Creutzfeldt-Jakob Disease

Definition

Creutzfeldt-Jakob disease (CJD) is a transmissible, rapidly progressing, neurodegenerative disorder called a spongiform degeneration related to "mad cow disease."

Description

Before 1995, Creutzfeldt-Jakob disease was not well known outside the medical profession. Even within it, many practitioners did not know much about it. Most doctors had never seen a case. With the recognition of a so-called "new variant" form of CJD and the strong possibility that those with it became infected simply by eating contaminated beef, CJD has become one of the most talked-about diseases in the world. Additionally, the radical theory that the infectious agent is a normal protein that has been changed in its form also has sparked much interest.

First described in the early twentieth century independently by Creutzfeldt and Jakob, CJD is a neurodegenerative disease causing a rapidly progressing dementia ending in death, usually within eight months of symptom onset. It also is a very rare disease, affecting only about one in every million people throughout the world. In the United States, CJD is thought to affect about 250 people each year. CJD affects adults primarily between ages 50 and 75.

Spongiform encephalopathies

The most obvious pathologic feature of CJD is the formation of numerous fluid-filled spaces in the brain (vacuoles) resulting in a sponge-like appearance. CJD is one of several human "spongiform encephalopathies," diseases that produce this characteristic change in brain tissue. Others are kuru; Gerstmann-Straussler-Scheinker disease, a genetic disorder predominantly characterized by cerebellar ataxia (a kind of movement disorder); and fatal familial insomnia, with symptoms of progressive sleeplessness, weakness, and dysfunction of the nervous system that affects voluntary and involuntary movements and functions.

Kuru was prevalent among the Fore people in Papua, New Guinea, and spread from infected individuals after their deaths through the practice of ritual cannibalism, in which the relatives of the dead person honored him by consuming his organs, including the brain. Discovery of the infectious nature of kuru won the Nobel Prize for Carleton Gadjusek in 1976. The incubation period for kuru was between four to 30 years or more. While kuru has virtually disappeared since these cannibalistic practices stopped, several new cases continue to arise each year.

Cases of CJD have been grouped into three types: familial, iatrogenic, and sporadic.

• Familial CJD, representing 5-15% of cases, is inherited in an autosomal dominant manner, meaning that either parent may pass along the disease to a child, who then may develop CJD later in life.
• Iatrogenic CJD occurs when a person is infected during a medical procedure, such as organ donation, blood transfusion, or brain surgery. The rise in organ donation has increased this route of transmission; grafts of infected corneas and dura mater (the tissue covering the brain) have been shown to transmit CJD. Another source is hormones concentrated from the pituitary glands of cadavers, some of whom carried CJD, for use in people with growth hormone deficiencies. Iatrogenic infection from exposure to nerve-containing tissue represents a small fraction of all cases. The incubation period after exposure to the infectious agent is very long and is estimated to be from less than 10 to more than 30 years. It remains unlikely, but not impossible, that blood from patients with CJD is infectious to others by transfusion.
• Sporadic CJD represents at least 85% of all cases. Sporadic cases have no identifiable source of infection. Death usually follows first symptoms within eight months.

Animal forms and "mad cow disease"

Six forms of spongiform encephalopathies are known to occur in other mammals: scrapie in sheep, recognized for more than 200 years; chronic wasting disease in elk and mule deer in Wyoming and Colorado; transmissible mink encephalopathy; exotic ungulate encephalopathy in some types of zoo animals; feline spongiform encephalopathy in domestic cats; and bovine spongiform encephalopathy (BSE) in cows.

BSE was first recognized in Britain in 1986. Besides the spongiform changes in the brain, BSE causes dementia-like behavioral changes—hence the name "mad cow disease." BSE was thought to be an altered form of scrapie, transmitted to cows when they were fed sheep offal (slaughterhouse waste) as part of their feed, but researchers believe it is a primary cattle disease spread by contaminated feed.

The use of slaughterhouse offal in animal feed has been common in many countries and has been practiced for at least 50 years. The trigger for the BSE epidemic in Great Britain seems to have come in the early 1980s, when the use of organic solvents for preparation of offal was altered there. It is possible that these solvents had been destroying the agent called a prion, thereby preventing infection, and that the change in preparation procedure opened the way for the agent to "jump species" and cause BSE in cows that consumed scrapie-infected meal. The slaughter of infected (but not yet visibly sick) cows at the end of their useful farm lives, and the use of their carcasses for feed, spread the infection rapidly and widely. For at least a year after BSE was first recognized in British herds, infected bovine remains continued to be incorporated into feed, spreading the disease still further. Although milk from infected cows never has been shown to pass the infectious agent, passage from infected mother to calf may have occurred through unknown means. Researchers also have tried to confirm how to stop infection of the human food chain once the disease spread among cows. In 2003, a study reported that it spread through nervous system tissue in processed meat and that proper temperature and pressure controls could help ensure safety of commercial beef.

Beginning in 1988, the British government took steps to stop the spread of BSE, banning the use of bovine offal in feed and other products and ordering the slaughter of infected cows. By then, the slow-acting agent had become epidemic in British herds. In 1992, it was diagnosed in more than 25,000 animals (1% of the British herd). By mid-1997, the cumulative number of BSE cases in the United Kingdom had risen to more than 170,000. The feeding ban stemmed the tide of the epidemic; however, the number of new cases each week fell from a peak of 1,000 in 1993 to less than 300 two years later.

The export of British feed and beef to member countries was banned by the European Union, but cases of BSE had developed in Europe by then as well; however, by mid-1997, only about 1,000 cases had been identified. In 1989, the United States banned import of British beef and began monitoring United States herds in 1990. In December 2003, the first and only case (as of late March 2004) of BSE was discovered in the United States. This prompted recommendations of new safeguards to prevent further spread. Among these were regulations banning animal blood in cattle feed.

Variant CJD: The human equivalent of mad cow disease

From the beginning of the BSE epidemic, scientists and others in Britain feared that BSE might jump species again to infect humans who had consumed infected beef. This, however, had never occurred in scrapie from sheep, a disease known for hundreds of years. In 1996, the first report of this possibility occurred and the fear seemed to be realized with the first cases of a new variant of Creutzfeldt-Jacob disease, termed nvCJD, now just vCJD. Its victims are much younger than the 60-65 year old average for CJD, and the time from symptom onset to death has averaged 12 months or more instead of eight. The disease appears to cause more psychiatric symptoms early on. EEG abnormalities characteristic of CJD are not typically seen in vCJD.

By early 2004, CJD had claimed 143 victims in Great Britain and 10 in other countries. It is of major concern that the number of cases per year seems to be increasing by a factor of 1.35 each year. The only known case in the United States to date had been acquired while the person had been in Great Britain.

Evidence is growing stronger that vCJD is in fact caused by BSE:

• almost all of the cases so far have occurred in Great Britain, the location of the BSE epidemic

• BSE injected into monkeys produces a disease very similar to vCJD
• BSE and vCJD produce the same brain lesions after the same incubation period when injected into laboratory mice
• brain proteins isolated from vCJD victims, but not from the other forms of CJD, share similar molecular characteristics with brain proteins of animals that died from BSE

Researchers now treat the BSE-vCJD connection as solidly established.

Assuming that BSE is the source, the question that has loomed from the beginning has been how many people will eventually be affected. Epidemiological models once placed estimates at tens of thousands, but in 2003, scientists predicted a quicker end to the epidemic and have substantially lowered the numbers expected to contract the disease. The exact incubation period of vCJD in humans is about 10 to 20 years or longer, so it is more difficult to predict the number of cases. Researchers know that some people are more susceptible to vCJD, including young people age 10 to 20 years old.

Causes and symptoms

Causes

It is clear that Creutzfeldt-Jakob disease is caused by an infectious agent, but it is not yet clear what type of agent that is. Originally assumed to be a virus, evidence is accumulating that, instead, CJD is caused by a protein called a prion (PREE-on, for "proteinaceous infectious particle") transmitted from victim to victim. The other spongiform encephalopathies also are hypothesized to be due to prion infection.

If this hypothesis is proven true, it would represent one of the most radical new ideas in biology since the discovery of deoxyribonucleic acid (DNA). All infectious diseases, in fact all life, use nucleic acids—DNA or ribonucleic acid (RNA)—to code the instructions needed for reproduction. Inactivation of the nucleic acids destroys the capacity to reproduce. However, when these same measures are applied to infected tissue from spongiform encephalopathy victims, infectivity is not destroyed. Furthermore, purification of infected tissue to concentrate the infectious fraction yields protein, not nucleic acid. While it remains possible that some highly stable nucleic acid remains hidden within the purified protein, this is seemingly less and less likely as further experiments are done. The "prion hypothesis," as it is called, is now widely accepted, at least provisionally, by most researchers in the field. The most vocal proponent of the hypothesis, Stanley Prusiner, was awarded the Nobel Prize in 1997 for his work in the prion diseases.

