Skip to main content

Advertisement

Log in

Fungal Infections of the Central Nervous System

  • Central Nervous System Infections (J Lyons, Section Editor)
  • Published:
Current Infectious Disease Reports Aims and scope Submit manuscript

Abstract

Fungal infections of the central nervous system have manifold presentations and courses that depend largely on both host and organism characteristics. Although subjects with impaired immunity are generally at higher risk for severe disease, several fungal organisms are considered primary pathogens and can also cause disease in otherwise immunocompetent individuals. Herein, we describe the epidemiology, presentation, diagnosis, and management of central nervous system complications of several fungal pathogens.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Murthy JM, Sundaram C. Fungal infections of the central nervous system. Handb Clin Neurol. 2014;121:1383–401.

    Article  CAS  PubMed  Google Scholar 

  2. Clark TA, Hajjeh RA. Recent trends in the epidemiology of invasive mycoses. Curr Opin Infect Dis. 2002;15:569–74.

    Article  PubMed  Google Scholar 

  3. Murthy JM. Fungal infections of the central nervous system: the clinical syndromes. Neurol India. 2007;55:221–5.

    Article  CAS  PubMed  Google Scholar 

  4. Marra CM. Bacterial and fungal brain infections in AIDS. Semin Neurol. 1999;19:177–84.

    Article  CAS  PubMed  Google Scholar 

  5. Rees JR, Pinner RW, Hajjeh RA, Brandt ME, Reingold AL. The epidemiological features of invasive mycotic infections in the San Francisco Bay area, 1992–1993: results of population-based laboratory active surveillance. Clin Infect Dis: Off Publ Infect Dis Soc Am. 1998;27:1138–47.

    Article  CAS  Google Scholar 

  6. Schoch CL, Robbertse B, Robert V, Vu D, Cardinali G, Irinyi L, et al. Finding needles in haystacks: linking scientific names, reference specimens and molecular data for Fungi. Database: J Biol Databases Curation. 2014;2014.

  7. Park BJ, Wannemuehler KA, Marston BJ, Govender N, Pappas PG, Chiller TM. Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. Aids. 2009;23:525–30.

    Article  PubMed  Google Scholar 

  8. Chang YC, Stins MF, McCaffery MJ, Miller GF, Pare DR, Dam T, et al. Cryptococcal yeast cells invade the central nervous system via transcellular penetration of the blood–brain barrier. Infect Immun. 2004;72:4985–95.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Sloan DJ, Parris V. Cryptococcal meningitis: epidemiology and therapeutic options. Clin Epidemiol. 2014;6:169–82.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Chen J, Varma A, Diaz MR, Litvintseva AP, Wollenberg KK, Kwon-Chung KJ. Cryptococcus neoformans strains and infection in apparently immunocompetent patients, China. Emerg Infect Dis. 2008;14:755–62.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Kwon-Chung KJ, Fraser JA, Doering TL, Wang Z, Janbon G, Idnurm A, et al. Cryptococcus neoformans and Cryptococcus gattii, the etiologic agents of cryptococcosis. Cold Spring Harb Perspect Med. 2014;4:a019760.

    Article  PubMed  Google Scholar 

  12. Chen SC, Slavin MA, Heath CH, Playford EG, Byth K, Marriott D, et al. Clinical manifestations of Cryptococcus gattii infection: determinants of neurological sequelae and death. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2012;55:789–98.

    Article  Google Scholar 

  13. Engelthaler DM, Hicks ND, Gillece JD, Roe CC, Schupp JM, Driebe EM, et al. Cryptococcus gattii in North American Pacific Northwest: whole-population genome analysis provides insights into species evolution and dispersal. mBio. 2014;5:e01464–01414. This population-level genome study of C. gattii infections in the Pacific Northwest, an area where the climate was not previously known to harbor this organism, describes environmental origins of the yeast and divergence from previously accepted clinical presentations of C. gattii infections.

    Article  PubMed Central  PubMed  Google Scholar 

  14. Harris JR, Lockhart SR, Debess E, Marsden-Haug N, Goldoft M, Wohrle R, et al. Cryptococcus gattii in the United States: clinical aspects of infection with an emerging pathogen. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2011;53:1188–95.

