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Progressive multifocal leukoencephalopathy

Brief review of pathogenesis and clinical features of Progressive multifocal leukoencephalopathy, PML.

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Progressive multifocal leukoencephalopathy

  1. 1. 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
  2. 2. 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.
  3. 3. 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.
  4. 4. 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.
  5. 5.  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.
  6. 6. 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.
  7. 7. 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
  8. 8.  Progressive Multifocal Leukoencephalopathy Patients at Mayo Clinic: Non-AIDS PML−Associated Diseases (n=58)
  9. 9. Brain MRI findings
  10. 10.  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.
  11. 11. 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.
  12. 12. 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
  13. 13. 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.
  14. 14. © 2013 American Academy of Neurology
  15. 15.  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.
  16. 16. 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
  17. 17. 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.
  18. 18. 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
  19. 19. Treatment options
  20. 20. 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).
  21. 21. 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
  22. 22. Tan, Koralnik, The Lancet Neurology, Volume 9, Issue 4, April 2010, Pages 425-437