MI: Prion Disease Flashcards
What is the rapid plasma reagent test?
Screening test for active syphilis
Name a CSF marker that supports the diagnosis of sCJD
14-3-3
What is a characteristic finding of CJD on a diffusion-weight MRI?
High signal in the caudate/putamen or at least in cortical regions (temporal, parietal, occipital)
What does ‘prion’ stand for?
Protein-only infectious agent
What are prion diseases and what do they cause?
- Rare transmissible spongiform encephalopathies caused by prions
- They lead to spongiform vacuolisation of the brain and rapid neurodegeneration
What is the prion protein gene and on which chromosome is it found?
PRNP gene, chromosome 20
What is a possible physiological role of the normal prion protein?
It may have some role in copper metabolism
Describe the structure of the normal prion protein.
Alpha-helix
Describe the structure of an abnormal prion protein.
Beta-pleated sheet
Why is the abnormal prion protein difficult to get rid of?
Resistant to proteases and radiation
How does prion replication take place?
Seeding of an abnormal prion protein (PrPsc) seems to act as a template which promotes the conversion of PrP to the insoluble PrPsc
List some types of prion disease. Which type is most common?
Sporadic CJD (80%)
Acquired (<5%)
- Kuru
- Variant CJD (results from BSE epidemic)
- Iatrogenic CJD
Genetic (15%)
- PRNP mutations e.g. fatal familial insomnia, Gerstmann-Straussler-Sheinker syndrome
Give some examples of inherited prion diseases. What are they caused by?
- Fatal familial insomnia
- Gerstmann-Straussler-Sheinker syndrome
Caused by PRNP gene mutations
Describe the clinical features of sporadic CJD.
Rapid dementia with:
- Myoclonus
- Cerebellar dysfunction
- Cortical blindness
- Akinetic mutism
- LMN signs
NOTE: usually in older people (>65)
What is the epidemiology and prognosis of sporadic CJD?
- Mean age of onset 65 years (range 45-75 years)
- Prognosis - death with 6 months
What are some possible causes of sporadic CJD?
No known cause
- Somatic PRNP mutation
- Spontaneous conversion of PrP into PrPsc
- Environmental exposure to prions
How might sCJD be diagnosed?
- EEG - abnormal in 2/3
- MRI
- CSF
- Neurogenetics
- Brain biopsy
- Autopsy - must be done by experience pathologist
Describe the EEG appearance in sporadic CJD.
Triphasic complexes
Describe the MRI appearance of sporadic CJD.
Increased intensity on DWI MRI of the basal ganglia and cortex
Which markers will be raised in the CSF of a patient with CJD?
14-3-3
S100
What is the only way of confirming a diagnosis of CJD?
Brain biopsy (usually at autopsy)
Describe the histological appearance of CJD.
Spongiform vacuolisation
NOTE: there are amyloid plaques but these are different from the plaques seen in Alzheimer’s disease
List the differential diagnosis for CJD.
- Alzheimer’s disease
- Vascular dementia
- Mixed dementia (AD + vascular)
- CNS neoplasms
- Cerebral vasculitis
- Paraneoplastic syndromes
- Other CJD types (familial, variant)
What is variant CJD?
CJD in younger people that has resulted from the BSE epidemic
What animal disease is vCJD linked to?
Bovine spongiform encephalopathy (Mad cow disease)
Describe the epidemiology and clinical features of vCJD
- Younger age of onset - median age 26 years
- Median survival 14 months
- Psychiatric onset - dysphoria, anxiety, delusions, hallucinations
- Followed by neurological symptoms - peripheral sensory symptoms, ataxia, myoclonus, chorea, dementia
What is a characteristic MRI feature of vCJD?
Pulvinar sign - bilateral hyperintensity in the posterior thalamus
How is the use of CSF markers different in vCJD?
14-3-3 and S100 are NOT useful in vCJD diagnosis
Which investigation is most useful for vCJD?
Tonsillar biopsy
- Prions localise in lymphoid tissue
- 100% sensitive and specific
- May be positive during incubation period before symptom onset
NOTE: this is not useful in sCJD
Describe the role of neurogenetics in vCJD.
Almost 100% of patients are MM at codon 129 (in the PRNP gene)
List some causes of iatrogenic CJD.
- Human cadaveric growth hormone
- Corneal transplants
- Neurosurgical procedures e.g. dural grafts (pre-1991)
- Blood transfusions
Outline the clinical features of iatrogenic CJD.
- Starts with progressive ataxia
- Dementia and myoclonus occur at a later stage
Speed of symptom progession in iatrogenic CJD depends on route of innoculation (CNS innoculation is fastest)
What is the inheritance pattern of inherited prion disease?
Autosomal dominant
Which specific polymorphism in the PRNP gene is significant in inheried prion disease
MM (methionine-methionine) polymorphism at codon 129
What are some alternative diagnoses for someone presenting with features suggestive of prion disease?
- Spinocerebellar ataxia
- Huntington’s disease
What is crucial to ask in the history when assessing inherited prion diseases?
Family history
Describe the clinical features of Gerstmann-Straussler-Sheinker syndrome.
- Slowly progressive ataxia
- Diminished reflexes
- Dementia
Onset age 30-70 years with 2-10 year mean survival
NOTE: PRNP P102L mutation is most common
Describe the clinical features of fatal familial insomnia.
- Untreatable insomnia
- Dysautonomia (blood pressure and heart rate dysregulation)
- Ataxia
- Late cognitive decline
- (Thalamic degeneration)
NOTE:** PRNP D178N** mutation is most common
What is Kuru?
- Prion diorder from Papua New Guinea that was spread due to the tradition of endo-cannibalism
- Characterised by progessive cerebellar syndrome with late or absent dementia
- Death occured within 2 years
Outline the principles of treament of CJD.
Symptomatic
- Clonazepam for clonus
- (Valproate, levetiracetam, priacetam)
Delaying prion conversion
- Quinacrine
- Pentosan (intraventricular administration)
- Tetracycline
Anti-prion antibody
- Blocks peripheral prion replication and progession to disease in mice but cannot access CNS
Depletion of neuronal cellular prion protein
- Prevents diease onset in mice and blocks neuronal cell loss and reverses early spongiosis
Where should possible cases be reported to?
- National prion clinic (Queen Square, UCL)
- NCJDSU in Edinburgh
