Creutzfeldt-Jakob Disease (CJD) is a rare, and invariably fatal brain disorder. It belongs to a group of diseases called the transmissible spongiform encephalopathies (TSEs), affecting both humans and animals and leading to the appearance of tiny holes within the brain tissue, giving it a “spongy”appearance. In 1996, several cases of a new form of CJD were reported in the United Kingdom. Because it differed in many ways from the so-called classical form of the disease, it was named variant CJD (vCJD, also known as new variant CJD, or CJD-nv). Since then, there have been around 200 cases of vCJD reported around the world. Exposure to bovine spongiform encephalopathy (also known as “mad cow”disease), a TSE of cattle, through consuming beef, appears to be the cause of vCJD. Control of BSE has led to a dramatic fall in the number of cases of vCJD. However, there is still a risk that the disease could be transmitted through blood donated by an infected, but asymptomatic, individual.
The classical form of CJD has been known since the early years of the twentieth century. It is a rare disease, affecting around one in a million of the population around the world. About 15% of classical cases are inherited, while the rest are sporadic, arising for no obvious reason. The classical form usually affects people over 50 and is marked by ataxia (unsteadiness on the feet), dementia, (a sharp decline in mental performance), blurred vision, and slurred speech. The majority of patients with classical CJD die within six months of the onset of symptoms. vCJD, on the other hand, has been found largely among teenagers and young adults, although there have been cases in older people. It begins with psychiatric symptoms, such as anxiety and depression, and persistent pain and odd sensations in the face and limbs. Later, ataxia and sudden jerky movements set in, along with progressive dementia. The time course of vCJD is longer, with death usually occurring around a year after the onset of symptoms. There are also significant differences in brain imaging, electroencephalogram, and pathology data between classical and vCJD.
The infective agent in all TSEs, including CJD, is neither a bacterium nor a virus, but an entity known as a prion, which is best described as an infectious protein. A prion is an abnormally-shaped version of a protein that occurs naturally in the brain. When the normal prion protein comes into contact with the abnormal version, it is converted into the abnormal version and can go on to corrupt other normal prion protein molecules. This cascade of damage then spreads throughout the brain. In sporadic cases of CJD, there may be a spontaneous change of a normal prion protein molecule into the abnormal form; no risk factors for this are known, however. In inherited CJD, there are mutations in the gene for prion protein which may render a person more susceptible to prion infection. All reported cases of vCJD have involved individuals who have spent time in a country affected by BSE, which provides at least indirect evidence for the mode of transmission—consumption of BSE-contaminated beef. Meanwhile, there have been a few cases of so-called iatrogenic CJD where the disease has been transmitted from one person to another through contaminated human growth hormone (which used to be extracted from the pituitary glands of human cadavers) or instruments used in brain surgery. There have also been three cases of vCJD arising among recipients of blood from an asymptomatic donor who later developed the disease. However, there have been no cases of direct person-to-person transmission of vCJD.
WORDS TO KNOW
ATAXIA: Ataxia is an unsteadiness in walking or standing which is associated with brain diseases such as kuru or Creutzfeldt-Jakob disease
CADAVER: The body of a deceased human, especially one designated for scientific dissection or other research.
DEMENTIA: Dementia, which is from the Latin word dement meaning “away mind,” is a progressive deterioration and eventual loss of mental ability that is severe enough to interfere with normal activities of daily living, lasts more than six months, is not present since birth, and is not associated with a loss or alteration of consciousness. Dementia is a group of symptoms caused by gradual death of brain cells. Dementia is usually caused by degeneration in the cerebral cortex, the part of the brain responsible for thoughts, memories, actions, and personality. Death of brain cells in this region leads to the cognitive impairment that characterizes dementia.
PRIONS: Prions are proteins that are infectious. Indeed, the name prion is derived from “proteinaceous infectious particles.” The discovery of prions and confirmation of their infectious nature overturned a central dogma that infections were caused by intact organisms, particularly microorganisms such as bacteria, fungi, parasites, or viruses. Since prions lack genetic material, the prevailing attitude was that a protein could not cause disease.
SPONGIFORM: Spongiform is the clinical name for the appearance of brain tissue affected by prion diseases, such as Creutzfeld-Jakob disease or bovine spongiform encephalopathy. The disease process leads to the formation of tiny holes in brain tissue, giving it a spongy appearance.
Most of the cases of vCJD have occurred in the United Kingdom. As of February 2007, there had been 162 primary cases (contracted, presumably, though contaminated beef) of which six are still alive. Recent research suggests that blood may be a very efficient carrier of vCJD. Prion infection in vCJD can be detected in tonsil tissue but not in blood. The U.K. Health Protection Agency is carrying out an anonymized survey of 100,000 tonsil samples that should reveal how many people are potentially incubating vCJD. As this is a new disease, little is known of its incubation time. However, kuru, a human TSE discovered in Papua New Guinea in the 1950s, can have an incubation period of up to 40 years. Without knowing more about the details of how vCJD is transmitted, it is impossible to say how many more cases of vCJD may occur.
There is no proven cure for any form of CJD at present. However, there are three potential drug treatments under investigation—quinacrine, pentosan polysulphate, and flupirtine. There is some evidence that pentosan polysulphate, given as an injection into the brain, could prolong survival, and the United Kingdom Medical Research Council (MRC) is analyzing data on a number of patients who have received this treatment. One report suggests that flupirtine can improve cognition in CJD but it does not appear to prolong survival. The MRC is currently carrying out a clinical trial on flupirtine.
