Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment

Nature Reviews Neurology volume 12, pages 662–674 (2016)Cite this article

Subjects

Key Points

  • Opportunistic infections of the CNS, such as cryptococcal meningitis, cerebral toxoplasmosis, and tuberculous meningitis, are a major cause of morbidity and mortality in HIV-positive individuals

  • Cerebral toxoplasmosis should be suspected in patients with AIDS who present with movement disorders; progressive multifocal leukoencephalopathy (PML) should be suspected in those patients with AIDS who present with cortical blindness

  • Cerebrospinal fluid sample analyses can facilitate diagnosis of PML, cryptococcal or tuberculous meningitis and cytomegalovirus encephalitis

  • A definitive diagnosis of cerebral toxoplasmosis requires a combination of serological testing, MRI findings, and in certain cases, brain biopsy

  • On MRI, toxoplasmosis often manifests with several brain abscesses with predilection for the basal ganglia, whereas PML typically manifests as diffuse white matter lesions with predilection for the subcortical U fibres

  • In patients with HIV or AIDS, treatment with antiretroviral drugs in the setting of opportunistic infections can lead to a paradoxical worsening of symptoms, caused by immune reconstitution inflammatory syndrome

Abstract

Nearly 30 years after the advent of antiretroviral therapy (ART), CNS opportunistic infections remain a major cause of morbidity and mortality in HIV-positive individuals. Unknown HIV-positive disease status, antiretroviral drug resistance, poor drug compliance, and recreational drug abuse are factors that continue to influence the morbidity and mortality of infections. The clinical and radiographic pattern of CNS opportunistic infections is unique in the setting of HIV infection: opportunistic infections in HIV-positive patients often have characteristic clinical and radiological presentations that can differ from the presentation of opportunistic infections in immunocompetent patients and are often sufficient to establish the diagnosis. ART in the setting of these opportunistic infections can lead to a paradoxical worsening caused by an immune reconstitution inflammatory syndrome (IRIS). In this Review, we discuss several of the most common CNS opportunistic infections: cerebral toxoplasmosis, progressive multifocal leukoencephalopathy (PML), tuberculous meningitis, cryptococcal meningitis and cytomegalovirus infection, with an emphasis on clinical pearls, pathological findings, MRI findings and treatment. Moreover, we discuss the risk factors, pathophysiology and management of IRIS. We also summarize the challenges that remain in management of CNS opportunistic infections, which includes the lack of phase II and III clinical trials, absence of antimicrobials for infections such as PML, and controversy regarding the use of corticosteroids for treatment of IRIS.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Level of immunosuppression and risk of opportunistic infections.
Figure 2: Pathological features of opportunistic infections of the CNS.
Figure 3: MRI findings in opportunistic infections of the CNS.
Figure 4: Paradoxical immune reconstitution inflammatory syndrome.
Figure 5: Cellular tropism of organisms causing opportunistic infections in the CNS.

Similar content being viewed by others

References

  1. Wong, A. A., Pabbaraju, K., Wong, S. & Tellier, R. Development of a multiplex real-time PCR for the simultaneous detection of herpes simplex and varicella zoster viruses in cerebrospinal fluid and lesion swab specimens. J. Virol. Methods 229, 16–23 (2016).

    Article  CAS  PubMed  Google Scholar 

  2. Garvey, L. et al. HIV-associated central nervous system diseases in the recent combination antiretroviral therapy era. Eur. J. Neurol. 18, 527–534 (2011).

    Article  PubMed  Google Scholar 

  3. Lanoy, E. et al. Survival after neuroAIDS: association with antiretroviral CNS Penetration-Effectiveness score. Neurology 76, 644–651 (2011).

    Article  CAS  PubMed  Google Scholar 

  4. Caniglia, E. C. et al. Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions. Neurology 83, 134–141 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ferguson, D. J. & Hutchison, W. M. The host-parasite relationship of Toxoplasma gondii in the brains of chronically infected mice. Virchows Arch. A Pathol. Anat. Histopathol. 411, 39–43 (1987).

    Article  CAS  PubMed  Google Scholar 

  6. Chew, W. K., Wah, M. J., Ambu, S. & Segarra, I. Toxoplasma gondii: determination of the onset of chronic infection in mice and the in vitro reactivation of brain cysts. Exp. Parasitol. 130, 22–25 (2012).

