Creutzfeldt-Jakob [CJ] disease

Introduction

Creutzfeldt-Jakob [CJ] disease is a subacute spongiform encephalopathy & a rare form of a dementia associated with protease-resistant isoform(s) of prion protein.

Etiology

• protease-resistant isoform(s) of prion protein
• iatrogenic transmission has occurred by:
  • corneal transplants
  • EEG depth electrodes
  • cadaveric dural grafts
  • growth & gonadotropic hormones from cadaveric pituitary glands
  • blood transfusions
• transmission from consumption of cattle
  • bovine spongiform encephalopathy (mad cow disease) produces a variant of CJD disease
• no known risk factors
• male/female ratio ~1 (49/51)
• familial form (see genetics)

Epidemiology

• uncommon disorder: incidence is 0.5-1.5/million
  • incidence 2007-2020 is 1.5-1.6/million
• most common human prion disease
• peak incidence of CJ occurs between 50-75 years of age
  • new variant form occurs in younger patients (mean age 29)
• 90% of cases are sporadic & 10% are familial
• iatrogenic cases are rare
• no seasonal distribution

Pathology

(also see scrapie)

• precipitation of PrPSc in brain, see prion protein
• PrPSc found in:
  • brain (100%)
  • spleen (36%)
  • skeletal muscle (25%)
  • tears
• brain biopsy typically shows characteristic neuropathologic features of spongiform encephalopathy
  • neuronal loss & astrogliosis
  • spongiform change in cortex
  • signs of inflammation are absent

Genetics

• 10-15% have family history consistent with autosomal dominant mode of inheritance
• 20 different mutations in prion protein have been described
• polymorphisms at codon 129 (Met/Met Met/Val Val/Val) of the prion protein may influence disease susceptibility
  • most CJ patients have the Met/Met form
  • all new-variant CJD patients have the Met/Met form

Clinical manifestations

• presentation of dementia & prominent neurologic signs
• rapidly progressive mental deterioration (100%)
  • occurs over a period of weeks to months
  • death within 1 year
  • dementia
    • compromise of activities of daily living
  • confusion
  • behavioral & psychiatric disturbances predominate dominate in variant CJD
    • bizarre behavior & hallucinations may occur
    • social withdrawal
    • emotional blunting
    • anhedonia
  • diorientation, inattention, inhibition
• disturbances of gait, vision & balance
• cerebellar ataxia (> 50%, 100% in new-variant form)
• myoclonic jerks (> 80%); startle myoclonus (late)
• cortical blindness (> 20%)
• abnormal extraocular movements (> 20%)
  • horizonal gaze nystagmus
• pyramidal tract signs (> 50%)
• extrapyramidal signs (> 50%)
• vestibular dysfunction (< 20%)
• seizures (< 20%)
• sensory deficits (< 20%)
  • persistent painful sensory symptoms in variant form
• cranial nerve abnormalities uncommon
• autonomic abnormalities (< 20%)

* frequency of sign/symptoms in parentheses [from ref 6]

Laboratory

• CSF:
  • normal CSF exmamination
  • CSF 14-3-3, CSF tau, CSF S100b, CSF NSE in combination of some use
    • CSF 14-3-3 of no benefit; insufficiently sensitive or specific
    • CSF 14-3-3 sensitivity ~92%, specificity ~80% for CJD
  • CSF cystatin-C in CSF may be of use
  • report of ability to detect small amounts of PRPSc in CSF (83% sensitivity, 100% specificity)
  • CSF real time quaking-induced conversion assay is the most sensitive & specific test for prion proteins in CSF
• misfolded prion protein is detectable in tear fluid
• brain biopsy sometimes necessary to establish diagnosis
  • immunoblots or prepared sections stain for pathologic protease-resistant isoform of prion protein
  • PRNP gene mutation
    • sequence analysis of the prion gene (PRNP) shows mutations in familial, but not sporadic or iatrogenic cases

Diagnostic procedures

• distinct periodic EEG
  • bilateral synchronous repetitive sharp waves
    • pseudo-periodic sharp-wave complexes
    • frontally predominant bi/triphasic waves
    • lateralizing epileptiform discharges
  • slow background
  • sensitivity of 67%, specificity of 86%
  • new-variant form does not show characteristic EEG changes

Radiology

• neuroimaging: CT & MRI may show atrophy
  • hyperintensities on diffusion-weighted MRI
    • cortical ribboning
    • increased T2 signal in basal ganglia associated with shorter survival
    • case involving basal ganglia & insular cortex

* MRI images

Differential diagnosis

• bismuth subsalicylate toxicity (EEG distinguishes)
• 7% misdiagnosis of treatable cause
  • see causes of dementia

Management

• invariably fatal
  • majority of patients die within 6 months
  • 96% die within 2 years
• brain material may transmit disease to laboratory animals
• brain material is extremely resistant to disinfection
  • disinfect contaminated tissue with formic acid
• quinacrine & chlorpromazine may have some activity
  • quinacrine 300 mg/day does not improve 2-month survival of patients with CJD
• doxycycline no better than placebo
• immunotherapy with antibodies that block binding of PrPSc to PrPc may be useful in the future
• prevention:
  • absorption to specific resins may prevent transmission through blood transfusion

More general terms

• transmissible spongiform encephalopathy (prion disease)

More specific terms

• variant Creutzfeldt-Jakob disease (vCJD)

Additional terms

• bovine spongiform encephalopathy; mad cow disease; BSE
• CD230 or major prion protein (PrP)
• scrapie
• WHO diagnostic criteria for Creutzfeldt-Jakob disease (CJD)

Patient information

Creutzfeldt-Jakob disease patient information

Database

• OMIM: https://mirror.omim.org/entry/123400