ccf neuro res rapidly progressive dementia 2013 03-27
TRANSCRIPT
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March 27, 2013
Rapidly Progressive DementiaRapidly Progressive DementiaRapidly Progressive DementiaRapidly Progressive Dementia
Presented by: Brian Appleby, M.D.
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ObjectivesObjectivesObjectivesObjectives
Understand common biases and Understand common biases and misinformation related to:misinformation related to:
- Diagnosing prion disease/rapidly Diagnosing prion disease/rapidly progressive dementia (RPD)progressive dementia (RPD)
- Failing to diagnose prion diseaseFailing to diagnose prion disease
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““IT IT ISIS A PRION DISEASE” A PRION DISEASE”““IT IT ISIS A PRION DISEASE” A PRION DISEASE”
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#1 Rule#1 Rule#1 Rule#1 Rule
Prion DiseasePrion Disease
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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 Difficulty in accepting different diagnosisdiagnosis
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Forest through the TreesForest through the TreesForest through the TreesForest through the Trees
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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
• PSWCs on EEGPSWCs on EEG• Brain MRI findingsBrain MRI findings
Zerr I, Brain 2009
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≥ ≥ 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)
1.1. High signal High signal abnormality in basal abnormality in basal gangliaganglia
2.2. High signal High signal abnormality in ≥ 2 abnormality in ≥ 2 cortical regionscortical regions• TemporalTemporal• Parietal Parietal • OccipitalOccipital
Frontal
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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
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Without DementiaWithout DementiaWithout DementiaWithout Dementia
• KuruKuru• Sporadic CJDSporadic CJD
- Oppenheimer-Brownell variantOppenheimer-Brownell variant- PRNPPRNP codon 129 VV homozygotes codon 129 VV homozygotes
• Iatrogenic CJDIatrogenic CJD- hGH, gonadotrophinshGH, gonadotrophins
• Variant CJDVariant CJD• Genetic prion diseasesGenetic prion diseases
- Gerstmann-Sträussler Scheinker diseaseGerstmann-Sträussler Scheinker disease- Fatal familial insomniaFatal familial insomnia
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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
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MyoclonusMyoclonusMyoclonusMyoclonusCaviness JN, Lancet Neurol, 2004
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Clinical data in sCJD (light shaded bars) and non-sCJD patients (dark shaded bars)
* p < 0.05, ** p < 0.01, and *** p < 0.001 sCJD includes both probable and definite patients.
Cuadrado-Corrales N, BMC Neurol 2006
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Classic CJD PhenotypeClassic CJD PhenotypeClassic CJD PhenotypeClassic CJD Phenotype
Appleby BS, Arch Neurol 2009
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Appleby BS & Lyketsos CG, Expert Opin Pharmacother, 2011
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Appleby BS, Expert Opin Pharmacother 2011
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UCSF (RPD/CJD Referrals)UCSF (RPD/CJD Referrals)UCSF (RPD/CJD Referrals)UCSF (RPD/CJD Referrals)
Geschwind MD, Ann Neurol 2008
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Non-Prion RPD’sNon-Prion RPD’sNon-Prion RPD’sNon-Prion RPD’s
Diagnosis Percentage
Neurodegenerative 39%
Autoimmune 22%
Unknown 12%
Infectious 6%
Psychiatric 6%
Malignancy 6%
Geschwind MD, Ann Neurol 2008
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Potentially Treatable Disorders Potentially Treatable Disorders Misdiagnosed as Prion DiseaseMisdiagnosed as Prion DiseasePotentially Treatable Disorders Potentially Treatable Disorders Misdiagnosed as Prion DiseaseMisdiagnosed as Prion Disease
Disorder % of Potentially Treatable Disorders
Autoimmune 37%
Neoplasms 35%
Infections 20%
Metabolic/Toxic Encephalopathies 8%
Chitravas N, Ann Neurol 2011
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Chitravas N, Ann Neurol 2011
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DIAGNOSTIC TEST RESULTSDIAGNOSTIC TEST RESULTSDIAGNOSTIC TEST RESULTSDIAGNOSTIC TEST RESULTS““It is a prion disease”It is a prion disease”
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14-3-314-3-314-3-314-3-3
14-3-3 Prion protein
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CSF 14-3-3CSF 14-3-3CSF 14-3-3CSF 14-3-3
Cuadrado-Corrales N, BMC Neurol 2006
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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
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Hamlin C, Neurology 2012
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EEGEEGEEGEEG
CJD Non-CJD Total
PSWC’s 10 2 12
No PSWC’s 5 12 17
Total 15 14 29
