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Research paper
Inflammatory natalizumab-associated PML: baseline characteristics, lesion evolution and relation with PML-IRIS
  1. Mike P Wattjes1,2,
  2. Martijn T Wijburg2,3,
  3. Jeroen van Eijk4,
  4. Stephan Frequin5,
  5. Bernard M J Uitdehaag3,
  6. Frederik Barkhof2,6,
  7. Clemens Warnke7,8,
  8. Joep Killestein3
  9. On behalf of the Dutch-Belgian Natalizumab-Associated PML Study Group
    1. 1 Department of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
    2. 2 Department of Radiology and Nuclear Medicine, Neuroscience Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
    3. 3 Department of Neurology, Neuroscience Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
    4. 4 Department of Neurology, Jeroen Bosch Ziekenhuis, s’Hertogenbosch, The Netherlands
    5. 5 Department of Neurology, St Antonius Hospital, Nieuwegein, The Netherlands
    6. 6 Institutes of Neurology and Healthcare Engineering, UCL, London, UK
    7. 7 Department of Neurology, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany
    8. 8 Department of Neurology, University Hospital of Cologne, Cologne, Germany
    1. Correspondence to Dr Mike P Wattjes, Department of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Carl-Neuberg-Straße 1, D-30625 Hannover, Germany; wattjes.mike{at}


    Background and objective Natalizumab-associated progressive multifocal leukoencephalopathy (NTZ-PML) patients may show imaging signs suggestive of inflammation at diagnosis (‘inflammatory PML’), reminiscent of PML-immune reconstitution inflammatory syndrome (PML-IRIS). We investigated the imaging characteristics of inflammatory NTZ-PML lesions and PML-IRIS to determine differentiating and overlapping features.

    Methods We scored the presence, localisation and pattern of imaging characteristics of inflammation on brain MRI scans of inflammatory NTZ-PML patients. The imaging characteristics were followed up until the occurrence of PML-IRIS.

    Results Ten out of the 44 NTZ-PML patients included showed signs suggestive of inflammation at the time of diagnosis. The inflammation pattern at diagnosis was similar to the pattern seen at PML-IRIS, with contrast enhancement representing the most frequent sign of inflammation (90% at diagnosis, 100% at PML-IRIS). However, the severity of inflammation differed, with absence of swelling and low frequency of perilesional oedema (10%) at diagnosis, as compared with the PML-IRIS stage (40%).

    Conclusion Patterns of inflammation at the time of PML diagnosis and at the PML-IRIS stage overlap but differ in their severity of inflammation. This supports histopathological evidence that the inflammation seen at both stages of the same disease shares a similar underlying pathophysiology, representing the immune response to the JC virus to a variable extend.

    • multiple sclerosis
    • magnetic resonance imaging
    • progressive multifocal leukoencephalopathy
    • natalizumab

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    • Contributors MPW, MTW collected the data, analysed the data and wrote the manuscript. FB, SF, BMJU, CW and JK interpreted the data and edited the manuscript. All authors reviewed and agreed on the final versions of the manuscript.

    • Funding The MS Centre Amsterdam is funded by a programme grant (14-358e) from the Stichting voor MS Research (Voorschoten, The Netherlands). CW was supported by a grant from the Hertie-Foundation (P1150063).

    • Competing interests MPW has received consultancy fees from Biogen, Novartis and Roche. FB serves as a consultant for Bayer-Schering Pharma, Sanofi-Aventis, Biogen, Teva, Novartis, Roche, Synthon BV, Genzyme and Jansen Research. JK has accepted consulting fees from Merck-Serono, TEVA, Biogen, Genzyme and Novartis. BMJU has received consultancy fees from Novartis, Merck Serono, Biogen and Danone Research. MTW does not report any competing interest. The VUmc has received financial support for research activities from Bayer Schering Pharma, Biogen, Glaxo Smith Kline, Merck Serono, Novartis and Teva. JE received consultancy fees and/or lecture fees from Biogen, Genzyme, Teva, Merck and Novartis. The authors had full editorial control of the manuscript and provided their final approval of all content.

    • Ethics approval Institutional review board of the VU University Medical Center Amsterdam, The Netherlands.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement None.

    • Collaborators Bob W van Oosten and Chris H. Polman (VU University Medical Center, Amsterdam, The Netherlands), Dorine A Siepman and Rogier Hintzen (Erasmus MC, University Medical Center Rotterdam, The Netherlands), Jop Mostert (Rijnstate Hospital, Department of Neurology, Arnhem, The Netherlands), Wibe Moll (Maasstad Hospital, Rotterdam, The Netherlands), Alex EL van Golde (ZGT Hospital, Almelo, The Netherlands), Stephan TFM Frequin (St Antonius Hospital, Nieuwegein, The Netherlands), Paul A D Bouma (Tergooi, Blaricum, Hilversum, The Netherlands), Bénédicte Quivron (CH Jolimont, La Louvière, Belgium), Jean Braeckeveldt (Epicura, Baudour, Belgium), Erik van Munster and Jeroen van Eijk (Department of Neurology, Jeroen Bosch Ziekenhuis, s’Hertogenbosch, The Netherlands), Thea Heersema (Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands), Jaap de Graaf (Isala Hospital, Zwolle, The Netherlands).