Progressive multifocal leukoencephalopathy

From Wikipedia, the free encyclopedia - View original article

Progressive multifocal leukoencephalopathy
Classification and external resources
Jump to: navigation, search
Progressive multifocal leukoencephalopathy
Classification and external resources

Progressive multifocal leukoencephalopathy (PML), also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease characterized by progressive damage (-pathy) or inflammation of the white matter (leuko-) of the brain (-encephalo-) at multiple locations (multifocal).

It occurs almost exclusively in people with severe immune deficiency, such as transplant patients on immunosuppressive medications,[1] those receiving certain kinds of chemotherapy, receiving natalizumab (Tysabri) for multiple sclerosis,[2] on long-term efalizumab (Raptiva) for psoriasis,[3] brentuximab (Adcetris) for Hodgkin's Lymphoma,[4] or those with AIDS.

It is caused by the JC virus, which is normally present and kept under control by the immune system. Immunosuppressive drugs prevent the immune system from controlling the virus.


The cause of PML is a type of polyomavirus called the JC virus (JCV), after the initials of the patient from whose tissue the virus was first successfully cultured. Recent publications indicate 39%[5] to 58%[6] of the general population are seropositive for antibodies to JCV, indicating current or previous infection with the virus. JCV causes persistent asymptomatic infection in approximately one-third of the adult population, based on viral shedding into the urine from the site of asymptomatic infection in the kidney. The virus causes disease only when the immune system has been severely weakened.

Prior to the advent of effective antiretroviral therapy, as many as 5% of people with AIDS eventually developed PML.[7] It is unclear why PML occurs more frequently in AIDS than in other immunosuppressive conditions; some research suggests the effects of HIV on brain tissue, or on JCV itself, make JCV more likely to become active in the brain and increase its damaging inflammatory effects.[8]

Contributing Causes[edit]

Cases have been reported of PML being caused by pharmacological agents which modify immune response. This could be due in part to an existing impaired immune response, or to 'drug combination therapies,' rather than to individual drugs. These include efalizumab, belatacept,[9] rituximab,[10] natalizumab,[2] infliximab,[11] cytotoxic chemotherapy,[12] corticosteroids,[13] and various transplant drugs such as tacrolimus.[14]


PML is a demyelinating disease, in which the myelin sheath covering the axons of nerve cells is gradually destroyed, impairing the transmission of nerve impulses. It affects the subcortical white matter, particularly that of the parietal and occipital lobes. PML destroys oligodendrocytes and produces intranuclear inclusions. PML is similar to another demyelinating disease, multiple sclerosis, but progresses much more quickly. The breakdown of myelin is commensurate with the degree of immunocompromise.


Symptoms include weakness or paralysis, vision loss, impaired speech, and cognitive deterioration. The lesions affecting the parietal and occipital lobes can lead to a phenomenon known as alien hand syndrome.


T2-weighted MRI showing progressive multifocal leukoencephalopathy

PML is diagnosed by testing for JC virus DNA in cerebrospinal fluid or in a brain biopsy specimen. Characteristic evidence of the damage caused by PML in the brain can also be detected on MRI images, which classically show multifocal nonenhancing lesions without mass effect. The most common area of involvement is the cortical white matter, but the brainstem and cerebellum may also be involved.


There is no known cure. In some cases, the disease slows or stops if the patient's immune system improves; some AIDS patients with PML have been able to survive for several years, with the advent of highly active antiretroviral therapy (HAART).

AIDS patients who start HAART after being diagnosed with PML tend to have a slightly longer survival time than patients who were already on HAART and then develop PML.[15] A rare complication of effective HAART is immune reconstitution inflammatory syndrome (IRIS), in which increased immune system activity actually increases the damage caused by the infection; although IRIS can often be managed with medication, it is extremely dangerous when it occurs in PML.[16]

Other antiviral agents that have been studied as possible treatments for PML include cidofovir[17] and interleukin-2, but this research is still preliminary.

