Editing Progressive multifocal leukoencephalopathy

{{Short description|Viral disease affecting human brains}}
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'''Progressive multifocal leukoencephalopathy''' ('''PML''') is a rare and often fatal [[virus|viral]] disease characterized by progressive damage (''-pathy'') or [[inflammation]] of the [[white matter]] (''leuko-'') of the [[Human brain|brain]] (''-encephalo-'') at multiple locations (''multifocal''). It is caused by the [[JC virus]], which is normally present and kept under control by the immune system. The JC virus is harmless except in cases of weakened immune systems. In general, PML has a mortality rate of 30–50% in the first few months, and those who survive can be left with varying degrees of neurological disabilities.

PML occurs almost exclusively in patients with severe [[immune deficiency]], most commonly among patients with [[acquired immune deficiency syndrome]] (AIDS), but people on chronic [[immunosuppressive]] medications including [[chemotherapy]] are also at increased risk of PML, such as patients with transplants, [[Hodgkin's lymphoma]], [[multiple sclerosis]], [[psoriasis]], [[rheumatoid arthritis]], and other autoimmune diseases.

==Signs and symptoms==
Symptoms can develop over several weeks to months, and they depend on location of damage in the brain and the degree of damage. The most prominent symptoms are "clumsiness, progressive weakness, and visual, speech, and sometimes personality changes".<ref name=NIH/>
The lesions affecting the [[Parietal lobe|parietal]] and [[Occipital lobe|occipital]] lobes of the brain can lead to a phenomenon known as [[alien hand syndrome]].<ref>{{cite journal |last1=Panikkath |first1=Ragesh |last2=Panikkath |first2=Deepa |last3=Mojumder |first3=Deb |last4=Nugent |first4=Kenneth |title=The alien hand syndrome |journal=Proceedings (Baylor University. Medical Center) |volume=27 |issue=3 |pages=219–220 |pmc=4059570 |year=2014 |pmid=24982566 |doi=10.1080/08998280.2014.11929115 }}</ref>

==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 |archive-url=https://web.archive.org/web/20150807054009/http://www.fda.gov/Drugs/DrugSafety/ucm456919.htm |url-status=dead |archive-date=August 7, 2015 |website=US Food and Drug Administration |access-date=31 December 2018}}</ref>

==Pathogenesis==
PML is a [[demyelinating disease]], in which the [[myelin]] sheath covering the [[axon]]s 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 [[oligodendrocyte]]s and produces intranuclear inclusions. It is similar to another demyelinating disease, MS, but progresses much more quickly. The breakdown of myelin is proportional to the degree of immunocompromise.<ref>{{Cite web|url=https://radiopaedia.org/articles/progressive-multifocal-leukoencephalopathy?lang=us|title=Progressive multifocal leukoencephalopathy {{!}} Radiology Reference Article {{!}} Radiopaedia.org|last=Radswiki|website=Radiopaedia|language=en-US|access-date=2019-03-09}}</ref>

==Diagnosis==
PML is diagnosed in a patient with a progressive course of the disease, finding JC virus [[DNA]] in [[cerebrospinal fluid|spinal fluid]] together with consistent white-matter lesions on brain [[magnetic resonance imaging]] (MRI); alternatively, a brain [[biopsy]] is diagnostic<ref name=NIH/> when the typical histopathology of demyelination, bizarre astrocytes, and enlarged oligodendroglial nuclei are present, coupled with techniques showing the presence of JC virus.<ref name=AAN>{{cite journal|author1=Berger JR|author2=Aksamit AJ|author3=Clifford DB|title=PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section|journal=Neurology|date=9 April 2013|volume=80|issue=15|pages=1430–8|doi=10.1212/WNL.0b013e31828c2fa1|pmid=23568998|display-authors=etal|pmc=3662270}}</ref>

