Progressive multifocal leukoencephalopathy (PML) is caused by reactivation of the JC virus. The disease usually occurs in patients with impaired cell-mediated immunity, particularly patients with HIV infection. PML results in subacute and progressive CNS demyelination, multifocal neurologic deficits, and death, usually within a year. Diagnosis is with 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therapy may slow down the progression, and patients taking immunosuppressants may improve when those drugs are withdrawn.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

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 who develop PML 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. Increasingly, PML is occurring as a complication of immunomodulatory therapy (eg, natalizumabSome Trade Names
TYSABRI
Click for Drug Monograph
, rituximabSome 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 DNA

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 may show low-density, nonenhancing lesions but is significantly less sensitive than MRI.

CSF is analyzed for JC viral DNA 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 mainly supportive. Experimental use of drugs such as cidofovirSome Trade Names
VISTIDE
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and other antivirals has failed to provide benefit. Highly active antiretroviral therapy (HAART) in AIDS patients has improved outcome in PML, increasing the 1-yr survival rate from 10 to 50%. However, patients treated with aggressive antiretroviral therapy may develop immune reconstitution inflammatory syndrome (IRIS—see Human Immunodeficiency Virus (HIV): Treatment); in IRIS, the recovering immune system produces an intense inflammatory response against the JC virus, thus worsening symptoms. Imaging done after IRIS develops shows greater contrast enhancement of the lesions and may show significant cerebral edema. Corticosteroids may be helpful. Depending on the severity of IRIS and of AIDS, clinicians may decide to withdraw HAART.

Withdrawal of immunosuppressants may result in clinical improvement. However, patients who stop taking these drugs are also at risk of developing IRIS.

If PML develops in patients taking natalizumabSome Trade Names
TYSABRI
Click for Drug Monograph
or another immunodulatory drug, the drug should be stopped, and plasma exchange should be done to remove residual circulating drug.

Key Points

• Reactivation of the ubiquitous JC virus, usually due to impaired cell-mediated immunity, leads to PML.
• PML commonly causes clumsiness, hemiparesis, aphasia, dysarthria, hemianopia, and cognitive impairment.
• Do MRI and test CSF for JC virus DNA in patients who have impaired cell-mediated immunity and unexplained progressive brain dysfunction.
• Treat patients supportively, and manage underlying disorders as indicated (eg, by withdrawing natalizumabSome Trade Names
  TYSABRI
  Click for Drug Monograph
  , by initiating or withdrawing HAART).

Last full review/revision November 2012 by John E. Greenlee, MD

Content last modified December 2012