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Progressive multifocal leukoencephalopathy is caused by reactivation of the JC virus. The disease usually occurs in patients with impaired cell-mediated immunity. It causes subacute and progressive CNS demyelination, multifocal neurologic deficits, and death, usually within a year. Diagnosis is with contrast-enhanced CT or MRI plus CSF PCR. In AIDS patients, highly active antiretroviral therapy may slow down the progression, and patients taking immunosuppressants may improve when those drugs are withdrawn. Treatment is otherwise supportive.

Etiology

Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of the JC virus, a ubiquitous human papovavirus that is typically acquired during childhood and remains latent in the kidneys and possibly other sites (eg, mononuclear cells, CNS). The reactivated virus has a tropism for oligodendrocytes. Most patients have depressed cell-mediated immunity due to AIDS (the most common risk factor), reticuloendothelial system disorders (eg, leukemia, lymphoma), or other conditions (eg, Wiskott-Aldrich syndrome, organ transplantation). The risk in AIDS increases with increasing HIV viral load; prevalence of PML has decreased because of widespread use of more effective antiretrovirals. Rarely, PML occurs as a complication of immunomodulatory therapy (eg, natalizumab Some Trade Names
TYSABRI
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, rituximab Some Trade Names
RITUXAN
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).

Symptoms and Signs

Clumsiness may be the first symptom. Hemiparesis is the most common finding. Aphasia, dysarthria, and hemianopia are also common. Multifocal cortical damage produces cognitive impairment in two thirds of patients. Sensory, cerebellar, and brain stem deficits may be present. Headaches and convulsive seizures are rare and occur most often in patients with AIDS. Gradual, relentless progression culminates in death, usually 1 to 9 mo after symptoms begin.

Diagnosis

• MRI
• CSF testing for JC viral antigen

PML is suspected in patients with unexplained progressive brain dysfunction, particularly in those with depressed cell-mediated immunity. Provisional diagnosis is made by contrast-enhanced MRI, which shows single or multiple white matter lesions on T2-weighted images. A contrast agent enhances, usually faintly and peripherally, 5 to 15% of lesions. CT usually shows low-density, nonenhancing lesions but is significantly less sensitive than MRI.

CSF is analyzed for JC viral antigen using PCR; a positive result with compatible neuroimaging findings is nearly pathognomonic. Routine CSF analysis is usually normal.

Serologic tests are not helpful. Stereotaxic biopsy can provide a definitive diagnosis but is rarely warranted.

Treatment

• Supportive care

Treatment is supportive. Experimental use of drugs such as cidofovir Some Trade Names
VISTIDE
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and other antivirals has failed to provide benefit. However, highly active antiretroviral therapy (HAART) in AIDS patients has improved outcome in PML, increasing the 1-yr survival rate from 10% to 50%. Withdrawal of immunosuppressants may also result in clinical improvement.

However, using aggressive antiretroviral therapy (or stopping immunosuppressants) has been associated with immune reconstitution inflammatory syndrome (IRIS—see Human Immunodeficiency Virus (HIV): Treatment), in which the recovering immune system produces an intense inflammatory response against the JC virus, thus worsening symptoms. If IRIS develops, imaging shows new contrast enhancement of the lesions and may show significant cerebral edema. Corticosteroids may be helpful.

Last full review/revision December 2009 by Michael Jacewicz, MD

Content last modified December 2009