Leukoencephalopathy

ALSO KNOWN AS: Multifocal demyelinating disease, progressive multifocal leukoencephalopathy (PML), chemotherapy-induced leukoencephalopathy, toxic leukoencephalopathy, megalencephalic leukoencephalopathy with subcortical cyst

RELATED CONDITIONS: Acute hemorrhagic leukoencephalopathy, leukoencephalopathy with vanishing white matter, multiple sclerosis

DEFINITION: Leukoencephalopathy is a life-threatening, rapidly progressing disease of the nerves and muscles that affects patients who have a suppressed immune system. It is thought to be caused by a reactivated viral infection that changes form to take advantage of a suppressed immune system. In this disease, the myelin sheath, composed of the fatty tissue that forms a protective covering of the nerve fibers (sometimes called white matter), is destroyed.

Risk factors: This disease occurs only in patients who have had their immune systems suppressed by another disease or for medical procedures that depend on a suppressed immune system, such as organ transplant. It is considered an opportunistic infection that takes advantage of a suppressed immune system to damage some part of the body or one of its systems.

This disease is also linked to the JC virusa polyomavirus named after the initials of the first patient diagnosed with this virus. More than 85 percent of adults have been exposed to the JC virus, mostly in childhood. Some studies show that 85 percent of children are exposed to this virus before age nine, but this virus stays dormant in most of the population.

This disease is a rare side effect of some types of cancer treatment that suppress the immune system, which may happen with some types of chemotherapy or with certain types of procedures, such as a bone marrow transplant. Cancer patients, particularly those with Hodgkin disease, leukemia, lymphoma, or sarcoidosis who have received chemotherapy treatment with methotrexate or radiation therapy, are at risk of developing this disease. However, the disease is not limited to cancer patients and may be developed by those who have other immunocompromising diseases or factors such as acquired immunodeficiency syndrome (AIDS) or organ transplants. Patients with multiple sclerosis (MS) or Crohn’s disease taking the drug natalizumab (Tysabri) are at an increased risk of developing progressive multifocal leukoencephalopathy.

Other factors that likely increase risk in combination with a suppressed immune system are exposure to toxic substances, injuries, ischemia (decreased blood flow to a body part), and some metabolic disorders.

Etiology and the disease process: This disease is likely caused by the activation of the JC virus. Most people exposed to this virus never develop the disease, even if they have a suppressed immune system.

The virus lies dormant, mostly in the kidneys, until the immune system is suppressed somehow. In cancer patients, this suppression is usually through radiation or chemotherapy as part of a treatment strategy. The virus becomes active, taking advantage of the suppressed immune system, and changes into a form that can attack the brain. It begins destroying or interfering with the myelin sheath formation. The myelin sheath is the fatty substance that covers and protects the nerve fibers in the brain and spinal column. Like other myelin-attacking diseases, such as MS, the process of destroying the myelin is not entirely understood.

This loss of the myelin protective sheath keeps nerve signals from traveling to the rest of the body. Other abnormalities or cell growths may begin to occur in the brain. These complications further damage healthy brain cells, eventually leading to a progressive loss of muscle coordination and mental dysfunction. These symptoms are highly varied and depend on the location (where in the brain or spinal column) and the severity (how deep or wide) of the damage to the myelin sheath. Eventually, this disease results in seizures and coma before death. The patient usually dies within a year of diagnosis.

Incidence: This disease occurs only in patients with a suppressed immune system. Even in those patients, only a few people will develop this disease. Only about 5 percent of people living with AIDS will develop this disease, and the incidence for patients with cancer is even less. However, the incidence of this disease began rising in the early twenty-first century, as more people with cancers underwent treatments that suppressed the immune system and began surviving longer. The National Institutes of Health Office of Rare Diseases classifies it as rare. It affects less than two hundred thousand people in the United States. This number includes patients with AIDS as well as cancer patients.

Symptoms: Symptoms include clumsiness, difficulty walking, facial weakness, fatigue, headaches, loss of muscle coordination, loss of appetite, loss of speech, memory failure, mental dysfunction or deterioration, paralysis on one side of the body, partial or total blindness (sometimes affecting half of the vision in each eye), seizures, slow movements, stammering, stuttering, and weakness. Symptoms may vary greatly because they depend on where the myelin sheath is destroyed in the brain or spinal column and how much damage has occurred.

Screening and diagnosis: Diagnosis can be uncertain at first. The disease is suspected in patients with compromised immune systems who develop unexplained brain dysfunction. Magnetic resonance imaging (MRI) or computed tomography (CT) scans may suggest this disease by showing lesions or sores on the myelin or white matter in the brain or spinal column. Spinal fluid may be analyzed to determine if the JC virus is present, which can help strengthen a diagnosis. Blood tests do not help diagnose this disease. There is no effect on the blood, only on the nerves and muscles.

The only sure diagnosis is done by stereotactic biopsy—a special type of tissue removal using a computer and a three-dimensional scanning device—of the brain tissue in the affected area. However, this type of biopsy is not generally warranted for this disease because a brain biopsy is a high-risk procedure, especially for those with an already compromised immune system. Generally, the diagnosis of the disease is made by observing its rapid progression, with symptoms becoming more pronounced and widespread.

Treatment and therapy: Antiviral medications may help by reducing the viral load in the body, increasing the body’s T-cell count, and generally improving the immune system. However, these medications often have toxic side effects or are not tolerated well by patients, particularly those who already have suppressed immune systems.

Other attempts to slow the progress of this disease include altering chemotherapy or removing nonvital transplanted organs so immune-suppressing drug therapy can be stopped. Still, these treatments have inconclusive results. Treatment is generally supportive, which means the treatment attempts to reduce the severity of the symptoms and make a patient as comfortable as possible without addressing the cause of the disease.

Prognosis, prevention, and outcomes: There is no cure for leukoencephalopathy, nor is there any way to prevent the disease other than attempts to keep the immune system healthy and functioning properly.

Prognosis and outcomes are very poor, with most patients (80 percent) dying within six months to a year of diagnosis. Those who survive this disease (about 20 percent) are often left with severe mental and physical disabilities.

Bibliography

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Smith, Matt, "What Is Progressive Multifocal Leukoencephalopathy?" WebMD, 2 Mar. 2023, www.webmd.com/brain/progressive-multifocal-leukoencephalopathy-facts.