Progressive Neurologic Disease in Immunosuppressed Patients

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Progressive Neurologic Disease in
Immunosuppressed Patients

• Clinical Grand Rounds
• Edward L. Goodman, MD, FACP
• November 16, 2005

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Outline

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

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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.

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MRI Scan Obtained Two Months before the First
Hospital Admission
Koralnik, I. J. et al. N Engl J Med
20043501882-1893
5
MRI Study Showing Progression of the Lesion over
Time
Koralnik, I. J. et al. N Engl J Med
20043501882-1893
6
Specimen from a Stereotactic Brain Biopsy
Koralnik, I. J. et al. N Engl J Med
20043501882-1893
7
Identification of Polyomavirus JC in a Biopsy
Specimen of the Brain
Koralnik, I. J. et al. N Engl J Med
20043501882-1893
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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.

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Doses and Timing of Treatments for Multiple
Sclerosis
Kleinschmidt-DeMasters, B. et al. N Engl J Med
2005353369-374
10
MRI Findings (Panels A, B, and C) and Autopsy
Findings (Panel D)
Kleinschmidt-DeMasters, B. et al. N Engl J Med
2005353369-374
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Histologic and MRI Findings
Kleinschmidt-DeMasters, B. et al. N Engl J Med
2005353369-374
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Case 3

• 60 yo man with Crohns 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

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Peripheral-Blood Neutrophil and Lymphocyte Counts
in Relation to Natalizumab Therapy
Van Assche, G. et al. N Engl J Med
2005353362-368
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Initial MRI Findings
Van Assche, G. et al. N Engl J Med
2005353362-368
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Histologic Findings
Van Assche, G. et al. N Engl J Med
2005353362-368
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Time Course of JC Viral Load in Serum and Brain
Van Assche, G. et al. N Engl J Med
2005353362-368
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Causes of Leukoencephalopathy in Adults
Koralnik, I. J. et al. N Engl J Med
20043501882-1893
18
JC Virus

• Taxonomy
• Epidemiology
• Pathogenicity
• Diagnostic Microbiology
• Clinical Manifestation
• Treatment

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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

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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

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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 200336 1047-52

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Anti-viral therapy

• No evidence of benefit in AIDS patients with
• Topothecan (Royal et al. J Neurobiology
  20039411-419)
• Cidofovir (Marra CM et al. A pilot study of
  cidofovir for PML in AIDS. AIDS
  2002161791-1797)
• IFN-alfa2B (Geschwind et al.J Neurobiology
  20017375-381
• Cytosine arabinoside (Hall et al N Eng J Med
  19983381345-1351)
• Non AIDS patients
• One retrospective study on Cytosine arabinoside
  stabilized PML in 7/19 (Aksamit AJ. J Neurovirol
  20017386-390)

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What can we learn from the Natalizumab experience?

• Monoclonal antibody against a4 integrin
• Inhibits binding of cells expressing a4ß1 and
  a4ß7 integrins to adhesion molecules on
  endothelium
• Limiting diapedesis of lymphocytes into organs,
  the proposed mechanism for
• MS
• Crohns

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Natalizumab contd

• But JC virus thought to be carried to CNS by
  lymphocytes, so
• Inhibiting lymphocyte entry into CNS shouldnt
  precipitate PML, unless
• Other means of JC getting into CNS
• Cell free virus, or
• Was JC virus latent already in CNS?

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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 Crohns or MS

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Bibliography

• Berger JR, Koralnik IJ. Progressive Multifocal
  Leukoencephalopathy and Natalizumab- Unforseen
  Consequences. N Eng J Med 2005353414-416
• 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 2003361047-1052
• Kleinschmidt-DeMasters BK, Tyler KL. Progressive
  Multifocal Leukoencephalopathy Complicating
  Treatment with Natalizumab and Interferon Beta-1a
  for Multiple Sclerosis. New Eng J Med
  2005353369-374

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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
  20043501882-1893.
• Koralnik IJ. New insights into progressive
  multifocal leucoencephalopathy. Current Opinion
  in Neurology 2004 17365-370.
• Langer-Gould A, Atlas SW et al. Progressive
  Multifocal Leukocncephalopathy in a Patient
  Treated with Natalizumab. N Eng J Med
  2005353375-381
• Sabath BF, Major EO. Traffice of JC Virus from
  Sites of Initial Infection to the BrainThe 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 Crohns Disease. N Eng J Med
  2005353362-368