1. Prion Disease: A Rare
Neurological Phenomenon
Brian S. Appleby, M.D.
Associate Professor
Department of Neurology
University Hospitals Case Medical Center

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

3. Disclosures
• No relevant financial disclosures
• Off-label uses of:
– Quinacrine
– Pentosan Polysulphate
– Doxycycline
– Various medications for symptomatic treatment

4. What is a prion?
•
•
•
•
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
Genetic CJD
Fatal familial insomnia
Gerstmann-Sträussler-Scheinker
Kuru
Iatrogenic CJD
Variant CJD

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

8. Adapted from: Appleby BS, Arch Neurol 2009

9. Epidemiology
• 1 new case per million individuals per year
across the entire population (all ages)
• 1/10,000 US deaths per year
• OH=10.5 million people
– 10.5 new cases/yr
– ~2.5 cases living past one year
– Would not be unusual to have 13 active cases in
OH
Holman RC, PLoS ONE 2010

10. Definitive Diagnosis
Immunohistochemistry
H & E Staining

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 (PSWCs)

13. MRI (DWI/FLAIR)

14. Diagnostic Test Comparison
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. 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, 20th Annual Report, 2011

23. Chronic Wasting Disease (CWD)

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

25. Quinacrine
1. 30 sCJD/2vCJD, no sig diff in survival time (Haik
S, Neurology, 2004)
2. PRION-1 (UK), 45 sCJD/2 iCJD, 18 vCJD, 42
gCJD, no sig diff in survival time (Collinge J, Lancet
Neurol, 2009)
3. UCSF, no sig diff in survival time (Geshwind MD,
Neurology 2013)

26. Individuals with less impairment and better functioning chose quinacrine
Individuals with more impairment and less functioning declined quinacrine
Only 2 of 107 subjects chose randomization
Collinge J et al, Lancet Neurol 2009

27. Doh-ura K, J Virol 2004

28. “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

29. Doxycycline
• French study-no difference in survival time
(Brandel J-P, Prion 2013, Banff, Canada)
• Italian study-reportedly negative
• German study-possible slight prolongation of
survival time in codon 129 MM (Zerr I, Prion 2008,
Madrid, Spain)
• Italian study: prophylactic use in FFI carriers

30. Future Clinical Trials
• UK MRC: monoclonal Ab against PrPc in
symptomatic prion disease (date TBD)

31. CARE AND MANAGEMENT

32. Goals

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

34. 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

35. Diagnosis Phase
• Discuss process with patient and family
• Don’t forget about present needs
• Refer to 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

36. Caring Phase
• Frequent reassessment/symptomatic
treatment
• Limit visits to few individuals of short
durations
• Assess caregiver requirements
• Hospice/Respite care

37. 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

38. Afterwards
• Arrange requested post-mortems prior to
death (www.cjdsurveillance.com)
• Frequent check-ins with family/caregivers
• If postmortem performed, communicate
results (in person if possible)
• Encourage contact as needed

39. Risk Assessment

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

41. 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)

42. Resources
www.cjdfoundation.org
www.cjdsurveillance.com
CDC, http://www.cdc.gov/ncidod/dvrd/prions
Monthly CJD Support Group through Cleveland
Alz Assoc and CJD Foundation
Myself: bsa35@case.edu

43. Current Studies
• Blood and urine bioassay study with FDA
• Factors affecting initial diagnoses of prion
disease
• Art therapy in prion disease
• Future study looking at non-invasive
diagnostic test using RT-QuIC (detects actual
prion protein, very specific to diagnosis)

44. Case #1
•
•
•
•
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

46. Case #2
• 61 y.o. WF from St. Maarten’s Island with a
history of alcohol abuse
• 2 mo. h/o ataxia, apathy, myoclonus, and
cognitive impairment
• Vitamin B12=249, folate=8.6, MCV=98

47. Exam
General: Vacant look, utilization behavior
Speech: Dysarthric, apraxic, latent
Thought Content: Appeared to be responding to
visual hallucinations
MMSE: 12/30
Motor: Mild rigidity UE (L>R), myoclonus
Gait: Ataxic, requires 2 person assist, dysmetria
(L>R)

48. Brain MRI (DWI)

49. Summary
• Diagnosing CJD can be difficult and frustrating
• Getting a proper diagnosis and managing the
care of a patient with CJD is stressful, but very
doable, and extremely rewarding
• Care and management of patients with prion
disease is supportive and entails several disease
specific interventions

50. Thank You
• Patients and families
• CJD Foundation
• National Prion Disease Pathology Surveillance
Center
• CJD Support Group Network (Australia)
• UH-CMC Brain Health and Memory Center
• Staff at Foley Eldercare Center
• Dr. Paul Brown, Florence Kranitz, Deana Simpson