This document provides information on diagnosing Creutzfeldt-Jakob Disease (CJD). It discusses the importance of considering other treatable causes of rapidly progressive dementias before diagnosing CJD. It outlines the diagnostic criteria for probable sporadic CJD, including having at least two clinical signs and one positive diagnostic test result. The document discusses various diagnostic tests used for CJD like CSF 14-3-3, EEG, and brain MRI findings. It notes that conditions other than CJD can produce positive 14-3-3 results and that genetic mutations may have unknown or age-related penetrance. Finally, it provides a case report example of a patient initially responding to psychiatric treatment before being found to have a

1. Diagnosing Creutzfeldt-Jakob Disease
October 20, 2012
Brian Appleby, M.D.
Staff, Cleveland Clinic Lou Ruvo
Center for Brain Health

2. Objectives
• Understand the diagnostic approach to
rapidly progressive dementias (RPD)
• Describe diagnostic tools for CJD
• Understand common misunderstandings
related to diagnosing prion diseases

3. Appleby BS & Lyketsos CG, Expert Opin Pharmacother, 2011

4. Appleby BS, Expert Opin Pharmacother 2011

5. #1 Rule
Prion Disease

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

7. UCSF (RPD/CJD Referrals)
Geschwind MD, Ann Neurol 2008

8. Treatable Disorders at Autopsy Misdiagnosed
as Prion Disease
Disorder % of Potentially Treatable
Disorders
Autoimmune 37%
Neoplasms 35%
Infections 20%
Metabolic/Toxic 8%
Encephalopathies
Chitravas N, Ann Neurol 2011

9. Chitravas N, Ann Neurol 2011

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

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

12. Sporadic CJD Phenotype
Appleby BS, Arch Neurol 2009

13. Prion diseases without Dementia
• Kuru
• Sporadic CJD
- Oppenheimer-Brownell variant
- PRNP codon 129 VV homozygotes
• Iatrogenic CJD
- hGH, gonadotrophins, dura mater grafts
• Variant CJD
• Genetic prion diseases
- Gerstmann-Sträussler Scheinker disease
- Fatal familial insomnia

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

15. Myoclonus
Caviness JN, Lancet Neurol, 2004

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

17. Adapted from: Appleby BS, Arch Neurol 2009

18. Cuadrado-Corrales N, BMC Neurol 2006

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

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

21. EEG
Parchi P, Ann Neurol 1999

22. ≥ 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, Brain 2009

23. Brain MRI
Zerr I, Brain 2009

24. Mutation=gCJD
• Other conditions happen (Kranitz FJ & Simpson DM,
CNS Neurol Disord Drug Targets 2009)
• Largely unknown penetrance
- E200K, age related (Chapman J, Neurology 1994)
- Octapeptide repeat insertions
• Polymorphisms are not mutations

25. Case Report
• 36 y.o. SWF, father died of gCJD (E200K-
129V)
• Several month h/o head tremor, anxiety, poor
concentration, imbalance
• Brain MRI, EEG, 14-3-3 negative
• Responded to psychiatric treatment
• Mutation came back positive