Diagnosing Creutzfeldt-Jakob DiseaseDiagnosing Creutzfeldt-Jakob DiseaseDiagnosing Creutzfeldt-Jakob DiseaseDiagnosing Creutzfeldt-Jakob Disease

October 20, 2012October 20, 2012

Brian Appleby, M.D.Brian Appleby, M.D.

Staff, Cleveland Clinic Lou Ruvo Staff, Cleveland Clinic Lou Ruvo Center for Brain HealthCenter for Brain Health

ObjectivesObjectivesObjectivesObjectives

• Understand the diagnostic approach to Understand the diagnostic approach to rapidly progressive dementias (RPD)rapidly progressive dementias (RPD)

• Describe diagnostic tools for CJDDescribe diagnostic tools for CJD• Understand common misunderstandings Understand common misunderstandings

related to diagnosing prion diseasesrelated to diagnosing prion diseases

Appleby BS & Lyketsos CG, Expert Opin Pharmacother, 2011

Appleby BS, Expert Opin Pharmacother 2011

#1 Rule#1 Rule#1 Rule#1 Rule

Prion DiseasePrion Disease

Why?Why?Why?Why?

• Consequences of missing other diagnosesConsequences of missing other diagnoses- TreatableTreatable- ReversibleReversible- Different PrognosisDifferent Prognosis- Repeated work-ups laterRepeated work-ups later- Difficulty in accepting different diagnosisDifficulty in accepting different diagnosis

UCSF (RPD/CJD Referrals)UCSF (RPD/CJD Referrals)UCSF (RPD/CJD Referrals)UCSF (RPD/CJD Referrals)

Geschwind MD, Ann Neurol 2008

Treatable Disorders at Autopsy Misdiagnosed Treatable Disorders at Autopsy Misdiagnosed as Prion Diseaseas Prion Disease

Treatable Disorders at Autopsy Misdiagnosed Treatable Disorders at Autopsy Misdiagnosed as Prion Diseaseas Prion Disease

Disorder % of Potentially Treatable Disorders

Autoimmune 37%

Neoplasms 35%

Infections 20%

Metabolic/Toxic Encephalopathies

8%

Chitravas N, Ann Neurol 2011

Chitravas N, Ann Neurol 2011

Probable Sporadic CJDProbable Sporadic CJDProbable Sporadic CJDProbable Sporadic CJD

≥≥2 Clinical Signs2 Clinical Signs

• DementiaDementia• Visual or cerebellarVisual or cerebellar• Pyramidal or Pyramidal or

extrapyramidal extrapyramidal • Akinetic mutismAkinetic mutism

≥ ≥ 1 Diagnostic Test Result1 Diagnostic Test Result• CSF 14-3-3 and <2 yrs CSF 14-3-3 and <2 yrs

durationduration• PSWC’s on EEGPSWC’s on EEG• Brain MRI findingsBrain MRI findings

Zerr I, Brain 2009

Probable Sporadic CJDProbable Sporadic CJDProbable Sporadic CJDProbable Sporadic CJD

≥≥2 Clinical Signs2 Clinical Signs

• DementiaDementia• Visual or cerebellarVisual or cerebellar• Pyramidal or Pyramidal or

extrapyramidal extrapyramidal • Akinetic mutismAkinetic mutism

≥ ≥ 1 Diagnostic Test Result1 Diagnostic Test Result• CSF 14-3-3 and <2 yrs CSF 14-3-3 and <2 yrs

durationduration• PSWC’s on EEGPSWC’s on EEG• Brain MRI findingsBrain MRI findings

Appleby BS, Arch Neurol 2009

Sporadic CJD PhenotypeSporadic CJD PhenotypeSporadic CJD PhenotypeSporadic CJD Phenotype

Prion diseases without DementiaPrion diseases without DementiaPrion diseases without DementiaPrion diseases without Dementia

• KuruKuru• Sporadic CJDSporadic CJD

- Oppenheimer-Brownell variantOppenheimer-Brownell variant- PRNPPRNP codon 129 VV homozygotes codon 129 VV homozygotes

• Iatrogenic CJDIatrogenic CJD- hGH, gonadotrophins, dura mater graftshGH, gonadotrophins, dura mater grafts

