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Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-seronegative patients

Gary M Cox, MD
John R Perfect, MD
Section Editor
Carol A Kauffman, MD
Deputy Editor
Jennifer Mitty, MD, MPH


Cryptococcus neoformans meningoencephalitis is the most frequently encountered manifestation of cryptococcosis. The term "meningoencephalitis" is more appropriate than "meningitis" since histopathological examination has demonstrated that the brain parenchyma is almost always involved.

Cryptococcal meningoencephalitis is an important opportunistic infection in immunosuppressed patients. Issues related to patients with HIV are discussed in detail separately. (See "Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-infected patients" and "Treatment of Cryptococcus neoformans meningoencephalitis in HIV-infected patients" and "Clinical management and monitoring during antifungal therapy of the HIV-infected patient with cryptococcal meningoencephalitis".)

The pathogenesis, clinical manifestations, and diagnosis of cryptococcal meningoencephalitis in HIV-seronegative patients will be reviewed here. Other issues related to C. neoformans infection are discussed separately. Cryptococcus gattii infection is also presented separately. (See "Microbiology and epidemiology of Cryptococcus neoformans infection" and "Treatment of Cryptococcus neoformans meningoencephalitis and disseminated infection in HIV seronegative patients" and "Cryptococcus neoformans infection outside the central nervous system" and "Cryptococcus gattii infection: Microbiology, epidemiology, and pathogenesis" and "Cryptococcus gattii infection: Clinical features and diagnosis" and "Cryptococcus gattii infection: Treatment".)


C. neoformans causes infection following inhalation through the respiratory tract. The organism disseminates hematogenously and has a propensity to localize to the central nervous system (CNS). The basis for the tropism for the CNS is uncertain, but a number of hypotheses have been proposed:

The cerebrospinal fluid (CSF) is a favorable growth medium for the organism as it lacks the factors present in serum that inhibit cryptococcal growth [1]. In the serum, the organism activates the alternative complement pathway, but complement activity in the CSF is very low [2].


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Literature review current through: Sep 2016. | This topic last updated: Jun 7, 2016.
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  1. Igel HJ, Bolande RP. Humoral defense mechanisms in cryptococcosis: substances in normal human serum, saliva, and cerebrospinal fluid affecting the growth of Cryptococcus neoformans. J Infect Dis 1966; 116:75.
  2. Diamond RD, May JE, Kane MA, et al. The role of the classical and alternate complement pathways in host defenses against Cryptococcus neoformans infection. J Immunol 1974; 112:2260.
  3. Kwon-Chung KJ, Rhodes JC. Encapsulation and melanin formation as indicators of virulence in Cryptococcus neoformans. Infect Immun 1986; 51:218.
  4. Wong B, Perfect JR, Beggs S, Wright KA. Production of the hexitol D-mannitol by Cryptococcus neoformans in vitro and in rabbits with experimental meningitis. Infect Immun 1990; 58:1664.
  5. Pappas PG, Perfect JR, Cloud GA, et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis 2001; 33:690.
  6. Cox, GM, Perfect, JR. Cryptococcus neoformans var neoformans and gattii and Trichosporon species. In: Topley and Wilson's Microbiology and Microbial Infections, 9th ed, Ajello, Edward (Ed), Arnold Press, London 1997.
  7. Husain S, Wagener MM, Singh N. Cryptococcus neoformans infection in organ transplant recipients: variables influencing clinical characteristics and outcome. Emerg Infect Dis 2001; 7:375.
  8. Vilchez RA, Fung J, Kusne S. Cryptococcosis in organ transplant recipients: an overview. Am J Transplant 2002; 2:575.
  9. Shaariah W, Morad Z, Suleiman AB. Cryptococcosis in renal transplant recipients. Transplant Proc 1992; 24:1898.
  10. Singh N, Alexander BD, Lortholary O, et al. Cryptococcus neoformans in organ transplant recipients: impact of calcineurin-inhibitor agents on mortality. J Infect Dis 2007; 195:756.
  11. Dismukes WE, Cloud G, Gallis HA, et al. Treatment of cryptococcal meningitis with combination amphotericin B and flucytosine for four as compared with six weeks. N Engl J Med 1987; 317:334.
  12. Diamond RD, Bennett JE. Prognostic factors in cryptococcal meningitis. A study in 111 cases. Ann Intern Med 1974; 80:176.
  13. Shaunak S, Schell WA, Perfect JR. Cryptococcal meningitis with normal cerebrospinal fluid. J Infect Dis 1989; 160:912.
  14. Saag MS, Powderly WG, Cloud GA, et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. N Engl J Med 1992; 326:83.
  15. Tanner DC, Weinstein MP, Fedorciw B, et al. Comparison of commercial kits for detection of cryptococcal antigen. J Clin Microbiol 1994; 32:1680.
  16. Hansen J, Slechta ES, Gates-Hollingsworth MA, et al. Large-scale evaluation of the immuno-mycologics lateral flow and enzyme-linked immunoassays for detection of cryptococcal antigen in serum and cerebrospinal fluid. Clin Vaccine Immunol 2013; 20:52.
  17. Chanock SJ, Toltzis P, Wilson C. Cross-reactivity between Stomatococcus mucilaginosus and latex agglutination for cryptococcal antigen. Lancet 1993; 342:1119.
  18. McManus EJ, Jones JM. Detection of a Trichosporon beigelii antigen cross-reactive with Cryptococcus neoformans capsular polysaccharide in serum from a patient with disseminated Trichosporon infection. J Clin Microbiol 1985; 21:681.
  19. Westerink MA, Amsterdam D, Petell RJ, et al. Septicemia due to DF-2. Cause of a false-positive cryptococcal latex agglutination result. Am J Med 1987; 83:155.
  20. Blevins LB, Fenn J, Segal H, et al. False-positive cryptococcal antigen latex agglutination caused by disinfectants and soaps. J Clin Microbiol 1995; 33:1674.
  21. Boom WH, Piper DJ, Ruoff KL, Ferraro MJ. New cause for false-positive results with the cryptococcal antigen test by latex agglutination. J Clin Microbiol 1985; 22:856.
  22. Wilson DA, Sholtis M, Parshall S, et al. False-positive cryptococcal antigen test associated with use of BBL Port-a-Cul transport vials. J Clin Microbiol 2011; 49:702.
  23. Charlier C, Dromer F, Lévêque C, et al. Cryptococcal neuroradiological lesions correlate with severity during cryptococcal meningoencephalitis in HIV-positive patients in the HAART era. PLoS One 2008; 3:e1950.
  24. Graybill JR, Sobel J, Saag M, et al. Diagnosis and management of increased intracranial pressure in patients with AIDS and cryptococcal meningitis. The NIAID Mycoses Study Group and AIDS Cooperative Treatment Groups. Clin Infect Dis 2000; 30:47.
  25. Hospenthal DR, Bennett JE. Persistence of cryptococcomas on neuroimaging. Clin Infect Dis 2000; 31:1303.
  26. Einsiedel L, Gordon DL, Dyer JR. Paradoxical inflammatory reaction during treatment of Cryptococcus neoformans var. gattii meningitis in an HIV-seronegative woman. Clin Infect Dis 2004; 39:e78.