Current Neurology and Neuroscience Reports

, Volume 7, Issue 6, pp 461–469 | Cite as

Progressive multifocal leukoencephalopathy



Progressive multifocal leukoencephalopathy (PML) was a rare disease until the advent of the HIV/AIDS pandemic. Recent interest in the disorder has been spurred by its appearance in patients treated with the monoclonal antibodies natalizumab and rituximab. Unless the accompanying underlying immune deficit can be reversed, PML typically progresses to death fairly rapidly. Treatment directed against the JC virus has been unhelpful, but an increased understanding of disease pathogenesis may result in effective therapeutic strategies.


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References and Recommended Reading

  1. 1.
    Berger JR, Koralnik IJ: Progressive multifocal leukoencephalopathy and natalizumab—unforeseen consequences. N Engl J Med 2005, 353:414–416.PubMedCrossRefGoogle Scholar
  2. 2.
    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.PubMedCrossRefGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 4.
    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.PubMedCrossRefGoogle Scholar
  5. 5.
    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.PubMedCrossRefGoogle Scholar
  6. 6.
    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, 176:632–636.PubMedCrossRefGoogle Scholar
  7. 7.
    Cavanagh JB, Greenbaum D, Marshall AH, Rubinstein LJ: Cerebral dymyelination associated with disorders of the reticuloendothelial system. Lancet 1959, 2:524–529.PubMedCrossRefGoogle Scholar
  8. 8.
    Silverman L, Rubinstein LJ: Electron microscopic observations on a case of progressive multifocal leukoencephalopathy. Acta Neuropathol (Berl) 1965, 5:215–224.CrossRefGoogle Scholar
  9. 9.
    ZuRhein G: Particles resembling papovavirions in human cerebral demyelinating disease. Science 1965, 148:1477–1479.PubMedCrossRefGoogle Scholar
  10. 10.
    Padgett BL, Walker DL, ZuRhein GM, et al.: Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 1971, 1:1257–1260.PubMedCrossRefGoogle Scholar
  11. 11.
    Frisque RJ, Bream GL, Cannella MT: Human polyomavirus JC virus genome. J Virol 1984, 51:458–469.PubMedGoogle Scholar
  12. 12.
    Frisque RJ, Martin JD, Padgett BL, Walker DL: Infectivity of the DNA from four isolates of JC virus. J Virol 1979, 32:476–482.PubMedGoogle Scholar
  13. 13.
    London WT, Houff SA, Madden DL, et al.: Brain tumors in owl monkeys inoculated with a human polyomavirus (JC virus). Science 1978, 201:1246–1249.PubMedCrossRefGoogle Scholar
  14. 14.
    Walker DL, Padgett BL, ZuRhein GM, et al.: Human papovavirus (JC): induction of brain tumors in hamsters. Science 1973, 181:674–676.PubMedCrossRefGoogle Scholar
  15. 15.
    ZuRhein G: Polyona-like virions in a human demyelinating disease. Acta Neurol Pathol (Berl) 1967, 8:57–68.CrossRefGoogle Scholar
  16. 16.
    Khalili K, Rappaport J, Khoury G: Nuclear factors in human brain cells bind specifically to the JCV regulatory region. EMBO J 1988, 7:1205–1210.PubMedGoogle Scholar
  17. 17.
    Padgett BL, Walker DL, ZuRhein GM, Varakis JN, et al.: Differential neurooncogenicity of strains of JC virus, a human polyoma virus, in newborn Syrian hamsters. Cancer Res 1977, 37:718–720.PubMedGoogle Scholar
  18. 18.
    Dorries K: Progressive multifocal leucoencephalopathy: analysis of JC virus DNA from brain and kidney tissue. Virus Res 1984, 1:25–38.PubMedCrossRefGoogle Scholar
  19. 19.
    Martin JD, King DM, Slauch JM, Frisque RJ: Differences in regulatory sequences of naturally occurring JC virus variants. J Virol 1985, 53:306–311.PubMedGoogle Scholar
  20. 20.
    Koralnik IJ, Wüthrich C, Dang X, et al.: JC virus granule cell neuronopathy: a novel clinical syndrome distinct from progressive multifocal leukoencephalopathy. Ann Neurol 2005, 57:576–580.PubMedCrossRefGoogle Scholar
  21. 21.
    Richardson EP Jr, Webster HD: Progressive multifocal leukoencephalopathy: its pathological features. Prog Clin Biol Res 1983, 105:191–203.PubMedGoogle Scholar
