Progressive Neurologic Progressive Neurologic Disease in Disease in Immunosuppressed Immunosuppressed PatientsPatients

Clinical Grand RoundsClinical Grand Rounds

Edward L. Goodman, MD, Edward L. Goodman, MD, FACPFACP

November 16, 2005November 16, 2005

Case Presentation #1Case Presentation #1 66 year old man 19 years s/p LRD renal transplant 66 year old man 19 years s/p LRD renal transplant

admitted with left sided weakness. Also has admitted with left sided weakness. Also has alcoholic cirrhosis, IDDM, CAD, cholelithiasis, alcoholic cirrhosis, IDDM, CAD, cholelithiasis, bilateral THR.bilateral THR.

Two months earlier MRI revealed white matter Two months earlier MRI revealed white matter lesions.lesions.

Meds include NPH and Insulin lispro, azathioprine, Meds include NPH and Insulin lispro, azathioprine, prednisone, pantoprazole, B12, folic acid, B6, C prednisone, pantoprazole, B12, folic acid, B6, C vit, gabapentin, quetiapine, spirinolactone, vit, gabapentin, quetiapine, spirinolactone, lactulose, lorazepam.lactulose, lorazepam.

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

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

MRI Scan Obtained Two Months before the First Hospital Admission

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

MRI Study Showing Progression of the Lesion over Time

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

Specimen from a Stereotactic Brain Biopsy

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

Identification of Polyomavirus JC in a Biopsy Specimen of the Brain

Case #2Case #2

41 yo woman with MS 1999 treated 41 yo woman with MS 1999 treated with interferon, methylprednisone with interferon, methylprednisone and finally Natalizumab.and finally Natalizumab.

November 2004 new and different November 2004 new and different CNS symptoms developed. Work CNS symptoms developed. Work up failed to reveal an etiology.up failed to reveal an etiology.

Just prior to death, CSF sent for Just prior to death, CSF sent for PCR for JC virus was positive.PCR for JC virus was positive.

Doses and Timing of Treatments for Multiple Sclerosis

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

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

Histologic and MRI Findings

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

Case #3Case #3

60 yo man with Crohn’s became 60 yo man with Crohn’s became confused while on Natalizumab.confused while on Natalizumab.

CT showed nonenhancing CT showed nonenhancing hypodense lesions in white matter hypodense lesions in white matter of right frontal lobe, left frontal of right frontal lobe, left frontal and right temporal lobes.and right temporal lobes.

Brain biopsy performedBrain biopsy performed Died three months laterDied three months later

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

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

Initial MRI Findings

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

Histologic Findings

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

Time Course of JC Viral Load in Serum and Brain

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

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

Causes of Leukoencephalopathy in Adults

PolyomavirusesPolyomaviruses

Small, non enveloped virus, 42 nmSmall, non enveloped virus, 42 nm Circular double stranded DNA, 5000 bpCircular double stranded DNA, 5000 bp Two human species, one animalTwo human species, one animal

– BK virusBK virus 50% seroprevalence by 3-4 years50% seroprevalence by 3-4 years 100% by 10-11 years100% by 10-11 years

– JC virusJC virus 80% prevalence in adults80% prevalence in adults

– SV40 contaminated inactivated poliovirus SV40 contaminated inactivated poliovirus vaccine 1955-61vaccine 1955-61

PathophysiologyPathophysiology

Site of entry unknown -?tonsilsSite of entry unknown -?tonsils Latency in kidneys/bone Latency in kidneys/bone

marrow/lymphaticsmarrow/lymphatics– Periodically reactivatePeriodically reactivate– Shed in urineShed in urine

With immunosuppressionWith immunosuppression– Hematogenous spread to brainHematogenous spread to brain– Infects oligodendrocytesInfects oligodendrocytes– Leads to demyelinationLeads to demyelination

Management IssuesManagement Issues

PML has been described in up to PML has been described in up to 5% of AIDS patients5% of AIDS patients

This represents a large pool from This represents a large pool from which to study natural history and which to study natural history and treatmenttreatment– Berenguer et al. Clinical Course and Prognostic Features of PML Berenguer et al. Clinical Course and Prognostic Features of PML

in Patients Treated with HAART. CID 2003;36: 1047-52in Patients Treated with HAART. CID 2003;36: 1047-52

Anti-viral therapyAnti-viral therapy

No evidence of benefit in AIDS patients withNo evidence of benefit in AIDS patients with– Topothecan Topothecan (Royal et al. J Neurobiology 2003;9:411-419)(Royal et al. J Neurobiology 2003;9:411-419)

– Cidofovir Cidofovir (Marra CM et al. A pilot study of cidofovir for PML in (Marra CM et al. A pilot study of cidofovir for PML in AIDS. AIDS 2002;16:1791-1797)AIDS. AIDS 2002;16:1791-1797)

– IFN-alfa2B IFN-alfa2B (Geschwind et al.J Neurobiology 2001;7:375-381(Geschwind et al.J Neurobiology 2001;7:375-381