A prion is an altered form of a normal brain protein. The normal protein has a helical shape along part of its length. In the prion form, a sheet structure replaces the helix. According to the hypothesis, when the normal form interacts with the prion form, some of its helical part is converted to a sheet, thus creating a new prion capable of transforming other normal forms. In this way, the disease process resembles crystallization more than typical viral infection, in which the virus commands the host's cellular machinery to reproduce more of the virus. Build-up of the sheet form causes accumulation of abnormal protein clumps and degeneration of brain cells, which is thought to cause the disease.

The brain protein affected by the prion, called PrP, is part of the membrane of brain cells, but its exact function is unknown. Exposure to the infectious agent is, of course, still required for disease development. Prion diseases are not contagious in the usual sense, and transmission from an infected person to another person requires direct inoculation of infectious material.

Familial CJD, on the other hand, does not require exposure, but develops through the inheritance of other, more disruptive mutations in the gene for the normal PrP protein. The other two inherited human prion diseases, Gerstmann-Straussler-Scheinker disease and fatal familial insomnia, involve different mutations in the same gene.

The large majority of CJD cases are sporadic, meaning they have no known route of infection or genetic link. Causes of sporadic CJD are likely to be diverse and may include spontaneous genetic mutation, spontaneous protein changes, or unrecognized exposure to infectious agents. It is highly likely that future research will identify more risk factors associated with sporadic CJD.

Symptoms

About one in four people with CJD begin their illness with weakness, changes in sleep patterns, weight loss, or loss of appetite or sexual drive. A person with CJD may first complain of visual disturbances, including double vision, blurry vision, or partial loss of vision. Some visual symptoms are secondary to cortical blindness related to death of nerve cells in the occipital lobe of the brain responsible for vision. This form of visual loss is unusual in that patients may be unaware that they are unable to see. These symptoms may appear weeks to months before the onset of dementia.

The most characteristic symptom of CJD is rapidly progressing dementia, or loss of mental function. Dementia is marked by:

• memory losses
• impaired abstraction and planning
• language and comprehension disturbances
• poor judgment
• disorientation
• decreased attention and increased restlessness
• personality changes and psychosis
• hallucinations

Muscle spasms and jerking movements, called myoclonus, are also a prominent symptom of CJD. Balance and coordination disturbance (ataxia), is common in CJD, and is more pronounced in nvCJD. Stiffness, difficulty moving, and other features representing Parkinson's disease are seen and can progress to akinetic mutism, which is a state of being unable to speak or move.

Diagnosis

CJD is diagnosed by a clinical neurological exam and electroencephalography (EEG), which shows characteristic spikes called triphasic sharp waves. Magnetic resonance imaging (MRI) or computed tomography scans (CT) should be done to exclude other forms of dementia, and in CJD typically shows atrophy or loss of brain tissue. Lumbar puncture, or spinal tap, may be done to rule out other causes of dementia (as cell count, chemical analysis, and other routine tests are normal in CJD) and to identify elevated levels of marker proteins known as 14-3-3. Another marker, neuron-specific enolase, may also be increased in CJD. CJD is conclusively diagnosed after death by brain autopsy. Scientists are investigating whether testing lymphatic tissue such as the tonsil may be an early tool in vCJD diagnosis. Additionally, recent studies have suggested that other blood tests may be useful as well.

Treatment

There is no cure for CJD, and no treatment that slows the progression of the disease. Drug therapy and nursing care are aimed at minimizing psychiatric symptoms and increasing patient comfort. However, the rapid progression of CJD frustrates most attempts at treatment, since decreasing cognitive function and more prominent behavioral symptoms develop so quickly. Despite the generally grim prognosis, a few CJD patients progress more slowly and live longer than the average; for these patients, treatment will be more satisfactory. Scientists are investigating whether some medicines that can "break" the abnormal protein form may be useful and whether a vaccine could help.

Prognosis

Creutzfeldt-Jakob disease has proven invariably fatal, with death following symptom onset by an average of eight months. About 5% of patients live longer than two years. Death from vCJD has averaged approximately 12 months after onset. However, in 2003, clinicians reported improvement in a patient with vCJD who received a new experimental drug called Pentosan.

Prevention

There is no known way to prevent sporadic CJD, by far the most common type. Not everyone who inherits the gene mutation for familial CJD will develop the disease, but at present, there is no known way to predict who will and who will not succumb. The incidence of iatrogenic CJD has fallen with recognition of its sources, the development of better screening techniques for infected tissue, and the use of sterilization techniques for surgical instruments that inactivate prion proteins. Fortunately, scientists are making progress. In 2003, researchers announced that they had uncovered the basis for diagnosing, treating and possibly preventing prion diseases such as vCJD. Their research possibly could lead to a vaccine and immunotherapy drugs.

KEY TERMS

Autosomal dominant inheritance— A pattern of inheritance in which a trait will be expressed if the gene is inherited from either parent.

Encephalopathy— Brain disorder characterized by memory impairment and other symptoms.

Iatrogenic— Caused by a medical procedure.

Nucleic acids— The cellular molecules DNA and RNA that act as coded instructions for the production of proteins and are copied for transmission of inherited traits.

Strategies for prevention of vCJD are a controversial matter, as they involve a significant sector of the agricultural industry and a central feature of the diet in many countries. The infectious potential of contaminated meat is unknown, because the ability to detect prions within meat is limited. Surveillance of North American herds strongly suggests there is no BSE here, and strict regulations on imports of European livestock make future outbreaks highly unlikely. Therefore, avoidance of all meat originating in North America, simply on grounds of BSE risk, is a personal choice unsupported by current data.

Resources

PERIODICALS

Brown, Paul, et al. "Ultra-high Pressure Inactivation of Prion Infectivity in Processed Meat: A Practical Method to Prevent Human Infection." Proceedings of the National Academy of Sciences of the United States May 13, 2003: 6093-6095.

"GP Sees Patient with vCJD Improve." Pulse June 23, 2003: 12.

Kaye, Donald. "FDA Launches New Mad Cow Rules to Protect U.S. Food, Feed." Clinical Infectious Diseases March 15, 2004: 3-5.

"Large Human Mad Cow Epidemic Unlikely—Scientists." Clinical Infectious Diseases April 15, 2003: i.

"Report Appears to Confirm Blood-borne Transmission of Creutzfeldt-Jakob Disease." Blood Weekly January 8, 2004: 28.

"Researchers Discover Possible Diagnosis, Treatment, Vaccine." Immunotherapy Weekly June 25, 2003: 2.

"Scientists Predict Swift End to vCJD Epidemic." British Medical Journal May 24, 2003: 1104-1111.

"U.S. Lawmakers Want Increase in Mad Cow Testing." Healthcare Purchasing News March 2004: 85.

CREUTZFELDT-JAKOB DISEASE

Creutzfeldt-Jakob disease is one of the transmissible spongiform encephalopathies, a family of diseases affecting humans and animals (see Table 1). They are transmissible, in that susceptible animals inoculated with diseased tissue will develop a similar disease; spongiform, in that, under a microscope, small spaces (vacuoles) in brain tissue are invisible, giving the appearance of a sponge; and encephalopathies, in that they affect the brain.

The disease was first reported by Hans Creutzfeldt in 1920 and Alfons Jakob in 1921. A related, exclusively familial disease, Gerstmann-Sträussler-Scheinker syndrome, was reported in 1928. Creutzfeldt-Jakob disease is a dementia characterized by a rapid progression and a multitude of varying cognitive and motor deficits.

The first advance in understanding the diseases occurred with the recognition that kuru, a disease afflicting only the Fore people of New Guinea, caused similar changes in brain tissue. Kuru is a rapidly progressive dementia (over months) characterized by cerebellar degeneration, causing clumsiness and difficulty walking (ataxia), tremor, and slurred speech. It has been linked to the Fore's practice of eating the brains of deceased relatives. Dr. D. C. Gadjusek, of the National Institutes of Health, hypothesized that ingestion of brain tissue caused the disease, and demonstrated in 1966 that inoculation of brain tissue from kuru patients into chimpanzees' brains caused the disease. Shortly afterward transmissibility was also demonstrated for Creutzfeldt-Jakob disease and Gerstmann-Str;äussler-Scheinker syndrome. Gadjusek and a colleague, Baruch S. Blumberg, were awarded the 1976 Nobel Prize in Medicine for this work.

Prions

The demonstration of transmissibility produced a search for the infectious agent. Initially researchers believed that a virus must be involved, but by the early 1980s the prion hypothesis had been proposed. "Prion" is a term coined by Dr. Stanley Prusiner in 1982 to indicate that the agent is both a protein and infectious. Prusiner, a University of California neurologist, received the 1997 Nobel Prize in medicine for his work on this new class of infectious agent.

