286 International Journal of Infectious Diseases I Volume 7, Number 42003

based solely upon its reputation or the immuno- competent state of the host. Aggressive diagnostic approaches and careful interpretation of cultures might help to improve the natural history of this disease, which otherwise is invariably fatal.

REFERENCES

1. Sekhon AS, Galbraith .I, Mielke SW, Garg AK, Sheehan G. Cerebral phaeohyphomycosis caused by Xylohypha bantiana, with a review of the literature. Em J Epidemiol 1992; 8(3):387-390.

2. Yoshimori RN, Moore RA, Itabashi HH, Fujikawa DG. Phaeohyphomycosis of brain: granulomatous encephalitis caused by Drechslera spicifera. Am J Clin Path01 1982; 77(3):363-370.

3. Hironaga M, Watanabe S. Cerebral phaeohyphomycosis caused by Cladosporium bantianum: a case in a female who had cutaneous alternariosis in her childhood. Sabouraudia 1980; 18(3):229-235.

4. Revankar S, Patterson JE, Sutton DA, Pullen R, Rinaldi M. Disseminated phaeohyphomycosis: review of an emerging mycosis. Clin Infect Dis 2002; 34:467-476.

5. Palaoglu S, Sav A, Basak T, Yalcinlar Y, Scheithauer BW. Cerebral phaeohyphomycosis. Neurosurgery 1993; 33(5): 894-897.

6. Walz R, Bianchin M, Chavez ML, Cerski MR, Sever0 LC. Cerebral phaeohyphomycosis caused by Cladophialo- phora bantiana in a Brazilian drug abuser. J Med Vet Mycol 1997; 35:427-431.

7. Sutton DA, Slifkin M,Yakulis R, Rinaldi M. US case report of cerebral phaeohyphomycosis caused by Ramichlo- ridium obovoideum (R mackenziei): criteria for identific- ation, therapy, and review of other known dematiaceous neurotropic taxa. J Clin Microbial 1998; 36(30):708-715.

8. Banerjee U, Mohapatra AK, Sarkar C, Chaudhery R.

Cladosporiosis (cerebral phaeohyphomycosis) of brain- a case report. Mycopathologia 1989; 105(3):163-166.

9. al-Hedaithy SS, Jamjoom ZA, Saeed ES. Cerebral phaeohyphomycosis caused by Fonsecaea pedrosoi in Saudi Arabia. APMIS Suppl 1988; 3:94-100.

10. Krcmery V Jr, Spanik S, Danisovicova A, Jesenska Z, Blahova M. Aureobasidium mansoni meningitis in a leukemia patient successfully treated with amphotericin B. Chemotherapy 1994; 40(1):70-71.

11. McGinnis MR, Campbell G, Gourley WK, Lucia HL. Phaeohyphomycosis caused by Bipolaris spicifera: an informative case. Eur J Epidemiol 1992; 8(3):383-386.

12. Morton SJ, Midthun K, Merz WG. Granulomatous encephalitis caused by Bipolaris hawaiiensis. Arch Path01 Lab Med 1986; 110:1183-1185.

13. Adam R, Paquin ML, Peterson EA, et al. Phaeo- hyphomycosis caused by the fungal genera Bipolaris and Exserohilum. A report of 9 cases and review of the literature. Medicine 1986; 65:203-217.

14. 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 filamen- tous and dimorphic fungi and yeasts. J Clin Microbial 1998; 36(10):2950-2956.

15. Lirng JF, Tien RD, Osumi AK, Madden JF, McLendon RP, Sexton D. Cerebral phaeohyphomycosis complicated with brain abscess: a case report. Zhonghua Yi Xue Za Zhi (Taipei) 1995; 55(6):491-495.

16. Naim-Ur-Rahman, el Sheikh Mahgoub, Abu Aisha H, Laajam M, Yaqoub B, Chagla AH. Cerebral phaeo- hyphomycosis. Bull Sot Path01 Exot Filiales 1987; 80(3):320-328.

17. Rinaldi MG, Phillips P, Schwartz JG, et al. Human Curvularia infections. Report of five cases and review of the literature. Diagn Microbial Infect Dis 1987; 6(l): 27-39.