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Journal of Neurology, Neurosurgery, and Psychiatry logoLink to Journal of Neurology, Neurosurgery, and Psychiatry
. 2005 Jan;76(1):82–87. doi: 10.1136/jnnp.2004.045336

Factors influencing PCR detection of viruses in cerebrospinal fluid of patients with suspected CNS infections

N Davies 1, L Brown 1, J Gonde 1, D Irish 1, R Robinson 1, A Swan 1, J Banatvala 1, R Howard 1, M Sharief 1, P Muir 1
PMCID: PMC1739313  PMID: 15608000

Abstract

Background: Polymerase chain reaction (PCR) is used to detect viruses in the cerebrospinal fluid (CSF) of patients with neurological disease. However, data to assist its use or interpretation are limited.

Objective: We investigated factors possibly influencing viral detection in CSF by PCR, which will also help clinicians interpret positive and negative results.

Methods: CSF from patients with was tested for human herpesviruses types 1–6, JC virus, enteroviruses, and Toxoplasma gondii. The likelihood of central nervous system (CNS) infection was classified as likely, possible, or unlikely. PCR findings in these categories were compared using single variable and logistic regression analysis.

Results: Of 787 samples tested, 97 (12%) were PCR positive for one or more viruses. Of episodes likely to be CNS viral infections, 30% were PCR positive compared to 5% categorised as unlikely. The most frequent positive findings were Epstein Barr virus (EBV), enteroviruses, and herpes simplex virus (HSV). Enteroviruses and HSV were found predominantly in the likely CNS viral infection group, whereas EBV was found mainly in the unlikely group. Positive PCR results were more likely when there were 3–14 days between symptom onset and lumbar puncture, and when CSF white cell count was abnormal, although a normal CSF did not exclude a viral infection.

Conclusions: The diagnostic yield of PCR can be maximised by using sensitive assays to detect a range of pathogens in appropriately timed CSF samples. PCR results, in particular EBV, should be interpreted cautiously when symptoms cannot readily be attributed to the virus detected.

