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Research paper
Early diagnosis of progressive multifocal leucoencephalopathy: longitudinal lesion evolution
  1. Cristina Scarpazza1,2,
  2. Alessio Signori3,
  3. Luca Prosperini4,
  4. Maria Pia Sormani3,
  5. Mirco Cosottini5,
  6. Ruggero Capra1,
  7. Simonetta Gerevini6
  8. for the Italian PML Group
    1. 1 Multiple Sclerosis Centre, Spedali Civili, Brescia, Italy
    2. 2 Department of General Psychology, University of Padova, Padova, Italy
    3. 3 Department of Health Sciences, University of Genoa, Genoa, Italy
    4. 4 Department of Neurosciences, San Camillo-Forlanini Hospital, Rome, Italy
    5. 5 Department of Translational Research and New Surgical and Medical Technologies, University of Pisa, Pisa, Italy
    6. 6 Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
    1. Correspondence to Dr Cristina Scarpazza, Regional Multiple Sclerosis Center, ASST - Spedali Civili di Brescia, Brescia 25018, Italy; cristina.scarpazza{at}; Dr Ruggero Capra, Regional Multiple Sclerosis Center, ASST - Spedali Civili di Brescia, Brescia 25018, Italy; ruggero.capra{at}


    Objective Early diagnosis of natalizumab-related progressive multifocal leucoencephalopathy (NTZ-PML) in multiple sclerosis has been deemed a major priority by the regulatory agencies but has yet to become a reality. The current paper aims to: (1) investigate whether patients with NTZ-PML pass through a prolonged presymptomatic phase with MRI abnormalities, (2) estimate the longitudinal PML lesion volume increase during the presymptomatic phase and (3) estimate the presymptomatic phase length and its impact on therapy duration as a risk stratification parameter.

    Methods All Italian patients who developed NTZ-PML between 2009 and 2018 were included. The data of patients with available prediagnostic MRI were analysed (n=41). Detailed clinical and neuroradiological information was available for each participant.

    Results (1) PML lesions were detectable in the presymptomatic phase in 32/41 (78%) patients; (ii) the lesion volume increased by 62.8 % for each month spent in the prediagnostic phase; (3) the prediagnostic phase length was 150.8±74.9 days; (4) PML MRI features were detectable before the 24th month of therapy in 31.7 % of patients in our cohort.

    Conclusions Considering the latency of PML clinical manifestation, the presymptomatic phase length supports the usefulness of MRI surveillance every 3–4  months. Early diagnosis could prompt a better outcome for patients due to the relationship between lesion volume and JC virus infection. The insight from this study might also have an impact on risk stratification algorithms, as therapy duration as a parameter of stratification appears to need reassessment.

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    • RC and SG contributed equally.

    • Collaborators Marta Altieri; Maria Pia Amato; Carlo Alberto Artusi; Fabio Bandini; Valeria Barcella; Antonio Bertolotto; Vincenzo Brescia Morra; Marco Capobianco; Guido Cavaletti; Paola Cavalla; Diego Centonze; Maurizia Chiusole; Marinella Clerico; Cinzia Cordioli; Giangaetano D’Aleo; Giovanna De Luca; Milena De Riz; Nicola De Rossi; Luciano Deotto; Luca Durelli; Mario Falcini; Claudio Ferrante; Ernesta Ferrari; Maria Luisa Fusco; Claudio Gasperini; Angelo Ghezzi; Luigi Grimaldi; Mario Guidotti; Alice Laroni; Alessandra Lugaresi; Lucia Moiola; Paola Naldi; Chiara Pane; Barbara Palmeri; Patrizia Perrone; Matteo Pizzorno; Carlo Pozzilli; Monica Rezzonico; Maria Rosa Rottoli; Marco Rovaris; Giuseppe Salemi; Marco Salvetti; Giuseppe Santuccio; Elio Scarpini; Edoardo Sessa; Claudio Solaro; Gianola Stenta; Giulietta Tabiadon; Carla Tortorella; Maria Trojano; Paola Valentino; Maira Rosa Rottoli.

    • Contributors CS, SG and RC had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: CS, SG and RC. Acquisition, analysis or interpretation of data: all authors. Drafting of the manuscript: CS, LP and AS. Critical revision of the manuscript for important intellectual content: SG, MC, MPS and RC. Statistical analysis: AS, MPS and CS. Final approval of the version to be published: all authors.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests SC and AS have nothing to disclose. LP declares received consulting fees from Biogen and Novartis; speaker honoraria from Biogen, Genzyme, Novartis and Teva; travel grants from Biogen, Genzyme, Novartis and Teva; research grants from the Italian MS Society (Associazione Italiana Sclerosi Multipla) and Genzyme. LP also acts as member of steering committee Agenzia Italiana del Farmaco on natalizumab. RC received consulting fees from TEVA, Biogen, Merck Serono, Genzyme, Roche, GeNeuro, Novartis and Medday. MPC received speaker honoraria from Biogen. SG received speaker honoraria from Biogen and Novartis. RC received consulting fees from Novartis, Biogen and lecture fees and/or travel grants from Novartis, Biogen, Celgene, Genzyme and Sanofi-Aventis. These relationships are not related to the content in the manuscript. No other disclosures were reported.

    • Patient consent Not required.

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