Progressive Multifocal

LeukoencephalopathyAM 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

Progressive Multifocal Leukoencephalopathy

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

JCV Infection

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

Epidemiology

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

Clinical Manifestations

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

Natural History

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

Inflammatory PML

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

Cerebellar Dysfunction

Multifocal areas of white matter demyelination

Do not exhibit mass effect

Lesions often bilateral and localize preferentially to periventricular areas and subcortical white matter

Neuroradiologic Appearance

Reactive gliosis with enlarged astrocytes

Can confirm presence of JCV-infected cells by immunohistochemistry

Findings on Biopsy

Findings on Biopsy

Viral Inclusions in Oligodendrocytes

http://content.nejm.org/content/vol353/issue4/images/large/10f2.jpeg

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

Diagnosis

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

Differential Diagnosis

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

Treatment

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

Take Home Points

Langer-Gould et. Al. Progressive Multifocal Leukoencephalopahty in a Patient treated with Natalizumab. NEJM353:375; July 28, 2005.

Epker et.al. PML: a review and an extended report of five patients with different immune compromised states. Eur J Intern Med. 2009 May; 20 (3) 261-7

Uptodate.com

References