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Kat's Pathology > Prion Disease > Flashcards

Prion Disease Flashcards

1
Q

What are prion diseases (2)

A

Protein-only infectious agent

Rare transmissible spongiform encephalopathies in humans + animals

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2
Q

What is the neurological sequelae like in prion disease

A

Rapid neuro-degeneration

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3
Q

What is the treatment for prion disease

A

Currently untreatable

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4
Q

What gene is prion protein on

A

Chromosome 20

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5
Q

What does prion protein gene code for

A

PrP is predominantly expressed in the CNS

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6
Q

What is the normal PrP structure (2)

A

Alpha-helical configuration

Protease sensitive

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7
Q

What is the abnormal PrPsc structure (2)

A

Beta-sheet configuration

Protease/radiation resistant

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8
Q

How does prion protein propagate throughout the CNS

A

Seen of PrPsc acts as a template which promotes irreversible conversion of PrP to insoluble PrPsc (i.e. conformational change in PrP)

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9
Q

What triggers PrP change to PrPsc

A

Unknown in sporadic cases

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10
Q

How is prion disease classified in humans (3)

A

Sporadic (80%)
Acquired (<5%)
Genetic (15%)

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11
Q

What is a sporadic prion disease in humans

A

Creutzfeldt-Jakob disease

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12
Q

What are some acquired forms of prion disease (3)

A

Kuru
Variant CJD
Iatrogenic CJD (GH, blood, surgery)

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13
Q

What is the cause of genetic prion disease

A

PRNP mutations (e.g. Gertsmann-Straussler-Sheinker syndrome, Familial Fatal Insomnia)

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14
Q

What are the clinical features of sporadic CJD (5)

A 
Rapid onset dementia, with: 
Myoclonus 
Cortical blindness
Akinetic mutism 
LMN signs
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15
Q

What is the mean age of onset for sporadic CJD

A

65 years (range from 45-75 years)

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16
Q

What is the incidence of sporadic CJD

A

1/million/year

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17
Q

What is the prognosis for sporadic CJD

A

Death within 6 months

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18
Q

What are some proposed causes of sporadic CJD (3)

A

Somatic PRNP mutation
Spontaneous conversion of PrPc to PrPsc
Environmental exposure to prions

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19
Q

How is sporadic CJD diagnosed (7)

A 
EEG 
MRI
CSF
Neurogenetics to rule out genetic cause 
Tonsillar biopsy is NOT useful 
Brain biopsy 
Autopsy
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20
Q

What is seen on the EEG of a patient with sporadic CJD (2)

A

Periodic, triphasic complexes (non-specific)

2/3rds are abnormal only

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21
Q

What is seen on the MRI of a patient with sporadic CJD (2)

A

Basal ganglia - increased signal

Cortical/striatal signal change on DWI MRI

22
Q

What is seen on the CSF of a patient with sporadic CJD

A

14-3-3- protein, S100

23
Q

What is seen histologically in sporadic CJD (2)

A

Spongiform vacuolation

PrP amyloid plaques

24
Q

What is the differential diagnosis for sporadic CJD (8)

A 
AD
Vascular dementia 
Mixed dementia (AD and vascular) 
CNS neoplasm (glioma, metastases)
Cerebral vasculitis
Paraneoplastic syndrome 
Familial CJD
vCJD
25
Q

What is the age of presentation for vCJD

A

Younger than for sCJD (median age 26 years)

26
Q

What is the median survival time for vCJD

A

14 months

27
Q

What are the clinical signs of vCJD (9)

A

Psychiatric onset: dysphoria, anxiety, paranoia, hallucinations
Neurological: ataxia, myoclonus, chorea, dementia

28
Q

How is vCJD diagnosed (8)

A

MRI brain - positive pulvinar sign
EEG - non-specific slow waves
CSF - 14-3-3, S100 not useful
Neurogenetics (almost 100% are MM at codon 129 so far)
Tonsilar biopsy is 100% sensitive and specific
(Brain biopsy)
Autopsy
PrPcs type 4t detectable in CNS + most lympho-retucular tissues

