NR ANLF
AU Belay,E.D.; Maddox,R.A.; Gambetti,P.; Schonberger,L.B.
TI Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States
QU Neurology 2003 Jan 28; 60(2): 176-81
PT journal article
AB Transmissible spongiform encephalopathies (TSEs) attracted increased attention in the mid-1980s because of the emergence among UK cattle of bovine spongiform encephalopathy (BSE), which has been shown to be transmitted to humans, causing a variant form of Creutzfeldt-Jakob disease (vCJD). The BSE outbreak has been reported in 19 European countries, Israel, and Japan, and human cases have so far been identified in four European countries, and more recently in a Canadian resident and a US resident who each lived in Britain during the BSE outbreak. To monitor the occurrence of emerging forms of CJD, such as vCJD, in the United States, the Centers for Disease Control and Prevention has been conducting surveillance for human TSEs through several mechanisms, including the establishment of the National Prion Disease Pathology Surveillance Center. Physicians are encouraged to maintain a high index of suspicion for vCJD and use the free services of the pathology center to assess the neuropathology of clinically diagnosed and suspected cases of CJD or other TSEs.
VT
Received May 7, 2002. Accepted in final form August 28, 2002
Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are neurodegenerative disorders that occur in humans and animals. They are believed to be caused by the accumulation in neurons of an abnormal isoform of a membrane glycoprotein known as the prion protein. TSEs in humans generally occur as a rare, sporadic disease with no recognizable pattern of transmission or as a familial disease associated with prion protein gene mutations.[1] Iatrogenic transmission of Creutzfeldt-Jakob disease (CJD) is relatively uncommon, but may occur in outbreaks (e.g., human growth hormone-associated CJD) that can be controlled with the implementation of appropriate preventive measures.[2-4] In the 1980s, the emergence in Europe of a large outbreak of bovine spongiform encephalopathy (BSE) in cattle and, more recently, an outbreak of a new variant form of CJD (vCJD) in humans linked with food-borne transmission of the BSE agent has raised serious concerns about the geographic spread and ultimate number of cases of these diseases. In April 2002, a probable case of vCJD was identified in a Florida resident who was born in Britain and raised there throughout the 1980s, a period when the BSE outbreak was rising and no control measures to prevent human exposure were instituted. Increased concern about the occurrence of TSEs led to increased surveillance and implementation of BSE control measures in the United States and other countries currently free of endemic BSE and vCJD.
The presumed food-borne transmission of BSE to humans has also raised concerns about the possible zoonotic transmission of chronic wasting disease (CWD) of deer and elk.[5] CWD was first recognized in the late 1960s among captive mule deer housed in research facilities in Fort Collins, CO. Since then, the disease has been shown to be endemic among free-ranging deer and elk in northeastern Colorado and southeastern Wyoming.[6] From 2000 through 2002, CWD in free-ranging deer was detected in locations outside of the known endemic areas in western Colorado, Nebraska, New Mexico, South Dakota, Wisconsin, and Saskatchewan, Canada. Beginning in 1996, outbreaks of CWD in privately-owned elk farms were reported in different parts of the United States and Canada, including Alberta, Colorado, Kansas, Montana, Nebraska, Oklahoma, Saskatchewan, and South Dakota.[7]
Bovine spongiform encephalopathy. BSE was first identified as an emerging TSE in 1986 in the United Kingdom where it caused a major outbreak among cattle that is now on the decline. Statistical models have indicated that the first BSE cases may have occurred in the early 1980s.[8] As of June 30, 2002, over 179,300 cases of BSE had been confirmed in Great Britain; 1,032 of the cases occurred in 2001 and 665 during the first half of 2002.[9] However, the actual number of cattle infected with the BSE agent has been estimated to be around 1 million.[10] BSE is believed to have resulted from the feeding of cattle with contaminated protein-rich meat-and-bone meal produced by rendering discarded animal carcasses.[11] The leading hypotheses for the origin of BSE include contamination of the meat-and-bone meal by an agent causing scrapie in sheep or by a spontaneously occurring, unrecognized BSE in cattle. Before the late 1970s, rendering of carcasses to produce meatand- bone meal had included a solvent extraction and solvent recovery steps that subjected the rendered material to prolonged heating in the presence of a hydrocarbon solvent. Omission of these treatment steps in the late 1970s and early 1980s in most rendering plants in the United Kingdom is believed to have contributed to the emergence of BSE by allowing passage of the infective agent to the finished product.[11] As more cattle died of BSE, their carcasses continued to be rendered and fed to other cattle, and this practice amplified the BSE outbreak until the use of ruminant protein in ruminant feed was banned in the United Kingdom in 1988.[11,12] Consistent with the 2- to 8-year incubation period of the disease in cattle, the BSE outbreak in the United Kingdom declined beginning in 1993, about 5 years after the feed ban, although cases continue to occur at a much lower rate. The continued occurrence of BSE, particularly among cattle born after the 1988 ban, was primarily attributed to cross-contamination of cattle feed by feed intended for nonruminant species that could have been contaminated by BSE.[13]
