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Performance of PML diagnostic criteria in natalizumab-associated PML: data from the Dutch-Belgian cohort
  1. Martijn T Wijburg1,2,
  2. Clemens Warnke3,4,
  3. Frederik Barkhof2,5,
  4. Bernard M J Uitdehaag1,
  5. Joep Killestein1,
  6. Mike P Wattjes2,6
  1. 1 Department of Neurology, Neuroscience Amsterdam, VUmc MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
  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, Medical Faculty, University of Düsseldorf, Düsseldorf, Germany
  4. 4 Department of Neurology, Medical Faculty, University of Köln, Köln, Germany
  5. 5 Institutes of Neurology and Healthcare Engineering, UCL, London, UK
  6. 6 Department of Diagnostic and Interventional Neuroradiology, Hannover Medical School, Hannover, Germany
  1. Correspondence to Martijn T Wijburg, Departments of Neurology and Radiology & Nuclear Medicine, VUmc MS Center Amsterdam, VU University Medical Center, Amsterdam 1081 HZ, The Netherlands; m.wijburg{at}


Objective To test the current progressive multifocal leukoencephalopathy (PML) diagnostic criteria by applying them to patients previously diagnosed with natalizumab (NTZ)-associated PML in a real-world clinical setting.

Methods Patients from the Dutch-Belgian NTZ-PML cohort (n=28) were reviewed at the time of first diagnostic work-up and during follow-up, using the PML diagnostic criteria as proposed in a consensus statement from the American Academy of Neurology.

Results At first diagnostic work-up, 18 patients (64.3%) met the criteria for high diagnostic certainty for PML (‘definite PML’ or ‘probable PML’). During follow-up, this increased to 20 patients (71.4%) as JC virus DNA was detected in cerebrospinal fluid of two additional patients. Nonetheless, 28.6% of patients were still classified as ‘possible PML’ or ‘not PML’ (6 (21.5%) and 2 (7.1%) patients, respectively) despite a very high suspicion for PML based on lesion evolution and signs of PML-immune reconstitution inflammatory syndrome on MRI, and development of compatible symptoms.

Conclusions The current case definition of PML has low sensitivity for diagnosis of NTZ-PML in a real-world clinical setting in which MRI is frequently used for PML screening. This may delay diagnosis and appropriate management of PML, and may complicate a valid estimation of PML incidence during NTZ therapy.

  • progressive multifocal leukoencephalopathy
  • diagnosis
  • JC virus
  • natalizumab
  • multiple sclerosis

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  • Contributors Conceptualisation and design of the study: MTW, CW, JK and MPW. Acquisition and analysis of data: MTW, JK, FB, BMJU and MPW. Drafting of a significant portion of the manuscript or figures: MTW, CW, FB, BMJU, JK and MPW.

  • Funding The MS Center Amsterdam is funded by a programme grant (14-358e) from the Stichting voor MS Research (Voorschoten, The Netherlands). CW received support from the Charcot foundation and the Hertie foundation (P1150063) for this work. FB is supported by NIHR-BRC-UCLH.

  • Disclaimer None of the funders had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.

  • Competing interest CW has received consultancy or speaking fees from Novartis, Bayer, Biogen and Teva. BMJU has received consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche and Teva. FB serves as a consultant for Bayer-Schering Pharma, Sanofi-Aventis, Biogen, Teva, Novartis, Roche, Synthon BV, Genzyme and Jansen Research. JK has received consultancy fees from Merck-Serono, Teva, Biogen, Genzyme and Novartis. MPW has received consultancy fees from Biogen and Roche.

  • Patient consent Not required.

  • Ethics approval Medisch Etische Toetsings Commissie, VUmc.

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