NORD gratefully acknowledges Igor J. Koralnik, MD, Professor of Neurology and Edith L. Graham, MD, Assistant Professor of Neurology, Northwestern University, Feinberg School of Medicine, Chicago, IL, for assistance in the preparation of this report.
Progressive multifocal leukoencephalopathy (PML) (1) is a neurological disorder characterized by destruction of cells that produce myelin, an oily substance that helps protect nerve cells in the brain and spinal cord, also known as central nervous system (CNS) white matter. It is caused by a virus called JC virus (JCV), named after the initials of the patient in whom it was first discovered. The virus is widespread, found in up to 85% of the general adult population. It remains inactive in healthy individuals and causes disease only when the immune system has been severely weakened, such as in people with HIV/AIDS, hematological malignancies and those receiving certain immunosuppressant medications. Altogether, PML occurs in approximately one in 200,000 people. Each year, it is estimated that 4,000 people develop PML in the United States and Europe combined. The term “progressive” in PML means that the disease continues to get worse and often leads to serious brain damage. The term “multifocal” means that JCV causes disease in multiple parts of the brain. However, it is possible for an individual with PML to have only one brain lesion instead of several lesions. The term “leukoencephalopathy” means that the disease affects mainly the white matter of the brain or myelin, although in some patients the gray matter neurons are also involved.
Symptoms of PML vary from person to person because lesions may occur anywhere in the central nervous system. Most patients present with subacute neurological damage, which may include some degree of mental impairment and a variety of other symptoms such as vision loss, speech disturbances, facial drooping, weakness, problems with coordination, gait and sensory loss. In addition, approximately one third of PML patients can present with seizures during the course of their disease.
The disease course of PML used to be considered invariably progressive, with most non-HIV-related cases leading to a fatal outcome within months after the diagnosis. However, it is now known that there are a small number of HIV-positive patients who, having developed PML, will experience disease stabilization and prolonged survival.(2)
CD4+ and CD8+ T lymphocytes are types of immune cells that are of major importance to the health of the immune system. They help to mediate the immune response against many infectious organisms. In a patient with an active HIV infection, the levels of these lymphocytes are greatly decreased. However, antiretroviral medications, which are now a standard part of HIV treatment, have enabled the crucial CD4 and CD8 lymphocytes to rise to within normal levels.
Before the availability of medications used to fight HIV (antiretrovirals), only 10% of HIV-positive patients with PML lived for more than a year. With the advent of antiretroviral therapy (ART), one-year survival has increased to 50% on average.(3) ART increases the crucial lymphocyte levels, thus enabling the immune system, under certain circumstances, to fight off the JC virus. However, among these patients, those who are able to mount a strong immune response mediated by T lymphocytes which are directed specifically against JCV have a better outcome. Those patients have a one year survival of 73% compared to 46% for those who do not have T cells capable of recognizing JCV.
Because formation of new white matter by CNS cells (remyelination) does not occur in affected areas, 80% of PML survivors do not experience much regression of their symptoms. They may be left with permanent neurological dysfunction, similar to patients who have suffered a stroke. Nevertheless, PML patients may have extended survival up to 15 years and beyond if the initial cause of immunosuppression is under control, for example in HIV-infected patients treated by ART or in cancer patients successfully treated with chemotherapy. In these patients, the disease is not active anymore and they have burnt-out PML.
The JC virus usually enters the bloodstream during childhood. It can be found via blood tests in healthy children with no symptoms of PML. Because the virus is also frequently found in the urine of healthy individuals, it is possible that the initial infection may occur through urine-oral contamination.
After primary infection, the virus remains inactive in the kidneys and lymphoid organs. Indeed, JCV can be found in the urine samples of approximately 30% of people, regardless of their immune status.(4) JCV also has been detected in bone marrow samples, including patients with PML, HIV, leukemia, and bone marrow transplant recipients, but also in bone marrow of some HIV-negative patients without immunosuppression.(5) Other studies have suggested that JCV is also latent in the normal digestive system and tonsils, and there is growing evidence that JCV can also remain latent in the brain.(6)
The exact mechanisms that lead to JCV activation and the development of PML have not been entirely elucidated, but as explained above, most cases occur in the setting of profound cellular immune dysfunction. Studies of the type of blood cells that carries JCV have shown an association with B lymphocytes blood cells that mainly produce antibodies as well as other types of leukocytes including T lymphocytes, monocytes, polymorphonuclear leukocytes and cell-free plasma.(7)
Despite the possible participation of the blood cells in transporting the JC virus throughout the body, the virus is rarely detected in routine blood tests of healthy individuals. While it is believed that PML is usually caused by activation of a dormant JC virus, it may also occur as a new infection in adults who have become severely immune-compromised.