In 1989, the concern that BSE may cross species and infect humans precipitated a ban in the United Kingdom to exclude specified risk materials (e.g., brain, spinal cord, distal ileum) from cattle products destined for human consumption.[12] The UK preventive measures were increasingly tightened, and a policy was put in place in 1996 to prevent cattle aged >30 months, regardless of their health status, from entering the human or animal food chains.[13]
Elsewhere in Europe, through 1999, the occurrence of BSE among native cattle had been reported in Belgium, France, Ireland, Liechtenstein, Luxembourg, Netherlands, Portugal, and Switzerland.[14]
From 2000 through 2001, the reported incidence of BSE rose in some of these European countries, and initial indigenous BSE cases were detected in Austria, the Czech Republic, Denmark, Finland, Germany, Greece, Italy, Japan, Slovakia, Slovenia, and Spain. The growing number of countries with endemic BSE led to increased public concern about the safety of European and Japanese cattle products. In response to these BSE outbreaks, the European Commission proposed a temporary prohibition of the use of animal protein in all farmed animals, pending re-evaluation of other control measures adopted by the member states.[15] These control measures, which varied by country, included ruminant feed bans, removal of specified risk materials, such as the brain and spinal cord, from cattle products intended for human use, and mandatory brain testing of cattle older than 30 months that are destined for human consumption. Most recently, during the first half of 2002, Israel and Poland reported their first indigenous BSE cases. BSE in imported cattle only, in the absence of indigenous cases, was reported in Canada (1 case), Falkland Islands (1 case), and Oman (2 cases).[14]
Since 1989, to prevent the introduction of BSE into the United States, the US Department of Agriculture (USDA) restricted the importation of live cattle and certain cattle products from the United Kingdom and other BSE-endemic countries. In 1997, this restriction was expanded to prohibit importation of cattle and certain cattle products from all European countries, and most recently from Japan and Israel. In addition, the USDA trained veterinarians and veterinary laboratory workers on the clinical and pathologic manifestations of BSE and instituted an ongoing BSE surveillance program.[16] As of September 2002, these USDA surveillance efforts, including analysis of brain specimens from 36,594 cattle, had detected no evidence of the occurrence of BSE in the United States. To provide protection against the spread of BSE should it be introduced into the United States, the Food and Drug Administration (FDA) published a final rule in 1997 that prohibited the use of most mammalian protein, particularly ruminant tissues, in the manufacture of ruminant feed.[17,18]
Variant Creutzfeldt-Jakob disease. Variant CJD was reported as a distinct disease entity in April 1996 after the UK government's expert advisory committee announced its conclusion that the BSE agent may have crossed the species barrier, causing an outbreak of the disease in humans.[19] The possibility that BSE could cross the species barrier to infect humans had been suspected about 6 years earlier with the identification among domestic cats in the United Kingdom of feline spongiform encephalopathy, whose agent characteristics were similar to the BSE agent. Transmission of the BSE agent presumably via ingestion of contaminated feed has also been reported in exotic ungulates and wild cats in British zoos.[11]
As of October 4, 2002, a total of 138 vCJD cases had been reported: 128 definite or probable cases in the United Kingdom (includes one UK resident who was hospitalized and died in Hong Kong), 6 in France, and 1 each in Canada, Ireland, Italy, and the United States.[12,20-22] The Canadian, Irish and US cases resided in the United Kingdom during a key exposure period of the UK population to the BSE agent. The continued occurrence of vCJD cases only in persons who have lived in BSE-endemic areas, particularly the United Kingdom where most BSE cases were identified, and several animal and molecular laboratory studies provide strong evidence that vCJD is causally linked with BSE.[23-27]
Statistical analysis of the numbers of definite and probable vCJD cases reported through June 2000 indicated an increasing trend for the vCJD outbreak in the United Kingdom.[28] However, the persistency of this increasing trend or the eventual magnitude of the vCJD outbreak remains unknown. From statistical models, UK researchers had predicted that the total number of vCJD cases would likely range between 70 and 136,000, depending upon various assumptions about the mean incubation period.[29] Two recently published studies using other statistical models suggested that the UK vCJD outbreak might not exceed several hundred clinical cases.[30,31] One of these studies pointed out the possibility that the incubation period could be so long that even if millions of persons were infected with the agent of vCJD, a large majority of these people could die of other competing causes before they developed the TSE illness.[31] Such infected persons could pose a potential, albeit unknown, risk for secondary transmission of the agent (e.g., transmissions by contaminated surgical instruments).
