Progressive Multifocal Leukoencephalopathy in HIV-Uninfected Individuals.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system (CNS) caused by the human neurotropic polyomavirus JC (JCV). The disease occurs virtually exclusively in immunocompromised individuals, and, prior to the introduction of antiretroviral therapy, was seen most commonly in the setting of HIV/AIDS. More recently, however, the incidence of PML in HIV-uninfected persons has increased with broader use of immunosuppressive and immunomodulatory medications utilized in a variety of systemic and neurologic autoimmune disorders. In this review, we discuss the epidemiology and clinical characteristics of PML in HIV-uninfected individuals, as well as diagnostic modalities and the limited treatment options. Moreover, we describe recent findings regarding the neuropathogenesis of PML, with specific focus on the unique association between PML and natalizumab, a monoclonal antibody that prevents trafficking of activated leukocytes into the CNS that is used for the treatment of multiple sclerosis.
Division of Neuroimmunology and Neuro-Infectious Diseases, Department of Neurology, The Johns Hopkins University School of Medicine, Meyer 6-113, 600 N. Wolfe Street, Baltimore, MD, 21287, USA.
Deanna
D
Saylor
Division of Neuroimmunology and Neuro-Infectious Diseases, Department of Neurology, The Johns Hopkins University School of Medicine, Meyer 6-113, 600 N. Wolfe Street, Baltimore, MD, 21287, USA. avenkat2@jhmi.edu.
Arun
A
Venkatesan
Dimethyl fumarate; Multiple sclerosis; Natalizumab; Progressive multifocal leukoencephalopathy; Systemic lupus erythematosus
Ann Neurol. 2014 Jul;76(1):140-7
24895208
J Neurol Neurosurg Psychiatry. 2016 Feb;87(2):117-25
26492930
Intern Med. 2015;54(8):965-70
25876582
Int J STD AIDS. 1996 Aug-Sep;7(5):337-46
8894823
WMJ. 2014 Dec;113(6):242-5
25745699
Antimicrob Agents Chemother. 2009 May;53(5):1840-9
19258267
J Neuroimmunol. 2008 Feb;194(1-2):153-64
18178259
J Neurovirol. 2016 Aug;22(4):464-71
26676826
N Engl J Med. 2005 Jul 28;353(4):362-8
15947080
Curr Opin Neurol. 2015 Jun;28(3):288-94
25887767
Arch Neurol. 2008 Nov;65(11):1538-9
19001176
Clin Neuropathol. 2016 Mar-Apr;35(2):66-71
26754416
Cancer. 2014 Aug 15;120(16):2464-71
24771533
Leuk Lymphoma. 2003 Oct;44(10):1815-8
14692540
Ann Neurol. 2014 Jun;75(6):925-34
24687904
Neurology. 2014 Aug 19;83(8):727-32
25037207
J Virol. 2015 Jan 15;89(2):1340-7
25392214
Arthritis Rheum. 2009 Dec;60(12):3761-5
19950261
Handb Clin Neurol. 2014;123:357-76
25015495
J Virol. 1984 Aug;51(2):458-69
6086957
Neurologia. 2016 Mar 8;:null
26968822
Exp Oncol. 2011 Dec;33(4):239-41
22217715
Clin Infect Dis. 2006 Jul 1;43(1):16-24
16758413
J Infect Dis. 2011 Mar 1;203(5):578-86
21227915
Age Ageing. 2016 Jul;45(4):564-5
27056083
AJNR Am J Neuroradiol. 2015 Dec;36(12):2296-302
26316568
Rev Med Virol. 2016 Mar;26(2):102-14
26663440
J Rheumatol. 2006 May;33(5):1018-20
16511935
Neurology. 2013 Apr 9;80(15):1430-8
23568998
JAMA Neurol. 2014 May;71(5):596-602
24664166
Open Forum Infect Dis. 2014 Aug 26;1(2):ofu074
25734144
J Neurovirol. 1998 Feb;4(1):59-68
9531012
Mult Scler. 2016 Jul;22(8):1048-60
26432858
Autoimmun Rev. 2008 Dec;8(2):144-6
18700172
J Neurovirol. 2015 Dec;21(6):688-90
26139016
Ann Neurol. 2009 Jun;65(6):742-8
19557867
J Neurol. 2000 Apr;247(4):306-8
10836626
Arch Neurol. 2009 Feb;66(2):255-8
19204164
Neurology. 2016 Apr 19;86(16):1516-23
27009257
Lupus. 2016 May;25(6):617-26
26743322
N Engl J Med. 2006 Mar 2;354(9):924-33
16510746
J Neurovirol. 2003 Jun;9(3):411-9
12775425
Neurology. 2016 May 10;86(19):1843-5
27164718
N Engl J Med. 2005 Jul 28;353(4):369-74
15947079
Ann Neurol. 2014 Dec;76(6):802-12
25273271
Arthritis Rheum. 2006 Mar;54(3):1020-2
16508984
Lupus. 2012 Jan;21(1):100-2
21976399
J Virol. 2014 May;88(9):5177-83
24554653
Neurology. 2013 Sep 3;81(10):865-71
23925765
JAMA Neurol. 2014 Aug;71(8):1030-5
24979548