29
Q

What is seen on MRI of vCJD

A

Positive pulvinar sign

30
Q

What are the neurogenetics of vCJD

A

Almost 100% are MM at codon 129

31
Q

What is the significance of tonisllar biopsy in vCJD (5)

A

100% sensitive and specific for vCJD
Early clinical diagnosis
Eliminates need for further investigation (e.g. brain biopsy to exclude other treatable causes)
Important for therapeutic trials and early treatment
may be positive during incubation period before clinical onset (sheep scrapie, mouse models)

32
Q

What is the histological finding in vCJD

A

Florid plaques

33
Q

How is iatrogenic CJD transferred (5)

A

Human cadaveric growth hormone
Corneal transplants
neurosurgical procedures e.g. dural gradts pre-1991
Blood transfusions, other blood products
Other surgical procedures (appendicectomy and tonsillectomy in vCJD)

34
Q

What are the clinical features of iatrogenic CJD (3)

A

Progressive ataxia initially
Dementia and myoclonus later stages
Speed of progression depends on route of inoculation (CNS inoculation fastest)

35
Q

What are some important screening questions for prion disease for before surgery/donation (3)

A

Neurosurgical operations before 1991
Family history suggestive of prion disease
Neurological problems suggesting prion disease

36
Q

What is important to do if operating on someone who may have prion disease

A

Sterilisation + disposal of surgical instruments vital
Theoretical concern regarding possibility of iatrogenic transmission of vCJD through transfusion, IVIg, surgical procedures etc… this could become a major public health issue.

37
Q

What are the possible genetics of prion disease (3)

A

Codon 129 polymorphism
Specific PRNP mutation
Related to other neuro-genetic conditions (e.g. Huntington’s, spinocerebellar ataxia)

38
Q

What codon 129 mutations are associated with prion disease

A

Methionine-Methionine (MM)

Not Methionine-Valine or Valine-Valine

39
Q

What is the mode of inheritance for prion protein mutations

A

Autosomal dominant

40
Q

What family history is relevant in familial prion disease (4)

A

Dementia
MS
Ataxia
Psychiatric

41
Q

What is seen on the EEG in familial prion disease

A

Non-specific

42
Q

What is seen on the MRI in familial prion disease

A

Basal ganglia: sometimes high signal

43
Q

What is the most important investigation in familial prion disease

A

Neurogenetics

44
Q

What are the clinical features of Grestmann-Straussler-Scheinker syndrome (GSS) (6)

A 
Slowly progressive ataxias 
Diminished reflexes
Dementia 
Onset age 30-70 years
Survival 2-10 years 
PRNP P102L, but several other mutations
45
Q

What are the clinical features of fatal familial insomnia (FFI) (5)

A 
Untratable insomnia
Dysautonomia 
Ataxia 
(Thalamic degeneration) 
Mutation: PRNP D178N +/- pyramidal/extrapyramidal signs and late cognitive decline
46
Q

What is Kuru

A

Prion disease from the Fore tribes of Papua New Guinea highlands.
There was an epidemic in 1950/60s (women and children)
Last endo-canibalistic feast in 1957
Longest incubation - up to 45 years
NO MM’s left
Progressive cerebellar syndrome (death within 2 years)
Dementai was late or absent

47
Q

What is the treatment for CJD (4)

A

Symptomatic
Delayed prion conversion
Anti-prion antibody
Depletion of neuronal cellular prion protein

48
Q

What is involved in the symptomatic treatment of prion disease (2)

A

Clonazepam - myoclonus

valproate, levetiracetam, piracetam

49
Q

What is involved in treating to delay prion conversion (3)

A

Quinacrine
Pentosan (intra-ventricular adminstration)
Tetracycline

50
Q

What is anti-prion antibody

A

Treatment aimed at preventing peripheral prion replication and blocks progression to disease in infected mice, but does not penetrate into CNS

51
Q

What is involved in treating for depletion of neuronal cellular prion proteins

A

Prevents onset of disease in mice and blocks neuronal cell loss + reverses early spongiosis

Kat's Pathology (105 decks)

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