• Variant CJDVariant CJD• Genetic prion diseasesGenetic prion diseases

- Gerstmann-Sträussler Scheinker diseaseGerstmann-Sträussler Scheinker disease- Fatal familial insomniaFatal familial insomnia

Probable Sporadic CJDProbable Sporadic CJDProbable Sporadic CJDProbable Sporadic CJD

≥≥2 Clinical Signs2 Clinical Signs

• DementiaDementia• Visual or cerebellarVisual or cerebellar• Pyramidal or Pyramidal or

extrapyramidal extrapyramidal • Akinetic mutismAkinetic mutism

≥ ≥ 1 Diagnostic Test Result1 Diagnostic Test Result• CSF 14-3-3 and <2 yrs CSF 14-3-3 and <2 yrs

durationduration• PSWC’s on EEGPSWC’s on EEG• Brain MRI findingsBrain MRI findings

Myoclonus

MyoclonusMyoclonusMyoclonusMyoclonusCaviness JN, Lancet Neurol, 2004

Probable Sporadic CJDProbable Sporadic CJDProbable Sporadic CJDProbable Sporadic CJD

≥≥2 Clinical Signs2 Clinical Signs

• DementiaDementia• Visual or cerebellarVisual or cerebellar• Pyramidal or Pyramidal or

extrapyramidal extrapyramidal • Akinetic mutismAkinetic mutism

≥ ≥ 1 Diagnostic Test Result1 Diagnostic Test Result• CSF 14-3-3 and <2 yrs CSF 14-3-3 and <2 yrs

durationduration• PSWC’s on EEGPSWC’s on EEG• Brain MRI findingsBrain MRI findings

Zerr I, Brain 2009

Disease duration

Adapted from: Appleby BS, Arch Neurol 2009

Cuadrado-Corrales N, BMC Neurol 2006

Conditions with CSF 14-3-3Conditions with CSF 14-3-3Conditions with CSF 14-3-3Conditions with CSF 14-3-3

Berg D, Nat Rev Neurosci 2003

• TBI• Seizures

EEGEEGEEGEEG

CJD Non-CJD Total

PSWC’s 10 2 12

No PSWC’s 5 12 17

PSWC’s

Steinhoff BJ, Arch Neurol 1996

EEGEEGEEGEEG

Parchi P, Ann Neurol 1999

≥ ≥ 1 of the Following1 of the Following(FLAIR and/or DWI)(FLAIR and/or DWI)≥ ≥ 1 of the Following1 of the Following(FLAIR and/or DWI)(FLAIR and/or DWI)

High signal abnormality in High signal abnormality in basal gangliabasal ganglia

High signal abnormality in ≥ High signal abnormality in ≥ 2 cortical regions2 cortical regions• TemporalTemporal• Parietal Parietal • OccipitalOccipital

Frontal

Zerr I, Brain 2009

Brain MRIBrain MRIBrain MRIBrain MRI

Zerr I, Brain 2009

Mutation=gCJDMutation=gCJDMutation=gCJDMutation=gCJD

• Other conditions happen Other conditions happen (Kranitz FJ & Simpson DM, (Kranitz FJ & Simpson DM, CNS Neurol Disord Drug Targets CNS Neurol Disord Drug Targets 2009)2009)

• Largely unknown penetranceLargely unknown penetrance- E200K, age related E200K, age related (Chapman J, (Chapman J, NeurologyNeurology 1994) 1994) - Octapeptide repeat insertionsOctapeptide repeat insertions

• Polymorphisms are not mutationsPolymorphisms are not mutations

Case ReportCase ReportCase ReportCase Report

• 36 y.o. SWF, father died of gCJD (E200K-36 y.o. SWF, father died of gCJD (E200K-129V)129V)

• Several month h/o head tremor, anxiety, poor Several month h/o head tremor, anxiety, poor concentration, imbalanceconcentration, imbalance

• Brain MRI, EEG, 14-3-3 negativeBrain MRI, EEG, 14-3-3 negative• Responded to psychiatric treatmentResponded to psychiatric treatment• Mutation came back positiveMutation came back positive