Progressive multifocal leukoencephalopathy
Progressive multifocal leukoencephalopathy (PML) is a rare and serious neurological disease characterized by widespread loss of myelin, the protective covering of nerve fibers within the brain's white matter. It predominantly affects individuals with compromised immune systems, leading to various neurological deficits that can progress rapidly and often result in a fatal outcome. The disease is caused by the reactivation of the JC virus (JCV), a common virus that typically remains dormant in the body but can become active in those with weakened immunity, such as individuals with AIDS or those undergoing immunosuppressive therapies.
Symptoms of PML can vary widely and may include clumsiness, cognitive decline, visual disturbances, and muscle weakness, reflecting the disease's impact on different areas of the brain. Diagnosis is primarily through MRI imaging, which reveals characteristic lesions, combined with cerebrospinal fluid analysis for JCV antigens. While there is no established treatment for PML, supportive care and measures to enhance immune function are critical. Recent advancements in highly active antiretroviral therapy (HAART) have improved survival rates among patients with HIV-related PML. Preventative strategies include the careful management of immunosuppressive therapies and potential use of certain medications that may block JCV entry into cells.
Progressive multifocal leukoencephalopathy
- ANATOMY OR SYSTEM AFFECTED: Brain, central nervous system
- ALSO KNOWN AS: Progressive multifocal leukodystrophy
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 brainstem 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, brainstem, and spinal cord.
Treatment and Therapy
No cure 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. These measures may slow the progression of the disease.
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.
"Progressive Multifocal Leukoencephalopathy (PML)." Cleveland Clinic, 26 May 2021, my.clevelandclinic.org/health/diseases/6101-progressive-multifocal-leukoencephalopathy-pml. Accessed 4 Feb. 2025.