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Creutzfeldt-Jakob Disease and Related Transmissible Spongiform Encephalopathies  

Creutzfeldt-Jakob disease is the major transmissible spongiform encephalopathy (or prion disease) in humans. The incidence of Creutzfeldt-Jakob disease has not changed in

Transmissible Spongiform Encephalopathies

A number of transmissible spongiform encephalopathies have been described in animals and humans (Table 1). All have incubation periods of months to years, and all gradually increase in severity and lead to death over a period of months. None evoke an immune response, and all share a common noninflammatory pathologic process restricted to the central nervous system. The only macromolecules thus far associated with infection are isoforms of a host membrane sialoglycoprotein called prion protein (PrP). These transmissible agents appear to have common mechanisms of pathogenesis and possibly a common origin. Some have spread across species barriers (transmissible mink encephalopathy and possibly new-variant Creutzfeldt-Jakob disease); some have reached epidemic proportions by entering the food chain (transmissible mink encephalopathy, bovine spongiform encephalopathy, and kuru); and others have been transmitted by inheritance of mutations in Creutzfeldt-Jacob Disease, spongiform encephalopathies, spongeform, Cruitzfeldt, Crutzfeldt, Jackob, mad cow disease, mad-cow, Jacob, Creutzfeldt

Scrapie is a subacute, progressive ataxia of sheep and goats. Animals affected by scrapie have been recognized by shepherds for over 200 years, and for many years the disorder was regarded as an inherited, degenerative disease of the brain and spinal cord. In 1936 scrapie was reported to be transmitted from sheep to sheep with an incubation period in excess of one year; nevertheless, controversy continues to this day about the natural mode of transmission and the relative role of genetic susceptibility. The disease has been experimentally transmitted to many species, but although amplification occurs in some neural cell lines, no in vitro assay has been developed. Therefore, most of our knowledge of the nature of prions comes from

Recurrent outbreaks of transmissible spongiform encephalopathy have occurred on mink ranches in Wisconsin, and isolated outbreaks have been reported in Canada, Finland, Germany, and Russia. Feed contaminated with tissue from scrapie-affected sheep was assumed to be the mode of transmission, but recent observations suggest that tissue from other infected animal species may also have been involved. Chronic wasting disease of deer and elk is a transmissible spongiform encephalopathy found in captive animals in the western United States and

*Within each category (animal or human diseases), diseases are listed in the order in which they were recognized to be transmissible.

These diseases all appear to have a , spongiform encephalopathies, spongeform, Cruitzfeldt, Crutzfeldt, Jackob, mad cow disease, mad-cow

Kuru was the first human spongiform encephalopathy shown to be transmissible. This subacute, uniformly fatal disease of cerebellar degeneration reached epidemic proportions among the Fore ethnic group in a remote mountainous area of New Guinea. The disease was spread by ritual cannibalism and has gradually disappeared over the 40 years since the practice ceased. The similarities in the epidemiology, clinical course, and histopathological features of kuru and scrapie led to the suggestion that transmission of kuru to

Creutzfeldt-Jakob disease occurs as both a sporadic and a familial disease. Its epidemiologic and clinical patterns are different from those of scrapie and kuru, but it produces similar spongiform changes in the nervous system. These similarities prompted studies of transmission

Species barriers exist against all transmissible spongiform encephalopathies, but these barriers are more impenetrable in some species

Nature of Prions

Studies of the scrapie agent and more limited studies of prions of human origin indicate that the agents are resistant to treatments that inactivate nucleic acids and viruses (alcohol, formalin, ionizing radiation, proteases, and nucleases) but that they are inactivated by

Pathogenesis

In lambs exposed to scrapie-infected flocks, infectivity is first found at about one year of age in the lymphatic tissues and intestines, suggesting transmission by way of the alimentary tract. Infectivity in the brain is found at about two years of age, and infectivity slowly increases in the brain, with resultant spongiform changes and clinical disease during the

Sporadic Creutzfeldt-Jakob Disease

Early Recognition and Epidemiology

Creutzfeldt-Jakob disease was first described clinically and pathologically in the 1920s. However, the patient described by Creutzfeldt and three of the five patients described by Jakob would not fulfill present-day criteria for the diagnosis. Subsequently, an array of eponyms was applied to similar diseases with differing clinical presentations or topographic distributions of pathological findings. The experimental

The disease occurs worldwide with an incidence of 0.5 to 1.5 cases per million population per year. There is no seasonal distribution, no

Many series and case-control studies have searched for risk factors. By analogy to other spongiform en-cephalopathies, dietary factors, exposure to animals, and occupational exposures have been scrutinized. The incidence in Australia and New Zealand, which are free of scrapie, is similar to that in the United Kingdom, where scrapie in sheep is endemic. Neither consumption of brains and offal nor lifetime

Clinical Disease

Eighty percent of sporadic cases of Creutzfeldt-Jakob disease arc diagnosed in persons between 50 and 70 years of age. About one-third of patients initially express vague feelings of fatigue, disordered sleep, or decreased appetite. Another third initially have neurologic

A diagnosis of Creutzfeldt-Jakob disease is suggested by the typical clinical course of inexorable progression, with the dissolution of cognitive abilities from week to week or even day to day, and the development of myoclonic jerking, particularly startle myoclonus, in

Risks of Infection from Patients and Tissues

Consistent experimental transmission of infectivity has been possible with homogenates of brain, spinal cord, and cye tissue. Transmission occurs in less than half of the attempts with preparations of lung, liver, kidney, spleen, lymph node, and cerebrospinal fluid. Transmission to primates has never occurred with any body fluid other than cerebrospinal fluid. Universal precautions should be applied when caring for

Biopsies and autopsies require similar precautions. There is no justification for refusing to perform an autopsy or biopsy. The risk is less than that of a biopsy or autopsy on a patient who is seropositive for hepatitis B virus or the human immunodeficiency virus. Indeed, the risk is theoretical and has not been demonstrated. Safety gloves, disposable aprons, and eye and mouth coverings should be used in handling tissues.

