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What is PML?

Overview

Progressive multifocal leukoencephalopathy (PML) is a rare (in the general population) but serious demyelinating disease of the brain, often resulting in severe disability or death, caused by lytic infection of oligodendrocytes by the JC polyomavirus (JCV).1

 

Recent data about the prevalence of JCV exposure in the general population is limited. However, a 2009 study of 400 healthy blood donors showed 58% of the study population to have been exposed,2 and exposure in the general adult population with multiple sclerosis has been estimated at 54.9%3. Despite high prevalence of JCV infection in the human population, which typically leads to a chronic, asymptomatic infection, incidence of PML in the general population is very low. While wild-type JCV infection is benign, PML is associated with the presence of virus that acquires certain rare genetic alterations. The emergence of PML is also dependent on impairment of host immune function, thus the susceptibility to this disease is driven by the convergence of rare viral and host factors. PML is primarily seen in patients with HIV-AIDS, but has also been associated with hematologic malignancies, Systemic Lupus Erythematosus, and most recently has been reported to be associated with certain immunosuppressive or immunomodulatory therapies.

 

MRI imagery


PATHOPHYSIOLOGY

The pathogenesis of PML is not well understood. It is known that the development of PML, while dependent on the presence of the JC virus, is the result of a confluence of specific viral and host risk factors.

 

JCV infection is chronic; kidney appears to be the primary site of infection and approximately 19-27% of adults shed JCV in their urine with prevalence of shedding dependent on gender and age.1 JCV is rarely found in blood, and while there have been reports of JCV in brain, bone marrow, tonsil and peripheral blood lymphocytes, viral tropism and lifecycle beyond kidney is not understood. It is therefore unclear how JCV accesses the central nervous system (CNS) and ultimately infects oligodendrocytes in the brain. Recent data suggest that viral mutations in the VP1 capsid protein and/or the noncoding control regions (NCCRs) might result in a change in tropism or replication capacity that is permissive for pathogenic demyelinating brain infection.4,5

 

The conversion of JCV from a common benign peripheral infection to a rare pathogenic brain infection is dependent on the convergence of host and viral factors. In addition to viral mutations, significant changes to host immune function are also required. HIV-AIDS is the most common context where PML is observed,6 but it is also associated with pathological conditions and certain therapeutics that result in significant immune suppression or immune modulation.

 

PROGNOSISJCV Prognosis

PML prognosis varies depending on comorbidities. If left unmanaged, the mortality rate is 30-50% within the first three months of diagnosis.7 In some cases, intervention can improve the chance of survival, although it is likely that some significant neurological deficits will be permanent. Recent observations indicate that restoration of immune function can support viral clearance and may allow for resolution of PML. However, return of function also frequently leads to an immune reconstitution inflammatory syndrome (IRIS) that may be associated with relevant brain inflammation and dramatically worsened pathological and clinical picture. Early diagnosis via clinical vigilance and restoration of immune function, while managing inflammatory syndrome, is currently the only course to attempt to maximize patient outcome until an effective therapy is identified.

 

The PML Consortium encourages health care professionals to review risk factors frequently by checking this site and other credible sources on a regular basis.  Health care professionals are also encouraged to be vigilant in monitoring at-risk patients for signs and symptoms of PML.

 

Disclaimer: The information on this website is for informational purposes only and is not being provided for the purposes of medical advice. View site Terms of Use.

 


 

1 Bruce Brew, Nicholas Davies, et. al. Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol. 2010 Dec;6(12):667.

2 Egli A, Infanti L, et.al. Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis. 2009 Mar 15, 199(6): 837-46.

3 Gorelik L, et.al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 2010 Sep;68(3): 295-303.

3 Bloomgren G et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012 May 17;366(20):1870-80.

3 Carl E. Reid et. al. Sequencing and Analysis of JC Virus DNA From Natalizumab-Treated PML Patients. J Infect Dis. 2011 July 15; 204(2): 237–244. doi:  10.1093/infdis/jir256.

4 Yogo YS, Sugimoto C. The archetype concept and regulatory region rearrangement. In: Khalili K, Stoner GL, editors. Human polyomaviruses: molecular and clinical perspectives. New York, NY: Wiley-Liss; 2001. pp. 127–48.

5 Gorelik L. In PML patients JC virus (JCV) VP1 protein undergoes selective mutations that change its receptor specificity. J Infect Dis. 2011;204(1):103–14. doi:10.1093/infdis/JIR198.

6 Steiner I, Berger JR. Update on Progressive Multifocal Leukoencephalopathy. Curr Neurol Neurosci Rep. 2012 Sep 19.

7 Bruce Brew, Nicholas Davies, et. al. Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol. 2010 Dec;6(12):673.