CHAPTER SIX
DEMYELINATIVE DISEASES

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

Progressive multifocal leukoencephalopathy (PML) is a deadly demyelinative disease of the CNS due to lytic infection of oligodendrocytes by the ubiquitous opportunistic polyoma virus JC(JCV). Most persons acquire this virus at a young age. After primary infection, it remains latent in the kidneys and lymphoid tissues for life. The virus is reactivated when cellular immunity is suppressed. Most PML cases occur in patients with AIDS, cancer and inflammatory disorders, and organ transplant recipients. Recently, PML has been reported in patients who had received natalizumab, a new drug for treatment of multiple sclerosis and Crohn's disease. The incidence of PML has increased due to the AIDS pandemic and the widespread use of immunosuppressive drugs. BK, a member of the same virus family, causes nephropathy in renal allografts, leading to graft loss.

Clinically, PML is characterized by a variety of neurologic deficits (visual loss, paralysis, dementia) evolving rapidly and causing death in a few months. The disease may get worse when the immune system is reconstituted after antiretroviral therapy. Rare cases of aseptic meningitis and JCV infection of cerebellar granular neurons causing ataxia have been reported. On magnetic resonance imaging (MRI), PML lesions are located in the subcortical white matter and are hyperintense on T2-weighted and FLAIR sequences. They show no contrast enhancement or mass effect. The CSF is either normal or shows a few lymphocytes.

PML-myelin stain	PML-myelin stain

Pathologically, PML begins with small demyelinative foci at the cortex-white matter junction. Confluence of these foci results in large irregular white matter lesions that involve the cerebrum, cerebellum, and brainstem. Myelin is destroyed; axons are relatively spared. The nuclei of infected oligodendrocytes are packed with viral particles that cause them to enlarge and have a ground glass appearance. PML is a lytic infection leading to oligodendrocyte destruction.

PML-intranuclear inclusion	PML-atypical astrocytes	PML-viral particle in a nucleus

Polyoma viruses can also become incorporated into the host genome and cause neoplastic transformation. Such a non-lytic infection involves astrocytes and causes pronounced atypia, suggesting neoplastic change (see picture on the right). Inflammation is usually minimal, except when the immune system recovers with antiretrovirals. Such cases show brisk inflammation, resembling encephalitis. There is no peripheral nerve demyelination or disease in any other organ system. The diagnosis of PML can be made by microscopic examination of a brain biopsy with immunohistochemistry and in situ hybridization for JCV. The diagnosis can also be established with CSF PCR for JCV but this is less sensitive in patients undergoing antiretroviral therapy.

In addition to its clinical significance, PML is interesting as a model of demyelination due to a lytic infection of myelin-producing cells. Neurotropic mouse hepatitis virus and canine distemper virus are animal models of virus-induced demyelination, similar to PML.

Further reading: Koralnik I J. Progressive Multifocal Leukoencephalopathy Revisited: Has the Disease Outgrown its Name? Ann Neurol 2006;60:162-173 PubMed

Updated: August, 2006