Leukoencephalopathy is a term that describes a group of disorders affecting the white matter of the brain and spinal cord. These conditions involve damage to myelin, the protective fatty coating around nerve fibers, and can lead to serious neurological problems ranging from movement difficulties to changes in thinking and personality.

Understanding Leukoencephalopathy

The brain and spinal cord contain different types of tissue, and among them is what doctors call white matter. This white matter gets its name from myelin, an oily substance that wraps around nerve cells like insulation around electrical wires. When myelin breaks down or disappears, the nerves cannot send signals properly throughout the body. This breakdown process is what happens in various forms of leukoencephalopathy.^[1]

Leukoencephalopathy is not a single disease but rather a description of what happens in the brain when white matter becomes damaged. The term itself breaks down into parts: “leuko” refers to white matter, “encephalo” means brain, and “pathy” indicates disease. Several different conditions can cause this white matter damage, each with its own causes and patterns of progression.^[2]

Types and Epidemiology

One of the most discussed forms is progressive multifocal leukoencephalopathy, commonly known by its initials PML. This rare brain infection attacks the cells that produce myelin. PML is progressive, meaning it gets worse over time. It is also multifocal, which means it typically affects multiple areas of the brain rather than just one spot.^[3]

PML is rare in the general population. Studies show that approximately one in every two hundred thousand people will develop this condition, translating to about four thousand people per year across the United States and Europe combined. However, these numbers have shifted over time based on changes in the populations most at risk.^[12]

Before effective treatments for HIV became available, as many as five percent of people living with HIV eventually developed PML, making it one of the defining illnesses of AIDS. The landscape changed dramatically with the introduction of antiretroviral therapy, which are drugs that help restore immune system function in people with HIV. This treatment breakthrough has allowed as many as half of all people with HIV-related PML to survive, though they may still face lasting challenges.^[1]

Another form is leukoencephalopathy with vanishing white matter, which is progressive and mainly affects the brain and spinal cord, known together as the central nervous system. This disorder causes deterioration of the white matter, with the myelin that normally insulates nerve fibers gradually disappearing. While childhood onset is most common for this type, some milder forms may not become evident until adolescence or adulthood. The prevalence of this condition is unknown, but despite being rare, it is believed to be one of the most common inherited diseases affecting white matter.^[2]

Causes

The causes of leukoencephalopathy vary depending on the specific type. PML is caused by a virus called the JC virus, named after the initials of the first person identified with it, John Cunningham. This virus is also known as human polyomavirus 2. What makes this virus particularly interesting is how common it is—up to eighty-five percent of all adults carry the JC virus in their bodies.^[3]

Experts are not completely certain how people first get the JC virus, but there is evidence suggesting that children may pick it up through contaminated food or water. The virus has also been found in urine samples, suggesting it may be transmitted through what scientists delicately call urine-oral contamination. Studies show that eighty-five percent of children are exposed to this virus before they reach age nine.^[6][13]

In most people, the JC virus remains completely inactive throughout their lives, causing no symptoms whatsoever. It typically lies dormant in the kidneys and other tissues. The virus only becomes dangerous when something happens to weaken a person’s immune system significantly. When immune defenses drop, the virus can acquire mutations and gain the ability to infect the central nervous system, where it causes the devastating damage seen in PML.^[1]

Leukoencephalopathy with vanishing white matter, by contrast, has genetic causes. Mutations in five different genes—EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5—can cause this condition. These genes provide instructions for making parts of a protein called eIF2B, which helps regulate how cells produce proteins. Most mutations occur in the EIF2B5 gene, accounting for about sixty-five percent of cases. These mutations cause partial loss of the protein’s function, making it harder for cells to regulate protein production and cope with changing conditions and stress.^[2]

Risk Factors

PML almost exclusively occurs in people who have severely weakened immune systems. The immune system acts as the body’s defense force, and when it cannot function properly, normally harmless viruses can cause serious problems. Several conditions and circumstances can create this vulnerability.^[1]

HIV and AIDS remain the most common underlying conditions associated with PML worldwide. The virus that causes AIDS directly attacks the immune system, creating the perfect environment for the JC virus to reactivate and cause disease. Even with modern treatments, people living with HIV need to remain vigilant about their immune system health.^[5]

Certain types of cancer significantly increase PML risk. People with blood and bone marrow cancers like leukemia, as well as cancers of the lymphatic system such as lymphoma or Hodgkin disease, face elevated risk. These cancers directly affect the cells that make up the immune system. Historically, before the AIDS pandemic in the 1980s, people with these blood-related cancers and organ transplant recipients made up most PML cases.^[3]

Organ transplant recipients also face risk because they must take immunosuppressant medicines—drugs specifically designed to keep the body from rejecting the transplanted organ. While these medications are necessary for transplant success, they work by deliberately weakening the immune system’s responses, which can allow the JC virus to reactivate.^[6]

The increased use of biological immunosuppressive and immunomodulatory agents has contributed to a progressively larger proportion of PML cases in recent years. People with autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, or systemic lupus erythematosus (lupus) may receive treatments that affect their immune system. Some of these medications, including natalizumab and rituximab, which are monoclonal antibodies (laboratory-made proteins that act like human antibodies), can increase PML risk.^[5]

For leukoencephalopathy with vanishing white matter, the risk factors are different because the condition is inherited. The disease is caused by mutations passed down through families. Other factors that likely increase risk in this condition, especially when combined with the genetic mutations, include exposure to toxic substances, injuries, decreased blood flow to parts of the body, and certain metabolic disorders.^[13]

