Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy is a rare and often fatal brain infection caused by a common virus that most people carry harmlessly, but which can become dangerous when the immune system is severely weakened.

Table of contents

• What is progressive multifocal leukoencephalopathy?
• What causes PML?
• Who is at risk?
• Signs and symptoms
• How doctors diagnose PML
• Treatment approaches
• Outlook and prognosis

What is progressive multifocal leukoencephalopathy?

Progressive multifocal leukoencephalopathy (PML) is a rare brain infection that affects the white matter of the brain. The white matter contains myelin, an oily substance that protects nerve cells (called neurons) in the brain and spinal cord^[1][2].

The name describes the nature of the disease. “Progressive” means the condition gets worse over time. “Multifocal” indicates it typically affects multiple parts of the brain. “Leukoencephalopathy” means the disorder primarily affects the white matter of the brain^[2].

PML causes the cells that produce myelin to break down. This damage leads to brain injury that can result in serious problems with movement, thinking, vision, and speech^[2].

What causes PML?

PML is caused by the JC virus (JCV), named after the initials of John Cunningham, the first person identified with it. Another name for this virus is human polyomavirus 2^[2].

The JC virus is extremely common. Between 39% and 90% of adults carry the virus, and up to 85% of all adults have antibodies to it, indicating current or previous infection^[2][3]. Experts believe that children may pick up the virus through food or water. The virus is also found in urine, so it may be spread through contamination^[2].

In most people, the JC virus remains inactive and harmless. It causes persistent infection without symptoms, typically in the kidneys. The virus causes disease only when the immune system has been severely weakened^[1][3].

Who is at risk?

PML occurs almost exclusively in people with severely weakened immune systems. It is rare and typically develops in those with specific medical conditions or treatments that compromise immune function^[1].

You may be at risk of developing PML if you have:

• HIV/AIDS. PML is most common among individuals with HIV-1 infection. Prior to effective antiretroviral therapy, as many as 5% of people living with HIV-1 eventually developed PML, which is considered an AIDS-defining illness^[1][3]
• Cancers affecting the blood and bone marrow, such as leukemia
• Cancers of the lymphatic system, such as lymphoma or Hodgkin disease^[1][2]
• Autoimmune diseases, including rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (lupus)^[1][2]

You may also be at risk if you are an organ transplant recipient taking immunosuppressant medicines (drugs to keep your body from rejecting the organ)^[2]. People undergoing chronic corticosteroid therapy are also at increased risk^[1].

Some medications used to treat autoimmune conditions can increase the risk of PML. Certain monoclonal antibodies, particularly natalizumab (used to treat multiple sclerosis), rituximab, efalizumab, and eculizumab, have been associated with PML^[4]. Natalizumab was withdrawn from the market after being linked with cases of PML, then returned in 2006 with special safety measures^[3].

Signs and symptoms

Symptoms of PML can develop over several weeks to months. They vary according to the location and amount of damage in the brain. For most people, PML symptoms start subtly^[1][2].

The first symptoms of PML may include:

• Clumsiness or lack of coordination
• Progressive weakness
• Difficulty speaking or thinking^[1][2]

As the infection progresses, additional symptoms may appear:

• Dementia (a decline in mental function)
• Speech loss
• Vision loss or partial blindness
• Personality changes^[1][2]

Some people may experience headaches or seizures, although these symptoms are rare, mainly occurring in people with end-stage HIV infection^[5].

The progression of symptoms leads to increasingly severe disability. People with PML eventually become bedbound. Because PML is a progressive disorder, it will get worse over time^[2][5].

How doctors diagnose PML

Your healthcare provider will perform a physical exam and check your symptoms. Unexplained, progressively worsening symptoms in people with a weakened immune system suggest progressive multifocal leukoencephalopathy^[5].

Doctors can diagnose PML with tests that look at your brain and spinal cord. You may have:

• A brain MRI (magnetic resonance imaging), which can pick up images of white matter lesions on your brain^[2]
• A spinal tap (lumbar puncture), to sample and evaluate your cerebrospinal fluid (the fluid that surrounds tissue in your brain and spinal cord). The polymerase chain reaction (PCR) technique is used to detect the JC virus’s DNA in the cerebrospinal fluid^[2][5]
• A brain biopsy, in rare cases, to help confirm the diagnosis of PML^[2]

A diagnosis of PML can be made following brain biopsy or by combining observations of a progressive course of the disease, consistent white matter lesions visible on an MRI scan, and the detection of the JC virus in spinal fluid^[1].

Treatment approaches

Currently, there are no effective drugs that block virus infection without toxicity. The best available therapy is reversal of the immune-deficient state^[1].

PML treatment focuses on strengthening your immune system. The approach depends on what caused your immune system to weaken:

If you have HIV-associated PML, immediately beginning antiretroviral therapy (ART) will benefit most individuals. These are drugs to reduce HIV in your body. Current HIV therapy using ART effectively restores immune system function and allows as many as half of all people with HIV-PML to survive^[1].

If you are taking immunosuppressants or other medications that affect the immune system (such as natalizumab), stopping the medications may cause PML to subside. Plasma exchange may be used to remove the medication from the blood, particularly when the medication is natalizumab. This procedure helps accelerate the removal of the therapeutic agents that put people at risk for PML^[1][5].

Several new drugs that laboratory tests found effective against infection are being used in people with PML with special permission of the U.S. Food and Drug Administration (FDA)^[1].

People who are treated may sometimes have an inflammatory reaction in the regions of the brain affected by PML. This is called PML-IRIS (immune reconstitution inflammatory syndrome), which can present from 1 week to 26 months after the initiation of treatment^[1][4].

Outlook and prognosis

The outlook for individuals with PML depends on the severity of the underlying disease and treatment received^[1].

In general, PML has a mortality rate of 30-50% in the first few months following diagnosis. Death is common within 1 to 9 months of when symptoms start, but a few people survive longer (about 2 years)^[3][5][6].

However, the outlook varies according to the underlying condition and response to treatment. People who develop PML while taking a medication that suppresses the immune system (such as natalizumab) may recover once the medication is stopped. However, many continue to have problems related to the infection and can be left with varying degrees of neurological disabilities^[3][5].

With timely treatment, some people can slow the disease’s progression^[2].