In the advent of the human immunodeficiency virus (HIV) epidemic, PML was soon recognized as a major opportunistic infection of acquired immunodeficiency syndrome (AIDS) occurring in up to 5% of patients.(8) Based on a study of 91 cases of PML from 1994 to 2019, 49% of PML patients have HIV infection, 31% have hematological malignancies, 30% have exposure to chemotherapeutic medications and 19% have exposure to monoclonal antibody therapies.(9)
Among patients with lymphoproliferative disorders, such as chronic lymphocytic leukemia, it has been found that those treated with certain medications that interfere with life cycles of blood cells (i.e. fludarabine) might be at increased risk for developing PML. Studies have shown a 3% incidence of PML in patients receiving these types of medications.(10) In addition, rare cases of PML have been diagnosed in HIV-negative patients with other types of drug-induced or idiopathic CD4 and CD8 T cell suppression, as well as in patients with no obvious source of immunosuppression.(11)
In February, 2005, two biotechnology companies, Biogen Idec and Elan, voluntarily withdrew a promising new drug for treatment for relapsing/remitting multiple sclerosis (MS) and Crohn’s disease called Tysabri (natalizumab). This drug was taken off the market after the discovery of two people with MS who developed PML after taking Tysabri.(12)
However, after a review of the data by an independent adjudication committee, the “Peripheral and Central Nervous System Drug Advisory Committee of the US Food and Drug Administration”, Tysabri was allowed back on the market. It has become available again as of August 2006 for MS patients. The risk of PML increases with duration of treatment, with the greatest increase in risk occurring after 2 years of therapy (13) Improved risk stratification (14) and clinical monitoring including the mandatory TOUCH® Prescribing Program Database has led to a decline in PML cases associated with Tysabri.(15) As of February 2021, there have been 853 cases of Tysabri-associated PML in MS (850) and Crohn’s (3) patients in the world. The risk of PML can be determined by anti-JCV antibody serostatus. In patients who are negative for anti-JCV antibody, the risk of PML is 1/10,000. However, if patients are JCV seropositive and have received immunosuppressant medications prior to Tysabri, the risk of PML goes up to 6/1,000 after 24 months of continuous therapy.(16)
Other disease modifying therapies have been associated with PML. Tecfidera (dimethyl fumarate) poses a risk of 0.02/1000 (1/50,000), of which the majority were associated with an absolute lymphocyte count (ALC) < 800.(17, 18) As of February 2020, Gilenya (fingolimod) has been associated with 54 cases (37 monotherapy, 17 Tysabri carry over) and has a risk of 0.13/1000 (1/8000). Ocrevus (ocrelizumab) has been associated with 10 cases as of December 2020, 8 from Tysabri carry over, 1 from Gilenya carry over and 1 in a 78-year-old man with lymphopenia.(19, 20)
The brain MRI is the first step in diagnosing PML. Cerebrospinal fluid, collected via a spinal tap, is also a dependable way to diagnose PML. Based on the 2013 consensus criteria, the diagnosis of PML can be made by the presence of positive CSF JC virus PCR in conjunction with typical clinical and imaging findings. Alternatively, brain biopsy may be necessary in some patients to confirm the diagnosis.(33) Due to the expanded population of individuals at risk for PML, early diagnosis has become of critical importance.
Treatment
There is no specific treatment for JCV. In HIV-positive patients with PML, optimization of ART is the best therapeutic option, and in HIV-negative patients, removal or decrease of any potential source of immunosuppression is recommended.(34) Because PML has a high mortality rate, numerous drugs have been tried empirically. Mefloquine inhibits JCV replication in vitro, and few case reports have shown a beneficial effect in PML (35); however, this medication did not benefit PML patients in a randomized controlled trial (clinicaltrials.gov number NCT00746941). A single study showed benefit of treatment with filgrastim (also known as granulocyte‐colony stimulating factor G‐CSF) in 17 natalizumab-induced PML patients.(36) Targeted cytokine therapy with interleukin-7 (IL7) has been shown to improve cell-mediated immunity and enhance immune reconstitution for PML in several patients.(37, 38, 39) Moreover, two immune checkpoint inhibitors, pembrolizumab and nivolumab, have been recently reported to improve outcomes in patients with PML from various etiologies in three small cohorts,(40, 41, 42) although clinical trials are warranted.(43) Additionally, a few centers have reported results of case reports or small series with adoptive transfer of T cells programmed to detect and kill cells infected with the JC virus.(44, 45, 46) Every patient may have a different presentation, and require personalized management. This can be best determined through an office visit, or if this is not practical, through a “cyberconsult”.(47)
For information or to schedule a cyberconsult, contact:
Igor J. Koralnik, M.D. FAAN, FANA
Archibald Church Professor of Neurology
Chief, Division of Neuro-Infectious Diseases & Global Neurology
Davee Department of Neurology
Director, Global Neurology Program
Global Health Institute
Morton 7-615, 320E Superior St.