– Cytosine arabinoside Cytosine arabinoside (Hall et al N Eng J Med (Hall et al N Eng J Med 1998;338:1345-1351)1998;338:1345-1351)

Non AIDS patientsNon AIDS patients– One retrospective study on Cytosine arabinoside One retrospective study on Cytosine arabinoside

stabilized PML in 7/19 stabilized PML in 7/19 (Aksamit AJ. J Neurovirol (Aksamit AJ. J Neurovirol 2001;7:386-390)2001;7:386-390)

What can we learn from What can we learn from the Natalizumab the Natalizumab experience?experience? Monoclonal antibody against Monoclonal antibody against αα4 4

integrinintegrin– Inhibits binding of cells expressing Inhibits binding of cells expressing

αα44ββ1 and 1 and αα44ββ7 integrins to adhesion 7 integrins to adhesion molecules on endotheliummolecules on endothelium

– Limiting diapedesis of lymphocytes into Limiting diapedesis of lymphocytes into organs, the proposed mechanism fororgans, the proposed mechanism for

MSMS Crohn’sCrohn’s

Natalizumab cont’dNatalizumab cont’d

But JC virus thought to be carried But JC virus thought to be carried to CNS by lymphocytes, soto CNS by lymphocytes, so– Inhibiting lymphocyte entry into CNS Inhibiting lymphocyte entry into CNS

shouldn’t precipitate PML, unlessshouldn’t precipitate PML, unless Other means of JC getting into Other means of JC getting into

CNSCNS– Cell free virus, orCell free virus, or– Was JC virus latent already in CNS?Was JC virus latent already in CNS?

ConclusionConclusion

Consider PML in immunosuppressed Consider PML in immunosuppressed patients withpatients with– Progressive mulifocal neurologic diseaseProgressive mulifocal neurologic disease– Non enhancing white matter disease on MRINon enhancing white matter disease on MRI

Send CSF for JC virus DNA by PCRSend CSF for JC virus DNA by PCR Try and halt immunosuppression or Try and halt immunosuppression or

improve immune status improve immune status – e.g, HAART in AIDS patientse.g, HAART in AIDS patients– Halting immunomodulatory therapy in Crohn’s Halting immunomodulatory therapy in Crohn’s

or MSor MS

BibliographyBibliography

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

Berenguer J, Miralles P et al. Clinical Course and Berenguer J, Miralles P et al. Clinical Course and Prognostic Factors of Progressive Multifocal Prognostic Factors of Progressive Multifocal Leukoencephalopathy in Patients Treated with Leukoencephalopathy in Patients Treated with Highly Active Antiretroviral Therapy. Clinical Highly Active Antiretroviral Therapy. Clinical Infectious Diseases 2003;36:1047-1052Infectious Diseases 2003;36:1047-1052

Kleinschmidt-DeMasters BK, Tyler KL. Progressive Kleinschmidt-DeMasters BK, Tyler KL. Progressive Multifocal Leukoencephalopathy Complicating Multifocal Leukoencephalopathy Complicating Treatment with Natalizumab and Interferon Beta-Treatment with Natalizumab and Interferon Beta-1a for Multiple Sclerosis. New Eng J Med 1a for Multiple Sclerosis. New Eng J Med 2005;353:369-3742005;353:369-374

Bibliography continuedBibliography continued

Koralnik IJ, Schellingerhout D and Frosch MP. Cases 14-Koralnik IJ, Schellingerhout D and Frosch MP. Cases 14-2004: A 66 Year-Old Man with Progressive Neurologic 2004: A 66 Year-Old Man with Progressive Neurologic Deficits. N Eng J Med 2004;350;1882-1893.Deficits. N Eng J Med 2004;350;1882-1893.

Koralnik IJ. New insights into progressive multifocal Koralnik IJ. New insights into progressive multifocal leucoencephalopathy. Current Opinion in Neurology 2004; leucoencephalopathy. Current Opinion in Neurology 2004; 17:365-370.17:365-370.

Langer-Gould A, Atlas SW et al. Progressive Multifocal Langer-Gould A, Atlas SW et al. Progressive Multifocal Leukocncephalopathy in a Patient Treated with Leukocncephalopathy in a Patient Treated with Natalizumab. N Eng J Med 2005;353:375-381Natalizumab. N Eng J Med 2005;353:375-381

Sabath BF, Major EO. Traffice of JC Virus from Sites of Initial Sabath BF, Major EO. Traffice of JC Virus from Sites of Initial Infection to the Brain:The Path to Progressive Multifocal Infection to the Brain:The Path to Progressive Multifocal Leukoencephalopathy. J Inf Dis 2002; 186(Suppl2):S180-186Leukoencephalopathy. J Inf Dis 2002; 186(Suppl2):S180-186

Von Assche G, Van Ranst M et al. Progressive Multifocal Von Assche G, Van Ranst M et al. Progressive Multifocal Leukoencephalopathy after Natalizumab Therapy for Leukoencephalopathy after Natalizumab Therapy for Crohn’s Disease. N Eng J Med 2005;353:362-368Crohn’s Disease. N Eng J Med 2005;353:362-368