J Virol. 2010 Oct;84(20):10448-56
20686041
JAMA Neurol. 2014 Apr;71(4):487-9
24515530
Brain. 2004 Sep;127(Pt 9):1970-8
15215217
AIDS. 2014 Mar 13;28(5):793-5
24445368
J Neurovirol. 2015 Dec;21(6):623-31
25404234
J Neurol Sci. 2016 Mar 15;362:155-9
26944139
Arthritis Rheum. 2010 Nov;62(11):3191-5
20722036
Neurol Neuroimmunol Neuroinflamm. 2016 Mar 31;3(3):e223
27088119
N Engl J Med. 2012 May 17;366(20):1870-80
22591293
Clin Radiol. 2010 Jun;65(6):431-9
20451009
Sci Transl Med. 2015 Sep 23;7(306):306ra150
26400911
Sci Transl Med. 2015 Sep 23;7(306):306ra151
26400912
Eur J Clin Microbiol Infect Dis. 2012 Aug;31(8):1719-26
22678348
Eur Radiol. 2008 Jul;18(7):1526-8
18560918
J Neurovirol. 2015 Dec;21(6):645-52
25052191
Eur J Neurol. 2014 Feb;21(2):299-304
24894998
Neurology. 2009 Apr 28;72(17):1458-64
19129505
Clin Rev Allergy Immunol. 2012 Dec;43(3):302-7
22674017
J Clin Virol. 2013 Jul;57(3):243-8
23619054
Microbiol Immunol. 2016 Apr;60(4):253-60
26935240
CNS Drugs. 2015;29(10):879-91
26507833
J Gen Virol. 2010 Dec;91(Pt 12):3042-52
20826618
BMC Neurol. 2015 Jul 08;15:108
26152311
Neurol Neuroimmunol Neuroinflamm. 2016 Jan 27;3(1):e195
26848486
Neurology. 2003 Sep 23;61(6):775-82
14504320
Ann Neurol. 2015 Oct;78(4):501-14
26150206
J Neurovirol. 2016 Aug;22(4):533-5
26843383
Am J Transplant. 2014 Aug;14 (8):1817-27
25041339
N Engl J Med. 2015 Apr 9;372(15):1476-8
25853765
Adv Exp Med Biol. 2006;577:274-87
16626043
Neurology. 2009 Feb 3;72(5):402-9
19188571
J Infect Public Health. 2015 Sep-Oct;8(5):493-7
25666327
Blood. 2008 Apr 1;111(7):3439-41
18195093
J Neurovirol. 2015 Dec;21(6):637-44
25771865
J Neurol Sci. 2015 Jul 15;354(1-2):86-90
26003226
Ann Neurol. 2015 Nov;78(5):722-30
26290222
Neurology. 2013 Sep 10;81(11):964-70
23935178
J Neurovirol. 2013 Aug;19(4):351-8
23733308
J Infect Dis. 2009 Jan 1;199(1):77-83
19007313
Ann Neurol. 2005 Apr;57(4):576-80
15786466
N Engl J Med. 1998 May 7;338(19):1345-51
9571254
Acta Neuropathol. 1976 Oct 15;36(2):101-15
1007902
Ann Neurol. 2015 Apr;77(4):560-70
25623836
Transplantation. 2008 Nov 27;86(10 ):1474-8
19034021
Neuropathology. 2009 Aug;29(4):485-93
19019177
N Engl J Med. 2005 Jul 28;353(4):375-81
15947078
Neurology. 2011 May 17;76(20):1697-704
21576685
BMJ Case Rep. 2014 Jan 08;2014:null
24403383
Neurology. 2016 Jan 26;86(4):399-400
26718572
Lupus. 2005;14(12):964-6
16425577
AJNR Am J Neuroradiol. 1996 Mar;17(3):597-600
8881262
J Neurovirol. 2001 Aug;7(4):323-8
11517411
Clin Infect Dis. 2014 Dec 1;59(11):1588-92
25214510
Ann Neurol. 2016 Mar;79(3):404-18
26874214
J Neurovirol. 2003 Aug;9(4):498-507
12907394
J Neurovirol. 2001 Aug;7(4):353-7
11517416
Neurology. 2013 Oct 15;81(16):1400-8
24049136
Neurology. 2012 Feb 7;78(6):436-7
22282644
Neuropathology. 2012 Jun;32(3):280-4
21981108
J Clin Neurosci. 2012 Aug;19(8):1167-9
22658241
J Cell Physiol. 2016 Oct;231(10 ):2115-27
26831433
J Neurovirol. 2015 Dec;21(6):691-3
26242918
J Gen Virol. 2012 Mar;93(Pt 3):651-61
22071512
Ann Neurol. 2014 May;75(5):659-69
24752885
J Neuroophthalmol. 2015 Sep;35(3):296-305
26132966
Neurology. 2015 Jul 7;85(1):104-6
26041329
N Engl J Med. 2015 Apr 9;372(15):1474-6
25853764
Neurology. 2016 Jan 26;86(4):375-81
26718566
AIDS. 2008 Sep 12;22(14):1759-67
18753934
Brain. 1958 Mar;81(1):93-111
13523006
J Neurol Sci. 2014 Sep 15;344(1-2):198-202
24972818
Braz J Infect Dis. 2011 Nov-Dec;15(6):609-12
22218525
Ann Neurol. 1982 Feb;11(2):199-202
7073254
J Virol. 2011 Jul;85(14):7256-63
21543472
J Infect Dis. 2009 Mar 15;199(6):837-46
19434930
Ther Adv Drug Saf. 2012 Oct;3(5):227-39
25083238
Neurology. 2015 Apr 7;84(14):1501-2
25846998
F1000Res. 2015 Dec 10;4:null
26918152
J Virol. 1990 Jun;64(6):3139-43
2159570
Rheumatology (Oxford). 2002 Jul;41(7):826-7
12096236
Infection. 2003 Dec;31(6):374-8
14735377
Acta Neuropathol. 2015 Mar;129(3):467-8
25604548
N Engl J Med. 2014 Jun 19;370(25):2408-17
24896819
Science. 2004 Nov 19;306(5700):1380-3
15550673