    Article  CAS  Google Scholar 

  15. Byrnes 3rd EJ, Bartlett KH, Perfect JR, Heitman J. Cryptococcus gattii: an emerging fungal pathogen infecting humans and animals. Microbes Infect / Institut Pasteur. 2011;13:895–907.

    Article  CAS  Google Scholar 

  16. Saijo T, Chen J, Chen SC, Rosen LB, Yi J, Sorrell TC, et al. Anti-granulocyte-macrophage colony-stimulating factor autoantibodies are a risk factor for central nervous system infection by Cryptococcus gattii in otherwise immunocompetent patients. mBio. 2014;5:e00912–4.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Iverson SA, Chiller T, Beekmann S, Polgreen PM, Harris J. Recognition and diagnosis of Cryptococcus gattii infections in the United States. Emerg Infect Dis. 2012;18:1012–5.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Perfect JR. Fungal diagnosis: how do we do it and can we do better? Curr Med Res Opin. 2013;29 Suppl 4:3–11.

    Article  CAS  PubMed  Google Scholar 

  19. Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2010;50:291–322.

    Article  Google Scholar 

  20. Day JN, Chau TT, Wolbers M, Mai PP, Dung NT, Mai NH, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013;368:1291–302. This trial of combination flucytosine and amphotericin B or fluconazole and amphotericin B induction for CM compared to amphotericin alone showed significant mortality benefit for the amphotericin B/flucytosine group but not for the fluconazole/amphotericin B group.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Boulware DR, Meya DB, Muzoora C, Rolfes MA, Huppler Hullsiek K, Musubire A, et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N Engl J Med. 2014;370:2487–98.

    Article  PubMed  Google Scholar 

  22. de Vedia L, Arechavala A, Calderon MI, Maiolo E, Rodriguez A, Lista N, et al. Relevance of intracranial hypertension control in the management of Cryptococcus neoformans meningitis related to AIDS. Infection. 2013;41:1073–7.

    Article  PubMed  Google Scholar 

  23. Phillips P, Chapman K, Sharp M, Harrison P, Vortel J, Steiner T, et al. Dexamethasone in Cryptococcus gattii central nervous system infection. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2009;49:591–5.

    Article  Google Scholar 

  24. Shelburne 3rd SA, Darcourt J, White Jr AC, Greenberg SB, Hamill RJ, Atmar RL, et al. The role of immune reconstitution inflammatory syndrome in AIDS-related Cryptococcus neoformans disease in the era of highly active antiretroviral therapy. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2005;40:1049–52.

    Article  Google Scholar 

  25. Muller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M, et al. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010;10:251–61.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Bahr N, Boulware DR, Marais S, Scriven J, Wilkinson RJ, Meintjes G. Central nervous system immune reconstitution inflammatory syndrome. Curr Infect Dis Rep. 2013;15:583–93.

    Article  PubMed  Google Scholar 

  27. Antinori S. New insights into HIV/AIDS-associated Cryptococcosis. Isrn Aids. 2013;2013:471363.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Chang CC, Lim A, Omarjee S, Levitz SM, Gosnell BI, Spelman T, et al. Cryptococcosis-IRIS is associated with lower cryptococcus-specific IFN-gamma responses before antiretroviral therapy but not higher T-cell responses during therapy. J Infect Dis. 2013;208:898–906. This prospective study of 106 HIV patients with CM assessing markers of Cryptococcus-specific immune function before the initiation of cART shows that relative preservation of CM-specific immune function and hence ability to clear infection prior to initiation of cART lowers the risk of developing IRIS.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Boulware DR, Bonham SC, Meya DB, Wiesner DL, Park GS, Kambugu A, et al. Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome. J Infect Dis. 2010;202:962–70.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Siddiqui AA, Brouwer AE, Wuthiekanun V, Jaffar S, Shattock R, Irving D, et al. IFN-gamma at the site of infection determines rate of clearance of infection in cryptococcal meningitis. J Immunol. 2005;174:1746–50.

    Article  CAS  PubMed  Google Scholar 

  31. Johnson T, Nath A. Neurological complications of immune reconstitution in HIV-infected populations. Ann N Y Acad Sci. 2010;1184:106–20.