PSWC’s
Steinhoff BJ, Arch Neurol 1996
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5/56 Non-CJD Cases5/56 Non-CJD Cases5/56 Non-CJD Cases5/56 Non-CJD Cases
Steinhoff BJ, Ann Neurol 2004
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Brain MRIBrain MRIBrain MRIBrain MRI
Condition n
Infectious/inflammatory 9
Alzheimer’s disease 2
Dementia with Lewy bodies 2
Epilepsy 2
Intravascular lymphomatosis 1
Mitochondrial cytopathy 1
Unknown (with recovery) 2
Zerr I, Brain 2009
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THERE IS NOTHING WE CAN DOTHERE IS NOTHING WE CAN DOTHERE IS NOTHING WE CAN DOTHERE IS NOTHING WE CAN DO““It is a prion disease”It is a prion disease”
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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 exercisesLong acting benzodiazepines, Botulinum toxin injections
Constipation Bowel regimen (e.g., ducolax)
Dysphagia/Rumination Thickener, cueing
Behavioral/Environmental changes firstStart low and go slowRevaluate frequently
Hospice Referral
CJD Foundation (www.cjdfoundation.org)
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ETIOLOGICAL ISSUESETIOLOGICAL ISSUESETIOLOGICAL ISSUESETIOLOGICAL ISSUES““It is a prion disease”It is a prion disease”
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Evolution HappensEvolution HappensEvolution HappensEvolution Happens
CowsCows HumansHumans
Bovine spongiform encephalopathy“mad cow disease”
Human prion disease
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““It’s variant Creutzfeldt-Jakob disease”It’s variant Creutzfeldt-Jakob disease”Erroneous ExplanationsErroneous Explanations
““It’s variant Creutzfeldt-Jakob disease”It’s variant Creutzfeldt-Jakob disease”Erroneous ExplanationsErroneous Explanations
• Age at onsetAge at onset
• Psychiatric presentationPsychiatric presentation
• Prolonged illness durationProlonged illness duration
• They visited the UKThey visited the UK
• Eat a lot of hamburgersEat a lot of hamburgers
• Occupation=butcherOccupation=butcher
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227 total cases
Variant CJDVariant CJDVariant CJDVariant CJD
http://www.cjd.ed.ac.uk/vcjdworld.htm
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““It’s vCJD”It’s vCJD”Age at onsetAge at onset
““It’s vCJD”It’s vCJD”Age at onsetAge at onset
http://www.cjd.ed.ac.uk/vcjdworld.htm
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““It’s vCJD”It’s vCJD”Psychiatric PresentationPsychiatric Presentation
““It’s vCJD”It’s vCJD”Psychiatric PresentationPsychiatric Presentation
Appleby BS, J Neuropsychiatry Clin Neurosci 2007
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““It’s vCJD”It’s vCJD”Prolonged Illness DurationProlonged Illness Duration
““It’s vCJD”It’s vCJD”Prolonged Illness DurationProlonged Illness Duration
Adapted from: Appleby BS, Arch Neurol 2009
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““It’s vCJD”It’s vCJD”They visited the UKThey visited the UK
““It’s vCJD”It’s vCJD”They visited the UKThey visited the UK
18th Annual Report, CJD Surveillance in the UK 2009
MM
MV
BSE1980s
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““It’s iatrogenic CJD”It’s iatrogenic CJD”““It’s iatrogenic CJD”It’s iatrogenic CJD”
Brown P, Neurology 2006
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Brown P, Neurology 2006
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Mutation=gCJDMutation=gCJDMutation=gCJDMutation=gCJD
• Other conditions happen Other conditions happen (Kranitz FJ & Simpson (Kranitz FJ & Simpson DM, 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 insertions Octapeptide repeat insertions (Appleby (Appleby
BS, BS, Prion 2011Prion 2011))
• Polymorphisms are not mutations (e.g. Polymorphisms are not mutations (e.g. codon 129)codon 129)
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Case ReportCase ReportCase ReportCase Report
• 36 y.o. SWF, father died of gCJD 36 y.o. SWF, father died of gCJD (E200K-129V)(E200K-129V)
• Several month h/o head tremor, anxiety, Several month h/o head tremor, anxiety, poor concentration, imbalancepoor concentration, 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
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““IT IT IS NOT IS NOT A PRION DISEASE”A PRION DISEASE”““IT IT IS NOT IS NOT A PRION DISEASE”A PRION DISEASE”Biases and MisinformationBiases and Misinformation
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Appleby BS, Prion 2009
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(Log-rank test, χ2= 25.3, p<0.001)
Appleby BS, Arch Neurol 2009
““Too long duration”Too long duration”““Too long duration”Too long duration”
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CSF 14-3-3CSF 14-3-3CSF 14-3-3CSF 14-3-3
Geschwind MD, Arch Neurol 2003
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EEGEEGEEGEEG
Parchi P, Ann Neurol 1999
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Brain MRIBrain MRIBrain MRIBrain MRI
Zerr I, Brain 2009
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