The prion protein is a normal constituent of the human body, and although the exact function is unknown, it is involved in neuron development and prevention of neuronal cell death. The abnormal form of the protein has an insoluble conformation; that is, the protein folds in such a way that it can not easily interact with other body molecules. Since the abnormal form is resistant to degradation by normal body enzymes, it is termed protease-resistant prion protein. The abnormal protein can both accumulate into plaques and induce normal prion protein, in a chain reaction, to transform into the abnormal conformation. The prion protein is concentrated in nervous tissue but can also be found in other tissues, particularly white blood cells and the lymphatic system.

The prion hypothesis explains many of the characteristics of the Transmissible Spongiform Encephalopathies: how a familial disease could be infectious (the inheritance is due to a mutation in the prion gene, but the resultant abnormal protein can induce the conformational chain reaction in people without the mutation); why the agent is so resistant to disinfection (most viruses or bacteria are more susceptible to heat or detergents than insoluble proteins are); and how a disease can be infectious without the involvement of any DNA. The best evidence for the prion hypothesis comes from work on self-propagating prions of yeast.

Clinical features

Creutzfeldt-Jakob disease occurs worldwide, with an incidence rate of one per million, most commonly between the ages of fifty and seventy. There are familial forms of the disease, due to mutations in the prion protein gene, best studied in populations in Slovakia and among Libyan Jews. The disease can be iatrogenic, caused by exposure to infectious tissue, such as corneal transplants, dura mater grafts, contaminated surgical instruments, and medications made from human brain tissue, most notably human growth hormone. The time between exposure and onset of the disease can be many years. Most cases, however, are sporadic, or random. There has never been a known case of person-to-person infection. Although it can theoretically be transmitted by blood transfusion, no such case has been identified. There was much interest in the 1970s and 1980s in dietary risk factors, particularly ingestion of animal brains, but this has not been supported by more recent studies. Preliminary data reported in September of 2000 suggest that variant Creutzfeldt-Jakob disease can be passed on through blood transfusions and from a mother to her fetus.

The diagnostic criteria for Creutzfeldt-Jakob disease are presented in Table 2, and are self-explanatory. Often patients with Creutzfeldt-Jakob disease, particularly those with myoclonus, have a typical pattern of sharp waves on their electroencephalograph. Elevated levels of the 14-3-3 protein, a neuronal protein of unknown function, have been found in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease, and occasionally other cerebral diseases. If Creutzfeldt-Jakob disease is suspected, testing for this protein can help confirm the diagnosis.

Creutzfeldt-Jakob disease progresses rapidly, with a median duration from onset to death of four and a half months. There is no effective treatment for any of the Transmissible Spongiform Encephalopathies. Treatment is limited to comfort care and, if appropriate, genetic counseling. The search for possible therapies involves agents that may stimulate the body to break down the abnormal prion protein, that may disrupt the conformational chain reaction, or that may prevent spread of the prion to the nervous system in an exposed individual.

The epidemic of Bovine Spongiform Encephalopathy in the United Kingdom in the 1980s produced fears that this disease might enter the food chain, and affect humans and other species. This fear has proven true, although the eventual magnitude is as yet unknown. New diseases with prions identical to that causing bovine spongiform encephalopathy have been found in humans, cats, and zoo animals, most likely from prion-contaminated food. This new human disease, variant Creutzfeldt-Jakob disease, differs in that it typically affects people in their twenties and thirties; psychiatric symptoms are prominent; and the pathological appearance is different, with many prion protein-containing plaques found throughout the cortex. Only people with a prion protein gene coding for the amino acid methionine at codon 129 on both gene copies (homozygous for methionine) are susceptible to the disease. People homozygous for valine, or heterozygous for both valine and methionine, are not known to be susceptible to the new variant. Cases have occurred only in Great Britain and France. It is difficult to know if an epidemic will occur, but the incidence increased by 33 percent between 1994 and 2000. Some of this increase may reflect new diagnostic methods.

Not all scientists support the prion hypothesis. They hypothesize that a cofactor, probably a virus, is also present. The works by Manuelidis and Balter cited in the bibliography present these alternative views.

Chris MacKnight

See also Dementia.

BIBLIOGRAPHY

Balter, M. "Prions: A Lone Killer or a Vital Accomplice." Science 286 (22 October 1999): 660–662.

Caughey, B. "Transmissible Spongiform Encephalopathies, Amyloidoses and Yeast Proteins: Common Threads?" Nature Medicine 6 (2000): 751–754.

Collinge, J. "Variant Creutzfeldt-Jakob Disease." Lancet 354 (24 July 1999): 317–323.

MacKnight, C. "Clinical Implications of Bovine Spongiform Encephalopathy." Clinical Infectious Diseases 32 (2001): 1726–1731.

Manuelidis, L. "Dementias, Neurodegeneration, and Viral Mechanisms of Disease from the Perspective of Human Transmissible Encephalopathies." Annals of the New York Academy of Sciences 724 (1994): 259–281.

Prusiner, S. B., ed. Prion Biology and Diseases. Cold Spring Harbor Monograph Series, no. 38. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory, 1999.

Soto, C.; Kascsak, R. J.; Saborio, G. P.; Aucou Turier, P.; Wisniewski, T.; Prelli, F.; Kascsak, R.; Mendez, E.; Harris, D. A.; Ironside, J.; Tagliavini, F.; Carp, R. I.; and Frangione, B. "Reversion of Prion Protein Conformational Changes by Synthetic B-sheet Breaker Peptides." Lancet 355 (January 15, 2000): 192–197.

Supattapone, S.; Nguyen, H.-O. B.; Cohen, F. E.; Prusiner, S. B.; and Scott, M. R. "Elimination of Prions by Branched Polyamines and Implications for Therapeutics." Proceedings of the National Academy of Sciences 96 (1999): 14529–14534.

Wilson, K.; Code, C.; and Rickettsm. N. "Risk of Acquiring Creutzfeldt-Jakob Disease from Blood Transfusions: Systematic Review of Case-Control Studies." British Medical Journal 321 (1 July 2000): 17–19.

World Health Organization. "Transmissible Spongiform Encephalopathies." World Wide Web document. www.who.int

Creutzfeldt-Jakob disease

Definition

Creutzfeldt-Jakob disease (CJD) is a transmissible, rapidly progressing, fatal neurodegenerative disorder related to "mad cow disease."

Description

Before 1995, Creutzfeldt-Jakob disease was little known outside the medical profession. Indeed, most physicians did not know much about the disease, and few had ever seen a patient with the disease. But with the discovery of a "new variant" form, the possibility that those with the disease became infected simply by eating beef, and the radical theory that the infectious agent is a rogue protein, CJD has become one of the most talked about diseases in the world, and has taken on a significance far beyond the small number of deaths it currently causes each year.

First described in the 1920s, CJD is a neurodegenerative disease causing a rapidly progressing dementia which ends in death, usually within eight months of the onset of symptoms. It is also a very rare disease, affecting only about one in every million people in the population worldwide. In the United States, CJD is thought to affect about 250 people each year. CJD affects adults of all ages, but is rare in young adults and most common between ages 50 and 75.

Spongiform encephalopathies

The most obvious pathologic feature of CJD is the formation of numerous, fluid-filled spaces in the brain (vacuoles), giving the brain a sponge-like appearance. CJD is one of several human spongiform encephalopathies, diseases that produce this characteristic change in brain tissue. Others include kuru; Gerstmann-Straussler-Scheinker dis- ease, predominantly characterized by cerebellar ataxia; and fatal familial insomnia, associated with progressive insomnia, autonomic system dysfunction, and weakness caused by motor system dysfunction.

Kuru was prevalent among the Fore people in Papua New Guinea,. The disease was spread from infected individuals after their deaths through the practice of ritual cannibalism, in which the relatives of the dead person honored him by consuming his organs, including the brain. Discovery of the infectious nature of kuru won the Nobel Prize for Carleton Gadjusek in 1976 and also alerted the medical world to the possibility of slow-acting infectious agents, collectively termed slow-virus diseases. The incubation period for kuru was four to 30 years or more. While kuru has virtually disappeared following the cessation of cannibalistic practices, several new cases continue to arise each year.

Cases of CJD have been grouped into three types: familial, iatrogenic, and sporadic.

• Familial CJD, representing 5–15% of cases, is inherited in an autosomal dominant manner, meaning that either parent may pass along the disease to a child, who may then develop CJD later in life.
• Iatrogenic CJD occurs when a person is infected during a medical procedure, such as organ donation and transplantation, blood transfusion, or brain surgery. The rise in organ donation has increased this route of transmission. Grafts of infected corneas and dura mater (the tissue covering the brain) have been linked with the transmission of CJD. Another source is hormones concentrated from the pituitary glands of cadavers, some of whom carried CJD, for use in people with growth hormone deficiencies. Iatrogenic infection represents a small fraction of all cases. The incubation period between exposure to the infectious agent is very long and is estimated to be from less than 10 to more than 30 years.
• Sporadic CJD represents at least 85% of all cases. Sporadic cases have no identifiable source of infection. Death usually follows the appearance of the first symptoms within eight months.

