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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.

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.

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.

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.

Table 1. Transmissible Spongiform Encephalopathies (Prion Diseases)*

Animal diseases

Scrapie (sheep and goats)

Transmissible mink encephalopathy Wasting disease of deer and elk Bovine spongiform encephalopathy Transmissible spongiform encephalopathy of captive wild ruminants

Feline spongiform encephalopathy

Human diseases


Sporadic Creutzfeldt-Jakob disease Familial Creutzfeldt-Jakob disease Gerstmann-Straussler -Scheinker disease Fatal familial insomnia

New-variant Creutzfeldt-Jakob disease†

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

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.

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.


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.

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 disease occurs worldwide with an incidence of 0.5 to 1.5 cases per million population per year.

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.

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 spongiform 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.

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.

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.

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 PrPres-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 PrPres is positive. These findings led to sequence analysis of the gene for PrP, which found a mutation at codon 178.

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.

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.

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 2006, 22 cases of what is now called new-variant Creutzfeldt-Jakob disease were reported. These patients are younger than those with the more.