Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) is a disease of the white matter of the brain, caused by a virus infection that targets cells that make myelin.
The symptoms of PML are related to the location and amount of damage the virus does in the brain.
PML evolves over the course of several weeks to months.
PML symptoms: weakness, clumsiness, visual, speech, and sometimes personality changes.
Symptom progression can lead to life-threatening disability and frequently death.
Polyomavirus JC (often called JC virus) is carried by a majority of people and is harmless except among those with lowered immune defenses.
Results from the reactivation of latent John Cunningham (JC) infection of B lymphocytes that pass through the blood brain barrier and infect the oligodendrocytes, with widespread destruction of the white matter.
A fatal CNS D mild radiating process caused by reactivation of the neurotropic JCV, a double-stranded circular DNA virus belonging to the Polyomaviridae family.
JCV virus-polyomavirus-2 is ubiquitous in the adult population.
JCV virus infection believed to occur as a primary infection in early childhood through fecal-oral route.
JCV virus can be detected in gastrointestinal epithelial cells.
JCV virus adds troponin to oligodendrocytes, peripheral blood cells and renal epithelial cells that contain alpha(2,6)-and alpha(2,3)-linked sialic residues of N-linked glycoproteins that act as a receptor for JCV entry.
Oligodendrocytes are susceptible to infection by the JC virus, which causes progressive multifocal leukoencephalopathy (PML), a condition that specifically affects white matter, typically in immunocompromised patients.
The JCV virus remains latent until T-cell mediated immunosuppression occurs, when it can reactivate and lead to widespread lysis of oligodendrogliocytes and subsequent CNS demyelination and deterioration.
Serology studies reveal 50-60% of adults age 20-50 years demonstrated antibodies to JCV.
Eosinophilic intranuclear inclusions in oligodendrocytes.
Immunocompromised patients, particularly those with depressed cellular mediated immunity, are at risk.
The disease is rare.
Occurs in patients undergoing chronic corticosteroid or immunosuppressive therapy for organ transplant, or individuals with cancer
Patients with autoimmune conditions such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus are at risk for PML as well.
An aggressive, opportunistic brain infection caused by the JC virus.
The JC virus is a ubiquitous polyomavirus estimated to latentky infect the kidneys in more than 50% of healthy adults.
In the presence of cellular immunodeficiency, JC virus can undergo genetic rearrangement in non-coding regions and can transform into a neurotropic virus able to infect glial cells and cause PML.
PML is most common among individuals with HIV-1 infection / acquired immune deficiency syndrome (AIDS).
Prior to effective antiretroviral therapy, as many as 5 percent of persons infected with HIV-1 eventually developed PML.
Current HIV therapy using antiretroviral drugs (ART), effectively restores immune system function, and allows as many as half of all HIV-PML patients to survive.
Associated with impaired T cell function.
Reported to occur in patients that have received stem cell transplants associated with rituximab treatment.
Associated with monoclonal antibodies and other chemotherapy treatments.
Associated with solid organ and allogeneic bone marrow transplantations.
A similar illness seen in patients with rheumatic diseases treated with TNF antagonists.
Most die within 1 year of diagnosis.
Prognosis may be better in patients with higher CD4+ lymphocyte counts.
Occurs in up to 5% of patients with AIDS.
Seen in approximately 1-3% of HIV-1 seropositive patients.
Diagnosed in .07% of patients immunosuppressed secondary to hematologic cancer.
Transplant patients have hemiparesis, apathy and confusion as presentation.
With the onset of AIDS significant increase in incidence.
Can be a fatal complication of organ transplantation.
Found on autopsy in 0.8% of liver transplanted patients.
Large white matter lesions seen on MRI.
Lesions do not enhance on contrast imaging and are multiple.
Etiologic agent is the JC virus.
JC virus infection is an asymptomatic process in childhood which remains latent in kidneys and lymphoid organs.
High sensitivity and high specificity for the detection of the JC virus in the spinal fluid using the polymerase chain reaction test making it the diagnostic test.
Associated with speech impairment and weakness.
Subcortical multifocal white matter lesions are the primary feature on neuroimaging.
Mental status is unchanged on presentation.
Confirmed cases have been rarely reported with the use of efalizumab (Raptiva), mycophenolate mofetil and natalizumab (Tysabri), brenttuximab and ruxolitinib.
Seen in approximately one in 850 natalizumab treated individuals who have multiple sclerosis.
The incidence of PML in natalizumab (Tysabri) treated patients increases with dosing, and for patients who receive more than 24 doses the incidence is 1 in 400.
Associated with rituximab (Rituxan) use, with a median age of 61 years.
Associated with a 100% case fatality rate among patients diagnosed with PML within 3 months after the last dose of rituximab (Carson KR).
52 cases of PML associated with treatment of B cell lymphomas, 2 patients with SLE, 1 patient with rheumatoid arthritis, 1 with autoimmune pancytopenia, one with ITP all treated with rituximab.
Diagnosis should be considered in the differential of any immunocompromised patient presents with progressive neurologic decline.
Diagnosis can be made by brain biopsy or by observing the progressive course of the disease, white matter lesions visible on a magnetic resonance imaging (MRI) scan, and the detection of the JC virus in spinal fluid.
Pathologic confirmation through brain biopsy is the gold standard for diagnosis, but
CSF PCR results for JCV is confirmatory and can circumvent the need for brain biopsy.
No effective treatment presently available.
There are no effective drugs that block virus infection without toxicity.
Clinical reversal may be achieved by plasma exchange to accelerate the removal of the therapeutic agents that put patients at risk for PML.
Anti-retroviral therapy for HIV will benefit most individuals with HIV associated PML.
Hexadecyloxypropyl-Cidofovir is being studied as a treatment option for JVC because of its ability to suppress JVC by inhibiting viral DNA replication.
The incidence of death depends on the nature of the underlying cause and the degree of immunosuppression.
Mortality rate of 30-50 percent in the first few months following diagnosis.
Patients who survive can be left with severe neurological disabilities.
Treatment with cytosine arabinoside associated with stabilization of the disease in 37% of patients.
Improvement reported with infusion of donor T cells targeting the BK virus.
PD-1 expressions os upregulated on CD4 positive and CD8 positive cells in patients with PML it is specifically enrichrd on JC virus specific CD8 positive cells.
In some patients with PML pembrolizumab reduces JC viral load and increases in CD4 and CD 8 positive activity against the JC virus along with clinical improvement or stabilization of the disease.