MI: Prion Disease Pt.2

Question 1

Describe the histological appearance of CJD.

Answer 1

Spongiform vacuolisation

NOTE: there are amyloid plaques but these are different from the plaques seen in Alzheimer’s disease

Question 2

List the differential diagnosis for CJD.

Answer 2

• Alzheimer’s disease
• Vascular dementia
• Mixed dementia (AD + vascular)
• CNS neoplasms
• Cerebral vasculitis
• Paraneoplastic syndromes
• Other CJD types (familial, variant)

Question 3

What is variant CJD?

Answer 3

CJD in younger people that has resulted from the BSE epidemic

Question 4

What animal disease is vCJD linked to?

Answer 4

Bovine spongiform encephalopathy (Mad cow disease)

Question 5

Describe the epidemiology and clinical features of vCJD

Answer 5

• 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

Question 6

What is a characteristic MRI feature of vCJD?

Answer 6

Pulvinar sign - bilateral hyperintensity in the posterior thalamus

Hockey stick sign

Question 7

How is the use of CSF markers different in vCJD?

Answer 7

14-3-3 and S100 are NOT useful in vCJD diagnosis

Question 8

Which investigation is most useful for vCJD?

Answer 8

Tonsillar biopsy

• Prions localise in lymphoid tissue
• Type 4t
• 100% sensitive and specific
• May be positive during incubation period before symptom onset

NOTE: this is not useful in sCJD

Question 9

Describe the role of neurogenetics in vCJD.

Answer 9

Almost 100% of patients are MM at codon 129 (in the PRNP gene)

Question 10

List some causes of iatrogenic CJD.

Answer 10

• Human cadaveric growth hormone
• Corneal transplants
• Neurosurgical procedures e.g. dural grafts (pre-1991)
• Blood transfusions

Question 11

Outline the clinical features of iatrogenic CJD.

Answer 11

• 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)

Question 12

What is the inheritance pattern of inherited prion disease?

Answer 12

Autosomal dominant

Question 13

Which specific polymorphism in the PRNP gene is significant in inheried prion disease

Answer 13

MM (methionine-methionine) polymorphism at codon 129

(may confer earlier onset)

Question 14

What are some alternative diagnoses for someone presenting with features suggestive of prion disease?

Answer 14

• Spinocerebellar ataxia
• Huntington’s disease

Question 15

What is crucial to ask in the history when assessing inherited prion diseases?

Answer 15

Family history

Question 16

Describe the clinical features of Gerstmann-Straussler-Sheinker syndrome.

Answer 16

• Slowly progressive ataxia
• Diminished reflexes
• Dementia

Onset age 30-70 years with 2-10 year mean survival

NOTE: PRNP P102L mutation is most common

Question 17

Describe the clinical features of fatal familial insomnia.

Answer 17

• Untreatable insomnia / paranoia
• Progressing to hallucinations and weight loss
• Then a mute period
• Dysautonomia (BP and HR dysregulation)
• Ataxia
• Late cognitive decline
• (Thalamic degeneration)
• Death 1-18/12 after start of symptoms

NOTE: PRNP D178N mutation is most common

Question 18

What is Kuru?

Answer 18

• 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

Question 19

Outline the principles of treament of CJD.

Answer 19

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

Question 20

Where should possible cases be reported to?

Answer 20

• National prion clinic (Queen Square, UCL)
• NCJDSU in Edinburgh