Skip to main content

Advertisement

SpringerLink
Log in

Progressive Multifocal Leukoencephalopathy in Primary Immunodeficiencies

  • Original Article
  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Purpose

Progressive multifocal leukoencephalopathy (PML) is a rare but severe demyelinating disease caused by the polyomavirus JC (JCV) in immunocompromised patients. We report a series of patients with primary immune deficiencies (PIDs) who developed PML.

Methods

Retrospective observational study including PID patients with PML. Clinical, immunological, imaging features, and outcome are provided for each patient.

Results

Eleven unrelated patients with PIDs developed PML. PIDs were characterized by a wide range of syndromic or genetically defined defects, mostly with combined B and T cell impairment. Genetic diagnosis was made in 7 patients. Before the development of PML, 10 patients had recurrent infections, 7 had autoimmune and/or inflammatory manifestations, and 3 had a history of malignancies. Immunologic investigations showed CD4+ lymphopenia (median 265, range 50–344) in all cases. Six patients received immunosuppressive therapy in the year before PML onset, including prolonged steroid therapy in 3 cases, rituximab in 5 cases, anti-TNF-α therapy, and azathioprine in 1 case each. Despite various treatments, all but 1 patient died after a median of 8 months following PML diagnosis.

Conclusion

PML is a rare but fatal complication of PIDs. Many cases are secondary to immunosuppressive therapy warranting careful evaluation before initiation subsequent immunosuppression during PIDs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

PID:

Primary immune deficiency

PML:

Progressive multifocal leukoencephalopathy

JCV:

Polyomavirus JC

PCR:

Polymerase chain reaction

CSF:

Cerebrospinal fluid

MRI:

Magnetic resonance imaging

CID:

Combined immunodeficiencies

CVID:

Common variable immunodeficiency

HSCT:

Hematopoietic stem cell transplantation

References

  1. Ferenczy MW, Marshall LJ, Nelson CDS, Atwood WJ, Nath A, Khalili K, et al. Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev. 2012;25:471–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Berger JR, Aksamit AJ, Clifford DB, Davis L, Koralnik IJ, Sejvar JJ, et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology. 2013;80:1430–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Fischer A, Provot J, Jais J-P, Alcais A, Mahlaoui N, Members of the CEREDIH French PID study group. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2017;140:1388–1393.e8.

    Article  CAS  PubMed  Google Scholar 

  4. Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova J-L, Chatila T, et al. International Union of Immunological Societies: 2017 primary immunodeficiency diseases committee report on inborn errors of immunity. J Clin Immunol. 2018;38:96–128.

    Article  PubMed  Google Scholar 

  5. Pérez de Diego R, Sancho-Shimizu V, Lorenzo L, Puel A, Plancoulaine S, Picard C, et al. Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis. Immunity. 2010;33:400–11.

    Article  CAS  PubMed  Google Scholar 

  6. Zerbe CS, Marciano BE, Katial RK, Santos CB, Adamo N, Hsu AP, et al. Progressive multifocal leukoencephalopathy in primary immune deficiencies: Stat1 gain of function and review of the literature. Clin Infect Dis Off Publ Infect Dis Soc Am. 2016;62:986–94.

    Article  CAS  Google Scholar 

  7. Haider S, Nafziger D, Gutierrez JA, Brar I, Mateo N, Fogle J. Progressive multifocal leukoencephalopathy and idiopathic CD4+lymphocytopenia: a case report and review of reported cases. Clin Infect Dis Off Publ Infect Dis Soc Am. 2000;31:E20–2.

    Article  CAS  Google Scholar 

  8. Rueger MA, Miletic H, Dorries K, Wyen C, Eggers C, Deckert M, et al. Long-term remission in progressive multifocal leukoencephalopathy caused by idiopathic CD4+ T lymphocytopenia: a case report. Clin Infect Dis Off Publ Infect Dis Soc Am. 2006;42:e53–6.

    Article  CAS  Google Scholar 

  9. Patel A, Patel J, Ikwuagwu J. Treatment of progressive multifocal leukoencephalopathy and idiopathic CD4+ lymphocytopenia. J Antimicrob Chemother. 2010;65:2489–92.

