Editing Progressive multifocal leukoencephalopathy (section)

==Cause==

===JC virus infection===
The cause of PML is a type of [[polyomavirus]] called the [[JC virus]] (JCV), after the initials of the person (John Cunningham) from whose tissue the virus was first successfully cultured. Publications indicate 39<ref>{{cite journal|doi=10.1371/journal.ppat.1000363|title=Seroepidemiology of Human Polyomaviruses|year=2009|editor1-last=Atwood|editor1-first=Walter J.|last1=Kean|first1=Jaime M.|last2=Rao|first2=Suchitra|last3=Wang|first3=Michael|last4=Garcea|first4=Robert L.|journal=PLOS Pathogens|volume=5|issue=3|pages=e1000363|pmid=19325891|pmc=2655709 |doi-access=free }}</ref> to 58%<ref>{{cite journal|doi=10.1086/597126|title=Prevalence of Polyomavirus BK and JC Infection and Replication in 400 Healthy Blood Donors|year=2009|last1=Egli|first1=Adrian|last2=Infanti|first2=Laura|last3=Dumoulin|first3=Alexis|last4=Buser|first4=Andreas|last5=Samaridis|first5=Jacqueline|last6=Stebler|first6=Christine|last7=Gosert|first7=Rainer|last8=Hirsch|first8=Hans H.|journal=The Journal of Infectious Diseases|volume=199|issue=6|pages=837–46|pmid=19434930|doi-access=free}}</ref> of the general population are seropositive for antibodies to JCV, indicating current or previous infection with the virus. Other publications put the percentage at 70 to 90% of the general population.<ref name="shakel">{{cite journal|author1=Laura A. Shackelton |author2=Andrew Rambaut |author2-link=Andrew Rambaut |author3=Oliver G. Pybus |author4=Edward C. Holmes |year=2006|title=JC Virus evolution and its association with human populations|journal=Journal of Virology|volume=80|issue=20|pages=9928–9933 |doi=10.1128/JVI.00441-06|pmc=1617318|pmid=17005670}}</ref> JCV causes persistent asymptomatic infection in about 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.<ref>{{Cite journal |last1=Cortese |first1=Irene |last2=Reich |first2=Daniel S. |last3=Nath |first3=Avindra |date=January 2021 |title=Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease |journal=Nature Reviews Neurology |language=en |volume=17 |issue=1 |pages=37–51 |doi=10.1038/s41582-020-00427-y |pmid=33219338 |pmc=7678594 |issn=1759-4766}}</ref>

===Immunosuppression===
PML is most common in people with HIV1 infection; prior to the advent of effective [[HAART|antiretroviral therapy]], as many as 5% of people with AIDS eventually developed PML.<ref name="NIH">{{cite web|date=14 February 2014|title=Progressive Multifocal Leukoencephalopathy Information Page|url=https://www.ninds.nih.gov/disorders/all-disorders/progressive-multifocal-leukoencephalopathy-information-page|access-date=11 September 2020|work=National Institute of Neurological Disorders and Stroke|publisher=National Institutes of Health|df=dmy-all}}</ref> Why PML occurs more frequently in people with AIDS than in other immunosuppressive conditions is unclear; 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.<ref name="pmid12709870">{{cite journal |title=Progressive multifocal leukoencephalopathy in acquired immunodeficiency syndrome: explaining the high incidence and disproportionate frequency of the illness relative to other immunosuppressive conditions |journal=[[J. Neurovirol.]] |volume=9 Suppl 1 |issue= 2|pages=38–41 |year=2003 |pmid=12709870 |doi=10.1080/13550280390195261 |last1=Berger |first1=Joseph|s2cid=17171153 }}</ref>

PML can still occur in people on immunosuppressive therapy, such as [[efalizumab]], [[belatacept]], and various transplant drugs, which are meant to weaken the immune system.<ref name="pmid21777829" />

===Multiple sclerosis medications===
[[Natalizumab]] (Tysabri) was approved in 2004 by the FDA for the treatment of multiple sclerosis (MS). It supposedly works by preventing white blood cells from entering the brain. It was subsequently [[list of withdrawn drugs|withdrawn from the market]] by its manufacturer after it was linked with three cases of PML.<ref name="pmid21777829">{{cite journal|title=Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring|journal=Lancet Neurology|date=August 2011|volume=10|issue=8|pages=745–58|doi=10.1016/S1474-4422(11)70149-1|pmid=21777829|last1=Kappos|first1=Ludwig|last2=Bates|first2=David|last3=Edan|first3=Gilles|last4=Eraksoy|first4=Mefkûre|last5=Garcia-Merino|first5=Antonio|last6=Grigoriadis|first6=Nikolaos|last7=Hartung|first7=Hans-Peter|last8=Havrdová|first8=Eva|last9=Hillert|first9=Jan|last10=Hohlfeld|first10=Reinhard|last11=Kremenchutzky|first11=Marcelo|last12=Lyon-Caen|first12=Olivier|last13=Miller|first13=Ariel|last14=Pozzilli|first14=Carlo|last15=Ravnborg|first15=Mads|last16=Saida|first16=Takahiko|last17=Sindic|first17=Christian|last18=Vass|first18=Karl|last19=Clifford|first19=David B|last20=Hauser|first20=Stephen|last21=Major|first21=Eugene O|last22=O'Connor|first22=Paul W|last23=Weiner|first23=Howard L|last24=Clanet|first24=Michel|last25=Gold|first25=Ralf|last26=Hirsch|first26=Hans H|last27=Radü|first27=Ernst-Wilhelm|last28=Sørensen|first28=Per Soelberg|last29=King|first29=John|s2cid=15639613|hdl=2078.1/124907}}</ref> All three initial cases were taking natalizumab in combination with [[interferon beta-1a]].<ref name="pmid21777829"/> After a safety review, the drug was returned to the market in 2006 as a monotherapy for MS under a special prescription program.<ref name="pmid21777829"/> 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.<ref name="pmid21777829"/> 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 three- and four-fold.<ref name="pmid21777829"/> The estimated [[prevalence]] of PML in MS is 1.5 cases per thousand natalizumab users.<ref name="pmid21777829"/> Around 20% of MS patients with PML die, and most of the rest are very disabled.<ref name="pmid21777829"/> One case study describes an MS patient who, during a 4-year course of [[dimethyl fumarate]], developed PML and died.<ref>{{Cite web | url=https://www.gov.uk/drug-safety-update/dimethyl-fumarate-tecfidera-fatal-pml-in-a-ms-patient-with-severe-prolonged-lymphopenia | title=Dimethyl fumarate (Tecfidera): Fatal PML in an MS patient with severe, prolonged lymphopenia}}</ref>

[[Fingolimod]] (Gilenya) was [https://www.drugs.com/history/gilenya.html approved in 2010] by the FDA for MS.  In 2015, the first case of PML and a case of "probable PML" were reported by two Gilenya users that could not be tied to previous immunosuppressant therapies.  These new cases are now being added to the drug information sheet included with every prescription (i.e. the "drug label").<ref>{{cite web |title=FDA Drug Safety Communication: FDA warns about cases of rare brain infection with MS drug Gilenya (fingolimod) in two patients with no prior exposure to immunosuppressant drugs |url=https://www.fda.gov/Drugs/DrugSafety/ucm456919.htm |website=US Food and Drug Administration |access-date=31 December 2018}}</ref>