Symptoms

The symptoms of leukoencephalopathy vary considerably depending on which type a person has and which parts of the brain are affected. In PML, symptoms typically start subtly and may be easy to overlook at first. The location and amount of damage in the brain determine exactly what symptoms appear, and these can evolve over the course of several weeks to months.^[1]

Early symptoms of PML often include clumsiness or a lack of coordination. People may find themselves stumbling or having difficulty with tasks that require precise movements. Progressive weakness is another common early sign, with people noticing their muscles do not work as well as they used to. Difficulty speaking or thinking clearly may also emerge, with words becoming harder to find or thoughts more difficult to organize.^[3]

As PML progresses and more brain tissue becomes damaged, symptoms become more severe and disabling. Many people develop dementia, which means a decline in memory, reasoning, and other thinking abilities that is severe enough to interfere with daily life. Speech may deteriorate further until some people lose the ability to speak entirely. Vision problems can develop, with some people experiencing partial blindness. Personality changes may occur, with individuals behaving differently than they did before the illness.^[6]

While less common, some people with PML experience headaches or seizures, though these symptoms are relatively rare and tend to occur mainly in people with end-stage HIV infection. The progression of symptoms leads to increasingly severe disability, and many people eventually become bedbound as the disease advances. The condition is often fatal, with death commonly occurring within one to nine months after symptoms begin, though a few people survive longer.^[8]

In leukoencephalopathy with vanishing white matter, most people show no signs or symptoms at birth. During early childhood, affected children may have slightly delayed development of motor skills such as crawling or walking. Most affected individuals begin developing motor symptoms during early childhood, including abnormal muscle stiffness called spasticity and difficulty coordinating movements known as ataxia. Mental functioning may also deteriorate, though this is usually not as pronounced as the movement problems.^[2]

The progression of leukoencephalopathy with vanishing white matter is generally uneven, with periods of relative stability interrupted by episodes of rapid decline. People with this condition are particularly vulnerable to stresses such as infection, mild head trauma, other injuries, or even extreme fright. These stresses may trigger the first symptoms or worsen existing ones, and can cause affected individuals to become lethargic or even fall into a coma.^[2]

Prevention

Preventing leukoencephalopathy depends largely on understanding and managing risk factors, particularly for PML. Since the JC virus is so common in the general population and typically acquired in childhood, preventing initial infection is not a realistic strategy. Instead, prevention efforts focus on protecting immune system function and careful monitoring of people at risk.^[9]

For people living with HIV, the most important preventive measure is maintaining strong immune system function through consistent antiretroviral therapy. These medications help keep HIV under control, which in turn keeps the immune system strong enough to prevent the JC virus from reactivating. Regular monitoring of immune system markers helps doctors ensure treatments are working effectively.^[5]

For people who need treatments that suppress or modify the immune system, such as those with multiple sclerosis or other autoimmune conditions, prevention involves careful risk assessment before starting therapy. A blood test can detect the presence and level of antibodies to the JC virus in the blood. When someone is infected with the JC virus, their body develops antibodies to fight it, and these antibodies can be measured. This testing can help estimate a person’s risk of developing PML if they take certain medications.^[9]

People starting treatment with certain high-risk medications should have this blood test at the beginning of treatment, along with an MRI scan of the brain. Even if the initial test is negative, it should be repeated every six months, because a person could become infected with the JC virus at any time. If previous blood tests found low levels of JC virus infection, continued testing remains important to monitor any changes.^[9]

The risk of PML can continue even after stopping a medication that suppresses the immune system, because it can take several months for immune function to fully recover. This means monitoring should continue for a period after discontinuing these treatments. Some cases of PML have been associated with a previous medication rather than the one a person was taking when PML developed, highlighting the importance of this extended vigilance.^[9]

Pathophysiology

Understanding what happens inside the body during leukoencephalopathy helps explain why symptoms develop and progress as they do. The pathophysiology—the changes in normal bodily functions caused by disease—differs between types of leukoencephalopathy but centers on damage to myelin and the cells that produce it.^[1]

In PML, the disease process begins when the JC virus reactivates in someone with a weakened immune system. The virus undergoes mutations that allow it to travel from its dormant sites to the central nervous system. Once in the brain, the virus specifically targets and infects two types of brain cells: oligodendrocytes, which are the cells responsible for making and maintaining myelin, and astrocytes, which are support cells that help neurons function properly.^[5]

When the JC virus infects oligodendrocytes, it causes what doctors call a lytic infection, meaning the virus reproduces inside the cells and eventually causes them to break apart and die. As more and more oligodendrocytes die, less myelin gets produced and existing myelin starts to break down. This process is called demyelination. Without their myelin insulation, nerve fibers cannot transmit signals efficiently, leading to the neurological symptoms people experience.^[1]

The damage in PML typically occurs in multiple areas of the brain simultaneously, which is why it is called “multifocal.” These damaged areas appear as lesions on brain imaging scans. The specific locations of these lesions determine which symptoms appear—damage to areas controlling movement causes weakness and coordination problems, while damage to areas involved in speech causes communication difficulties.^[3]

In leukoencephalopathy with vanishing white matter, the underlying mechanism is different. The genetic mutations affect proteins involved in regulating how cells produce other proteins—a fundamental cellular process. When cells face stress or changing conditions, they need to quickly adjust their protein production. The mutated proteins cannot perform this regulation effectively, making cells in the white matter particularly vulnerable to stress.^[2]

Researchers believe that cells in the white matter may be especially dependent on proper regulation of protein synthesis for their survival and function. When this regulation fails due to the genetic mutations, these cells deteriorate and die. Over time, the white matter literally disappears, which is why the condition is called “vanishing white matter.” The brain tissue in affected areas is replaced by fluid-filled spaces, visible on imaging studies.^[2]