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 update on clinical trials for prion

disease

“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 disease (CJD)

• Dementia• Difficulty with gait• Incoordination• Abnormal movements• Weakness• Visual disturbances• Rapid progression

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

What Clinicians See

Initial Diagnoses

Appleby BS et al, Prion 2008

#1 Rule for Diagnosing Prion Disease

Prion Disease

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

Why?

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

Conditions with CSF 14-3-3

Berg D et al, Nat Rev Neurosci 2003

• TBI• Seizures

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 cortical regions• Temporal• Parietal • Occipital Frontal

Zerr I et al, Brain 2009

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, and cognitive impairment

• Vitamin B12=249, folate=8.6, MCV=98

ExamGeneral: Vacant look, utilization behaviorSpeech: Dysarthric, apraxic, latent Thought Content: Appeared to be responding to visual hallucinationsMMSE: 12/30Motor: Mild rigidity UE (L>R), myoclonusGait: Ataxic, requires 2 person assist, dysmetria (L>R)

Brain MRI (DWI)

Experimental Treatment

Compound• Quinacrine • Pentosan polysulphate• Doxycycline

Outcome• no effect• may have effect in vCJD• verdict is unclear

Individuals with less impairment and better functioning chose quinacrineIndividuals with more impairment and less functioning declined quinacrine

Only 2 of 107 subjects chose randomization

Collinge J et al, Lancet Neurol 2009

“On the basis of the available evidence,the best possible outcome that couldbe expected after treatment withintraventricular PPS is that there maybe some temporary slowing or haltingof the disease progression. However,there is little likelihood of significantclinical improvement. Nor is there alikelihood of permanent halting ofdisease progression.”

CJD Support Network Newsletter, March 2004

German Observational StudyGroup 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

Symptomatic TreatmentSymptom 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

Thank You

• Patients and families• CJD Foundation• National Prion Disease Pathology Surveillance

Center• CJD Support Group Network