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Molecular diagnosis of central nervous system infections

Cathy A Petti, MD
Christopher R Polage, MD
Section Editor
Stephen B Calderwood, MD
Deputy Editor
Anna R Thorner, MD


Molecular diagnostic tests and nucleic acid amplification tests (NATs) are used synonymously in reference to test methods that detect deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) specific to infectious organisms (eg, bacteria, viruses) as a means of diagnosis. Such tests have dramatically impacted both the diagnosis and management of infectious diseases [1]. This is particularly true for central nervous system (CNS) infections where rapid, accurate identification of a pathogen and prompt initiation of antimicrobial therapy are potentially lifesaving.

The increasing availability and use of molecular tests for the detection of microorganisms from cerebrospinal fluid (CSF) has redefined our approach to common CNS infections, such as meningitis, encephalitis, and brain mass lesions (particularly in HIV-infected individuals or other immunocompromised hosts), and improved our ability to identify the etiologic agent responsible for other CNS syndromes, such as transverse myelitis.

The unique aspects of molecular testing as applied to CNS infections and guidance in the use and interpretation of molecular testing for pathogens commonly encountered in the management of patients with CNS infections will be reviewed here. Management of specific CNS infections is discussed in the appropriate topics. (See "Aseptic meningitis in adults" and "Viral meningitis: Clinical features and diagnosis in children" and "Viral encephalitis in adults" and "Acute viral encephalitis in children: Clinical manifestations and diagnosis" and "Herpes simplex virus type 1 encephalitis" and "PCR testing for the diagnosis of herpes simplex virus in patients with encephalitis or meningitis" and "Japanese encephalitis: Epidemiology, diagnosis, treatment, and prevention" and "Arthropod-borne encephalitides" and "Clinical features and diagnosis of acute bacterial meningitis in adults".)


Molecular methods are particularly well suited for the diagnosis of central nervous system (CNS) infections because cerebrospinal fluid (CSF) and spinal and brain tissue are normally sterile body sites, where any evidence of a microorganism is likely to represent infection, and infections, when present, are typically monomicrobial. Furthermore, CSF typically lacks common inhibitors of nucleic acid amplification methods (eg, polymerase chain reaction [PCR]) such as heme, endonucleases, and exonucleases that can lead to false-negative results [2]. As a result, direct detection of nucleic acids from CNS samples may be less prone to common causes of false-positive (eg, contamination or presence of nonpathogenic colonization) or false-negative (eg, inhibition) results compared with other body sites.

Targeted nucleic acid detection methods are often more sensitive than conventional culture-based or antigen detection methods and may detect organisms that are nonviable or uncultivable. However, except for herpes simplex virus (HSV) and JC virus, the true clinical sensitivity of most molecular tests for CNS infections is not known because there are few studies utilizing a reference standard (eg, brain biopsy) for comparison.


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Literature review current through: Sep 2016. | This topic last updated: Dec 2, 2015.
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  1. Yang S, Rothman RE. PCR-based diagnostics for infectious diseases: uses, limitations, and future applications in acute-care settings. Lancet Infect Dis 2004; 4:337.
  2. Debiasi RL, Tyler KL. Molecular methods for diagnosis of viral encephalitis. Clin Microbiol Rev 2004; 17:903.
  3. FDA news release. FDA allows marketing of the first nucleic acid-based test to detect multiple pathogens from a single sample of cerebrospinal fluid. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm466360.htm (Accessed on November 20, 2015).
  4. Wilson MR, Naccache SN, Samayoa E, et al. Actionable diagnosis of neuroleptospirosis by next-generation sequencing. N Engl J Med 2014; 370:2408.
  5. Tang YW, Hibbs JR, Tau KR, et al. Effective use of polymerase chain reaction for diagnosis of central nervous system infections. Clin Infect Dis 1999; 29:803.
  6. Simko JP, Caliendo AM, Hogle K, Versalovic J. Differences in laboratory findings for cerebrospinal fluid specimens obtained from patients with meningitis or encephalitis due to herpes simplex virus (HSV) documented by detection of HSV DNA. Clin Infect Dis 2002; 35:414.
  7. Davies NW, Brown LJ, Gonde J, et al. Factors influencing PCR detection of viruses in cerebrospinal fluid of patients with suspected CNS infections. J Neurol Neurosurg Psychiatry 2005; 76:82.
  8. Tunkel AR, Glaser CA, Bloch KC, et al. The management of encephalitis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2008; 47:303.
  9. Chesky M, Scalco R, Failace L, et al. Polymerase chain reaction for the laboratory diagnosis of aseptic meningitis and encephalitis. Arq Neuropsiquiatr 2000; 58:836.
  10. Glaser CA, Honarmand S, Anderson LJ, et al. Beyond viruses: clinical profiles and etiologies associated with encephalitis. Clin Infect Dis 2006; 43:1565.
  11. Christie LJ, Honarmand S, Talkington DF, et al. Pediatric encephalitis: what is the role of Mycoplasma pneumoniae? Pediatrics 2007; 120:305.
  12. Ward KN, Leong HN, Thiruchelvam AD, et al. Human herpesvirus 6 DNA levels in cerebrospinal fluid due to primary infection differ from those due to chromosomal viral integration and have implications for diagnosis of encephalitis. J Clin Microbiol 2007; 45:1298.
  13. Granerod J, Cunningham R, Zuckerman M, et al. Causality in acute encephalitis: defining aetiologies. Epidemiol Infect 2010; 138:783.
  14. Venkatesan A, Tunkel AR, Bloch KC, et al. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis 2013; 57:1114.