Prion diseases are a group of closely related neurodegenerative conditions in mammals, in which a prior protein (PrP) forms abnormal conformations and aggregates. These are para-infectious agents which can be transmitted between hosts.

Epidemiology

Rare: 1-2 cases per million annually.
Acquired (1) sporadically (90%), (2) genetically, or (3) infectiously (very rare, less than 1% of cases)
Presents in late-middle or late life, with a peak incidence in the 8th decade of life. Can be younger (teens), and genetic forms tend to present the most in the 60's.
Two human outbreaks of prion disease
- Kuru - epidemic in tribes in New Guinea, due to ritualistic cannibalism
- Variant CJD - due to eating meat from infected cattle with bovine spongiform encephalopathy, "Mad Cow Disease". Arose in Great Britain in 1994. Incredibly rare - only 228 documented cases.
Scrapie in sheep, and chronic wasting disease in elk are endemic but not known to pass to humans
Iatrogenic spread:
- Blood and blood products from donors with variant CJD
- Sporadic CJD has not been transmitted through blood products
- Possible through contaminated surgical instruments, corneal transplants
Genetic causes are due to specific mutations in the PRNP gene

Pathobiology

PrP is a cell surface glycoprotein normally produced in the brain and other tissues. In prion diseases, an abnormally folded PrP named PRP(Sc) accumulates and recruits the normal PrP into more PrP(Sc) which forms beta-sheet aggregates in the brain.

The mechanism by which PrP aggregates cause neuronal dysfunction and death is unknown.

Enterally spread PrP: prions replicate in the enteric lymphatics, then spread to the CNS via sympathetic nerves in the lymphatic tissue. Once in the CNS, prions spread trans-synaptically.

Clinical Manifestations

Sporadic CJD (the most common prion disease in humans)
1. Prodrome of psychiatric disturbances is present in 25% of patients: anxiety, depression, altered sleep
2. Cognitive dysfunction
3. Motor signs (ataxia, bradykinesia, spasticity), myoclonus is characteristic
4. Vague somatic sensory disturbances
5. The decrements of neurologic degeneration occurs over the span of weeks.
6. Variants in the typical presentation occur:
  1. Gertmann-Straussler-Scheinker syndrome: prominent ataxia with slower decline.
  2. Fatal familial insomnia: anxiety and depression and sleep disturbance followed by ataxia and motor signs
Variant CJD: much younger mean age at onset (26 years age) with more prominent psychiatric and sensory signs early in the disease, followed by a later emergence of dementia and motor signs.
Iatrogenic CJD: resembles sporadic CJD, can overlap with the presentation of Gertmann-Straussler-Scheinker syndrome.
Variable protease encephalopathy: presents similarly to frontal lobe dementia

Diagnosis of Prion Disease

Consider prion disease for any patient with rapidly worsening cognitive impairment or Dementia. This generally will involve CSF Analysis (via LP) and neuroimaging (MR, EEG).

The RT-QuIC PrP amplification assay works by assuming the presence of PrP(Sc) acts as a "seed" and propagates in the presence of catalysts and PrP. This reaction is detected and quantified, and has an exceptionally high specificity and sensitivity.

Assay/Test	Interpretation and Utility
CSF RT-QuIC amplification assay	Specificity >99%
CSF 14-3-3 and tau	complements the prion amplification assays
MRI T2 FLAIR and DWI basal ganglia and thalamic hyperintensity	2/3 of CJD cases
EEG	periodic large-amplitude triphasic complexes
Biochemical and histologic examination of brain tissue	Biopsy or autopsy, the definitive diagnostic method

CDC Diagnostic Criteria for Sporadic CJD

Definite: Diagnosed by standard neuropathological techniques; and/or immunocytochemically; and/or Western blot confirmed protease-resistant PrP; and /or presence of scrapie-associated fibrils.
Probable:
1. Neuropsychiatric disorder plus positive RT-QuIC in cerebrospinal fluid (CSF) or other tissues, OR
2. Rapidly progressive dementia; and at least two out of the following four clinical features:
  1. Myoclonus
  2. Visual or cerebellar signs
  3. Pyramidal/extrapyramidal signs
  4. Akinetic mutism
3. AND a positive result on at least one of the following:
  1. typical EEG (periodic sharp wave complexes) during an illness of any duration
  2. positive 14-3-3 CSF assay with a disease duration <2 years
  3. High signal in caudate/putamen on magnetic resonance imaging (MRI) brain scan or at least two cortical regions (temporal, parietal, occipital) either on diffusion-weighted imaging (DWI) or fluid attenuated inversion recovery (FLAIR)
4. AND without routine investigations indicating an alternative diagnosis

Treatment

These diseases are universally incurable. No treatment improves the course of disease. The majority of patients with sporadic CJD die within a year of diagnosis after progressing to a state of akinetic mutism.

References

Goldman-Cecil Medicine, Ch 387 Prion Diseases
Zerr, Inga. “Laboratory Diagnosis of Creutzfeldt–Jakob Disease.” New England Journal of Medicine 386, no. 14 (April 7, 2022): 1345–50. https://doi.org/10.1056/NEJMra2119323.
Diagnostic Criteria | Creutzfeldt-Jakob Disease, Classic (CJD) | Prion Disease | CDC