IN CONTEXT: REAL-WORLD QUESTIONS
About 5–10% of all CJD cases are inherited. These cases arise from a mutation, or change, in the gene (called PRPN, which stands for prion-related protein) that controls formation of the normal prion protein. While prions themselves do not contain genetic information and do not require genes to reproduce themselves, infectious prions can arise if a mutation occurs in the gene for the body's normal prions. If the prion gene is altered in a person's sperm or egg cells, the mutation can be transmitted to the person's offspring. However, not all people with mutations in the prion gene develop CJD. This suggests that the mutations merely increase susceptibility to CJD and that other, still-unknown factors also play a role in the disease.
IN CONTEXT: EFFECTIVE RULES AND REGULATIONS
After inquires in the late 1990s, authorities in the United Kingdom moved to screen out blood donations from donors who unknowingly carry vCJD. Because transmissible spongiform encephalopathies (TSEs) have a long incubation period, however, (in the case of the disease Kuru, up to forty years) it is not clear how many more cases of vCJD will emerge. The BSE episode highlighted the problem of zoonotic disease—that is, the transmission of disease from animals to humans. The recent outbreak of H5N1 related avian flu (“bird flu”) proves this is a continuing concern.
There are a number of drugs which can relieve symptoms and make the patient more comfortable, such as valproate and clonazepam for jerking movements. Eventually, all patients with CJD will require 24-hour nursing care, as they will lose the ability to do anything for themselves.
Prevention of vCJD depends upon elimination of exposure to BSE-contaminated beef. A number of measures have been adopted in Britain and elsewhere to this end. There remains the possibility that people could become infected through CJD-contaminated blood and blood products. The 20 remaining people who received blood from an infected donor in the United Kingdom have been banned from giving blood. In the United States, there are restrictions on people who have resided in the U.K. acting as blood donors, in case they are incubating vCJD.
In 1986, bovine spongiform encephalopathy (BSE) appeared in cattle in the United Kingdom. Researchers identified cattle feed containing remnant parts of slaughtered cows, especially parts of the brain and nervous system, as the likely culprit spreading the disease. The U.K. government banned the use of cattle remnants in feed. In 1992, incidence of the BSE in U.K. cattle peaked in 1992 with 36,700 confirmed, about 1% of the U.K. cattle herd. Despite the epidemic of “mad cow disease,” consumers were assured that British beef products were safe to eat. In 1996, researchers identified BSE-contaminated beef as the probable cause of vCJD in humans.
The link between BSE and vCJD had widespread social and economic effects. The United Kingdom cattle heard was culled of possibly infected animal, resulting in losses to herders. As the emergence of vCDJ received global media attention, consumption of beef within the U.K. dropped dramatically, some estimate as much as 40% in 1996-7. The meat slaughtering and packing industry was scrutinized, revealing slaughtering practices that carried the possibility of BSE-tainted nervous system tissue entering ground beef. Other European nations temporarily banned the import of U.K. beef products and began to evaluate their own herds for BSE. By 2005, BSE had been found in Europe, Asia, North America, and the Falkland Islands, a British territory off of the coast of Argentina. The vCJD epidemic peaked in Britain in 2000, with 28 cases. In 2006, there were five cases. After the U.K., France has had the highest number of vCJD cases. In the U.S., there have been three cases. Worldwide, there have been 201 cases of vCJD in 11 countries.
The vCJD epidemic also prompted fears about the safety of the international supply of human blood, plasma, tissues, and organs. Many nations excluded, or continue to exclude, donors who resided for several months in parts of Europe and the United Kingdom during 1980–2000. People who received transfusions or organ or tissue transplants in the U.K. are also excluded as potential donors in several countries. The three cases of transfusion-associated vCJD in the U.K. came from a pool of 23 recipients of blood from the infected donor. The latest case developed vCJD symptoms eight years after receiving a transfusion. Because the term of incubation for vCJD remains unknown, others who received the contaminated blood remain at risk. Tests that screen donated blood for vCJD are currently under development.
CJD, including vCJD, is still a very rare disease and one which is poorly understood. Although the U.S. researcher Stanley Prusiner was awarded the 1997 Nobel Prize for Medicine or Physiology for his work on prions, there is still much to be learned about how these unconventional infective agents work. For example, the routes of transmission of prion diseases are not yet well established. There is no straightforward diagnostic test, such as a blood test, for CJD. Adding to the difficulty of making an unambiguous diagnosis, most neurologists never have seen a case of CJD even when symptoms are present. The disease, like other TSEs, may be present without symptoms for many years, putting people at risk of infection. However, current research aims to better understand all forms of CJD and other prion-transmitted diseases.
Ridley, R.M, and H.F. Baker. Fatal Protein: The Story of CJD, BSE and Other Prion Disease. Oxford: Oxford University Press, 1998.
Centers for Disease Control and Prevention (CDC). “vCJD (Variant Creutzfeldt-Jakob disease).” January 4, 2007 <http://www.cdc.gov/ncidod/dvrd/cjd/> (accessed February 21, 2007).
U.K. Creutzfeldt-Jakob Disease Surveillance Unit. “National Creutzfeldt-Jakob Disease Surveillance Unit.” February 5, 2007 <http://www.cjd.ed.ac.uk> (accessed February 21, 2007).