  22. 22.
    Elphick GF, Querbes W, Jordan JA, et al.: The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science 2004, 306:1380–1383.PubMedCrossRefGoogle Scholar
  23. 23.
    Chapagain ML, Verma S, Mercier F, et al.: Polyomavirus JC infects human brain microvascular endothelial cells independent of serotonin receptor 2A. Virology 2007, 364:55–63.PubMedCrossRefGoogle Scholar
  24. 24.
    Pho MT, Ashok A, Atwood WJ: JC virus enters human glial cells by clathrin-dependent receptor-mediated endocytosis. J Virol 2000, 74:2288–2292.PubMedCrossRefGoogle Scholar
  25. 25.
    Querbes W, Benmerah A, Tosoni D, et al.: A JC virus-induced signal is required for infection of glial cells by a clathrin-and eps15-dependent pathway. J Virol 2004, 78:250–256.PubMedCrossRefGoogle Scholar
  26. 26.
    Querbes W, O’Hara BA, Williams G, Atwood WJ: Invasion of host cells by JC virus identifies a novel role for caveolae in endosomal sorting of noncaveolar ligands. J Virol 2006, 80:9402–9413.PubMedCrossRefGoogle Scholar
  27. 27.
    Richardson-Burns SM, Kleinschmidt-DeMasters BK, DeBiasi RL, Tyler KL: Progressive multifocal leukoencephalopathy and apoptosis of infected oligodendrocytes in the central nervous system of patients with and without AIDS. Arch Neurol 2002, 59:1930–1936.PubMedCrossRefGoogle Scholar
  28. 28.
    Seth P, Diaz F, Tao-Cheng JH, Major EO: JC virus induces nonapoptotic cell death of human central nervous system progenitor cell-derived astrocytes. J Virol 2004, 78:4884–4891.PubMedCrossRefGoogle Scholar
  29. 29.
    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, 72:9918–9923.PubMedGoogle Scholar
  30. 30.
    Caldarelli-Stefano R, Vago L, Omodeo-Zorini E, et al.: Detection and typing of JC virus in autopsy brains and extraneural organs of AIDS patients and non-immunocompromised individuals. J Neurovirol 1999, 5:125–133.PubMedCrossRefGoogle Scholar
  31. 31.
    Yogo Y, Kitamura T, Sugimoto C, et al.: Sequence rear-rangement in JC virus DNAs molecularly cloned from immunosuppressed renal transplant patients. J Virol 1991, 65:2422–2428.PubMedGoogle Scholar
  32. 32.
    Henson J, Saffer J, Furneaux H: The transcription factor Sp1 binds to the JC virus promoter and is selectively expressed in glial cells in human brain. Ann Neurol 1992, 32:72–77.PubMedCrossRefGoogle Scholar
  33. 33.
    Major EO, Amemiya K, Tornatore CS, et al.: Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev 1992, 5:49–73.PubMedGoogle Scholar
  34. 34.
    Houff SA, Major EO, Katz DA, et al.: Involvement of JC virus-infected mononuclear cells from the bone marrow and spleen in the pathogenesis of progressive multifocal leukoencephalopathy. N Engl J Med 1988, 318:301–305.PubMedCrossRefGoogle Scholar
  35. 35.
    Tornatore C: Detection of JC viral genome in the lymphocytes of non-PML HIV positive patients: association with B cell lymphopenia. Neurology 1992, 42(Suppl 3):211.Google Scholar
  36. 36.
    Major EO, Amemiya K, Elder G, Houff SA: Glial cells of the human developing brain and B cells of the immune system share a common DNA binding factor for recognition of the regulatory sequences of the human polyomavirus, JCV. J Neurosci Res 1990, 27:461–471.PubMedCrossRefGoogle Scholar
  37. 37.
    Tornatore C, Berger JR, Houff SA, et al.: Detection of JC virus DNA in peripheral lymphocytes from patients with and without progressive multifocal leukoencephalopathy. Ann Neurol 1992, 31:454–462.PubMedCrossRefGoogle Scholar
  38. 38.
    Berger JR, Miller CS, Mootoor Y, et al.: JC virus detection in bodily fluids: clues to transmission. Clin Infect Dis 2006, 43:e9–e12.PubMedCrossRefGoogle Scholar
  39. 39.
    Walker D, Padgett B: The epidemiology of human polyomaviruses. In Polyomaviruses and Human Neurological Disease. Edited by Sever J, Madden D. New York: Alan R. Liss, Inc.; 1983:99–106.Google Scholar
  40. 40.
