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Progressive Multifocal Leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) is a rare and usually fatal viral disease that is characterized by progressive damage or inflammation of the white matter of the brain at multiple locations. It's an opportunistic viral infection of the central nervous system (CNS) that typically occurs in people with an immune deficiency due to immunosuppressive medications. It's normally kept under control by the immune system, causing no problems. If the immune system is weakened and the body is less able to fight an infection, the virus can reactivate and cause serious and potentially fatal inflammation and damage to the brain known as PML.

The cause of PML is a type of polyomavirus called the John Cunningham or JC virus, a common infection completely unrelated to MS. The virus is widespread, with some estimates showing 86% of the general population presenting antibodies, but it usually remains latent, causing PML to arise or activate only when the immune system has been severely weakened. More recent estimates are showing the general population up to 50% having the JC virus. PML is a demyelinating disease, just as in multiple sclerosis (MS). It affects the white matter, which is mostly composed of axons from the outermost parts of the brain or cortex.

The risk of developing the infection has been identified as a potential side effect of treatment with some of the disease modifying drugs for MS, in particular Tysabri (natalizumab).

When you are infected with the JC virus you develop antibodies to the virus. A blood test can detect the presence and level of these antibodies and help give an estimate of your risk of developing PML. The test indicates your relative level of risk which can help you and your doctor make decisions about treatment options.

To understand what PML is, let's break its name up into what it means:

Progressive multifocal leuko encephalo pathy

  • Progressive because the damage it causes becomes more severe over time.
  • Multifocal means multiple locations within the brain.
  • Leuko means white.
  • Encephalo means brain.
  • Pathy means disease.

Typical symptoms associated with PML are diverse, since they are related to the location and amount of damage in the brain, and evolve over the course of several days to several weeks. The most prominent symptoms include paralysis, clumsiness, progressive weakness, vision loss, impaired speech, and cognitive deterioration including personality changes.

PML destroys oligodendrocytes and produces intranuclear inclusions. Since it destroys the cells that produce myelin (unlike MS, in which myelin itself is attacked but can be replaced), it progresses much more quickly.

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The JC Virus

The JC Virus was first discovered in 1971. It's a common virus that is unrelated to MS that many people have been exposed to, typically in childhood.

The virus is dormant in most people who are exposed don't know it or have any symptoms. But for people with weakened immune systems, such as people taking Tysabri, the virus is able to mutate, spread to the brain, and multiply. This infection causes damage that can lead to symptoms that may be similar to MS symptoms, so it's important to recognize the common signs and symptoms of PML.

The JC Virus more specifically is a polyomavirus and is the sole genus of viruses within the family polyomaviridae. Polyomaviruses are DNA-based (double-stranded DNA,~5000 base pairs, circular genome), small (40 to 50 nanometers in diameter), and icosahedral in shape, and don't have a lipoprotein envelope. They are potentially oncogenic (tumor-causing); they often persist as latent infections in a host without causing disease, but may produce tumors in a host of a different species, or a host with an ineffective immune system.

Five polyomaviruses have been found in humans:
JC virus can infect the respiratory system, kidneys, or brain (sometimes causing PML in the latter case).
BK virus produces a mild respiratory infection and can affect the kidneys of immunosuppressed transplant patients. Both of these viruses are very widespread: Approximately 80% of the adult population in the United States have antibodies to BK and JC.
Two recently discovered polyomaviruses, KI virus (Karolinska Institute) and WU virus (Washington University), both viruses are closely related to each other and have been isolated from respiratory secretions.
In January 2008, a new species, Merkel cell polyomavirus, was described as the likely causative agent of Merkel skin cancer.

JC Virus and PML

Having the JC Virus doesn't necessarily mean you'll get PML, but it does put you at a higher risk. To determine if you have been exposed to the JC Virus, your doctor may recommend taking the JC Virus Test. Remember, this test does not diagnose PML, but it is an important step in assessing your level of risk for PML. An MRI is one of the tools that can be helpful in the early identification of PML.

JC Virus Antibodies & Testing

Recent studies have looked into JC virus antibodies and assay testing for patients. Those patients were either positive or negative for the antibody. It's felt that those who test negative for the JC virus antibody are not at risk of PML at the time of the test or in the immediate future. Those who test positive will need to be monitored more closely for signs of PML.

