Progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML), also known as progressive multifocal leukoencephalitis, is a rare and usually fatal viral disease that is characterized by progressive damage (-pathy) or inflammation (-itis) of the white matter (leuko-) of the brain (-encephalo-) at multiple locations (multifocal). It occurs almost exclusively in people with severe immune deficiency, e.g. transplant patients on immunosuppressive medications, or AIDS patients.

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Cause and epidemiology

The cause of PML is a type of polyomavirus called the JC virus (JCV), after the initials of the patient in whom it was first discovered. The virus is widespread, with 86% of the general population presenting antibodies, but it usually remains latent, causing disease only when the immune system has been severely weakened.

About 2-5% of AIDS patients develop PML. It is unclear why PML occurs more frequently in AIDS than in other immunosuppressive conditions; some research suggests that the effects of HIV on brain tissue, or on JCV itself, make JCV more likely to become active in the brain and increase its damaging inflammatory effects (Berger, 2003).

There are case reports of PML being caused by pharmacological agents, although there is some speculation this could be due in part to the existing impaired immune response or 'pharm combos' rather than individual drugs. Rituxan([1] and Natalizumab (branded Tysabri), [2].

Disease process

PML is a demyelinating disease, in which the myelin sheath covering the axons of nerve cells is gradually destroyed, impairing the transmission of nerve impulses. It affects the white matter, which is mostly composed of axons from the outermost parts of the brain (cortex). Symptoms include weakness or paralysis, vision loss, impaired speech, and cognitive deterioration. PML is similar to another demyelinating disease, multiple sclerosis, but since it destroys the cells that produce myelin (unlike MS, in which myelin itself is attacked but can be replaced), it progresses much more quickly. Most patients die within four months of onset. PML destroys oligodendrocytes and produces intranuclear inclusions.

Diagnosis

PML is diagnosed by testing for JC virus DNA in cerebrospinal fluid or in a brain biopsy specimen. Characteristic evidence of the damage caused by PML in the brain can also be detected on MRI images.

Treatment

There is no known cure. In some cases, the disease slows or stops if the patient's immune system improves; some AIDS patients with PML have been able to survive for several years, with the advent of highly active antiretroviral therapy (HAART).

AIDS patients who start HAART after being diagnosed with PML tend to have a slightly longer survival time than patients who were already on HAART and then develop PML (Wyen et al., 2004). A rare complication of effective HAART is immune reconstitution inflammatory syndrome (IRIS), in which increased immune system activity actually increases the damage caused by the infection; though IRIS is often manageable with other types of infections, it is extremely dangerous if it occurs in PML (Vendrely et al., 2005).

Other antiviral agents that have been studied as possible treatments for PML include cidofovir and interleukin-2, but this research is still preliminary.

Cytarabine (A.K.A. ARA-C), a chemotherapy drug approved by the US FDA to treat certain cancers, has been prescribed on an experimental basis for a small number of non-AIDS PML patients. Cytarabine is reported to have stabilized the neurological condition of a minority of these patients (Aksamit, 2001). One patient regained some cognitive function lost by PML (Langer-Gould et al., 2005).

References

• Aksamit, A. J. (2001) Treatment of non-AIDS progressive multifocal leukoencephalopathy with cytosin arabinoside. J Neurovirol 2001;7:386.
• Berger, J.R. (2003) Progressive multifocal leukoencephalopathy in acquired immunodeficiency syndrome: explaining the high incidence and disproportionate frequency of the illness relative to other immunosuppressive conditions. Journal of Neurovirology 9 (supplement), 38-41. PMID 12709870
• Langer-Gould, A., Atlas, S. W., Bollen, A. W., Pelletier, D. (2005) Progressive Multifocal Leukoencephalopathy in a Patient Treated with Natalizumab. N Engl J Med 2005;353:375-81.
• Vendrely, A., Bienvenu, B., Gasnault, J., Thiebault, J.B., Salmon, D. and Gray, F. (2005) Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy. Acta Neuropathologica 109, 449-455. PMID 15739098
• Wyen, C., Hoffmann, C., Schmeisser, N., Wohrmann, A., Qurishi, N., Rockstroh, J., Esser, S., Rieke, A., Ross, B., Lorenzen, T., Schmitz, K., Stenzel, W., Salzberger, B. and Fatkenheuer, G. (2004) Progressive multifocal leukencephalopathy in patients on highly active antiretroviral therapy: survival and risk factors of death. Journal of Acquired Immune Deficiency Syndrome 37, 1263-1268. PMID 15385733

See also

• Leukoencephalopathy with vanishing white matter