Skip to main content

Advertisement

SpringerLink
Log in

The Changing Landscape of Progressive Multifocal Leukoencephalopathy

  • Published:
Current Infectious Disease Reports Aims and scope Submit manuscript

Abstract

Progressive multifocal leukoencephalopathy (PML) is a rare but devastating neurologic disease that affects the immunosuppressed population. The etiologic agent is a polyomavirus, JC virus—a double-stranded DNA virus with a high prevalence of infection globally. PML is believed to occur from reactivation of the latent virus infection caused by immunosuppression. After 1980, a dramatic increase in the incidence and prevalence of PML was attributed to the HIV/AIDS pandemic, with a decline noted after the introduction of highly active antiretroviral treatment (HAART). Newer populations are being added to the risk pool for the development of PML with the introduction of biologic agents that target specific arms of the immune system. Natalizumab and efalizumab seem to have the highest risk for the development of PML, although PML can develop with the other biologic agents. As more patients are treated with these agents, effective risk mitigation strategies are needed to prevent PML.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Astrom KE, Mancall EL, Richardson Jr EP. Progressive multifocal leuko-encephalopathy; a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin’s disease. Brain. 1958;81:93–111.

    Article  PubMed  CAS  Google Scholar 

  2. Padgett BL, Walker DL, ZuRhein GM, et al. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet. 1971;1(7712):1257–60.

    Article  PubMed  CAS  Google Scholar 

  3. Dorries K. Progressive multifocal leucoencephalopathy: analysis of JC virus DNA from brain and kidney tissue. Virus Res. 1984;1:25–38.

    Article  PubMed  CAS  Google Scholar 

  4. Monaco MC, Jensen PN, Hou J, et al. Detection of JC virus DNA in human tonsil tissue: evidence for site of initial viral infection. J Virol. 1998;72:9918–23.

    PubMed  CAS  Google Scholar 

  5. Berger JR, Miller CS, Mootoor Y, et al. JC virus detection in bodily fluids: clues to transmission. Clin Infect Dis. 2006;43:e9–12.

    Article  PubMed  Google Scholar 

  6. Taguchi F, Kajioka J, Miyamura T. Prevalence rate and age of acquisition of antibodies against JC virus and BK virus in human sera. Microbiol Immunol. 1982;26:1057–64.

    PubMed  CAS  Google Scholar 

  7. Walker D, Padgett B. The epidemiology of human polyomaviruses. In: Sever J, Madden D, editors. Polyomaviruses and human neurological disease. New York: Alan R. Liss; 1983. p. 99–106.

    Google Scholar 

  8. Walker D, Padgett B. Progressive multifocal leukoencephalopathy. In: Fraenkel-Conrat H, Wagner R, editors. Comprehensive virology. New York: Plenum; 1983. p. 161–93.

    Google Scholar 

  9. Knowles WA, Pipkin P, Andrews N, et al. Population-based study of antibody to the human polyomaviruses BKV and JCV and the simian polyomavirus SV40. J Med Virol. 2003;71:115–23.

    Article  PubMed  Google Scholar 

  10. Matos A, Duque V, Beato S, et al. Characterization of JC human polyomavirus infection in a Portuguese population. J Med Virol. 2010;82:494–504.

    Article  PubMed  CAS  Google Scholar 

  11. Wickham S, Lu B, Ash J, Carr DJ. Chemokine receptor deficiency is associated with increased chemokine expression in the peripheral and central nervous systems and increased resistance to herpetic encephalitis. J Neuroimmunol. 2005;162:51–9.

    Article  PubMed  CAS  Google Scholar 

  12. Solomon T, Winter PM. Neurovirulence and host factors in flavivirus encephalitis—evidence from clinical epidemiology. Arch Virol Suppl. 2004;18:161–70.

    PubMed  Google Scholar 

  13. Weber F, Goldmann C, Kramer M, et al. Cellular and humoral immune response in progressive multifocal leukoencephalopathy. Ann Neurol. 2001;49:636–42.

    Article  PubMed  CAS  Google Scholar 

  14. Padgett BL, Walker DL. Prevalence of antibodies in human sera against JC virus, an isolate from a case of progressive multifocal leukoencephalopathy. J Infect Dis. 1973;127:467–70.

    Article  PubMed  CAS  Google Scholar 

  15. Berger JR, Scott G, Albrecht J, et al. Progressive multifocal leukoencephalopathy in HIV-1-infected children. AIDS. 1992;6:837–41.

    Article  PubMed  CAS  Google Scholar 

  16. • Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol. 2010;68:295–303. These authors describe the utility of a two-step assay for identifying patients at risk for developing PML based on the presence of antibodies to the JC virus.

