Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Epidemiology, clinical manifestations, and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-infected patients

Gary M Cox, MD
John R Perfect, MD
Section Editor
John G Bartlett, MD
Deputy Editor
Jennifer Mitty, MD, MPH


Disseminated Cryptococcus neoformans infection is a serious opportunistic infection that occurs in patients with untreated AIDS [1]. Although cryptococcal infection begins in the lungs, meningitis is the most frequently encountered manifestation of cryptococcosis among those with advanced immunosuppression. However, the infection is more properly characterized as "meningoencephalitis" rather than meningitis since the brain parenchyma is almost always involved on histologic examination [2,3].

The clinical manifestations and diagnosis of C. neoformans meningoencephalitis in AIDS patients will be reviewed here. Treatment and monitoring of AIDS patients with cryptococcal meningoencephalitis is found elsewhere. The microbiology, clinical manifestations, and treatment of this infection in other patient populations, such as transplant patients, are discussed elsewhere. C. gattii infection is also presented separately. (See "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" and "Microbiology and epidemiology of Cryptococcus neoformans infection" and "Clinical manifestations and diagnosis of Cryptococcus neoformans meningoencephalitis in HIV-seronegative patients" and "Cryptococcus neoformans: Treatment of 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".)


Globally, it has been estimated that approximately 957,900 cases of cryptococcal meningoencephalitis occur each year, resulting in more than 600,000 deaths [4,5]. The vast majority of cases occur among patients with AIDS and a CD4 count <100 cells/microL. The region with the highest number of estimated cases in 2006 was sub-Saharan Africa (720,000 cases; range, 144,000 to 1.3 million), followed by South and Southeast Asia (120,000 cases; range, 24,000 to 216,000) [4]. Although the incidence of cryptococcal meningoencephalitis has declined in patients who have access to antiretroviral therapy (ART) [6], cryptococcal disease remains a leading cause of mortality in the developing world where access to ART is limited and HIV prevalence remains high [7].

Early diagnosis and treatment may help reduce cryptococcal meningitis-related mortality [8]. One way to diagnose cryptococcal infection early in the course disease is through the detection of serum cryptococcal antigen (CrAg), which can be detected at least three weeks prior to the onset of neurologic symptoms. The prevalence of antigenemia has been found to vary depending upon the geographical area. As an example, in the United States, the prevalence of cryptococcal antigenemia among patients with a CD4 count <100 cells/microL was reported to be approximately 3 percent, whereas in Uganda the prevalence among such patients was 13.5 percent [9,10]. A discussion on the use of screening and early therapy to prevent meningoencephalitis is found elsewhere. (See "Treatment of Cryptococcus neoformans meningoencephalitis in HIV-infected patients", section on 'Screening and treatment of early infection'.)


