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Progressive Multifocal Leukoencephalopathy (PML)

Resource for Patients and their Families

PML is an infectious, though not contagious, disease of the brain. It is caused by reactivation of a common virus, human polyomavirus JC (JCV), which is found in up to 86% of the adult population. Typically, JCV is acquired during childhood, probably through a urine-oral route, after which it remains present but inactive in the body, residing in the kidneys, tonsils, bone marrow and possibly brain.

Most people infected with JC virus never have a problem.  However, in a small percentage of the JCV-positive population, usually in immunocompromised individuals, JC virus gets reactivated and causes PML. Before the AIDS epidemic, PML was a rarity, mostly seen in transplant recipients or patients with hematological malignancies. About 5% of untreated patients with AIDS develop PML, and PML is still a major cause of death among AIDS patients even treated with combined antiretroviral therapy (cART). PML has also been associated with the use of monoclonal antibodies used for the treatment of multiple sclerosis (Natalizumab/Tysabri®) and lymphoma (Rituximab/Rituxan®).

Classic PML is characterized by the destruction of white matter of the brain. White matter is partly composed of nerve cell projections, wrapped in a myelin sheath that acts as insulation, the same way plastic coating around a wire protects the integrity and speed of the signal within. And, just like with a wire, destruction of insulation (demyelination) causes a short circuit and breakdown in signaling communication. Depending on the location of PML lesions in the brain, a variety of neurological symptoms can be present.

Although the disease was originally considered to be devoid of inflammation, since the advent of cART, we are confronted with PML in the setting of an immune reconstitution inflammatory syndrome (IRIS). PML-IRIS is a paradoxical worsening or occurrence of new symptoms when the immune system is recovering. In the setting of HIV disease, this is often accompanied by a rise in CD4 count and a decrease in HIV viral load. All natalizumab-associated PML cases have an IRIS phenomenon.

Diagnosis of PML and PML-IRIS can be made by detection of JCV in the CSF or on brain biopsy (laboratory and histologically confirmed PML). However, since the advent of cART, the sensitivity of JCV PCR has dropped, and often PML diagnosis is made on clinical and radiological data (possible PML).

There is currently no treatment available for PML. All treatments are focused on reconstituting a PML patient's immune system, since a JCV-specific T-cell response is associated with PML survival. Examples are administering cART to HIV patients and stopping natalizumab and plasma exchange in natalizumab-treated MS patients.