Characteristic evidence of PML on brain [[CT scan]] images are multifocal, non[[Radiocontrast agent|contrast]] enhancing hypodense lesions without [[mass effect (medicine)|mass effect]], but MRI is far more sensitive than CT.<ref name=AAN/> The most common area of involvement is the cortical white matter of [[frontal lobe|frontal]] and [[parietal lobe|parieto]] [[occipital lobe]]s, but lesions may occur anywhere in the brain, such as the [[basal ganglia]], [[external capsule]], and [[posterior cranial fossa]] structures such as the brain stem and cerebellum.<ref name=AAN/>
Although typically multifocal, natalizumab-associated PML is often monofocal, predominantly in the frontal lobe.<ref name=AAN/>

==Treatment==
No drugs effectively inhibit or cure the virus infection without toxicity. Therefore, treatment aims at reversing the immune deficiency to slow or stop the disease progress. In patients on immunosuppression, this means stopping the drugs or using plasma exchange to accelerate the removal of the biologic agent that put the person at risk for PML.<ref name=NIH/>

In HIV-infected people, this may mean starting [[antiretroviral drug|highly active antiretroviral therapy]] (HAART). AIDS patients starting 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.<ref>{{cite journal | year = 2004 | title = Progressive multifocal leukencephalopathy in patients on highly active antiretroviral therapy: survival and risk factors of death | journal = Journal of Acquired Immune Deficiency Syndromes | volume = 37 | issue = 2| pages = 1263–1268 | pmid = 15385733 | doi = 10.1097/01.qai.0000136093.47316.f3 | last1 = Wyen | first1 = Christoph | last2 = Hoffmann | first2 = Christian | last3 = Schmeier | first3 = Norbert | last4 = Hoffmann | first4 = Andrej | last5 = Qurishi | first5 = Nazifa | last6 = Rockstroh | first6 = Jürgen | last7 = Esser | first7 = Stefan | last8 = Rieke | first8 = Ansgar | last9 = Ross | first9 = Birgit | last10 = Lorenzen | first10 = Thore | last11 = Schmitz | first11 = Karina | last12 = Stenzel | first12 = Werner | last13 = Salzberger | first13 = Bernd | last14 = Fätkenheuer | first14 = Gerd | s2cid = 23613081 | doi-access = free }}</ref> Some AIDS patients with PML have been able to survive for several years, with HAART.<ref>{{cite journal |last1=Gray |first1=Françoise |last2=Salmon |first2=Dominique |last3=Thiebault |first3=Jean Baptiste |last4=Gasnault |first4=Jacques |last5=Bienvenu |first5=Boris |last6=Vendrely |first6=Aurélie |s2cid=23865244 |title=Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy |journal=Acta Neuropathologica |volume=109 |issue=4 |pages=449–455 |ref=21|doi=10.1007/s00401-005-0983-y |pmid=15739098 |year=2005 }}</ref> 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 JCV infection; although IRIS can often be managed with medication, it is extremely dangerous in PML.<ref>{{cite journal |title=Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy |journal=Acta Neuropathol. |volume=109 |issue=4 |pages=449–55 |date=April 2005 |pmid=15739098 |doi=10.1007/s00401-005-0983-y |last1=Vendrely  |first1=Aurélie  |last2=Bienvenu  |first2=Boris  |last3=Gasnault  |first3=Jacques  |last4=Thiebault  |first4=Jean Baptiste  |last5=Salmon  |first5=Dominique  |last6=Gray  |first6=Françoise|s2cid=23865244 }}</ref>

[[Cidofovir]] was studied as possible treatment for PML<ref name="pmid11408993">{{cite journal |title=Use of cidofovir in progressive multifocal leukoencephalopathy |journal=Ann Pharmacother |volume=35 |issue=6 |pages=741–4 |date=June 2001 |pmid=11408993 |doi=10.1345/aph.10338 |url=http://www.theannals.com/cgi/pmidlookup?view=long&pmid=11408993 |last1=Segarra-Newnham |first1=Marisel |last2=Vodolo |first2=Kristen M |s2cid=32026770 |url-access=subscription }}{{dead link|date=April 2018 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> and has been used on a case-by-case basis, working in some, but not others.

