Outcomes of persons with blastomycosis involving the central nervous system

Abstract

Blastomyces dermatitidis is a dimorphic fungus which is potentially life-threatening if central nervous system (CNS) dissemination occurs. Sixteen patients with proven or probable CNS blastomycosis are presented. Median duration of symptoms was 90 days; headache and focal neurologic deficit were the most common presenting symptoms. Magnetic resonance imaging (MRI) consistently demonstrated an abnormality, compared to 58% of computed tomography scans. Tissue culture yielded the pathogen in 71% of histology-confirmed cases. All patients who completed treatment of an amphotericin B formulation and extended azole-based therapy did not relapse. Initial nonspecific symptoms lead to delayed diagnosis of CNS blastomycosis. A high index of suspicion is necessary if there is history of contact with an area where B. dermatitidis is endemic. Diagnostic tests should include MRI followed by biopsy for tissue culture and pathology. Optimal treatment utilizes a lipid-based amphotericin B preparation with an extended course of voriconazole.

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.