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Original Investigation
July 2018

Association of Progressive Multifocal Leukoencephalopathy Lesion Volume With JC Virus Polymerase Chain Reaction Results in Cerebrospinal Fluid of Natalizumab-Treated Patients With Multiple Sclerosis

Author Affiliations
  • 1Department of Neurology, Neuroscience Amsterdam, VUmc Multiple Sclerosis Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
  • 2Department of Radiology and Nuclear Medicine, Neuroscience Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands
  • 3Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands
  • 4Department of Neurology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany
  • 5Department of Neurology, Medical Faculty, University of Köln, Köln, Germany
  • 6Institutes of Neurology and Healthcare Engineering, University College London, London, United Kingdom
  • 7Department of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
JAMA Neurol. 2018;75(7):827-833. doi:10.1001/jamaneurol.2018.0094
Key Points

Question  Is there an association between the magnetic resonance imaging characteristics of progressive multifocal leukoencephalopathy, especially lesion volume, and the results of polymerase chain reaction for JC virus in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis?

Findings  In this cross-sectional study that included 56 patients, patients with small progressive multifocal leukoencephalopathy lesion volumes had a significantly higher probability for undetectable JC virus DNA or low JC virus copy numbers in cerebrospinal fluid.

Meaning  Strict pharmacovigilance by magnetic resonance imaging will lead to identification of smaller progressive multifocal leukoencephalopathy lesions that associate with a higher likelihood of negative polymerase chain reaction results, which hampers a formal diagnosis of progressive multifocal leukoencephalopathy and may complicate patient treatment.


Importance  The JC virus (JCV) was named after the first patient to be described with progressive multifocal leukoencephalopathy (PML), John Cunningham. Detection of JC virus DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR), and of specific lesions by brain magnetic resonance imaging (MRI), are both considered essential for the diagnosis of natalizumab-associated PML (NTZ-PML) in patients with multiple sclerosis. However, strict pharmacovigilance by MRI can result in detection of patients with small lesions and undetectable JCV DNA in CSF.

Objective  To investigate the association of PML lesion characteristics on MRI with both qualitative and quantitative JCV PCR results in CSF of patients with NTZ-PML.

Design, Setting and Participants  This was a retrospective, cross-sectional study conducted from January 2007 to December 2014 in patients considered to have NTZ-PML based on a set of predefined criteria. Follow-up was at least 6 months. Data of patients from the Dutch-Belgian NTZ-PML cohort and patients treated at multiple medical centers in Belgium and the Netherlands and selected for research purposes were included as a convenience sample.

Main Outcomes and Measures  Brain MRI scans were analyzed for PML lesion volume, location, dissemination, and signs of inflammation. Associations of the qualitative and quantitative CSF JCV PCR results with PML MRI characteristics were calculated.

Results  Of the 73 patients screened, 56 were included (37 were women). At inclusion, 9 patients (16.1%) had undetectable JCV DNA in CSF. Patients with a positive PCR had larger total PML lesion volumes than those with undetectable JCV DNA (median volume, 22.9 mL; interquartile range, 9.2-60.4 mL vs median volume, 6.7 mL; interquartile range, 4.9-14.7 mL; P = .008), and logistic regression showed that a lower PML lesion volume significantly increased the probability for undetectable JCV DNA. There was a positive correlation between PML lesion volume and JCV copy numbers (Spearman ρ, 0.32; P = .03). Progressive multifocal leukoencephalopathy lesion volume was higher in patients with PML symptoms and in patients with more widespread lesion dissemination. No association was found between PCR results and PML lesion dissemination, signs of inflammation, or PML symptoms.

Conclusions and Relevance  Smaller NTZ-PML lesions are associated with a higher likelihood of undetectable JCV DNA in CSF. This may preclude a formal diagnosis of PML and can complicate patient treatment in patients with small MRI lesions highly suggestive of PML detected early through pharmacovigilance.