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Update on PML: Lessons from the HIV uninfected and new insights in pathogenesis and treatment

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Abstract

Significant advances in our understanding of progressive multifocal leukoencephalopathy (PML) and its causative agent, JC virus, have been made since PML was first described 50 years ago. However, immune reconstitution remains the only proven, effective therapy in this devastating central nervous system disorder. Early diagnosis and adjustments of immune suppressants and modulator agents are critical in managing PML in HIV-negative patients. This review summarizes recent advances in our understanding of PML in HIV-uninfected patients in oncology, rheumatology, organ transplantation, and idiopathic immune deficiency and in association with novel therapeutics. Brain MRI data from our case series of brain biopsy-proven HIV-negative PML patients indicate the presence of an inflammatory/immune reaction in brain tissues, which was confirmed by immunocytologic analysis. Future studies to better understand PML pathogenesis in HIV-negative individuals may help uncover new potential therapeutic targets and improve PML outcomes.

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References and Recommended Reading

  1. Astrom KE, Mancall EL, Richardson EP Jr: 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. Richardson EP Jr: Progressive multifocal leukoencephalopathy. N Engl J Med 1961, 265:815–823.

    PubMed  Google Scholar 

  3. Langer-Gould A, Atlas SW, Green AJ, et al.: Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005, 353:375–381.

    Article  PubMed  CAS  Google Scholar 

  4. Kleinschmidt-DeMasters BK, Tyler KL: Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005, 353:369–374.

    Article  PubMed  CAS  Google Scholar 

  5. Van Assche G, Van Ranst M, Sciot R, et al.: Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005, 353:362–368.

    Article  PubMed  Google Scholar 

  6. Calabrese LH, Molloy ES, Huang D, Ransohoff RM: Progressive multifocal leukoencephalopathy in rheumatic diseases: evolving clinical and pathologic patterns of disease. Arthritis Rheum 2007, 56:2116–2128.

    Article  PubMed  Google Scholar 

  7. Lima MA, Koralnik IJ: New features of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy and natalizumab. J Neurovirol 2005, 11(Suppl 3):52–57.

    Article  PubMed  CAS  Google Scholar 

  8. Berger JR: Progressive multifocal leukoencephalopathy. Curr Neurol Neurosci Rep 2007, 7:461–469.

    Article  PubMed  CAS  Google Scholar 

  9. Kitchen A, Miyamoto MM, Mulligan CJ: Utility of DNA viruses for studying human host history: case study of JC virus. Mol Phylogenet Evol 2008, 46:673–682.

    Article  PubMed  CAS  Google Scholar 

  10. Zheng HY, Nishimoto Y, Chen Q, et al.: Relationships between BK virus lineages and human populations. Microbes Infect 2007, 9:204–213.

    Article  PubMed  CAS  Google Scholar 

  11. Khalili K, White MK, Lublin F, et al.: Reactivation of JC virus and development of PML in patients with multiple sclerosis. Neurology 2007, 68:985–990.

    Article  PubMed  CAS  Google Scholar 

  12. Polo C, Perez JL, Mielnichuck A, et al.: Prevalence and patterns of polyomavirus urinary excretion in immunocompetent adults and children. Clin Microbiol Infect 2004, 10:640–644.

    Article  PubMed  CAS  Google Scholar 

  13. Drachenberg CB, Hirsch HH, Papadimitriou JC, et al.: Polyomavirus BK versus JC replication and nephropathy in renal transplant recipients: a prospective evaluation. Transplantation 2007, 84:323–330.

    Article  PubMed  Google Scholar 

  14. Aksamit AJ: Review of progressive multifocal leukoencephalopathy and natalizumab. Neurologist 2006, 12:293–298.

    Article  PubMed  Google Scholar 

  15. Garcia-Suarez J, de Miguel D, Krsnik I, et al.: Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies. Am J Hematol 2005, 80:271–281.

    Article  PubMed  CAS  Google Scholar 

  16. US Food and Drug Administration: U.S. BL 103705/5230 amendment: RITUXAN® (Rituximab)—Genentech, Inc. Available at http://www.fda.gov/cder/foi/label/2006/103705s5230-s5231lbl.pdf. Accessed May 2008.

  17. Dorries K, Sbiera S, Drews K, et al.: Association of human polyomavirus JC with peripheral blood of immuno-impaired and healthy individuals. J Neurovirol 2003, 9(Suppl 1):81–87.

    Article  PubMed  Google Scholar 

  18. US Food and Drug Administration: Information for healthcare professionals: rituximab (marketed as Rituxan). Available at http://www.fda.gov/cder/drug/InfoSheets/HCP/rituximab.pdf. Accessed May 2008.

  19. Lee J, Richardson SK, Melhem ER, et al.: Progressive multifocal leukoencephalopathy from JC virus in a patient with advanced mycosis fungoides. J Am Acad Dermatol 2007, 57:893–895.

    Article  PubMed  Google Scholar 

  20. Verma S, Cikurel K, Koralnik IJ, et al.: Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera. J Infect Dis 2007, 196:709–711.