    Article  PubMed  Google Scholar 

  7. McCabe, R. E., Brooks, R. G., Dorfman, R. F. & Remington, J. S. Clinical spectrum in 107 cases of toxoplasmic lymphadenopathy. Rev. Infect. Dis. 9, 754–774 (1987).

    Article  CAS  PubMed  Google Scholar 

  8. Zhang, Y. H. et al. Activated microglia contribute to neuronal apoptosis in toxoplasmic encephalitis. Parasit. Vectors 7, 372 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Luft, B. J. et al. Outbreak of central-nervous-system toxoplasmosis in western Europe and North America. Lancet 1, 781–784 (1983).

    Article  CAS  PubMed  Google Scholar 

  10. Coelho, L. et al. Trends in AIDS-defining opportunistic illnesses incidence over 25 years in Rio de Janeiro, Brazil. PLoS ONE 9, e98666 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Laing, R. B., Flegg, P. J., Brettle, R. P., Leen, C. L. & Burns, S. M. Clinical features, outcome and survival from cerebral toxoplasmosis in Edinburgh AIDS patients. Int. J. STD AIDS 7, 258–264 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Jones, J. L., Kruszon-Moran, D., Rivera, H. N., Price, C. & Wilkins, P. P. Toxoplasma gondii seroprevalence in the United States 2009–2010 and comparison with the past two decades. Am. J. Trop. Med. Hyg. 90, 1135–1139 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Montoya, J. G. & Liesenfeld, O. Toxoplasmosis. Lancet 363, 1965–1976 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Antinori, A. et al. Prevalence, associated factors, and prognostic determinants of AIDS-related toxoplasmic encephalitis in the era of advanced highly active antiretroviral therapy. Clin. Infect. Dis. 39, 1681–1691 (2004).

    Article  PubMed  Google Scholar 

  15. Leon Ruiz, M. A. Novel case of solitary cerebral toxoplasmosis mimicking glioblastoma as the first presentation of HIV. J. Clin. Neurol. 12, 248–250 (2016).

    Article  PubMed  Google Scholar 

  16. Nath, A., Hobson, D. E. & Russell, A. Movement disorders with cerebral toxoplasmosis and AIDS. Mov. Disord. 8, 107–112 (1993).

    Article  CAS  PubMed  Google Scholar 

  17. Mattos, J. P., Rosso, A. L., Correa, R. B. & Novis, S. A. Movement disorders in 28 HIV-infected patients. Arq. Neuropsiquiatr. 60, 525–530 (2002).

    Article  PubMed  Google Scholar 

  18. Herrera Rubio, J., Farinas, M. C., Tejido, R., Garcia Palomo, J. D. & Tejido, R. [Aspecific chorioretinitis as initial manifestation of HIV infection and diffuse Toxoplasma encephalitis]. Med. Clin. (Barc.) 106, 198–199 (in Spanish) (1996).

    CAS  Google Scholar 

  19. Gray, F. et al. Diffuse “encephalitic” cerebral toxoplasmosis in AIDS. Report of four cases. J. Neurol. 236, 273–277 (1989).

    Article  CAS  PubMed  Google Scholar 

  20. de-la-Torre, A. et al. Clinical patterns of uveitis in two ophthalmology centres in Bogota, Colombia. Clin. Exp. Ophthalmol. 37, 458–466 (2009).

    Article  PubMed  Google Scholar 

  21. Rodriguez, A. et al. Referral patterns of uveitis in a tertiary eye care center. Arch. Ophthalmol. 114, 593–599 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Crosson, J. N., Laird, P. W., Grossniklaus, H. E. & Hendrick, A. M. Toxoplasma chorioretinitis diagnosed by histopathology in a patient with AIDS. Retin. Cases Brief Rep. 9, 162–163 (2015).

    Article  PubMed  Google Scholar 

  23. Cochereau-Massin, I. et al. Ocular toxoplasmosis in human immunodeficiency virus-infected patients. Am. J. Ophthalmol. 114, 130–135 (1992).

    Article  CAS  PubMed  Google Scholar 

  24. Furtado, J. M., Toscano, M., Castro, V. & Rodrigues, M. W. Roth spots in ocular toxoplasmosis. Ocul. Immunol. Inflamm. http://dx.doi.org/10.3109/09273948.2015.1047035 (2015).