    Article  CAS  PubMed  Google Scholar 

  10. Al Shekaili L, Sheikh F, Al Gazlan S, Al Dhekri H, Al Mousa H, Al Ghonaium A, et al. Novel mutation in DOCK8-HIES with severe phenotype and successful transplantation. Clin Immunol Orlando Fla. 2017;178:39–44.

    Article  CAS  Google Scholar 

  11. Aschermann Z, Gomori E, Kovacs GG, Pal E, Simon G, Komoly S, et al. X-linked hyper-IgM syndrome associated with a rapid course of multifocal leukoencephalopathy. Arch Neurol. 2007;64:273–6.

    Article  PubMed  Google Scholar 

  12. Dhalla F, Murray S, Sadler R, Chaigne-Delalande B, Sadaoka T, Soilleux E, et al. Identification of a novel mutation in MAGT1 and progressive multifocal leucoencephalopathy in a 58-year-old man with XMEN disease. J Clin Immunol. 2015;35:112–8.

    Article  PubMed  Google Scholar 

  13. Schröder C, Baerlecken NT, Pannicke U, Dörk T, Witte T, Jacobs R, et al. Evaluation of RAG1 mutations in an adult with combined immunodeficiency and progressive multifocal leukoencephalopathy. Clin Immunol Orlando Fla. 2017;179:1–7.

    Article  CAS  Google Scholar 

  14. Maffucci P, Filion CA, Boisson B, Itan Y, Shang L, Casanova J-L, et al. Genetic diagnosis using whole exome sequencing in common variable immunodeficiency. Front Immunol. 2016;7:220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. de Villartay J-P, Lim A, Al-Mousa H, Dupont S, Déchanet-Merville J, Coumau-Gatbois E, et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest. 2005;115:3291–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Morelon E, Dautry-Varsat A, Le Deist F, Hacein-Bay S, Fischer A, de Saint Basile G. T-lymphocyte differentiation and proliferation in the absence of the cytoplasmic tail of the common cytokine receptor gamma c chain in a severe combined immune deficiency X1 patient. Blood. 1996;88:1708–17.

    CAS  PubMed  Google Scholar 

  17. Bozic C, Subramanyam M, Richman S, Plavina T, Zhang A, Ticho B. Anti-JC virus (JCV) antibody prevalence in the JCV epidemiology in MS (JEMS) trial. Eur J Neurol. 2014;21:299–304.

    Article  CAS  PubMed  Google Scholar 

  18. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870–80.

    Article  CAS  PubMed  Google Scholar 

  19. Amend KL, Turnbull B, Foskett N, Napalkov P, Kurth T, Seeger J. Incidence of progressive multifocal leukoencephalopathy in patients without HIV. Neurology. 2010;75:1326–32.

    Article  CAS  PubMed  Google Scholar 

  20. Power C, Gladden JG, Halliday W, Del Bigio MR, Nath A, Ni W, et al. AIDS- and non-AIDS-related PML association with distinct p53 polymorphism. Neurology. 2000;54:743–6.

    Article  CAS  PubMed  Google Scholar 

  21. Engsig FN, Hansen A-BE, Omland LH, Kronborg G, Gerstoft J, Laursen AL, et al. Incidence, clinical presentation, and outcome of progressive multifocal leukoencephalopathy in HIV-infected patients during the highly active antiretroviral therapy era: a nationwide cohort study. J Infect Dis. 2009;199:77–83.

    Article  PubMed  Google Scholar 

  22. Gobert D, Bussel JB, Cunningham-Rundles C, Galicier L, Dechartres A, Berezne A, et al. Efficacy and safety of rituximab in common variable immunodeficiency-associated immune cytopenias: a retrospective multicentre study on 33 patients. Br J Haematol. 2011;155:498–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Moshous D, Meyts I, Fraitag S, Janssen CEI, Debré M, Suarez F, et al. Granulomatous inflammation in cartilage-hair hypoplasia: risks and benefits of anti-TNF-α mAbs. J Allergy Clin Immunol. 2011;128:847–53.