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Selected References

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  1. Andersson S. O., Björkstén B., Burman L. A. A comparative study of meningoencephalitis epidemics caused by echovirus type 7 and coxsackievirus type B5. Clinical and virological observations during two epidemics in northern Sweden. Scand J Infect Dis. 1975;7(4):233–237. doi: 10.3109/inf.1975.7.issue-4.02. [DOI] [PubMed] [Google Scholar]
  2. Bergström T. Polymerase chain reaction for diagnosis of varicella zoster virus central nervous system infections without skin manifestations. Scand J Infect Dis Suppl. 1996;100:41–45. [PubMed] [Google Scholar]
  3. Cinque P., Brytting M., Vago L., Castagna A., Parravicini C., Zanchetta N., D'Arminio Monforte A., Wahren B., Lazzarin A., Linde A. Epstein-Barr virus DNA in cerebrospinal fluid from patients with AIDS-related primary lymphoma of the central nervous system. Lancet. 1993 Aug 14;342(8868):398–401. doi: 10.1016/0140-6736(93)92814-a. [DOI] [PubMed] [Google Scholar]
  4. Cinque P., Cleator G. M., Weber T., Monteyne P., Sindic C. J., van Loon A. M. The role of laboratory investigation in the diagnosis and management of patients with suspected herpes simplex encephalitis: a consensus report. The EU Concerted Action on Virus Meningitis and Encephalitis. J Neurol Neurosurg Psychiatry. 1996 Oct;61(4):339–345. doi: 10.1136/jnnp.61.4.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. DeBiasi R. L., Tyler K. L. Polymerase chain reaction in the diagnosis and management of central nervous system infections. Arch Neurol. 1999 Oct;56(10):1215–1219. doi: 10.1001/archneur.56.10.1215. [DOI] [PubMed] [Google Scholar]
  6. Domingues R. B., Tsanaclis A. M., Pannuti C. S., Mayo M. S., Lakeman F. D. Evaluation of the range of clinical presentations of herpes simplex encephalitis by using polymerase chain reaction assay of cerebrospinal fluid samples. Clin Infect Dis. 1997 Jul;25(1):86–91. doi: 10.1086/514494. [DOI] [PubMed] [Google Scholar]
  7. Fodor P. A., Levin M. J., Weinberg A., Sandberg E., Sylman J., Tyler K. L. Atypical herpes simplex virus encephalitis diagnosed by PCR amplification of viral DNA from CSF. Neurology. 1998 Aug;51(2):554–559. doi: 10.1212/wnl.51.2.554. [DOI] [PubMed] [Google Scholar]
  8. Ivers Louise C., Kim Arthur Y., Sax Paul E. Predictive value of polymerase chain reaction of cerebrospinal fluid for detection of Epstein-Barr virus to establish the diagnosis of HIV-related primary central nervous system lymphoma. Clin Infect Dis. 2004 May 5;38(11):1629–1632. doi: 10.1086/420934. [DOI] [PubMed] [Google Scholar]
  9. Jeffery K. J., Read S. J., Peto T. E., Mayon-White R. T., Bangham C. R. Diagnosis of viral infections of the central nervous system: clinical interpretation of PCR results. Lancet. 1997 Feb 1;349(9048):313–317. doi: 10.1016/S0140-6736(96)08107-X. [DOI] [PubMed] [Google Scholar]
  10. Kahlon J., Chatterjee S., Lakeman F. D., Lee F., Nahmias A. J., Whitley R. J. Detection of antibodies to herpes simplex virus in the cerebrospinal fluid of patients with herpes simplex encephalitis. J Infect Dis. 1987 Jan;155(1):38–44. doi: 10.1093/infdis/155.1.38. [DOI] [PubMed] [Google Scholar]
  11. Kennedy C. R., Chrzanowska K., Robinson R. O., Tyrrell D. A., Valman H. B., Webster A. D. A major role for viruses in acute childhood encephalopathy. Lancet. 1986 May 3;1(8488):989–991. doi: 10.1016/s0140-6736(86)91268-7. [DOI] [PubMed] [Google Scholar]
  12. Kwok S., Higuchi R. Avoiding false positives with PCR. Nature. 1989 May 18;339(6221):237–238. doi: 10.1038/339237a0. [DOI] [PubMed] [Google Scholar]
  13. Lakeman F. D., Whitley R. J. Diagnosis of herpes simplex encephalitis: application of polymerase chain reaction to cerebrospinal fluid from brain-biopsied patients and correlation with disease. National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. J Infect Dis. 1995 Apr;171(4):857–863. doi: 10.1093/infdis/171.4.857. [DOI] [PubMed] [Google Scholar]
  14. Linde A., Klapper P. E., Monteyne P., Echevarria J. M., Cinque P., Rozenberg F., Vestergaard B. F., Ciardi M., Lebon P., Cleator G. M. Specific diagnostic methods for herpesvirus infections of the central nervous system: a consensus review by the European Union Concerted Action on Virus Meningitis and Encephalitis. Clin Diagn Virol. 1997 Aug;8(2):83–104. doi: 10.1016/s0928-0197(97)00015-9. [DOI] [PubMed] [Google Scholar]
  15. Minjolle Sophie, Arvieux C., Gautier A. L., Jusselin I., Thomas R., Michelet C., Colimon Ronald. Detection of herpesvirus genomes by polymerase chain reaction in cerebrospinal fluid and clinical findings. J Clin Virol. 2002 Jul;25 (Suppl 1):S59–S70. doi: 10.1016/s1386-6532(02)00035-5. [DOI] [PubMed] [Google Scholar]
