DESCRIPTION

Creutzfeldt-Jakob Disease (CJD), first identified in the 1920s by German neuropsychiatrists Hans Creutzfeldt and Alfons Jakob, is a rare fatal brain disorder, which causes a rapid, progressive dementia and associated neuromuscular disturbances. The disease is often referred to as a subacute spongiform encephalopathy because it usually produces microscopic vacuoles in neurons that appear "sponge-like". The disease causes fatal degradation of brain tissue and produces a dementia that affects men and women, often between the ages of 50 and 65. There is no record of anyone recovering from the disease and there is no known treatment.

Creutzfeldt-Jakob disease is found worldwide but is relatively rare, affecting about 0.9 people per million in the United States. CJD can afflict anyone. The disease affects both men and women of diverse ethnic backgrounds usually between the ages of 50 to 75 years. The mean age of death is 67 years. Deaths from Creutzfeldt-Jakob disease are uncommon in people under age 50. In people age 70 to 74 years, the disease causes 5.9 deaths per million people.

However, in the past two years, a new branch of the epidemic has shown itself in teenagers and young people who ate hamburgers, sausages and meat pies infected with bovine spongiform encephalopathy (BSE) or mad cow disease. Called new variant CJD (nvCJD), it has claimed 23 lives to date, a figure many believe to be just the start of a frightening new stage in accidental CJD transmission.

CJD is among a group of rare human diseases that induce neurological disaster - microscopic holes in the brain, sticky plaques of protein that prevent vital messages between nerve cells - and a plethora of symptoms including staggering, jerking, memory loss, personality change and dementia. Collectively, they are known as transmissible Spongiform Encephalopathies, or TSEs. Several theories about the elusive cause of TSE remain just that - despite two Nobel prizes among the elite group of scientists and researchers battling to identify the diseases' source.

Other human TSEs include kuru in Papua New Guinea, which is believed to be transmitted in the course of funerary rituals involving brains of corpses; Gerstmann-Sträussler-Schenker (G.S.S.) syndrome (occurring in persons with an apparent hereditary predisposition) and fatal familial and sporadic insomnia. CJD is the most common of all the human TSEs and is the disease most commonly mistaken for nvCJD.

CJD and its related diseases can incubate in humans for decades. Kuru cases are still emerging, despite the cessation of cannibalism in the late 1950s. Infection from blood transfusion remains a theoretical but frightening possibility. The legacy of accidental CJD transmission will continue for years to come.

CAUSE

Scientists recognize that a transmissible agent is responsible for causing Creutzfeldt-Jakob Disease, as shown by experiments involving the injection of CJD-affected brains into the normal brains of healthy animals. The identification of this transmissible agent has been the subject of much scientific inquiry and debate. Initially, the agent was thought to be a slow virus due to the unusually long incubation period between the time of exposure to the pathogen and the onset of symptoms. Further research, however, has indicated that this agent differs significantly from viruses and other conventional agents. Whereas viruses and other known infectious agents contain nucleic acids which house a cell's genetic material, researchers have been unable to identify any nucleic acids in the CJD agent. Additionally, the chemical and physical procedures that inactivate most viruses have proved ineffective in decreasing the infectivity of the CJD pathogen.

In contrast, the procedures that degrade protein have been found to inactivate the pathogen. Accordingly, a new theory regarding the transmissible agent has emerged and recently gained widespread acceptability. This theory holds that the transmissible agent is neither a virus nor other previously known infectious agent, but rather an unconventional agent consisting of protein. This newly-discovered pathogen is called a "prion", short for " proteinaceous infectious particle". Prions are thought to transform normal, benign protein molecules into infectious, deadly ones by altering the shape of the healthy molecules to the dangerous conformation. Creutzfeldt-Jakob Disease is probably caused by a prion - just how prions cause the disease symptoms remains unclear.

TSE are not only infectious, they are also inheritable in a very small number of cases. They have no cure and no treatment. Sporadic CJD occurs at a rate of one in each million of population in each country annually, mainly in elderly people. And those who have died of CJD (and who have incubated it in the decades before physical symptoms become apparent) have unwittingly transmitted the disease accidentally to others through routes including "donated" pituitary glands, brain lining called dura mater and corneal transplants. Whatever the cause - a yet-to-be identified virus, virino, or prion - TSEs are among the worst diseases yet identified. The infective agent resists heating to phenomenal temperatures, freezing, burial underground for years, the strongest of chemicals, and surgical sterilization.

Ignorance of these unusual properties led to inadvertent outbreaks of iatrogenic (doctor-induced) CJD through fledgling experiments on humans from the late 1950s infertility drugs, human growth hormone (hGH) injections in children, grafts of dura mater, corneal transplantation and re-use of surgical instruments.