    Article  PubMed  Google Scholar 

  17. Brooks BR, Walker DL. Progressive multifocal leukoencephalopathy. Neurol Clin. 1984;2:299–313.

    PubMed  CAS  Google Scholar 

  18. Berger JR, Pall L, Lanska D, Whiteman M. Progressive multifocal leukoencephalopathy in patients with HIV infection. J Neurovirol. 1998;4:59–68.

    Article  PubMed  CAS  Google Scholar 

  19. Selik RM, Karon JM, Ward JW. Effect of the human immunodeficiency virus epidemic on mortality from opportunistic infections in the United States in 1993. J Infect Dis. 1997;176:632–6.

    Article  PubMed  CAS  Google Scholar 

  20. Miller JR, Barrett RE, Britton CB, et al. Progressive multifocal leukoencephalopathy in a male homosexual with T- cell immune deficiency. N Engl J Med. 1982;307:1436–8.

    Article  PubMed  CAS  Google Scholar 

  21. Krupp LB, Lipton RB, Swerdlow ML, et al. Progressive multifocal leukoencephalopathy: clinical and radiographic features. Ann Neurol. 1985;17:344–9.

    Article  PubMed  CAS  Google Scholar 

  22. Berger JR, Kaszovitz B, Post MJ, Dickinson G. Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. A review of the literature with a report of sixteen cases. Ann Intern Med. 1987;107:78–87.

    PubMed  CAS  Google Scholar 

  23. Kure K, Llena JF, Lyman WD, et al. Human immunodeficiency virus-1 infection of the nervous system: an autopsy study of 268 adult, pediatric, and fetal brains. Hum Pathol. 1991;22:700–10.

    Article  PubMed  CAS  Google Scholar 

  24. Lang W, Miklossy J, Deruaz JP, et al. Neuropathology of the acquired immune deficiency syndrome (AIDS): a report of 135 consecutive autopsy cases from Switzerland. Acta Neuropathol. 1989;77:379–90.

    Article  PubMed  CAS  Google Scholar 

  25. Kuchelmeister K, Gullotta F, Bergmann M, et al. Progressive multifocal leukoencephalopathy (PML) in the acquired immunodeficiency syndrome (AIDS). A neuropathological autopsy study of 21 cases. Pathol Res Pract. 1993;189:163–73.

    PubMed  CAS  Google Scholar 

  26. Bacellar H, Munoz A, Miller EN, et al. Temporal trends in the incidence of HIV-1-related neurologic diseases: multicenter AIDS Cohort Study, 1985–1992. Neurology. 1994;44:1892–900.

    PubMed  CAS  Google Scholar 

  27. Berger JR. Progressive multifocal leukoencephalopathy in acquired immunodeficiency syndrome: explaining the high incidence and disproportionate frequency of the illness relative to other immunosuppressive conditions. J Neurovirol. 2003;9 Suppl 1:38–41.

    PubMed  CAS  Google Scholar 

  28. Singer C, Berger JR, Bowen BC, et al. Akinetic-rigid syndrome in a 13-year-old girl with HIV-related progressive multifocal leukoencephalopathy. Mov Disord. 1993;8:113–6.

    Article  PubMed  CAS  Google Scholar 

  29. Morriss MC, Rutstein RM, Rudy B, et al. Progressive multifocal leukoencephalopathy in an HIV-infected child. Neuroradiology. 1997;39:142–4.

    Article  PubMed  CAS  Google Scholar 

  30. Shankar SK, Satishchandra P, Mahadevan A, et al. Low prevalence of progressive multifocal leukoencephalopathy in India and Africa: is there a biological explanation. J Neurovirol. 2003;9 Suppl 1:59–67.

    PubMed  CAS  Google Scholar 

  31. Engsig FN, Hansen AB, Omland LH, 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 

  32. Christensen KL, Holman RC, Hammett TA, et al. Progressive multifocal leukoencephalopathy deaths in the USA, 1979–2005. Neuroepidemiology. 2010;35:178–84.

    Article  PubMed  Google Scholar 

  33. Amend KL, Turnbull B, Foskett N, et al. Incidence of progressive multifocal leukoencephalopathy in patients without HIV. Neurology. 2010;75:1326–32.

    Article  PubMed  CAS  Google Scholar 

  34. Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy: a national estimate of frequency in systemic lupus erythematosus and other rheumatic diseases. Arthritis Rheum. 2009;60:3761–5.

