Transcript Clinical Grand Rounds

Progressive Neurologic
Disease in
Immunosuppressed
Patients
Clinical Grand Rounds
Edward L. Goodman, MD, FACP
November 16, 2005
Case Presentation #1
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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.
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
Koralnik, I. J. et al. N Engl J Med 2004;350:1882-1893
Case #2
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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.
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 #3
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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
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
Causes of Leukoencephalopathy in Adults
Koralnik, I. J. et al. N Engl J Med 2004;350:1882-1893
Polyomaviruses
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Small, non enveloped virus, 42 nm
Circular double stranded DNA, 5000 bp
Two human species, one animal
– BK virus
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50% seroprevalence by 3-4 years
100% by 10-11 years
– JC virus
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80% prevalence in adults
– SV40 contaminated inactivated poliovirus vaccine
1955-61
Pathophysiology
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Site of entry unknown -?tonsils
Latency in kidneys/bone
marrow/lymphatics
– Periodically reactivate
– Shed in urine
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With immunosuppression
– Hematogenous spread to brain
– Infects oligodendrocytes
– Leads to demyelination
Management Issues
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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
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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)
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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?
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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
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Natalizumab cont’d
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But JC virus thought to be carried to
CNS by lymphocytes, so
– Inhibiting lymphocyte entry into CNS
shouldn’t precipitate PML, unless
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Other means of JC getting into CNS
– Cell free virus, or
– Was JC virus latent already in CNS?
Conclusion
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Consider PML in immunosuppressed patients
with
– Progressive mulifocal neurologic disease
– Non enhancing white matter disease on MRI
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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
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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
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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