Diagnostic Challenges ofCryptococcus neoformansin an Immunocompetent Individual Masquerading as Chronic Hydrocephalus

Abstract

Cryptococcus neoformans can cause disseminated meningoencephalitis and evade immunosurveillance with expression of a major virulence factor, the polysaccharide capsule. Direct diagnostic assays often rely on the presence of the cryptococcal glucuronoxylomannan capsular antigen (CrAg) or visualization of the capsule. Strain specific phenotypic traits and environmental conditions influence differences in expression that can thereby compromise detection and timely diagnosis. Immunocompetent hosts may manifest clinical signs and symptoms indolently, often expanding the differential and delaying appropriate treatment and diagnosis. We describe a 63-year-old man who presented with a progressive four-year history of ambulatory dysfunction, headache, and communicating hydrocephalus. Serial lumbar punctures (LPs) revealed elevated protein (153–300 mg/dL), hypoglycorrhachia (19–47 mg/dL), lymphocytic pleocytosis (89–95% lymphocyte, WBC 67–303 mg/dL, and RBC 34–108 mg/dL), and normal opening pressure (13–16 cm H2O). Two different cerebrospinal fluid (CSF) CrAg assays were negative. A large volume CSF fungal culture grew unencapsulated C. neoformans. He was initiated on induction therapy with amphotericin B plus flucytosine and consolidation/maintenance therapy with flucytosine, but he died following discharge due to complications. Elevated levels of CSF Th1 cytokines and decreased IL6 may have affected the virulence and detection of the pathogen.

<p>False-Negative Serum Cryptococcal Antigen Lateral Flow Immunoassay Result for a Patient with Disseminated Cryptococcal Disease</p>

“…Mahajan et al reported a case of unencapsulated C. neoformans with a negative CrAg. 13 India ink staining of the fluid in the positive blood culture bottles showed that the C. neoformans appeared as rounded cells with thick halos, indicating that the patient was not infected by an unencapsulated or weakly capsulated strain. Another case report described a false-negative serum CrAg result via LFA in an HIV-positive patient, as demonstrated by a blood culture from a matched sample that was positive for Cryptococcus spp.…”

False-negative result of serum cryptococcal antigen lateral flow assay in an HIV-infected patient with culture-proven cryptococcaemia

“…In general, a false-negative CrAg test may be the result of: low fungal load; prozone reaction due to high antigen titers; presence of immunocomplexes preventing release of glucuronoxilomanan-antigen; samples transported in inappropriate vials; or hypocapsular or acapsular strains of Cryptococcus spp [6] . Human infections caused by acapsular Cryptococcus or poorly encapsulated strains can be identified only after tissue biopsy or tissue culture [8,10,11].…”

Cryptococcus neoformans: Diagnostic Dilemmas, Electron Microscopy and Capsular Variants

“…There are a number of reports of capsule-deficient and acapsular isolates based on light microscopy and India ink staining—most recently that by Mahajan et al [19]. Environmental variables are known to influence capsule expression, in that cryptococcal strains exhibit physiological differences in vitro and in vivo, the polysaccharide capsule gets thicker with age and the changing environmental conditions associated with mammalian cell infection, and the capsule is much larger in vivo than under normal in vitro conditions [18,20,21,22].…”