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    Progressive Multifocal Leukoencephalopathy (PML)

    What is it?

    Progressive multifocal leukocencephalopathy (PML) is a life-threatening infection of the brain that can occur in people living with HIV. It is caused by a virus - the JC virus. The "JC" are the initials of the first patient to be diagnosed with PML. The virus is a polyomavirus, a family of viruses that also includes human papillomavirus (HPV).

    The "progressive" in PML means that it continues to get worse and often leads to serious brain damage. The "multifocal" means that the JC virus causes disease in several different parts of the brain. The "leukoencephalopathy" means that the disease affects the white matter of the brain. More specifically, the JC virus infects cells in the brain called oligodentrocytes. These cells are responsible for producing myelin, a fatty substance that helps protect nerves in the brain. If too much myelin is lost and not replaced by oligodentrocytes, the nerves become damaged and eventually stop working correctly.

    More than 70% of all adults in the United States are infected with the JC virus, usually during early childhood. However, the virus only becomes active in people who have compromised immune systems. The includes people undergoing immune-suppressive chemotherapy for cancer and people with damaged immune systems due to HIV. Prior to the use of combination anti-HIV drug therapy. It was estimated that between 3% and 10% of all people with AIDS developed PML. It usually occurs in people with vary low T-cell counts, but has been seen in some HIV-positive people with as many as 500 T-cells.

    PML is almost always progressive and fatal. Death usually occurs between one and four months after the first symptoms appear. However, there have been a number of reported cases with survival ranging from several months to years. What's more, up to 10% of people with PML spontaneously recover, either with or without treatment.

    What are the symptoms of PML?

    Symptoms of PML include mental deterioration, vision loss, speech disturbances, ataxia, paralysis, and coma. In rare cases, seizures may occur.

    How is PML diagnosed?

    Many of the symptoms of PML are similar to those seen with other HIV-related diseases. Thus, it is important to determine the exact cause of these symptoms so that the correct treatment can be started.

    The most accurate way to diagnose PML is by conducting a brain biopsy. To do this, a surgeon will need to remove a small piece of brain tissue and send it to a lab for analysis. However, a brain biopsy can be risky, especially for those with compromised immune systems. It is also possible to diagnose PML by analyzing magnetic resonance imaging scans of the brain and/or by looking for the JC virus in the fluid surrounding the spinal column. This requires a spinal tap - a needle inserted into the lower back to drain spinal fluid so that it can be analyzed.

    How is PML treated?

    Unfortunately, there are no treatments that have been proven to be effective for PML. A handful of drug treatments have been studied in clinical trials, including:

    • Cytarabine, also known as cytosine arabinoside for Ara-C, is approved for the treatment of certain cancers. Early studies of this drug suggested that it was a possible treatment for PML. However, a larger study conducted by the U.S. government did not find cytarabine to be particularly effective, whether the drug was injected into a vein or directly into the brain.
    • Even though clinical trial results do not support its use, cytarabine is still prescribed for some patients with PML. To receive cytarabine, a patient will need to have a shunt surgically implanted into his or her skull. This allows doctors to inject cytarabine, through the tube, directly into the brain. When treatment is started, cytarabine is administered every day for three days. After that, it is given twice a week for two weeks, followed by once-weekly intrathecal injections for life.
    • Topotecan is also used to treat certain cancers. Like cytarabine, early studies suggested that it was effective as a treatment for PML, but a larger study reported in early 2001 did not find it to be effective.
    • Cidofovir is approved for the treatment of cytomegalovirus. Early test tube studies found that it was effective against viruses similar to the JC virus. Two small studies involving humans suggested that it might be useful in treating PML. Larger studies are still needed to determine how effective cidofovir really is. Cidofovir can damage the kidneys, thus it should be combined with probenecid to help protect kidney function.
    • High - dose , delivered through an intravenous line, was one of the first treatments studied for PML. While it did help slow progression in some patients, few patients experienced a reversal of symptoms or were able to prevent death.

    The treatment of PML is not without hope, however. Combination anti-HIV drug therapy has been shown to be extremely beneficial for HIV-positive patients with PML. Because PML is most likely to occur in patients with suppressed immune systems - and anti-HIV therapy has been shown to significantly increased T-cell counts and the general health of the immune system - HIV-positive patients with PML are more likely to live longer and to see their symptoms improve, sometimes dramatically.

    Many researchers agree that HIV-positive patients with PML should use anti-HIV drugs that are known to cross the "blood-brain barrier" - a protective coat that lines blood vessels in the brain to prevent toxins from passing through. Many of the nucleoside analogues, especially, and the non-nucleoside analogues, particularly, easily pass through the blood-brain barrier, and are often used to treat patients with other HIV-related brain diseases . If AZT is used to help treat PML, researches suggest that a daily dose of 1,000 to 1,200 mg be used.

    Can PML be prevented?

    No, not at the present time. But because immune suppression plays a major role in the development of PML, the best possible way to prevent this diseases is to keep the immune system healthy. This includes starting anti-HIV therapy before the immune system becomes impaired.