Sponsored by:Creutzfeldt-Jakob diseaseDiagnosis and Management of Prion Diseases              March 21, 2013         Brian...
Disclosures•   No relevant financial disclosures•   Off-label uses of:    •   Quinacrine    •   Pentosan Polysulphate    •...
ObjectivesI.     Understand key elements of diagnosing CJDII.    Demonstrate strategies for managing patients with CJDIII....
“Pri-on”•   proteinaceous and infectious•   -ion (infectious, e.g. virion)•   No nucleic acid•   Non-degradable by typical...
Soto C, Trends Biochem Sci 2006
Etiologies                                     Kuru    Genetic CJD                      Iatrogenic CJD    Fatal familial i...
Age at Onset                                                    sCJD                                  gCJD                ...
Epidemiology     sCJD=1/1,000,000 people per year1/10,000 deaths per year in US due to CJD
Survival Time Adapted from: Appleby BS, Arch Neurol 2009
Definitive DiagnosisH&E      Immunohistochemistry
Probable sCJDAt least two clinical signs:1.Dementia2.Cerebellar or visual symptoms3.Pyramidal or extrapyramidal symptoms4....
Electroencephalogram (EEG) Periodic sharp wave complexes (PSWC’s)
MRI (DWI/FLAIR)
All stage CJDEarly stage CJD                  Satoh K, Dement Geriatr Cog Disord 2007
Genetic Prion Disease      Kovács GG, J Neurol 2002
Acquired Prion Disease•   Kuru•   Iatrogenic CJD (iCJD)•   Variant CJD (vCJD)
Kuru
Iatrogenic CJD    Brown P, Neurology 2006
Variant CJD227 total cases http://www.cjd.ed.ac.uk/vcjdworld.htm
vCJD Characteristics       Will RG, Lancet 1996
Pulvinar Sign   Zeidler M, Lancet 2000
MM                                                                         MV BSE1980’s         Creutzfeldt-Jakob Disease ...
Chronic Wasting Disease
Experimental Treatment•   Quinacrine and other tricyclic compounds•   Pentosan polysulphate (PPS)•   Doxycycline
QuinacrineI.     30 sCJD/2vCJD, no sig diff in survival time       (Haik S, Neurology, 2004)II.    PRION-1 (UK), 45 sCJD/2...
45 sCJD, 42 genetic prion disease, 18 vCJD, 2 iCJD            Quinacrine PO 1g/24hr                     then           Qui...
“PRION-1 was essentially an observational study of patients choosing to take quinacrine or not...”                 Colling...
Doh-ura K, J Virol 2004
Pentosan Polysulphate       Bone I, Eur J Neurol 2008
“On the basis of the available evidence, thebest possible outcome that could be expectedafter treatment with intraventricu...
DoxycyclineObservational study        Group                Number of cases                   Median survival timeDoxycycli...
Care and Management
Goals            EducationCommunication     Implementation
Intervals of CareI.     Pre-clinical/Presentation PhaseII.    Diagnostic PhaseIII.   Caring Phase
Preclinical/Presentation Phase•   Initial interactions with primary medical doctor•   At risk individuals should identify ...
Diagnosis Phase• Discuss   process with patient and family• Don’t   forget about present needs• Referto organizations and ...
Caring Phase• Frequentreassessment/symptomatic treatment• Limitvisits to few individuals of short durations• Assess   care...
Symptomatic TreatmentSymptom                  Suggested TreatmentPsychosis/Agitation      Low potency neuroleptics (e.g., ...
Afterwards• Arrange   requested post-mortems prior to  death (www.cjdsurveillance.com)• Frequent   check-ins with family/c...
Risk Assessment
Routine Clinical Care•   Standard Precautions Only•   No need for gowns, masks, isolation, etc.•   Consider the family
Surgery/Equipment•   WHO. WHO consultation on TSE in relation to biological    and pharmaceutical products. Geneva, Switze...
