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Pathology eLearning - Y5 > Prion Disease > Flashcards

Prion Disease Flashcards

1
Q

What are prion diseases?

A

Protein-only infectious agent

Rare transmissable spongiform encephalopathies in humans + animals

Rapid neuro-degeneration

Currently untreatable

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2
Q

What is the prion proton gene?

A

Encoded on chromosome 20.

Created prion protein which is predominantly expressed in the CNS.

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3
Q

What is the normal configuration of prion protein compared to PRPsc (scrapie isoform of the prion protein)?

A

Normal: Alpha-helical configuration, protease sensitive.

PRPsc: Beta-sheet configuration, protease/radiation resistant.

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4
Q

How does prion replication occur?

A

Seed of PrPSc acts as a template which promotes irreversible conversion of PrP to insoluble PrPSc ie. conformational change in PrP.

The trigger for this process remains unclear in sporadic cases.

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5
Q

What are classifications of prion disease?

A

Sporadic Creutzfeldt-Jakob Disease (80%)

Acquired (<5%):

  • Kuru
  • Variant CJD
  • Iatrogenic CJD:
    • GH
    • Blood
    • Surgery

Genetic (15%):

  • PRNP mutations: e.g. Gerstmann-Straussler-Sheinker syndrome
  • Familial Fatal Insomnia
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6
Q

What are the clinical features of sporadic CJD?

A

Rapid dementia with:

  • Myoclonus
  • Cortical blindness
  • Akinetic mutism
  • LMN signs
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7
Q

What is the epidemiology of sporadic CJD?

A

Mean age onset 65 yrs (range 45-75 yrs)

Incidence 1/million/year

Death within 6/12

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8
Q

What is the aetiology of sporadic CJD?

A

Cause uncertain:

  • ?Somatic PRNP mutation
  • ?Spontaneous conversion of PrPc to PrPsc
  • ??Environmental exposure to prions
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9
Q

What are appropriate investigations for sporadic CJD?

A

EEG (electroencephalography):

  • Periodic, triphasic complexes (non-specific)
  • 2/3 abnormal

MRI:

  • Basal ganglia – increased signal
  • Cortical/striatal signal change on DWI MRI

CSF: 14-3-3 protein, S100

Neurogenetics to r/o genetic cause

Tonsillar biopsy NOT useful

Brain biopsy

Autopsy – by experienced pathologist

•

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10
Q

What is this?

A

MRI scan - sporadic CJD

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11
Q

What is this?

A

Spongiform Vacuolation

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12
Q

What is this?

A

PrP Amyloid Plaques

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13
Q

What are differential diagnoses for sporadic CJD?

A
  • Alzheimer’s disease
  • Vascular dementia
  • Mixed dementia (AD + vascular)
  • CNS neoplasm eg. glioma, metastases
  • Cerebral vasculitis
  • Paraneoplastic syndrome
  • Familial CJD
  • vCJD
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14
Q

Which statement is NOT true of sporadic CJD?

A. Median survival time is <6 months

B. Tonsillar biopsy is diagnostic

C. EEG usually shows periodic complexes

D. Mean age of onset is 65 years old

E. CSF markers (S100, 14-3-3) of neuronal damage may be elevated

A

B. Tonsillar biopsy is diagnostic

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15
Q

What is the epidemiology of variant CJD/BSE?

A

Younger age of onset (median age 26 yrs)

Median survival time 14 months

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16
Q

What are clinical features of variant CJD/BSE?

A

Psychiatric onset:

  • Dysphoria, anxiety, paranoia, hallucinations

Then neurological:

  • Peripheral sensory symptoms
  • Ataxia
  • Myoclonus
  • Chorea
  • Dementia
17
Q

What are appropriate investigations for vCJD?

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)

Tonsil biopsy 100% sensitive and specific.

(Brain biopsy)

Autopsy

PrPSc type 4t detectable in CNS + most lympo-reticular tissues

18
Q

What is this?

A

MRI Pulvinar Sign

19
Q

How are tonsillar biopsies used in vCJD?

A

100% sensitivity and specificity 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)

20
Q

What is this?

A

vCJD Florid Plaques

21
Q

Which statement is true of variant CJD?

A. The disease mainly affects elderly people

B. vCJD is more rapidly progressive than sporadic CJD

C. The initial symptoms are always neurological

D. Tonsillar biopsy is often diagnostic

E. EEG is usually abnormal

A

D. Tonsillar biopsy is often diagnostic

22
Q

What are risk factors for iatrogenic CJD?

A

Human cadaveric growth hormone

Corneal transplants

Neurosurgical procedures eg. dural grafts, pre-1991

Blood transfusions, other blood products

Other surgical procedures - ?appendicectomy and tonsillectomy in vCJD

23
Q

What are clinical features of iCJD?

A

Progressive ataxia initially

Dementia and myoclonus later stages

Speed of progression depends on route of inoculation (CNS inoculation fastest)

24
Q

What are questions which should be asked to determine iCJD?

A

Neurosurgical operations before 1991?

Family history suggestive of prion disease

Neurological problems suggesting prion disease

25
Q

What is a concern about surgery in iCJD patients?

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.

26
Q

What are the three components of prion genetics?

A

Codon 129 polymorphism:

  • Methionine – Methionine (MM)
  • Methionine – Valine (MV)
  • Valine – Valine (VV)

Specific PRNP mutations (~30 so far)

Consider other neuro-genetic conditions eg. Huntington’s, spinocerebellar ataxia

27
Q

What is the mode of inheritence for prion protein mutations?

A

Mendelian

Autosomal dominant

28
Q

What are clinical features of familial prion disease (GSS, FFI, CJD)?

A

F.H. crucial:

  • Dementia
  • “MS”
  • Ataxia
  • Psychiatric
29
Q

What are appropriate investigations for familial prion disease?

A

EEG: Non-specific

MRI: Basal ganglia: Sometimes high signal

Neurogenetics crucial

If negative: SCA / Huntington’s

Autopsy

30
Q

What is Gerstmann-Straussler-Scheinker syndrome (GSS)?

A

Inherited Prion Disease

  • Slowly progressive ataxia
  • Diminished reflexes
  • Dementia
  • Onset age 30-70 years
  • Survival 2-10 years
  • PRNP P102L, but several other mutations
31
Q

What is Fatal Familial Insomnia (FFI)?

A

Inherited Prion Disease

  • Untreatable insomnia
  • Dysautonomia
  • Ataxia (thalamic degeneration)
  • PRNP D178N
  • +/-pyramidal/extrapyramidal signs
  • Late cognitive decline
32
Q

What is the epidemiology of Kuru?

A

Foré tribes – Papua New Guinea highlands

Epidemic 1950’s/1960’s

  • Women
  • Children

Last endo-cannibalistic feast 1957

Longest incubation: Up to 45 years

No MM’s left

33
Q

What are clinical features of Kuru?

A

Progressive cerebellar syndrome: Death within 2 years

Dementia late or absent

34
Q

What is the management of CJD?

A

Symptomatic: Clonazepam – mycolonus (valproate, levetiracetam, piracetam)

Delaying prion conversion:

  • Quinacrine
  • Pentosan (intra-ventricular administration)
  • Tetracycline

Anti-prion antibody: Prevents peripheral prion replication and blocks progression to disease in infected mice but does not get into CNS.

Depletion of neuronal cellular prion protein: Prevents onset of disease in mice and blocks neuronal cell loss + reverses early spongiosis.

Pathology eLearning - Y5 (17 decks)

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