Creutzfeldt-Jakob disease

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

Differential Diagnosis

• Alzheimer dementia
• Vascular dementia
• Frontotemporal dementia
• Dementia with Lewy bodies
• Parkinson disease
• Cerebral lymphoma
• Paraneoplastic syndrome
• Psychiatric disorders
• Huntington disease
• Hashimoto encephalitis

Pathophysiology

• 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^

Syndromes

Sporadic CJD (sCJD)

• 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

Genetic CJD (gCJD)

• 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

Gerstmann-Straüssler-Scheinker Syndrome (GSS)

• Prominent early ataxia and corticospinal tract degeneration
• Dementia is a late feature
• Lasts for 3 months to 13 years

Fatal Familial Insomnia (FFI)

• 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

Variant CJD (vCJD)

• 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

Iatrogenic CJD (iCJD)

• 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

Diagnosis

CSF

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)

• Optimal cutoffs based on a Canadian study ** Standard threshold

• CSF itself usually bland, non-inflammatory

Imaging

• 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

Other

• 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

Management

• Supportive care
• Pentosan polysulfate may prolong life by weeks

Disinfection Practices

• 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

Case Definitions

Sporadic CJD

Possible

• 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

Probable

• 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

Definite

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

Variant CJD

• 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