• Clinical science

Creutzfeldt-Jakob disease

Abstract

Creutzfeldt-Jakob disease (CJD) is a neurodegenerative condition that is caused by misfolded protein particles (prions). Prion diseases are very rare overall. CJD is the most common prion disease in humans. In most cases, no direct cause of CJD can be established. However, there are also familial forms due to gene mutation or acquired forms as prion particles can be transmitted between individuals, making CJD an infectious disease. Accumulation of prion particles in the brain eventually leads to neuronal degeneration and clinical onset of the disease. The cardinal symptoms of CJD are rapidly progressive dementia and myoclonus. Most patients die within 12 months following disease manifestation. Imaging, EEG, and cerebrospinal fluid (CSF) tests provide diagnostic evidence, although a definite diagnosis can only be made via biopsy or autopsy. To date, no curative treatment is available.

Epidemiology

  • CJD is the most common prion disease in humans.
  • Sporadic form:
    • Mean age of onset: ∼ 60 years (incubation period usually 20–30 years)
    • Incidence: ∼ 1:1.000.000

References:[1][2][3]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

CJD is divided into three different types:

References:[4][1][5][6][7]

Pathophysiology

  • CJD is caused by “infectiousprions (PrPSc) that are usually produced endogenously but may also be acquired (see “Etiology”).
  • PrPSc → conformational change of physiological PrPc formation of condensation centers + PrPSc accumulationplaque formation; neuronal cell death progression to spongiform encephalopathy (seen as intracytoplasmic vacuoles within the neurons of cerebral and cerebellar cortex on H&E)

References:[6][8][9][10]

Clinical features

  • Latency period varies greatly, but ∼ 10 years is common and ≥ 30 years has been recorded
  • Prodromal symptoms (nonspecific): e.g., sleep disorders, headaches, fatigue
  • Rapidly progressing dementia
  • Other neuropsychiatric symptoms: e.g., visual hallucinations, depression
  • Myoclonus: can often be triggered by startling (e.g., loud noises)
  • Seizures
  • Cerebellar disturbances (e.g., gait instability) and extrapyramidal deficits
  • Akinetic mutism
  • Autonomic problems (e.g., sweating)

Rapidly progressive dementia and myoclonic jerks are the hallmarks of Creutzfeldt-Jakob disease!

References:[1][11][12]

Diagnostics

Instrumental diagnostics

  • CSF analysis: neuron‑specific enolase, S100 protein, tau protein, 14-3-3 protein
  • Imaging: MRI
  • EEG: triphasic periodic sharp‑wave complexes
  • Brain biopsy: Diagnosis can only be confirmed by biopsy/autopsy and subsequent neuropathological examination.

Diagnostic criteria (according to the World Health Organization)

WHO have defined a set of criteria for the diagnosis of CJD.

  1. Progressive dementia
  2. Two or more of the following symptoms:
    • Myoclonus (quick, involuntary muscle contractions)
    • Cerebellar or visual disturbances
    • Pyramidal or extrapyramidal symptoms
    • Akinetic mutism
  3. One or both of the following findings:
    • Triphasic periodic sharp-wave complexes on electroencephalogram (EEG) → regardless of clinical duration of the disease
    • Detection of 14-3-3 protein in CSF + clinical duration leading to death in less than 2 years
  4. Routine diagnostics do not provide evidence of an alternate cause

References:[1][13]

Differential diagnoses

Other diseases commonly associated with the development of dementia:

The differential diagnoses listed here are not exhaustive.

Treatment

  • No curative therapy available
  • Symptomatic treatment and eventually palliative care

Following disease manifestation, most patients die within 12 months, usually from complications such as pneumonia!

References:[1]