What is PML?

Patient Expert

No, this is not the beginning of a Scrabble ® game. PML stands for Progressive Multifocal Leukoencephalopathy. Is that even more confusing? Let's pull apart the alphabet soup and learn more about this disease that you may have heard something about. There is a childhood virus that some of us get, but don't even realize, called the JC virus. Most people have no idea that they contracted the virus. The JC virus can get reactivated and cause a serious brain disease called PML in rare occasions when a person's immune system, (our internal defense against foreign invaders like bacteria and viruses), isn't working correctly. An immune system is said to be suppressed if it isn't working correctly.

PML was originally described in the early 1950s by a team of doctors, including my mentor, Eliot Mancall, MD, and published in the scientific journal Brain. Mancall's team saw PML in people who also had a kind of cancer, lymphoma, which attacks cells called lymphocytes that make up white blood cells. Lymphocytes are important in stopping infections from getting out of control. If someone has uncontrolled lymphoma, white blood cells can't do their job effectively, and the JC virus (named after the initials of the first patient whom the virus was grown from) may be able to spread to the brain where it may cause an infection. This infection is called PML.

The infection is progressive (meaning it gets worse over time), it generally involves different parts (multifocal) of the brain (encephalopathy; encephalos - brain). Since PML affects many different parts of the brain and its white matter (leuko - white), PML can cause many types of symptoms, such as weakness of an arm or leg, imbalance, problems with language, not seeing out of a portion of the eyes (visual field cut) and seizures. There is currently no cure for PML but treatment aims at removing the cause and getting the immune system back into a balance so that it can help fight off the infection.

So, how does infection with a virus in childhood lead to a serious brain condition? Normally, after someone is infected with the JC virus, it is controlled by the immune system. The JC virus hides out in the kidneys and bone marrow among other places, and is prevented from spreading to the brain and growing there by the immune system's army of white blood cells.

Historically, as treatments for lymphoma improved, and uncontrolled lymphomas decreased, PML became less common. But, in the 1980's and 1990's, as HIV/AIDS became a public health problem, PML started to be seen again. AIDS stops the immune system from fighting off infections such as the JC virus. Without the body's proper defenses, the JC virus would spread in people with HIV/AIDS and cause PML in the brain. With the advent of effective antiretroviral treatments for HIV/AIDS treatment, PML has become much rarer in individuals with HIV.

More recently, in 2006 three people on a new drug in development, Natalizumab (also known as Tysabri) developed PML. Natalizumab was being studied for the treatment of Multiple Sclerosis (MS) and Crohn's Disease. Two of the people found to have PML were in the MS clinical trial, while another person was in the Crohn's study. Natalizumab works in MS by preventing white blood cells from sticking to the blood brain barrier (BBB), which controls substances that enter the central nervous system (CNS) from the blood. MS is an autoimmune disease, where the body's immune system attacks nerves and their covering (myelin). Natalizumab helps people with MS by preventing misdirected white blood cells from getting into brain, optic nerves and spinal cord. However, the same reason Natalizumab is effective at preventing misguided white blood cells from causing damage in people with MS is the same reason it may put someone at a risk for developing PML - white blood cells can't get into the CNS to do their job. If someone was exposed to the JC virus in childhood, and now they are on Natalizumab, the JC virus may spread to the brain and, with white blood cells blocked from entering the CNS, the JC virus may get out of hand and cause PML.

Now that we know that people taking Natalizumab are at risk to develop PML, scientists have been trying to figure out what puts some people at greater risk than others. Since the link between Natalizumab and PML in MS patients was found, over a hundred people have developed PML around the world while on the drug. It looks like some risk factors to develop PML (aside from being exposed to the JC virus in the past, usually in childhood) are: the length of time a person is on Natalizumab, and whether they have been on other medications that suppress the immune system in the past. One goal of future research will be to refine our understanding of these risk factors earlier and see if we can develop ways to predict which people would be at greatest risk to develop PML while on Natalizumab.

Disclosure: Dr. Kantor has received financial support from Biogen Idec in the past.