    Berger JR, Scott G, Albrecht J, et al.: Progressive multifocal leukoencephalopathy in HIV-1-infected children. AIDS 1992, 6:837–841.PubMedCrossRefGoogle Scholar
  41. 41.
    Weber T, Weber F, Petry H, Lüke W: Immune response in progressive multifocal leukoencephalopathy: an overview. J Neurovirol 2001, 7:311–317.PubMedCrossRefGoogle Scholar
  42. 42.
    Padgett BL, Walker DL: Virologic and serologic studies of progressive multifocal leukoencephalopathy. Prog Clin Biol Res 1983, 105:107–117.PubMedGoogle Scholar
  43. 43.
    Gibson PE, Field AM, Gardner SD, Coleman DV: Occurrence of IgM antibodies against BK and JC polyomaviruses during pregnancy. J Clin Pathol 1981, 34:674–679.PubMedCrossRefGoogle Scholar
  44. 44.
    Katz DA, Berger JR, Hamilton B, et al.: Progressive multifocal leukoencephalopathy complicating Wiskott-Aldrich syndrome. Report of a case and review of the literature of progressive multifocal leukoencephalopathy with other inherited immunodeficiency states. Arch Neurol 1994, 51:422–426.PubMedGoogle Scholar
  45. 45.
    Hamilton RS, Gravell M, Major EO: Comparison of antibody titers determined by hemagglutination inhibition and enzyme immunoassay for JC virus and BK virus. J Clin Microbiol 2000, 38:105–109.PubMedGoogle Scholar
  46. 46.
    Berger JR: Are saliva and oropharyngeal secretions a source of JCV infection?. J Neurovirol 2005, 11(Suppl 2):83.Google Scholar
  47. 47.
    Weber F, Goldmann C, Krämer M, et al.: Cellular and humoral immune response in progressive multifocal leukoencephalopathy. Ann Neurol 2001, 49:636–642.PubMedCrossRefGoogle Scholar
  48. 48.
    Brooks BR, Walker DL: Progressive multifocal leukoencephalopathy. Neurol Clin 1984, 2:299–313.PubMedGoogle Scholar
  49. 49.
    Berger JR, Pall L, Lanska D, Whiteman M, et al.: Progressive multifocal leukoencephalopathy in patients with HIV infection. J Neurovirol 1998, 4:59–68.PubMedGoogle Scholar
  50. 50.
    Wong MC, Suite ND, Labar DR: Seizures in human immunodeficiency virus infection. Arch Neurol 1990, 47:640–642.PubMedGoogle Scholar
  51. 51.
    Berger JR, Levy RM, Flomenhoft D, Dobbs M: Predictive factors for prolonged survival in acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy. Ann Neurol 1998, 44:341–349.PubMedCrossRefGoogle Scholar
  52. 52.
    Ormerod LD, Rhodes RH, Gross SA, et al.: Ophthalmologic manifestations of acquired immune deficiency syndrome-associated progressive multifocal leukoencephalopathy. Ophthalmology 1996, 103:899–906.PubMedGoogle Scholar
  53. 53.
    Bauer W, Chamberlain W, Horenstein S: Spinal demyelination in progressive multifocal leukoencephalopahty [abstract]. Neurology 1969, 19:287.Google Scholar
  54. 54.
    Shintaku M, Matsumoto R, Sawa H, Nagashima K: Infection with JC virus and possible dysplastic ganglion-like transformation of the cerebral cortical neurons in a case of progressive multifocal leukoencephalopathy. J Neuropathol Exp Neurol 2000, 59:921–929.PubMedGoogle Scholar
  55. 55.
    von Einsiedel RW, Fife TD, Aksamit AJ, et al.: Progressive multifocal leukoencephalopathy in AIDS: a clinicopathologic study and review of the literature. J Neurol 1993, 240:391–406.CrossRefGoogle Scholar
  56. 56.
    Henin D, Smith TW, De Girolami U, et al.: Neuropathology of the spinal cord in the acquired immunodeficiency syndrome. Hum Pathol 1992, 23:1106–1114.PubMedCrossRefGoogle Scholar
  57. 57.
    Whiteman ML, Post MJ, Berger JR, et al.: Progressive multifocal leukoencephalopathy in 47 HIV-seropositive patients: neuroimaging with clinical and pathologic correlation. Radiology 1993, 187:233–240.PubMedGoogle Scholar
  58. 58.
    Nelson PK, Masters LT, Zagzag D, Kelly PJ: Angiographic abnormalities in progressive multifocal leukoencephalopathy: an explanation based on neuropathologic findings. AJNR Am J Neuroradiol 1999, 20:487–494.PubMedGoogle Scholar
  59. 59.
