diagnosis of creutzfeldt-jakob disease
TRANSCRIPT
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