A most striking feature of patients with vCJD compared with patients who have classic CJD is their unusually young age at the time of illness onset.[18,32] On the basis of the initially reported 110 vCJD deaths in the United Kingdom, the median age at death was 28 years; 60% died at <30 years of age, and approximately 13% died as teenagers (R.G. Will, personal communication, 2002). In addition to the age distribution, the clinicopathologic profile of patients with vCJD and immunoblot characteristics of the vCJD agent differed from that seen in patients with classic CJD (table 1). The UK patients with vCJD usually presented with early and persistent psychiatric symptoms, commonly with depression, anxiety, and withdrawal.[32] Some of the patients were initially regarded as having a primary psychiatric illness and were treated by a psychiatrist early in the course of the disease. Evaluation of the clinical manifestations of the first 100 patients with vCJD in the United Kingdom indicated that the onset of frank neurologic signs such as gait disturbance, slurring of speech, and tremor was usually delayed by several months after illness onset.[32,33] The most striking early neurologic sign in some of these patients was persistent dysesthesia or paresthesia. Other neurologic signs, including chorea, dystonia, and myoclonus, frequently developed late during the course of the illness (see the Appendix). None of the vCJD cases reported to date had the EEG tracing of periodic triphasic complexes often seen in patients with sporadic CJD. In addition, a prominent, symmetric pulvinar high signal on T2-weighted or proton density-weighted MRI has been reported in about 78% of patients with vCJD.[34] This prominent pulvinar high signal has been designated the "pulvinar sign." The MRI high signals have been shown to correlate with underlying neuropathologic findings of astrocytosis and neuronal loss. The polymorphic codon 129 of the prion protein gene in all patients with vCJD on whom genetic studies have been performed was shown to be homozygous for methionine.[31]
Neuropathologic evaluation of a brain autopsy specimen is required for a confirmatory diagnosis of vCJD. In addition to the presence of the typical spongiosis, gliosis, and neuronal loss that are considered a hallmark of CJD, the neuropathologic characteristics of vCJD include the presence of numerous amyloid plaques that are surrounded by a halo of spongiform changes, resembling the "florid plaques" first described in experimental transmission of Icelandic scrapie in mice.[35] In addition, immunohistochemical staining demonstrates marked accumulation of the diseaseassociated prion protein in diffuse or pericellular deposits in the cerebrum and cerebellum. Detection of the protease-resistant prion protein by immunohistochemical and immunoblot analyses outside of the brain in lymph nodes, spleen, and tonsils of patients with vCJD has been reported.[36,37] On immunoblot analysis, the protease-resistant prion protein fragment from patients with vCJD characteristically has a glycoform ratio that has not been described in sporadic CJD.[38]
Table Clinical and laboratory characteristics distinguishing variant Creutzfeldt-Jakob disease (CJD) from the classic form of CJD
Characteristics Variant CJD Classic CJD
Median age at death, y 28 68
Clinical presentation Psychiatric or sensory symptoms; delayed appearance of neurologic signs
Dementia associated with neurologic signs
Median illness duration, mo 13 4
Periodic short waves on EEG tracings Absent In about 75% of patients Symmetrical pulvinar high signal on MRI In over 75% of patients Not reported
Codon 129 genotype Methionine/methionine Polymorphic
Numerous "florid plaques" on neuropathology In all patients Absent
Immunohistochemical analysis of brain tissue Marked accumulation of PrPres Variable
Increased glycoform ratio on immunoblot analysis of PrPres In all patients Not reported
Presence of infective agent in lymphoid tissues Readily detected Not readily detected
PrPres - Protease-resistant prion protein.
The reason for the predominant occurrence of vCJD among patients under 30 years of age is unknown. Differential consumption of potentially contaminated meat products by the younger population has been suggested as a possible contributory factor to the age distribution of vCJD.[39] However, vCJD has been confirmed in a 74-year-old man who died in 1999, 7 months after illness onset.[40] The older patient's clinical and pathologic phenotype and methionine homozygosity at codon 129 were similar to that of other patients with vCJD. He presented with psychiatric symptoms and was initially admitted to a psychiatric unit and treated for a psychotic illness. The patient became increasingly forgetful and unsteady and had recurrent falls. He had complaints of various episodes of pain for which no cause could be established. Histopathologic examination of the brain autopsy tissue showed the presence of florid plaques in large numbers in the cerebral and cerebellar cortices. Although clearly an outlier, the identification of vCJD in a patient at 74 years of age indicates that some persons in older age groups can potentially be susceptible to contracting vCJD.
