Clinical Assessment &
Management of Prion Disease
Brian S. Appleby, M.D.
Associate Professor
Department of Neurology
Objectives
• Understand how clinicians diagnose prion
disease
• Describe tools used to diagnose prion disease
• Provide up...
“If it looks like a duck, quacks like a
duck, then it’s probably a duck.”
Dr. Edward Tsou (GUH)
Horses versus Zebras
Diagnostic Syndromes
Pneumonia
• Malaise
• Cough
• Fever
• Chest/back pain
• Shortness of breath

Creutzfeldt-Jakob diseas...
What Clinicians See

Appleby BS et al, Arch Neurol 2009
Appleby BS et al, Arch Neurol 2009
Initial Diagnoses

Appleby BS et al, Prion 2008
#1 Rule for Diagnosing Prion
Disease

Prion Disease
Why?
• Consequences of missing other diagnoses
– Treatable
– Reversible
– Different Prognosis
– Repeated work-ups later
– ...
Probable Sporadic CJD
≥2 Clinical Signs
• Dementia
• Visual or cerebellar
• Pyramidal or
extrapyramidal
• Akinetic mutism
...
Conditions with CSF 14-3-3

• TBI
• Seizures
Berg D et al, Nat Rev Neurosci 2003
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
EEG

Parchi P et al, Ann Neurol 1999
≥ 1 of the Following
(FLAIR and/or DWI)
• High signal abnormality in
basal ganglia
• High signal abnormality in
≥ 2 cortic...
Brain MRI

Zerr I et al, Brain 2009
Hamlin C et al, Neurology 2012
“Forest through the Trees”
Case Example
• 61 y.o. WF from St. Maarten’s Island with a
history of alcohol abuse
• 2 mo. h/o ataxia, apathy, myoclonus,...
Exam
General: Vacant look, utilization behavior
Speech: Dysarthric, apraxic, latent
Thought Content: Appeared to be respon...
Brain MRI (DWI)
Experimental Treatment
Compound
• Quinacrine
• Pentosan polysulphate
• Doxycycline

Outcome
• no effect
• may have effect ...
Individuals with less impairment and better functioning chose quinacrine
Individuals with more impairment and less functio...
“On the basis of the available evidence,
the best possible outcome that could
be expected after treatment with
intraventri...
German Observational Study
Group

Number of cases

Median survival time

Doxycycline treated

21

292 days

Untreated (his...
Symptomatic Treatment
Symptom

Suggested Treatment

Psychosis/Agitation

Low potency neuroleptics (e.g., quetiapine)

Myoc...
Thank You
• Patients and families
• CJD Foundation
• National Prion Disease Pathology Surveillance
Center
• CJD Support Gr...
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Clinical Assessment & Management of Prion Disease

  1. 1. Clinical Assessment & Management of Prion Disease Brian S. Appleby, M.D. Associate Professor Department of Neurology
  2. 2. Objectives • Understand how clinicians diagnose prion disease • Describe tools used to diagnose prion disease • Provide update on clinical trials for prion disease
  3. 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. 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. 5. What Clinicians See Appleby BS et al, Arch Neurol 2009 Appleby BS et al, Arch Neurol 2009
  6. 6. Initial Diagnoses Appleby BS et al, Prion 2008
  7. 7. #1 Rule for Diagnosing Prion Disease Prion Disease
  8. 8. Why? • Consequences of missing other diagnoses – Treatable – Reversible – Different Prognosis – Repeated work-ups later – Difficulty in accepting different diagnosis
  9. 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. 10. Conditions with CSF 14-3-3 • TBI • Seizures Berg D et al, Nat Rev Neurosci 2003
  11. 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. 12. EEG Parchi P et al, Ann Neurol 1999
  13. 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. 14. Brain MRI Zerr I et al, Brain 2009
  15. 15. Hamlin C et al, Neurology 2012
  16. 16. “Forest through the Trees”
  17. 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. 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. 19. Brain MRI (DWI)
  20. 20. Experimental Treatment Compound • Quinacrine • Pentosan polysulphate • Doxycycline Outcome • no effect • may have effect in vCJD • verdict is unclear
  21. 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. 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. 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. 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. 25. Thank You • Patients and families • CJD Foundation • National Prion Disease Pathology Surveillance Center • CJD Support Group Network

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