Chicago, IL 60611
T: (312) 503 1345 F: (312) 503 3950
Appt line: (312) 695-7950
Clinic Fax: (312) 695-5747
Email: [email protected]
https://www.neurology.northwestern.edu/divisions/neuroinfectious-disease/index.html
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For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
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Some current clinical trials also are posted on the following page on the NORD website:
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3. Marzocchetti A, Tompkins T, Clifford DB, Gandhi RT, Kesari S, Berger JR, Simpson DM, Prosperi M, De Luca A, Koralnik IJ. Determinants of survival in progressive multifocal leukoencephalopathy. Neurology 2009; 73:1551-8.
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5. Tan CS, Dezube BJ, Bhargava P, Autissier P, Wuthrich C, Miller J, Koralnik IJ. Detection of JC virus DNA and proteins in the bone marrow of HIV-positive and HIV-negative patients: implications for viral latency and neurotropic transformation. J Infect Dis 2009;199:881-8.
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8. Berger JR, Kaszovitz B, Post MJ, Dickinson G. Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. A review of the literature with a report of sixteen cases. Ann Intern Med 1987;107:78-87.
9. Anand P, Hotan GC, Vogel A, Venna N, Mateen FJ. Progressive multifocal leukoencephalopathy: A 25-year retrospective cohort study. Neurol Neuroimmunol Neuroinflamm. 2019;6(6):e618.
10. Garcia-Suarez J, de Miguel D, Krsnik I, Banas H, Arribas I, Burgaleta C. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies. Am J Hematol 2005;80:271-81.
11. Gheuens S, Pierone G, Peeters P, Koralnik IJ. Progressive multifocal leukoencephalopathy in individuals with minimal or occult immunosuppression. J Neurol Neurosurg Psychiatry 2010;81: 247-54.
12. Berger JR, Koralnik IJ. Progressive multifocal leukoencephalopathy and natalizumab–unforeseen consequences. N Engl J Med 2005;353:414-6.
13. Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870-80.
14. Ho PR, Koendgen H, Campbell N, Haddock B, Richman S, Chang I. Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. Lancet Neurol. 2017;16(11):925-933.
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16. TYSABRI® (natalizumab): PML Incidence in Patients Receiving TYSABRI. Biogen Medical Information. Updated April 1, 2021.
17. Jordan AL, Yang J, Fisher CJ, Racke MK, Mao-Draayer Y. Progressive multifocal leukoencephalopathy in dimethyl fumarate-treated multiple sclerosis patients [published online ahead of print, 2020 Aug 18]. Mult Scler. 2020;1352458520949158.
18. Fox R, et al. Update on the risk estimates of progressive multifocal leukoencephalopathy related to fingolimod. MSVirtual 2020, Abstract FC02.02.
19. Ocrelizumab & PML. Genentech Medical Information. Updated December 2020.
20. Patel A, Sul J, Gordon ML, et al. Progressive Multifocal Leukoencephalopathy in a Patient With Progressive Multiple Sclerosis Treated With Ocrelizumab Monotherapy [published online ahead of print, 2021 Mar 16]. JAMA Neurol. 2021;e210627.
21. Tan K, Roda R, Ostrow L, McArthur J, Nath A. PML-IRIS in patients with HIV infection. Clinical manifestations and treatment with steroids. Neurology 2009;28;72(17):1458-64.
22. Gheuens S, Ngo L, Wang X, Alsop DC, Lenkinski RE, Koralnik IJ. Metabolic profile of PML lesions in patients with and without IRIS: An observational study. Neurology 2012;79:1041-8.
23. Du Pasquier RA, Corey S, Margolin DH, Williams K, Pfister LA, De Girolami U, Mac Key JJ, Wuthrich C, Joseph JT, Koralnik IJ. Productive infection of cerebellar granule cell neurons by JC virus in an HIV+ individual. Neurology 2003;61:775-82.