[[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, and stabilized the neurological condition of a minority of these patients.<ref>{{cite journal |title=Treatment of non-AIDS progressive multifocal leukoencephalopathy with cytosine arabinoside |journal=J. Neurovirol. |volume=7 |issue=4 |pages=386–90 |date=August 2001 |pmid=11517422 |doi= 10.1080/13550280152537292|last1=Aksamit |first1=A J|s2cid=12159275 }}</ref>  One patient regained some cognitive function lost as a result of PML.<ref>{{cite journal  |title=Progressive multifocal leukoencephalopathy in a patient treated with natalizumab |journal=N. Engl. J. Med. |volume=353 |issue=4 |pages=375–81 |date=July 2005 |pmid=15947078 |doi=10.1056/NEJMoa051847 |last1=Langer-Gould  |first1=Annette  |last2=Atlas  |first2=Scott W.  |last3=Green  |first3=Ari J.  |last4=Bollen  |first4=Andrew W.  |last5=Pelletier  |first5=Daniel|doi-access=free}}</ref>

In June 2010, the first [[case report]] appeared of a PML patient being successfully treated with the antimalarial drug [[mefloquine]] with activity against the JC virus. The patient cleared the virus and had no further neurological deterioration.<ref>{{cite journal |title=Mefloquine in the treatment of progressive multifocal leukoencephalopathy |journal= J Neurol Neurosurg Psychiatry |volume= 82|issue= 4|pages= 452–455|date=June 2010 |pmid= 20562463|doi= 10.1136/jnnp.2009.190652|url=http://jnnp.bmj.com/content/early/2010/06/19/jnnp.2009.190652.full |last1=Gofton |first1=T. E. |last2=Al-Khotani |first2=A. |last3=O'Farrell |first3=B. |last4=Ang |first4=L. C. |last5=McLachlan |first5=R. S.|s2cid= 19877728 |url-access=subscription }}</ref> Two case reports of using [[interleukin-2]] successfully have been published.<ref>{{cite journal|author1=Buckanovich RJ1, Liu G, Stricker C|s2cid=24949477|title=Nonmyeloablative allogeneic stem cell transplantation for refractory Hodgkin's lymphoma complicated by interleukin-2 responsive progressive multifocal leukoencephalopathy.|journal=Ann Hematol|date=July 2002|volume=81|issue=7|pages=410–3|pmid=12185517|doi=10.1007/s00277-002-0481-4|display-authors=etal}}</ref> Some success have been reported with [[mirtazapine]], but this has not been demonstrated in clinical trials.<ref>{{cite journal|last1=Jamilloux|first1=Y|last2=Kerever|first2=S|last3=Ferry|first3=T|last4=Broussolle|first4=C|last5=Honnorat|first5=J|last6=Sève|first6=P|s2cid=34008609|title=Treatment of Progressive Multifocal Leukoencephalopathy With Mirtazapine.|journal=Clinical Drug Investigation|date=October 2016|volume=36|issue=10|pages=783–9|pmid=27401779|doi=10.1007/s40261-016-0433-8}}</ref>
A number of drugs work against JC virus in [[cell culture]], but no proven, effective therapy is known in humans.<ref>{{cite journal |title=Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. |journal=Clin. Microbiol. Rev. |volume=25 |issue=3 |pages=471–506 |date=July 2012 |pmid=22763635 |doi= 10.1128/CMR.05031-11|last1=Ferenczy |first1=MW | last2 = Marshall | first2 = LJ | last3 = Nelson | first3 = CD | last4 = Atwood | first4 = WJ | last5 = Nath | first5 = A | last6 = Khalili | first6 = K | last7 = Major | first7 = EO | pmc=3416490}}</ref>
For example, [[Brincidofovir]] (1-O-hexadecyloxypropyl-cidofovir /CMX001) available as Tembexa, suppresses JCV,<ref>{{cite journal |title=CMX001 (1-O-hexadecyloxypropyl-cidofovir) inhibits polyomavirus JC replication in human brain progenitor-derived astrocytes. |journal=Antimicrob. Agents Chemother. |volume=55 |issue=5 |pages=2129–36 |date=May 2011 |pmid= 21402853 |doi=10.1128/AAC.00046-11|last1 = Gosert | first1 = R | last2 = Rinaldo | first2 = C.H. | last3 = Wernil | first3 = M | last4 = Major | first4 = EO| last5 = Hirsch | first5 = HH | pmc=3088264}}</ref> but has been found to have toxicity at therapeutic dosage.<ref>{{cite journal |last1=Rainer |first1=Gosert |last2=Rinaldo |first2=Christine |last3=Wernli |first3=Marion |last4=Major |first4=Eugene |last5=Hirsch |first5=Hans |title=CMX001 (1-O-Hexadecyloxypropyl-Cidofovir) Inhibits Polyomavirus JC Replication in Human Brain Progenitor-Derived Astrocytes |journal=Antimicrobial Agents and Chemotherapy |volume=55 |issue=5 |pages=2129–2136 |pmc=3088264 |year=2011 |pmid=21402853 |doi=10.1128/AAC.00046-11 }}</ref>
Infusion of donor T cells specific to the related BK polyomavirus has shown possible effect in treating PML in one small study by Katy Rezvani's group, but needs further study.<ref>{{Cite journal|last1=Muftuoglu|first1=Muharrem|last2=Olson|first2=Amanda|last3=Marin|first3=David|last4=Ahmed|first4=Sairah|last5=Mulanovich|first5=Victor|last6=Tummala|first6=Sudhakar|last7=Chi|first7=T. Linda|last8=Ferrajoli|first8=Alessandra|last9=Kaur|first9=Indreshpal|display-authors=3|date=2018-10-11|title=Allogeneic BK Virus–Specific T Cells for Progressive Multifocal Leukoencephalopathy|journal=New England Journal of Medicine|language=en|volume=379|issue=15|pages=1443–1451|doi=10.1056/nejmoa1801540|pmid=30304652|pmc=6283403|issn=0028-4793}}</ref>
In December 2021, Cellevolve announced it is launching a clinical trial for the treatment of PML utilizing BK virus specific T-cells (VSTs).<ref>{{cite web |title=Cellevolve Announces Global Partnership with QIMR Berghofer Medical Research Institute to Advance Novel Off-the Shelf T-cell Therapy in the First Randomized Cell Therapy Trial for Progressive Multifocal Leukoencephalopathy (PML) |url=https://www.businesswire.com/news/home/20211201005654/en/Cellevolve-Announces-Global-Partnership-with-QIMR-Berghofer-Medical-Research-Institute-to-Advance-Novel-Off-the-Shelf-T-cell-Therapy-in-the-First-Randomized-Cell-Therapy-Trial-for-Progressive-Multifocal-Leukoencephalopathy-PML |website=BUSINESS WIRE |date=December 2021 |access-date=3 May 2022}}</ref>

