Progressive multifocal leukoencephalopathy

Definition

Progressive multifocal leukoencephalopathy is a rare, fatal disease of the white matter of the brain that almost solely strikes individuals who already have weakened immune systems.

Description

In progressive multifocal leukoencephalopathy, myelin (the substance that wraps around nerve fibers, providing insulation and speeding nerve transmission) is progressively destroyed. Although the disease is caused by a very prevalent virus (called JC virus), it only develops in individuals who are immunocompromised (have weakened immune systems).

Multiple areas of the brain are affected by the demyelination associated with progressive multifocal leukoencephalopathy. Additionally, other abnormalities and bizarre cells take up residence within the brain, causing destruction of normal brain tissue and impairing normal function.

Demographics

The causative virus in progressive multifocal leukoencephalopathy, JC virus, is extremely common. It is thought to be present in upwards of 85% of all children before the age of nine, and probably is present in an even greater percentage of adults. However, the JC virus does not actually cause any symptoms or disease, except in individuals who have severely compromised immune systems. About 62.2% of all progressive multifocal leukoencephalopathy cases occur in individuals with lymphatic cancers (lymphoproliferative disease, such as Hodgkin's disease and other lymphomas); 6.5% occur in individuals with cancer of bone marrow cells (myeloproliferative disease or leukemias); 2.2% occur in individuals with carcinomatous disease (cancers that affect the lining of tissues or organs of the body); and 10% occur in individuals with any of a number of acquired immunodeficiency states (such as systemic lupus erthematosus, sarcoidosis, and organ transplant survivors). Among patients with Acquired Immunodeficiency Syndrome (AIDS ), about 10% of patients develop progressive multifocal leukoencephalopathy. Only 5.6% of all cases of progressive multifocal leukoencephalopathy occur in individuals with no other underlying source of immunocompromise.

Causes and symptoms

Although much is left to be defined about the mechanism whereby progressive multifocal leukoencephalopathy affects an individual, researchers believe that the JC virus resides in the kidneys of most individuals. In normal, nonimmunocompromised individuals, the virus stays within the kidneys, doing no harm. In immunocompromised individuals, the virus is reactivated, travels through the circulatory system to the brain, and selectively destroys myelinated nerve cells.

Patients with progressive multifocal leukoencephalopathy experience a range of symptoms that grow gradually worse over time, including headache and difficulties with speech, thinking, walking, weakness, vision problems (even blindness), memory problems, confusion, slowness of movement, paralysis of half of the body, and seizures . Eventually, patients lapse into a coma and die, usually within just months of the onset of their initial symptoms.

Diagnosis

Diagnosis is usually suggested by a patient's characteristic symptoms of progressive multifocal leukoencephalopathy, in combination with evidence of white matter destruction visualized on CT or MRI scanning of the brain. Specialized tests on cerebrospinal fluid (called polymerase chain reactions) may demonstrate the presence of JC virus DNA. However, only brain biopsy can result in an absolutely definitive diagnosis.

Treatment team

Patients with progressive multifocal leukoencephalopathy are usually seen by neurologists, as well as by hematologist/oncologists for patients with lymphoma or leukemia, infectious disease specialists for patients with AIDS, and a rheumatologist for individuals with specific autoimmune disease.

Treatment

There are no treatments available to cure progressive multifocal leukoencephalopathy. Some degree of slowing of the relentless progression of the disease has been noted in certain patients treated with the AIDS drug AZT.

Prognosis

Progressive multifocal leukoencephalopathy is uniformly fatal, usually within one to four months of the initial symptoms. A few patients have had brief remissions in the disease progression, and have lived for several years beyond diagnosis.

Resources

BOOKS

Berger, Joseph R., and Avindra Nath. "Progressive Multifocal Leukoencephalopathy." In Cecil Textbook of Internal Medicine, edited by Lee Goldman, et al. Philadelphia: W. B. Saunders Company, 2000.