Animal forms and "mad cow disease"

Six different forms of spongiform encephalopathy are known to occur in other mammals: scrapie in sheep, recognized for more than 200 years; chronic wasting dis- ease in elk and mule deer in Wyoming and Colorado; transmissible mink encephalopathy; exotic ungulate encephalopathy in some types of zoo animals; feline spongiform encephalopathy in domestic cats; and bovine spongiform encephalopathy (BSE) in cows. All of these are classified as slow-virus diseases.

BSE was first recognized in Britain in 1986. Besides the spongiform changes in the brain, BSE causes dementia-like behavioral changes. This is the origin of the name "mad cow disease." BSE is thought to be an altered form of scrapie that was transmitted to cows when sheep offal (slaughterhouse waste) was included in their feed.

The use of slaughterhouse offal in animal feed has been common in many countries and has been practiced for at least 50 years. The trigger for the BSE epidemic in Britain seems to have come in the early 1980s, when the use of organic solvents for preparation of offal was halted there. It seems likely that these solvents had destroyed the scrapie agent, thereby preventing infection. The change in preparation procedure opened the way for the agent to "jump species" and cause BSE in cows that consumed scrapie-infected meal. The slaughter of infected (but not yet visibly sick) cows at the end of their useful farm lives, and the use of their carcasses for feed, spread the infection rapidly and widely. For at least the first year after BSE was initially recognized in British herds, infected bovine remains continued to be incorporated into feed, spreading the disease still further. It is thought that most cows with BSE became infected as a result of eating meal containing offal from other cows, not sheep. Although milk from infected cows has never been shown to contain or pass the infectious agent, passage from infected mother to calf has occurred through unknown means.

Beginning in 1988, the British government took steps to stop the spread of BSE, banned the use of bovine offal in feed and other products, and ordered the slaughter of infected cows. By then, the slow-acting agent had become epidemic in British herds. In 1992, it was diagnosed in over 25,000 animals (1% of the British herd). By mid-1997, the cumulative number of BSE cases in the United Kingdom had risen to more than 170,000. The feeding ban apparently did slow the spread of the epidemic. The number of new cases each week fell from a peak of 1,000 in 1993 to fewer than 300 two years later.

The export of British feed and beef to member countries was banned by the European Union, but cases of BSE had developed in Europe by then. About 1,000 cases were identified in Europe by 1997. In 1989, the United States banned the import of British beef and began monitoring U.S. herds in 1990. As of 2001, the U.S. Department of Agriculture reports that BSE has not been detected in the United States. One case has been reported in Canada in a cow imported from Britain.

New-variant CJD: the jump to humans

From the beginning of the BSE epidemic, scientists and others in Britain feared that BSE might jump species again to infect humans who had consumed infected beef. In 1995, this fear seemed to be realized with the first cases of a new variant of Creutzfeldt-Jacob disease, termed nvCJD. Its victims, 81 as of the beginning of 2001, tend to be much younger than the 60–65 average for CJD, and the time from symptom onset to death has averaged 12 months instead of eight. EEG abnormalities characteristic of CJD are not typically seen in nvCJD.

Evidence is growing stronger that nvCJD is in fact caused by BSE.

• The majority of cases have occurred in Britain, the location of the original BSE epidemic
• BSE injected into monkeys produces a disease very similar to nvCJD
• BSE and nvCJD produce the same brain lesions after the same incubation period when injected into laboratory mice
• Brain proteins isolated from nvCJD victims, but not from the other forms of CJD, share similar molecular characteristics with brain proteins of animals that died from BSE.

While definitive proof is still lacking as of 2001, many researchers feel that the connection between BSE and nvCJD has been strongly established.

Assuming that BSE is the source, the question that has loomed from the beginning is the number of people that will eventually be affected. Epidemiological models of infectious disease produce estimates ranging from less than 100 to tens of thousands, depending on the assumptions used by those creating the mathematical models. The incubation period of nvCJD in humans is not known, nor are the genetic and environmental risk factors that influence susceptibility. The quantity of infectious agent needed to cause the disease is not known with precision. It is estimated that humans have eaten between one and two million infected cattle, most in the earliest stages of the epidemic. Estimates cannot be based on the very few cases that have developed to date. These cases could represent the very few people with the right combination of exposure and susceptibility to a relatively fast-developing infection, or they could be the first few victims of a slower-acting, more highly infectious agent. Only time will tell.

Causes and symptoms

Causes

It is clear that Creutzfeldt-Jakob disease is caused by an infectious agent, but it is not yet clear what type of agent that is. Originally assumed to be a virus, evidence is accumulating that, instead, CJD is caused by a protein called a "prion," (proteinaceous infectious particle) that is transmitted between persons who have CJD. The other spongiform encephalopathies are also hypothesized to be due to prion infection.

If this hypothesis is proved true, it would represent one of the most radical new ideas in biology since the discovery of DNA. All infectious diseases, in fact, all life, use nucleic acids—DNA or RNA—to code the instructions needed for reproduction. Inactivation of nucleic acids destroys the capacity to reproduce. However, when these same measures are applied to infected tissue from spongiform encephalopathy victims, infectivity is not destroyed. Furthermore, purification of infected tissue to concentrate the infectious fraction yields protein, not nucleic acid. While it remains possible that some highly stable nucleic acid remains hidden within the purified protein, this appears less and less likely as further experiments are done. The "prion hypothesis," as it is called, is now widely accepted, at least provisionally, by most researchers in the field. The most vocal proponent of the hypothesis, Stanley Prusiner, was awarded the Nobel Prize in 1997 for his work on prion diseases.

A prion is an altered form of a normal brain protein. The normal protein has a helical shape along part of its length. In the prion form, a sheet structure replaces the helix. According to the hypothesis, when the normal form interacts with the prion form, its helical part is converted to a sheet, thus creating a new prion capable of transforming other normal forms. In this way, the disease process resembles crystallization more than typical viral infection, in which the virus commands the host's cellular machinery to reproduce more of the virus. Build up of the sheet form causes accumulation of abnormal protein clumps and degeneration of brain cells, causing dementia and ultimately death.

The brain protein affected by the prion, called PrP, is part of the membrane of brain cells, but its exact function is unknown. It is composed of about 250 subunits, called amino acids, coded for by a gene on chromosome 20. Slight genetic differences, called polymorphisms, give rise to two slightly different normal protein forms: subunit 129 is a "methionine" in one form, but is "valine" in the other. A person may have all of one, all of the other, or a mixture of the two, depending on the individual's genetic inheritance. Both forms have the normal helical structure, and function normally. However, susceptibility to prion conversion is influenced by subunit 129: a person with a mixture of forms is more resistant to conversion, and a person with all valine appears to be somewhat more susceptible than one with all methionine. Exposure to the infectious agent is, of course, still required for disease development. Prion diseases are not contagious in the usual sense, and transmission from an infected person to another person requires direct inoculation of infectious material.

Familial CJD, on the other hand, does not require exposure but develops through the inheritance of other, more disruptive mutations in the gene for the normal PrP protein. Researchers believe these mutations increase the likelihood that the protein will spontaneously "flip" to the sheet form; once created, these abnormal proteins can then convert other normal-form molecules. The other two inherited human prion diseases, Gerstmann- Straussler-Scheinker disease and fatal familial insomnia, involve different mutations in the same gene.

The large majority of CJD cases are sporadic, meaning they have no known route of infection or genetic link. Causes of sporadic CJD are likely to be diverse and may include spontaneous genetic mutation, spontaneous protein changes, or unrecognized exposure to infectious agents. It is highly likely that future research will identify more risk factors associated with sporadic CJD.

Symptoms

About one in four people with CJD begin their illness with weakness, changes in sleep patterns, weight loss, or loss of appetite or sexual drive. A person with CJD may first complain of visual disturbances, including double vision , blurry vision, or partial loss of vision. Some visual symptoms are secondary to cortical blindness related to death of nerve cells in the occipital lobe of the brain responsible for vision. This form of visual loss is unusual in that patients may be unaware that they are unable to see. These symptoms may appear weeks or months before the onset of dementia.

The most characteristic symptom of CJD is rapidly progressing dementia, or loss of mental function. Dementia is marked by:

• memory losses
• impaired abstraction and planning
• language and comprehension disturbances
• poor judgment
• disorientation
• decreased attention and increased restlessness
• personality changes and psychosis
• hallucinations

Muscle spasms and jerking movements, called myoclonus, are also a prominent symptom of CJD. Balance and coordination disturbance (ataxia) is common in CJD and is more pronounced in nvCJD. Stiffness, difficulty moving, and other features characteristic of Parkinson's disease may develop and can progress to akinetic mutism, or a state of being unable to speak or move.