  16. Quereda C., Corral I., Laguna F., Valencia M. E., Tenorio A., Echeverria J. E., Navas E., Martín-Dávila P., Moreno A., Moreno V. Diagnostic utility of a multiplex herpesvirus PCR assay performed with cerebrospinal fluid from human immunodeficiency virus-infected patients with neurological disorders. J Clin Microbiol. 2000 Aug;38(8):3061–3067. doi: 10.1128/jcm.38.8.3061-3067.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Rorabaugh M. L., Berlin L. E., Heldrich F., Roberts K., Rosenberg L. A., Doran T., Modlin J. F. Aseptic meningitis in infants younger than 2 years of age: acute illness and neurologic complications. Pediatrics. 1993 Aug;92(2):206–211. [PubMed] [Google Scholar]
  18. Schlesinger Y., Tebas P., Gaudreault-Keener M., Buller R. S., Storch G. A. Herpes simplex virus type 2 meningitis in the absence of genital lesions: improved recognition with use of the polymerase chain reaction. Clin Infect Dis. 1995 Apr;20(4):842–848. doi: 10.1093/clinids/20.4.842. [DOI] [PubMed] [Google Scholar]
  19. Schloss Lottie, van Loon Anton M., Cinque Paola, Cleator Graham, Echevarria José-Manuel, Falk Kerstin I., Klapper Paul, Schirm Jurjen, Vestergaard Bent Faber, Niesters Hubert. An international external quality assessment of nucleic acid amplification of herpes simplex virus. J Clin Virol. 2003 Oct;28(2):175–185. doi: 10.1016/s1386-6532(03)00003-9. [DOI] [PubMed] [Google Scholar]
  20. Simko Jeffry P., Caliendo Angela M., Hogle Kay, Versalovic James. 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 Jul 17;35(4):414–419. doi: 10.1086/341979. [DOI] [PubMed] [Google Scholar]
  21. Sköldenberg B., Forsgren M., Alestig K., Bergström T., Burman L., Dahlqvist E., Forkman A., Frydén A., Lövgren K., Norlin K. Acyclovir versus vidarabine in herpes simplex encephalitis. Randomised multicentre study in consecutive Swedish patients. Lancet. 1984 Sep 29;2(8405):707–711. doi: 10.1016/s0140-6736(84)92623-0. [DOI] [PubMed] [Google Scholar]
  22. Stahl H. D., Hubner B., Seidl B., Liebert U. G., van der Heijden I. M., Wilbrink B., Kraan M. C., Emmrich F., Tak P. P. Detection of multiple viral DNA species in synovial tissue and fluid of patients with early arthritis. Ann Rheum Dis. 2000 May;59(5):342–346. doi: 10.1136/ard.59.5.342. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tang Y. W., Hibbs J. R., Tau K. R., Qian Q., Skarhus H. A., Smith T. F., Persing D. H. Effective use of polymerase chain reaction for diagnosis of central nervous system infections. Clin Infect Dis. 1999 Oct;29(4):803–806. doi: 10.1086/520439. [DOI] [PubMed] [Google Scholar]
  24. Van Vliet K. E., Muir P., Echevarria J. M., Klapper P. E., Cleator G. M., Van Loon A. M. Multicenter proficiency testing of nucleic acid amplification methods for the detection of enteroviruses. J Clin Microbiol. 2001 Sep;39(9):3390–3392. doi: 10.1128/JCM.39.9.3390-3392.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Verboon-Maciolek M. A., Nijhuis M., van Loon A. M., van Maarssenveen N., van Wieringen H., Pekelharing-Berghuis M. A., Krediet T. G., Gerards L. J., Fleer A., Diepersloot R. J. A. Diagnosis of enterovirus infection in the first 2 months of life by real-time polymerase chain reaction. Clin Infect Dis. 2003 Jun 20;37(1):1–6. doi: 10.1086/375222. [DOI] [PubMed] [Google Scholar]
  26. Weber T., Turner R. W., Frye S., Ruf B., Haas J., Schielke E., Pohle H. D., Lüke W., Lüer W., Felgenhauer K. Specific diagnosis of progressive multifocal leukoencephalopathy by polymerase chain reaction. J Infect Dis. 1994 May;169(5):1138–1141. doi: 10.1093/infdis/169.5.1138. [DOI] [PubMed] [Google Scholar]
  27. Weinberg Adriana, Li Shaobing, Palmer Megan, Tyler Kenneth L. Quantitative CSF PCR in Epstein-Barr virus infections of the central nervous system. Ann Neurol. 2002 Nov;52(5):543–548. doi: 10.1002/ana.10321. [DOI] [PubMed] [Google Scholar]
  28. Whitley R. J., Cobbs C. G., Alford C. A., Jr, Soong S. J., Hirsch M. S., Connor J. D., Corey L., Hanley D. F., Levin M., Powell D. A. Diseases that mimic herpes simplex encephalitis. Diagnosis, presentation, and outcome. NIAD Collaborative Antiviral Study Group. JAMA. 1989 Jul 14;262(2):234–239. [PubMed] [Google Scholar]
  29. Wildemann B., Haas J., Lynen N., Stingele K., Storch-Hagenlocher B. Diagnosis of cytomegalovirus encephalitis in patients with AIDS by quantitation of cytomegalovirus genomes in cells of cerebrospinal fluid. Neurology. 1998 Mar;50(3):693–697. doi: 10.1212/wnl.50.3.693. [DOI] [PubMed] [Google Scholar]

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