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Leukoencephalopathy is a disease occurring primarily in the white matter of the brain that involves defects in either the formation or the maintenance of the myelin sheath, a fatty coating that protects nerve cells. Leukoencephalopathy has several different forms and causes.

The symptoms of leukoencephalopathy reflect the mental deterioration that occurs as, at multiple sites within the brain, the myelin cover of nerve cells is eroded, leaving nerve cells exposed and with no protective insulation. Patients may exhibit problems with speech and vision, loss of mental function, uncoordinated movements, and extreme weakness and fatigue . Patients may have no desire to eat. The disease is usually progressive; patients continue to lose mental function, may have seizures, and finally lapse into a coma before death. Some patients stabilize, however, although loss of neurologic function is usually irreversible.

Leukoencephalopathy as it relates to cancer patients is primarily associated with methotrexate chemotherapy , which is used in treatment of many different types of cancer. Some other medications, including cytarabine , fludarabine , carmustine and fluorouracil in conjunction with levamisole . The disease may appear years after the administration of methotrexate. Although rare, the incidence of leukoencephalopathy is increasing, as stronger drugs are developed and increased survival times allow time for the side effects of the treatments to appear.

A devastating type of leukoencephalopathy, called multifocal, or disseminated, necrotizing leukoencephalopathy, has been shown to occur primarily when methotrexate or cytarabine therapy is used in conjunction with a large cumulative dose of whole head irradiation. This disease is characterized by multiple sites of necrosis of the nerve cells in the white matter of the brain, involving both the myelin coating and the nerve cells themselves. Although some patients may stabilize, the course is usually progressive, with patients experiencing relentless mental deterioration and, finally, death.

Although leukoencephalopathy is primarily associated with methotrexate therapy, this disease has also been observed in association with other chemotherapeutic drugs (like intrathecal cytarabine) and occasionally been reported in association with cancers that have not yet been treated.

Another, particularly lethal, type of leukoencephalopathy called progressive multifocal leukoencephalopathy (PML) is an opportunistic infection that occurs in cancer patients who experience long-term immunosuppression as a result of the cancer (as in leukemia or lymphoma ) or as a result of chemotherapy or immunosuppressive drugs. PML results when, due to chronic immunosuppression, the JC virus, widely found in the kidneys of healthy people, becomes capable of entering the brain. The virus infects the cells that produce myelin and causes multiple sites in the brain of nerve cells without the protective fatting coating. For reasons that are not completely clear, PML has a rapid and devastating clinical course, with death occurring typically less than six months after diagnosis.


It is only relatively recently that longer survival times for cancer patients have enabled scientists to identify an association of leukoencephalopathy with intensive chemotherapy (particularly methotrexate), especially when combined with large doses of whole head radiation. The causes of the neural degeneration observed are still not completely understood.

Most cases of leukoencephalopathy observed have occurred in patients who received methotrexate (either directly into the brain, through a tube in the skull, or intravenously) or who have received large doses of radiation to the head. Up to 50% of children who have received both treatments have developed necrotizing leukoencephalopathy, which differs from regular leukoencephalopathy in that the multiple sites of demyelinization also involve necrosis (the death of cells due to the degradative action of enzymes). Deterioration of the nerve tissue in necrotizing leukoencephalopathy appears to begin with the nerve and then spread into the myelin coating.

The method of action in PML is also not well understood. Long-term immunosuppression somehow appears to create an environment where the JC virus that inhabits most healthy human kidneys can mutate into a form that gains access to the brain. When in the brain, the virus infects and kills the cells that produce the myelin that forms a protective coating around the nerve.


Unfortunately, there is no cure for any form of leukoencephalopathy, and no treatments approved. Although some medications have shown some effect against the deterioration involved in this disease, those identified have been highly toxic themselves, and none so far have been effective enough to justify use. The treatment of people with this disorder, therefore, tends to concentrate on alleviating discomfort.

Since there are no effective treatments, prevention must be emphasized. As the risks of certain treatment choices have become more defined, physicians must pursue careful treatment planning to produce optimal chance of tumor eradication while avoiding increased risk of the onset of a fatal and incurable side effect. This is especially true in children. The cases observed have largely been in children, which implies that the developing brain is at higher risk of developing treatment-associated leukoencephalopathy.

Alternative and complementary therapies

There are no commonly used alternative treatments, although since the disease is incurable, there is little risk involved in trying nontraditional medications. Complementary therapies (yoga, t'ai chi, etc.) that improve patient well being are appropriate if the patient finds them helpful.



Abeloff, Martin. Clinical Oncology, 2nd ed. Camden Town:Churchhill Livingstone, Inc., 1999.

Mandell, Gerald. Principles and Practice of Infectious Diseases, 5th ed. St. Louis: Harcourt Health Sciences Group, 2000.

Pizzo, Philip, and David Poplack. Principles and Practice of Pediatric Oncology, 3rd ed. Philadelphia: Lippincott Williams & Wilkins, 1996.


Laxmi, S.N., et al. "Treatment-related Disseminated Necrotizing Leukoencephalopathy with Characteristic Contrast Enhancement of the White Matter." Radiation Medicine 14, no. 6 (November/December 1996): 303-7.


"Progressive Multifocal Leukoencephalopathy." A Healthy Me 5July 2001 <http://www.ahealthyme.com/article/gale/100083914>.

Wendy Wippel, M.Sc.