What is progressive multifocal leukoencephalopathy?

Definition

Progressive multifocal leukoencephalopathy (PML) is a rare subacute disease characterized by a widespread loss of myelin,
the fatty material that covers nerve fibers in the white matter of the nervous
system. Seen almost exclusively in persons with defective cellular immunity, PML
causes multifocal neurologic deficits and has in most cases a fatal course.

Causes

The disorder results from the reactivation, in immunocompromised persons, of
the JC virus (JCV). This ubiquitous human polyomavirus is typically acquired
during childhood and remains latent in the kidneys and possibly other sites. It is
unclear whether PML develops when a virus residing in the brain is reactivated or
when the activated virus seeds the nervous system through white blood
cells or in free form.

In the brain, glial cells support viral replication. The reactivated virus has
an affinity for oligodendrocytes, the cells that produce myelin, and presumably
destroys them.

Risk Factors

Most persons with PML have impaired cell-mediated immunity because of
acquired
immunodeficiency syndrome (AIDS), the most common risk
factor, or other conditions (such as leukemia, lymphoma, sarcoidosis, and
Wiskott-Aldrich syndrome). In AIDS, the risk increases with increasing
human
immunodeficiency virus (HIV) loads.

Rarely, PML occurs as a complication of chemotherapy,
monoclonal antibody therapy (natalizumab, rituximab) for disorders such as
multiple sclerosis and Crohn’s disease, or antirejection medication (tacrolimus,
mycophenolate mofetil) in transplant recipients.

Symptoms

Because of the high variability in lesion localization and extent, clinical
manifestations are diverse and insidious. Clumsiness may appear early. Cognitive
impairment, aphasia, hemiparesis, weakness, and visual disturbances
occur frequently. Cerebellar and brain stem deficits may be present. The disease
progresses gradually and relentlessly. For 80 percent of affected persons, the
disease culminates in death within nine months of onset. Spontaneous recovery,
however, has been reported.

Screening and Diagnosis

The disorder is suspected in persons with unexplained progressive brain
dysfunction, especially in those with impaired cell-mediated immunity. Provisional
diagnosis is made by contrast-enhanced magnetic resonance imaging (MRI), which
shows single or multiple white-matter lesions. Cerebrospinal
fluid is analyzed for JCV antigen using polymerase chain
reaction (PCR) amplification. A positive result, corroborated
with compatible neuroimaging findings, is nearly pathognomonic. Pathologic
examination of brain biopsy provides a definitive diagnosis. The biopsy will show
multiple areas of myelin loss (demyelination), mostly in the subcortical white
matter but also in the cerebellum, brain stem, and spinal cord.

Treatment and Therapy

No established treatment exists for PML. Providing supportive care and, if possible, improving immune function are essential.

Antivirals have failed to provide significant benefit. In persons with AIDS, however, highly active antiretroviral therapy (HAART) has improved outcomes and survival rates. Immune modulating (or immunomodulatory) agents such as interferon-alpha have been used experimentally, with promising results. Withdrawal of immunosuppressants or removal of monoclonal antibody by plasma exchange may also result in clinical improvement.

Prevention and Outcomes

Timely initiation of HAART therapy and judicious use of immunomodulatory medication constitute important prophylactic measures. Several studies have reported that certain antipsychotic drugs block JCV entry into the cell and may prevent PML development.

Bibliography

Antinori, A., A. Cingolani, and P. Lorenzini. “Clinical Epidemiology and Survival of Progressive Multifocal Leukoencephalopathy in the Era of Highly Active Antiretroviral Therapy.” Journal of Neurovirology 9 (2003): 47-53.

Bradley, Walter G., et al., eds. Neurology in Clinical Practice. 5th ed. Philadelphia: Butterworth Heinemann/Elsevier, 2007.

Jubelt, Burk. “Progressive Multifocal Leukoencephalopathy.” In Merritt’s Neurology, edited by Lewis P. Rowland. 11th ed. Philadelphia: Lippincott Williams & Wilkins, 2005.

Marzocchetti, A., et al. “Determinants of Survival in Progressive Multifocal Leukoencephalopathy.” Neurology 73 (2009): 1551-1558.