Roos, Karen L. "Viral Infections." In Textbook of Clinical Neurology, edited by Christopher G. Goetz. Philadelphia: W. B. Saunders Company, 2003.

Tyler, Kenneth L. "Viral Meningitis and Encephalitis." In Harrison's Principles of Internal Medicine, edited by Eugene Braunwald, et al. NY: McGraw-Hill Professional, 2001.

PERIODICALS

Pruitt, A. A. "Nervous System Infections in Patients with Cancer." Neurol Clin 21, no. 1 (February 1, 2003): 193–219

WEBSITES

National Institute of Neurological Disorders and Stroke (NINDS). NINDS Progressive Multifocal Leukoencephalopathy Information Page. May 29, 2002. (June 4, 2004). <http://www.ninds.nih.gov/health_and_medical/disorders/pml_doc.htm>.

Rosalyn Carson-DeWitt, MD

Progressive Multifocal Leukoencephalopathy

Definition

Progressive multifocal leukoencephalopathy (PML) is a rapidly progressive neuromuscular disease caused by opportunistic infection of brain cells (oligodendrocytes and astrocytes) by the JC virus (JCV).

Description

PML is an opportunistic infection associated with AIDS and certain cancers. It occurs in people with inadequate immune response and carries a poor prognosis. The incidence of PML, once quite rare, is rising as the numbers of people living with persistently compromised immune systems rises. An estimated 2-7% of people with HIV disease will develop PML. The infection also occurs among people undergoing long-term chemotherapy for cancer. PML is not considered a contagious disease. According to the Centers for Disease Control definition of AIDS, PML in the presence of HIV infection is sufficient to form a diagnosis of AIDS.

Causes and symptoms

Although at least 80% of the adults in the United States have been exposed to JC virus (as evidenced by the presence of antibodies to this virus), very few will develop PML. Little is certain about what causes JCV to produce active disease, but the virus persists in the kidneys of otherwise healthy people without making them ill. Recent evidence suggests that after prolonged compromise of the immune system, the virus changes into a form that can reach brain tissue and cause disease. In PML, the JCV infects and kills the cells (oligodendrocytes) that produce myelin, which is needed to form the sheath that surrounds and protects nerves.

About 45% of people with PML experience vision problems, most often a blindness affecting half of the visual field of each eye. Mental impairment affects about 38% of people with PML. Eventually, about 75% experience extreme weakness. Other symptoms include lack of coordination, paralysis on one side of the body (hemiparesis), and problems in speaking or using language.

Diagnosis

Diagnosis is difficult, but usually relies on a neurologist and radiologist assessing the white matter of the brain on a computed tomography scan or a magnetic resonance imaging (MRI). Tests of the cerebrospinal fluid can help distinguish between PML and other diseases, such as multiple sclerosis and acute hemorrhagic leukoencephalopathy. The rapid clinical progression in immunocompromised patients is another distinguishing factor.

Treatment

Currently, there is no known cure for PML, although it sometimes responds to treatment in patients with AIDS who are taking anti-HIV drugs (such as AZT, alpha-interferon, and peptide T). Although several agents have shown some potential in the last few years, such as the highly toxic cancer drug cytarabine, none are safe enough or sufficiently effective to be approved for PML.

Prognosis

PML is usually a very aggressive disease. The time between the onset of symptoms and death can be as little as one to six months. However, some patients infected with HIV have improved without receiving treatment specifically for PML.

Resources

PERIODICALS

Royal III, Walter. "Update on Progressive MultifocalLeukoencephalopathy." The Hopkins HIV Report 9 (March 1997).

KEY TERMS

Multifocal— Having many focal points. In progressive multifocal leukoencephalopathy, it means that damage caused by the disease occurs at multiple sites.

Opportunistic infection— A illness caused by infecting organisms that would not be able to produce disease in a person with a healthy immune system, but are able to take advantage of an impaired immune response.