    Article  PubMed  CAS  Google Scholar 

  21. Boren EJ, Cheema GS, Naguwa SM, et al.: The emergence of progressive multifocal leukoencephalopathy (PML) in rheumatic diseases. J Autoimmun 2008, 30:90–98.

    Article  PubMed  CAS  Google Scholar 

  22. National Institute of Neurological Disorders and Stroke: NINDS progressive multifocal leukoencephalopathy information page. Available at http://www.ninds.nih.gov/disorders/pml/pml.htm. Accessed May 2008.

  23. Harris HE: Progressive multifocal leucoencephalopathy in a patient with systemic lupus erythematosus treated with rituximab. Rheumatology (Oxford) 2008, 47:224–225.

    Article  CAS  Google Scholar 

  24. Yamamoto M, Takahashi H, Wakasugi H, et al.: Leukoencephalopathy during administration of etanercept for refractory rheumatoid arthritis. Mod Rheumatol 2007, 17:72–74.

    Article  PubMed  Google Scholar 

  25. Hayashi Y, Kimura A, Kato S, et al.: Progressive multifocal leukoencephalopathy and CD4+ T-lymphocytopenia in a patient with Sjögren syndrome. J Neurol Sci 2008 (Epub 2008 Jan 29).

  26. De Raedt S, Lacor P, Michotte A, et al.: Progressive multifocal leukoencephalopathy as first manifestation of sarcoidosis. Clin Neurol Neurosurg 2008, 110:186–189.

    Article  PubMed  Google Scholar 

  27. Shitrit D, Lev N, Bar-Gil-Shitrit A, Kramer MR: Progressive multifocal leukoencephalopathy in transplant recipients. Transpl Int 2005, 17:658–665.

    Article  PubMed  Google Scholar 

  28. van de Beek D, Patel R, Daly RC, et al.: Central nervous system infections in heart transplant recipients. Arch Neurol 2007, 64:1715–1720.

    Article  PubMed  Google Scholar 

  29. Thomas LD, Vilchez RA, White ZS, et al.: A prospective longitudinal study of polyomavirus shedding in lung-transplant recipients. J Infect Dis 2007, 195:442–449.

    Article  PubMed  CAS  Google Scholar 

  30. Rossi A, Delbue S, Mazziotti R, et al.: Presence, quantitation and characterization of JC virus in the urine of Italian immunocompetent subjects. J Med Virol 2007, 79:408–412.

    Article  PubMed  Google Scholar 

  31. Kharfan-Dabaja MA, Ayala E, Greene J, et al.: Two cases of progressive multifocal leukoencephalopathy after allogeneic hematopoietic cell transplantation and a review of the literature. Bone Marrow Transplant 2007, 39:101–107.

    Article  PubMed  CAS  Google Scholar 

  32. Adelman B, Sandrock A, Panzara MA: Natalizumab and progressive multifocal leukoencephalopathy. N Engl J Med 2005, 353:432–433.

    Article  PubMed  CAS  Google Scholar 

  33. Yousry TA, Major EO, Ryschkewitsch C, et al.: Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006, 354:924–933.

    Article  PubMed  CAS  Google Scholar 

  34. Stuve O, Marra CM, Jerome KR, et al.: Immune surveillance in multiple sclerosis patients treated with natalizumab. Ann Neurol 2006, 59:743–747.

    Article  PubMed  CAS  Google Scholar 

  35. Kappos L, Bates D, Hartung HP, et al.: Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. Lancet Neurol 2007, 6:431–441.

    Article  PubMed  Google Scholar 

  36. Ransohoff RM: Natalizumab and PML. Nat Neurosci 2005, 8:1275.

    Article  PubMed  CAS  Google Scholar 

  37. Ransohoff RM: “Thinking without thinking” about natalizumab and PML. J Neurol Sci 2007, 259:50–52.

    Article  PubMed  CAS  Google Scholar 

  38. Alvarez-Lafuente R, Garcia-Montojo M, De Las Heras V, et al.: Interferon-beta treatment and active replication of the JC virus in relapsing-remitting multiple sclerosis patients. Eur J Neurol 2007, 14:233–236.

    Article  PubMed  CAS  Google Scholar 

  39. Delbue S, Guerini FR, Mancuso R, et al.: JC virus viremia in interferon-beta-treated and untreated Italian multiple sclerosis patients and healthy controls. J Neurovirol 2007, 13:73–77.

    Article  PubMed  CAS  Google Scholar 

  40. Alvarez-Lafuente R, Garcia-Montojo M, De Las Heras V, et al.: JC virus in cerebrospinal fluid samples of multiple sclerosis patients at the first demyelinating event. Mult Scler 2007, 13:590–595.

    Article  PubMed  CAS  Google Scholar 

  41. Inhoff O, Doerries K, Doerries R, et al.: Disseminated cutaneous Kaposi sarcoma and progressive multifocal leukoencephalopathy in a patient with idiopathic CD4+ T lymphocytopenia. Arch Dermatol 2007, 143:673–675.

