Creutzfeldt-Jakob disease

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

Before 1995, Creutzfeldt-Jakob disease was little-known outside of the medical profession; even within it, most doctors did not know much about it, and hardly any had ever seen a case. But with the discovery of a "new variant" form, the possibility that those with it 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 asignificance 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 aboutone in every million members of 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.

The most obvious pathologic feature of CJD is the formation of numerous fluid-filled spaces in the brain (vacuoles), giving it 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, predominantly characterized by cerebellar ataxia;and fatal familial insomnia, associated with progressive insomnia, autonomicsystem disfunction, and weakness caused by motor system disfunction.

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 "madcow disease." BSE is thought to be an altered form of scrapie, transmitted to cows when they were fed sheep offal (slaughterhouse waste) as part of theirfeed.

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 been destroying the scrapie agent, thereby preventing infection, and that the change in preparation procedure opened the way for the agent to "jump species" and cause BSE in cows which 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. (It is thought that most cows with BSE became infected as a result of eating meal containing offal from othercows, not sheep.) Although milk from infected cows has never been shown to 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, 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% ofthe 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 U.S. herds in 1990. To date, no BSE has been detected in the United States, and only one casehas been reported in North America in a cow imported to Canada from Britain.

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, 23 in allas of early 1998, are much younger than the 60-65 average for CJD, and the time from symptom onset to death has averaged 12 months instead of eight. EEGabnormalities characteristic of CJD are not typically seen in nvCJD.

Evidence is growing stronger that nvCJD is in fact caused by BSE. While definitive proof was still lacking as of early 1998, many researchers now treat the BSE-nvCJD connection as solidly established.

Assuming that BSE is the source, the question that has loomed from the beginning has been is how many people will eventually be affected. Epidemiologicalmodels of infectious disease produce estimates ranging from less than one hundred to tens of thousands, depending on the assumptions used by the modelers.The incubation period of nvCJD in humans is not known, nor are the genetic and environmental risk factors which influence susceptibility, nor the quantity of infectious agent needed to cause the disease. It is estimated that between one and two million infected cattle have been eaten by humans, most in theearliest stages of the epidemic. Estimates cannot be based on the very few cases which have developed so far. 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.

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 bea 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 radicalnew ideas in biology since the discovery of DNA. All infectious diseases, infact all life, uses nucleic acids--DNA or RNA--to code the instructions needed for reproduction. Inactivation of the nucleic acids destroys the capacityto 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 seeming 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.

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, changesin sleep patterns, weight loss, or loss of appetite or sexual drive. A personwith CJD may first complain of visual disturbances, including double vision,blurry vision, or partial loss of vision. Some visual symptoms are secondaryto cortical blindness related to death of nerve cells in the occipital lobeof 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.

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, or a state of being unable to speak or move.

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 toexclude other forms of dementia, and in CJD typically shows atrophy or lossof 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.

There is no cure for CJD, and no treatment which slows the progression of thedisease. Drug therapy and nursing care are aimed at minimizing psychiatric symptoms and increasing patient comfort. However, the rapid progression of CJDfrustrates most attempts at treatment, since ever-worsening cognitive deficits 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.

Creutzfeldt-Jakob disease is invariably fatal, with death following symptom onset by an average of eight months. About 5% of patients live longer than twoyears. Death from nvCJD 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 thedisease, 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 prevention of nvCJD are a controversial matter, as they involve a significant sector of the agricultural industry and a central feature ofthe diet in many countries. The infectious potential of contaminated meat isunknown, 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 highlyunlikely. 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 EuropeanUnion, although some herds in these countries have developed low levels of infection as well.

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