1) To determine whether JC virus (JCV) DNA was present in the cerebrospinal fluid (CSF) and blood from patients with multiple sclerosis (MS) in comparison with controls and 2) to find out if our clinical material, based on presence of JCV DNA, included any patient at risk for progressive multifocal leukoencephalopathy (PML).
Methods
The prevalence of JCV DNA was analyzed in CSF and plasma from 217 patients with MS, 86 patients with clinically isolated syndrome (CIS), and 212 patients with other neurological diseases (OND). In addition, we analyzed CSF cells, the first report of JCV DNA in CSF cells in a single sample, and peripheral blood cells in a subgroup of MS (n = 49), CIS (n = 14) and OND (n = 53).
Results
A low copy number of JCV DNA was detected in one MS cell free CSF sample and in one MS CSF cell samples. None of these had any signs of PML or developed this disease during follow-up. In addition, two OND plasma samples were JCV DNA positive, whereas all the other samples had no detectable virus.
Conclusion
A low copy number of JCV DNA may occasionally be observed both in MS and other diseases and may occur as part of the normal biology of JC virus in humans. This study does not support the hypothesis that patients with MS would be at increased risk to develop PML, and consequently screening of CSF as a measurable risk for PML is not useful.
1 Yousry TA Major EO Ryschkewitsch C . Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med2006; 354: 924–933.
2.
2 Boster A Edan G Frohman E . Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician. Lancet Neurol2008; 7: 173–183.
3.
3 Astrom KE Mancall EL Richardsson EP . Progressive multifocal leukoencephalopathy; a hitherto unrecognized complication of chronic lymphatic leukemia and Hodgkin’s disease. Brain1958; 81: 93–111.
4.
4 Padgett BL Walker DL ZuRhein GM Eckroade RJ Dessel BH . Cultivation of papova-like virus from human brain with progresive multifocal leukoencephalopathy. Lancet1971; 1: 1257–1260.
5.
5 Sabath BF Major EO . Traffic of JC virus from sites of initial infection to the brain: the path to progressive multifocal leukoencephalopathy. J Infect Dis2002; 186: 180–186.
6.
6 Knowles WA Pipkin P Andrews N . Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol2003; 71: 115–123.
7.
7 Stolt A Sasnauskas K Koskela P Lehinen M Dillner J . Seroepidemiology of the human polyomaviruses. J Gen Virol2003; 84: 1499–1504.
8.
8 Dörries K ter Meulen V . Progressive multifocal leukoencephalopathy: detection of papovavirus JC in kidney tissue. J Med Virol1983; 11: 307–317.
9.
9 Houff SA Major EO Katz DA . Involvement of JC virus-infected mononuclear cells from the bone marrow and spleen in the pathogenesis of progressive multifocal leukoencephalopathy. N Engl J Med1988; 318: 301–305.
10.
10 Monaco MC Atwood WJ Gravell M Tornatore CS Major EO . JC virus infection of hematopoietic progenitor cells, primary B lymphocytes, and tonsillar stromal cells: implications for viral latency. J Virol1996; 70: 7004–7012.
11.
11 Jensen PN Major EO . Viral variant nucleotide sequences help expose leukocytic positioning in the JC virus pathway to the CNS. J Leukoc Biol1999; 65: 428–438.
12.
12 Khalili K White MK . Human demyelinating disease and the polyomavirus JCV. Mult Scler2006; 12: 133–142.
13.
13 Fong IW Britton CB Luinstra KE Toma E Mahony JB . Diagnostic value of detecting JC virus DNA in cerebrospinal fluid of patients with progressive multifocal leukoencephalopahty. J Clin Microbiol1995; 33: 484–486.
14.
14 Hammarin AL Bogdanovic G Svedhem V Pirskanen R Morfeldt L Grandien M . Analysis of PCR as a tool for detection of JC virus DNA in cerebrospinal fluid for diagnosis of progressive multifocal leukoencephalopahty. J Clin Microbiol1996; 34: 2929–2932.
15.
15 Ferrante P Omodeo-Zorini E Caldarelli-Stefano R . Detection of JC virus DNA in cerebrospinal fluid from multiple sclerosis patients. Mult Scler1998; 4: 49–54.
