Transmissible Spongiform Encephalopathies

Transmissible spongiform encephalopathies are diseases caused by prions. Prions differ from viruses in that they are small, infectious pathogens that do not contain nucleic acid. Recognized spongiform encephalopathies include Creutzfeldt-Jakob Disease (CJD), variant Creutzfeldt-Jakob Disease (vCJD), Kuru, fatal familial insomnia (FFI), and Gerstmann-Straussler syndrome (GSS). Common characteristics of these diseases include dementia, ataxia, and myoclonus. Unfortunately, these diseases are associated with long incubation periods (20+ years) and once symptoms occur, rapidly progress to death.

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Epidemiology and Etiology

Epidemiology

Spongiform encephalopathies are extremely rare.

Known human diseases:

  • Creutzfeldt-Jakob Disease (CJD)
  • Kuru
  • Fatal familial insomnia (FFI)
  • Gerstmann-Straussler syndrome (GSS) (incidence: 1 per 100 million new cases per year)

The most common spongiform encephalopathy is Creutzfeldt-Jakob disease. The variations are:

  1. Sporadic Creutzfeldt-Jakob disease (sCJD):
    • Incidence: 1 per 1,000,000 cases per year (90% of cases)
    • Mean age of onset is 62 years of age
  2. Variant Creutzfeldt-Jakob disease (vCJD) and iatrogenic Creutzfeldt-Jakob disease (iCJD): younger age of onset (not clearly defined)
  3. Genetic Creutzfeldt-Jakob disease (gCJD): clusters exist in North Africa, Israel, and Italy

Etiology

High-risk factors are:

  • Cannibalism (Kuru)
  • Family history of gCJD, GSS, or FFI

Pathophysiology

Prion diseases occur when a normal, ⍺-helical protein known as PrPc is converted into an abnormal, β-pleated protein known as PrPsc. 

  • Can be thought of as a “protein-misfolding” disease
  • Abnormal PrPsc is resistant to protease degradation, which facilitates conversion of PrPc into abnormal PrPsc. This constant conversion slowly replaces normal proteins.
  • PrPsc accumulates in lymphoreticular and secretory organs
    • Spreads to the central nervous system (CNS) → astrocytosis → loss of neurons → vacuolation of the brain 
    • This process causes the classic symptoms of spongiform encephalopathy:
      • Cerebellar ataxia
      • Dementia
      • Death

Transmission

There are 3 primary ways of developing spongiform encephalopathies:

  1. Acquired or infectious: 
    • Direct exposure to CNS-infected tissues, such as in a corneal transplant (iCJD)
    • Administration of cadaveric human pituitary hormones (iCJD)
    • Ingestion of food contaminated by bovine spongiform encephalopathy (BSE)-infected (“mad cow”) animal products (vCJD)
    • Cannibalism of CNS-infected tissues (Kuru)
  2. Genetics:
    • Mutation from parental PrPc into abnormal PrPsc (gCJD, FFI, GSS)
  3. Spontaneous: 
    • Sudden misfolding of PrPc into abnormal PrPsc (sCJD)
Mad cow disease transmission

Origins of prion diseases

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Clinical Presentation and Diagnosis

Transmissible spongiform encephalopathies are associated with extremely long incubation times (20–50 years) and once symptoms appear, the disease rapidly progresses to death.

No curative measures exist and the diseases are universally fatal.

SymptomsDiagnosis
Creutzfeldt-Jakob disease
  • Rapidly progressive dementia (over weeks to months)
  • Startle myoclonus
  • Ataxia
  • Death within 1 year of symptom onset
  • Head CT/MRI (magnetic resonance imaging): normal appearance
  • Cerebrospinal fluid (CSF): ↑ in 14-3-3 protein
  • Electroencephalogram (EEG): periodic sharp wave complexes
  • Post-mortem brain biopsy:
    • Intracytoplasmic vacuoles in the spongiform cortex
    • Accumulation of PrPsc on histopathology
    • Neuronal loss
Kuru
  • First stage: tremors (shivering), ataxia, postural instability
  • Second stage: loss of ambulation, myoclonus
  • Late stage: dementia
  • Death within 1 year of symptom onset
Unknown; few studies have been performed due to limited cases (mostly isolated to Papua New Guinea in the 1950s)
Fatal familial insomniaIn patients aged 23–73:
  • Progressive insomnia
  • Loss of normal circadian sleep-activity pattern
  • Myoclonus
  • Ataxia
  • Dysautonomia
  • Death within 1 year of symptom onset
Unclear; post-mortem brain biopsy
Gerstmann-Straussler-Scheinker syndromeIn patients mid-to-late 40s:
  • Progressive cerebellar degeneration (clumsiness, incoordination, ataxia)
  • Dementia
  • Death within 5 years of symptom onset
Post-mortem brain biopsy

Differential Diagnosis

Differential diagnosis includes diseases that are associated with rapidly progressing dementia, including the following:

  • Dementia with Lewy bodies:
    • Can be rapidly progressing
    • Associated with dementia, visual hallucinations, and syncope
    • Histologic findings: intracellular Lewy bodies (⍺-synuclein)
  • Frontotemporal dementia (Pick’s disease):
    • Associated with early changes in personality and behavior that progress to parkinsonism-like movement
    • MRI: frontotemporal lobe degeneration
  • Vascular dementia:
    • Generally stepwise decline in neurological function with late-onset memory impairment
    • MRI: multiple cortical infarctions
  • Alzheimer’s disease:
    • Most common cause of dementia in the elderly
    • Symptoms often develop gradually
    • MRI: cortical and hippocampal atrophy

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