    Article  PubMed  Google Scholar 

  35. • Clifford DB, De Luca A, Simpson DM, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 2010;9:438–46. This is an excellent publication describing clinical and radiologic features of PML as well as potential risk-mitigation strategies for the development of PML in patients treated with natalizumab.

    Article  PubMed  CAS  Google Scholar 

  36. Kappos L, Bates D, Hartung H-P, et al. Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. Lancet Neurol. 2007;6:431–41.

    Article  PubMed  Google Scholar 

  37. Berger JR, Koralnik IJ. Progressive multifocal leukoencephalopathy and natalizumab–unforeseen consequences. N Engl J Med. 2005;353:414–6.

    Article  PubMed  CAS  Google Scholar 

  38. Berger JR, Houff SA, Major EO. Monoclonal antibodies and progressive multifocal leukoencephalopathy. MAbs. 2009;1:583–9.

    Article  PubMed  Google Scholar 

  39. Major EO. Reemergence of PML in natalizumab-treated patients–new cases, same concerns. N Engl J Med. 2009;361:1041–3.

    Article  PubMed  CAS  Google Scholar 

  40. Lebwohl M, Tyring SK, Hamilton TK, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med. 2003;349:2004–13.

    Article  PubMed  CAS  Google Scholar 

  41. Carson KR, Evens AM, Richey EA, 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  PubMed  CAS  Google Scholar 

  42. Vincenti F, Larsen C, Durrbach A, et al. Costimulation blockade with belatacept in renal transplantation. N Engl J Med. 2005;353:770–81.

    Article  PubMed  CAS  Google Scholar 

  43. FDA’s Cardiovascular and Renal Drugs Advisory Committee: Briefing Document for March 2010 Meeting. Belatacept (BMS-224818). BLA 125288. January 25, 2010. Available at http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ucm201859.pdf.

  44. Gallamini A, Zaja F, Patti C, et al. Alemtuzumab (Campath-1H) and CHOP chemotherapy as first-line treatment of peripheral T-cell lymphoma: results of a GITIL (Gruppo Italiano Terapie Innovative nei Linfomi) prospective multicenter trial. Blood. 2007;110:2316–23.

    Article  PubMed  CAS  Google Scholar 

  45. Martin SI, Marty FM, Fiumara K, et al. Infectious complications associated with alemtuzumab use for lymphoproliferative disorders. Clin Infect Dis. 2006;43:16–24.

    Article  PubMed  CAS  Google Scholar 

  46. Fox EJ. Alemtuzumab in the treatment of relapsing-remitting multiple sclerosis. Expert Rev Neurother. 2010;10:1789–97.

    Article  PubMed  CAS  Google Scholar 

  47. • Berger JR. Progressive multifocal leukoencephalopathy and newer biological agents. Drug Saf. 2010;33:969–83. This review article describes the risks of PML with newer biologic agents, as well as potential risk-mitigation strategies.

    Article  PubMed  CAS  Google Scholar 

  48. Neff RT, Hurst FP, Falta EM, et al. Progressive multifocal leukoencephalopathy and use of mycophenolate mofetil after kidney transplantation. Transplantation. 2008;86:1474–8.

    Article  PubMed  Google Scholar 

  49. Egli A, Infanti L, Dumoulin A, et al. Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis. 2009;199:837–46.

    Article  PubMed  CAS  Google Scholar 

  50. Elphick GF, Querbes W, Jordan JA, et al. The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science. 2004;306:1380–3.

    Article  PubMed  CAS  Google Scholar 

  51. Nukuzuma S, Nakamichi K, Nukuzuma C, Takegami T. Inhibitory effect of serotonin antagonists on JC virus propagation in a carrier culture of human neuroblastoma cells. Microbiol Immunol. 2009;53:496–501.

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosure

Conflicts of Interest: S. Kedar: none; J. Berger: consultancy for Bayer, Biogen Idec, Eisai, Pfizer, Genentech, Perseid, Millennium, and GlaxoSmithKline; honoraria from Bayer, Biogen, EMD Serono, Teva, Millennium, Pfizer, Eisai, and Perseid.

Author information

Authors and Affiliations

  1. Department of Neurology, University of Kentucky College of Medicine, 740 S. Limestone St., Lexington, KY, 40515, USA

    Sachin Kedar & Joseph R. Berger

Authors
  1. Sachin Kedar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joseph R. Berger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Joseph R. Berger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kedar, S., Berger, J.R. The Changing Landscape of Progressive Multifocal Leukoencephalopathy. Curr Infect Dis Rep 13, 380–386 (2011). https://doi.org/10.1007/s11908-011-0196-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11908-011-0196-6

Keywords

Search

Navigation