MycologyOutcomes of persons with blastomycosis involving the central nervous system
Introduction
The thermally dimorphic fungus Blastomyces dermatitidis, which exists in the soil of moist wooded areas (Bakerspigel et al., 1986, Denton et al., 1961), can cause blastomycosis, a local or systemic infection in humans and animals. Primary infection almost always occurs via inhalation of aerosolized conidia released from disrupted soil (Saccente & Woods, 2010) but may rarely result from direct soft tissue inoculation through a break in the skin. B. dermatitidis is endemic to parts of the United States and Canada, including the Canadian province of Manitoba and the Kenora region of Ontario where the incidence rates are 0.62 and 7.1 cases per 100,000, respectively (Crampton et al., 2002). Both regions fall within the catchment area of 2 tertiary care hospitals in Winnipeg, Manitoba.
Pulmonary blastomycosis is the most common form of the infection. Subclinical pulmonary blastomycosis has been reported in 30% of at-risk forestry workers in areas where B. dermatitidis is endemic (Vaaler et al., 1990). If the host response is inadequate to control the initial infection, B. dermatitidis can disseminate via the lymphohematogenous route, the most frequent sites being skin, bone, and genitourinary tract (Saccente & Woods, 2010). Among persons diagnosed with extra-pulmonary blastomycosis, involvement of the central nervous system (CNS) is estimated in 5–10% (Gonyea, 1978, Saccente and Woods, 2010), and in up to 33% of cases in an older autopsy series (Fetter et al., 1967).
The diagnosis of pulmonary and extra-pulmonary blastomycosis can be made rapidly on histopathologic examination, but microbiologic cultures are considered the gold standard (Patel et al., 2010). Blastomycosis of the CNS may present with leptomeningitis, encephalitis, or as solitary or multiple brain or spinal cord abscesses (Bariola et al., 2010, Wylen and Nanda, 1999). B. dermatitidis on routine hematoxylin and eosin stain (H&E) is a double-walled, broad-based budding yeast in a granulomatous host-reaction with or without micro-abscess formation and central necrosis. Silver impregnation such as Grocott’s methenamine silver (GMS) can increase screening sensitivity while periodic acid-Schiff (PAS), in situ hybridization, and other histochemical stains can help differentiate B. dermatitidis from other fungi (Mukhopadhyay & Gal, 2010). Electron microscopy reveals nuclear material in viable yeast and shows cytoplasmic retraction in degenerate forms (Guccion et al., 1996, Jay et al., 1991).
To date, fewer than 125 cases of CNS blastomycosis have been reported, the majority representing single case reports or small series or published before the modern era of extended-spectrum azole therapy and MRI CNS imaging. Cases reported prior to 1965 have been previously summarized (Fetter et al., 1967). More recently described are 27 CNS biopsy specimens, 3 ventricular cytology specimens, 3 CNS autopsy specimens, 8 cerebrospinal fluid (CSF) cultures, and 19 probable CNS blastomycosis cases based on proven B. dermatitidis in an extra-CNS site (Bakleh et al., 2005, Borgia et al., 2006, Chander et al., 2007, Chowfin et al., 2000, Cook, 2001, Cooper et al., 1988, Friedman et al., 2000, Gershan et al., 1994, Gonyea, 1978, Harley et al., 1994, Kravitz et al., 1981, Mangham et al., 1983, Mohazab et al., 1997, Panicker et al., 2006, Raftopoulos et al., 1986, Szeder et al., 2007, Taillan et al., 1992, Ward et al., 1995, Wu et al., 2005, Wylen and Nanda, 1999). A case series of 22 patients presenting to 6 different tertiary care centers in the United States has also recently been reported (Bariola et al., 2010). Two separate guidelines published within the past 5 years have addressed the management of CNS blastomycosis (Chapman et al., 2008, Limper et al., 2011). The body of literature supporting current recommendations, however, remains limited.
The aim of this study is to correlate clinical manifestations, diagnostic techniques (imaging, microbiology, histopathology), and therapy of CNS blastomycosis. We present the largest series of patients with proven or probable CNS blastomycosis evaluated by a single infectious disease referral service.
Section snippets
Data collection
The study was approved by the Research Ethics Board, Faculty of Medicine, University of Manitoba. We identified and reviewed medical records of patients diagnosed with blastomycosis, with clinical or radiographic evidence of CNS involvement who received care at the Health Sciences Centre or Saint Boniface General Hospital, Winnipeg, Manitoba, from January 1988 through November 2011. These 2 facilities are Manitoba’s tertiary care hospitals. Cases of CNS blastomycosis were found by searching the
Clinical
Sixteen patients with probable or proven CNS blastomycosis were evaluated (Table 1), with the majority of cases diagnosed after the year 2000, and one case each diagnosed in 1988, 1994, and 1997. Nine cases (56%) were proven by culture and/or direct histopathologic evidence on biopsies from within the CNS or a contiguous compartment. Seven cases (44%) were considered probable CNS blastomycosis. The clinical features at time of diagnosis are shown in Table 1. The median age at diagnosis was 37
Discussion
The clinical manifestations of our patients parallel previously described observations in persons with CNS blastomycosis (Bariola et al., 2010, Ward et al., 1995). The most common presentations include meningitis and mass effects (intracranial, epidural, or spinal cord). A significant proportion (7 of 16, 44%) of patients described in this study were under the age of 18. This raises the question whether the risk of developing blastomycosis and subsequent dissemination to the CNS is related to
Summary
CNS blastomycosis is a relatively uncommon consequence of B. dermatitidis infection and should therefore be in the differential diagnosis of meningitis and masses of the central nervous system in persons who have had contact with areas in which B. dermatitidis is endemic. Securing a biopsy is critical. Our findings show that histopathology, in conjunction with MRI, plays an important role in the diagnosis as CSF and tissue culture have a lower sensitivity. Effective treatment of CNS
Acknowledgments
The authors would like to thank Assunta Rendina, Department of Clinical Microbiology, Diagnostic Services Manitoba, for her assistance with identification and interpretation of samples and Graeme Marchuk MD FRCSC, Neurosurgery Unit, Thunder Bay Regional Health Sciences Center, Thunder Bay Ontario, for his work to identify patients. Dr. Del Bigio holds the Canada Research Chair in Developmental Neuropathology. The authors have no conflicts of interest.
Biographical Sketch: Jonathan Bush is a fourth year anatomical pathology resident at the University of Manitoba and has an interest in pediatric pathology.
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Biographical Sketch: Jonathan Bush is a fourth year anatomical pathology resident at the University of Manitoba and has an interest in pediatric pathology.
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Joint first authorship.