Creutzfeldt-Jakob disease

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Creutzfeldt-Jakob disease
ICD-10	A81.0, F02.1
ICD-9	046.1
OMIM	123400
DiseasesDB	3166
MeSH	D007562

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

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.

Epidemiology and Demographics

Classic CJD has been recognized since the early 1920s. The most common form of classic CJD is believed to occur sporadically, caused by the spontaneous transformation of normal prion proteins into abnormal prions.

• This sporadic disease occurs worldwide, including the United States, at a rate of approximately one case per 1 million population per year, although rates of up to two cases per million are not unusual.
• The risk of CJD increases with age, and in persons aged over 50 years of age, the annual rate is approximately 3.4 cases per million.
• In recent years, the United States has reported fewer than 300 cases of CJD a year.

Whereas the majority of cases of CJD (about 85%) occur as sporadic disease, a smaller proportion of patients (5-15%) develop CJD because of inherited mutations of the prion protein gene. These inherited forms include Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia.

CJD deaths and age-adjusted death rate, USA, 1979-2004

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.

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 2006, its biological function is unknown. The other conformational state is very poorly water-soluble and readily forms protein aggregates.

People can also acquire CJD genetically through a mutation of a gene (needs to be defined). 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, death within a few months, although a few patients have been known to live as long as two years.

Stanley B. Prusiner 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 transmitted through cannibalism in Papua New Guinea when relatives would eat their dead relative's bodies 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.

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.

Clinical and Pathologic Characteristics of Classic CJD

Classic CJD characteristics, as compared to variant CJD, are presented in the table below.

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), and scrapie in sheep.

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 2006, its biological function is unknown. The other conformational state is very poorly water-soluble and readily forms protein aggregates.

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. 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, death within a few months, although a few patients have been known to live as long as two years.

Stanley B. Prusiner was awarded the Nobel Prize in physiology or medicine in 1997 for his discovery of prions. Yale University neuropathologist Laura Manuelidis has challenged this explanation for the disease. In January 2007 she and her colleagues published a study in the Proceedings of the National Academy of Science asserting that they have found a virus responsible for the diseases.

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.

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

As of 2007, there is 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.

Transmission

The defective protein can be transmitted by human growth hormone (hGH) products, 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.

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.

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.

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 Blooddonors 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.

History

The disease was first described by two German neurologists, Hans Gerhard Creutzfeldt and Alfons Maria Jakob. 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 disorder.