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Progressive Multifocal Leukoencephalopathy (PML)

By

John E. Greenlee

, MD, University of Utah School of Medicine

Last full review/revision Jul 2020| Content last modified Jul 2020
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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 demyelination in the central nervous system, multifocal neurologic deficits, and death, usually within 9 months. Diagnosis is with MRI plus cerebrospinal fluid analysis using polymerase chain reaction testing. 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therapy may slow down the progression, and patients taking immunosuppressants may improve when those drugs are withdrawn.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 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, central nervous system [CNS]). The reactivated virus has a tropism for oligodendrocytes.

Most patients who develop PML have depressed cell-mediated immunity due to

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. The drugs most frequently implicated include

  • The monoclonal antibody natalizumab

  • The antibody-drug conjugate brentuximab vedotin

But PML has occurred in patients taking other drugs (eg, rituximab, fingolimod, dimethyl fumarate). Measuring serum antibodies to JC virus (JC virus index) may help assess the risk of PML in patients taking natalizumab.

Symptoms and Signs

Clumsiness may be the first symptom of progressive multifocal leukoencephalopathy. 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 months after symptoms begin.

Diagnosis

  • MRI

  • Cerebrospinal fluid (CSF) testing for JC viral DNA

Progressive multifocal leukoencephalopathy is suspected in patients with unexplained progressive brain dysfunction, particularly in those with depressed cell-mediated immunity.

Provisional diagnosis of PML 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. Stereotactic biopsy can provide a definitive diagnosis but is rarely warranted.

Treatment

  • Supportive care

Treatment of progressive multifocal leukoencephalopathy is mainly supportive.

Experimental use of drugs such as cidofovir and other antivirals has failed to provide benefit. Antiretroviral therapy (ART) in AIDS patients has improved outcome in PML, increasing the 1-year survival rate from 10 to 50%. However, patients treated with aggressive antiretroviral therapy may develop immune reconstitution inflammatory syndrome (IRIS). 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 ART.

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 natalizumab, another immunomodulatory drug, or an immunosuppressant, 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 stopping natalizumab, another immunomodulatory drug, or an immunosuppressant or, in patients with AIDS, by initiating antiretroviral therapy and watching closely for development of immune reconstitution inflammatory syndrome).

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