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From: TSS ()
Variant Creutzfeldt-Jakob Disease Death, United States Suggested citation for this article The only variant Creutzfeldt-Jakob disease (vCJD) patient identified in the United States died in 2004, and the diagnosis was confirmed by analysis of autopsy tissue. The patient likely acquired the disease while growing up in Great Britain before immigrating to the United States in 1992. Additional vCJD patients continue to be identified outside the United Kingdom, including 2 more patients in Ireland, and 1 patient each in Japan, Portugal, Saudi Arabia and the Netherlands. The reports of bloodborne transmission of vCJD in 2 patients, 1 of whom was heterozygous for methionine and valine at polymorphic codon 129, add to the uncertainty about the future of the vCJD outbreak. Variant Creutzfeldt-Jakob disease (vCJD) was first reported in 1996 in the United Kingdom and has been causally linked to eating cattle products contaminated with the bovine spongiform encephalopathy (BSE) agent (1–3). Both vCJD and BSE are rapidly progressive neurodegenerative disorders classified as transmissible spongiform encephalopathies (TSEs) or prion diseases. TSEs are characterized by 1) incubation periods measured in years, 2) presence in the brain of an unconventional agent called a prion, 3) absence of inflammatory reaction, and 4) a neuropathologic feature consisting typically of spongiform lesions, astrogliosis, and neuronal loss. vCJD is distinguished from the more common TSE in humans, sporadic CJD, by the younger median age (28 years and 68 years, respectively) of the patients and by its clinical and neuropathologic manifestations. In 2002, the likely occurrence of vCJD was reported in a 22-year-old woman living in Florida and represented the first detection of the disease in North America (4). In this report, we describe this patient's illness and provide an update on the epidemiologic features of the ongoing vCJD outbreak worldwide, including recent reports of bloodborne transmission of vCJD. Case Report In late January 2002, the patient was transported to the United Kingdom, where her mother resided. During the ensuing 3 months, the patient's motor and cognitive deficits worsened, which caused falls resulting in minor injuries; she had difficulty taking care of herself, remembering her home telephone number, and making accurate mathematical calculations. She also experienced confusion, hallucination, dysarthria, bradykinesia, and spasticity. An electroencephalogram evaluation showed no abnormalities, but a brain magnetic resonance imaging (MRI) study showed the characteristic signal abnormalities in the pulvinar and metathalamic regions suggestive of vCJD. Western blot and immunohistochemical analyses of tonsillar biopsy tissue demonstrated the presence of protease-resistant prion protein, which supported the diagnosis of vCJD. By September 2002, the patient was bedridden. An experimental treatment with quinacrine was given to the patient for 3 months, but she showed little improvement. She remained in a state of akinetic mutism and died in June 2004, ≈32 months after illness onset. Figure 1 Figure 1. Histopathologic changes in frontal cerebral cortex of the patient who died of variant Creutzfeldt-Jakob disease... Figure 2. Immunohistochemical staining of cerebellar tissue of the patient who died of variant Creutzfeldt-Jakob disease... Figure 3. Number of deceased variant Creutzfeldt-Jakob disease patients worldwide... This patient is the only US resident with a confirmed diagnosis of vCJD. She was likely exposed to BSE while growing up in the United Kingdom from 1980 to 1992, which suggests an incubation period of 9–21 years (Table). The illness duration in this patient (≈32 months) was much longer than the median illness duration for patients in the United Kingdom with vCJD (14 months, range 6–40 months). Updates on vCJD Certain characteristics distinguishing vCJD from classic CJD raised early concerns about possible secondary bloodborne spread of vCJD, especially in light of the lack of experience with this newly emerged disease. Of specific concern was the detection of the agent in lymphoid tissues and the possibility of prionemia as the agent spreads from the gut to the brain. In 1997, to monitor for the possible bloodborne transmission of vCJD, researchers in the United Kingdom began investigating recipients of blood components obtained from donors who subsequently died of vCJD (5). As of February 2004, 48 recipients were identified, including 18 who had survived for at least 4 years after transfusion. Two of these 18 recipients had evidence of bloodborne transmission of vCJD. One of the 2 recipients was 62 years of age and had received 5 units of erythrocytes in 1996 (5). One of these units was traced to a 24-year-old donor in whom vCJD developed >3 years after the blood was donated. In 2002 (6.5 years after the transfusion), vCJD developed in the recipient, who 13 months after illness