The biggest TSE killer in humans is CJD. Since then, painstaking detective work by scientists in the United States, Europe and Japan has followed the course of the disease. There are three types of the disease: sporadic, genetic, and iatrogenic.

Sporadic Creutzfeldt-Jakob disease is the most common form and accounts for around 85 percent of all human prion disease. In such cases, the gene coding for the prion protein undergoes a spontaneous mutation. The gene then codes for the abnormal, infective form of the protein. A small number of mutant cells producing a small amount of prion protein can initiate a progressive infection. Recent research suggests that this occurs because the abnormal protein can transform normal molecules by causing them to change their configuration.

Genetic Creutzfeldt-Jakob disease causes 10 to 15 percent of prion disease cases. It occurs when a mutant prion gene is passed genetically from one generation to another. In families expressing the mutant gene, about half the members die of the disease.

Iatrogenic Creutzfeldt-Jakob disease results from an individual with the disease infecting a healthy individual. This is rare but known cases involve surgery or transfusion procedures such as corneal transplants or human growth hormone injection. The disease has been characterized only recently and it may take up to 20 years to express itself or may not be recognized until the patient dies. For these reasons, many individuals may have been infected inadvertently with Creutzfeldt-Jakob disease in the past and could be at risk of developing the disease. It is estimated that 25,000 such cases exist worldwide.

In Australia, more than 1500 women were treated with the injectable fertility drug, human pituitary gonadotrophin (hPG). It created miracle children, infamous multiple births - and tragedy. This Federal Government-sponsored hormone extract, made from pituitary glands sliced from the brains of bodies in morgues, has killed four women. One young man, among the 700-odd children who received hGH (human growth hormone) injections between 1967 and 1985 in Australia, has died. Despite intensive effort fuelled by an independent inquiry into the medical program that oversaw the use of these drugs, not every recipient has been traced and warned not to donate organs, tissues or blood. We have witnessed lawsuits by devastated relatives angered that no one has taken responsibility for hormone-induced CJD.

Creutzfeldt-Jakob disease is similar to bovine spongiform encephalopathy (BSE), a prion-related brain disease of cows discovered in the United Kingdom in 1986 and commonly known as mad cow disease. Mad cow disease can be transmitted from sheep to cows, but until recently there has been no significant evidence that beef contaminated with BSE can infect humans. Prions are generally species-specific—that is, they tend to affect species closely related to the organism originally producing the protein. For this reason, scientists thought it unlikely that humans could contract the disease from eating infected beef.

Nevertheless, in late March 1996 the British Ministry of Health announced the discovery of 10 cases of a newly described type of fatal CJD, called new variant CJD (nvCJD). The victims of nvCJD had distinct brain tissue abnormalities, they were all under the age of 42, and they had no hereditary record of the disease. Despite a lack of scientific evidence proving the cattle-human disease link, the British government admitted that the victims might have contracted the disease through contact with BSE-infected cattle. The announcement represented an about-face in the stance of the government, which had previously denied any possible link between BSE and human disease. Britain is about to enter a yearlong judicial inquiry into the BSE epidemic, which has taken human lives, resulted in the killing of about 200,000 cows. Rising concern over the possibility of transmission of BSE to humans from infected beef resulted in the banning of exported beef from the United Kingdom in 1996.

Although the hypothesis of the cattle-to-human transmission remains unproven, it is supported by the results of a number of scientific studies, including two released in 1997. Laboratory mice injected with brain tissue from BSE-infected cows and another group injected with brain tissue from nvCJD-infected humans both developed the same symptoms of brain degeneration and the infection was ultimately fatal in both groups. In addition, researchers found the same prion strain in both groups of mice. In one of the studies, researchers injected a third group of mice with tissue from humans who had died of classical CJD; these mice developed no symptoms and survived the trial.

In early 1998 scientists found that prions are found not only in the brain tissue of infected humans but in other organs and the blood as well. The potential public health problems have focused the attention of the medical community on the various forms of CJD and other prion diseases.

SYMPTOMS

The initial stage of the disease can be subtle with ambiguous symptoms of insomnia, depression, confusion, personality and behavioral changes, strange physical sensations, and problems with memory, coordination and sight. As the disease advances, the patient experiences a rapidly, progressive dementia and in most cases, involuntary and irregular jerking movements known as myoclonus. Problems with language, sight, muscular weakness, and coordination worsen. The patient may appear startled and become rigid. In the final stage of the disease, the patient loses all mental and physical functions. The patient may lapse into a coma and usually dies from an infection like pneumonia precipitated by the bedridden, unconscious state. Some 90 percent of cases progress to death within one year, sometimes within one month. The remaining 10 percent of cases develop dementia and may slowly decline over several years.

