1. Sponsored by:
Creutzfeldt-Jakob disease
Diagnosis and Management of Prion Diseases
March 21, 2013
Brian S. Appleby, M.D.
Lou Ruvo Center for Brain Health
Cleveland Clinic

2. Disclosures
• No relevant financial disclosures
• Off-label uses of:
• Quinacrine
• Pentosan Polysulphate
• Doxycycline

3. Objectives
I. Understand key elements of diagnosing CJD
II. Demonstrate strategies for managing patients with CJD
III. Demonstrate knowledge regarding CJD risks

4. “Pri-on”
• proteinaceous and infectious
• -ion (infectious, e.g. virion)
• No nucleic acid
• Non-degradable by typical sterilization

5. Soto C, Trends Biochem Sci 2006

6. Etiologies
Kuru
Genetic CJD Iatrogenic CJD
Fatal familial insomnia Variant CJD
Gerstmann-Sträussler-Scheinker

7. Age at Onset
sCJD
gCJD
vCJD
Adapted from: Appleby BS, J Neuropsychiatry Clin Neurosci 2007

8. Epidemiology
sCJD=1/1,000,000 people per year
1/10,000 deaths per year in US due to CJD

9. Survival Time
Adapted from: Appleby BS, Arch Neurol 2009

10. Definitive Diagnosis
H&E Immunohistochemistry

11. Probable sCJD
At least two clinical signs:
1.Dementia
2.Cerebellar or visual symptoms
3.Pyramidal or extrapyramidal symptoms
4.Akinetic mutism
At least one of the following:
1.PSWCs on EEG
2.14-3-3 in CSF and disease duration < 2 years
3.High signal abnormalities in basal ganglia or at least two
cortical regions (temporal, parietal, or occipital) on
DWI/FLAIR sequences on brain MRI
Zerr I, et al. Brain 2009

12. Electroencephalogram (EEG)
Periodic sharp wave complexes (PSWC’s)

13. MRI (DWI/FLAIR)

14. All stage CJD
Early stage CJD
Satoh K, Dement Geriatr Cog Disord 2007

15. Genetic Prion Disease
Kovács GG, J Neurol 2002

16. Acquired Prion Disease
• Kuru
• Iatrogenic CJD (iCJD)
• Variant CJD (vCJD)

17. Kuru

18. Iatrogenic CJD
Brown P, Neurology 2006

19. Variant CJD
227 total cases
http://www.cjd.ed.ac.uk/vcjdworld.htm

20. vCJD Characteristics
Will RG, Lancet 1996

21. Pulvinar Sign
Zeidler M, Lancet 2000

22. MM
MV
BSE
1980’s
Creutzfeldt-Jakob Disease in the UK, 18th Annual Report, 2009

23. Chronic Wasting Disease

24. Experimental Treatment
• Quinacrine and other tricyclic compounds
• Pentosan polysulphate (PPS)
• Doxycycline

25. Quinacrine
I. 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. 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. “PRION-1 was essentially an observational study
of patients choosing to take quinacrine or not...”
Collinge J, Lancet Neurol 2009

28. Doh-ura K, J Virol 2004

29. Pentosan Polysulphate
Bone I, Eur J Neurol 2008

30. “On the basis of the available evidence, the
best possible outcome that could be expected
after treatment with intraventricular PPS is
that there may be some temporary slowing or
halting of the disease progression. However,
there is little likelihood of significant clinical
improvement. Nor is there a likelihood of
permanent halting of disease progression.”
CJD Support Network Newsletter, March 2004

31. Doxycycline
Observational study
Group Number of cases Median survival time
Doxycycline treated 21 292 days
Untreated 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. Care and Management

33. Goals
Education
Communication Implementation

34. Intervals of Care
I. Pre-clinical/Presentation Phase
II. Diagnostic Phase
III. Caring Phase

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. 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. Caring Phase
• Frequentreassessment/symptomatic
treatment
• Limitvisits to few individuals of short
durations
• Assess caregiver requirements
• Hospice/Respite care

38. Symptomatic Treatment
Symptom Suggested Treatment
Psychosis/Agitation Low potency neuroleptics (e.g., quetiapine)
Myoclonus/Hyperstartle Long acting benzodiazepines (e.g., diazepam)
Anticonvulsants (e.g., valproic acid)
Seizures Anticonvulsants
Dystonia/Contractures Passive movement
Long acting benzodiazepines, Botulinum toxin
injections
Constipation Bowel regimen (e.g., dulcolax)
Dysphagia/Rumination Thickener, cueing
Behavioral/Environmental changes first
Start low and go slow
Re-evaluate frequently

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. Risk Assessment

41. Routine Clinical Care
• Standard Precautions Only
• No need for gowns, masks, isolation, etc.
• Consider the family

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. 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

45. 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

46. Thank You!