Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML), also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage (-pathy) or inflammation of the white matter (leuko-) of the brain (-encephalo-) at multiple locations (multifocal).

It occurs almost exclusively in people with severe immune deficiency, such as transplant patients on immunosuppressive medications, patients receiving certain kinds of chemotherapy, patients receiving natalizumab (Tysabri) for multiple sclerosis, psoriasis patients on long-term efalizumab (Raptiva) or AIDS patients.

It is caused by a virus, the JC virus, which is normally present and kept under control by the immune system. Immunosuppressive drugs prevent the immune system from controlling the virus.

Cause
The cause of PML is a type of polyomavirus called the JC virus (JCV), after the initials of the patient from whose tissue the virus was first successfully cultured. Recent publications indicate 39% to 58% of the general population are seropositive for antibodies to JCV, indicating current or previous infection with virus. The virus can cause persistent asymptomatic infection in approximately 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.

Prior to the advent of effective antiretroviral therapy, as many as 5 percent of people with AIDS eventually developed PML. It is unclear why PML occurs more frequently in AIDS than in other immunosuppressive conditions; some research suggests that 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.

Contributing causes
There are case reports of PML being caused by pharmacological agents, although there is some speculation this could be due in part to the existing impaired immune response or 'drug combination therapies' rather than individual drugs. These include efalizumab, belatacept, rituximab, infliximab, natalizumab, chemotherapy, corticosteroids, and various transplant drugs such as tacrolimus.

Disease process/Pathogenesis
PML is a demyelinating disease, in which the myelin sheath covering the axons of nerve cells is gradually destroyed, impairing the transmission of nerve impulses. It affects the sub-cortical white matter, particularly that of the parietal and occipital lobes. PML destroys oligodendrocytes and produces intranuclear inclusions. PML is similar to another demyelinating disease, multiple sclerosis, but progresses much more quickly.

Symptoms
Symptoms include weakness or paralysis, vision loss, impaired speech, and cognitive deterioration. In addition, the lesions affecting the parital lobe and occipital can lead to a phenomenon known as Alien hand syndrome.

Diagnosis
PML is diagnosed by testing for JC virus DNA in cerebrospinal fluid or in a brain biopsy specimen. Characteristic evidence of the damage caused by PML in the brain can also be detected on MRI images which classically show multifocal non-enhancing lesions without mass effect. The most common area of involvement is the cortical white matter, but the brainstem and cerebellum may also be involved.

Treatment
There is no known cure. In some cases, the disease slows or stops if the patient's immune system improves; some AIDS patients with PML have been able to survive for several years, with the advent of highly active antiretroviral therapy (HAART).

AIDS patients who start 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. 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 infection; although IRIS is often manageable with other types of drugs, it is extremely dangerous if it occurs in PML.

Other antiviral agents that have been studied as possible treatments for PML include cidofovir and interleukin-2, but this research is still preliminary.

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. It is reported to have stabilized the neurological condition of a minority of these patients. One patient regained some cognitive function lost as a result of PML.

In June 2010, the first case report appeared of a PML patient being successfully treated with mefloquine. Mefloquine is an antimalarial drug that can also act against the JC virus. Administration of mefloquine seemed to eliminate the virus from the patient's body and prevented further neurological deterioration.