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Progressive Neurologic Disease in Immunosuppressed Patients. Clinical Grand Rounds Edward L. Goodman, MD, FACP November 16, 2005. Case Presentation #1.

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progressive neurologic disease in immunosuppressed patients

Progressive Neurologic Disease in Immunosuppressed Patients

Clinical Grand Rounds

Edward L. Goodman, MD, FACP

November 16, 2005

case presentation 1
Case Presentation #1
  • 66 year old man 19 years s/p LRD renal transplant admitted with left sided weakness. Also has alcoholic cirrhosis, IDDM, CAD, cholelithiasis, bilateral THR.
  • Two months earlier MRI revealed white matter lesions.
  • Meds include NPH and Insulin lispro, azathioprine, prednisone, pantoprazole, B12, folic acid, B6, C vit, gabapentin, quetiapine, spirinolactone, lactulose, lorazepam.
  • Exam revealed mild left hemiparesis.
  • Labs were non revealing.
  • Brain biopsy diagnostic
  • Expired a few months later.
slide3
MRI Scan Obtained Two Months before the First Hospital Admission

Koralnik, I. J. et al. N Engl J Med 2004;350:1882-1893

slide4
MRI Study Showing Progression of the Lesion over Time

Koralnik, I. J. et al. N Engl J Med 2004;350:1882-1893

slide5
Specimen from a Stereotactic Brain Biopsy

Koralnik, I. J. et al. N Engl J Med 2004;350:1882-1893

slide6
Identification of Polyomavirus JC in a Biopsy Specimen of the Brain

Koralnik, I. J. et al. N Engl J Med 2004;350:1882-1893

case 2
Case #2
  • 41 yo woman with MS 1999 treated with interferon, methylprednisone and finally Natalizumab.
  • November 2004 new and different CNS symptoms developed. Work up failed to reveal an etiology.
  • Just prior to death, CSF sent for PCR for JC virus was positive.
slide8
Doses and Timing of Treatments for Multiple Sclerosis

Kleinschmidt-DeMasters, B. et al. N Engl J Med 2005;353:369-374

slide9
MRI Findings (Panels A, B, and C) and Autopsy Findings (Panel D)

Kleinschmidt-DeMasters, B. et al. N Engl J Med 2005;353:369-374

slide10
Histologic and MRI Findings

Kleinschmidt-DeMasters, B. et al. N Engl J Med 2005;353:369-374

case 3
Case #3
  • 60 yo man with Crohn’s became confused while on Natalizumab.
  • CT showed nonenhancing hypodense lesions in white matter of right frontal lobe, left frontal and right temporal lobes.
  • Brain biopsy performed
  • Died three months later
slide12
Peripheral-Blood Neutrophil and Lymphocyte Counts in Relation to Natalizumab Therapy

Van Assche, G. et al. N Engl J Med 2005;353:362-368

slide13
Initial MRI Findings

Van Assche, G. et al. N Engl J Med 2005;353:362-368

slide14
Histologic Findings

Van Assche, G. et al. N Engl J Med 2005;353:362-368

slide15
Time Course of JC Viral Load in Serum and Brain

Van Assche, G. et al. N Engl J Med 2005;353:362-368

slide16
Causes of Leukoencephalopathy in Adults

Koralnik, I. J. et al. N Engl J Med 2004;350:1882-1893

polyomaviruses
Polyomaviruses
  • Small, non enveloped virus, 42 nm
  • Circular double stranded DNA, 5000 bp
  • Two human species, one animal
    • BK virus
      • 50% seroprevalence by 3-4 years
      • 100% by 10-11 years
    • JC virus
      • 80% prevalence in adults
    • SV40 contaminated inactivated poliovirus vaccine 1955-61
pathophysiology
Pathophysiology
  • Site of entry unknown -?tonsils
  • Latency in kidneys/bone marrow/lymphatics
    • Periodically reactivate
    • Shed in urine
  • With immunosuppression
    • Hematogenous spread to brain
    • Infects oligodendrocytes
    • Leads to demyelination
management issues
Management Issues
  • PML has been described in up to 5% of AIDS patients
  • This represents a large pool from which to study natural history and treatment
    • Berenguer et al. Clinical Course and Prognostic Features of PML in Patients Treated with HAART. CID 2003;36: 1047-52
anti viral therapy
Anti-viral therapy
  • No evidence of benefit in AIDS patients with
    • Topothecan (Royal et al. J Neurobiology 2003;9:411-419)
    • Cidofovir (Marra CM et al. A pilot study of cidofovir for PML in AIDS. AIDS 2002;16:1791-1797)
    • IFN-alfa2B (Geschwind et al.J Neurobiology 2001;7:375-381
    • Cytosine arabinoside (Hall et al N Eng J Med 1998;338:1345-1351)
  • Non AIDS patients
    • One retrospective study on Cytosine arabinoside stabilized PML in 7/19 (Aksamit AJ. J Neurovirol 2001;7:386-390)
what can we learn from the natalizumab experience
What can we learn from the Natalizumab experience?
  • Monoclonal antibody against α4 integrin
    • Inhibits binding of cells expressing α4β1 and α4β7 integrins to adhesion molecules on endothelium
    • Limiting diapedesis of lymphocytes into organs, the proposed mechanism for
      • MS
      • Crohn’s
natalizumab cont d
Natalizumab cont’d
  • But JC virus thought to be carried to CNS by lymphocytes, so
    • Inhibiting lymphocyte entry into CNS shouldn’t precipitate PML, unless
  • Other means of JC getting into CNS
    • Cell free virus, or
    • Was JC virus latent already in CNS?
conclusion
Conclusion
  • Consider PML in immunosuppressed patients with
    • Progressive mulifocal neurologic disease
    • Non enhancing white matter disease on MRI
  • Send CSF for JC virus DNA by PCR
  • Try and halt immunosuppression or improve immune status
    • e.g, HAART in AIDS patients
    • Halting immunomodulatory therapy in Crohn’s or MS
bibliography
Bibliography
  • Berger JR, Koralnik IJ. Progressive Multifocal Leukoencephalopathy and Natalizumab- Unforseen Consequences. N Eng J Med 2005;353:414-416
  • Berenguer J, Miralles P et al. Clinical Course and Prognostic Factors of Progressive Multifocal Leukoencephalopathy in Patients Treated with Highly Active Antiretroviral Therapy. Clinical Infectious Diseases 2003;36:1047-1052
  • Kleinschmidt-DeMasters BK, Tyler KL. Progressive Multifocal Leukoencephalopathy Complicating Treatment with Natalizumab and Interferon Beta-1a for Multiple Sclerosis. New Eng J Med 2005;353:369-374
bibliography continued
Bibliography continued
  • Koralnik IJ, Schellingerhout D and Frosch MP. Cases 14-2004: A 66 Year-Old Man with Progressive Neurologic Deficits. N Eng J Med 2004;350;1882-1893.
  • Koralnik IJ. New insights into progressive multifocal leucoencephalopathy. Current Opinion in Neurology 2004; 17:365-370.
  • Langer-Gould A, Atlas SW et al. Progressive Multifocal Leukocncephalopathy in a Patient Treated with Natalizumab. N Eng J Med 2005;353:375-381
  • Sabath BF, Major EO. Traffice of JC Virus from Sites of Initial Infection to the Brain:The Path to Progressive Multifocal Leukoencephalopathy. J Inf Dis 2002; 186(Suppl2):S180-186
  • Von Assche G, Van Ranst M et al. Progressive Multifocal Leukoencephalopathy after Natalizumab Therapy for Crohn’s Disease. N Eng J Med 2005;353:362-368
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