Progressive multifocal leukoencephalopathy: Treatment and prognosis
- Igor J Koralnik, MD
Igor J Koralnik, MD
- Jean Schweppe Armour Professor of Neurology and Medicine
- Rush Medical College
- Chair, Department of Neurological Sciences
- Section Chief, Neuroinfectious Disease
- Rush University Medical Center
Progressive multifocal leukoencephalopathy (PML) is an often fatal demyelinating disease of the central nervous system that occurs almost exclusively in immunosuppressed individuals. This disease is caused by the polyomavirus JC (JCV). (See "Virology, epidemiology, and pathogenesis of JC polyomavirus, BK polyomavirus, and other human polyomaviruses" and "Progressive multifocal leukoencephalopathy: Epidemiology, clinical manifestations, and diagnosis".)
This topic will review the various approaches that have been employed to treat PML. Other aspects of JC viral infection and PML are discussed elsewhere. (See "Virology, epidemiology, and pathogenesis of JC polyomavirus, BK polyomavirus, and other human polyomaviruses" and "Progressive multifocal leukoencephalopathy: Epidemiology, clinical manifestations, and diagnosis".)
APPROACH TO TREATMENT
There is no specific treatment for PML, which has a high mortality rate. Therefore, the main approach is restoring the host adaptive immune response, a strategy that appears to prolong survival [1,2]. Implementation of this strategy differs according to the clinical setting:
●Initiating or optimizing effective antiretroviral therapy (ART) for patients with HIV infection
●Withdrawing immunosuppressive drugs (when possible) for patients without HIV infectionTo continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Tan CS, Koralnik IJ. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010; 9:425.
- Calabrese L. A rational approach to PML for the clinician. Cleve Clin J Med 2011; 78 Suppl 2:S38.
- Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and treatment of opportunistic infections in HIV-infected adults and adolescents: Progressive Multifocal Leukoencephalopathy/JC Virus Infection: Recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the Infectious Diseases Society of America. https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/346/pml-jcv (Accessed on July 17, 2017).
- Elliot B, Aromin I, Gold R, et al. 2.5 year remission of AIDS-associated progressive multifocal leukoencephalopathy with combined antiretroviral therapy. Lancet 1997; 349:850.
- Albrecht H, Hoffmann C, Degen O, et al. Highly active antiretroviral therapy significantly improves the prognosis of patients with HIV-associated progressive multifocal leukoencephalopathy. AIDS 1998; 12:1149.
- Cinque P, Casari S, Bertelli D. Progressive multifocal leukoencephalopathy, HIV, and highly active antiretroviral therapy. N Engl J Med 1998; 339:848.
- Antinori A, Ammassari A, Giancola ML, et al. Epidemiology and prognosis of AIDS-associated progressive multifocal leukoencephalopathy in the HAART era. J Neurovirol 2001; 7:323.
- Antinori A, Cingolani A, Lorenzini P, et al. Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA). J Neurovirol 2003; 9 Suppl 1:47.
- Crowder CD, Gyure KA, Drachenberg CB, et al. Successful outcome of progressive multifocal leukoencephalopathy in a renal transplant patient. Am J Transplant 2005; 5:1151.
- 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.
- Wenning W, Haghikia A, Laubenberger J, et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N Engl J Med 2009; 361:1075.
- Lindå H, von Heijne A, Major EO, et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med 2009; 361:1081.
- 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.
- Vermersch P, Kappos L, Gold R, et al. Clinical outcomes of natalizumab-associated progressive multifocal leukoencephalopathy. Neurology 2011; 76:1697.
- Tan IL, McArthur JC, Clifford DB, et al. Immune reconstitution inflammatory syndrome in natalizumab-associated PML. Neurology 2011; 77:1061.
- Dahlhaus S, Hoepner R, Chan A, et al. Disease course and outcome of 15 monocentrically treated natalizumab-associated progressive multifocal leukoencephalopathy patients. J Neurol Neurosurg Psychiatry 2013; 84:1068.