  25. Gagliuso, D. J., Teich, S. A., Friedman, A. H. & Orellana, J. Ocular toxoplasmosis in AIDS patients. Trans. Am. Ophthalmol. Soc. 88, 63–86 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Belaz, S., Gangneux, J. P., Dupretz, P., Guiguen, C. & Robert-Gangneux, F. A. 10-year retrospective comparison of two target sequences, REP-529 and B1, for Toxoplasma gondii detection by quantitative PCR. J. Clin. Microbiol. 53, 1294–1300 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Colombo, F. A. et al. Diagnosis of cerebral toxoplasmosis in AIDS patients in Brazil: importance of molecular and immunological methods using peripheral blood samples. J. Clin. Microbiol. 43, 5044–5047 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Meira, C. S. et al. IgG4 specific to Toxoplasma gondii excretory/secretory antigens in serum and/or cerebrospinal fluid support the cerebral toxoplasmosis diagnosis in HIV-infected patients. J. Immunol. Methods 395, 21–28 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Marra, C. M., Krone, M. R., Koutsky, L. A. & Holmes, K. K. Diagnostic accuracy of HIV-associated central nervous system toxoplasmosis. Int. J. STD AIDS 9, 761–764 (1998).

    Article  CAS  PubMed  Google Scholar 

  30. Mathews, C., Barba, D. & Fullerton, S. C. Early biopsy versus empiric treatment with delayed biopsy of non-responders in suspected HIV-associated cerebral toxoplasmosis: a decision analysis. AIDS 9, 1243–1250 (1995).

    Article  CAS  PubMed  Google Scholar 

  31. Neville, A. J. et al. Clinically available medicines demonstrating anti-toxoplasma activity. Antimicrob. Agents Chemother. 59, 7161–7169 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Vidadala, R. S. et al. Development of an orally available and central nervous system (CNS) penetrant Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitor with minimal human ether-a-go-go-related gene (hERG) activity for the treatment of toxoplasmosis. J. Med. Chem. 59, 6531–6546 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Gorelik, L. et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann. Neurol. 68, 295–303 (2010).

    Article  PubMed  Google Scholar 

  34. Engsig, F. N. et al. Incidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nationwide cohort study. J. Infect. Dis. 199, 77–83 (2009).

    Article  PubMed  Google Scholar 

  35. Fong, I. W. & Toma, E. The natural history of progressive multifocal leukoencephalopathy in patients with AIDS. Canadian PML Study Group. Clin. Infect. Dis. 20, 1305–1310 (1995).

    Article  CAS  PubMed  Google Scholar 

  36. Worthley, D. L., Sandhu, A. & Norton, G. Progressive multifocal leukoencephalopathy: a confused woman, an ambitious virus and an unusual MRI. Intern. Med. J. 32, 266–267 (2002).

    Article  CAS  PubMed  Google Scholar 

  37. Saito, H., Sakai, H., Fujihara, K., Fujihara, K. & Itoyama, Y. Progressive multifocal leukoencephalopathy in a patient with acquired immunodeficiency syndrome (AIDS) manifesting Gerstmann's syndrome. Tohoku J. Exp. Med. 186, 169–179 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Willott, R. H., Sunman, W. & Munshi, S. K. Progressive multifocal leukoencephalopathy masquerading as cerebellar infarction. Age Ageing 45, 564–565 (2016).

    Article  PubMed  Google Scholar 

  39. Stockhammer, G. et al. Progressive multifocal leukoencephalopathy presenting with an isolated focal movement disorder. Mov. Disord. 15, 1006–1009 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Jeyaraman, V. A. et al. Isolated cortical blindness without simultaneous neurological involvement in progressive multifocal leukoencephalopathy in a patient with human immune deficiency virus infection. J. Ophthalmic Inflamm. Infect. 3, 3 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Boster, A. L. et al. Lessons learned from fatal progressive multifocal leukoencephalopathy in a patient with multiple sclerosis treated with natalizumab. JAMA Neurol. 70, 398–402 (2013).

    Article  PubMed  Google Scholar 

  42. Koralnik, I. J. et al. JC virus granule cell neuronopathy: a novel clinical syndrome distinct from progressive multifocal leukoencephalopathy. Ann. Neurol. 57, 576–580 (2005).

    Article  PubMed  Google Scholar 

  43. Casado, J. L. et al. Continued declining incidence and improved survival of progressive multifocal leukoencephalopathy in HIV/AIDS patients in the current era. Eur. J. Clin. Microbiol. Infect. Dis. 33, 179–187 (2014).