Cytarabine (also known as ARA-C), a chemotherapy drug used to treat certain cancers, has been prescribed on an experimental basis for a small number of non-AIDS PML patients. It is reported to have stabilized the neurological condition of a minority of these patients.[18] One patient regained some cognitive function lost as a result of PML.[19]

In June 2010, the first case report appeared of a PML patient being successfully treated with mefloquine. Mefloquine is an antimalarial drug that can also act against the JC virus. Administration of mefloquine seemed to eliminate the virus from the patient's body and prevented further neurological deterioration.[20]

While a number of therapies work against JC Virus in cell culture, there is no proven, effective therapy in humans.[21] Some therapies, such as 1-O-hexadecyloxypropyl-cidofovir (CMX001),[22] have been found to have toxicity at therapeutic dosage, while the number of patients treated with other therapies is too low to demonstrate effectiveness.

In multiple sclerosis[edit]

Natalizumab was approved in 2004 by the FDA for multiple sclerosis (MS). It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of PML.[2] All 3 initial cases were taking natalizumab in combination with interferon beta-1a.[2] After a safety review the drug was returned to the market in 2006 as a monotherapy for MS under a special prescription program.[2] As of May 2011, over 130 cases of PML had been reported in MS patients, all in patients who had taken natalizumab for more than a year.[2] While none of them had taken the drug in combination with other disease-modifying treatments, previous use of MS treatments increases the risk of PML between 3 and 4-fold.[2] The estimated prevalence of PML in MS is 1.5 cases per thousand natalizumab users.[2] Around 20% of MS patients with PML die, and most of the rest are very disabled.[2]

See also[edit]


