Final Diagnosis -- Cryptococcal meningoencephalitis



After more than a century since its initial description in 1894, Cryptococcus continues to be a significant cause of morbidity and mortality, particularly following the advent of Human Immunodeficiency virus (HIV) infections and post-transplant immunosuppressive therapy.

The two main species of Cryptococcus pathogenic to humans are C. neoformans (serogroups A and D) and C. gattii (serogroups B and C). These variants differ in their geographic distribution, host preference and symptoms of infection. Although serogroups A and D are more common in the U.S., rare C. gatti outbreaks have been reported in North America. [1] The organism is transmitted via the respiratory tract, typically from the environment (such as avian guano). Human-to-human transmission is rare. Inhaled yeast forms are deposited into the pulmonary alveoli. From there, the most common initial site of dissemination is the central nervous system. [1,4]

Cryptococcus neoformans is a round-to-oval yeast-like fungal organism, typically 2 to 15 micrometers in size, though occasionally larger. The organism demonstrates a thick mucopolysaccharide capsule, visible as a clear area around a central core. [6] The capsule is the main virulence factor of this organism, and it is largely composed of two polysaccharides, glucuronoxylomannan (GXM) and galactoxylomannan (galXM). [7]

Other morphologic forms of C. neoformans exist, although they were not readily seen in this case. Such forms include budding yeasts with narrow necks and occasional sunburst forms that are difficult to distinguish from stain precipitates. Nonetheless, a definitive diagnosis of the organism can be made by means of culture from the cerebrospinal fluid.

Wright-Giemsa and Calcofluor white stains are useful in the identification of these organisms. India ink stain highlights the capsule as a negative space. Periodic acid-Schiff (PAS) and Gomori Methenamine Silver (GMS) stain the organisms, leaving the capsule unstained (Image 3).

Culture of the CSF may take several days to grow; in this case, taking four days. Determination of Cryptococcus polysaccharide capsular antigen levels may also be helpful to confirm infection; they are detectable in most body fluids, either by ELISA or latex agglutination methods. Sensitivity and specificity of the latex test are high (93-100%, and 93-98% respectively), as are the sensitivity and specificity of the ELISA test (99% and 97%, respectively). [1]

Recommendations for treatment of adults by the American Thoracic Society (2009) are as follows:

Cryptococcus is a significant cause of morbidity and mortality in transplant patients, particularly due to immunosuppressive therapy required to prevent organ rejection. The incidence of C. neoformans in transplant patients ranges from 0.6 to 2.6%, although some institutions have reported figures as high as 5% [2]. Immunocompromised patients, especially those on post-transplant immunosuppressive therapy such as this patient, are at increased risk of infection by this organism. This transplant patient's immunosuppressive therapy included Cellcept and Prograf. Out of 5,521 consecutive organ transplant recipients at UPMC from January 1989 through January 1999, 28 were diagnosed with cryptococcal meningitis. Mortality among those recipients with cryptococcal meningitis was 50%. [9] It occurs more frequently in patients with CD4 counts lower than 100/microL [3].

At initial presentation, this patient was treated empirically with Ceftriaxone, Vancomycin and Acyclovir, but was switched to Amphotericin B and Flucytosine upon discovery of cryptococcal infection. His functional status did not improve, and Fluconazole was added to his regimen. His intracerebral pressure continued to increase, necessitating daily lumbar punctures for relief. Unfortunately, he later became hypotensive with decreased responsiveness, and did not respond to pressor support. A cranial CT scan showed diffuse cerebral edema, concerning for brain death. A cerebral perfusion scan found no identifiable perfusion to the supratentorial and infratentorial structures, which confirmed brain death in this patient.

The diagnosis of cryptococcal meningoencephalitis is definitively established by culturing the organism from the CSF. C. neoformans takes 3-5 days to grow in the laboratory. Therefore, in any patient with symptoms worrisome for meningitis, especially in immunosuppressed patients, the recognition of the morphology of Cryptococcus on cerebrospinal fluid smear preparations is important, and may allow for initiation of antifungal therapy as early as possible, especially when culture or antigen studies are still pending.


  1. Huston SM, Mody CH. Cryptococcosis: An emerging respiratory mycosis. Clin Chest Med 2009; 30:253-264.
  2. Mayhall, CG. Hospital Epidemiology and Infection Control. 3rd ed. New York, NY: Lippincott Williams and Wilkins; 2004:1000-1001.
  3. Jarvis, JN, Harrison, TS. HIV-associated cryptococcal meningitis. AIDS 2007; 21:2119.
  4. Merz WG, Hay RJ. Cryptococcus. Topley and Wilson's Microbiology and Microbial Infections (10th Ed). Arnold Press, London 2007.
  5. Lee, SC, Dickson, DW, Casadevall, A. Pathology of cryptococcal meningoencephalitis: Analysis of 27 patients with pathogenetic implications. Hum Pathol 1996; 27:839.
  6. Rosai, J. Rosai and Ackerman's Surgical Pathology. 9th ed. New York, NY: Mosby; 2004:2490-2491.
  7. Zaragoza O, Rodrigues ML, De Jesus, M, Frases S, Dadachova, E, Casadevall, A. The capsule of the fungal pathogen Cryptococcus neoformans. Advances in Applied Microbiology 2009; 68:133-216.
  8. Limper AH, Knox HS, Sarosi GA, et al. American Thoracic Society statement on treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2009, in review.
  9. Vilchez WG, Eidelman B, Fung J, Kormos R, Kusne S. Cryptococcal meningitis: an analysis among 5,521 consecutive organ transplant patients. Transplant Infectious Disease 2002; 4(4):183-188.
  10. Johnson KS, Sexton DJ. Cerebrospinal Fluid: Physiology and utility of an examination in disease states. In: UpToDate Online, Rose, BD (Ed), UpToDate, Waltham, MA, 2009.

Contributed by Milon Amin, MD, Shveta Hooda, MD and Lydia Contis, MD

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