    Article  CAS  PubMed  Google Scholar 

  32. Sitapati AM, Kao CL, Cachay ER, Masoumi H, Wallis RS, Mathews WC. Treatment of HIV-related inflammatory cerebral cryptococcoma with adalimumab. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2010;50:e7–10.

    Article  Google Scholar 

  33. Saccente M. Central nervous system histoplasmosis. Curr Treat Options Neurol. 2008;10:161–7.

    Article  PubMed  Google Scholar 

  34. Sifuentes-Osornio J, Corzo-Leon DE, Ponce-de-Leon LA. Epidemiology of invasive fungal infections in Latin America. Curr Fungal Infect Rep. 2012;6:23–34.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Centers for Disease C, Prevention. Histoplasmosis in a state where it is not known to be endemic—Montana, 2012–2013. MMWR Morb Mortal Wkly Rep. 2013;62:834–7.

    Google Scholar 

  36. Trofa D, Nosanchuk JD. Histoplasmosis of the central nervous system. J Neuroparasitol. 2012;3:1–7.

    Article  Google Scholar 

  37. Nguyen FN, Kar JK, Zakaria A, Schiess MC. Isolated central nervous system histoplasmosis presenting with ischemic pontine stroke and meningitis in an immune-competent patient. JAMA Neurol. 2013;70:638–41.

    Article  PubMed  Google Scholar 

  38. Mikulska M, Furfaro E, Del Bono V, Raiola AM, Di Grazia C, Bacigalupo A, et al. (1–3)-beta-D-glucan in cerebrospinal fluid is useful for the diagnosis of central nervous system fungal infections. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2013;56:1511–2.

    Article  Google Scholar 

  39. Wheat LJ, Freifeld AG, Kleiman MB, Baddley JW, McKinsey DS, Loyd JE, Kauffman CA, Infectious Diseases Society of A. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2007;45:807–25.

    Article  Google Scholar 

  40. Saccente M, Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010;23:367–81.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Friedman JA, Wijdicks EF, Fulgham JR, Wright AJ. Meningoencephalitis due to Blastomyces dermatitidis: case report and literature review. Mayo Clin Proc. 2000;75:403–8.

    Article  CAS  PubMed  Google Scholar 

  42. Bariola JR, Perry P, Pappas PG, Proia L, Shealey W, Wright PW, et al. Blastomycosis of the central nervous system: a multicenter review of diagnosis and treatment in the modern era. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2010;50:797–804.

    Article  Google Scholar 

  43. Bush JW, Wuerz T, Embil JM, Del Bigio MR, McDonald PJ, Krawitz S. Outcomes of persons with blastomycosis involving the central nervous system. Diagn Microbiol Infect Dis. 2013;76:175–81.

    Article  PubMed  Google Scholar 

  44. Chapman SW, Dismukes WE, Proia LA, Bradsher RW, Pappas PG, Threlkeld MG, Kauffman CA, Infectious Diseases Society of A. Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2008;46:1801–12.

    Article  Google Scholar 

  45. Marsden-Haug N, Goldoft M, Ralston C, Limaye AP, Chua J, Hill H, et al. Coccidioidomycosis acquired in Washington State. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2013;56:847–50.

    Article  Google Scholar 

  46. Litvintseva AP, Marsden-Haug N, Hurst S, Hill H, Gade L, Driebe EM, Ralston C, Roe C, Barker BM, Goldoft M, Keim P, Wohrle R, Thompson GR, 3rd, Engelthaler DM, Brandt ME, Chiller T. 2014. Valley Fever: Finding new places for an old disease: Coccidioides immitis found in Washington State soil associated with recent human infection. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. This is a CDC report on discovery of Coccidioides immitis in regions outside its previously acknowledged endemic habitat of the hot, dry Southwest.

  47. Lammering JC, Iv M, Gupta N, Pandit R, Patel MR. Imaging spectrum of CNS coccidioidomycosis: prevalence and significance of concurrent brain and spinal disease. AJR Am J Roentgenol. 2013;200:1334–46.