- Landi D, De Rossi N, Zagaglia S, et al. No evidence of beneficial effects of plasmapheresis in natalizumab-associated PML. Neurology 2017; 88:1144.
- Dong-Si T, Gheuens S, Gangadharan A, et al. Predictors of survival and functional outcomes in natalizumab-associated progressive multifocal leukoencephalopathy. J Neurovirol 2015; 21:637.
- Schröder A, Lee DH, Hellwig K, et al. Successful management of natalizumab-associated progressive multifocal leukoencephalopathy and immune reconstitution syndrome in a patient with multiple sclerosis. Arch Neurol 2010; 67:1391.
- 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.
- Berger JR, Koralnik IJ. Progressive multifocal leukoencephalopathy and natalizumab--unforeseen consequences. N Engl J Med 2005; 353:414.
- Groothuis DR, Benalcazar H, Allen CV, et al. Comparison of cytosine arabinoside delivery to rat brain by intravenous, intrathecal, intraventricular and intraparenchymal routes of administration. Brain Res 2000; 856:281.
- Vennegoor A, Wattjes MP, van Munster ET, et al. Indolent course of progressive multifocal leukoencephalopathy during natalizumab treatment in MS. Neurology 2011; 76:574.
- Clifford DB. Lessons from the clinic: a case of natalizumab-associated PML. Neurology 2011; 76:574.
- Martinez JV, Mazziotti JV, Efron ED, et al. Immune reconstitution inflammatory syndrome associated with PML in AIDS: a treatable disorder. Neurology 2006; 67:1692.
- Tan K, Roda R, Ostrow L, et al. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 2009; 72:1458.
- 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. N Engl J Med 1998; 338:1345.
- 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.
- Aksamit AJ. Treatment of non-AIDS progressive multifocal leukoencephalopathy with cytosine arabinoside. J Neurovirol 2001; 7:386.
- Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS 2002; 16:1791.
- 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.
- Gasnault J, Kousignian P, Kahraman M, et al. Cidofovir in AIDS-associated progressive multifocal leukoencephalopathy: a monocenter observational study with clinical and JC virus load monitoring. J Neurovirol 2001; 7:375.
- Berenguer J, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis 2003; 36:1047.
- De Luca A, Ammassari A, Pezzotti P, et al. Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. AIDS 2008; 22:1759.
- Osorio S, de la Cámara R, Golbano N, et al. Progressive multifocal leukoencephalopathy after stem cell transplantation, unsuccessfully treated with cidofovir. Bone Marrow Transplant 2002; 30:963.
- Herrlinger U, Schwärzler F, Beck R, et al. Progressive multifocal leukoencephalopathy: cidofovir therapy in three patients with underlying hematological disease. J Neurol 2003; 250:612.
- Royal W 3rd, Dupont B, McGuire D, et al. Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy. J Neurovirol 2003; 9:411.
- Elphick GF, Querbes W, Jordan JA, et al. The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science 2004; 306:1380.
- Verma S, Cikurel K, Koralnik IJ, et al. Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera. J Infect Dis 2007; 196:709.
- Lima MA, Auriel E, Wüthrich C, et al. Progressive multifocal leukoencephalopathy as a complication of hepatitis C virus treatment in an HIV-negative patient. Clin Infect Dis 2005; 41:417.
- Cettomai D, McArthur JC. Mirtazapine use in human immunodeficiency virus-infected patients with progressive multifocal leukoencephalopathy. Arch Neurol 2009; 66:255.
- Giacomini PS, Rozenberg A, Metz I, et al. Maraviroc and JC virus-associated immune reconstitution inflammatory syndrome. N Engl J Med 2014; 370:486.
- Martin-Blondel G, Cuzin L, Delobel P, et al. Is maraviroc beneficial in paradoxical progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome management? AIDS 2009; 23:2545.
- Middel A, Arends JE, van Lelyveld SF, et al. Clinical and immunologic effects of maraviroc in progressive multifocal leukoencephalopathy. Neurology 2015; 85:104.
