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Neurological Sciences

, Volume 40, Issue 10, pp 2119–2124 | Cite as

Four cases of natalizumab-related PML: a less severe course in extended interval dosing?

  • Cristina ScarpazzaEmail author
  • Nicola De Rossi
  • Giulietta Tabiadon
  • Maria Vittoria Turrini
  • Simonetta Gerevini
  • Ruggero CapraEmail author
Original Article

Abstract

Background

Progressive multifocal leukoencephalopathy (PML) is a severe adverse event of natalizumab (NTZ). The administration of NTZ with extended interval dosing (EID) has been proposed as a strategy to potentially reduce the incidence of PML while maintaining its therapeutic efficacy.

Methods

In the current paper, we describe 4 cases of NTZ-PML in EID included in the Italian PML cohort.

Results

The patients developed PML after at least 38 NTZ infusions. Their John Cunningham virus (JCv) index was > 1.5, and patients had not previously used immunosuppressant. Two patients were asymptomatic at PML onset, while two had mild motor impairment of the right hand and anomia, respectively. All of them had undetectable viral load but one (37 JCv copies/ml). In all patients, MRI revealed unilobar lesions with deferred contrast enhancement suggestive of immune reconstitution. The clinical course ended with a favorable clinical outcome (ΔEDSS up to 1).

Conclusions

Although PML in EID seems to occur less frequently than in conventional dosing regimen, strict monitoring of high-risk patients contributed to the indolent course observed in the four described cases, characterized by a prolonged pre-symptomatic phase, paucisymptomatic onset, low JCv load, less severe functional impairment during immune reconstitution, and a mild disability burden.

Keywords

Multiple sclerosis Progressive multifocal leukoencephalopathy Extended doses regimen Natalizumab Early diagnosis 

Notes

Authors’ contributions

Conceived the study: CS, RC. Collected the data: CS, GT, NDR, MVT. Analyzed the data: CS, SG, RC. Critically reviewed the data: GT, NDR, MVT. Drafted the manuscript: CS, RC. Critically reviewed the manuscript: GT, NDR, MVT. All the authors approved the final version of the manuscript.

Compliance with ethical standards

Ethical standards

This study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Patients provided written informed consent for the publication of data. Retrospective analysis of patients’ data was approved by the ethical committee of the Spedali Civili of Brescia.

Conflict of interest

Dr. Scarpazza, Dr. Tabiadon, and Dr. Turrini have no conflicts of interest. Dr. De Rossi received consulting fees from Biogen, Merk-Serono, and Genzyme. Dr. Gerevini declares consulting fees or honorarium from Novartis and Biogen and payment for lectures including service on speaker bureaus from Novartis and Biogen. Dr. Capra received payment for lectures from Novartis, Biogen, and Genzyme.

