History and exam
Key diagnostic factors
common
cognitive impairment
Cognitive problems are the most common first symptom in sporadic Creutzfeldt-Jakob disease (sCJD). Impairment is usually mild in variant CJD (vCJD). Dementia may occur in vCJD or genetic CJD; however, usually appears later in the course of the disease.[11][71]
Memory loss and difficulty with executive functioning (e.g., organising, planning, and multitasking) typically precede cerebellar and other motor and behavioural symptoms.
limb and/or gait ataxia
myoclonus
Highly suggestive of the diagnosis of sCJD, but can occur later in the disease.
May also exacerbate existing pain conditions such as osteoarthritis.
parkinsonism
Parkinsonism can occur in patients with sCJD.
May be the presenting sign of genetic CJD.
psychiatric symptoms
visual changes
May include diplopia, hallucinations, and other visual distortions.[72]
uncommon
insomnia, dysautonomia
Fatal familial insomnia typically presents as a syndrome of insomnia and dysautonomia.[75]
positive family history
About 60% of patients with prion disease that is found to be genetic were not known to have family history of prion disease. Further inspection will often find family history of Alzheimer's or Parkinson's disease cases that were likely misdiagnosed.[22]
Gathering a detailed family history, including ages and causes of death, is important. Some family members may have carried a prion protein gene (PRNP) mutation, but died from other causes prior to the onset of Creutzfeldt-Jakob disease symptoms.
non-specific or constitutional symptoms
Vertigo, headaches, and dizziness may precede the disease by weeks or even months.[73]
Other diagnostic factors
Risk factors
strong
genetic predisposition
Genetic prion diseases are caused by a mutation in the gene encoding the endogenous prion protein (PRNP) located on chromosome 20.[6] To date more than 40 different PRNP mutations have been identified, each presenting with its own disease phenotype (i.e., Gerstmann-Straussler-Scheinker, fatal familial insomnia, and familial Creutzfeldt-Jakob disease). PRNP mutations are transmitted in an autosomal dominant manner and most have 100% penetrance, but rare cases of CJD have occurred in association with PRNP polymorphisms that may be incidental, not causal.[6][7]
Onset and clinical manifestations of all forms of prion disease are often strongly influenced by the polymorphic codon 129 of PRNP and the prion type (type 1 or 2). Codon 129 can be either methionine (M) or valine (V). Homozygotic combinations (e.g., MM or VV) result in higher risk for developing prion disease.
prion-contaminated surgical instruments
Iatrogenic transmission of prion disease can occur by several means. First, the affected patient may not be properly diagnosed, leading to the omission of Creutzfeldt-Jakob disease (CJD) precautions during highly infectious medical procedures (e.g., corneal transplant, dura mater graft, deep brain electrodes). Second, prions are very resistant to common sterilising practices. When prion proteins undergo conformational changes, the resulting prions become resistant to proteases and heat, and insoluble to denaturing agents.[1][49]
When other patients are then exposed to these prion-contaminated medical instruments, they can become inadvertently infected. Fortunately, the incidence of CJD is low, placing patients at low risk for contracting iatrogenic CJD from such procedures.
There have also been two cases of vCJD acquired by researchers through lab-based exposure to BSE.[50]
transfusion of blood or blood products (variant Creutzfeldt-Jakob disease)
To date there have been five cases of prion disease transmitted via the transfusion of blood (or blood products), two of whom died from other causes before developing symptoms of prion disease, but in whom PrPSc was found in the spleen. All five involved the variant form of Creutzfeldt-Jakob disease (vCJD).[10][29][30][31][51]
In efforts to prevent future incidences, all blood centres in the US and Canada previously included prion-related screening questions prior to donation and prohibited blood donation from at-risk people until recently. Given the lack of new vCJD cases since 2016, prior blood transfusion restrictions for donors living in the UK in the 1980s have now been lifted and the risk of contracting vCJD from blood products is now considered near zero.
There is no convincing evidence for blood transmission of prion disease subtypes other than vCJD.[32][33][52]
consumption of UK beef from 1980 to 1996
Strong only for variant Creutzfeldt-Jakob disease (vCJD).
Bovine spongiform encephalopathy (BSE), also known as mad cow disease, is a form of prion disease affecting cattle. This condition gained additional attention when it was discovered that BSE could be transmitted to humans by consumption of beef, causing a new human form of prion disease called vCJD. Consumption of BSE has led to 230 vCJD cases in 12 countries, the vast majority of which occurred in the UK.[53]
weak
consumption of US beef
The risk of acquiring prion disease from consumption of BSE in the US is unknown, but is believed to be very low. Most cattle in the US are not tested, however, so the extent of BSE that might be entering the food supply is not known, but thought to be quite remote. As of August 2018, only 6 BSE-affected cattle have been identified in the US (1 of which was born in Canada) and 20 in Canada (1 of which was imported from the UK in 1993). The last case detected in Canada was in 2015. In the US, there was 1 new case in 2017 and 1 in 2018, with the last case before that in 2012, with the last 5 cases being atypical BSE, not the typical type of BSE associated with causing variant Creutzfeldt-Jakob disease (vCJD).[54][55] Efforts have been put in place in Canada, and to a lesser extent in the US, to reduce the risk of BSE from occurring.[12][28][56]
Efforts to intercept the process of BSE transmission in the US include screening a percentage of bovine for prion pathogen (PrPSc) in their brain tissue, eliminating mammalian protein from cattle feed, and banning the importation of beef from Europe.[49]
deer, elk, moose hunting in endemic regions of US and Canada
Chronic wasting disease (CWD) is a prion disease afflicting North American deer, moose, and elk. It has also been found in South Korea, Norway, Finland, and Sweden. The epidemic core of CWD is Wyoming, Colorado, and Nebraska, but a total of 34 US states and five Canadian provinces are now affected.
Intraspecies transmission occurs horizontally, and animals follow a similar decline to that seen in other species, including a rapid regression of cognitive and motor function.[57] No cases of cervid-to-human transmission of prion disease have been reported, although experimental transmission to squirrel monkeys has occurred.[58]
Although the impact of CWD on wildlife and human safety remains under investigation, hunting activity confers a low risk for acquiring prion disease, although hunters are encouraged to have heads tested for CWD and advised not to consume animals proven to be affected by CWD.[59][60][61]
use of human growth hormone
Over 150 cases of iatrogenic Creutzfeldt-Jakob disease (iCJD) transmission have been documented in patients who received human growth hormone (GH).
The two largest series of reported GH contamination occurred in the US and in France. Investigations have traced some of the contamination back to the 1980s when the main source of GH was still the National Hormone and Pituitary Program in the US.
Prior to 1977, the protocol being used to extract pituitary tissues from cadavers lacked a vital purification step, which led to the contamination of pooled GH and consequentially to the infection of patients using those products. The programme was discontinued and stricter policies were developed in the manufacturing of GH.[62]
The risk of transmission for iCJD through the use of GH has been greatly reduced by the availability of recombinant GH. The risk of infection from receiving contaminated GH today is considered nil.[8]
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