Fungal Meningitis

Gottfreðsson, Magnús; Perfect, John R.

doi:10.1055/s-2000-9394

Cited by 117 publications

(93 citation statements)

References 120 publications

(156 reference statements)

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“…Infection by Cryptococcus neoformans, an encapsulated fungal organism, has increased considerably over recent years (Mitchell & Perfect, 1995;Gottfredsson & Perfect, 2000;Kwon-Chung et al, 2000). The expanded use of immunosuppressive drugs and the onset of AIDS have contributed to this epidemic.…”

Section: Introductionmentioning

confidence: 99%

Cryptococcus neoformans induces alterations in the cytoskeleton of human brain microvascular endothelial cells

Chen

Stins

Huang

et al. 2003

Journal of Medical Microbiology

168

200

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The fungal pathogen Cryptococcus neoformans has a predilection for the central nervous system (CNS), resulting in devastating meningoencephalitis. At present, it is unclear how C. neoformans traverses the blood-brain barrier (BBB) and causes CNS infection. The present study has examined and characterized the interaction of C. neoformans with human brain microvascular endothelial cells (HBMEC), which constitute the BBB. Adhesion of and transcytosis of HBMEC by C. neoformans was inoculum-and time-dependent and occurred with both encapsulated and acapsulated strains. C. neoformans induced marked morphological changes in HBMEC, for example membrane ruffling, irregular nuclear morphology and swelling of the mitochondria and the ER. These findings suggest that C. neoformans induced actin cytoskeletal reorganization of the host cells. In addition, it was observed that the dephosphorylated form of cofilin was increased during cryptococcal adherence to HBMEC, concomitant with the actin rearrangement. Cryptococcal binding to HBMEC was increased in the presence of Y27632, a Rho kinase (ROCK)-specific inhibitor. Since ROCK activates LIM kinase (LIMK), which phosphorylates cofilin (inactive form), this suggests the involvement of the ROCK!LIMK!cofilin pathway. In contrast, the phosphatase inhibitor sodium orthovanadate decreased adherence of Cryptococcus to HBMEC, concomitant with the increase of phosphorylation of cofilin. Furthermore, the tight junction marker protein occludin became Tritonextractable, indicating alteration of tight junctions in brain endothelial cells. This is the first demonstration that C. neoformans is able to adhere to and transcytose across the HBMEC monolayer and alter the cytoskeleton morphology in HBMEC. Further characterization of the interactions between C. neoformans and HBMEC should help the development of novel strategies to prevent cryptococcal meningitis and its associated morbidity.

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Section: Introductionmentioning

confidence: 99%

Cryptococcus neoformans induces alterations in the cytoskeleton of human brain microvascular endothelial cells

Chen

Stins

Huang

et al. 2003

Journal of Medical Microbiology

168

200

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“…neoformans is an encapsulated budding yeast that causes fatal infections, especially in immunocompromised individuals, including patients with HIV infection (3). After the aerosolized fungal cells are inhaled, they multiply in the lung, resulting in infection (4,5). From there, extrapulmonary dissemination occurs, leading to infection of the bloodstream and subsequent hematogenous dissemination to target organs (3,6).…”

Section: Introductionmentioning

confidence: 99%

Real-time imaging of trapping and urease-dependent transmigration of Cryptococcus neoformans in mouse brain

Shi¹,

Li²,

Zheng³

et al. 2010

J. Clin. Invest.

185

259

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Infectious meningitis and encephalitis is caused by invasion of circulating pathogens into the brain. It is unknown how the circulating pathogens dynamically interact with brain endothelium under shear stress, leading to invasion into the brain. Here, using intravital microscopy, we have shown that Cryptococcus neoformans, a yeast pathogen that causes meningoencephalitis, stops suddenly in mouse brain capillaries of a similar or smaller diameter than the organism, in the same manner and with the same kinetics as polystyrene microspheres, without rolling and tethering to the endothelial surface. Trapping of the yeast pathogen in the mouse brain was not affected by viability or known virulence factors. After stopping in the brain, C. neoformans was seen to cross the capillary wall in real time. In contrast to trapping, viability, but not replication, was essential for the organism to cross the brain microvasculature. Using a knockout strain of C. neoformans, we demonstrated that transmigration into the mouse brain is urease dependent. To determine whether this could be amenable to therapy, we used the urease inhibitor flurofamide. Flurofamide ameliorated infection of the mouse brain by reducing transmigration into the brain. Together, these results suggest that C. neoformans is mechanically trapped in the brain capillary, which may not be amenable to pharmacotherapy, but actively transmigrates to the brain parenchyma with contributions from urease, suggesting that a therapeutic strategy aimed at inhibiting this enzyme could help prevent meningitis and encephalitis caused by C. neoformans infection.

