MICRO: Prion disease Flashcards
Case example:
- 75-year-old retired businessman, recently returned from Ghana
- Complaints –> paraesthesia, unsteadiness, tremor
- General examination – normal
- Neurological examination:
- Ataxic gait
- Gaze evoked horizontal nystagmus on L gaze
- L UMN VII weakness
- No other cranial nerve abnormalities
- L UL pronator drift
- Jerky irregular resting tremor
- Mild L limb spasticity
- Mild L UL/LL pyramidal weakness
- Mild L hyperreflexia
- Flexor plantar responses bilaterally
- Reduced JPS and patchy pinprick loss
- Gradual onset over 3/52 –> ascending tingling, jerky tremor left hand, walking with a stick
- Other parts of the history:
- PMHx
- Right hemisphere stroke, no residual deficit
- Hypertension
- Hyperlipidaemia
- Obesity
- Falciparum malaria 1988
- Syphilis (treated >40 yrs. ago)
- DHx
- Perindopril, simvastatin, clopidogrel
- FHx
- Sister died from “MND”
- SHx
- Lives alone; alcohol 20 U/week; non-smoker; MSM
- PMHx
Initial working diagnosis –> small sequential cerebral infarcts
- Initial investigations:
- CRP<5
- ESR 15
- TPPA+ RPR– (test for syphilis)
- ANA >1/640; ANCA–ve, HIV -ve
- Protein electrophoresis normal
- FBC, LFT, B12, folate normal
- ECG, echo, CXR normal
- CT head: small vessel disease, nil acute
- Carotid duplex normal
- MRI brain: old ischaemic changes only, nil acute
- Patient continued to decline à more tremulous, increasingly dysarthric and ataxic, remained fully orientated, diplopia
- More differential diagnoses:
- Creutzfeldt Jacob Disease (CJD)
- Primary cerebral vasculitis
- Paraneoplastic encephalitis
- Whipple’s disease
- Corticobasal degeneration
- Coeliac disease
- Tropical infection
- More investigations:
- Anti-neuronal Ab –ve, tumour markers -ve
- CSF examination:
- Opening pressure 18.5 cm H2O, acellular
- Protein 0.45, glucose 3.9
- OCB -ve
- 14-3-3, S100, NSE all normal level (14-3-3 is a marker of rapid neuro-degeneration)
- MRI brain +/- gadolinium with DWI
- EEG: unremarkable
- Whole body CT: nil of note
- Small bowel biopsy: normal
- Whole body FDG-PET scan
- No evidence of malignancy
- Evidence parietal hypometabolism R>L
- Later on, in the case:
- 30 days later:
- Oculomotor signs
- Almost anarthric
- Severe myoclonus
- Ataxic breathing
- Orientated where intelligible
- Continued rapid deterioration; no response to antibiotics or high dose steroids
- Died on day 41 à post mortem confirmed sporadic CJD
- 30 days later:
Define prion disease.
Prion = a protein-only infectious agent
Cause rare transmissible spongiform encephalopathies in humans and animals
They do contain DNA, but they are only made of protein
What happens when prions enter the brain?
Prions trigger a cascade where existing prion proteins become rapidly affected and develop the abnormal isoform of the prion protein
–> spongiform vacuolisation of the brain
–> rapid neurodegeneration
Where is the prion protein gene? What is its normal function?
Prion protein gene = found on chromosome 20
Function: encodes a prion protein. Normal function of prion protein poorly understood but thought to have some role in copper metabolism
Normal protein does NOT cause any issues.
Polymorphisms of the gene are found on codon 129
What are the 3 polymorphisms of the prion protein gene which can predispose to prion disease?
- MM – predisposes to prion disease
- MV
- VV
- V = Valine*
- M = Methionine*
Compare and contrast the protein structures of normal and abnormal prion protein.
Normal protein = PrP
- Has an alpha-helical structure
- It is protease-sensitive and sensitive to radiation
Abnormal protein = PrPSc
- Beta-pleated sheet configuration
- RESISTANT to proteases and radiation
- Difficult to get rid of e.g. surgical instruments contaminated with diseased prions are impossible to clean
Where are prion proteins normally expressed?
PrP predominantly expressed in the CNS
How do prions replicate? What is the trigger?
Seed of the abnormal prion protein (PrPSc) begins to act as a template to promote conversion of PrP into insoluble PrPSc –> rapid neurodegeneration i.e. a conformational change in PrP occurs
The trigger for this process is unclear in sporadic cases
How are prion diseases classified? What is the most common form? Give an example of each.
Sporadic (80%) - Creutzfeldt-Jakob Disease
Genetic (15%) e.g. FFI, Gerstmann-Straussler-Sheinker syndrome
Acquired (5%) e.g. Kuru , variant CJD, iatrogenic CJD
What are the causes of iatrogenic CJD?
- Growth hormone (from cadavers)
- Blood
- Surgery
Compare and contrast the features of sporadic vs variant CJD.
What is the main cause of variant CJD and what polymorphism is present?
- Results from earlier BSE (bovine spongiform encephalopathy) epidemic
- Average age: 25-30 years
- 100% codon 129 MM polymorphism
sporadic
What are the clinical features of sporadic CJD?
- DEMENTIA
- Myoclonus (jerky irregular tremor)
- Cortical blindness
- Akinetic mutism
- LMN signs
What is the epidemiology of sporadic CJD?
- Mean age: 65 years (range 45-75 years)
- Death within <6 months
- Incidence: 1/million/year
What are 3 possible causes of sCJD?
-
Cause is uncertain; could be due to…
- Somatic PRNP mutation
- Spontaneous conversion of PrP to PrPSc
- Environmental exposure to prions
What is seen on EEG in sCJD?
“an EEG that looks like an ECG”
- Periodic, triphasic complexes (but these are non-specific – appears in hepatic encephalopathy, lithium toxicity)
- 2/3 patients with confirmed CJD will have an abnormal EEG
What is seen on MRI in sCJD?
- Increased signal in basal ganglia –>
- Increased intensity on DWI (diffusion-weighted imaging) MRI of the cortex and basal ganglia
What do these other investigations for sCJD show?
- Neurogenetics
- Tonsillar biopsy
- Brain biopsy
- Histology
- Neurogenetics (look for genetic cause)
- Tonsillar biopsy (may be used in vCJD but NOT in CJD)
- Brain biopsy (only way of confirming CJD but this is often done at autopsy)
- Histology = spongiform vacuolation (left) & amyloid plaques (right)
B
Summarise the history of BSE.
There was an epidemic of BSE in the 1990s AKA “Mad Cow Disease”
Due to feeding of cow meat to the cows, which propagated the disease
1995-1996 gave rise to the first reported cases of atypical CJD in teenagers and young people (<30yo)
Peaked presentations in 2000 (n= ~165 to date), only 7 new cases since 2008.
What do investigations show in vCJD?
- MRI = high intensity in the putamen shown = pulvinar sign
- EEG = non-specific slow waves
- CSF = 14-3-3- and S100 are NOT useful as death is slow so no rapid neurodegeneration
- Neurogenetics = almost 100% are MM at codon 129 (suggests that this genotype confers an increased risk of vCJD)
- Tonsil biopsy = 100% sensitive and specific.
- Brain biopsy = at autopsy only, PrPSctype 4T detectable in CNS and most lymphoreticular tissues
- Histology = florid plaques
D – critical for diagnosis of variant CJD. Initial symptoms are psychiatric followed by neurological.
A – all bar 1 have been MM.