    Article  CAS  PubMed  Google Scholar 

  44. Khanna, N. et al. Incidence and outcome of progressive multifocal leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. Clin. Infect. Dis. 48, 1459–1466 (2009).

    Article  PubMed  Google Scholar 

  45. Tan, K., Roda, R., Ostrow, L., McArthur, J. & Nath, A. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 72, 1458–1464 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Clifford, D. B. et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 9, 438–446 (2010).

    Article  CAS  PubMed  Google Scholar 

  47. Berger, J. R. et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology 80, 1430–1438 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Kuker, W. et al. Progressive multifocal leukoencephalopathy: value of diffusion-weighted and contrast-enhanced magnetic resonance imaging for diagnosis and treatment control. Eur. J. Neurol. 13, 819–826 (2006).

    Article  CAS  PubMed  Google Scholar 

  49. Astrom, K. E., Mancall, E. L. & Richardson, E. P. Jr. Progressive multifocal leuko-encephalopathy; a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin's disease. Brain 81, 93–111 (1958).

    Article  CAS  PubMed  Google Scholar 

  50. Marra, C. M. et al. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS 16, 1791–1797 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Aksamit, A. J. Treatment of non-AIDS progressive multifocal leukoencephalopathy with cytosine arabinoside. J. Neurovirol. 7, 386–390 (2001).

    Article  CAS  PubMed  Google Scholar 

  52. Clifford, D. B. et al. A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes. J. Neurovirol. 19, 351–358 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cettomai, D. & McArthur, J. C. Mirtazapine use in human immunodeficiency virus-infected patients with progressive multifocal leukoencephalopathy. Arch. Neurol. 66, 255–258 (2009).

    Article  PubMed  Google Scholar 

  54. Blumberg, H. M. et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am. J. Respir. Crit. Care Med. 167, 603–662 (2003).

    Article  PubMed  Google Scholar 

  55. Kwan, C. K. & Ernst, J. D. HIV and tuberculosis: a deadly human syndemic. Clin. Microbiol. Rev. 24, 351–376 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Jarvis, J. N. et al. Adult meningitis in a setting of high HIV and TB prevalence: findings from 4961 suspected cases. BMC Infect. Dis. 10, 67 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Simmons, C. P. et al. Pretreatment intracerebral and peripheral blood immune responses in Vietnamese adults with tuberculous meningitis: diagnostic value and relationship to disease severity and outcome. J. Immunol. 176, 2007–2014 (2006).

    Article  CAS  PubMed  Google Scholar 

  58. Marais, S., Pepper, D. J., Marais, B. J. & Torok, M. E. HIV-associated tuberculous meningitis—diagnostic and therapeutic challenges. Tuberculosis (Edinb.) 90, 367–374 (2010).

    Article  Google Scholar 

  59. Marais, S. et al. Tuberculous meningitis: a uniform case definition for use in clinical research. Lancet Infect. Dis. 10, 803–812 (2010).

    Article  PubMed  Google Scholar 

  60. Thwaites, G. E. et al. Comparison of conventional bacteriology with nucleic acid amplification (amplified mycobacterium direct test) for diagnosis of tuberculous meningitis before and after inception of antituberculosis chemotherapy. J. Clin. Microbiol. 42, 996–1002 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Raja, S. et al. Technology for automated, rapid, and quantitative PCR or reverse transcription-PCR clinical testing. Clin. Chem. 51, 882–890 (2005).

    Article  CAS  PubMed  Google Scholar 

  62. Boehme, C. C. et al. Rapid molecular detection of tuberculosis and rifampin resistance. N. Engl. J. Med. 363, 1005–1015 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zignol, M. et al. Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007–2010. Bull. World Health Organ. 90, 111–119D (2012).

    Article  PubMed  Google Scholar 

  64. World Health Organization. Multidrug-resistant tuberculosis (MDR-TB): 2013 Update. http://www.who.int/tb/challenges/mdr/MDR_TB_FactSheet.pdf (2013).

  65. Syed Ahamed Kabeer, B. et al. Role of interferon γ release assay in active TB diagnosis among HIV infected individuals. PLoS ONE 4, e5718 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Kaur, H. et al. Prospective analysis of 55 cases of tuberculosis meningitis (TBM) in North India. J. Clin. Diagn. Res. 19, DC15–DC19 (2015).

    Google Scholar 

  67. Singh, A. K. et al. Paradoxical reaction in tuberculous meningitis: presentation, predictors and impact on prognosis. BMC Infect. Dis. 16, 306 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 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. AIDSinfo. https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf (accessed July 31 2016).