Those studies found that the number of patients tested for the antibody, there were 50% that tested positive and 50% that tested negative.  These figures, at this early stage, are showing that if a patient tested positive, then their risk of PML increased to 1 in 500.  For those that tested negative, their risk of PML is close to zero. Put together, this matches the current figures of a 1 in 1000 chance of developing PML for all patients together.

As of mid-2013, the figures are showing that those using Tysabri and having a negative JC virus result will have about a 1 in 2000 chance of contracting PML. For those with the JC virus, their chance of contracting PML increases with the number of antibodies does. A titer test can determine where each person stands and their associated risk.

The titer test looks for the number of antibodies. When a result is under 1, there has been the feeling that it is safe. A result that is above 1 has those more concerned and a change of treatment may be suggested.

Many of those who have tested positive for the antivirus have chosen to remain on Tysabri even knowing the additional risk involved. Again the benefits seems to outweigh the risk since the alternatives are few. With more alternatives arriving, this will probably change.

JC Virus in Natalizumab Users: Test for Virus Exposure Approved

Commercial availability of a JC virus antibody assay will change practice in caring for patients with MS.

Patients with MS or Crohn disease who are taking natalizumab face an increased risk for PML if they have been exposed to JC virus, the FDA warned in January. The agency also announced approval of a new blood test to detect JC virus antibodies.

JC virus is common and usually harmless, the agency said, but its presence can be dangerous in patients taking immunomodulating drugs like natalizumab. Other risk factors associated with developing PML while on natalizumab are treatment with natalizumab for longer than 2 years and previous treatment with immunosuppressant drugs such as methotrexate or cyclophosphamide (but not prior use of first-line injectable immunomodulatory agents, interferon-beta, or glatiramer acetate).

The FDA estimates that patients with all three risk factors face about a 1% risk for PML with natalizumab therapy (11 cases per 1000 patients treated).

Natalizumab's label will be changed to reflect the new information.

Comment: Commercial availability of a JC virus antibody assay will change practice in caring for patients with MS. The risk for PML with natalizumab was previously said to be about 1 in 1000, but recent safety data provided by the manufacturer indicate that the overall incidence of PML is more than double that (2.11 per 1000 as of February 2012). The major advance for patient safety is recognition that the PML risk can be stratified by three risk factors (treatment duration >2 years, prior immunosuppressant use, and JC virus antibody seropositivity). As highlighted by the FDA, in patients with all three risk factors, the risk for PML is very high (>1 in 100). On the other end of the spectrum, the PML risk with natalizumab appears to be quite low in patients who are JC virus–seronegative. For these patients, the manufacturer estimates the PML risk to be about 1 in 10,000, with a 95% confidence interval potentially as high as 1 in 2000 and as low as zero, based on the lack of observed PML cases in JC virus–seronegative patients to date and the false-negative rate of the assay (3%). The seroconversion rate for JC virus in MS patients is about 2% per year; the optimal frequency of testing for the virus in patients taking natalizumab remains to be defined. This is a fast-moving field, so further refinement of these numbers is likely as more safety data become available.

This report published in Journal Watch Neurology by Jeffrey M. Gelfand, MD on February 28, 2012

Signs of PML

Typical symptoms associated with PML progress quickly over days to weeks, and can include:

personality or behavioral changes
disturbances of vision
change in thinking, memory, & orientation leading to confusion
onset of seizures, clumsiness or progressive weakness on one side of the body, or clumsiness of limbs

The progression of deficits can lead to death or severe disability over weeks or months. If individuals experience new, unusual symptoms, they should contact their physician immediately.

PML Consortium

The PML Consortium is a joint effort between several companies to identify more effective methods of predicting and preventing, and potentially, in the future, treating, PML. The mission of the Consortium is to perform research to reduce occurrence, morbidity and mortality of PML through a multi-company, not-for-profit, collaborative approach with shared strategy, investment, data acquisition and analysis and communication.

The PML Consortium website pmlconsortium.org provides an accessible, centralized source of information about PML for patients, caregivers and health care professionals.