Progressive multifocal leukoencephalopathy
|Progressive multifocal leukoencephalopathy|
|Classification and external resources|
Progressive multifocal leukoencephalopathy (PML), also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease 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, those receiving certain kinds of chemotherapy, receiving natalizumab (Tysabri) for multiple sclerosis, on long-term efalizumab (Raptiva) for psoriasis, brentuximab (Adcetris) for Hodgkin's Lymphoma, or those with AIDS.
It is caused by 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.
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 the virus. JCV causes 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% 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 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.
Cases have been reported of PML being caused by pharmacological agents which modify immune response. This could be due in part to an existing impaired immune response, or to 'drug combination therapies,' rather than to individual drugs. These include efalizumab, belatacept, rituximab, natalizumab, infliximab, cytotoxic chemotherapy, corticosteroids, and various transplant drugs such as tacrolimus.
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 subcortical 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. The breakdown of myelin is commensurate with the degree of immunocompromise.
Symptoms include weakness or paralysis, vision loss, impaired speech, and cognitive deterioration. The lesions affecting the parietal and occipital lobes can lead to a phenomenon known as alien hand syndrome.
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 nonenhancing lesions without mass effect. The most common area of involvement is the cortical white matter, but the brainstem and cerebellum may also be involved.
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 can often be managed with medication, it is extremely dangerous when it occurs in PML.
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.
While a number of therapies work against JC Virus in cell culture, there is no proven, effective therapy in humans. Some therapies, such as 1-O-hexadecyloxypropyl-cidofovir (CMX001), have been found to have toxicity at therapeutic dosage, while the number of patients treated with other therapies is too low to demonstrate effectiveness.
In multiple sclerosis
Natalizumab was approved in 2004 by the FDA for multiple sclerosis (MS). It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of PML. All 3 initial cases were taking natalizumab in combination with interferon beta-1a. After a safety review the drug was returned to the market in 2006 as a monotherapy for MS under a special prescription program. As of May 2011, over 130 cases of PML had been reported in MS patients, all in patients who had taken natalizumab for more than a year. While none of them had taken the drug in combination with other disease-modifying treatments, previous use of MS treatments increases the risk of PML between 3 and 4-fold. The estimated prevalence of PML in MS is 1.5 cases per thousand natalizumab users. Around 20% of MS patients with PML die, and most of the rest are very disabled.
- Joseph Berger (neurologist)
- Leukoencephalopathy with vanishing white matter
- Toxic leukoencephalopathy
- Pedro Zamora
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- Overview at NIH
- Overview at Cleveland Clinic
- HIV-1 Associated Opportunistic Infections: PML at eMedicine
- MedlinePlus Encyclopedia Progressive multifocal leukoencephalopathy
- PML Disease Support Website