Symptoms — Symptoms of cryptococcal meningoencephalitis typically begin indolently over a period of one to two weeks. The most common symptoms are fever, malaise, and headache [2]. Stiff neck, photophobia, and vomiting are seen in one-fourth to one-third of patients. Patients rarely present with coma and fulminant death in days.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jan 04, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Bamba S, Lortholary O, Sawadogo A, et al. Decreasing incidence of cryptococcal meningitis in West Africa in the era of highly active antiretroviral therapy. AIDS 2012; 26:1039.
  2. Cox GM, Perfect JR. Cryptococcus neoformans var neoformans and gattii and Trichosporon species. In: Topley and Wilson's Microbiology and Microbial Infections, 9th Ed, Edward LA (Ed), Arnold Press, London 1997.
  3. Lee SC, Dickson DW, Casadevall A. Pathology of cryptococcal meningoencephalitis: analysis of 27 patients with pathogenetic implications. Hum Pathol 1996; 27:839.
  4. Park BJ, Wannemuehler KA, Marston BJ, et al. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009; 23:525.
  5. Desalermos A, Kourkoumpetis TK, Mylonakis E. Update on the epidemiology and management of cryptococcal meningitis. Expert Opin Pharmacother 2012; 13:783.
  6. Mirza SA, Phelan M, Rimland D, et al. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992-2000. Clin Infect Dis 2003; 36:789.
  7. Jarvis JN, Harrison TS. HIV-associated cryptococcal meningitis. AIDS 2007; 21:2119.
  8. World Health Organization. Rapid advice: diagnosis, prevention and management of cryptococcal disease in HIV-infected adults, adolescents, and children. http://whqlibdoc.who.int/publications/2011/9789241502979_eng.pdf?ua=1 (Accessed on March 03, 2014).
  9. McKenney J, Bauman S, Neary B, et al. Prevalence, correlates, and outcomes of cryptococcal antigen positivity among patients with AIDS, United States, 1986-2012. Clin Infect Dis 2015; 60:959.
  10. Meya DB, Manabe YC, Castelnuovo B, et al. Cost-effectiveness of serum cryptococcal antigen screening to prevent deaths among HIV-infected persons with a CD4+ cell count < or = 100 cells/microL who start HIV therapy in resource-limited settings. Clin Infect Dis 2010; 51:448.
  11. Murakawa GJ, Kerschmann R, Berger T. Cutaneous Cryptococcus infection and AIDS. Report of 12 cases and review of the literature. Arch Dermatol 1996; 132:545.
  12. Rex JH, Larsen RA, Dismukes WE, et al. Catastrophic visual loss due to Cryptococcus neoformans meningitis. Medicine (Baltimore) 1993; 72:207.
  13. 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.
  14. Sánchez-Portocarrero J, Pérez-Cecilia E. Intracerebral mass lesions in patients with human immunodeficiency virus infection and cryptococcal meningitis. Diagn Microbiol Infect Dis 1997; 29:193.
  15. Troncoso A, Fumagalli J, Shinzato R, et al. CNS cryptococcoma in an HIV-positive patient. J Int Assoc Physicians AIDS Care (Chic) 2002; 1:131.
  16. Brouwer AE, Rajanuwong A, Chierakul W, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004; 363:1764.
  17. Darras-Joly C, Chevret S, Wolff M, et al. Cryptococcus neoformans infection in France: epidemiologic features of and early prognostic parameters for 76 patients who were infected with human immunodeficiency virus. Clin Infect Dis 1996; 23:369.
  18. Garlipp CR, Rossi CL, Bottini PV. Cerebrospinal fluid profiles in acquired immunodeficiency syndrome with and without neurocryptococcosis. Rev Inst Med Trop Sao Paulo 1997; 39:323.
  19. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf (Accessed on August 08, 2017).
  20. Jarvis JN, Percival A, Bauman S, et al. Evaluation of a novel point-of-care cryptococcal antigen test on serum, plasma, and urine from patients with HIV-associated cryptococcal meningitis. Clin Infect Dis 2011; 53:1019.
  21. Boulware DR, Rolfes MA, Rajasingham R, et al. Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast. Emerg Infect Dis 2014; 20:45.
  22. Tanner DC, Weinstein MP, Fedorciw B, et al. Comparison of commercial kits for detection of cryptococcal antigen. J Clin Microbiol 1994; 32:1680.
  23. Chanock SJ, Toltzis P, Wilson C. Cross-reactivity between Stomatococcus mucilaginosus and latex agglutination for cryptococcal antigen. Lancet 1993; 342:1119.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. Asawavichienjinda T, Sitthi-Amorn C, Tanyanont V. Serum cyrptococcal antigen: diagnostic value in the diagnosis of AIDS-related cryptococcal meningitis. J Med Assoc Thai 1999; 82:65.
  30. Micol R, Lortholary O, Sar B, et al. Prevalence, determinants of positivity, and clinical utility of cryptococcal antigenemia in Cambodian HIV-infected patients. J Acquir Immune Defic Syndr 2007; 45:555.
  31. Powderly WG, Cloud GA, Dismukes WE, Saag MS. Measurement of cryptococcal antigen in serum and cerebrospinal fluid: value in the management of AIDS-associated cryptococcal meningitis. Clin Infect Dis 1994; 18:789.
  32. Aberg JA, Watson J, Segal M, Chang LW. Clinical utility of monitoring serum cryptococcal antigen (sCRAG) titers in patients with AIDS-related cryptococcal disease. HIV Clin Trials 2000; 1:1.
  33. Larsen RA, Bozzette S, McCutchan JA, et al. Persistent Cryptococcus neoformans infection of the prostate after successful treatment of meningitis. California Collaborative Treatment Group. Ann Intern Med 1989; 111:125.
  34. Lortholary O, Poizat G, Zeller V, et al. Long-term outcome of AIDS-associated cryptococcosis in the era of combination antiretroviral therapy. AIDS 2006; 20:2183.
  35. Lanoy E, Guiguet M, Bentata M, et al. Survival after neuroAIDS: association with antiretroviral CNS Penetration-Effectiveness score. Neurology 2011; 76:644.
  36. 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.
  37. Robinson PA, Bauer M, Leal MA, et al. Early mycological treatment failure in AIDS-associated cryptococcal meningitis. Clin Infect Dis 1999; 28:82.
  38. Bratton EW, El Husseini N, Chastain CA, et al. Comparison and temporal trends of three groups with cryptococcosis: HIV-infected, solid organ transplant, and HIV-negative/non-transplant. PLoS One 2012; 7:e43582.