|Classification and external resources|
Tonsil biopsy in variant CJD. Prion Protein immunostaining.
Creutzfeldt–Jakob disease or CJD (pronounced /ˈkrɔɪtsfɛlt ˈjɑkɔp/) (sometimes incorrectly referred to as mad cow disease) is a degenerative neurological disorder (brain disease) that is incurable and invariably fatal. It is the most common among the types of transmissible spongiform encephalopathy found in humans.
The disease was first described by German neurologist Hans Gerhard Creutzfeldt in 1920 and shortly afterwards by Alfons Maria Jakob, giving it the name Creutzfeldt–Jakob. Some of the clinical findings described in their first papers do not match current criteria for Creutzfeldt–Jakob disease, and it has been speculated that at least two of the patients in initial studies were suffering from a different ailment.
Transmissible spongiform encephalopathy diseases are caused by prions. The diseases are thus sometimes called prion diseases. Other prion diseases include Gerstmann–Sträussler–Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru in humans, as well as bovine spongiform encephalopathy (BSE, commonly known as mad cow disease) in cattle, chronic wasting disease (CWD) in elk and deer, and scrapie in sheep. Alpers' syndrome in infants is also thought to be a transmissible spongiform encephalopathy caused by a prion.
The prion that is believed to cause Creutzfeldt–Jakob exhibits at least two stable conformations. One, the native state, is water-soluble and present in healthy cells. As of 2007, its biological function is presumably in transmembrane transport or signaling. The other conformational state is very poorly water-soluble and readily forms protein aggregates.
People can also acquire CJD genetically through a mutation of the gene that codes for the prion protein (PRNP). This only occurs in 5–10% of all CJD cases.
The CJD prion is dangerous because it promotes refolding of native proteins into the diseased state. The number of misfolded protein molecules will increase exponentially, and the process leads to a large quantity of insoluble prions in affected cells. This mass of misfolded proteins disrupts cell function and causes cell death. Mutations in the gene for the prion protein can cause a misfolding of the dominantly alpha helical regions into beta pleated sheets. This change in conformation disables the ability of the protein to undergo digestion. Once the prion is transmitted, the defective proteins invade the brain and are produced in a self-sustaining feedback loop, causing exponential spread of the prion, leading to death within a few months, although a few patients have lived as long as two years.
Stanley B. Prusiner of University of California, San Francisco (UCSF) was awarded the Nobel Prize in physiology or medicine in 1997 for his discovery of prions. For more than a decade, Yale University neuropathologist Laura Manuelidis has been challenging this explanation for the disease. In January 2007 she and her colleagues published an article in the Proceedings of the National Academy of Science and reported that they have found a virus-like particle (but without finding nucleic acids so far) in less than 10% of the cells a scrapie-infected cell line and in a mouse cell line infected by a human CJD agent.
Although CJD is the most common human prion disease, it is still rare, occurring in about one out of every one million people every year. It usually affects people aged 45–75, most commonly appearing in people between the ages of 60–65. The exception to this is the more recently-recognised 'variant' CJD (vCJD), which occurs in younger people.
CDC monitors the occurrence of CJD in the United States through periodic reviews of national mortality data. According to the CDC:
In The Lancet (June 2006), a University College London team suggested that it may take more than 50 years for vCJD to develop, from their studies of kuru, a similar disease in Papua New Guinea. The reasoning behind the claim is that kuru was possibly transmitted through cannibalism in Papua New Guinea when family members would eat the body of a dead relative as a sign of mourning. In the 1950s, the practice was banned, thereby preventing any further possible transmission. In the late 20th century, however, kuru reached epidemic proportions in certain Papua New Guinean communities, therefore suggesting that vCJD may also have a similar incubation period of 30 to 50 years. A critique to this theory is that while mortuary cannibalism was banned in Papua New Guinea in the 1950s, that does not necessarily mean that the practice ended. Fifteen years later Jared Diamond was informed by Papuans that the practice continued. There is dispute as to whether the Fore ever practiced cannibalism, due to the fact that nobody ever observed them and that Kuru could have passed to the Fore through the preparing of the dead body for burial.
These researchers noticed a genetic variation in some kuru patients that has been known to promote long incubation periods. They have also proposed that individuals who contracted CJD in the early 1990s represent a distinct genetic subpopulation, with unusually short incubation periods for BSE. This means that there may be many more vCJD patients who have longer incubation periods, which may surface many years later.
In 1997 a number of Kentuckians contracted the disease. It was discovered that all the victims had a penchant for squirrel brains. See: http://www.guardian.co.uk/uk/2008/aug/03/bse.medicalresearch for recent concerns.
The first symptom of CJD is rapidly progressive dementia, leading to memory loss, personality changes and hallucinations. This is accompanied by physical problems such as speech impairment, jerky movements (myoclonus), balance and coordination dysfunction (ataxia), changes in gait, rigid posture, and seizures. The duration of the disease varies greatly, but sporadic (non-inherited) CJD can be fatal within months or even weeks (Johnson, 1998). In some people, the symptoms can continue for years. In most patients, these symptoms are followed by involuntary movements and the appearance of an atypical diagnostic electroencephalogram tracing.
