Progressive multifocal leukoencephalopathy (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" (loo-ko-en-sef-a-lop-a-thee) means that the disease affects the white matter of the brain. More specifically, the JC virus infects cells in the brain called oligodendrocytes. 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 oligodendrocytes, the nerves become damaged and eventually stop working correctly.
More than 85 percent of adults worldwide are infected with the JC virus, usually during early childhood. However, the virus only becomes active in people who have compromised immune systems. This includes people undergoing immune-suppressive chemotherapy for cancer and people with damaged immune systems due to HIV. Prior to the use of combination antiretroviral (ARV) therapy, it was estimated that between 3 and 7 percent of all people with AIDS developed PML. It usually occurs in people with very low CD4 cell counts (less than 100), but has been seen in some HIV-positive people with as many as 500 CD4 cells.
In the early years of the AIDS epidemic, PML was almost always progressive and fatal. Death usually occurred between one and four months after the first symptoms appeared. While a PML diagnosis today remains potentially rapid in its progression and possibly fatal, improvements in our ability to stabilize the immune system using HIV drugs has helped to improve the prognosis associated with this opportunistic infection.
What are the symptoms?
Symptoms of PML include mental deterioration, vision loss, speech disturbances, ataxia (inability to coordinate movements), paralysis, and coma. In rare cases, seizures may occur. Because lesions and nerve damage can occur anywhere in the brain, the initial symptoms may be different among people with the disease.
How is PML diagnosed?
Many of the symptoms of PML are similar to those seen with other HIV-related diseases (e.g., toxoplasmosis, cryptococcal meningitis, and lymphoma of the central nervous system). Thus, it is important to determine the exact cause of these symptoms so that the correct treatment can be started.
Diagnosis is based partly on the symptoms being experienced, combined with an examination of the results of a magnetic resonance imagine (MRI) scan. Typically, lesions will show up as white or dark spots on the MRI. Most brain specialists can make a confident diagnosis based on the clinical exam and an MRI. The most accurate way to diagnose PML, however, 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 (MRI) 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 or prevented?
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, but results have been disappointing. Examples of treatments tested in clinical trials include cytosine arabinoside (Cytosar-U, DepoCyt), topotecan (Hycamtin), cidofovir (Vistide), and high-dose intravenous zidovudine (Retrovir). Some proved to be too toxic to use, while others failed to improve symptoms or survival.
The medications cyproheptadine (Periactin) and mirtazapine (Remeron), typically used to control psychotic symptoms, such as hallucinations and delusions, have been studied with encouraging results in test-tube studies (clinical trials are necessary to evaluate their effectiveness and safety in humans with PML). There have also been encouraging results using interferon-alfa, an injectable medication frequently used to treat various viral infections.
Even without the availability of approved treatments for PML, there are still encouraging options available. ARV 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 ARV therapy has been shown to significantly increase CD4 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. A significant number of people on ARV therapy may still develop PML and have disease progression, however, but emerging evidence suggests that such individuals may benefit from "intensifying" their ARV therapy by adding other drugs to which their virus is sensitive.
Many researchers agree that HIV-positive patients with PML should use 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 zidovudine (Retrovir) and abacavir (Ziagen), and the non-nucleoside analogues, particularly nevirapine (Viramune), easily pass through the blood-brain barrier, and are often used to treat patients with other HIV-related brain diseases. If zidovudine is used to help treat PML, some experts suggest that a daily dose of 1,000 to 1,200 mg (twice the regular zidovudine dose) be used.
A syndrome—called immune reconstitution inflammatory syndrome (IRIS)—where antiretroviral treatment can actually exacerbate the symptoms of an opportunistic infection due to a strengthened immune response, has been commonly reported with PML. Some providers use corticosteroids preventatively for a short period when starting ARV therapy in people who've been diagnosed with PML.
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 disease is to keep the immune system healthy. This includes starting ARV therapy before the immune system becomes impaired. If a person has gone into remission after starting ARV therapy, the chance is quite low that they will have a recurrence of the disease.
Are there any experimental treatments?
If you would like to find out if you are eligible for any clinical trials that include new therapies for the treatment or prevention of PML, visit ClinicalTrials.gov, a site run by the U.S. National Institutes of Health. The site has information about all HIV-related clinical studies in the United States. For more info, you can call their toll-free number at 1-800-HIV-0440 (1-800-448-0440) or email firstname.lastname@example.org.
Last Revised: January 18, 2016