Progressive neurologic disease in immunosuppressed patients
This presentation is the property of its rightful owner.
Sponsored Links
1 / 33

Progressive Neurologic Disease in Immunosuppressed Patients PowerPoint PPT Presentation


  • 57 Views
  • Uploaded on
  • Presentation posted in: General

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

Download Presentation

Progressive Neurologic Disease in Immunosuppressed Patients

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


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.


Progressive neurologic disease in immunosuppressed patients

MRI Scan Obtained Two Months before the First Hospital Admission

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


Progressive neurologic disease in immunosuppressed patients

MRI Study Showing Progression of the Lesion over Time

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


Progressive neurologic disease in immunosuppressed patients

Specimen from a Stereotactic Brain Biopsy

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


Progressive neurologic disease in immunosuppressed patients

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.


Progressive neurologic disease in immunosuppressed patients

Doses and Timing of Treatments for Multiple Sclerosis

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


Progressive neurologic disease in immunosuppressed patients

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


Progressive neurologic disease in immunosuppressed patients

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


Progressive neurologic disease in immunosuppressed patients

Peripheral-Blood Neutrophil and Lymphocyte Counts in Relation to Natalizumab Therapy

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


Progressive neurologic disease in immunosuppressed patients

Initial MRI Findings

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


Progressive neurologic disease in immunosuppressed patients

Histologic Findings

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


Progressive neurologic disease in immunosuppressed patients

Time Course of JC Viral Load in Serum and Brain

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


Progressive neurologic disease in immunosuppressed patients

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


  • Login