Diagnosis

CJD is diagnosed by a clinical neurological exam and electroencephalography (EEG), which shows characteristic spikes called triphasic sharp waves. Magnetic resonance imaging (MRI) or computed tomography scans (CT) should be performed to exclude other forms of dementia. CJD typically shows atrophy or loss of brain tissue. Lumbar puncture, or spinal tap, may be done to rule out other causes of dementia and to identify elevated levels of marker proteins known as 14-3-3. Cell count, chemical analysis, and other routine tests are normal in CJD. Another marker, neuron-specific enolase, may also be increased in CJD. A conclusive diagnosis of CJD can only be accomplished after death using material obtained from a brain autopsy .

Treatment

There is no cure for CJD. There is no treatment that slows the progression of the disease. Drug therapy and nursing care are intended to minimize psychiatric symptoms and increase comfort for affected persons. However, the rapid progression of CJD frustrates most attempts at treatment, since ever-worsening cognitive deficits and more prominent behavioral symptoms develop so quickly. Despite the generally grim prognosis, a few individuals with CJD progress more slowly and live longer than the average. For these persons, treatment will be more satisfactory.

Prognosis

Creutzfeldt-Jakob disease is invariably fatal, with death following symptom onset by an average of eight months. About 5% of patients live longer than two years. Death from nvCJD has averaged approximately 12 months after onset.

Health care team roles

Physicians are usually involved in initial identification of CJD. Nurses may provide supportive care. Radiologists obtain CT and MRI scans. Surgeons or physicians obtain spinal fluid. Pathologists and laboratory technicians process samples of bodily fluids and tissues.

Prevention

There is no known way to prevent sporadic CJD, by far the most common type. Not everyone who inherits the gene mutation for familial CJD will develop the disease, but at present, there is no known way to predict who will and who won't succumb. The incidence of iatrogenic CJD has fallen with recognition of its sources, the development of better screening techniques for infected tissue, and the use of sterilization techniques for surgical instruments , which inactivate prion proteins.

Strategies for preventing nvCJD are a controversial matter, as they involve a significant sector of the agricultural industry and a central dietary element in many countries. The infectious potential of contaminated meat is unknown, because the ability to detect prions within meat is limited. Surveillance of North American herds strongly suggests that no cases of BSE have been confirmed as of 2001. Strict regulations on imports of European livestock make future outbreaks highly unlikely. Therefore, avoidance of all meat originating in North America simply on grounds of BSE risk is a personal choice unsupported by current data. The ban on the export of British beef continues in countries of the European Union, although some herds in these countries have developed low levels of infection as well.

Resources

BOOKS

Adams, Raymond D., Maurice Victor, and Allan H. Ropper. Adam's & Victor's Principles of Neurology, 6th ed. New York: McGraw Hill, 1997.

Chen, Irvin, and Rafi Ahmed. Persistent Viral Infections. New York: John Wiley & Sons, 1999.

Donnelley, Christl, and Neil M. Ferguson. Statistical Aspects of BSE and VCJD: Models for Epidemics. Boca Raton, FL: CRC Press, 1999.

Rampton, Sheldon, and John C. Stauber. Mad Cow USA: Could the Nightmare Happen Here? Monroe, ME: Common Courage Press, 1997.

Ratzan, Scott C. Mad Cow Crisis: Health and the Public Good. New York: New York University Press, 1998.

PERIODICALS

Bosch, X. "European Concern Over BSE Transmission." Journal of the American Medical Association 285(2001): 397-398.

Deslyse, J.P., et al. "Screening Slaughtered Cattle for BSE." Nature, vol. 409, no. 6819(2001): 476-478.

Lemonick, M.D. "Can It Happen Here? Panic Over Mad Cow Has Already Infected Europe. Now It's Our Turn." Time, vol. 157, no. 4(2001): 58-59.

Steelman, V.M. "Creutzfeld-Jakob Disease: Recommendations for Infection Control." American Journal of Infection Control 22(2001): 312-318.

Stockdale, T. "Contaminated Material Caused Creutzfeldt- Jakob Disease (CJD) in Some Undersized Children Who Were Treated With Growth Hormone (GH)." Nutrition and Health 14(2000): 141-142.

Thompson, C. "In Search of a Cure for CJD." Nature, vol. 409, no. 6821(2001): 660-661.

Whitelaw, K. "Sacre Boeuf, It's Mad Cow. A Beef Scare in France." U.S. News and World Report, vol. 129, no. 21(2000): 53.

ORGANIZATIONS

American Academy of Neurology, 1080 Montreal Avenue, St. Paul, MN 55116. (651) 695-1940. Fax: (651) 695-2791. <http://www.aan.com/>. [email protected].

Centers for Disease Control and Prevention, 1600 Clifton Road, Atlanta, GA 30333. (404) 639-3534 or (800) 311-3435. <http://www.cdc.gov/ncidod/eid/vol7no1/brown.htm>. <http://www.cdc.gov/netinfo.htm>.

Creutzfeldt-Jakob Disease Foundation, P.O. Box 611625, Miami, FL 33261-1625. (305) 891-7579. Fax: (954) 436-7591. <http://cjdfoundation.org/>. [email protected].

Creutzfeldt-Jakob Disease Support Network, Birchwood, Heath Top, Ashley Heath, Market Drayton, Shropshire, England. (011) 0163-067-3993. <http://glaxocentre.merseyside.org/cjd1.html>. E-mail: Gill Turner, [email protected].

National Creutzfeldt-Jakob Disease Surveillance Unit, Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. 011-0131-537-2128. Fax: 011-0131-343-1404. <http://www.cjd.ed.ac.uk/>. [email protected].

OTHER

British Medical Journal. <http://www.bmj.com/cgi/collection/mad_cow>.

Human BSE Foundation. <http://www.humanbse.org.uk/>.

Information Concerning BSE for the Scientific World. <http://sparc.airtime.co.uk/bse/>.

National Institute of Neurological Diseases and Stroke. <http://www.ninds.nih.gov/health_and_medical/pubs/creutzfeldt-jakob_disease_fact_sheet.htm>.

Tufts University. <http://tuftsneurology.org/webres/prion.htm>.

University of Minnesota. <http://www.biomed.lib.umn.edu/hw/creutzfeld.html>.

University of Nottingham. <http://omni.ac.uk/browse/mesh/detail/C0022336L0022336.html>.

KEY TERMS

Autosomal dominant inheritance —A pattern of inheritance in which a trait is expressed if the gene is inherited from either parent.

Encephalopathy —A brain disorder characterized by memory impairment and other symptoms.

Iatrogenic —Caused by a medical procedure.

Nucleic acids —The cellular molecules DNA and RNA, which act as coded instructions for the production of proteins and which are copied for transmission of inherited traits.

L. Fleming Fallon, Jr., MD, PhD, DrPH

Creutzfeldt-Jakob Disease

Definition

Creutzfeldt-Jakob disease (CJD) is a transmissible, rapidly progressing, fatal neurodegenerative disorder related to "mad cow disease."

Description

Before 1995, Creutzfeldt-Jakob disease was little known outside the medical profession. Indeed, most physicians did not know much about the disease, and few had ever seen a patient with the disease. But with the discovery of a "new variant" form, the possibility that those with the disease became infected simply by eating beef, and the radical theory that the infectious agent is a rogue protein, CJD has become one of the most talked about diseases in the world, and has taken on a significance far beyond the small number of deaths it currently causes each year.

First described in the 1920s, CJD is a neurodegenerative disease causing a rapidly progressing dementia which ends in death, usually within eight months of the onset of symptoms. It is also a very rare disease, affecting only about one in every million people in the population worldwide. In the United States, CJD is thought to affect about 250 people each year. CJD affects adults of all ages, but is rare in young adults and most common between ages 50 and 75.

Spongiform encephalopathies

The most obvious pathologic feature of CJD is the formation of numerous, fluid-filled spaces in the brain (vacuoles), giving the brain a sponge-like appearance. CJD is one of several human spongiform encephalopathies, diseases that produce this characteristic change in brain tissue. Others include kuru; Gerstmann-Straussler-Scheinker disease, predominantly characterized by cerebellar ataxia; and fatal familial insomnia, associated with progressive insomnia, autonomic system dysfunction, and weakness caused by motor system dysfunction.

Kuru was prevalent among the Fore people in Papua New Guinea. The disease was spread from infected individuals after their deaths through the practice of ritual cannibalism, in which the relatives of the dead person honored him by consuming his organs, including the brain. Discovery of the infectious nature of kuru won the Nobel Prize for Carleton Gadjusek in 1976 and also alerted the medical world to the possibility of slow-acting infectious agents, collectively termed slow-virus diseases. The incubation period for kuru was four to 30 years or more. While kuru has virtually disappeared following the cessation of cannibalistic practices, several new cases continue to arise each year.

