triphasic

Creutzfeldt-Jakob disease

[kroits-felt yah-kawp]

Creutzfeldt-Jakob disease (CJD) is a very rare and incurable degenerative neurological disorder (brain disease) that is ultimately fatal. Among the types of transmissible spongiform encephalopathy found in humans, it is the most common.

History

The disease was first described by German neurologists, Hans Gerhard Creutzfeldt and Alfons Maria Jakob, in 1921. Some of the clinical findings described in their first papers do not match current criteria for Creutzfeldt-Jakob disease, and it is considered highly likely that at least two of the patients in initial studies were suffering from a different ailment.

Causes

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) 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.

Incidence and prevalence

Although CJD is the most common human prion disease, it is still rare and only occurs in about one out of every one million people. 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:

CJD occurs worldwide at a rate of about 1 case per million population per year.
On the basis of mortality surveillance from 1979 to 1994, the annual incidence of CJD remained stable at approximately 1 case per million persons in the United States.
In the United States, CJD deaths among persons younger than 30 years of age are extremely rare (fewer than 5 deaths per billion per year.)
The disease is found most frequently in patients 55–65 years of age, but cases can occur in persons older than 90 years and younger than 55 years of age.
In more than 85% of cases, the duration of CJD is less than 1 year (median: 4 months) after onset of symptoms.

New concerns on incidence and prevalence

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.

Symptoms

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 a typical 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.

Diagnosis

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

Electroencephalography — often has characteristic triphasic spikes
Cerebrospinal fluid analysis for 14-3-3 protein
MRI of the brain — often shows high signal intensity in the caudate nucleus and putamen bilaterally on T2-weighted images.

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, even is 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)," PrP^Sc, 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.

Clinical and Pathologic Characteristics:

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

An abnormal signal in the posterior thalami on T2- and diffusion-weighted images and fluid-attenuated inversion recovery sequences on brain magnetic resonance imaging (MRI); in the appropriate clinical context, this signal is highly specific for vCJD. (Source: CDC)

Treatment

There is currently no cure for CJD, a fatal disease, and the search for viable treatments 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 that 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.

Transmission

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. 10 to 15% 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 were not affected, the women and children ate the brain and contracted the disease from infected brain 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 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.

Blood donor restrictions

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 and 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.

On May 28, 2002, the United States Food and Drug Administration instituted a policy that excludes from donation anyone who spent at least 6 months in certain Western European countries, (or 3 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 5 years or more of civilian travel in Western European countries (6 months or more if military). The 3-month restriction on travel to the UK, however, has not been changed.

The American Red Cross' policy is as follows: Since January 1, 1980-December 31, 1996 spending a total time of 3 months or more in Channel Islands, England, Falkland Islands, Isle of Man, Gibraltar, Northern Ireland, Scotland, and Wales would preclude you from donating. Since January 1, 1980 to present, spending a total time of 5 years or more in the above countries and countries in Europe. (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.

The Singapore Red Cross precludes potential donors who have spent a cumulative time of three months or more in the United Kingdom between 1980 and 1996.

In New Zealand anyone who lived in the UK, France or the Republic of Ireland for a total of six months or more between 1980 and 1996 is permanently deferred from donating blood in New Zealand

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 Jan. 1, 1980 to Dec. 31, 1996. In 2000, the same policy was applied to people who have resided in France, for at least three months from Jan. 1980 to Dec. 1996. Canada will not accept blood from a person who has spent more than 6 months in a Western European country since January 1, 1980.

The Association of Blood Donors of Denmark precludes potential donors who have spent a cumulative time of at least twelve months in the United Kingdom between 1 January 1980 and 31 December 1996.

The Swiss Blutspendedienst SRK precludes potential donors who have spent a cumulative time of at least six months in the United Kingdom between 1 January 1980 and 31 December 1996.

Sperm donor restrictions

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 e.g. Scandinavian sperm. The risk, however, is insignificant, since artificial insemination is very different from the route of transmission of mad cow disease. The prevalence of mad cow disease is one in a million, probably less for donors. If prevalence was the case, the infectious proteins would then have to cross the blood-testis barrier and the sperm would have to be swallowed orally to make transmission possible.

Cultural references

George Balanchine, the esteemed choreographer, was found to have traces of Creutzfeldt-Jakob disease in his brain after his death. Indeed, his final years showed evidence of related symptoms.

The disease was also featured in an episode of the X-Files, Our Town, in which a group of cannibals eat the whole body (brain and all) of their fellow humans in order to stay young forever. They contract the disease from one of their victims, and it passes through the whole town, killing them.

During the fourth season of the TV series House, in episode four (Guardian Angels (House)), House's job applicants suspect the patient of having contracted CJD after doing cosmetic work on a cadaver with similar symptoms at a funeral parlour. To test the diagnosis the team dig up the grave and carry out a brain biopsy, which is negative.

The lead character in the BBC TV series "Bodies", Rob Lake (Max Beesley) begins to exhibit symptoms consistent with vCJD during the series finale. The episode closes with the character sitting down with a consultant colleague who specialises in neurology to hear his test results - but these are not revealed to the viewer.

A character in an episode of the TV series Bones is discovered to have CJD and is also a cannibal due to insanity; the characters make a point that they may never know which came first, he could have contracted the disease because of his cannibalism, or he could be a cannibal because the CJD has caused him to lose his mind; Since he worked with corpses, it is conceivable that he could have accidentally gotten infected blood or bone dust in his mouth, causing temporarily mild insanity which lead him to cannibalism, thus causing the CJD.