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
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