March 27, 2013

Rapidly Progressive DementiaRapidly Progressive DementiaRapidly Progressive DementiaRapidly Progressive Dementia

Presented by: Brian Appleby, M.D.

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

““IT IT ISIS A PRION DISEASE” A PRION DISEASE”““IT IT ISIS A PRION DISEASE” A PRION DISEASE”

#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 Difficulty in accepting different diagnosisdiagnosis

Forest through the TreesForest through the TreesForest through the TreesForest through the Trees

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

≥ ≥ 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

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

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

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

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

Classic CJD PhenotypeClassic CJD PhenotypeClassic CJD PhenotypeClassic CJD Phenotype

Appleby BS, Arch Neurol 2009

Appleby BS & Lyketsos CG, Expert Opin Pharmacother, 2011

Appleby BS, Expert Opin Pharmacother 2011

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

Geschwind MD, Ann Neurol 2008

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

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

Chitravas N, Ann Neurol 2011

DIAGNOSTIC TEST RESULTSDIAGNOSTIC TEST RESULTSDIAGNOSTIC TEST RESULTSDIAGNOSTIC TEST RESULTS““It is a prion disease”It is a prion disease”

14-3-314-3-314-3-314-3-3

14-3-3 Prion protein

CSF 14-3-3CSF 14-3-3CSF 14-3-3CSF 14-3-3

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

Hamlin C, Neurology 2012

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

5/56 Non-CJD Cases5/56 Non-CJD Cases5/56 Non-CJD Cases5/56 Non-CJD Cases

Steinhoff BJ, Ann Neurol 2004

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

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”

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)

ETIOLOGICAL ISSUESETIOLOGICAL ISSUESETIOLOGICAL ISSUESETIOLOGICAL ISSUES““It is a prion disease”It is a prion disease”

Evolution HappensEvolution HappensEvolution HappensEvolution Happens

CowsCows HumansHumans

Bovine spongiform encephalopathy“mad cow disease”

Human prion disease

““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

227 total cases

Variant CJDVariant CJDVariant CJDVariant CJD

http://www.cjd.ed.ac.uk/vcjdworld.htm

““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

““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

““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

““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

““It’s iatrogenic CJD”It’s iatrogenic CJD”““It’s iatrogenic CJD”It’s iatrogenic CJD”

Brown P, Neurology 2006

Brown P, Neurology 2006

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)

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

““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

Appleby BS, Prion 2009

(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”

CSF 14-3-3CSF 14-3-3CSF 14-3-3CSF 14-3-3

Geschwind MD, Arch Neurol 2003

EEGEEGEEGEEG

Parchi P, Ann Neurol 1999

Brain MRIBrain MRIBrain MRIBrain MRI

Zerr I, Brain 2009