The symptoms of CJD are caused by the progressive death of the brain's nerve cells, which is associated with the build-up of abnormal prion proteins. When brain tissue from a CJD patient is examined under a microscope, many tiny holes can be seen where whole areas of nerve cells have died. The word "spongiform" in "transmissible spongiform encephalopathies" refers to the "spongy" appearance of the brain tissue.
The diagnosis of CJD is suspected when there are typical clinical symptoms and signs such as rapidly progressing dementia with myoclonus. Further investigation can then be performed to support the diagnosis including
Diffusion Weighted Imaging (DWI) images are the most sensitive. In about 24% of cases DWI shows only cortical hyperintensity; in 68%, cortical and subcortical abnormalities; and in 5%, only subcortical anomalies. The involvement of the thalamus can be found in sCJD, is even stronger and constant in vCJD.
Clinical testing for CJD has always been an issue. Diagnosis has mostly been based on clinical and physical examination of symptoms. In recent years, studies have shown that the tumour marker Neuron-specific enolase (NSE) is often elevated in CJD cases.
In one third of patients with sporadic CJD, deposits of "prion protein (scrapie)," PrPSc, can be found in the skeletal muscle and/or the spleen. Diagnosis of vCJD can be supported by biopsy of the tonsils, which harbour significant amounts of PrPSc; however, biopsy of brain tissue is the definitive diagnostic test.
|Characteristic||Classic CJD||Variant CJD|
|Median age at death||68 years||28 years|
|Median duration of illness||4–5 months||13–14 months|
|Clinical signs and symptoms||Dementia; early neurologic signs||Prominent psychiatric/behavioral symptoms; painful dysesthesias;
delayed neurologic signs
|Periodic sharp waves on electroencephalogram||Often present||Often absent|
|Signal hyperintensity in the caudate nucleus and putamen on diffusion-weighted and FLAIR MRI||Often present||Often absent|
|"Pulvinar sign" on MRI||Not reported||Present in >75% of cases|
|Immunohistochemical analysis of brain tissue||Variable accumulation.||Marked accumulation of protease-resistant prion protein|
|Presence of agent in lymphoid tissue||Not readily detected||Readily detected|
|Increased glycoform ratio on immunoblot analysis of
protease-resistant prion protein
|Not reported||Marked accumulation of protease-resistant prion protein|
|Presence of amyloid plaques in brain tissue||May be present||May be present|
As of 2010 no generally accepted treatment for CJD exists; the disease is invariably fatal and research continues. An experimental treatment was given to a Northern Irish teenager, Jonathan Simms, beginning in January 2003. The medication, called pentosan polysulphate (PPS) and used to treat interstitial cystitis, is infused into the patient's lateral ventricle within the brain. PPS does not seem to stop the disease from progressing, and both brain function and tissue continue to be lost. However, the treatment is alleged to slow the progression of the otherwise untreatable disease, and may have contributed to the longer than expected survival of the seven patients who were studied. The CJD Therapy Advisory Group to the UK Health Departments advises that data are not sufficient to support claims that pentosan polysulphate is an effective treatment and suggests that further research in animal models is appropriate. A 2007 review of the treatment of 26 patients with PPS finds no proof of efficacy because of the lack of accepted objective criteria.
Scientists have investigated using RNA interference to slow the progression of scrapie in mice. The RNA blocks production of the protein that the CJD process transforms into prions. This research is unlikely to lead to a human therapy for many years.
Both amphotericin B and doxorubicin have been investigated as potentially effective against CJD, but as yet there is no strong evidence that either drug is effective. Further study has been taken with other medical drugs, but none are effective.
Dr. Michael Geschwind, Dr. Bruce Miller and Dr. Stanley Prusiner from University of California, San Francisco are currently running a treatment trial for sporadic CJD using quinacrine, a medicine originally created for malaria. Pilot studies showed quinacrine permanently cleared abnormal prion proteins from cell cultures, but results have not yet been published on the clinical study.
The defective protein can be transmitted by human growth hormone (hGH) products, Immunoglobulins (IVIG), corneal grafts, dural grafts or electrode implants (acquired or iatrogenic form: iCJD); it can be inherited (hereditary or familial form: fCJD); or it may appear for the first time in the patient (sporadic form: sCJD). In the hereditary form, a mutation occurs in the gene for PrP, PRNP. Ten to fifteen percent of CJD cases are inherited. (CDC)
The disease has also been shown to result from usage of HGH drawn from the pituitary glands of cadavers who died from Creutzfeldt–Jakob Disease, though the known incidence of this cause is (as of April 2004) quite small. The risk of infection through cadaveric HGH usage in the US only ceased when the medication was withdrawn in 1985.
It is thought that humans can contract the disease by consuming material from animals infected with the bovine form of the disease. The only suspected cases to arise thus far have been vCJD, although there are fears — based on animal studies — that consuming beef or beef products containing prion particles can also cause the development of classic CJD. When BSE material infects humans the resulting disease is known as (new) variant CJD Disease (nvCJD).