==Prognosis==
One-third to one-half of people with PML die in the first few months following diagnosis, depending on the severity of their underlying disease. Survivors can be left with variable degrees of neurological disability.<ref name=NIH/>

== See also ==
* [[Joseph Berger (neurologist)]]
* [[Leukoencephalopathy]]
* [[Leukoencephalopathy with vanishing white matter]]
* [[Toxic leukoencephalopathy]]
* [[Pedro Zamora]]
* [[It's My Party (film)]]

==References==
{{Reflist}}

== External links ==
* [https://web.archive.org/web/20150104180601/http://www.ninds.nih.gov/disorders/pml/pml.htm Overview] at [[NIH]]
* {{eMedicine|neuro|450|HIV-1 Associated Opportunistic Infections: PML}}
* {{MedlinePlusEncyclopedia|000674|Progressive multifocal leukoencephalopathy}}
{{Medical resources
| DiseasesDB     = 10718
| ICD11          = {{ICD11|8A45.02}}
| ICD10          = {{ICD10|A81.2}}
| ICD9           = {{ICD9|046.3}}
| ICDO           = 
| OMIM           = 
| MedlinePlus    = 000674
| eMedicineSubj  = radio
| eMedicineTopic = 573
| MeshID         = D007968
| Orphanet       = 217260
}}
{{Viral diseases}}
{{CNS diseases of the nervous system}}

[[Category:Brain disorders]]
[[Category:Viral infections of the central nervous system]]
[[Category:Rare diseases]]
[[Category:Slow virus diseases]]
[[Category:Rare infectious diseases]]