New Variant form of CJD New variant Creutzfeldt-Jakob disease (nvCJD or vCJD) is a rare and fatal human neuro-degenerative condition. Like Creutzfeldt-Jakob disease (CJD), vCJD is classified as a transmissible spongiform encephalopathy (TSE) because of characteristic spongy degeneration of the brain and its ability to be transmitted. vCJD is a new disease which was first described in March 1996.

In contrast to the classic form of CJD, the new variant form, that experts in the United Kingdom believe might be related to the BSE outbreak in cattle, predominantly affects younger persons (median age at death: 27.5 years as of October 2000). The hypothesis of a link between vCJD and BSE was first raised because of the association of these two TSEs in time and place. More recent evidence supporting a link includes identification of pathological features similar to vCJD in brains of macaque monkeys inoculated with BSE. A vCJD-BSE link is further supported by the demonstration that vCJD is associated with a molecular marker that distinguishes it from other forms of CJD and which resembles that seen in BSE transmitted to a number of other species. Studies of the distribution of the infectious agent in the brains of mice artificially infected with tissues from humans with vCJD and cows with BSE showed nearly identical patterns. The most recent and powerful evidence comes from studies showing that the transmission characteristics of BSE and vCJD in laboratory mice are almost identical, strongly indicating that they are due to the same causative agent.

NvCJD has atypical clinical features, with prominent psychiatric or sensory symptoms at the time of clinical presentation and delayed onset of neurological abnormalities, including ataxia within weeks or months, dementia and myoclonus late in the illness, a duration of illness of at least 6 months, and a diffusely abnormal non-diagnostic electroencephalogram. Early in the illness, patients usually experience psychiatric symptoms, which most commonly take the form of depression or, less often, a schizophrenia-like psychosis. Unusual sensory symptoms, such as "stickiness" of the skin, have been experienced by half of the cases early in the illness. Neurological signs, including unsteadiness, difficulty walking and involuntary movements, develop as the illness progresses and, by the time of death, patients become completely immobile and mute.

The characteristic neuropathologic profile of nvCJD includes, in both the cerebellum and cerebrum, numerous kuru-type amyloid plaques surrounded by vacuoles and prion protein (PrP) accumulation at high concentration indicated by immunohistochemical analysis.

DIAGNOSIS

A diagnosis of CJD should be considered when an adult patient develops a rapid dementia and myoclonus. Unfortunately, confirming a diagnosis of CJD has historically been difficult as traditional laboratory tests have been ineffective in detecting CJD. The disease does not induce a fever or other systemic manifestations. The cerebrospinal fluid most often appears normal, except for an occasional elevation in the protein content. Magnetic resonance imaging ("MRI"), position emission tomography ("PET"), and x-rays have not been helpful in diagnosing CJD. A computed tomography ("CT") brain scan is usually normal, but may show some atrophy, a nondiagnostic finding seen in many other neurological conditions. The most helpful test has been the electroencephalogram ("EEG"), which measures brain wave activity. The EEG often shows a characteristic abnormal pattern, typically observed in later stages of the disease, but the EEG does not confirm a CJD diagnosis.

Accordingly, a definitive diagnosis of CJD has traditionally required a brain biopsy or autopsy that can detect the characteristic changes in the brain tissue caused by the disease. Moreover, a brain biopsy may sometimes produce a false-negative result if the biopsied area was unaffected by the disease. At the present time, however, a new test is being developed to diagnose CJD by examining the cerebrospinal fluid. Additional tests proposed to confirm a diagnosis of CJD include identifying the presence of the deadly prion protein, identifying the prion gene mutation, and transmitting the disease from the human patient to animals.

The difficulties involved in diagnosing CJD may have prevented the identification of the disease in some cases. Because brain biopsy for diagnosing CJD is invasive, costly and risky, it is often not performed. Additionally, some physicians may not even consider the possibility of a CJD diagnosis since the disease is deemed to be rare and the clinical symptoms of CJD can often be attributed to other ailments. Consequently, CJD may be mistaken for a variety of psychological illnesses and other neurological disorders like Alzheimer's disease, Pick's Disease, Huntington's Disease, cerebral hematomas and vascular irregularities. The extent to which such misdiagnosis may have occurred is presently unknown.

TREATMENT

At the present time, there is no known effective treatment or cure for CJD. The disease is inevitably fatal.

PREVENTION

According to the Animal and Plant Health Inspection Service of the U.S. Department of Agriculture, BSE has not been detected in the United States, despite active surveillance efforts since May 1990. As of October 31, 2000, 11,700 bovine brain specimens had been examined by an ongoing BSE surveillance system in the United States, and no evidence of BSE was seen. Further, to prevent BSE from entering the United States, severe restrictions were placed on the importation of live ruminants and certain ruminant products from countries where BSE was known to exist. These restrictions were later extended to include importation of ruminants and certain ruminant products from all European countries.

