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progressive multifocal leukoencephalopathy (PML)
An opportunistic infection of the brain in an immunocompromised host, 1st described by Astome, Mancall & Richardson in 1958
The causative agent was isolated from the post mortem brain of a patient JC, by using cultures of human fetal glial cells.
Etiology:
1) polyomavirus: JC virus (majority) & SV40 (2 cases)
2) risk factors
a) immunodeficiency, especially AIDS
b) myeloproliferative disorders
c) chronic infections
3) a small number of patients do not have any underlying disease or recognized immunodeficiency [4]
Epidemiology:
1) patients are generally middle-aged
2) antibodies to JC virus in 80% of adults
Pathology:
1) focal demyelination resulting from failure of infected oligodendrocytes to maintain myelination
a) sparing of axons is relative
b) central part of larger lesions may exhibit frank necrosis with phagocytic reaction (microglia & macrophages) indistinguishable from an infarct
2) gross pathology
a) brain may appear grossly normal at autopsy
b) may be some cortical atrophy
c) multiple grey foci distributed throughout centrum semiovale &, to a lesser extent cerebellum & brainstem
d) may be large & confluent, even cystic changes in white matter
3) histopathology:
a) multiple foci of demyelination, sometimes confluent
b) large, abnormal astrocytes
1] often multinucleate
2] numerous, large processes
c) a few chronic inflammatory cells, mostly lymphocytes
d) intranuclear inclusions, basophilic or eosinophilic, within large swollen oligodendrocyte nuclei
-> numerous at periphery of demyelinated foci
e) granule cell loss & foci of demyelination may be seen in the cerebellum
Clinical manifestations:
1) insidious onset
2) dementia is often presenting symptom [2]
3) confusion
3) personality change
4) hemianopsia, diplopia or other visual field disturbance
5) motor weakness, hemiparesis (focal or asymmetric)
Laboratory:
1) cerebrospinal fluid:
a) cell count, protein, glucose is normal
b) PCR for JC virus from CSF
c) serology: antibodies to JC virus (high titer)
2) brain biopsy:
a) detection of viral particles (EM)
1] 30 nm viral particles
2] found profusely in oligodendrocytes
3] rarely found in astrocytes
4] never found in neurons
b) antigen by immunocytochemistry
c) viral genome by in situ hybridization or PCR
d) viral cultures generally not done (see above)
e) diagnostic [2]
3) see ARUP consult [5]
Radiology:
1) CT or MRI shows white matter demyelination
2) hypodense, non-enhancing lesions more prominently visualized on T2-weighted MRI scans
- hyperintense (white) areas on T2-weighted images
- fluid-attenuated inversion recovery sequences
3) hypointense (dark) areas on T1-weighted images
4) usually no mass effect.
Differential diagnosis:
1) AIDS dementia complex
2) toxoplasmosis (mass effect, enhancing lesions)
3) primary CNS lymphoma (mass effect, enhancing lesions)
Management:
- initiation of antiretroviral therapy to reverse the immunosuppression that interferes with the normal host response to JCV.
- prior to effective antiretroviral therapy prognosis was poor
a) death generally occurs within 1-6 months
b) a few patients appear to have remissions & survive for years
Interactions
disease interactions
General
demyelinating disease
leukoencephalopathy
viral encephalitis
Properties
PATHOLOGY:
astrocytosis
viral inclusion
ETIOLOGY: polyomavirus
References
- Harrison's Principles of Internal Medicine, 13th ed.,
Companion Handbook, Isselbacher et al (eds), McGraw-Hill
Inc. NY 1995, pg 719
- Medical Knowledge Self Assessment Program (MKSAP) 11, 14,
American College of Physicians, Philadelphia 1998, 2006
- Greenfield's Neuropathology, 5th ed., 1992 p. 336, 367-70
- Gheuens S et al.
Progressive multifocal leukoencephalopathy in individuals with
minimal or occult immunosuppression.
J Neurol Neurosurg Psychiatry 2010 Mar; 81:247
PMID: 19828476
- ARUP Consult: JC Virus - PML
The Physician's Guide to Laboratory Test Selection & Interpretation
https://www.arupconsult.com/content/jc-virus
- National Institute of Neurological Disorders and Stroke (NINDS)
NINDS Progressive Multifocal Leukoencephalopathy Information Page
https://www.ninds.nih.gov/Disorders/All-Disorders/Progressive-Multifocal-Leukoencephalopathy-Information-Page
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