Cases of CJD have been grouped into three types: familial, iatrogenic, and sporadic.

• Familial CJD, representing 5-15% of cases, is inherited in an autosomal dominant manner, meaning that either parent may pass along the disease to a child, who may then develop CJD later in life.
• Iatrogenic CJD occurs when a person is infected during a medical procedure, such as organ donation and transplantation, blood transfusion, or brain surgery. The rise in organ donation has increased this route of transmission. Grafts of infected corneas and dura mater (the tissue covering the brain) have been linked with the transmission of CJD. Another source is hormones concentrated from the pituitary glands of cadavers, some of whom carried CJD, for use in people with growth hormone deficiencies. Iatrogenic infection represents a small fraction of all cases. The incubation period between exposure to the infectious agent is very long and is estimated to be from less than 10 to more than 30 years.
• Sporadic CJD represents at least 85% of all cases. Sporadic cases have no identifiable source of infection. Death usually follows the appearance of the first symptoms within eight months.

Animal forms and "mad cow disease"

Six different forms of spongiform encephalopathy are known to occur in other mammals: scrapie in sheep, recognized for more than 200 years; chronic wasting disease in elk and mule deer in Wyoming and Colorado; transmissible mink encephalopathy; exotic ungulate encephalopathy in some types of zoo animals; feline spongiform encephalopathy in domestic cats; and bovine spongiform encephalopathy (BSE) in cows. All of these are classified as slow-virus diseases.

BSE was first recognized in Britain in 1986. Besides the spongiform changes in the brain, BSE causes dementia-like behavioral changes. This is the origin of the name "mad cow disease." BSE is thought to be an altered form of scrapie that was transmitted to cows when sheep offal (slaughterhouse waste) was included in their feed.

The use of slaughterhouse offal in animal feed has been common in many countries and has been practiced for at least 50 years. The trigger for the BSE epidemic in Britain seems to have come in the early 1980s, when the use of organic solvents for preparation of offal was halted there. It seems likely that these solvents had destroyed the scrapie agent, thereby preventing infection. The change in preparation procedure opened the way for the agent to "jump species" and cause BSE in cows that consumed scrapie-infected meal. The slaughter of infected (but not yet visibly sick) cows at the end of their useful farm lives, and the use of their carcasses for feed, spread the infection rapidly and widely. For at least the first year after BSE was initially recognized in British herds, infected bovine remains continued to be incorporated into feed, spreading the disease still further. It is thought that most cows with BSE became infected as a result of eating meal containing offal from other cows, not sheep. Although milk from infected cows has never been shown to contain or pass the infectious agent, passage from infected mother to calf has occurred through unknown means.

Beginning in 1988, the British government took steps to stop the spread of BSE, banned the use of bovine offal in feed and other products, and ordered the slaughter of infected cows. By then, the slow-acting agent had become epidemic in British herds. In 1992, it was diagnosed in over 25,000 animals (1% of the British herd). By mid-1997, the cumulative number of BSE cases in the United Kingdom had risen to more than 170,000. The feeding ban apparently did slow the spread of the epidemic. The number of new cases each week fell from a peak of 1,000 in 1993 to fewer than 300 two years later.

The export of British feed and beef to member countries was banned by the European Union, but cases of BSE had developed in Europe by then. About 1,000 cases were identified in Europe by 1997. In 1989, the United States banned the import of British beef and began monitoring U.S. herds in 1990. As of 2001, the U.S. Department of Agriculture reports that BSE has not been detected in the United States. One case has been reported in Canada in a cow imported from Britain.

New-variant CJD: the jump to humans

From the beginning of the BSE epidemic, scientists and others in Britain feared that BSE might jump species again to infect humans who had consumed infected beef. In 1995, this fear seemed to be realized with the first cases of a new variant of Creutzfeldt-Jacob disease, termed nvCJD. Its victims, 81 as of the beginning of 2001, tend to be much younger than the 60-65 average for CJD, and the time from symptom onset to death has averaged 12 months instead of eight. EEG abnormalities characteristic of CJD are not typically seen in nvCJD.

Evidence is growing stronger that nvCJD is in fact caused by BSE.

• The majority of cases have occurred in Britain, the location of the original BSE epidemic
• BSE injected into monkeys produces a disease very similar to nvCJD
• BSE and nvCJD produce the same brain lesions after the same incubation period when injected into laboratory mice
• Brain proteins isolated from nvCJD victims, but not from the other forms of CJD, share similar molecular characteristics with brain proteins of animals that died from BSE.

While definitive proof is still lacking as of 2001, many researchers feel that the connection between BSE and nvCJD has been strongly established.

Assuming that BSE is the source, the question that has loomed from the beginning is the number of people that will eventually be affected. Epidemiological models of infectious disease produce estimates ranging from less than 100 to tens of thousands, depending on the assumptions used by those creating the mathematical models. The incubation period of nvCJD in humans is not known, nor are the genetic and environmental risk factors that influence susceptibility. The quantity of infectious agent needed to cause the disease is not known with precision. It is estimated that humans have eaten between one and two million infected cattle, most in the earliest stages of the epidemic. Estimates cannot be based on the very few cases that have developed to date. These cases could represent the very few people with the right combination of exposure and susceptibility to a relatively fast-developing infection, or they could be the first few victims of a slower-acting, more highly infectious agent. Only time will tell.

Causes and symptoms

Causes

It is clear that Creutzfeldt-Jakob disease is caused by an infectious agent, but it is not yet clear what type of agent that is. Originally assumed to be a virus, evidence is accumulating that, instead, CJD is caused by a protein called a "prion," (proteinaceous infectious particle) that is transmitted between persons who have CJD. The other spongiform encephalopathies are also hypothesized to be due to prion infection.

If this hypothesis is proved true, it would represent one of the most radical new ideas in biology since the discovery of DNA. All infectious diseases, in fact, all life, use nucleic acids—DNA or RNA—to code the instructions needed for reproduction. Inactivation of nucleic acids destroys the capacity to reproduce. However, when these same measures are applied to infected tissue from spongiform encephalopathy victims, infectivity is not destroyed. Furthermore, purification of infected tissue to concentrate the infectious fraction yields protein, not nucleic acid. While it remains possible that some highly stable nucleic acid remains hidden within the purified protein, this appears less and less likely as further experiments are done. The "prion hypothesis," as it is called, is now widely accepted, at least provisionally, by most researchers in the field. The most vocal proponent of the hypothesis, Stanley Prusiner, was awarded the Nobel Prize in 1997 for his work on prion diseases.

A prion is an altered form of a normal brain protein. The normal protein has a helical shape along part of its length. In the prion form, a sheet structure replaces the helix. According to the hypothesis, when the normal form interacts with the prion form, its helical part is converted to a sheet, thus creating a new prion capable of transforming other normal forms. In this way, the disease process resembles crystallization more than typical viral infection, in which the virus commands the host's cellular machinery to reproduce more of the virus. Build up of the sheet form causes accumulation of abnormal protein clumps and degeneration of brain cells, causing dementia and ultimately death.

The brain protein affected by the prion, called PrP, is part of the membrane of brain cells, but its exact function is unknown. It is composed of about 250 subunits, called amino acids, coded for by a gene on chromosome 20. Slight genetic differences, called polymorphisms, give rise to two slightly different normal protein forms: subunit 129 is a "methionine" in one form, but is "valine" in the other. A person may have all of one, all of the other, or a mixture of the two, depending on the individual's genetic inheritance. Both forms have the normal helical structure, and function normally. However, susceptibility to prion conversion is influenced by subunit 129: a person with a mixture of forms is more resistant to conversion, and a person with all valine appears to be somewhat more susceptible than one with all methionine. Exposure to the infectious agent is, of course, still required for disease development. Prion diseases are not contagious in the usual sense, and transmission from an infected person to another person requires direct inoculation of infectious material.

Familial CJD, on the other hand, does not require exposure but develops through the inheritance of other, more disruptive mutations in the gene for the normal PrP protein. Researchers believe these mutations increase the likelihood that the protein will spontaneously "flip" to the sheet form; once created, these abnormal proteins can then convert other normalform molecules. The other two inherited human prion diseases, Gerstmann-Straussler-Scheinker disease and fatal familial insomnia, involve different mutations in the same gene.

The large majority of CJD cases are sporadic, meaning they have no known route of infection or genetic link. Causes of sporadic CJD are likely to be diverse and may include spontaneous genetic mutation, spontaneous protein changes, or unrecognized exposure to infectious agents. It is highly likely that future research will identify more risk factors associated with sporadic CJD.