onset. An autopsy confirmed the diagnosis of vCJD. The second patient potentially linked with bloodborne transmission of vCJD was an elderly person who received a unit of erythrocytes in 1999. vCJD developed in the donor of the unit 18 months after blood was donated (6). The recipient died of a ruptured aortic aneurysm 5 years after the transfusion. Tests of the patient's spleen and cervical lymph node detected protease-resistant prion protein with a Western blot mobility pattern and glycoform ratio similar to those seen in other vCJD patients. These results and the absence of neurologic symptoms and brain pathologic findings indicated that this patient had a subclinical vCJD infection. Prion protein gene sequencing showed heterozygosity for methionine and valine at codon 129, which indicated that persons not homozygous for methionine (>50% of the population) can be infected by the vCJD agent. In the United States, the risk of bloodborne transmission of vCJD is low because of the absence of indigenous vCJD and the geographic-based donor deferral policy instituted by the Food and Drug Administration in 1999. This policy excludes from donating blood in the United States persons who resided in or had extended visits to the United Kingdom or other European countries during periods of greatest concern for BSE exposure (7). The exact incubation period for foodborne vCJD is unknown. However, a range of possible incubation periods was estimated for 4 vCJD patients who likely acquired the disease during their residence in the United Kingdom and for 5 vCJD patients reported as part of a cluster in Leicestershire, England (Table). The median of the estimated range of incubation periods for these 9 vCJD patients was 13 years. The incubation period for the vCJD patient linked to bloodborne transmission was shorter (6.5 years). This finding could be the result of direct transmission of the agent into the bloodstream and adaptation of the agent to the human population, thus reducing or eliminating the species barrier (Table). Conclusions In June 2005, the US Department of Agriculture confirmed BSE in an ≈12-year-old cow born and raised in Texas. This is the first time an indigenous BSE case was detected in the United States. A previous BSE-positive cow identified in Washington State was imported from Canada (3) where, to date, 4 additional BSE cases have been identified. The identification of BSE in North America and the likelihood of bloodborne transmission of vCJD underscore the need to continue surveillance to monitor the occurrence of vCJD in the United States (3). The case-patient described in this report illustrates the need for physicians to remain vigilant for the possibility of vCJD in patients with the signs and symptoms described. Physicians should report suspected vCJD cases to local and state health departments. Because the clinical manifestation of vCJD can overlap that of sporadic CJD, brain autopsies should be sought in all suspected cases to establish the diagnosis and to help monitor the occurrence of vCJD and other potentially emerging forms of CJD. Free state-of-the art prion disease diagnostic testing is available from the National Prion Disease Pathology Surveillance Center (http://www.cjdsurveillance.com), which was established to facilitate autopsy performance and testing (8). Physicians are encouraged to use the services of the surveillance center to evaluate neuropathologic changes in their patients with suspected or clinically diagnosed prion disease. Acknowledgments Dr Belay is a medical epidemiologist in the Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention. His research areas of interest include the interspecies transmission of prion diseases, Kawasaki syndrome, and Reye syndrome. References -------------------------------------------------------------------------------- -------------------------------------------------------------------------------- -------------------------------------------------------------------------------- http://www.cdc.gov/ncidod/EID/vol11no09/05-0371.htm Corinne Ida Lasmézas, Emmanuel Comoy, Stephen Hawkins, Christian Herzog, Franck Mouthon, Timm Konold, Frédéric Auvré, Evelyne Correia, Nathalie Lescoutra-Etchegaray, Nicole Salès, Gerald Wells, Paul Brown, Jean-Philippe Deslys Published online January 27, 2005 http://www.thelancet.com/journal/journal.isa It is clear that the designing scientists must also have shared Mr Bradley’s surprise at the results because all the dose levels right down to 1 gram triggered infection. 