  69. Regazzi, M., Carvalho, A. C., Villani, P. & Matteelli, A. Treatment optimization in patients co-infected with HIV and Mycobacterium tuberculosis infections: focus on drug-drug interactions with rifamycins. Clin. Pharmacokinet. 53, 489–507 (2014).

    Article  CAS  PubMed  Google Scholar 

  70. Luetkemeyer, A. F. Current issues in the diagnosis and management of tuberculosis and HIV coinfection in the United States. Top. HIV Med. 18, 143–148 (2010).

    PubMed  Google Scholar 

  71. Thwaites, G. E. et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N. Engl. J. Med. 351, 1741–1751 (2004).

    Article  CAS  PubMed  Google Scholar 

  72. Torok, M. E. et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)—associated tuberculous meningitis. Clin. Infect. Dis. 52, 1374–1383 (2011).

    Article  PubMed  Google Scholar 

  73. Daikos, G. L., Cleary, T., Rodriguez, A. & Fischl, M. A. Multidrug-resistant tuberculous meningitis in patients with AIDS. Int. J. Tuber. Lung Dis. 7, 394–398 (2003).

    CAS  Google Scholar 

  74. Patel, V. B. et al. Multidrug-resistant tuberculous meningitis in KwaZulu-Natal, South Africa. Clin. Infect. Dis. 38, 851–856 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Dodt, K. K. et al. Development of cytomegalovirus (CMV) disease may be predicted in HIV-infected patients by CMV polymerase chain reaction and the antigenemia test. AIDS 11, F21–F28 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Rhein, J. et al. Efficacy of adjunctive sertraline for the treatment of HIV-associated cryptococcal meningitis: an open-label dose-ranging study. Lancet Infect. Dis. 16, 809–818 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Albarillo, F. & O'Keefe, P. Opportunistic neurologic infections in patients with acquired immunodeficiency syndrome (AIDS). Curr. Neurol. Neurosci. Rep. 16, 10 (2016).

    Article  CAS  PubMed  Google Scholar 

  78. Jarvis, J. N. et al. Determinants of mortality in a combined cohort of 501 patients with HIV-associated cryptococcal meningitis: implications for improving outcomes. Clin. Infect. Dis. 58, 736–745 (2014).

    Article  PubMed  Google Scholar 

  79. Jarvis, J. N. et al. Screening for cryptococcal antigenemia in patients accessing an antiretroviral treatment program in South Africa. Clin. Infect. Dis. 48, 856–862 (2009).

    Article  CAS  PubMed  Google Scholar 

  80. French, N. et al. Cryptococcal infection in a cohort of HIV-1-infected Ugandan adults. AIDS 16, 1031–1038 (2002).

    Article  PubMed  Google Scholar 

  81. Liechty, C. A. et al. Asymptomatic serum cryptococcal antigenemia and early mortality during antiretroviral therapy in rural Uganda. Trop. Med. Int. Health 12, 929–935 (2007).

    Article  PubMed  Google Scholar 

  82. Mfinanga, S. et al. Cryptococcal meningitis screening and community-based early adherence support in people with advanced HIV infection starting antiretroviral therapy in Tanzania and Zambia: an open-label, randomised controlled trial. Lancet 385, 2173–2182 (2015).

    Article  PubMed  Google Scholar 

  83. Hardison, S. E. et al. Pulmonary infection with an interferon-γ-producing Cryptococcus neoformans strain results in classical macrophage activation and protection. Am. J. Pathol. 176, 774–785 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Boulware, D. R. et al. Human immune response varies by the degree of relative cryptococcal antigen shedding. Open Forum Infect. Dis. 3, ofv194 (2016).

    Article  PubMed  Google Scholar 

  85. Tan, I. L., Smith, B. R., von Geldern, G., Mateen, F. J. & McArthur, J. C. HIV-associated opportunistic infections of the CNS. Lancet Neurol. 11, 605–617 (2012).

    Article  PubMed  Google Scholar 

  86. Kammalac Ngouana, T. et al. Cryptoccocal meningitis in Yaounde (Cameroon) HIV infected patients: diagnosis, frequency and Cryptococcus neoformans isolates susceptibility study to fluconazole. J. Mycol. Med. 25, 11–16 (2015).