    Article  PubMed  Google Scholar 

  48. Zunt JR, Baldwin KJ. Chronic and subacute meningitis. Continuum. 2012;18:1290–318.

    PubMed  Google Scholar 

  49. Arsura EL, Johnson R, Penrose J, Stewart K, Kilgore W, Reddy CM, et al. Neuroimaging as a guide to predict outcomes for patients with coccidioidal meningitis. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2005;40:624–7.

    Article  Google Scholar 

  50. Ragland AS, Arsura E, Ismail Y, Johnson R. Eosinophilic pleocytosis in coccidioidal meningitis: frequency and significance. Am J Med. 1993;95:254–7.

    Article  CAS  PubMed  Google Scholar 

  51. de Almeida SM. Central nervous system paracoccidioidomycosis: an overview. Braz J infect Dis: Off Publ Braz Soc Infect Dis. 2005;9:126–33.

    Article  Google Scholar 

  52. de Almeida SM, Queiroz-Telles F, Teive HA, Ribeiro CE, Werneck LC. Central nervous system paracoccidioidomycosis: clinical features and laboratorial findings. J Infect. 2004;48:193–8.

    Article  PubMed  Google Scholar 

  53. Marques da Silva SH, Colombo AL, Blotta MH, Lopes JD, Queiroz-Telles F, Pires de Camargo Z. Detection of circulating gp43 antigen in serum, cerebrospinal fluid, and bronchoalveolar lavage fluid of patients with paracoccidioidomycosis. J Clin Microbiol. 2003;41:3675–80.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  54. Gasparetto EL, Liu CB, de Carvalho NA, Rogacheski E. Central nervous system paracoccidioidomycosis: imaging findings in 17 cases. J Comput Assist Tomogr. 2003;27:12–7.

    Article  PubMed  Google Scholar 

  55. Le T, Huu Chi N, Kim Cuc NT, Manh Sieu TP, Shikuma CM, Farrar J, et al. AIDS-associated Penicillium marneffei infection of the central nervous system. Clin Infect Dis: Off Pub Infect Dis Soc Am. 2010;51:1458–62.

    Article  Google Scholar 

  56. Hu Y, Zhang J, Li X, Yang Y, Zhang Y, Ma J, et al. Penicillium marneffei infection: an emerging disease in mainland China. Mycopathologia. 2013;175:57–67.

    Article  PubMed  Google Scholar 

  57. Scott EN, Kaufman L, Brown AC, Muchmore HG. Serologic studies in the diagnosis and management of meningitis due to Sporothrix schenckii. N Engl J Med. 1987;317:935–40.

    Article  CAS  PubMed  Google Scholar 

  58. Hardman S, Stephenson I, Jenkins DR, Wiselka MJ, Johnson EM. Disseminated Sporothix schenckii in a patient with AIDS. J Infect. 2005;51:e73–7.

    Article  CAS  PubMed  Google Scholar 

  59. Cuomo CA, Rodriguez-Del Valle N, Perez-Sanchez L, Abouelleil A, Goldberg J, Young S, et al. Genome sequence of the pathogenic fungus Sporothrix schenckii (ATCC 58251). Genome Announc. 2014;2.

  60. Kauffman CA, Bustamante B, Chapman SW, Pappas PG, Infectious Diseases Society of A. Clinical practice guidelines for the management of sporotrichosis: 2007 update by the infectious diseases society of America. Clin Infect Dis: Off Publ Infect Dis Soc Am. 2007;45:1255–65.

    Article  Google Scholar 

  61. Rodrigues AM, de Hoog GS, de Cassia PD, Brihante RS, Sidrim JJ, Gadelha MF, et al. Genetic diversity and antifungal susceptibility profiles in causative agents of sporotrichosis. BMC Infect Dis. 2014;14:219.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Jennifer Lyons, Mark Etherton, and Claire Jacobs have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by the author.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jennifer L. Lyons.

Additional information

This article is part of the Topical Collection on Central Nervous System Infections

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jacobs, C.S., Etherton, M.R. & Lyons, J.L. Fungal Infections of the Central Nervous System. Curr Infect Dis Rep 16, 449 (2014). https://doi.org/10.1007/s11908-014-0449-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11908-014-0449-2

Keywords

Navigation