Creutzfeldt-Jakob disease surveillance in the United States.
The emergence of BSE and vCJD in Europe created a concern that US residents might be exposed to BSE-contaminated cattle products from Europe or to possibly unrecognized BSE in the United States. For example, concern was raised about the possibility that US residents who traveled or resided in the United Kingdom or other BSE-endemic countries since 1980 could potentially have been exposed to the BSE agent. In April 2002, the first case of vCJD in a US resident was reported in a 22-year-old Florida patient who was born and raised in Britain and moved to the United States in 1992. As of October 2002, the patient, whose illness began in November 2001, was still alive. Her illness fulfills UK criteria for probable vCJD.
In 1998, the American Medical Association Council on Scientific Affairs called for increased CJD surveillance to monitor the possible occurrence of vCJD in the United States.[41] Among other recommendations, the council indicated that physicians should become knowledgeable about BSE to be able to advise their patients about the possible risk of exposure to the BSE agent during travel abroad. To facilitate such advice to travelers, CDC provides a traveler's advisory about the possible risk of BSE exposure during travel to Europe.[42] There is also a concern about a possible, albeit theoretical, risk of secondary person-to-person transmission of the vCJD agent via blood and blood products. This risk is considered theoretical because no convincing evidence for transmission of either classic CJD or vCJD via blood or blood products has been reported in the human population. However, the world's limited experience with vCJD, the presence of the vCJD agent in lymphoid tissues of infected patients, and transmission of the BSE agent by blood transfusion in an experimental sheep model during the incubation period contributed to the concern about the possible transmission of the vCJD agent through the blood supply.[43] This concern is further complicated by the long incubation period of the disease. Because the incubation period is measured in years or decades, should blood-borne transmissions occur in humans, many recipients would have been exposed before the first blood-borne infection is detected. Additional concerns have also been raised about the potential for person-to-person spread of the vCJD agent by surgical instruments coming in contact with infected tissues, such as lymphoid tissues of patients incubating vCJD.
Because the most likely source of exposure to the BSE agent for US residents is consumption of contaminated food in the United Kingdom, the FDA in 1999 instituted a deferral policy to exclude from donating blood any person who traveled to the United Kingdom for a cumulative period of 6 months or more between 1980 and 1996. The Transmissible Spongiform Encephalopathy Advisory Committee of the FDA recently recommended further tightening the UK travel criteria to a cumulative period of 3 months or more and added additional deferral criteria, including the exclusion of donors who visited or resided in other European countries for a cumulative period of 5 years or more during 1980 to the present.[44]
In 1996, after vCJD was reported in the United Kingdom, the CDC enhanced its CJD surveillance to monitor the possible occurrence of the disease in the United States. One enhancement, which focused on the striking difference in age distribution of vCJD, included periodic review of national CJD mortality data to monitor any increase in the occurrence of CJD among unusually young patients. In collaboration with state and local health authorities, the CDC initiated follow-up investigations of patients with CJD younger than 55 years through reviews of their clinical and neuropathologic records. In addition, in collaboration with the American Association of Neuropathologists, the CDC established the National Prion Disease Pathology Surveillance Center at Case Western Reserve University, Cleveland, OH.[45,46] Through its contacts with US pathologists, this center helps to monitor for the occurrence of vCJD and other potentially emerging human TSEs in the United States regardless of the age of the patient or clinical diagnosis. It also makes available state-of the- art free diagnostic services for physiciandiagnosed or suspected cases of TSE in humans. Physicians are encouraged to make all efforts to arrange for a brain autopsy in all such cases and to take advantage of the free diagnostic services provided by the National Prion Disease Pathology Surveillance Center to assess the neuropathology of the patients. Given the many unknowns associated with TSEs, such assessments would not only help to confirm clinical diagnoses of these diseases, but also help to monitor the occurrence of a new TSE, such as vCJD or possibly a human form of CWD, in the United States. More detailed information about the activities of the Center can be obtained at its website.[47]
Is chronic wasting disease transmissible to humans or cattle?
