Published on January 9, 2014
Progressive Multifocal Leukoencephalopathy A rare but often fatal disease caused by the reactivation of the JC virus. Daniel Vela-Duarte, MD PGY-3. Department of Neurology Loyola University Medical Center January, 2014
Introduction, History First described as a neuropathological entity in 1958 Suspected viral infection based on the pathologic appearance of the inclusion-bearing oligodendrocytes. in 1971, a brain from a patient with PML was cultured. The virus was isolated, named JC virus (James Cunningham) Before the HIV epidemic, it was a disease mainly seen in individuals with hematological malignancies, organ transplant recipients and chronic inflammatory disorders. Suspected viral infection based on the pathologic appearance of the inclusion-bearing oligodendrocytes.
Introduction From 9675 cases of PML, 82% with HIV, 8% with hematological cancers, 3% with solid organ cancers and 0.44% with rheumatologic diseases. Inmumodulators Natalizumab for multiple sclerosis and Crohn’s disease Rituximab for lupus, Efalizumab for psoriasis.
Prevalence of JC Virus Using whole JC virions, seroprevalence of 60% was detected individuals aged 20–29 years in the USA. By use of a haemagglutination inhibition assay based on viruslike particles containing the JC virus, VP1 major capsid proteins, Knowles and colleagues, reported a seroprevalence of up to 50% in individuals aged 60–69 years in England and Wales. The use of recombinant VP1 protein and quantitative enzyme immunoassay could detect IgG antibodies in up to 86% of healthy individuals in Germany.
The virus is acquired in childhood or young adulthood and becomes latent in lymphocytes, spleen, kidney, bone marrow, and other lymphoid tissue. It also may establish latency in the brain. With immunosuppression, JC virus replicates in oligodendrocytes; kills them, causing demyelination; and nonproductively infects astrocytes, causing bizarre histologic changes.
Clinical presentation Infection of oligodendrocytes and astrocytes, therefore deficits are associated with demyelination in the brain. Unifocal syndrome of cerebral or brainstem dysfunction Generally, subacute presentation No involvement of the optic nerve and spinal cord.
Clinical manifestations Motor system involvement causes corticospinal tract findings Cortical sensory loss Ataxic cerebellar deficits Focal visual field defects Cortical deficits: Aphasia, visual-spatial disorientation could occur with subcortical lesions Patients with more immunopreserved status may have a slower clinical course, mimicking brain tumors such as CNS lymphoma or glioma
Progressive Multifocal Leukoencephalopathy Patients at Mayo Clinic: Non-AIDS PML−Associated Diseases (n=58)
Brain MRI findings
T2-weighted FLAIR brain MRI Bifrontal PML lesions including involvement of the corpus callosum mimicking glioma or lymphoma. T2-weighted FLAIR brain MRI Left cerebellar and pontine PML lesion. T2-weighted FLAIR brain MRI. Right frontal large PML lesion with tiny left frontal lesions.
Brain MRI scan of progressive multifocal leukoencephalopathy (PML). All are T2-weighted fluidattenuated inversion recovery images except D, which is a T1 postgadolinium image. B. Multifocal right-greater-than-left subcortical frontal PML lesions. © 2013 American Academy of Neurology A. Single superficial subcortical left frontal PML lesion. C, D. Symmetric bioccipital PML lesions that show trace enhancement after gadolinium.
A 47-year old HIV infected man with jerking of his right hand Teaching NeuroImages Neurology Resident and Fellow Section January 7, 2014 82:e8 © 2013 American Academy of Neurology
Case A 47- year old with longstanding HIV infection presented with with 3-week history of clumsiness and shaking of his right hand. Clinical examination revealed a slow, irregular distal tremor of the right upper limb present at rest and posture (Video) Katchanov et al.
© 2013 American Academy of Neurology
The imaging of his brain revealed a demyelinating lesion affecting the right middle cerebellar peduncle and adjacent cerebellar white matter The CSF PCR for JC-virus was strongly positive establishing the diagnosis of progressive multifocal leukoencephalopathy (PML). Holmes tremor is a rare manifestation of PML.
Diagnostic tests Detection of JCV DNA in CSF -by PCR amplification- is required for a definite dx of PML. The PCR technique is, however, less sensitive in patients with HIV receiving HAART. When JCV DNA is not detected in the CSF, PML can be confirmed by a stereotactic brain biopsy JCV DNA in the biopsy sample by in situ hybridization is required for diagnosis of PML. Histological features include: focal areas of demyelination, enlarged oligodendrocytes containing intranuclear inclusions, Large 'bizarre-looking' astrocytes, Llipid-laden macrophages
Neuropathology Gross and microscopic appearance of PML lesions affecting the superficial subcortical gray-white matter junction in the cerebral hemisphere. A. Coronal section of fixed PML brain. The subcortical white matter is undermined by multifocal punctate coalescent demyelinating lesions (black arrows). B. Luxol fast blue stain shows a microscopic demyelinated lesion (between opposing black arrows) in the white matter immediately subcortical.
Management Goal: restoration of immune function. Immunosuppressant or immunomodulatory therapy should be stopped if possible. Questionable treatment (Poor effectiveness, lack of trials) Cytosine arabinoside 2 mg/kg/d for 5 days, single course Cidofovir 5 mg/kg once weekly for 2 weeks, then every 2 weeks for 2 months
Clinical pearls What factors confer an increased risk of developing PML in a patient taking natalizumab? Positive status with respect to anti-JC virus antibodies Increased duration of natalizumab treatment Prior use of immunosuppressants, alone or in combination, were associated with discrete levels of PML risk in patients with multiple sclerosis. The risk of PML increased with increasing duration of treatment, with the greatest increase in risk occurring after 2 years of therapy (25 to 48 N Engl J Med. 2012 May 17;366(20). Risk of natalizumab-associated progressive multifocal leukoencephalopathy. months).
PML-IRIS. (Immune reconstitution inflammatory syndrome) Inflammatory reaction after initiation of cART or after cessation of immunosuppressive therapy in HIV-negative patients. (nonAIDS PML patients) This immune reconstitution is inferred by an increase in Tlymphocyte counts Acute and usually transient clinical worsening not consistent with the expected course of previously or newly diagnosed PML. MRI: Gadolinium-enhancing lesions, edema of previous PML lesions with possible mass effect
Tan, Koralnik, The Lancet Neurology, Volume 9, Issue 4, April 2010, Pages 425-437
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