    Fong IW, Britton CB, Luinstra KE, et al.: Diagnostic value of detecting JC virus DNA in cerebrospinal fluid of patients with progressive multifocal leukoencephalopathy. J Clin Microbiol 1995, 33:484–486.PubMedGoogle Scholar
  60. 60.
    McGuire D, Barhite S, Hollander H, Miles M: JC virus DNA in cerebrospinal fluid of human immunodeficiency virus-infected patients: predictive value for progressive multifocal leukoencephalopathy [published erratum appears in Ann Neurol 1995, 37(5):687]. Ann Neurol 1995, 37:395–399.PubMedCrossRefGoogle Scholar
  61. 61.
    Weber T, Turner RW, Frye S, et al.: Progressive multifocal leukoencephalopathy diagnosed by amplification of JC virus-specific DNA from cerebrospinal fluid. AIDS 1994, 8:49–57.PubMedCrossRefGoogle Scholar
  62. 62.
    Du Pasquier RA, Corey S, Margolin DH, et al.: Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual. Neurology 2003, 61:775–782.PubMedGoogle Scholar
  63. 63.
    Richardson EP Jr: Our evolving understanding of progressive multifocal leukoencephalopatha. Ann NY Acad Sci 1974, 230:358–364.PubMedCrossRefGoogle Scholar
  64. 64.
    Arbusow V, Strupp M, Pfister HW, et al.: Contrast enhancement in progressive multifocal leukoencephalopathy: a predictive factor for long-term survival? [letter]. J Neurol 2000, 247:306–308.PubMedCrossRefGoogle Scholar
  65. 65.
    Post MJ, Yiannoutsos C, Simpson D, et al.: Progressive multifocal leukoencephalopathy in AIDS: are there any MR findings useful to patient management and predictive of patient survival? AIDS Clinical Trials Group, 243 Team. AJNR Am J Neuroadiol 1999, 20:1896–1906.Google Scholar
  66. 66.
    Du Pasquier RA, Clark KW, Smith PS, et al.: JCV-specific cellular immune response correlates with a favorable clinical outcome in HIV-infected individuals with progressive multifocal leukoencephalopathy. J Neurovirol 2001, 7:318–322.PubMedCrossRefGoogle Scholar
  67. 67.
    Koralnik IJ: Overview of the cellular immunity against JC virus in progressive multifocal leukoencephalopathy. J Neurovirol 2002, 8(Suppl 2):59–65.PubMedCrossRefGoogle Scholar
  68. 68.
    Koralnik IJ, Du Pasquier RA, Letvin NL: JC virus-specific cytotoxic T lymphocytes in individuals with progressive multifocal leukoencephalopathy. J Virol 2001, 75:3483–3487.PubMedCrossRefGoogle Scholar
  69. 69.
    De Luca A, Giancola ML, Ammassari A, et al.: The effect of potent antiretroviral therapy and JC virus load in cerebrospinal fluid on clinical outcome of patients with AIDS-associated progressive multifocal leukoencephalopathy. J Infect Dis 2000, 182:1077–1083.PubMedCrossRefGoogle Scholar
  70. 70.
    Hou J, Major EO: The efficacy of nucleoside analogs against JC virus multiplication in a persistently infected human fetal brain cell line. J Neurovirol 1998, 4:451–456.PubMedCrossRefGoogle Scholar
  71. 71.
    De Luca A, Ammassari A, Cingolani A, et al.: Disease progression and poor survival of AIDS-associated progressive multifocal leukoencephalopathy despite highly active antiretroviral therapy. AIDS 1998, 12:1937–1938.PubMedGoogle Scholar
  72. 72.
    Wyen C, Hoffmann C, Schmeisser N, et al.: Progressive multifocal leukencephalopathy in patients on highly active antiretroviral therapy: survival and risk factors of death. J Acquir Immune Defic Syndr 2004, 37:1263–1268.PubMedCrossRefGoogle Scholar
  73. 73.
    Du Pasquier RA, Koralnik IJ: Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol 2003, 9(Suppl 1):25–31.PubMedCrossRefGoogle Scholar
  74. 74.
    Safdar A, Rubocki RJ, Horvath JA, et al.: Fatal immune restoration disease in human immunodeficiency virus type 1-infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstitution. Clin Infect Dis 2002, 35:1250–1257.PubMedCrossRefGoogle Scholar
  75. 75.
    Hoffmann C, Horst HA, Albrecht H, Schlote W: Progressive multifocal leucoencephalopathy with unusual inflammatory response during antiretroviral treatment. J Neurol Neurosurg Psychiatry 2003, 74:1142–1144.PubMedCrossRefGoogle Scholar
  76. 76.
