Prion Diseases of the Central Nervous System

Prions cause rare but relentlessly progressive and rapidly fatal neurodegenerative diseases characterized by dementia and ataxia. The cause of disease is an abnormally folded prion protein. In humans, prion diseases occur by three mechanisms: sporadic (spontaneous), familial (genetic), and acquired (infectious or transmissible). In patients of any age presenting with otherwise unexplained rapidly progressive dementia and ataxia, diagnosis of a prion disease should be considered (Table 5); the infectious forms are now rare (Table 6). Prion diseases have no known therapy.

Sporadic Creutzfeldt-Jakob Disease

  • Question 86

Spontaneous (sporadic) disease is the most common form of Creutzfeldt-Jakob disease (CJD), with an incidence of 1 per million worldwide. No environmental risk factors are known. Clinical manifestations include rapidly progressive dementia, usually over 4 to 6 months. Ataxia, myoclonus, and pyramidal and extrapyramidal signs may be observed. Loss of vision is not uncommon, and patients become comatose before dying. The diagnosis can be made by clinical history and MRI; a cerebrospinal fluid analysis positive for either total Tau or 14-3-3 protein may also be useful.

Transmissible Prion Diseases

Variant CJD (vCJD) is the human form of bovine spongiform encephalopathy. It generally affects younger persons (age 15-50 years), frequently presenting with rapidly progressive neuropsychiatric manifestations (depression, withdrawal) and peripheral neuropathy, followed by cerebellar ataxia, involuntary movements, and cognitive decline over a 12-month period. Because vCJD can be transmitted through blood products and tissue, it is a serious public health concern worldwide. Probable vCJD is diagnosed by typical MRI findings (“hockey stick sign” in the posterior thalamus) and tonsil biopsy to detect scrapie-associated prion protein in a patient with a compatible clinical presentation (see Table 5).

Iatrogenic CJD is exceedingly rare, but transmission has been documented with contaminated cadaveric pituitary-derived human growth hormone and gonadotropin, dura mater, stereotactic electroencephalography needles, neurosurgical instruments, corneal transplants, medical instruments, implanted electroencephalography electrodes, and blood transfusions.

Familial Prion Disease

Many mutations have been associated with the prion protein gene. All are autosomally dominant. These include the gradually progressive Gerstmann-Sträussler-Scheinker syndrome and the rapidly progressive fatal familial insomnia.

Key Points

  • Prion disease should be included in the differential diagnosis of a patient of any age presenting with otherwise unexplained rapidly progressive dementia and ataxia.
  • Spontaneous Creutzfeldt-Jakob disease is the most common form of prion disease and has no known risk factors.