Case•   57 y.o. AAM professional, h/o 3 TBI’s•   Some short term memory problems x 3 months•   More distractible, still wo...
Summary• Diagnosing   CJD can be difficult and frustrating• Getting a proper diagnosis and managing the care of a patient ...
Thank You!
Georgetown University Hospital Dept of Medicine Grand Rounds
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Georgetown University Hospital Dept of Medicine Grand Rounds

  1. 1. Sponsored by:Creutzfeldt-Jakob diseaseDiagnosis and Management of Prion Diseases March 21, 2013 Brian S. Appleby, M.D. Lou Ruvo Center for Brain Health Cleveland Clinic
  2. 2. Disclosures• No relevant financial disclosures• Off-label uses of: • Quinacrine • Pentosan Polysulphate • Doxycycline
  3. 3. ObjectivesI. Understand key elements of diagnosing CJDII. Demonstrate strategies for managing patients with CJDIII. Demonstrate knowledge regarding CJD risks
  4. 4. “Pri-on”• proteinaceous and infectious• -ion (infectious, e.g. virion)• No nucleic acid• Non-degradable by typical sterilization
  5. 5. Soto C, Trends Biochem Sci 2006
  6. 6. Etiologies Kuru Genetic CJD Iatrogenic CJD Fatal familial insomnia Variant CJD Gerstmann-Sträussler-Scheinker
  7. 7. Age at Onset sCJD gCJD vCJDAdapted from: Appleby BS, J Neuropsychiatry Clin Neurosci 2007
  8. 8. Epidemiology sCJD=1/1,000,000 people per year1/10,000 deaths per year in US due to CJD
  9. 9. Survival Time Adapted from: Appleby BS, Arch Neurol 2009
  10. 10. Definitive DiagnosisH&E Immunohistochemistry
  11. 11. Probable sCJDAt least two clinical signs:1.Dementia2.Cerebellar or visual symptoms3.Pyramidal or extrapyramidal symptoms4.Akinetic mutismAt least one of the following:1.PSWCs on EEG2.14-3-3 in CSF and disease duration < 2 years3.High signal abnormalities in basal ganglia or at least twocortical regions (temporal, parietal, or occipital) onDWI/FLAIR sequences on brain MRI Zerr I, et al. Brain 2009
  12. 12. Electroencephalogram (EEG) Periodic sharp wave complexes (PSWC’s)
  13. 13. MRI (DWI/FLAIR)
  14. 14. All stage CJDEarly stage CJD Satoh K, Dement Geriatr Cog Disord 2007
  15. 15. Genetic Prion Disease Kovács GG, J Neurol 2002
  16. 16. Acquired Prion Disease• Kuru• Iatrogenic CJD (iCJD)• Variant CJD (vCJD)
  17. 17. Kuru
  18. 18. Iatrogenic CJD Brown P, Neurology 2006
  19. 19. Variant CJD227 total cases http://www.cjd.ed.ac.uk/vcjdworld.htm
  20. 20. vCJD Characteristics Will RG, Lancet 1996
  21. 21. Pulvinar Sign Zeidler M, Lancet 2000
  22. 22. MM MV BSE1980’s Creutzfeldt-Jakob Disease in the UK, 18th Annual Report, 2009
  23. 23. Chronic Wasting Disease
  24. 24. Experimental Treatment• Quinacrine and other tricyclic compounds• Pentosan polysulphate (PPS)• Doxycycline
  25. 25. QuinacrineI. 30 sCJD/2vCJD, no sig diff in survival time (Haik S, Neurology, 2004)II. PRION-1 (UK), 45 sCJD/2 iCJD, 18 vCJD, 42 gCJD, no sig diff in survival time (Collinge J, Lancet Neurol, 2009)III. UCSF, midpoint survival analyses, no sig diff btwn comparison groups (Log rank, p=0.4) (Geschwind M, 6th CJD Family Conference, 2008)
  26. 26. 45 sCJD, 42 genetic prion disease, 18 vCJD, 2 iCJD Quinacrine PO 1g/24hr then Quinacrine 100mg PO TID Only 2 of 107 subjects chose randomization
  27. 27. “PRION-1 was essentially an observational study of patients choosing to take quinacrine or not...” Collinge J, Lancet Neurol 2009