Cannibalism has also been implicated as a transmission mechanism for abnormal prions, causing the disease known as kuru, found primarily among women and children of the Fore tribe in Papua New Guinea. While the men of the tribe ate the body of the deceased and rarely contracted the disease, the women and children, who ate the less desirable body parts, were 8 times more likely to contract the disease from infected tissue.
Prions, the infectious agent of CJD, may not be inactivated by means of routine surgical instrument sterilization procedures. The World Health Organization and the US Centers for Disease Control and Prevention recommend that instrumentation used in such cases be immediately destroyed after use; secondary to destruction, it is recommended that heat and chemical decontamination be used in combination to process instruments that come in contact with high-infectivity tissues. No cases of iatrogenic transmission of CJD have been reported subsequent to the adoption of current sterilization procedures, or since 1976. Copper–hydrogen peroxide has been suggested as an alternative to the current recommendation of sodium hydroxide or sodium hypochlorite. Thermal depolymerization also destroys prions in infected organic and inorganic matter, since the process dissolves protein at the molecular level.
In 2004 a new report published in the Lancet medical journal showed that vCJD can be transmitted by blood transfusions. The finding alarmed healthcare officials because a large epidemic of the disease might arise in the near future. There is no test to determine if a blood donor is infected during in the latent phase of vCJD. In reaction to this report, the British government banned anyone who had received a blood transfusion since January 1980 from donating blood. From 1999 there was a ban in the UK for using UK blood to manufacture factional products such as albumin.
On May 28, 2002, the United States Food and Drug Administration instituted a policy that excludes from donation anyone who spent at least six months in certain Western European countries, (or three months in the United Kingdom), from 1980 to 1996. Given the large number of U.S. military personnel and their dependents residing in Europe, it was expected that over 7% of donors would be deferred due to the policy. Later changes to this policy have relaxed the restriction to a cumulative total of five years or more of civilian travel in Western European countries (six months or more if military). The three-month restriction on travel to the UK, however, has not been changed.
The American Red Cross's policy is as follows: During the period January 1, 1980 to December 31, 1996, spending a total time of three months or more in the Channel Islands, England, the Falkland Islands, the Isle of Man, Gibraltar, Northern Ireland, Scotland, and Wales precludes individuals from donating. Since January 1, 1980 to present, spending a total time of five years or more in the above countries and countries in Europe. People with a biologic relative who has been diagnosed with CJD or vCJD are unable to donate. Biologic relative in this setting means mother, father, sibling, grandparent, aunt, uncle or children. (For complete listing, please go to Redcross.org)
A similar policy applies to potential donors to the Australian Red Cross' Blood Service, precluding people who have spent a cumulative time of six months or more in the United Kingdom between 1980 and 1996.
In New Zealand anyone who has lived in the UK, France or the Republic of Ireland for a total of six months or more between 1980 and 1996 is prohibited from donating blood.
Similar regulations are in place in Germany, where anyone who has spent six months or more living in the UK between January 1980 and December 1996 is permanently barred from donating blood.
As of 1999, Health Canada announced a policy to defer individuals from donating blood if they have lived within the United Kingdom for one month or more from January 1, 1980 to December 31, 1996. In 2000, the same policy was applied to people who have resided in France, for at least three months from January 1980 to December 1996. Canada will not accept blood from a person who has spent more than six months in a Western European country since January 1, 1980.
In the U.S., the FDA has banned import of any donor sperm, motivated by a risk of Creutzfeldt–Jakob disease, inhibiting the once popular import of, for example, Scandinavian sperm. The risk, however, is not known, since artificial insemination has not been studied as a route of transmission. It is also not known whether prions cross the blood–testis barrier.
The disease was featured in an episode of The X-Files, "Our Town", in which a group of cannibals eat the entire body (including the brain) of their fellow humans in order to stay young forever. They contract the disease from one of their victims, and it passes through a part of the town, killing 28.
In Law & Order: Criminal Intent: "Dramma Giocoso" in season 5 episode 16, original air date 4/9/06—a young violinist is pushed to her death at the opera house, and Detectives Logan and Barek focus on the arrogant conductor until they receive jarring medical news that violinist's mother, a famous opera star in love with the conductor, has Creutzfeldt–Jakob disease CJD, which changes everything about the case catapulting her to the position of prime suspect in the murder.
During the fourth season of the TV series House, in episode four "Guardian Angels", House's job applicants suspect the patient of having contracted CJD after doing cosmetic work on a cadaver with similar symptoms at a funeral parlor. To test the diagnosis, the team digs up the grave and carry out a brain biopsy, which is negative. In the end she is revealed to have ergotism.
The disease also appeared in a third season episode of Veronica Mars entitled "Mars, Bars." A basketball coach with the disease is found murdered. The protagonist of Libba Bray's novel Going Bovine is diagnosed with Creutzfeldt–Jakob disease.