Creutzfeldt-Jakob disease (CJD) is a transmissible, rapidly progressing, fatal neurodegenerative disorder called a spongioform degeneration that seems to be related to “mad cow disease.”
Creutzfeldt-Jakob disease (CJD) affects many areas of the brain. At UCSF, CJD is sometimes called the “great mimicker” because it causes symptoms that occur in many other neurological diseases.
Before 1995, Creutzfeldt-Jakob disease was little-known outside of 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” or simply variant form of CJD with 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 has also sparked much interest.
First described in the first part of the twentieth century independently by Cretzfeldt and Jakob, CJD is a neurodegenerative disease causing a rapidly progressing dementia ending 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 in the population through out 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.
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 predominantly characterized by cerebellar ataxia (a kind of movement disorder); and fatal familial insomnia, associated with progressive insomnia, autonomic system disfunction, and weakness caused by motor system dysfunction.
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 following the cessation of these 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, 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 between 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 it is now thought to be more likely to be 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 has never been shown to pass the infectious agent, passage from infected mother to calf may have occurred through unknown means.
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 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 did stem 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. To date, no BSE has been detected in the United States, and only one case has been reported in North America in a cow imported to Canada from Great Britain.
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 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 deoxyribonucleic acid (DNA). All infectious diseases, in fact all life, uses 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. 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: sub-unit 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 their 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. All the cases of vCJD tested have had just methionine at 129. 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 may more spontaneously “flip” to the sheet form; once created, these 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.
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.
First symptoms vary widely and may include the following:
* memory losses
* impaired abstraction and planning
* language and comprehension disturbances
* poor judgment
* decreased attention and increased restlessness
* personality changes and psychosis
* Behavioral and personality changes
* Confusion and memory problems
* Lack of coordination
* Strange physical sensations
* Vision problems
As the disease advances, patients may experience a rapidly progressive dementia and in most cases involuntary and irregular jerking movements called myoclonus.
Patients also may appear startled and become rigid. In advanced stages of the disease, patients have difficulties with movement, swallowing and talking. In the final stage, patients lose all mental and physical function and may lapse into a coma. Many patients die from an infection such as pneumonia.
The average duration of disease – from the onset of symptoms to death – is four to six months. Ninety percent of patients die within a year. Some cases progress very rapidly, lasting only a few weeks before the patient’s death, and others may last two or three years, especially if the disease occurs at an early age.
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.
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.
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 vCJD has averaged approximately 12 months after onset.
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 that inactivate prion proteins.
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. 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.
By Larry I. Lutwick MDThe Gale Group Inc.