    Article  CAS  PubMed  Google Scholar 

  24. Berger JR. Classifying PML risk with disease modifying therapies. Mult Scler Relat Disord. 2017;12:59–63.

    Article  PubMed  Google Scholar 

  25. Tuccori M, Focosi D, Blandizzi C, Del Tacca M, Petrini M. Re: rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst. 2009;101:1288–9 author reply 1289-1290.

    Article  CAS  PubMed  Google Scholar 

  26. Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood. 2009;113:4834–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies. Arthritis Rheum. 2012;64:3043–51.

    Article  CAS  PubMed  Google Scholar 

  28. Berger JR, Malik V, Lacey S, Brunetta P, Lehane PB. Progressive multifocal leukoencephalopathy in rituximab-treated rheumatic diseases: a rare event. J Neuro-Oncol. 2018;24:323–31.

    CAS  Google Scholar 

  29. Lavagna A, Bergallo M, Daperno M, Sostegni R, Costa C, Leto R, et al. Infliximab and the risk of latent viruses reactivation in active Crohn’s disease. Inflamm Bowel Dis. 2007;13:896–902.

    Article  PubMed  Google Scholar 

  30. Jamilloux Y, Cohen-Aubart F, Chapelon-Abric C, Maucort-Boulch D, Marquet A, Pérard L, et al. Efficacy and safety of tumor necrosis factor antagonists in refractory sarcoidosis: a multicenter study of 132 patients. Semin Arthritis Rheum. 2017;47:288–94.

    Article  CAS  PubMed  Google Scholar 

  31. Schmedt N, Andersohn F, Garbe E. Signals of progressive multifocal leukoencephalopathy for immunosuppressants: a disproportionality analysis of spontaneous reports within the US Adverse Event Reporting System (AERS). Pharmacoepidemiol Drug Saf. 2012;21:1216–20.

    Article  CAS  PubMed  Google Scholar 

  32. McGuigan C, Craner M, Guadagno J, Kapoor R, Mazibrada G, Molyneux P, et al. Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group. J Neurol Neurosurg Psychiatry. 2016;87:117–25.

    Article  CAS  PubMed  Google Scholar 

  33. Laroni A, Giacomazzi CG, Grimaldi L, Gallo P, Sormani MP, Bertolotto A, et al. Urinary JCV-DNA testing during natalizumab treatment may increase accuracy of PML risk stratification. J Neuroimmune Pharmacol Off J Soc NeuroImmune Pharmacol. 2012;7:665–72.

    Article  CAS  Google Scholar 

  34. Viscidi RP, Khanna N, Tan CS, Li X, Jacobson L, Clifford DB, et al. JC virus antibody and viremia as predictors of progressive multifocal leukoencephalopathy in human immunodeficiency virus-1-infected individuals. Clin Infect Dis Off Publ Infect Dis Soc Am. 2011;53:711–5.

    Article  CAS  Google Scholar 

  35. Sahraian MA, Radue E-W, Eshaghi A, Besliu S, Minagar A. Progressive multifocal leukoencephalopathy: a review of the neuroimaging features and differential diagnosis. Eur J Neurol. 2012;19:1060–9.

    Article  CAS  PubMed  Google Scholar 

  36. Wattjes MP, Vennegoor A, Steenwijk MD, de Vos M, Killestein J, van Oosten BW, et al. MRI pattern in asymptomatic natalizumab-associated PML. J Neurol Neurosurg Psychiatry. 2015;86:793–8.

    Article  PubMed  Google Scholar 

  37. Clifford DB, De Luca A, DeLuca A, Simpson DM, Arendt G, Giovannoni G, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 2010;9:438–46.

    Article  CAS  PubMed  Google Scholar 

  38. Balduzzi A, Lucchini G, Hirsch HH, Basso S, Cioni M, Rovelli A, et al. Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient. Bone Marrow Transplant. 2011;46:987–92.

    Article  CAS  PubMed  Google Scholar 

  39. Kunschner L, Scott TF. Sustained recovery of progressive multifocal leukoencephalopathy after treatment with IL-2. Neurology. 2005;65:1510.