  28. 28. Doh-ura K, J Virol 2004
  29. 29. Pentosan Polysulphate Bone I, Eur J Neurol 2008
  30. 30. “On the basis of the available evidence, thebest possible outcome that could be expectedafter treatment with intraventricular PPS isthat there may be some temporary slowing orhalting of the disease progression. However,there is little likelihood of significant clinicalimprovement. Nor is there a likelihood ofpermanent halting of disease progression.” CJD Support Network Newsletter, March 2004
  31. 31. DoxycyclineObservational study Group Number of cases Median survival timeDoxycycline treated 21 292 daysUntreated 581 169 days Log Rank test, p<0.001 PRNP codon 129 MM, p=0.019 MV, p=0.133 VV, p=0.54 Zerr I, Prion 2008, Madrid, Spain
  32. 32. Care and Management
  33. 33. Goals EducationCommunication Implementation
  34. 34. Intervals of CareI. Pre-clinical/Presentation PhaseII. Diagnostic PhaseIII. Caring Phase
  35. 35. Preclinical/Presentation Phase• Initial interactions with primary medical doctor• At risk individuals should identify “physician champions” Kranitz FJ & Simpson DM. CNS Neurol Disord Drug Targets 2009
  36. 36. Diagnosis Phase• Discuss process with patient and family• Don’t forget about present needs• Referto organizations and clinicians familiar with the illness• Discharge planning (before discharge)• Must establish a “key worker” Douglas M, Patients with nvCJD and their families 1999
  37. 37. Caring Phase• Frequentreassessment/symptomatic treatment• Limitvisits to few individuals of short durations• Assess caregiver requirements• Hospice/Respite care
  38. 38. Symptomatic TreatmentSymptom Suggested TreatmentPsychosis/Agitation Low potency neuroleptics (e.g., quetiapine)Myoclonus/Hyperstartle Long acting benzodiazepines (e.g., diazepam) Anticonvulsants (e.g., valproic acid)Seizures AnticonvulsantsDystonia/Contractures Passive movement Long acting benzodiazepines, Botulinum toxin injectionsConstipation Bowel regimen (e.g., dulcolax)Dysphagia/Rumination Thickener, cueing Behavioral/Environmental changes first Start low and go slow Re-evaluate frequently
  39. 39. Afterwards• Arrange requested post-mortems prior to death (www.cjdsurveillance.com)• Frequent check-ins with family/caregivers• Ifpostmortem performed, communicate results (in person if possible)• Encourage contact as needed
  40. 40. Risk Assessment
  41. 41. Routine Clinical Care• Standard Precautions Only• No need for gowns, masks, isolation, etc.• Consider the family
  42. 42. Surgery/Equipment• WHO. WHO consultation on TSE in relation to biological and pharmaceutical products. Geneva, Switzerland; 2003• WHO. WHO guidelines on tissue infectivity distribution in TSE. Geneva, Switzerland; 2005• Transfusion Medicine Epidemiological Review (TMER) ( http://www.cjd.ed.ac.uk/TMER/TMER.htm)
  43. 43. Case• 57 y.o. AAM professional, h/o 3 TBI’s• Some short term memory problems x 3 months• More distractible, still working full time• MMSE=24/30 (-1 calculation, -3 orientation, -2 recall)• mild left upper extremity dysmetria
  44. 44. Summary• Diagnosing CJD can be difficult and frustrating• Getting a proper diagnosis and managing the care of a patient with CJD is stressful• Care and management of patients with prion disease is supportive and entails several disease specific interventions
  45. 45. Thank You!

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