Creutzfeldt-Jakob Disease (CJD)

Creutzfeldt-Jakob Disease (CJD) is a rare, fatal, rapidly progressive dementia. It affects about 1 in every 1 million people per year worldwide. CJD has a rapid course and usually appears in late life. There is a very short survival time, death usually occurs within one year of symptom onset.

• There are approximately 1 or 2 cases per million people.
• The peak age for the sporadic CJD is 67 years.
  • Individuals with iatrogenic (iCJD) and variant (vCJD) tend to be much younger

• The disease is fatal, and 90% will die within 1 year.^[1][2]
• End-stage sCJD is generally characterized by akinetic mutism.
  • Spasticity and myoclonus become highly prevalent and some patients develop seizures.

Major or mild neurocognitive disorder (NCD) due to prion disease includes the group of subacute spongiform encephalopathies including Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, kuru, Gerstmann-Sträussler-Scheinker syndrome, and fatal familial insomnia.

The most common subtypes of Creutzfeldt-Jakob disease are:

• Sporadic (sCJD), origin not known, but not thought to be acquired (85-95%)
• Genetic (gCJD), mutations of the gene encoding prion protein that area genetically passed on (5-15%)
• Iatrogenic (iCJD), current practices have essentially eliminated this type; previously caused by cadaveric human pituitary hormones, dural graft transplants, corneal graft transplants (<1%)
• Variant (vCJD), a distinct, acquired prion disease, related to a single bovine prion strain responsible for BSE has infected humans to cause vCJD (<1%)

The criteria are met for major or mild neurocognitive disorder.

There is insidious onset, and rapid progression of impairment is common.

There are motor features of prion disease, such as myoclonus or ataxia, or biomarker evidence.

The neurocognitive disorder is not attributable to another medical condition and is not better expiated by another mental disorder.

CJD should always be considered in a patient with the combination of the 2 cardinal clinical features:

1. Rapid, progressive mental deterioration including dementia and behavioural abnormalities. Poor concentration, memory, hypersomnia and insomnia, and poor judgment may be early signs. Psychiatric symptoms including depression, apathy, anxiety, and visual hallucinations^[3] may also occur.
2. Myoclonus and abnormal movements (including ataxia, chorea, or dystonia). A myoclonus provoked by startle reflex is also common. Startle myoclonus is present in almost all patients at some point during the disease course.

• CJD is caused by transmissible agents known as prions. Prions are small, infectious, protein-containing particles (PrPSc) that replicate over a period of time, replacing normal prion proteins (PrPC) and leading to neurotoxicity.
• The most common type is sporadic Creutzfeldt-Jakob disease (sCJD). Variant CJD (vCJD) is much rarer and is associated with transmission of bovine spongiform encephalopathy, also known as “Mad Cow disease.” There is a genetic component in up to 15% of cases of CJD, associated with an autosomal dominant mutation.

• Prion disease is diagnosed with least one of the characteristic biomarker features: cortical ribboning or lesions on magnetic resonance imaging with DWI (diffusion-weighted imaging)^[4] or FLAIR (fluid-attenuated inversion recovery).
• MRI typically shows abnormal hyperintense signal in the putamen and head of the caudate as well.

• Tau or 14-3-3 protein in cerebrospinal fluid can be used to discriminate CJD from other neurodegenerative diseases.^[5]
  • It is important to note that 14-3-3 and tau is a non-specific finding for CJD.
• Real-time quaking-induced conversion (RT-QuIC), also called protein misfolding cyclic amplification (PMCA) is the most sensitive and specific test for diagnosing sporadic CJD.

• Characteristic triphasic waves and periodic sharp-and-slow (discharges) wave complexes can be seen on electroencephalogram.^[6]
  • Periodic sharp wave complexes have high specificity for CJD but low sensitivity (i.e. - even if absent cannot rule out CJD)

• The gold standard diagnosis for CJD is neuropathologic examination (i.e. - brain biopsy)

• Myoclonus is present in >90% of patients at some point, but is often absent at presentation
• Nystagmus and ataxia can occur in up to half of all patients
• Startle myoclonus is present in almost all patients at some point during the disease course.
• Hyperreflexia, upper motor neuron signs such as the Babinski sign, and spasticity may be present
• Extrapyramidal signs including hypokinesia, bradykinesia, dystonia, and rigidity may occur.

• A consideration of other causes of rapidly progressive dementias should be considered (see article above)
• It is important to recognize that EEG has low sensitivity for CJD, and the non-specificity of CSF protein 14-3-3 elevation for CJD as well.
• One study found that up to 25% of cases diagnosed as sporadic CJD were actually other conditions, including: Alzheimer's disease, vascular dementia, frontotemporal lobar degeneration, mesial temporal sclerosis, and diffuse Lewy body dementia.^[7]
  • A non-exhaustive list from this pathological study of disorders misdiagnosed as CJD include: Alzheimer's disease, vascular dementia, dementia with Lewy bodies, frontotemporal degeneration (FTD), Parkinson's disease, corticobasal degeneration, corticostriatonigral degeneration, progressive supranuclear palsy, motor neuron disease, Huntington disease, hereditary ataxia, familial spastic paraplegia, encephalitis - undiagnosed, Hashimoto encephalopathy, immune-mediated or paraneoplastic encephalopathy, vasculitis, brain tumour, metastatic encephalopathy, primary CNS lymphoma, chronic epilepsy, multiple sclerosis, leukoencephalopathy, metabolic disorder, alcohol-induced atrophy, psychiatric disorders, and unclassified dementia.^[8]