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“…The morbidity and mortality rates associated with candidal meningitis are substantially high, especially in adults (5,14). Although amphotericin B-with or without flucytosine-has been recommended as the treatment of choice for candidal meningitis in many studies and case reports (6,10,13), an optimal therapeutic regimen has not been established. Although fluconazole has been reported to be effective in treating CNS candidiasis, there have also been several reports of therapeutic failures (1, 9, 13).…”

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confidence: 99%

“…In adults, it is seen most commonly in neurosurgical patients, immunocompromised patients, and patients with disseminated candidiasis (6,13). Although direct inoculation into the CNS and hematogenous spread have been postulated as the mechanisms accounting for candidal meningitis (6,13,14), the exact pathogenesis remains unknown. The clinical manifestations of candidal meningitis are variable, including altered consciousness, fever, meningismus, and focal neurological deficits (6,13).…”

mentioning

confidence: 99%

“…Although direct inoculation into the CNS and hematogenous spread have been postulated as the mechanisms accounting for candidal meningitis (6,13,14), the exact pathogenesis remains unknown. The clinical manifestations of candidal meningitis are variable, including altered consciousness, fever, meningismus, and focal neurological deficits (6,13). Unfortunately, these symptoms are usually nonspecific and indolent.…”

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confidence: 99%

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Refractory Candidal Meningitis in an Immunocompromised Patient Cured by Caspofungin

Liu

Chou

et al. 2004

J Clin Microbiol

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Candidal meningitis is a rare infectious disease that usually leads to substantial morbidity and mortality. We present a case of candidal meningitis refractory to systemic antifungal therapy (amphotericin B and fluconazole). A 63-year-old female with lymphoblastic lymphoma and myelodysplasia with leukemia transformation developed prolonged fever and headache on the seventh day following intrathecal prophylactic chemotherapy. A lumbar puncture showed neutrophilic pleocytosis, and a cerebrospinal fluid culture yielded Candida albicans. The clinical course was complicated by brain edema, subarachnoid hemorrhage, and hydrocephalus. Parenteral therapy with amphotericin B alone or amphotericin B in combination with fluconazole or intrathecal administration of amphotericin B failed to eradicate C. albicans in the cerebrospinal fluid. After 7 days of caspofungin therapy, however, the cerebrospinal fluid became sterile and the patient gradually regained consciousness. She was discharged 1 month after completing 4 weeks of caspofungin therapy. There were two critical issues we thought to be relevant to the favorable outcome of this case. First, isolation of C. albicans was achieved by inoculating enriched liquid medium with cerebrospinal fluid. Second, there is a potential therapeutic benefit of caspofungin in treating a fungal infection of the central nervous system. CASE REPORTA 63-year-old woman had lymphoblastic lymphoma and myelodysplasia with leukemia transformation, initially presenting as a neck mass, anemia, and thrombocytopenia. She received the first course of chemotherapy, consisting of a hyperCVAD regimen (cyclophosphamide, vincristine, epirubicin, and dexamethasone), on 23 December 2002 and the second course of chemotherapy on 14 February 2003 (day 1). The latter treatment included intrathecal methotrexate (day 2) and intrathecal cytosine arabinoside (day 8). Neutropenic fever developed 8 days after initiation of chemotherapy, accompanied by progressive headache and vomiting. The fever did not subside under parenteral treatment with vancomycin and meropenem. A lumbar puncture was therefore done on day 23, and study of the cerebrospinal fluid (CSF) revealed neutrophilic pleocytosis (white blood cell count, 1,500/mm 3 ; 87% neutrophils). The patient's consciousness deteriorated following the lumbar puncture, a phenomenon thought to be related to a subarachnoid hemorrhage and brain edema (Fig. 1A). The patient was treated for bacterial meningitis on the basis of the initial CSF data. An Omaya reservoir was inserted on day 27 because of hydrocephalus. CSF drawn from the Omaya reservoir on day 33 yielded Candida albicans. Amphotericin B (1 mg/kg of body weight per day) was given for central nervous system (CNS) candidiasis, starting on day 39. Brain magnetic resonance imaging (MRI) scans on day 41 showed hydrocephalus and hematoma over the premedullary space, which was thought to be the result of a rupture of a mycotic aneurysm (Fig. 1B). However, after 29 days of amphotericin B therapy, with a cumulative dose of...

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Fungal Meningitis

Cited by 117 publications

References 120 publications

Cryptococcus neoformans induces alterations in the cytoskeleton of human brain microvascular endothelial cells

Cryptococcus neoformans induces alterations in the cytoskeleton of human brain microvascular endothelial cells

Real-time imaging of trapping and urease-dependent transmigration of Cryptococcus neoformans in mouse brain

Refractory Candidal Meningitis in an Immunocompromised Patient Cured by Caspofungin

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