    Cinque P, Bossolasco S, Brambilla AM, et al.: The effect of highly active antiretroviral therapy-induced immune reconstitution on development and outcome of progressive multifocal leukoencephalopathy: study of 43 cases with review of the literature. J Neurovirol 2003, (9Suppl 1):73–80.PubMedCrossRefGoogle Scholar
  77. 77.
    Cinque P, Pierotti C, Viganò MG, et al.: The good and evil of HAART in HIV-related progressive multifocal leukoencephalopathy. J Neurovirol 2001, 7:358–363.PubMedCrossRefGoogle Scholar
  78. 78.
    Thurnher MM, Post MJ, Rieger A, et al.: Initial and follow-up MR imaging findings in AIDS-related progressive multifocal leukoencephalopathy treated with highly active antiretroviral therapy. AJNR Am J Neuroradiol 2001, 22:977–984.PubMedGoogle Scholar
  79. 79.
    Goodman A: The Pharmacological Basis of Therapeutics. New York: MacMillan Publishing Co.; 1985.Google Scholar
  80. 80.
    Bauer WR, Turel AP Jr, Johnson KP: Progressive multifocal leukoencephalopathy and cytarabine. Remission with treatment. J Am Med Assoc 1973, 226:174–176.CrossRefGoogle Scholar
  81. 81.
    Conomy J, Beard NS, Matsumoto H, Roessmann U: Cytarabine treatment of progressive multifocal leukoencephalopathy. JAMA 1974, 229:1313–1316.PubMedCrossRefGoogle Scholar
  82. 82.
    Lidman C, Lindqvist L, Mathiesen T, Grane P: Progressive multifocal leukoencephalopathy in AIDS. AIDS 1991, 5:1039–1041.PubMedCrossRefGoogle Scholar
  83. 83.
    O’Riordan T, Daly PA, Hutchinson M, et al.: Progressive multifocal leukoencephalopathy-remission with cytarabine. J Infect 1990, 20:51–54.PubMedCrossRefGoogle Scholar
  84. 84.
    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.PubMedCrossRefGoogle Scholar
  85. 85.
    Van Horn G, Bastian F, Moake J: Progressive multifocal leukoencephalopathy: failure of response to transfer factor and cytarabine. Neurology 1978, 28:794–797.PubMedGoogle Scholar
  86. 86.
    Hall CD, Dafni U, Simpson D, et al.: Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team [see comments]. N Engl J Med 1998, 338:1345–1351.PubMedCrossRefGoogle Scholar
  87. 87.
    Kerr DA, Chang CF, Gordon J, et al.: Inhibition of human neurotropic virus (JCV) DNA replication in glial cells by camptothecin. Virology 1993, 196:612–618.PubMedCrossRefGoogle Scholar
  88. 88.
    O’Reilly S: Efficacy of camptothecin in progressive multifocal leucoencephalopathy. Lancet 1997, 350:291.PubMedCrossRefGoogle Scholar
  89. 89.
    Vollmer-Haase J, Young P, Ringelstein EB: Efficacy of camptothecin in progressive multifocal leucoencephalopathy. Lancet 1997, 349:1366.PubMedCrossRefGoogle Scholar
  90. 90.
    Andrei G, et al.: Activities of various compounds against murine and primate polyomaviruses. Antimicrob Agents Chemother 1997, 41:587–593.PubMedGoogle Scholar
  91. 91.
    Sadler M, Snoeck R, Vandeputte M, De Clercq E: New treatments for progressive multifocal leukoencephalopathy in HIV-1-infected patients. AIDS 1998, 12:533–535.PubMedGoogle Scholar
  92. 92.
    Marra CM, Rajicic N, Barker DE, et al.: A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS 2002, 16:1791–1797.PubMedCrossRefGoogle Scholar
  93. 93.
    Steiger MJ, Tarnesby G, Gabe S, et al.: Successful outcome of progressive multifocal leukoencephalopathy with cytarabine and interferon. Ann Neurol 1993, 33:407–411.PubMedCrossRefGoogle Scholar
  94. 94.
    Vulliemoz S, Lurati-Ruiz F, Borruat FX, et al.: Favourable outcome of progressive multifocal leucoencephalopathy in two patients with dermatomyositis. J Neurol Neurosurg Psychiatry 2006, 77:1079–1082.PubMedCrossRefGoogle Scholar
  95. 95.
    Manley K, O’Hara BA, Gee GV, et al.: NFAT4 is required for JC virus infection of glial cells. J Virol 2006, 80:12079–12085.PubMedCrossRefGoogle Scholar

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© Current Medicine Group LLC 2007

Authors and Affiliations

  1. 1.Department of NeurologyUniversity of Kentucky College of MedicineLexingtonUSA

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