References

  1. 1.
    Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW, AFFIRM Investigators (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354(9):899–910CrossRefGoogle Scholar
  2. 2.
    Major EO, Yousry TA, Clifford DB (2018) Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned. Lancet Neurol 17(5):467–480CrossRefGoogle Scholar
  3. 3.
    Ho PR, Koendgen H, Campbell N, Haddock B, Richman S, Chang I (2017) Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol 16(11):925–933CrossRefGoogle Scholar
  4. 4.
    van Kempen ZL, Leurs CE, Witte BI, de Vries A, Wattjes MP, Rispens T, Killestein J (2018) The majority of natalizumab-treated MS patients have high natalizumab concentrations at time of re-dosing. Mult Scler 24(6):805–810CrossRefGoogle Scholar
  5. 5.
    Zhovtis Ryerson L, Frohman TC, Foley J, Kister I, Weinstock-Guttman B, Tornatore C, Pandey K, Donnelly S, Pawate S, Bomprezzi R, Smith D, Kolb C, Qureshi S, Okuda D, Kalina J, Rimler Z, Green R, Monson N, Hoyt T, Bradshaw M, Fallon J, Chamot E, Bucello M, Beh S, Cutter G, Major E, Herbert J, Frohman EM (2016) Extended interval dosing of natalizumab in multiple sclerosis. J Neurol Neurosurg Psychiatry 87(8):885–889CrossRefGoogle Scholar
  6. 6.
    Zhovtis Ryerson L et al. (2018) Natalizumab extended interval dosing is associated with a reduction in progressive multifocal leukoencephalopathy risk in the TOUCH registry. ACTRIMS Forum 2018, Oral and Poster Presentation.Google Scholar
  7. 7.
    Hervas JV et al (2015) Progressive multifocal leukoencephalopathy associated to natalizumab extended dosing regimen. Neurodegener Dis Manag 5(5):399–402CrossRefGoogle Scholar
  8. 8.
    Bomprezzi R, Pawate S (2014) Extended interval dosing of natalizumab: a two-center, 7-year experience. Ther Adv Neurol Disord 7(5):227–231CrossRefGoogle Scholar
  9. 9.
    Baldassari LE, Jones SE, Clifford DB, Fox RJ (2018) Progressive multifocal leukoencephalopathy with extended natalizumab dosing. Neurol Clin Pract 8(3):1–3CrossRefGoogle Scholar
  10. 10.
    Prosperini L, de Rossi N, Scarpazza C, Moiola L, Cosottini M, Gerevini S, Capra R, on behalf of the Italian PML study group (2016) Natalizumab-related progressive multifocal leukoencephalopathy in multiple sclerosis: findings from an Italian independent registry. PLoS One 11(12):e0168376CrossRefGoogle Scholar
  11. 11.
    Gagnier JJ et al (2013) The CARE guidelines: consensus-based clinical case reporting guideline development. BMJ Case Rep 2(5):38–43Google Scholar
  12. 12.
    Scarpazza C et al (2017) The still under-investigated role of cognitive deficits in PML diagnosis. MS Demyel Disord 2(2):1–9Google Scholar
  13. 13.
    Dong-Si T, Richman S, Wattjes MP, Wenten M, Gheuens S, Philip J, Datta S, McIninch J, Bozic C, Bloomgren G, Richert N (2014) Outcome and survival of asymptomatic PML in natalizumab-treated MS patients. Ann Clin Transl Neurol 1(10):755–764CrossRefGoogle Scholar
  14. 14.
    Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, Bartt R, Major EO, Nath A (2013) PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology 80(15):1430–1438CrossRefGoogle Scholar
  15. 15.
    Wijburg MT, Kleerekooper I, Lissenberg-Witte BI, de Vos M, Warnke C, Uitdehaag BMJ, Barkhof F, Killestein J, Wattjes MP (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. JAMA Neurol 75:827–833CrossRefGoogle Scholar
  16. 16.
    Wijburg MT et al (2019) Performance of PML diagnostic criteria in natalizumab-associated PML: data from the Dutch-Belgian cohort. J Neurol Neurosurg Psychiatry 90(1):44–46Google Scholar
  17. 17.
    Scarpazza C, Prosperini L, de Rossi N, Moiola L, Sormani MP, Gerevini S, Capra R, on behalf of the Italian PML group (2017) To do or not to do? Plasma exchange and timing of steroid administration in progressive multifocal leukoencephalopathy. Ann Neurol 82(5):697–705CrossRefGoogle Scholar
  18. 18.
    Wattjes MP, Wijburg MT, van Eijk J, Frequin S, Uitdehaag BMJ, Barkhof F, Warnke C, Killestein J (2018) Inflammatory natalizumab-associated PML: baseline characteristics, lesion evolution and relation with PML-IRIS. J Neurol Neurosurg Psychiatry 89(5):535–541CrossRefGoogle Scholar
  19. 19.
    McGuigan C et al (2016) Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. J Neurol Neurosurg Psychiatry 87(2):117–125Google Scholar
  20. 20.
    Scarpazza C, Signori A, Prosperini L, Sormani MP, Cosottini M, Capra R, Gerevini S (2019) Early diagnosis of progressive multifocal leucoencephalopathy: longitudinal lesion evolution. J Neurol Neurosurg Psychiatry 90(3):261–267CrossRefGoogle Scholar
  21. 21.
    Landi D, de Rossi N, Zagaglia S, Scarpazza C, Prosperini L, Albanese M, Buttari F, Mori F, Marfia GA, Sormani MP, Capra R, Centonze D, Italian PML study group (2017) No evidence of beneficial effects of plasmapheresis in natalizumab-associated PML. Neurology 88(12):1144–1152CrossRefGoogle Scholar
  22. 22.
    Hauser SL, Belachew S, Kappos L (2017) Ocrelizumab in primary progressive and relapsing multiple sclerosis. N Engl J Med 376(17):1694Google Scholar
  23. 23.
    Sellner J, Rommer PS (2019) A review of the evidence for a natalizumab exit strategy for patients with multiple sclerosis. Autoimmun Rev 18(3):255–261CrossRefGoogle Scholar
  24. 24.
    Pardo G, Jones DE (2017) The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations. J Neurol 264(12):2351–2374CrossRefGoogle Scholar

Copyright information

© Fondazione Società Italiana di Neurologia 2019

Authors and Affiliations

  1. 1.Regional Multiple Sclerosis CenterASST - Spedali Civili di BresciaMontichiariItaly
  2. 2.Department of General PsychologyUniversity of PadovaPadovaItaly
  3. 3.Department of NeurologyRegional General HospitalBolzanoItaly
  4. 4.Department of Neuroradiology, San Raffaele Scientific InstituteVita-Salute San Raffaele UniversityMilanItaly

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