24. Koralnik IJ, Wuthrich C, Dang X, Rottnek M, Gurtman A, Simpson D, Morgello S. JC virus granule cell neuronopathy: A novel clinical syndrome distinct from progressive multifocal leukoencephalopathy. Ann Neurol 2005;57:576-80.
25. Dang X, Vidal JE, Oliveira AC, Simpson DM, Morgello S, Hecht JH, Ngo LH, Koralnik IJ. JC virus granule cell neuronopathy is associated with VP1 C terminus mutants. J Gen Virol 2012;93:175-83.
26. Schippling S, Kempf C, Büchele F, Jelcic I, Bozinov O, Bont A, Linnebank M, Sospedra M, Weller M, Budka H, Martin R. JC virus granule cell neuronopathy and GCN-IRIS under natalizumab treatment. Ann Neurol 2013;74:622-6
27. Dang X, Koralnik IJ. Gone over to the dark side: natalizumab-associated JC virus infection of neurons in cerebellar gray matter. Editorial. Ann Neurol 2013, 74:503-7.
28. Agnihotri S, Dang X, Carter JL, Fife TD, Bord E, Batson S, Koralnik IJ. JCV granule cell neuronopathy in a natalizumab-treated patient with multiple sclerosis is associated with mutations in the VP1 capsid gene. Neurol 2014, 19:727-32
29. Wuthrich C, Dang X, Westmoreland S, McKay J, Maheshwari A, Anderson MP, Ropper AH, Viscidi RP, Koralnik IJ. Fulminant JC virus encephalopathy with productive infection of cortical pyramidal neurons. Ann Neurol 2009;65:742-8.
30. Dang X, Wuthrich C, Gordon J, Sawa H, Koralnik IJ. JC virus encephalopathy is associated with a novel agnoprotein-deletion JCV variant. PLoS ONE 7(4) 2012;e35793.
31. Agnihotri SP, Wuthrich C, Nauen D, Karimi R, Viscidi R, Trocoso J, Bord E, Batson S, Koralnik IJ. A fatal case of JC virus meningitis presenting with hydrocephalus in an HIV-seronegative patient. Ann Neurol 2014, 76:140-7
32. Miskin DP, Koralnik IJ. Novel syndromes associated with JC virus infection of neurons and meningeal cells: no longer a gray area. Curr Op Neurol 2015; 28:288-94
33. Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology. 2013;80(15):1430-1438.
34. Tan CS, Koralnik IJ. Chapter 144: JC, BK, and Other Polyomaviruses: Progressive Multifocal Leukoencephalopathy (PML). In Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. Elsevier. 2014:1931-9.
35. Brickelmaier M, Lugovskoy A, Kartikeyan R, et al. Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrob Agents Chemother. 2009;53(5):1840-1849.
36. Stefoski D, Balabanov R, Waheed R, Ko M, Koralnik IJ, Sierra Morales F. Treatment of natalizumab-associated PML with filgrastim. Ann Clin Transl Neurol. 2019;6(5):923-931.
37. Miskin DP, Chalkias SG, Dang X, Bord E, Batson S, Koralnik IJ. Interleukin-7 treatment of PML in a patient with idiopathic lymphocytopenia. Neurol Neuroimmunol Neuroinflamm. 2016;3(2):e213.
38. 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(11):1588-1592.
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40. Walter O, Treiner E, Bonneville F, Mengelle C, Vergez F, Lerebours F, Delobel P, Liblau R, Martin-Blondel G, Immune Checkpoint Inhibitors in PML Study Group. N Engl J Med. 2019 Apr 25; 380(17):1674-1676.
41. Cortese I, Muranski P, Enose-Akahata Y, Ha SK, Smith B, Monaco M, Ryschkewitsch C, Major EO, Ohayon J, Schindler MK, Beck E, Reoma LB, Jacobson S, Reich DS, Nath A. N Engl J Med. 2019 Apr 25; 380(17):1597-1605.
42. Hoang E, Bartlett NL, Goyal MS, Schmidt RE, Clifford DB. J Neurovirol. 2019 Apr; 25(2):284-287.
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44. Muftuoglu M, Olson A, Marin D, et al. Allogeneic BK Virus-Specific T Cells for Progressive Multifocal Leukoencephalopathy. N Engl J Med. 2018;379(15):1443-1451.
45. Berzero G, Basso S, Stoppini L, et al. Adoptive Transfer of JC Virus-Specific T Lymphocytes for the Treatment of Progressive Multifocal Leukoencephalopathy. Ann Neurol. 2021;89(4):769-779.
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