Progressive Neurologic Disease in Immunosuppressed Patients

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

2. 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.

3. MRI Scan Obtained Two Months before the First Hospital Admission Koralnik, I. J. et al. N Engl J Med 2004;350:1882-1893

4. MRI Study Showing Progression of the Lesion over Time Koralnik, I. J. et al. N Engl J Med 2004;350:1882-1893

5. Specimen from a Stereotactic Brain Biopsy Koralnik, I. J. et al. N Engl J Med 2004;350:1882-1893

6. Identification of Polyomavirus JC in a Biopsy Specimen of the Brain Koralnik, I. J. et al. N Engl J Med 2004;350:1882-1893

7. 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.

8. Doses and Timing of Treatments for Multiple Sclerosis Kleinschmidt-DeMasters, B. et al. N Engl J Med 2005;353:369-374

9. 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

10. Histologic and MRI Findings Kleinschmidt-DeMasters, B. et al. N Engl J Med 2005;353:369-374

11. 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

12. Peripheral-Blood Neutrophil and Lymphocyte Counts in Relation to Natalizumab Therapy Van Assche, G. et al. N Engl J Med 2005;353:362-368

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

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

15. Time Course of JC Viral Load in Serum and Brain Van Assche, G. et al. N Engl J Med 2005;353:362-368

16. Causes of Leukoencephalopathy in Adults Koralnik, I. J. et al. N Engl J Med 2004;350:1882-1893

17. 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

19. 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

22. 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

28. 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)

29. 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

30. 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?

31. 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

32. 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

33. 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