- Shahani L, Shah M, Tavakoli-Tabasi S. Immune reconstitution inflammatory syndrome in a patient with progressive multifocal leukoencephalopathy. BMJ Case Rep 2015; 2015.
- Agnihotri SP, Dang X, Carter JL, et al. JCV GCN in a natalizumab-treated MS patient is associated with mutations of the VP1 capsid gene. Neurology 2014; 83:727.
- Rodríguez M, Silva-Sánchez FA, Luna-Rivero C, et al. Maraviroc Failed to Control Progressive Multifocal Leukoencephalopathy-Associated IRIS in a Patient with Advanced HIV Infection. Case Rep Med 2014; 2014:381480.
- Alstadhaug KB, Croughs T, Henriksen S, et al. Treatment of progressive multifocal leukoencephalopathy with interleukin 7. JAMA Neurol 2014; 71:1030.
- Sospedra M, Schippling S, Yousef S, et al. Treating progressive multifocal leukoencephalopathy with interleukin 7 and vaccination with JC virus capsid protein VP1. Clin Infect Dis 2014; 59:1588.
- Miskin DP, Chalkias SG, Dang X, et al. Interleukin-7 treatment of PML in a patient with idiopathic lymphocytopenia. Neurol Neuroimmunol Neuroinflamm 2016; 3:e213.
- Brickelmaier M, Lugovskoy A, Kartikeyan R, et al. Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrob Agents Chemother 2009; 53:1840.
- Clifford DB, Nath A, Cinque P, et al. A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes. J Neurovirol 2013; 19:351.
- Koralnik IJ. Progressive multifocal leukoencephalopathy revisited: Has the disease outgrown its name? Ann Neurol 2006; 60:162.
- Berger JR, Pall L, Lanska D, Whiteman M. Progressive multifocal leukoencephalopathy in patients with HIV infection. J Neurovirol 1998; 4:59.
- 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.
- Marzocchetti A, Tompkins T, Clifford DB, et al. Determinants of survival in progressive multifocal leukoencephalopathy. Neurology 2009; 73:1551.
- Yiannoutsos CT, Major EO, Curfman B, et al. Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy. Ann Neurol 1999; 45:816.
- Bossolasco S, Calori G, Moretti F, et al. Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy. Clin Infect Dis 2005; 40:738.
- Koralnik IJ. Overview of the cellular immunity against JC virus in progressive multifocal leukoencephalopathy. J Neurovirol 2002; 8 Suppl 2:59.
- Du Pasquier RA, Kuroda MJ, Schmitz JE, et al. Low frequency of cytotoxic T lymphocytes against the novel HLA-A*0201-restricted JC virus epitope VP1(p36) in patients with proven or possible progressive multifocal leukoencephalopathy. J Virol 2003; 77:11918.
- 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.
- Du Pasquier RA, Autissier P, Zheng Y, et al. Presence of JC virus-specific CTL in the cerebrospinal fluid of PML patients: rationale for immune-based therapeutic strategies. AIDS 2005; 19:2069.
- Lima MA, Marzocchetti A, Autissier P, et al. Frequency and phenotype of JC virus-specific CD8+ T lymphocytes in the peripheral blood of patients with progressive multifocal leukoencephalopathy. J Virol 2007; 81:3361.
- 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.
- Katz-Brull R, Lenkinski RE, Du Pasquier RA, Koralnik IJ. Elevation of myoinositol is associated with disease containment in progressive multifocal leukoencephalopathy. Neurology 2004; 63:897.
- APPROACH TO TREATMENT
- HIV infection
- Immunosuppression without HIV infection
- Natalizumab-associated PML
- Inflammatory PML
- Pharmacologic agents
- - Cytarabine
- - Cidofovir
- - Topotecan
- - Mirtazapine
- - Maraviroc
- - Interleukin 7
- - Mefloquine
- NATURAL HISTORY AND PROGNOSIS
- Prognostic markers
- SUMMARY AND RECOMMENDATIONS