6. It also appears to me that Mr Bradley’s answer (that it would take less than say 100 grams) was probably given with the benefit of hindsight; particularly if one considers that later in the same answer Mr Bradley expresses his surprise that it could take as little of 1 gram of brain to cause BSE by the oral route within the same species. This information did not become available until the "attack rate" experiment had been completed in 1995/96. This was a titration experiment designed to ascertain the infective dose. A range of dosages was used to ensure that the actual result was within both a lower and an upper limit within the study and the designing scientists would not have expected all the dose levels to trigger infection. The dose ranges chosen by the most informed scientists at that time ranged from 1 gram to three times one hundred grams. It is clear that the designing scientists must have also shared Mr Bradley’s surprise at the results because all the dose levels right down to 1 gram triggered infection. [BBC radio 4 FARM news] http://www.maddeer.org/audio/BBC4farmingtoday2_1_03.ram http://www.fda.gov/ohrms/dockets/ac/03/slides/3923s1_OPH.htm 2) Infectious dose: To cattle: 1 gram of infected brain material (by oral ingestion) http://www.inspection.gc.ca/english/sci/bio/bseesbe.shtml Cristina Casalone *, Gianluigi Zanusso , Pierluigi Acutis *, Sergio Ferrari , Lorenzo Capucci , Fabrizio Tagliavini ¶, Salvatore Monaco ||, and Maria Caramelli * *Centro di Referenza Nazionale per le Encefalopatie Animali, Istituto Zooprofilattico Sperimentale del Piemonte, Liguria e Valle d'Aosta, Via Bologna, 148, 10195 Turin, Italy; Department of Neurological and Visual Science, Section of Clinical Neurology, Policlinico G.B. Rossi, Piazzale L.A. Scuro, 10, 37134 Verona, Italy; Istituto Zooprofilattico Sperimentale della Lombardia ed Emilia Romagna, Via Bianchi, 9, 25124 Brescia, Italy; and ¶Istituto Nazionale Neurologico "Carlo Besta," Via Celoria 11, 20133 Milan, Italy Transmissible spongiform encephalopathies (TSEs), or prion diseases, are mammalian neurodegenerative disorders characterized by a posttranslational conversion and brain accumulation of an insoluble, protease-resistant isoform (PrPSc) of the host-encoded cellular prion protein (PrPC). Human and animal TSE agents exist as different phenotypes that can be biochemically differentiated on the basis of the molecular mass of the protease-resistant PrPSc fragments and the degree of glycosylation. Epidemiological, molecular, and transmission studies strongly suggest that the single strain of agent responsible for bovine spongiform encephalopathy (BSE) has infected humans, causing variant Creutzfeldt-Jakob disease. The unprecedented biological properties of the BSE agent, which circumvents the so-called "species barrier" between cattle and humans and adapts to different mammalian species, has raised considerable concern for human health. To date, it is unknown whether more than one strain might be responsible for cattle TSE or whether the BSE agent undergoes phenotypic variation after natural transmission. Here we provide evidence of a second cattle TSE. The disorder was pathologically characterized by the presence of PrP-immunopositive amyloid plaques, as opposed to the lack of amyloid deposition in typical BSE cases, and by a different pattern of regional distribution and topology of brain PrPSc accumulation. In addition, Western blot analysis showed a PrPSc type with predominance of the low molecular mass glycoform and a protease-resistant fragment of lower molecular mass than BSE-PrPSc. Strikingly, the molecular signature of this previously undescribed bovine PrPSc was similar to that encountered in a distinct subtype of sporadic Creutzfeldt-Jakob disease. C.C. and G.Z. contributed equally to this work. ||To whom correspondence should be addressed. E-mail: salvatore.monaco@mail.univr.it . www.pnas.org/cgi/doi/10.1073/pnas.0305777101 snip...end full text ; http://www.bseinquiry.gov.uk/files/mb/m11b/tab01.pdf It was, however, performed in the USA in 1979, when it was shown that cattle inoculated with the scrapie agent endemic in the flock of Suffolk sheep at the United States Department of Agriculture in Mission, Texas, developed a TSE quite unlike BSE. 32 The findings of the initial transmission, though not of the clinical or neurohistological examination, were communicated in October 1988 to Dr Watson, Director of the CVL, following a visit by Dr Wrathall, one of the project leaders in the Pathology Department of the CVL, to the United States Department of Agriculture. 33 The results were not published at this point, since the attempted transmission to mice from the experimental cow brain had been inconclusive. The results of the clinical and histological differences between scrapie-affected sheep and cattle were published in 1995. Similar studies in which cattle were inoculated intracerebrally with scrapie inocula derived from a number of scrapie-affected sheep of different breeds and from different States, were carried out at the US National Animal Disease Centre. 34 The results, published in 1994, showed that this source of scrapie agent, though pathogenic for cattle, did not produce the same clinical signs of brain lesions characteristic of BSE. http://www.bseinquiry.gov.uk/report/volume2/chaptea3.htm Visit to USA ... info on BSE and Scrapie http://www.bseinquiry.gov.uk/files/yb/1988/10/00001001.pdf
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