    Article  PubMed  Google Scholar 

  40. Alstadhaug KB, Croughs T, Henriksen S, Leboeuf C, Sereti I, Hirsch HH, et al. Treatment of progressive multifocal leukoencephalopathy with interleukin 7. JAMA Neurol. 2014;71:1030–5.

    Article  PubMed  Google Scholar 

  41. Gasnault J, de Goër de Herve M-G, Michot J-M, Hendel-Chavez H, Seta V, Mazet A-A, et al. Efficacy of recombinant human interleukin 7 in a patient with severe lymphopenia-related progressive multifocal leukoencephalopathy. Open Forum Infect Dis. 2014;1:ofu074.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Pavlovic D, Patera AC, Nyberg F, Gerber M, Liu M. Progressive multifocal leukoencephalopathy: current treatment options and future perspectives. Ther Adv Neurol Disord. 2015;8:255–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Haematology, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, France et Université Paris Descartes, 149 rue de Sèvres, 75015, Paris, France

    Jérôme Hadjadj, Olivier Hermine & Felipe Suarez

  2. Department of Clinical Immunology and Internal Medicine, National Reference Center for Autoimmune diseases, Hôpitaux Universitaires de Strasbourg, Strasbourg, France

    Aurélien Guffroy

  3. Department of Adult Radiology, Necker Hospital, Paris, France

    Christophe Delavaud

  4. Department of Neurology, CHU Montpellier, Hôpital Guy de Chauliac, Montpellier, France

    Guillaume Taieb

  5. Department of Microbiology and Immunology, Childhood Immunology, KU Leuven, Leuven, Belgium

    Isabelle Meyts

  6. Department of Pediatrics, University Hospitals Leuven, Leuven, Belgium

    Isabelle Meyts

  7. Department of Infectious Diseases, CHU Saint-Etienne, Saint-Etienne, France

    Anne Fresard

  8. Department of Pathology - Université Claude Bernard Lyon1 - Institut NeuroMyogène CNRS UMR 5310 - INSERM U1217, Hospices Civils de Lyon, Lyon, France

    Nathalie Streichenberger

  9. Department of Virology, Université Paris Descartes et Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France

    Anne-Sophie L’Honneur & Flore Rozenberg

  10. Department of Hematology, University Hospital, Nancy, France

    Maud D’Aveni

  11. Sorbonne Paris Cité, Necker Pasteur Center for Infectious Diseases and Tropical Medicine, APHP-Hôpital Necker-Enfants Malades, IHU Imagine, Université Paris Descartes, Paris, France

    Claire Aguilar, Marc Lecuit & Olivier Lortholary

  12. Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Hôpital Universitaire Necker-Enfants Malades, Paris Descartes University, Paris, France

    Claire Aguilar, Nizar Mahlaoui, Olivier Hermine, Olivier Lortholary & Felipe Suarez

  13. Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, Assistance Publique Hôpitaux de Paris (APHP), Necker Medical School, Paris, France

    Jérémie Rosain & Capucine Picard

  14. INSERM U1163 & CNRS ERL 8254, Institut Imagine, Sorbonne Paris Cité, Paris, France

    Capucine Picard, Olivier Hermine & Felipe Suarez

  15. Pediatric Immuno-Haematology and Rheumatology Unit, Necker-Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France

    Capucine Picard & Nizar Mahlaoui

Authors
  1. Jérôme Hadjadj
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aurélien Guffroy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Christophe Delavaud
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guillaume Taieb
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Isabelle Meyts
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Anne Fresard
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nathalie Streichenberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anne-Sophie L’Honneur
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Flore Rozenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Maud D’Aveni
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Claire Aguilar
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jérémie Rosain
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Capucine Picard
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Nizar Mahlaoui
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Marc Lecuit
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Olivier Hermine
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Olivier Lortholary
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Felipe Suarez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Felipe Suarez.

Ethics declarations

This retrospective data collection was conducted according to the Helsinki Declaration and informed consent was obtained from the patients or their relatives.

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hadjadj, J., Guffroy, A., Delavaud, C. et al. Progressive Multifocal Leukoencephalopathy in Primary Immunodeficiencies. J Clin Immunol 39, 55–64 (2019). https://doi.org/10.1007/s10875-018-0578-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-018-0578-8

Keywords

Search

Navigation