Who Is at Risk for PML?

Patient Expert

While PML (progressive multifocal leukoencephalopathy) sounds scary, advances are being made in its diagnosis and treatment.

The first question is: who is at risk to get PML? The JC virus that causes PML is a common virus that many of us have had since childhood without even knowing it. Most people (with healthy immune systems) don't develop PML because the body's natural immune defenses are able to keep the virus in check. White blood cells (lymphocytes, leukocytes) constantly scavenge the body looking for viruses and stop them at the source. It is only in people where the immune system is suppressed that the JC virus can get out of hand and cause an infection in the brain. This infection is known as PML.

In the past few years, we have seen PML occur in individuals with multiple sclerosis who take a new medication, Natalizumab (also known as Tysabri ®). Although MS affects the immune system, the immune system of an MS patient becomes overactive and attacks the central nervous system (CNS). People with MS are still able to fight off infections; simply having MS does not place someone at risk for developing PML.

Natalizumab helps people with MS by preventing misdirected lymphocytes from entering the CNS through the blood brain barrier. This prevents misdirected lymphocytes from damaging the covering of nerves (known as myelin) and the nerves themselves (axons) in the CNS. However, if there aren't enough lymphoctytes getting into the CNS - which is good for MS symptoms - it may limit the immune system's ability to scavenge and destroying viruses. This is why for the first time in MS, we saw patients on Natalizumab develop an infection of the JC virus in the brain - PML.

Fortunately, only a minority of people on Natalizumab are at risk for developing PML and we are learning more about the factors that would increase or decrease risk. The first question is whether an individual has ever been exposed to the JC virus. If you don't have the JC virus in your body, then the JC virus shouldn't be able to get out of control and spread in the brain. We used to think that 80 percent of the population has been exposed to the JC virus; more recent research (including research sponsored by Natalizumab's manufacturer) suggests the actual ratio is more like 50 to 60 percent of people have been exposed to the virus.

Remember, the JC virus does not normally cause unique symptoms, so you can't tell simply from your history of flu-like episodes if you were exposed to it in the past or not. There is a simple blood test in development that can tell you whether you have been exposed to the JC virus. The blood test measures whether you have antibodies to the JC virus. These would appear as your body makes antibodies in response to foreign invaders, such as viruses.

The thinking is that if you have not been exposed to the JC virus, and the virus isn't in your body, you should be at low risk to develop PML even if you have MS and take Natalizumab. The JC virus is generally a virus that you get in childhood, so if your lab test shows that you have never gotten the virus, then you are probably not at risk for getting it now - but doctors are still researching this point.

As we learn more about the test for JC antibodies, we will hopefully develop some guidelines on how often you should be tested (if your test is negative, should you be tested again yearly to make sure that you aren't exposed to the JC virus?) and how likely a "false negative" test is. Like all lab tests, the JC antibody test isn't perfect and currently less than three percent of people produce an inaccurate test result, where the test indicates no exposure to the JC virus but the individual had been.

Even if someone is on Natalizumab and has been exposed to the JC virus in the past (with a positive JC virus antibody blood test), this doesn't mean they are certain to develop PML. In the past, doctors estimated that out of roughly every 1,000 people treated with Natalizumab, one person develops PML. However, as we learn more about who is developing PML, it looks like the risk is lower for people on Natalizumab for less than two years (currently the FDA says 0.3 cases per 1,000 people), a little more for people who stay on Natalizumab for two to three years (1.5 cases per 1,000 people) and 0.9 cases per 1,000 for people who stay on Natalizumab for more than three years. It is important to note that these numbers will keep changing as more people are treated with Natalizumab. It seems to take time for PML to develop, and it isn't something that suddenly happens right when Natalizumab is introduced. People who are on Natalizumab for longer than two years are at a higher risk for PML then people who are not.

A final area of risk consideration is whether someone with MS has taken immunosuppressant medications in the past (like certain chemotherapies). It appears that, in these cases, the immune system may be weakened and not able to fight off the JC virus as well, putting them at a greater risk to develop PML.

Once a person is determined to have PML, it is paramount to address the condition as quickly as possible. In the past, people didn't survive once they developed PML, whether they were people with MS or patients with other conditions where PML also developed, like AIDS. So far, however, more than 80 percent of the people with MS who have developed PML have survived. It seems that if PML is caught early enough, we can get the Natalizumab out of the person's bloodstream and activate the body's natural defenses to attack the JC virus and put an end to PML. MS patients' immune systems can fight off PML - unlike AIDS, for example - as the immune systems of people with MS are not compromised, but rather misdirected, while a person with AIDS is immunocompromised and has trouble fighting off infections.

For MS patients who develop PML, doctors can remove Natalizumab from the body using plasmapheresis, which is like cleaning the liquid part of the blood. Assuming the person is not otherwise immunocompromised, the person's own immune system should be able to fight off the JC virus and stop the PML. Sometimes, however, the immune system gets so agitated by the PML that it comes back with a vengeance and causes too much inflammation or swelling. This is called IRIS (immune reconstitution inflammatory syndrome). IRIS is usually treated with IV Corticosteroids.

The key to early detection is knowing if you are at risk for PML; if you have MS, this means that you are on a medication which has a risk for PML, like Natalizumab. The key three risk factors we know so far are whether you have ever been exposed to the JC virus, how long you have been on medicine associated with PML, and whether you have taken immunosuppressant medications.

With PML, different parts of the brain can be affected, making it difficult to differentiate from MS, but anyone on Natalizumab with new symptoms, including difficulties with speech, clumsiness, seizures, confusion or vision problems. Since PML symptoms and MS symptoms can often be similar, it is very important to alert your MS team if you are having any new symptoms. Early detection of PML can make a big difference to a person's ability to defeat it.