Symptoms

About one in four people with CJD begin their illness with weakness, changes in sleep patterns, weight loss, or loss of appetite or sexual drive. A person with CJD may first complain of visual disturbances, including double vision, blurry vision, or partial loss of vision. Some visual symptoms are secondary to cortical blindness related to death of nerve cells in the occipital lobe of the brain responsible for vision. This form of visual loss is unusual in that patients may be unaware that they are unable to see. These symptoms may appear weeks or months before the onset of dementia.

The most characteristic symptom of CJD is rapidly progressing dementia, or loss of mental function. Dementia is marked by:

• memory losses
• impaired abstraction and planning
• language and comprehension disturbances
• poor judgment
• disorientation
• decreased attention and increased restlessness
• personality changes and psychosis
• hallucinations

Muscle spasms and jerking movements, called myoclonus, are also a prominent symptom of CJD. Balance and coordination disturbance (ataxia) is common in CJD and is more pronounced in nvCJD. Stiffness, difficulty moving, and other features characteristic of Parkinson's disease may develop and can progress to akinetic mutism, or a state of being unable to speak or move.

Diagnosis

CJD is diagnosed by a clinical neurological exam and electroencephalography (EEG), which shows characteristic spikes called triphasic sharp waves. Magnetic resonance imaging (MRI) or computed tomography scans (CT) should be performed to exclude other forms of dementia. CJD typically shows atrophy or loss of brain tissue. Lumbar puncture, or spinal tap, may be done to rule out other causes of dementia and to identify elevated levels of marker proteins known as 14-3-3. Cell count, chemical analysis, and other routine tests are normal in CJD. Another marker, neuron-specific enolase, may also be increased in CJD. A conclusive diagnosis of CJD can only be accomplished after death using material obtained from a brain autopsy.

Treatment

There is no cure for CJD. There is no treatment that slows the progression of the disease. Drug therapy and nursing care are intended to minimize psychiatric symptoms and increase comfort for affected persons. However, the rapid progression of CJD frustrates most attempts at treatment, since ever-worsening cognitive deficits and more prominent behavioral symptoms develop so quickly. Despite the generally grim prognosis, a few individuals with CJD progress more slowly and live longer than the average. For these persons, treatment will be more satisfactory.

Prognosis

Creutzfeldt-Jakob disease is invariably fatal, with death following symptom onset by an average of eight months. About 5% of patients live longer than two years. Death from nvCJD has averaged approximately 12 months after onset.

Health care team roles

Physicians are usually involved in initial identification of CJD. Nurses may provide supportive care. Radiologists obtain CT and MRI scans. Surgeons or physicians obtain spinal fluid. Pathologists and laboratory technicians process samples of bodily fluids and tissues.

Prevention

There is no known way to prevent sporadic CJD, by far the most common type. Not everyone who inherits the gene mutation for familial CJD will develop the disease, but at present, there is no known way to predict who will and who will not succumb. The incidence of iatrogenic CJD has fallen with recognition of its sources, the development of better screening techniques for infected tissue, and the use of sterilization techniques for surgical instruments, which inactivate prion proteins.

Strategies for preventing nvCJD are a controversial matter, as they involve a significant sector of the agricultural industry and a central dietary element in many countries. The infectious potential of contaminated meat is unknown, because the ability to detect prions within meat is limited. Surveillance of North American herds strongly suggests that no cases of BSE have been confirmed as of 2001. Strict regulations on imports of European livestock make future outbreaks highly unlikely. Therefore, avoidance of all meat originating in North America simply on grounds of BSE risk is a personal choice unsupported by current data. The ban on the export of British beef continues in countries of the European Union, although some herds in these countries have developed low levels of infection as well.

KEY TERMS

Autosomal dominant inheritance— A pattern of inheritance in which a trait is expressed if the gene is inherited from either parent.

Encephalopathy— A brain disorder characterized by memory impairment and other symptoms.

Iatrogenic— Caused by a medical procedure.

Nucleic acids— The cellular molecules DNA and RNA which act as coded instructions for the production of proteins and which are copied for transmission of inherited traits.

Resources

BOOKS

Adams, Raymond D., Maurice Victor, and Allan H. Ropper. Adams & Victor's Principles of Neurology, 6th ed. New York: McGraw Hill, 1997.

Chen, Irvin, and Rafi Ahmed. Persistent Viral Infections. New York: John Wiley & Sons, 1999.

Donnelley, Christl, and Neil M. Ferguson. Statistical Aspects of BSE and VCJD: Models for Epidemics. Boca Raton, FL: CRC Press, 1999.

Rampton, Sheldon, and John C. Stauber. Mad Cow USA: Could the Nightmare Happen Here? Monroe, ME: Common Courage Press, 1997.

Ratzan, Scott C. Mad Cow Crisis: Health and the Public Good. New York: New York University Press, 1998.

PERIODICALS

Bosch, X. "European Concern Over BSE Transmission." Journal of the American Medical Association 285 (2001): 397-398.

Deslyse, J.P., et al. "Screening Slaughtered Cattle for BSE." Nature, vol. 409, no. 6819 (2001): 476-478.

Lemonick, M.D. "Can It Happen Here? Panic Over Mad Cow Has Already Infected Europe. Now It's Our Turn." Time 157, no. 4 (2001): 58-59.

Steelman, V.M. "Creutzfeld-Jakob Disease: Recommendations for Infection Control." American Journal of Infection Control 22 (2001): 312-318.

Stockdale, T. "Contaminated Material Caused Creutzfeldt-Jakob Disease (CJD) in Some Undersized Children Who Were Treated With Growth Hormone (GH)." Nutrition and Health 14 (2000): 141-142.

Thompson, C. "In Search of a Cure for CJD." Nature 409, no. 6821 (2001): 660-661.

Whitelaw, K. "Sacre Boeuf, It's Mad Cow. A Beef Scare in France." U.S. News and World Report 129, no. 21 (2000): 53.

ORGANIZATIONS

American Academy of Neurology. 1080 Montreal Avenue, St. Paul, MN 55116. (651) 695-1940. Fax: (651) 695-2791. 〈http://www.aan.com/〉. [email protected]

Centers for Disease Control and Prevention. 1600 Clifton Road, Atlanta, GA 30333. (404) 639-3534 or (800) 311-3435. 〈http://www.cdc.gov/ncidod/eid/vol7no1/brown.htm〉. 〈http://www.cdc.gov/netinfo.htm〉.

Creutzfeldt-Jakob Disease Foundation. P.O. Box 611625, Miami, FL 33261-1625. (305) 891-7579. Fax: (954) 436-7591. 〈http://cjdfoundation.org/〉. [email protected].

Creutzfeldt-Jakob Disease Support Network. Birchwood, Heath Top, Ashley Heath, Market Drayton, Shropshire, England. (011) 0163-067-3993. 〈http://glaxocentre.merseyside.org/cjd1.html〉. E-mail: Gill Turner, [email protected].

National Creutzfeldt-Jakob Disease Surveillance Unit. Western General Hospital, Crewe Road, Edinburgh, EH4 2XU, UK. 011-0131-537-2128. Fax: 011-0131 343-1404 〈http://www.cjd.ed.ac.uk/〉. [email protected].

OTHER

British Medical Journal. 〈http://www.bmj.com/cgi/collection/mad_cow〉.

Human BSE Foundation. 〈http://www.humanbse.org.uk/〉.

Information Concerning BSE for the Scientific World. 〈http://sparc.airtime.co.uk/bse/〉.

National Institute of Neurological Diseases and Stroke. 〈http://www.ninds.nih.gov/health_and_medical/pubs/creutzfeldt-jakob_disease_fact_sheet.htm〉.

Tufts University. 〈http://tuftsneurology.org/webres/prion.htm〉.

University of Minnesota. 〈http://www.biomed.lib.umn.edu/hw/creutzfeld.html〉.

University of Nottingham. 〈http://omni.ac.uk/browse/mesh/detail/C0022336L0022336.html〉.

Creutzfeldt-Jakob Disease

What Is Creutzfeldt-Jakob Disease?

How Common Is CJD?

Is the Disease Contagious?

What Are the Signs and Symptoms of CJD?

How Do Doctors Make the Diagnosis?

What Is the Treatment and Course of the Disease?

How Can CJD Be Prevented?

Resource

Creutzfeldt-Jakob (KROYTZ-felt YAH-kub) disease is a disorder of the brain that is ultimately fatal.

What Is Creutzfeldt-Jakob Disease?

Creutzfeldt-Jakob disease (CJD) is a very rare disorder that damages the tissues of the brain, causing a rapid decline in mental function and muscle coordination, eventually leading to death. It is believed that a tiny transmissible* protein particle called a prion triggers the disease, which is divided into three categories:

*transmissible

(trans-MIH-sih-bul) means able to be transferred or spread.