    Article  PubMed  Google Scholar 

  42. Narula S, LaRosa DF, Kamoun M, et al.: Progressive multifocal leukoencephalopathy in a patient with common variable immunodeficiency and abnormal CD8+ T-cell subset distribution. Ann Allergy Asthma Immunol 2007, 98:483–489.

    Article  PubMed  Google Scholar 

  43. Hecht JH, Glenn OA, Wara DW, Wu YW: JC virus granule cell neuronopathy in a child with CD40 ligand deficiency. Pediatr Neurol 2007, 36:186–189.

    Article  PubMed  Google Scholar 

  44. Takeda S, Yamazaki K, Miyakawa T, et al.: A 64-year-old man presenting MRIs of expansive multiple high intensity areas in the cerebral white matter, cerebellum and brainstem. Neuropathology 2007, 27:403–405.

    Article  PubMed  Google Scholar 

  45. Chang YY, Lan MY, Peng CH, et al.: Progressive multifocal leukoencephalopathy in an immunocompetent Taiwanese patient. J Formos Med Assoc 2007, 106:S60–S64.

    Article  PubMed  Google Scholar 

  46. Lavagna A, Bergallo M, Daperno M, 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 

  47. Huang D, Cossoy M, Li M, et al.: Inflammatory progressive multifocal leukoencephalopathy in human immunodeficiency virus-negative patients. Ann Neurol 2007, 62:34–39.

    Article  PubMed  Google Scholar 

  48. Koralnik IJ: Progressive multifocal leukoencephalopathy revisited: has the disease outgrown its name? Ann Neurol 2006, 60:162–173.

    Article  PubMed  Google Scholar 

  49. Owczarczyk K, Hilker R, Brunn A, et al.: Progressive multifocal leucoencephalopathy in a patient with sarcoidosis—successful treatment with cidofovir and mirtazapine. Rheumatology (Oxford) 2007, 46:888–890.

    Article  CAS  Google Scholar 

  50. Pohlmann C, Hochauf K, Rollig C, et al.: Chlorpromazine combined with cidofovir for treatment of a patient suffering from progressive multifocal leukoencephalopathy. Intervirology 2007, 50:412–417.

    Article  PubMed  CAS  Google Scholar 

  51. Viallard JF, Lazaro E, Ellie E, et al.: Improvement of progressive multifocal leukoencephalopathy after cidofovir therapy in a patient with a destructive polyarthritis. Infection 2007, 35:33–36.

    Article  PubMed  CAS  Google Scholar 

  52. Co JK, Verma S, Gurjav U, et al.: Interferon-alpha and — beta restrict polyomavirus JC replication in primary human fetal glial cells: implications for progressive multifocal leukoencephalopathy therapy. J Infect Dis 2007, 196:712–718.

    Article  PubMed  CAS  Google Scholar 

  53. Tashiro K, Doi S, Moriwaka F, et al.: Progressive multifocal leucoencephalopathy with magnetic resonance imaging verification and therapeutic trials with interferon. J Neurol 1987, 234:427–429.

    Article  PubMed  CAS  Google Scholar 

  54. Orba Y, Sunden Y, Suzuki T, et al.: Pharmacological cdk inhibitor R-Roscovitine suppresses JC virus proliferation. Virology 2008, 370:173–183.

    Article  PubMed  CAS  Google Scholar 

  55. Radhakrishnan S, Gordon J, Del Valle L, et al.: Intracellular approach for blocking JC virus gene expression by using RNA interference during viral infection. J Virol 2004, 78:7264–7269.

    Article  PubMed  CAS  Google Scholar 

  56. Santagata S, Kinney HC: Mechanism of JCV entry into oligodendrocytes. Science 2005, 309:381–382.

    Article  PubMed  CAS  Google Scholar 

  57. Focosi D, Kast RE, Maggi F, et al.: 5-HT2a inhibitors for progressive multifocal leukoencephalopathy: old drugs for an old disease. J Infect Dis 2008, 197:328–329.

    Article  PubMed  Google Scholar 

  58. Kast RE, Focosi D, Petrini M, Altschuler EL: Treatment schedules for 5-HT2A blocking in progressive multifocal leukoencephalopathy using risperidone or ziprasidone. Bone Marrow Transplant 2007, 39:811–812.

    Article  PubMed  CAS  Google Scholar 

  59. Du Pasquier RA, Kuroda MJ, Zheng Y, et al.: A prospective study demonstrates an association between JC virus-specific cytotoxic T lymphocytes and the early control of progressive multifocal leukoencephalopathy. Brain 2004, 127:1970–1978.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology S91, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    DeRen Huang

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  1. Elizabeth A. Hartman
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  2. DeRen Huang
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Correspondence to DeRen Huang.

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Hartman, E.A., Huang, D. Update on PML: Lessons from the HIV uninfected and new insights in pathogenesis and treatment. Curr HIV/AIDS Rep 5, 112–119 (2008). https://doi.org/10.1007/s11904-008-0018-0

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