    Article  CAS  PubMed  Google Scholar 

  87. Boulware, D. R. et al. Multisite validation of cryptococcal antigen lateral flow assay and quantification by laser thermal contrast. Emerg. Infect. Dis. 20, 45–53 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Troncoso, A. et al. CNS cryptococcoma in an HIV-positive patient. J. Int. Assoc. Physicians AIDS Care (Chic.) 1, 131–133 (2002).

    Article  Google Scholar 

  89. Charlier, C. et al. Cryptococcal neuroradiological lesions correlate with severity during cryptococcal meningoencephalitis in HIV-positive patients in the HAART era. PLoS ONE 3, e1950 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Loyse, A. et al. Neurological, visual, and MRI brain scan findings in 87 South African patients with HIV-associated cryptococcal meningoencephalitis. J. Infect. 70, 668–675 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Katchanov, J. et al. Cryptococcal meningoencephalitis relapse after an eight-year delay: an interplay of infection and immune reconstitution. Int. J. STD AIDS 26, 912–914 (2015).

    Article  CAS  PubMed  Google Scholar 

  92. Offiah, C. E. & Naseer, A. Spectrum of imaging appearances of intracranial cryptococcal infection in HIV/AIDS patients in the anti-retroviral therapy era. Clin. Radiol. 71, 9–17 (2016).

    Article  PubMed  Google Scholar 

  93. Cherian, J., Atmar, R. L. & Gopinath, S. P. Shunting in cryptococcal meningitis. J. Neurosurgery 125, 177–186 (2016).

    Article  Google Scholar 

  94. Chen, C. H. et al. Epidemiological characterization and prognostic factors in patients with confirmed cerebral cryptococcosis in central Taiwan. J. Venom. Anim. Toxins Incl. Trop. Dis. 21, 12 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Rolfes, M. A. et al. The effect of therapeutic lumbar punctures on acute mortality from cryptococcal meningitis. Clin. Infect. Dis. 59, 1607–1614 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Boulware, D. R. et al. Clinical features and serum biomarkers in HIV immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. PLoS Med. 7, e1000384 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Boulware, D. R. et al. Paucity of initial cerebrospinal fluid inflammation in cryptococcal meningitis is associated with subsequent immune reconstitution inflammatory syndrome. J. Infect. Dis. 202, 962–970 (2010).

    Article  CAS  PubMed  Google Scholar 

  98. Boulware, D. R. et al. Timing of antiretroviral therapy after diagnosis of cryptococcal meningitis. N. Engl. J. Med. 370, 2487–2498 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Day, J. N. et al. Combination antifungal therapy for cryptococcal meningitis. N. Engl. J. Med. 368, 1291–1302 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 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.Cytomegalovirus disease (N-1). AIDSinfo. https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. (accessed August 4 2016).

  101. Saag, M. S. et al. A comparison of itraconazole versus fluconazole as maintenance therapy for AIDS-associated cryptococcal meningitis. Clin. Infect. Dis. 28, 291–296 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. Yao, Y. et al. Voriconazole: a novel treatment option for cryptococcal meningitis. Infect. Dis. (Lond.) 47, 694–700 (2015).

    Article  CAS  Google Scholar 

  103. Warrilow, A. G. et al. The investigational drug VT-1129 is a highly potent inhibitor of cryptococcus species CYP51 but only weakly inhibits the human enzyme. Antimicrob. Agents Chemother. 60, 4530–4538 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Beardsley, J. et al. Adjunctive dexamethasone in HIV-associated cryptococcal meningitis. N. Engl. J. Med. 374, 542–554 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Anduze-Faris, B. M. et al. Induction and maintenance therapy of cytomegalovirus central nervous system infection in HIV-infected patients. AIDS 14, 517–524 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Silva, C. A. et al. Neurologic cytomegalovirus complications in patients with AIDS: retrospective review of 13 cases and review of the literature. Rev. Inst. Med. Trop. Sao Paulo 52, 305–310 (2010).

    Article  PubMed  Google Scholar 

  107. Kuo, I. C., Kempen, J. H., Dunn, J. P., Vogelsang, G. & Jabs, D. A. Clinical characteristics and outcomes of cytomegalovirus retinitis in persons without human immunodeficiency virus infection. Am. J. Ophthalmol. 138, 338–346 (2004).

    Article  PubMed  Google Scholar 

  108. Jabs, D. A. et al. Course of cytomegalovirus retinitis in the era of highly active antiretroviral therapy: 1. Retinitis progression. Ophthalmology 111, 2224–2231 (2004).

