AM Report May 4, 2009 Amy Auerbach

 Severe demyelinating disease of the central nervous system caused by reactivation of the polyomavirus JC  Occurs almost exclusively in immunosuppressed patients  Normally remains latent in kidneys and lymphoid organs  Can reactivate, spread to brain and induce lytic infection of oligodendrocytes

 Seroprevalence studies demonstrate antibodies in 60-80% of adults  Can be detected in tonsillar tissue and mucosa of GI tract- unclear pattern of transmission  Likely initially associated with viremia- seeding of kidney  Latent infection may be reactivated during periods of immunosuppression (T cell dysfunction)  JCV infects oligodendrocytes and astrocytes once it reaches the CNS

 Almost exclusively in immunocompromised patients  Initially described in lymphoproliferative and myeloproliferative disease  Rare patients with solid organ malignancies, granulomatous and inflammatory disease, solid organ transplant recipients  Opportunistic infection in HIV patients  Observed in patients treated with natalizumab- immunomodulatory drug used in Crohn’s disease and multiple sclerosis

 Altered mental status  Motor deficits (hemiparesis or monoparesis)  Limb ataxia, gait ataxia  Visual symptoms  Varied based on location of lesions in CNS  In HIV, pt’s with PML typically have CD4 count<200  Typically spares optic nerves and spinal cord

 Progressive disease course  Remyelination does not occur in affected areas of brain  Median survival time is now 1.8 years- many patients left with severe neurologic deficits- in patients with HIV infection  In patients without HIV infection- median survival is only 2.6 months

 Believed to be secondary to immune reconstitution therapy syndrome  Occurs after treatment with HAART in HIV patients- inflammatory reaction of PML lesions  Initial worsening but clinical outcome ultimately more favorable

 JCV can cause lytic infection of cerebellar granule cell neurons  Leads to ataxia and cerebellar atrophy  Separate disease process from white matter lesions in cerebellum from PML

 Multifocal areas of white matter demyelination  Do not exhibit mass effect  Lesions often bilateral and localize preferentially to periventricular areas and subcortical white matter

 Reactive gliosis with enlarged astrocytes  Can confirm presence of JCV- infected cells by immunohistochemi stry

Viral Inclusions in Oligodendrocytes

 PCR detection of JCV DNA in the CSF in patients with appropriate neurologic and neuroradiologic findings  “possible PML” if exclude primary CNS lymphoma, infectious etiologies but do not have JCV DNA in CSF

 In HIV infection: HIV encephalopathy  PML lesions typically asymmetric, well demarcated, focal neurologic deficits  HIV lesions tend to be poorly demarcated, associated with HIV CSF viral load  CNS Lymphoma: cortical involvement, positive CSF cytology or EBV PCR can help differentiate  Ischemic lesions, tumors

 HAART therapy in patients with HIV  Stop immunosuppressive therapy in patients on immunosuppression (transplant patients, inflammatory disorders)  Short term glucocorticoid therapy in patients with inflammatory PML and edema  Other treatments under evaluation: cytarabine, mirtazapine

1) PML is an opportunistic infection associated with impairment of cell-mediated immunity 2) New onset or clinical worsening may occur after initiation of HAART due to immune reconstitutions inflammatory syndrome 3) Primary differential includes HIV encephalopathy and CNS lymphoma 4) Brain biopsy or detection of JCV DNA in CSF needed for diagnosis

 Langer-Gould et. Al. Progressive Multifocal Leukoencephalopahty in a Patient treated with Natalizumab. NEJM353:375; July 28,  Epker et.al. PML: a review and an extended report of five patients with different immune compromised states. Eur J Intern Med May; 20 (3)  Uptodate.com