Leukoencephalopathy

Leukoencephalopathy refers to disorders affecting the white matter of the brain, the tissue that protects nerve cells and helps them communicate. These conditions can range from rare viral infections in people with weakened immune systems to inherited genetic disorders that progressively damage the brain’s protective coating.

Table of contents

• Progressive Multifocal Leukoencephalopathy (PML)
• Causes and Risk Factors
• Symptoms
• Diagnosis
• Treatment
• Leukoencephalopathy with Vanishing White Matter

Progressive Multifocal Leukoencephalopathy (PML)

Progressive multifocal leukoencephalopathy (PML) is a rare but serious brain infection that damages the white matter of your brain and spinal cord. The name describes key features of the disease: it gets progressively worse over time, typically affects multiple areas of the brain, and primarily damages the myelin—an oily substance that protects nerve cells and helps them work properly^[3].

PML is caused by the JC virus (JCV), named after the initials of the first person identified with it, John Cunningham. This virus is extremely common—up to 85% of all adults carry it^[3]. Most people are exposed to the JC virus during childhood, and it typically remains inactive in the body, causing no symptoms^[1].

The virus is thought to spread through person-to-person contact or contaminated food and water. Evidence suggests children may pick it up through food or water, and the virus can also be found in urine, so it may spread through urine-oral contamination^[3]. In healthy individuals, the JC virus establishes an asymptomatic persistent infection in the kidney, leading to its intermittent excretion in urine^[5].

Causes and Risk Factors

PML occurs almost exclusively in people with severely weakened immune systems. In these individuals, the normally dormant JC virus can reactivate and acquire mutations that allow it to infect the central nervous system^[5].

Before the development of effective treatments, PML occurred in about 5% of people living with HIV-1 infection, making AIDS the most common condition associated with PML^[1][5]. However, the increased use of biological immunosuppressive and immunomodulatory agents has contributed to a progressively larger proportion of cases^[5].

You may be at risk of developing PML if you have^[3]:

• HIV/AIDS
• Cancers in your blood and bone marrow, like leukemia
• Cancers of your lymphatic system, like lymphoma or Hodgkin disease
• Autoimmune diseases, like rheumatoid arthritis, multiple sclerosis, or lupus

People who are organ transplant recipients taking immunosuppressant medicines to prevent organ rejection are also at risk^[3]. Additionally, certain medications used to treat autoimmune conditions can increase PML risk. These include natalizumab and rituximab, which are monoclonal antibodies, as well as other biological therapies that affect the immune system^[1][8].

Treatment with some of the more effective disease-modifying drugs for multiple sclerosis can increase the risk of developing PML because they work by suppressing the immune system. The risk is greatest with natalizumab, but very rare cases have been seen with other medications^[9].

Symptoms

For most people, PML symptoms start subtly and may vary depending on which part of the brain has the infection. The symptoms can evolve over the course of several weeks to months^[1].

The first symptoms of PML may include^[3]:

• Clumsiness or lack of coordination
• Difficulty speaking or thinking
• Weakness

As the infection progresses, you may experience^[3]:

• Dementia
• Speech loss
• Vision loss
• Personality changes

Some people may experience headaches or epilepsy, although these symptoms are rare and occur mainly in people with end-stage HIV infection^[8]. The progression of deficits leads to life-threatening disability^[1]. Eventually, PML usually gets worse, and the condition is often fatal^[3].

Diagnosis

Your healthcare provider will perform a physical exam and check your symptoms. They can diagnose PML with tests that look at your brain and spinal cord^[3].

You may have a^[3]:

• Brain MRI (magnetic resonance imaging), which can pick up images of white matter lesions on your brain
• Spinal tap (lumbar puncture), to sample and evaluate your cerebrospinal fluid—the fluid that surrounds tissue in your brain and spinal cord
• Brain biopsy, in rare cases, to help confirm the diagnosis

A diagnosis of PML can be made 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 using the polymerase chain reaction (PCR) technique^[1][8].

Treatment

Currently, the best available therapy for PML is reversal of the immune-deficient state, since there are no effective drugs that block the virus infection without toxicity^[1]. PML treatment focuses on strengthening your immune system^[3].

For people with HIV-associated PML, immediately beginning antiretroviral therapy (ART)—drugs to reduce HIV in the body—will benefit most individuals. Current HIV therapy using ART, which effectively restores immune system function, allows as many as half of all people with HIV-PML to survive, although they may sometimes have an inflammatory reaction in the regions of the brain affected by PML^[1].

If people 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 used to treat multiple sclerosis^[8]. Reversal may be achieved by using plasma exchange to accelerate the removal of the therapeutic agents that put people at risk for PML^[1].

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). Innovative strategies have shown promise in promoting anti-JC virus immune responses, and include T-cell adoptive transfer or immune checkpoint inhibitor therapies^[5].

The outlook for individuals with PML depends on the severity of the underlying disease and treatment response^[1]. Death is common within 1 to 9 months of when symptoms start, but a few people survive longer, about 2 years. People who develop PML while taking a medication that suppresses the immune system may recover once the medication is stopped, however many continue to have problems related to the infection^[8].

Leukoencephalopathy with Vanishing White Matter

Leukoencephalopathy with vanishing white matter is a different type of progressive disorder that mainly affects the brain and spinal cord. This disorder causes deterioration of the central nervous system’s white matter, which consists of nerve fibers covered by myelin^[2].

In most cases, people with leukoencephalopathy with vanishing white matter show no signs or symptoms of the disorder at birth. Affected children may have slightly delayed development of motor skills such as crawling or walking. During early childhood, most affected individuals begin to develop motor symptoms, including abnormal muscle stiffness (spasticity) and difficulty with coordinating movements (ataxia). There may also be some deterioration of mental functioning, but this is not usually as pronounced as the motor symptoms^[2].

This condition is caused by mutations in genes that provide instructions for making parts of a protein that helps regulate overall protein production in the cell. Partial loss of this protein function makes it more difficult for the body’s cells to regulate protein synthesis and deal with changing conditions and stress^[2].

Progression of leukoencephalopathy with vanishing white matter is generally uneven, with periods of relative stability interrupted by episodes of rapid decline. People with this disorder are particularly vulnerable to stresses such as infection, mild head trauma or other injury, or even extreme fright. These stresses may trigger the first symptoms of the condition or worsen existing symptoms^[2].