KEYWORDS

for searching the Internet and other reference sources

Bovine spongiform encephalopathy (BSE)

Kuru

Mad cow disease

Prions

Scrapie

Transmissible spongiform encephalopathies

• Familial CJD accounts for up to about 10 percent of cases. In these instances, there exists a family history of the disease, suggesting that certain genes* shared by family members make them more susceptible to CJD.

*genes

(JEENS) are chemical structures composed of deoxyribonucleic acid (DNA) that help determine a person’s body structure and physical characteristics. Inherited from a person’s parents, genes are contained in the chromosomes found in the body’s cells.

• Sporadic cases, in which people have no known risk factors for the disease, make up about 85 percent of occurrences.
• Acquired CJD is the rarest form. Less than 5 percent of all cases result from exposure to infected brain or spinal tissue, usually during a medical procedure.

CJD belongs to a family of illnesses known as transmissible spongiform (SPUN-jih-form) encephalopathies (en-seh-fuh-LAH-puh-theez). Spongiform refers to the appearance of brain tissue affected by the disease—the damaged tissue is full of holes, much like a sponge. Other diseases in the CJD family include kuru*; bovine spongiform encephalopathy (BSE), which infects cattle and is known as mad cow disease; and scrapie*, which affects sheep. The disease generally affects people age 60 or older, but in 1996 scientists described a new form of CJD, called variant CJD or new variant CJD (vCJD). Variant CJD differs from classic CJD in that it typically affects people under the age of 30 and causes different symptoms. So far, cases of vCJD have been limited mostly to the United Kingdom and France, and all the people in whom vCJD has developed have been exposed to areas where BSE has been found.

*kuru

(KUR-ew) is a progressive, fatal brain disease characterized by tremors and loss of muscle coordination that is caused by eating contaminated brain tissue from other humans who had the disease.

*scrapie

(SKRAY-pee) is a fatal brain disorder of sheep that is characterized by itching of the skin and difficulty walking.

How Common Is CJD?

Creutzfeldt-Jakob disease remains extremely rare, occurring in about one in 1 million people each year.

Is the Disease Contagious?

Although CJD may be transmissible, it does not appear to spread through usual types of direct person-to-person contact. CJD can be transmitted through contact with infected brain or central nervous system* tissue or fluid, usually during a medical procedure. For example, the disease has been reported after cornea* transplants and dura mater* grafts*, following injection of human pituitary*–derived growth hormone*, and after contact with medical instruments used during brain surgery on a person with the disease. Cerebrospinal fluid can spread CJD, but there is no evidence of transmission through other body fluids, including saliva, blood, or urine. Variant CJD has occurred only where cases of BSE also have been found, leading researchers to theorize that eating beef from cattle with BSE could spread the agent and lead to CJD in humans. Although this explanation is widely accepted, it has not been proved.

*central nervous system

(SEN-trul NER-vus SIS-tem) is the part of the nervous system that includes the brain and spinal cord.

*cornea

(KOR-nee-uh) is the transparent circular layer of cells over the central colored part of the eyeball (the iris) through which light enters the eye.

*dura mater

(DUR-uh MAY-ter) is the outermost of three membranes covering the brain and spinal cord.

*grafts

are tissue or organ transplants.

*pituitary

(pih-TOO-ih-tare-e) is a small oval-shaped gland at the base of the skull that produces several hormones—substances that affect various body functions, including growth.

*growth hormone

is a chemical substance produced by the pituitary gland that regulates growth and other body functions.

Mad Cow Disease and the Human Connection

A disease called bovine spongiform encephalopathy (BSE or mad cow disease), which is similar to CJD but is found in cattle, has been linked to variant CJD. Cattle had long been fed ground-up carcasses from sheep and other livestock as a nutritional supplement. This practice may have caused an epidemic of BSE among cows in the United Kingdom that began in 1986. It is thought that the carcasses fed to the cows could have been those of animals infected with various forms of transmissible spongiform disease. In 1988 this feeding practice was banned in the United Kingdom. Millions of cows have since been slaughtered to protect the food supply, and the number of new BSE cases has dropped sharply.

What Are the Signs and Symptoms of CJD?

The most characteristic symptom of CJD is quickly worsening dementia*, including memory loss and impaired thinking. Patients often have problems with vision and muscle coordination. The inability to sleep, unusual sensations, and depression are also common. Many patients experience muscle jerking known as myoclonus (my-AH-kloh-nus), which consists of brief, rapid muscle contractions. If the disease is contracted from human tissue (such as from a transplanted cornea), symptoms may not appear for decades after exposure to the contaminated tissue. Variant

*dementia

(dih-MEN-sha) is a loss of mental abilities including memory, understanding, and judgment.

Prions: Are They “Infectious”?

Like bacteria, viruses, and parasites, prions, which are abnormal protein particles, have been linked to certain transmissible diseases. Yet prions are different from other infectious agents. While microorganisms* contain genetic material, prions do not, which means that they are not alive. According to the prion theory, the protein at first cannot transmit disease. Instead, it undergoes a change that allows it to fold into a different shape, its “infectious” form. When a prion enters a brain cell in the course of CJD, it binds to normal proteins, causing them to change shape. This sets off a chain reaction leading to cell death and the release of more prions to enter and affect more cells. As cells die, holes form in brain tissue giving it the characteristic “spongelike” appearance. Prions can be acquired during a medical procedure or from some other exposure to brain tissue or fluids containing brain tissue. In the inherited form of CJD, it is believed that a gene mutation* allows some normal proteins to change into prions under certain conditions.

*microorganisms

are tiny organisms that can be seen only using a microscope. Types of microorganisms include fungi, bacteria, and viruses.

*mutation

(myoo-TAY-shun) is a change in an organism’s gene or genes.

CJD at first causes psychiatric (sy-kee-AH-trik) symptoms, such as depression, anxiety (ang-ZY-uh-tee), or personality changes; dementia and myoclonus typically occur later than in classic CJD.

Variant Creutzfeld-Jakob disease has occurred only where cases of bovine spongiform encephalopathy also have been found, leading researchers to theorize that eating beef from cattle with BSE could spread the agent. In France and England whole herds of cattle have been put to death in an effort to prevent the spread of disease. AP/Wide World Photos

How Do Doctors Make the Diagnosis?

CJD can be diagnosed by a brain biopsy (BI-op-see), which requires removing a small piece of brain tissue during surgery to examine for signs of the disease, or by an autopsy*. Other, less invasive tests may point to a diagnosis of CJD or help identify another cause of the patient’s symptoms, such as meningitis or encephalitis. During a physical examination, the doctor checks for muscle twitching and spasms. An eye exam may show areas of blindness that the patient may not have noticed, and a spinal tap* and blood tests may identify certain proteins associated with CJD. An electroencephalogram (EEG) test records electrical activity in the brain and may show a pattern of brain waves seen in many patients with CJD, although the typical EEG findings are not present in vCJD. Some people with CJD have negative test results, making a diagnosis difficult without a brain biopsy.

*autopsy

(AW-top-see) is an examination of a body after death to look for the cause of death or the effects of a disease.

*spinal tap ,

also called a lumbar puncture, is a medical procedure in which a needle is used to withdraw a sample of the fluid surrounding the spinal cord and brain. The fluid is then tested, usually to detect signs of infection, such as meningitis, or other diseases.

What Is the Treatment and Course of the Disease?

Because CJD cannot be cured, the goal of treatment is to make the patient as comfortable as possible. Medications can help control aggressive behavior, lessen pain, and ease muscle jerks. Dementia can progress to loss of speech, the inability to take care of oneself, blindness, and even coma. As patients become bedridden, they are vulnerable to infections, such as pneumonia, and most eventually need to be hospitalized. Many patients die within a year after symptoms appear.

Genetically Engineered Bacteria to the Rescue

Growth hormone once was obtained from the pituitary glands of cadavers—that is, the bodies of people who have died—and patients who needed injections of growth hormone were at risk of getting CJD. Now growth hormone can be produced in laboratories by inserting the genes controlling the production of growth hormone into bacteria, thus avoiding the need to extract the hormone from human tissue and eliminating the risk of transmitting CJD.

How Can CJD Be Prevented?

No known measures can prevent the onset of CJD in a person whose brain tissue contains the prion. Because the ways by which the disease can be transmitted are still not well understood, blood banks forbid people with confirmed or suspected CJD or those who may be at high risk, such as persons with a family history of the disease, to donate blood, and doctors advise that they not be organ or tissue donors. Family members of a person with CJD may wish to have genetic counseling to learn more about any family risk. Special handling of surgical instruments can limit the chance of transmission during certain medical procedures, particularly those involving the brain.

See also

Encephalitis

Meningitis

Resource

Organization

Creutzfeldt-Jakob Disease Foundation, Inc., P.O. Box 5312, Akron, OH 44334. The foundation gives an overview of CJD and lists CJD-related websites, along with the latest news and research.

Telephone 800-659-1991 http://cjdfoundation.org