16.
16 Bogdanovic G Priftakis P Hammarin AL . Detection of JC virus in cerebrospinal fluid (CSF) samples from patients with progressive multifocal leukoencephalopathy but not in CSF samples from patients with herpes simplex encephalitis, enteroviral meningitis, or multiple sclerosis. J Clin Microbiol1998; 36: 1137–1138.
17.
17 Alvarez-Lafuente R García-Montojo M De Las Heras V Bartolomé M Arroyo R . JC virus in cerebrospinal fluid samples of multiple sclerosis patients at the first demyelinating event. Mult Scler2007; 13: 590–595.
18.
18 Franciotta D Bestetti A Bergamaschi R Piccolo G Persico A Cinque P . Failure to detect JC virus DNA in cerebrospinal fluid of multiple sclerosis patients. Mult Scler2006; 12: 674–675.
19.
19 Tornatore C Berger JR Houff SA . Detection of JC virus DNA in peripheral lymphocytes from patients with and without progressive multifocal leukoencephalopathy. Ann Neurol1992; 31: 454–462.
20.
20 Randhawa P Uhrmacher J Pasculle W . A comparative study of BK and JC virus infections in organ transplant recipients. J Med Virol2005; 77: 238–243.
21.
21 Dörries K Sbiera S Drews K Arendt G Eggers C Dörries R . Association of human polyomavirus JC with peripheral blood of immunoimpaired and healthy individuals. J Neurovirol2003; 9: 81–87.
22.
22 Lafon ME Dutronic H Dubois V . JC virus remains latent in peripheral blood B lymphocytes but replicates actively in urine from AIDS patients. J Infect Dis1998; 177: 152–155.
23.
23 Delbue S Guerini FR Mancuso R . JC virus viremia in interferon-beta-treated and untreated Italian multiple sclerosis patients and healthy controls. J Neurovirol2007; 13: 73–77.
24.
24 Alvarez-Lafuente R Garcia-Montojo M De Las Heras V Bartolome M Arroyo R . Interferon-beta treatment and active replication of the JC virus in relapsing-remitting multiple sclerosis patients. Eur J Neurol2007; 13: 233–236.
25.
25 Polman CH Reingold SC Edan G . Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol2005; 58: 840–846.
26.
26 Ryschkewitsch C Jensen P Hou J Fahle G Fisher S Major EO . Comparison of PCR-southern hybridization and quantitative real-time PCR for the detection of JC and BK viral nucleotide sequences in urine and cerebrospinal fluid. J Virol Methods2004; 121: 217–221.
27.
27 Hamilton RS Gravell M Major EO . Comparison of antibody titers determined by hemagglutination inhibition and enzyme immunoassay for JC virus and BK virus. J Clin Microbiol2000; 38: 105–109.
28.
28 Langer-Gould A Atlas SW Green AJ Bollen AW Pelletier D . Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med2005; 353: 375–381.
29.
29 Kleinschmidt-DeMasters BK Tyler KL . Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med2005; 353: 369–374.
30.
30 Eggers C Stellbrink HJ Buhk T Dörries K . Quantification of JC virus DNA in the cerebrospinal fluid of patients with human immunodeficiency virus-associated progressive multifocal leukoencephalopathy – a longitudinal study. J Infect Dis1999; 180: 1690–1694.
31.
31 Koralnik IJ Boden D Mai VX Lord CI Letvin NL . JC virus DNA load in the cerebrospinal fluid in patients with and without progressive multifocal leukoencephalopathy. Neurology1999; 52: 253–260.
32.
32 Boren EJ Cheema GS Naguwa SM Ansari AA Gershwin ME . The emergence of progressive multifocal leukoencephalopahty (PML) in rheumatic diseases. J Autoimmun2008; 30: 90–98.
33.
33 Calabrese LH Molloy ES Huang DR Ransohoff RM . Progressive multifocal leukoencephalopahty in rheumatic diseases: evolving clinical and pathological patterns of disease. Arthritis Rheum2007; 7: 2116–2128.
