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

2. Outline Three recent cases in NEJM (April 2004, July 2005 (3)) Three recent cases in NEJM (April 2004, July 2005 (3)) –Images –Pathology What can we learn from this and similar cases? What can we learn from this and similar cases? Interaction between immunosuppression and reactivation of JC Interaction between immunosuppression and reactivation of JC Leucoencephalopathy differential Dx Leucoencephalopathy differential Dx Biology of JC polyoma virus Biology of JC polyoma virus –Taxonomy –Seroprevalence –Pathogenesis Treatment of PML Treatment of PML –Reverse immunosuppression –Anti-viral therapy? Inferences on pathogenesis derived from Natalizumab induced cases Inferences on pathogenesis derived from Natalizumab induced cases

3. 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. 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. 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. 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. Exam revealed mild left hemiparesis. Labs were non revealing. Labs were non revealing. Brain biopsy diagnostic Brain biopsy diagnostic Expired a few months later. Expired a few months later.

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

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

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

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

8. Case #2 41 yo woman with MS 1999 treated with interferon, methylprednisone and finally Natalizumab. 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. 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. Just prior to death, CSF sent for PCR for JC virus was positive.

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

10. 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

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

12. Case #3 60 yo man with Crohn’s became confused while on Natalizumab. 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. CT showed nonenhancing hypodense lesions in white matter of right frontal lobe, left frontal and right temporal lobes. Brain biopsy performed Brain biopsy performed Died three months later Died three months later

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

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

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

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

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

18. JC Virus Taxonomy Taxonomy Epidemiology Epidemiology Pathogenicity Pathogenicity Diagnostic Microbiology Diagnostic Microbiology Clinical Manifestation Clinical Manifestation Treatment Treatment

19. Polyomaviruses Small, non enveloped virus, 42 nm Small, non enveloped virus, 42 nm Circular double stranded DNA, 5000 bp Circular double stranded DNA, 5000 bp Two human species, one animal Two human species, one animal –BK virus 50% seroprevalence by 3-4 years 50% seroprevalence by 3-4 years 100% by 10-11 years 100% by 10-11 years –JC virus 80% prevalence in adults 80% prevalence in adults –SV40 contaminated inactivated poliovirus vaccine 1955-61

21. Pathophysiology Site of entry unknown -?tonsils Site of entry unknown -?tonsils Latency in kidneys/bone marrow/lymphatics Latency in kidneys/bone marrow/lymphatics –Periodically reactivate –Shed in urine With immunosuppression With immunosuppression –Hematogenous spread to brain –Infects oligodendrocytes –Leads to demyelination

24. Management Issues PML has been described in up to 5% of AIDS patients PML has been described in up to 5% of AIDS patients This represents a large pool from which to study natural history and treatment 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

30. Anti-viral therapy No evidence of benefit in AIDS patients with 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 Non AIDS patients –One retrospective study on Cytosine arabinoside stabilized PML in 7/19 (Aksamit AJ. J Neurovirol 2001;7:386-390)

31. What can we learn from the Natalizumab experience? Monoclonal antibody against α4 integrin 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 MS Crohn’s Crohn’s

32. Natalizumab cont’d But JC virus thought to be carried to CNS by lymphocytes, so 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 Other means of JC getting into CNS –Cell free virus, or –Was JC virus latent already in CNS?

33. Conclusion Consider PML in immunosuppressed patients with 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 Send CSF for JC virus DNA by PCR Try and halt immunosuppression or improve immune status Try and halt immunosuppression or improve immune status –e.g, HAART in AIDS patients –Halting immunomodulatory therapy in Crohn’s or MS

34. Bibliography Berger JR, Koralnik IJ. Progressive Multifocal Leukoencephalopathy and Natalizumab- Unforseen Consequences. N Eng J Med 2005;353:414-416 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 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 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

35. 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, 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. 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 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 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 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