  1. ^ Mateen, FJ; Muralidharan, R; Carone, M; Van De Beek, D; Harrison, DM; Aksamit, AJ; Gould, MS; Clifford, DB; Nath, A (2011). "Progressive multifocal leukoencephalopathy in transplant recipients". Annals of neurology 70 (2): 305–22. doi:10.1002/ana.22408. PMID 21823157. 
  2. ^ a b c d e f g h i Kappos, Ludwig; Bates, David; Edan, Gilles; Eraksoy, Mefkûre; Garcia-Merino, Antonio; Grigoriadis, Nikolaos; Hartung, Hans-Peter; Havrdová, Eva; Hillert, Jan; Hohlfeld, Reinhard; Kremenchutzky, Marcelo; Lyon-Caen, Olivier; Miller, Ariel; Pozzilli, Carlo; Ravnborg, Mads; Saida, Takahiko; Sindic, Christian; Vass, Karl; Clifford, David B; Hauser, Stephen; Major, Eugene O; O'Connor, Paul W; Weiner, Howard L; Clanet, Michel; Gold, Ralf; Hirsch, Hans H; Radü, Ernst-Wilhelm; Sørensen, Per Soelberg; King, John (August 2011). "Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring". Lancet neurology 10 (8): 745–58. doi:10.1016/S1474-4422(11)70149-1. PMID 21777829. 
  3. ^
  4. ^ "FDA Approval for Brentuximab Vedotin". 
  5. ^ Kean, Jaime M.; Rao, Suchitra; Wang, Michael; Garcea, Robert L. (2009). "Seroepidemiology of Human Polyomaviruses". In Atwood, Walter J. PLoS Pathogens 5 (3): e1000363. doi:10.1371/journal.ppat.1000363. PMC 2655709. PMID 19325891. 
  6. ^ Egli, Adrian; Infanti, Laura; Dumoulin, Alexis; Buser, Andreas; Samaridis, Jacqueline; Stebler, Christine; Gosert, Rainer; Hirsch, Hans H. (2009). "Prevalence of Polyomavirus BK and JC Infection and Replication in 400 Healthy Blood Donors". The Journal of Infectious Diseases 199 (6): 837–46. doi:10.1086/597126. PMID 19434930. 
  7. ^ "National Institutes of Health, Progressive Multifocal Leukoencephalopathy Information Page". 
  8. ^ Berger, Joseph (2003). "Progressive multifocal leukoencephalopathy in acquired immunodeficiency syndrome: explaining the high incidence and disproportionate frequency of the illness relative to other immunosuppressive conditions". J. Neurovirol. 9 Suppl 1 (2): 38–41. doi:10.1080/713831410. PMID 12709870. 
  9. ^ "Drug to Help Transplants Wins Support". The Wall Street Journal. 2 March 2010. 
  10. ^ "Off-Label Use of Rituxan Linked to Fatal Leukoencephalopathy". 
  11. ^ Kumar, Deepak; Bouldin, Thomas W.; Berger, Robert G. (2010). "A case of progressive multifocal leukoencephalopathy in a patient treated with infliximab". Arthritis Rheum 62 (11): 3191–5. doi:10.1002/art.27687. PMID 20722036. 
  12. ^ Connolly, Roisin M.; Doherty, Colin P.; Beddy, Peter; O'Byrne, Ken (2007). "Chemotherapy induced reversible posterior leukoencephalopathy syndrome". Lung Cancer 56 (3): 459–63. doi:10.1016/j.lungcan.2007.01.012. PMID 17316891. 
  13. ^ Viallard, J. F.; Lazaro, E.; Ellie, E.; Eimer, S.; Camou, F.; Caubet, O.; Lafon, M. E.; Fleury, H.; Pellegrin, J. L. (2007). "Improvement of progressive multifocal leukoencephalopathy after cidofovir therapy in a patient with a destructive polyarthritis". Infection 35 (1): 33–6. doi:10.1007/s15010-006-5103-y. PMID 17297588. 
  14. ^ Junna, M. R; Rabinstein, A. A (2007). "Tacrolimus induced leukoencephalopathy presenting with status epilepticus and prolonged coma". J. Neurol. Neurosurg. Psychiatr. 78 (12): 1410–1. doi:10.1136/jnnp.2007.121806. PMC 2095620. PMID 18024699. 
  15. ^ Wyen, Christoph; Hoffmann, Christian; Schmeier, Norbert; Hoffmann, Andrej; Qurishi, Nazifa; Rockstroh, Jürgen; Esser, Stefan; Rieke, Ansgar; Ross, Birgit; Lorenzen, Thore; Schmitz, Karina; Stenzel, Werner; Salzberger, Bernd; Fätkenheuer, Gerd (2004). "Progressive multifocal leukencephalopathy in patients on highly active antiretroviral therapy: survival and risk factors of death". Journal of Acquired Immune Deficiency Syndrome 37 (2): 1263–1268. doi:10.1097/01.qai.0000136093.47316.f3. PMID 15385733. 
  16. ^ Vendrely, Aurélie; Bienvenu, Boris; Gasnault, Jacques; Thiebault, Jean Baptiste; Salmon, Dominique; Gray, Françoise (April 2005). "Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy". Acta Neuropathol. 109 (4): 449–55. doi:10.1007/s00401-005-0983-y. PMID 15739098. 
  17. ^ Segarra-Newnham, Marisel; Vodolo, Kristen M (June 2001). "Use of cidofovir in progressive multifocal leukoencephalopathy". Ann Pharmacother 35 (6): 741–4. doi:10.1345/aph.10338. PMID 11408993. 
  18. ^ Aksamit, A J (August 2001). "Treatment of non-AIDS progressive multifocal leukoencephalopathy with cytosine arabinoside". J. Neurovirol. 7 (4): 386–90. doi:10.1080/13550280152537292. PMID 11517422. 
  19. ^ Langer-Gould, Annette; Atlas, Scott W.; Green, Ari J.; Bollen, Andrew W.; Pelletier, Daniel (July 2005). "Progressive multifocal leukoencephalopathy in a patient treated with natalizumab". N. Engl. J. Med. 353 (4): 375–81. doi:10.1056/NEJMoa051847. PMID 15947078. 
  20. ^ Gofton, T. E.; Al-Khotani, A.; O'Farrell, B.; Ang, L. C.; McLachlan, R. S. (June 2010). "Mefloquine in the treatment of progressive multifocal leukoencephalopathy". J Neurol Neurosurg Psychiatry 82 (4): 452–455. doi:10.1136/jnnp.2009.190652. PMID 20562463. 
  21. ^ Ferenczy, MW; Marshall, LJ; Nelson, CD; Atwood, WJ; Nath, A; Khalili, K; Major, EO (July 2012). "Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain.". Clin. Microbiol. Rev. 25 (3): 471–506. doi:10.1128/CMR.05031-11. PMID 22763635. 
  22. ^ Gosert, R; Rinaldo, C.H.; Wernil, M; Major, EO last5 = Hirsch (May 2011). "CMX001 (1-O-hexadecyloxypropyl-cidofovir) inhibits polyomavirus JC replication in human brain progenitor-derived astrocytes.". Antimicrob. Agents. Chemother. 55 (5): 2129–36. doi:10.1128/AAC.00046-11. PMID 21402853. 

External links[edit]