The possibility that BSE can spread to humans has focused increased attention on the desirability of national Creutzfeldt-Jakob disease (CJD) surveillance to monitor the incidence of CJD in the United States. The Centers for Disease Control and Prevention (CDC) monitors the trends and current incidence of CJD in the United States by analyzing death certificate information from U.S. multiple cause-of-death data, compiled by the National Center for Health Statistics, CDC. (A summary of these data was published in the Journal of the American Medical Association on November 8, 2000 (Volume 284, No. 18, pp. 2322-3; available at http://jama.ama-assn.org/issues/v284n18/ffull/jlt1108-6.html).

By 4-year periods from 1987 through 1998, the average annual death rates have remained relatively constant, ranging from 0.98 cases per 1 million in 1987-1990 to 1.03 cases per 1 million in 1995-1998. In addition, CJD deaths in persons aged <30 years in the United States remain extremely rare (<5 cases per 1 billion per year). In contrast, in the United Kingdom, over half of the patients who died with new variant CJD were in this young age group.

The World Health Organization (WHO) From 1997-2000, WHO held a series of training courses worldwide, particularly in developing countries, with the intention of helping individual countries establish national surveillance of CJD and its variants. The first workshop, for West African countries, was held in Dakar, Senegal in June 1997. Similar workshops were held in Bangkok for Southeast Asian countries (October 1997), in Cairo for North African countries (February 1998) and in China for countries of the Western Pacific (July 1999) and for Eastern and Central European countries in May 2000. Another is planned for Mediterranean countries.

RELATED VIRUS SITES

Regularly updated numbers of reported BSE cases, by country, are available on the website of the Office International Des Epizooties at: http://www.oie.int/eng/info/en_esb.htm

Regularly updated numbers of bovine brain samples tested as part of the nationwide BSE surveillance program are available at: http://www.aphis.usda.gov/oa/bse/bsesurvey.html#charts

Recently published data show an increasing trend for the epidemic of new variant CJD in the United Kingdom. A listing of monthly updated numbers of new variant CJD cases in the United Kingdom is available at: http://www.doh.gov.uk/cjd/cjd_stat.htm

For the final opinion of the European Union's Scientific Steering Committee on the Geographic Risk of BSE, please see: http://www.europa.eu.int/comm/food/fs/sc/ssc/out113_en.pdf

In 1999, a review was conducted of the known information about a number of animal TSEs to try to proactively determine if there are any new TSE threats. Their principle recommendations were to eradicate BSE and to find out if BSE has infected sheep populations. The recommendations are available at: http://www.who.int/emc-documents/ under the heading ‘TSE’.

WHO published guidelines for infection control of TSEs in 2000. The full text is available at http://www.who.int/emc-documents/ under the heading ‘TSE’.

ARTICLES AND LINKS

“Notice to Readers: Public Health Service Recommendations for the Use of Vaccines Manufactured with Bovine-Derived Materials”; article found at http://www.cdc.gov/mmwr/. Excerpt from the article:

“The Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA) learned earlier this year (2000) that some vaccines were manufactured with bovine-derived materials obtained from countries in which bovine spongiform encephalopathy (BSE) or a substantial risk for BSE exists. The U.S. Department of Agriculture (USDA) publishes a list of these countries. This information was of concern because cases of variant Creutzfeldt-Jakob disease (vCJD) have been attributed to, among other possibilities, eating beef products from cattle infected with the agent of BSE. No evidence exists that cases of vCJD are related to the use of vaccines, and no cases of vCJD have been reported in the United States. Additional information about BSE or vaccines manufactured with bovine-derived materials from countries on the USDA list can be obtained from the FDA World-Wide Web site, http://www.fda.gov/cber/BSE/BSE.htm or from CBER's Office of Communications, Training and Manufacturers Assistance, telephone (800) 835-4709.”

CONDITION & SUPPORT SITES FOR CJD AND nvCJD

For additional information on CJD, contact the following organizations:

National Center For Infectious Diseases (NCID) – www.cdc.gov/ncidod

Creutzfeldt-Jakob Disease Foundation, Inc. P.O. Box 611625; North Miami, Fl. 33261-1625 E-Mail: crjakob@aol.com

National Institute of Neurological Disorders and Stroke National Institutes of Health; 31 Center Drive MSC 2540 Bethesda, Md. 20892-2540; (301) 496-5751 or (800) 352-9424 Website: http://www.nih.gov/ninds

National Organization For Rare Disorders (NORD) P.O. Box 8923 New Fairfield, Ct. 06812-1783 (203) 746-6518 E-Mail: orphan@nord-rdb.com Website: http://www.nord-rdb.com/~orphan