II. Epidemiology

  1. Incidence of Sporadic CJD: Less than one case per million
    1. Sporadic Jakob-Creutzfeldt Disease is the most common Prion Disease
  2. Age of onset: Mean 68 (range: 55-75 years old)

III. Causes: Human CJD

  1. See Prion Disease for Cow vCJD (Bovine Spongiform Encephalopathy, Mad Cow Disease)
  2. Sporadic Creutzfeldt-Jakob Disease (>80% of U.S. cases, all Sporadic CJD)
    1. By far, the most common form of Creutzfeldt-Jakob Disease (and the presentation reviewed on this page)
  3. Genetic Creutzfeldt-Jakob Disease (10-15% of U.S. cases)
    1. Most cases are familial and represented by 20 different mutations in prion-related Protein gene (PRNP)
      1. Most common PRNP Mutation is E200K (Sephardic Jews in Libya and Tunisia, Slovokians)
    2. Presents as rapidly progressive Dementia and Ataxia with onset ages 30 to 55 years old
    3. MRI Findings are similar to that seen in Sporadic Creutzfeldt-Jakob Disease
  4. Acquired (rare, <1% of U.S. CJD cases)
    1. Iatrogenic Creutzfeldt-Jakob Disease Causes
      1. Growth Hormone injections
      2. Corneal grafts
      3. Dural grafts
      4. Neurosurgical equipment
      5. Blood Transfusion (from donor infected with Variant Jakob-Creutzfeldt Disease)
    2. Variant Creutzfeldt-Jakob Disease (vCJD)
      1. Transmission from animals to humans (typically Bovine Spongiform Encephalopathy or BSE)
      2. Peak in UK BSE cases (1988-2005) followed by tens of thousands of UK cases (1994-2009)
        1. Since 2012, vCJD cases have been rare
        2. https://en.wikipedia.org/wiki/United_Kingdom_BSE_outbreak
      3. Onset in much younger cohort than in Sporadic CJD (mean age onset 27 years old)
      4. Almost all cases are due to Homozygous PRNP Mutation (Methionine at codon 129)
      5. Unlike other CJD forms, Prion Protein (PrP-Sc) is also found in lymphoreticular tissue (in addition to CNS)
      6. Presentation
        1. Initial psychiatric prodrome alone for 6 months
        2. Cgnitive disorder
        3. Cerebellar dysfunction and Movement Disorder (e.g. Myoclonus, Chorea)
      7. Diagnostics
        1. EEG, CSF and CSF biomarkers are typically non-diagnostic
          1. EEG will often show non-specific slowing
        2. MRI DWI shows thalamic hyperintensity with pulvinar sign positive in 75% of cases
          1. Pulvinar sign is bilateral hyperintensity of medial and posterior Thalamus
          2. Appears as "double hockey stick sign"
          3. Zeider (2000) Lancet 355:1412 [PubMed]

IV. Pathophysiology: Sporadic CJD

  1. See Prion Disease
  2. Classification of Sporadic CJD is based on 2 factors
    1. Prion gene polymorphism (PRNP) at codon 129 with Methionine (M) or Valine (V)
    2. Prion Protein Size (Type 1 - 21 kDa, Type 2 - 19 kDa)
  3. Presentations of Sporadic CJD vary based on classification (may have more than one variant)
    1. Rapidly progression Dementia with Myoclonus and variable Ataxia (40% of cases): MM1, MV1
    2. Rapidly progressive Ataxia (15% of cases): VV2
    3. Slower progression of Ataxia or Dementia (8% of cases): MV2
    4. Sporadic Fatal Familial Insomnia: MM2-Thalamic

V. Symptoms: Sporadic CJD

  1. Constitutional (early prodromal in one third of patients)
    1. Fatigue
    2. Headache
    3. Malaise
    4. Vertigo
    5. Altered nutritional intake and Unexplained Weight Loss
    6. Altered sleep
  2. Behavioral Changes (early finding in 20-30% or patients)
    1. Agitation and irritability (36% of cases)
    2. Depressed Mood
    3. Anger or agression
    4. Apathy
    5. Personality Change
  3. Memory Loss (40% of patients)
  4. Sensory Changes (9% of patients)
    1. Paresthesias
    2. Pain
  5. Executive Function Disturbance (early finding in 15%, present in 50% of patients overall)
    1. Aphasia
    2. Apraxia
    3. Neglect
    4. Acalculia

VI. Signs: Sporadic CJD

  1. Rapidly progressive Dementia
  2. Ataxia (esp. gait disturbance, and other cerebellar signs)
  3. Myoclonus
  4. Tremor
  5. Extrapyramidal signs
  6. Visual loss, disturbance or oculomotor defects such as Diplopia (7%)

VII. Labs: Sporadic CJD

  1. Brain Biopsy
    1. Amyloidosis
    2. Gliosis
    3. Nerve Cell Loss
    4. Vacuolation (Spongiform change)
    5. Prion Protein - Scrapie (PrP-Sc) deposition
  2. Immunohistochemistry or Western Blot
    1. Protease Resistant Prion Protein - Scrapie (PrP-Sc)
  3. CSF
    1. Typically normal (although CSF Protein may be mildly increased)
    2. CSF biomarkers (14-3-3, D100B, NSE, t-tau) have variable efficacy

VIII. Diagnostics: Sporadic CJD

  1. EEG (later findings)
    1. Slow wave background
    2. High voltage spikes at 1-2 Hz (may be biphasic or triphasic)

IX. Imaging: Sporadic CJD

  1. Brain MRI (diffusion weighted or DWI)
    1. Cortical or deep nuclei gray matter with restricted diffusion
      1. High Test Sensitivity (92-96%) and high Test Specificity (93-94%)
    2. Abnormal Hyperintensity (FLAIR imaging)
      1. Cortical gyri
      2. Caudate
      3. Putamen
      4. Thalamus

X. Resources

XI. Prognosis: Sporadic CJD

  1. Rapidly progressive neurogenerative condition with short-term mortality approaching 100%
  2. Mean survival: 6 months (90% mortality within 1 year)

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