Creutzfeldt-Jakob disease

General term for human prion disease, including sporadic, genetic, and infectiously-acquired forms

Differential Diagnosis

A prion protein gene PRNP encodes a protein, PrP^C^, that is expressed in the brain and reticuloendethelial system
Mutations of PRNP can create versions of PrP that folds abnormally, called PrP^Sc^
Misfolded PrP^Sc^ catalyzes other PrP^C^ molecules to misfold, thereby converting them into more PrP^Sc^

Age 45-75
Myoclonus, cerebellar signs and symptoms, and visual disturbance (includes cortical blindness)
May have prodromal symptoms including fatigue, insomnia, depression, weight loss, headaches, general malaise and ill-defined pain sensation
Pyramidal and extrapyramidal signs may also develop, with upper motor neuron signs on exam
Akinetic mutism commonly develops 2–3 months after the onset of symptoms
Rapid or subacute decline, with a median survival 7-9 months from symptom onset
Can detect 14-3-3 protein in CSF
Can have a variety of subtypes, including visual, cerebellar, thalamic, or striatal-predominant symptoms

Autosomal dominant mutations in PRNP with high penetrance, of which E200K is the most common worldwide
Median age of onset is 58 years
There are some specific forms

First described in Italian families
Starts with insomnia, autonomic hyperactivity (increased sweating, teraing, salivation, mild nocturnal hyperthermia, tachycardia, and hypertension)
Later, motor disturbances including ataxia, myoclonus, spasticity, hyperreflexia, and dysarthria
Dementia would be a late finding
Median age of onset is 50 to 56 years, but can occur from 19 to 83 years

Younger age (mean 26 years and range 12 to 74 years)
May be from bovine spongiform encephalopathy in people homozygous 129M polymorphism of PrP
- Large outbreak in UK starting in 1995 related to an outbreak of BSE in 1985
Can be transmitted via blood transfusion
Prominent neuropsychiatric features: depression, anxiety, emotional lability, irritability, aggressive behavior, social withdrawal, delusions and hallucination
Later, cerebellar syndrome with limb and gait ataxia, chorea, myoclonus, and dementia
Median survival 14 months
Can be diagnosed with PrP^Sc^ on tonsil biopsy

Transmitted by corneal and dura mater grafts, liver transplantation, growth hormone, neurosurgical procedures, and stereotactic EEG
Incubation period ranges from 16 months to 25 years
Presentation usually sCJD, but have also been cases of GSS and, rarely, vCJD

Marker	Sn	Sp	LR+	LR–
14-3-3	88% (82-93)	72% (69-75)	3.1 (2.8-3.6)	0.16 (0.1-0.26)
Tau >976*	91% (84-95)	88% (85-90)	7.4 (6.9-7.8)	0.1 (0.06-0.2)
Tau >1300**	84% (76-90)	92% (90-94)	10.9 (8.5-13.9)	0.17 (0.11-0.26)
S100B >2.5*	87% (80-92)	87% (84-91)	6.6 (6.1-7.1)	0.15 (0.09-0.2)
S100B >4.2**	52% (42-61)	97% (95-98)	15.3 (10.2-23.1)	0.5 (0.42-0.6)
Tau + S100B*			18 (12.9-25)	0.02 (0.01-0.09)
Tau + S100B + 14-3-3**			18.6 (13.1-26.3)	0.03 (0.01-0.1)

MRI is the most useful neuroimaging modality, especially with DWI
- Increased T2 FLAIR signals in striatum
- One sign is the "pulvinar sign"
CT only useful for exclusion of other causes

EEG can have characteristic abnormalities and should be routinely done
- Bilaterally synchronic periodic sharp wave complexes, but can be transient, and can also be absent at the start and towards the end
Histopathology of brain tissue biopsy or autopsy is still the gold standard
- Neuronal loss, vacuolation of the neuropil, spongiform changes

Risk of transmission
- High (>50%): brain, dura mater, spinal cord, and eye
- Low (10-20%, though no reported human cases): CSF, lymph nodes, kidneys, lung, and spleen
- None (0%): all other tissues
Standard precautions when caring for patients; no need for additional PPE
Equipment in disinfection and sterilization
- Types of equipment
  - Critical (surgical equipment)
  - Semicritical (endoscopes etc. that contact mucous membranes)
  - Noncritical (cuffs, floors, walls, etc)
- High-risk tissue exposure on a critical instrument in a high-risk patient (known or suspected CJD)
  - Autoclav for 121-132ºC for 60 minutes (gravity) or 134ºC for ≥18 min (prevacuum)
  - May be combined with sodium hydroxide, if the instrument can handle it
  - Instruments should be kept moist until they are cleaned
  - Items that cannot undergo this procedure should be discarded
- Other tissue exposures, or semicritical instrument, or not high-risk patient
  - Follow usual decontamination procedures
No extra precautions needed for burial

Progressive dementia, and
EEG atypical or not known, and
Duration <2 years, and
At least two of the following four clinical features:
- Myoclonus
- Visual or cerebellar disturbance
- Pyramidal/extrapyramidal dysfunction
- Akinetic mutism

Progressive dementia, and
At least two of the following four clinical features:
- Myoclonus
- A typical EEG, whatever the clinical duration of the disease, and/or
- A positive 14-3-3 assay for CSF, and
- A clinical duration to death < years

Neuropathologic confirmation, and/or
Confirmation of protease-resistant prion protein (immunocytochemistry or Western blot) and/or
The presence of scrapie-associated fibrils

I: Presentation
- A. Progressive neuropsychiatric disorder
- B. Duration of illness >6 months
- C. Routine investigations do not suggest an alternative diagnosis
- D. No history of potential iatrogenic exposure
- E. No evidence of a familial form of transmissible spongiform encephalopathy
II: Symptoms
- A. Early psychitric symptoms
- B. Persistent painful sensory symptoms
- C. Ataxia
- D. Myoclonus or chorea or dystonia
- E. Dementia
III: Investigations
- A. EEG does not chow the typical appearance of sCJD, or no EEG performed
- B. MRI brain scan shows bilateral symmetrical pulvinar high signal
IV: Pathology
- A. Positive tonsil biopsy

Definite: I.A and neuropathologic confirmation of vCJD

Probable: I and 4/5 of II and III.A and III.B, or I and IV.A

Possible: I and 4/5 of II and III.A