1. Clinical Assessment &
Management of Prion Disease
Brian S. Appleby, M.D.
Associate Professor
Department of Neurology

2. Objectives
• Understand how clinicians diagnose prion
disease
• Describe tools used to diagnose prion disease
• Provide update on clinical trials for prion
disease

3. “If it looks like a duck, quacks like a
duck, then it’s probably a duck.”
Dr. Edward Tsou (GUH)
Horses versus Zebras

4. Diagnostic Syndromes
Pneumonia
• Malaise
• Cough
• Fever
• Chest/back pain
• Shortness of breath
Creutzfeldt-Jakob disease (CJD)
•
•
•
•
•
•
•
Dementia
Difficulty with gait
Incoordination
Abnormal movements
Weakness
Visual disturbances
Rapid progression

5. What Clinicians See
Appleby BS et al, Arch Neurol 2009
Appleby BS et al, Arch Neurol 2009

6. Initial Diagnoses
Appleby BS et al, Prion 2008

7. #1 Rule for Diagnosing Prion
Disease
Prion Disease

8. Why?
• Consequences of missing other diagnoses
– Treatable
– Reversible
– Different Prognosis
– Repeated work-ups later
– Difficulty in accepting different diagnosis

9. Probable Sporadic CJD
≥2 Clinical Signs
• Dementia
• Visual or cerebellar
• Pyramidal or
extrapyramidal
• Akinetic mutism
≥ 1 Diagnostic Test Result
• CSF 14-3-3 and <2 yrs
duration
• PSWC’s on EEG
• Brain MRI findings
Zerr I et al, Brain 2009

10. Conditions with CSF 14-3-3
• TBI
• Seizures
Berg D et al, Nat Rev Neurosci 2003

11. EEG
CJD
Non-CJD
Total
PSWC’s
10
2
12
No PSWC’s
5
12
17
PSWC’s
Steinhoff BJ et al, Arch Neurol 1996

12. EEG
Parchi P et al, Ann Neurol 1999

13. ≥ 1 of the Following
(FLAIR and/or DWI)
• High signal abnormality in
basal ganglia
• High signal abnormality in
≥ 2 cortical regions
• Temporal
• Parietal
• Occipital
Frontal
Zerr I et al, Brain 2009

14. Brain MRI
Zerr I et al, Brain 2009

15. Hamlin C et al, Neurology 2012

16. “Forest through the Trees”

17. Case Example
• 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

18. 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)

19. Brain MRI (DWI)

20. Experimental Treatment
Compound
• Quinacrine
• Pentosan polysulphate
• Doxycycline
Outcome
• no effect
• may have effect in vCJD
• verdict is unclear

21. 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

22. “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

23. German Observational Study
Group
Number of cases
Median survival time
Doxycycline treated
21
292 days
Untreated (historical cntrl)
581
169 days
Log Rank test, p<0.001
p=0.019
PRNP codon 129 polymorphism
Zerr I, Prion 2008, Madrid, Spain

24. 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

25. Thank You
• Patients and families
• CJD Foundation
• National Prion Disease Pathology Surveillance
Center
• CJD Support Group Network