The occurrence of CWD in several states that were not known to be endemic foci for the disease has increased the concern about a widespread outbreak of CWD in many areas of the country, and its possible transmission to humans and domestic animals such as cattle. A recently published experimental study has demonstrated transmission of the CWD agent to cattle by intracerebral inoculation.[48] An experiment to determine susceptibility of cattle to CWD by oral challenge is currently in progress. The efficiency by which CWD-associated prions influence the conversion of prion protein from different sources, including cervids, cattle, and humans, has been evaluated by cell-free conversion experiments.[49,50] The cell-free prion protein conversion reactions are believed to assess the molecular compatibility of disease-associated prions from one species with normal prion protein obtained from different species. These cell-free conversion experiments indicated that the efficiency of CWDassociated prions in converting bovine prion protein was an average of at least 5- to 12-fold weaker than the homologous conversion of cervid prion protein and bovine prion protein. Similar experiments indicated that the efficiency of CWD-associated prions in converting human prion protein was over 14-fold weaker than the homologous conversion of cervid prion protein and over fivefold weaker than the homologous conversion induced by CJD-associated prions. Although conversion studies showed some degree of incompatibility of cervid prion protein with that of cattle and humans, the authors indicated that it may be premature to draw firm conclusions about CWD naturally transmitting to humans or cattle. Lack of efficient cellfree conversion of human prion protein by BSE-associated prions has also been reported, despite the fact that BSE has been shown to be transmitted to humans.[49] The authors of the cell-free conversion studies also indicated that other factors are important in determining in vivo transmission of TSE agents between species, including dose and strain of the agent, route of infection, stability of the agent inside and outside of the host, and the efficiency of agent delivery to the nervous system.
A recent epidemiologic and laboratory investigation of three unusually young patients with CJD who regularly consumed venison did not identify convincing evidence for a causal link between CWD and the patients' illness.5 Two of the patients, aged 28 and 30 years at death, were hunters, and the third patient, aged 28 years, consumed venison harvested by family members. None of the patients was reported to have consumed deer meat obtained from the known CWDendemic areas of Colorado and Wyoming. The patients' disease phenotype and the prion protein gene polymorphism at codon 129 were heterogeneous, possibly indicating lack of exposure to a similar agent. This was unlike patients with vCJD in whom the disease phenotype and codon 129 polymorphism had some homogeneity, owing to infection of the patients by the same agent of BSE. In addition, brain tissues from over 1,000 deer and elk harvested in the areas where the venison consumed by the three patients originated from tested negative for CWD.
Although strong evidence for CWD transmission to humans is lacking, it should be recognized that limited studies designed to seek such evidence have been conducted. Given the BSE experience in Europe where an animal TSE previously believed to be nonpathogenic to humans was later shown to be responsible for an outbreak of vCJD, both epidemiologic and laboratory studies and ongoing CJD surveillance remain critical for continuing to assess the risk, if any, of CWD transmission to humans.
Appendix
The following are prominent clinical features that lead to a suspected diagnosis of variant Creutzfeldt-Jakob disease (CJD):
1. Young age of the patient (commonly <55 years).
2. Early psychiatric symptoms or persistent painful sensory symptoms such as dysesthesia or paresthesia.
3. Dementia and delayed appearance of ataxia and at least one of the following three neurologic signs: myoclonus, chorea, or dystonia.
4. A normal or abnormal EEG but not the diagnostic EEG changes often seen in classic CJD.
5. A prominent, symmetrical pulvinar high signal on T2-weighted or proton density-weighted MRI.
6. Duration of illness of at least 6 months.
7. Routine investigations of the patient do not suggest an alternative non-CJD diagnosis.
8. No history of receipt of cadaveric human pituitary growth hormone or a dura mater graft.
9. No history of CJD in a first-degree relative or absence of prion protein gene mutation in the patient.
Acknowledgment
The authors thank John O'Connor for his suggestions and editorial assistance.
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MH Adult; Age Factors; Animal; Blood Donors/legislation & jurisprudence; Cattle; Communicable Diseases, Emerging/*epidemiology/prevention &; control/transmission; Creutzfeldt-Jakob Syndrome/*epidemiology/prevention & control/transmission; Deer; Encephalopathy, Bovine Spongiform/epidemiology/prevention &; control/transmission; Great Britain/epidemiology; Human; Middle Age; Population Surveillance; Risk; Risk Assessment; Travel/legislation & jurisprudence; United States/epidemiology; Wasting Disease, Chronic/epidemiology/prevention & control/transmission
AD
Ermias D. Belay, MD; Ryan A. Maddox, MPH; Lawrence B. Schonberger, MD - Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA;
Pierluigi Gambetti, MD; National Prion Disease Pathology Surveillance Center (Dr. Gambetti), Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA
Correspondence and reprint requests to Dr. Ermias D. Belay, 1600 Clifton Road, Mailstop A-39, Atlanta, GA 30333.
SP englisch
PO USA