Iatrogenic Creutzfeldt-Jakob Disease

The human-to-human transmission of a spongi-form encephalopathy was tragically demonstrated among the Fore people with kuru. Whether that unique epidemic originated with an index case of sporadic Creutzfeldt-Jakob disease or some other source will probably never be known.

Surgical Transmission

Physicians have inadvertently transmitted sporadic cases of Creutzfeldt-Jakob disease in the course of a variety of procedures (Table 3). The first suspected human transmission was reported in 1974 when rapidly progressive disease developed in a woman 18 months after she

†There were 22 cases in the United Kingdom and 1 in France. The 26-year-old French bodybuilder with new variant Creutzfeldt-Jakob disease may have received injections of bovine pituitary somatotropin.

Transmission by Pituitary Hormones

In 1985 Creutzfeldt-Jakob disease developed in four patients who had received human growth hormone, all of them under 40 years of age. Injection of the hormone, which was derived from pooled cadaveric human pituitary glands, had been discontinued 4 to 15 years before the onset of disease. Recombinant growth hormone was licensed promptly, but between 1963 and

Risks Associated with Blood Products

Although the hazards of injection or transplantation of affected human tissues are obvious, the possible hazards of transmission through human blood products are debatable. Several sorts of evidence have failed to demonstrate a role of human blood products. No epidemiologic evidence

Familial Creutzfeldt-Jakob Disease

Between 10 and 15 percent of persons with Creutzfeldt-Jakob disease have a family history consistent with an autosomal dominant inheritance of the disease. In most of these kindreds, point mutations, deletions, or insertions are found in the coding sequence of the gene for PrP on the

Distinctive Syndromes

Several mutations lead to phenotypes that have been regarded as different diseases. Gerstmann-Straussler-Scheinker disease is an autosomal dominant illness characterized by severe cerebellar ataxia and often spastic paraparesis. In some families myoclonus is not prominent, and dementia may develop late in the course of illness. The disease has a prolonged course of 5 to 11 years, yet the mean age at death is only 48 years. The neuropathological findings are distinct, with many PrP^res-positive amyloid plaques throughout the brain. In two different mutations in kindreds from Indiana and Sweden, neurofibrillary tangles were found in the cerebellum and neocortex -- pathological features akin to those of Alzheimer's disease. The most frequent mutation associated with Gerstmann-Straussler-Scheinker disease is at codon 102, but the syndrome has also been associated with mutations at other sites.

Fatal familial insomnia is an even stranger pheno-type, with a mutation in the gene for PrP. The illness is characterized by progressive insomnia, dysautonomia, and dementia, leading to death in 7 to 15 months. At autopsy, selective atrophy of the ventral and mediodorsal thalamic nuclei is evident. In some patients, spongiform changes are found in the thalamic nuclei, and immunocytochemical staining for PrP^res is positive. These findings led to sequence analysis of the gene for PrP, which found a mutation at codon 178. However, this mutation had also been found in

The Mad-Cow Outbreak

In the spring of 1985, several dairy cows in the United Kingdom were noted to have become apprehensive, developed aggressive behavior, and showed ataxia leading to falling. The pathological findings included spongiform lesions with gliosis and neuronal loss that resembled scrapie. Over the subsequent years, the number of affected cows rose sharply from 16 in 1986, to 7000 in 1989, and to 36,000 in the peak year of 1992. Over 170,000 cases of bovine spongiform encephalopathy have been confirmed in more than 34,000 herds, with no evidence of lateral transmission. The uniformity of the disease and its lesions, the explosiveness of the epidemic, and the wide distribution of cases throughout the

Bovine spongiform encephalopathy has been experimentally transmitted to a variety of species, including laboratory rodents and nonhuman primates. It has been transmitted orally to some species. Infectivity in cattle has been curiously limited to

New-Variant Creutzfeldt-Jakob Disease

Because of concern about cross-species transmission in the United Kingdom, a national surveillance unit for Creutzfeldt-Jakob disease was established in 1990. No unusual cases were noted during the first four years of monitoring, but between 1994 and 2002, 22 cases of what is now called new-variant Creutzfeldt-Jakob disease were reported. These patients are younger than those with the more familiar

Recent laboratory studies provide powerful evidence that the causative agents of new-variant Creutzfeldt-Jakob disease and bovine spongiform en-cephalopathy have a common origin. Glycosylation patterns of PrP^res and susceptibility studies in mice show that the patterns in brain tissue of patients with new-variant Creutzfeldt-lakob disease and animals with bovine spongiform encephalopathy are similar and are...