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Prion diseases are progressive, fatal, and untreatable degenerative brain disorders. They include Creutzfeldt-Jakob disease (CJD, the prototypic example), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal insomnia (FI), variant CJD (vCJD), and kuru. Prion diseases usually occur sporadically, with a worldwide annual incidence of about 1/1 million.
Prion diseases result from misfolding of a normal brain protein called prion protein (PrP), whose exact function is unknown. Misfolded prion proteins (or prions) induce previously normal PrP to misfold and are markedly resistant to degeneration (similar to β-amyloid, which they resemble), resulting in slow but inexorable proliferation. Gradual accumulation of prions causes gliosis and characteristic histologic vacuolar (spongiform) changes, resulting in dementia and other neurologic deficits. Symptoms and signs develop months to years after exposure.
Prion diseases can be caused by spontaneous or hereditary defects of the PrP gene, contained in the short arm of chromosome 20. Some defects cause familial CJD, some GSS, and others FI. Small abnormalities in particular codons may determine the predominant symptoms and rate of disease progression.
Prion diseases can also be transmitted by infected tissue. Cannibalism caused the spread of kuru in New Guinea, and prions can be transmitted via organ transplants. Prion diseases can be transmitted between species via the food chain (eg, in vCJD). Prion diseases occur in mink, elk, deer, domestic sheep and cattle, and other mammals. In several Western US states and Canada, chronic wasting disease of elk and deer, a prion disease, is a concern; whether this disease can be transmitted to people who hunt, butcher, or eat affected animals is unknown.
Prion diseases should be considered in all patients with dementia. Treatment of prion diseases is symptomatic. Prions resist standard disinfection techniques and pose risks to surgeons, pathologists, and technicians who handle contaminated tissues and instruments.
Creutzfeldt-Jakob
Disease (CJD)
Creutzfeldt-Jakob
disease is a sporadic or familial prion disease. Bovine spongiform
encephalopathy (mad cow disease) is a variant form. Symptoms include
dementia, myoclonus, and other CNS deficits; death occurs in 1 to
2 yr. Transmission can be prevented by taking precautions when handling
infected tissues and using bleach to clean contaminated instruments.
Treatment is supportive.
CJD typically affects people > 40 yr (median, about 60 yr). It occurs worldwide; incidence is higher among Northern African Jews. Most cases are sporadic, but 5 to 15% are familial, with autosomal dominant transmission. In the familial form, age at onset is earlier and duration of disease is longer. CJD can be transmitted iatrogenically (eg, after cadaveric corneal or dural transplants, use of stereotactic intracerebral electrodes, or use of growth hormone prepared from human pituitary glands).
vCJD is most common in the United Kingdom (UK). In the early 1980s, because of relaxed regulations for processing animal by-products, tissue from sheep infected with scrapie, a prion disease, was introduced into cattle feed. Thousands of cattle developed bovine spongiform encephalopathy (BSE), called mad cow disease. Some people who ate meat from affected cattle developed vCJD.
Because the incubation period in BSE is long, a connection between BSE and contaminated feed was not recognized in the UK until BSE had become an epidemic, which was controlled by massive slaughter of cattle. In the UK, the annual number of cases of vCJD between 2000 and 2002 has ranged from 17 to 28. Whether incidence is decreasing is unclear. Although vCJD has been restricted to the UK and Europe thus far, BSE has been reported in North American cattle.
Symptoms,
Signs, and Prognosis
About 70% of patients present with memory loss and confusion, which eventually occur in all patients; 15 to 20% present with incoordination and ataxia, which often develop early in the disease. Myoclonus provoked by noise or other sensory stimuli (startle myoclonus) often develops in the middle to late stages of disease. Although dementia, ataxia, and myoclonus are most characteristic, other neurologic abnormalities (eg, hallucinations, seizures, neuropathy, various movement disorders) can occur. Ocular disturbances (eg, visual field defects, diplopia, dimness or blurring of vision, visual agnosia) are common. Death typically occurs after 6 to 12 mo, commonly due to pneumonia. vCJD develops at a younger average age than in sporadic CJD, and life expectancy is longer (averaging 1.5 yr).
Diagnosis
and Prevention
CJD should be considered in elderly patients with rapidly progressive dementia, especially if accompanied by myoclonus or ataxia; however, CNS vasculitis, hyperthyroidism, and bismuth intoxication must be excluded. vCJD is considered in younger patients who have ingested processed beef in the UK; Wilson's disease should be excluded.
Diagnosis may be difficult. MRI may show cerebral atrophy. Diffusion-weighted MRI may show basal ganglia and cortical abnormalities. CSF is typically normal, but characteristic 14-3-3 protein is often detected. EEG may show characteristic periodic sharp waves. Brain biopsy is usually unnecessary.
Workers handling fluids and tissues from patients suspected of having CJD must wear gloves and avoid mucous membrane exposure. Contaminated skin can be disinfected by 5 to 10 min of exposure to 4% Na hydroxide, followed by extensive washing with water. Steam autoclaving of materials at 132° C for 1 h or immersion in 4% Na hydroxide or 10% Na hypochlorite solution for 1 h is recommended. Standard methods of sterilization (eg, exposure to formalin) are ineffective.
Gerstmann-Sträussler-Scheinker
Disease
GSS
disease is an autosomal dominant prion brain disease that begins
in middle age.
GSS occurs worldwide and is similar to but about 100-fold less common than CJD. It develops at an earlier age (40 vs 60 yr), and average life expectancy is longer (5 yr vs 6 mo).
Patients have cerebellar dysfunction with unsteady gait, dysarthria, and nystagmus. Gaze palsies, deafness, dementia, parkinsonism, hyporeflexia, and extensor plantar responses are also common. Myoclonus is much less common than in CJD. GSS disease should be considered in patients with characteristic symptoms and signs and a family history, particularly if they are ≤ 45 yr. Genetic testing can confirm the diagnosis.
Fatal Insomnia
Fatal
insomnia is a typically hereditary prion disorder causing difficulty
sleeping, motor dysfunction, and death.
FI, a very rare disease, usually results from an autosomal dominant mutation, but several sporadic cases have been identified. Average age at onset is 40 yr (ranging from the late 30s to the early 60s).
Common early symptoms include difficulty falling asleep and intermittent motor dysfunction (eg, myoclonus, spastic paresis). This stage can last for months but eventually progresses to severe insomnia, myoclonus, sympathetic hyperactivity (eg, hypertension, tachycardia, hyperthermia, sweating), and dementia. Death occurs in an average of 13 mo.
FI should be considered in patients with motor dysfunction, sleep disturbances, and a family history. Genetic testing can confirm the diagnosis.
Last full review/revision November 2005
Content last modified November 2005
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