    Article  PubMed  Google Scholar 

  109. Mofenson, L. M. et al. Guidelines for the prevention and treatment of opportunistic infections among HIV-exposed and HIV-infected children: recommendations from CDC, the National Institutes of Health, the HIV Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the American Academy of Pediatrics. MMWR. Recommendations and reports: morbidity and mortality weekly report. MMWR Recomm. Rep. 58, 1–166 (2009).

    PubMed  Google Scholar 

  110. Martin, D. F. et al. A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. N. Engl. J. Med. 346, 1119–1126 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Jabs, D. A., Ahuja, A., Van Natta, M., Dunn, J. P. & Yeh, S. Comparison of treatment regimens for cytomegalovirus retinitis in patients with AIDS in the era of highly active antiretroviral therapy. Ophthalmology 120, 1262–1270 (2013).

    Article  PubMed  Google Scholar 

  112. Morrison, V. L. et al. Intravitreal triamcinolone acetonide for the treatment of immune recovery uveitis macular edema. Ophthalmology 114, 334–339 (2007).

    Article  PubMed  Google Scholar 

  113. Alvarez-Uria, G., Naik, P. K., Pakam, R., Bachu, L. & Midde, M. Natural history and factors associated with early and delayed mortality in HIV-infected patients treated of tuberculosis under directly observed treatment short-course strategy: a prospective cohort study in India. Interdiscip. Perspect. Infect. Dis. 2012, 502012 (2012).

    PubMed  PubMed Central  Google Scholar 

  114. Luma, H. N. et al. Tuberculous meningitis: presentation, diagnosis and outcome in hiv-infected patients at the douala general hospital, cameroon: a cross sectional study. AIDS Res. Ther. 10, 16 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Xiao, J. et al. Spectrums of opportunistic infections and malignancies in HIV-infected patients in tertiary care hospital, China. PLoS ONE 8, e75915 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Infections of the Nervous System, National Institute for Neurologic Disorders and Stroke, National Institutes of Health, 10 Center Drive, Building 10/7C103, Bethesda, 28092, Maryland, USA

    Lauren N. Bowen, Bryan Smith & Avindra Nath

  2. Translational Neuroradiology Unit, National Institute for Neurologic Disorders and Stroke, National Institutes of Health, 10 Center Drive, Building 10/5C103, Bethesda, 20892, Maryland, USA

    Daniel Reich

  3. Department of Pathology, National Cancer Institute, National Institutes of Health, 10 Center Drive, Building 10 Magnuson CC 2A10, Bethesda, 20892, Maryland, USA

    Martha Quezado

Authors
  1. Lauren N. Bowen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bryan Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daniel Reich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Martha Quezado
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Avindra Nath
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.N., L.N.B. and B.S. wrote the article and participated in reviewing and editing of the manuscript. All authors researched data for the article and provided substantial contribution to discussion of content.

Corresponding author

Correspondence to Avindra Nath.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

FURTHER INFORMATION

AIDSinfo

PowerPoint slides

Glossary

Immune reconstitution inflammatory syndrome (IRIS)

In the context of HIV infection, effective antiretroviral therapy can normalise CD4+ T cell counts and thereby lead to immune reconstitution, which can result in a dysregulated inflammatory immune response against the infecting pathogen and the host and the subsequent paradoxical worsening of symptoms (paradoxical IRIS). Immune reconstitution can also result in a sudden presentation of the previously asymptomatic and therefore unrecognized opportunistic infection (unmasking IRIS).

Bradyzoites

The slowly dividing cellular stage of the Toxoplasma gondii parasite that makes up tissue cysts, and is able to evade the host immune system.

Tachyzoites

The infectious, motile cellular stage of the Toxoplasma gondii parasite that is efficient at disseminating the parasitic infection in the host.

Posterior uveitis

Inflammation of the choroid of the eye.

Mass effect

A focal lesion or inflammation of a structure or tissue of the brain causes increased pressure within the skull space, displacing an adjacent area of the brain, which often results in injury.

Heminested PCR

A series of PCR reactions that uses the products from the first PCR reaction as a template for the second, and uses one different primer in the second reaction to 'nest' within the first set of primer amplicons, thereby increasing specificity.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bowen, L., Smith, B., Reich, D. et al. HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment. Nat Rev Neurol 12, 662–674 (2016). https://doi.org/10.1038/nrneurol.2016.149

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2016.149

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing