Recent US Case of Variant Creutzfeldt-Jakob Disease—Global Implications

Variant Creutzfeldt-Jakob disease (vCJD) is a rare, fatal prion disease resulting from transmission to humans of the infectious agent of bovine spongiform encephalopathy. We describe the clinical presentation of a recent case of vCJD in the United States and provide an update on diagnostic testing. The location of this patient’s exposure is less clear than those in the 3 previously reported US cases, but strong evidence indicates that exposure to contaminated beef occurred outside the United States more than a decade before illness onset. This case exemplifies the persistent risk for vCJD acquired in unsuspected geographic locations and highlights the need for continued global surveillance and awareness to prevent further dissemination of vCJD.     

Variant Creutzfeldt-Jakob disease death, United States

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, Spain, 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.     

Update: Creutzfeldt-Jakob disease associated with cadaveric dura mater grafts--Japan, 1978-2008

Creutzfeldt-Jakob disease (CJD) is the most common of the human prion diseases (also known as transmissible spongiform encephalopathies), which, according to the leading hypothesis, are caused by an abnormal protein (i.e., prion) that is able to induce abnormal folding of normal cellular prion proteins. Annual worldwide incidence of these always fatal neurodegenerative diseases is estimated at 0.5-2.0 cases per million population. CJD can occur sporadically, or as a genetic disease, or can be transmitted iatrogenically. In 1996, a new human prion disease, variant CJD (vCJD), was first described in the United Kingdom. This disease was believed to have resulted from human consumption of cattle products contaminated with the prions responsible for bovine spongiform encephalopathy (BSE, commonly known as mad cow disease). That year, in part to check for possible vCJD cases, a national survey was conducted in Japan; 821 CJD cases were identified, including 43 cases associated with receipt of cadaveric dura mater grafts. A single brand of dural graft (Lyodura) produced by a German manufacturer before May 1987 was identified as the most likely vehicle of transmission in all but one case. By 2003, continued surveillance in Japan had identified a total of 97 such cases. Since then, an additional 35 cases have been identified. This report updates previous reports and summarizes the investigation of all 132 cases to date linked to dural grafts. The results suggest that, because of the long incubation period between graft receipt and symptom onset (possibly >24.8 years), continued surveillance in Japan might identify additional CJD cases associated with dural grafts.     

Source of variant Creutzfeldt-Jakob disease outside United Kingdom

We studied the occurrence of variant Creutzfeldt-Jakob disease (vCJD) outside the United Kingdom in relation to the incidence of indigenous bovine spongiform encephalopathy (BSE) and to the level of live bovines and bovine products imported from the UK during the 1980s and the first half of the 1990s. Our study provides evidence that a country's number of vCJD cases correlates with the number of live bovines it imported from the UK from 1980 to 1990 (Spearman rank correlation coefficient [r(s)] 0.73, 95% confidence interval [CI] 0.42-0.89, p < 0.001). Similar correlations were observed with the number of indigenous BSE cases (r(s) 0.70, 95% CI 0.37-0.87, p = 0.001) and carcass meat imported from the UK from 1980 to 1996 (r(s) 0.75, 95% CI 0.45-0.89; p < 0.001) Bovine imports from the UK may have been an important source of human exposure to BSE and may have contributed to the global risk for disease.     

BSE safety standards: An evaluation of public health policies of Japan, Europe, and USA

Since the advent of bovine spongiform encephalopathy (BSE) in the United Kingdom in 1986, new BSE cases have recently become rare. However, in Japan and the United States, positive cases have started to be seen recently. The rise in BSE cases paved the way for the human form of this disease, the variant Creutzfeldt-Jakob disease (vCJD). The observed trends in the UK may be attributed to effective implementation of public health policies coupled with increased vigilance through advancement in science and technology, or they may well be a reflection of the natural disease progression. We aim to discuss the BSE chronology of events, and compare examination methods, costs and cost-efficiency, management, and public policies of Japan, Europe, and the USA.     

Public health service recommendations for the use of vaccines manufactured with bovine-derived materials

The Center for Biologics Evaluation and Research (CBER), U.S. Food and Drug Administration (FDA) learned earlier this year 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. A list of these countries is published by the U.S. Department of Agriculture (USDA). 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.     

The new variant of Creutzfeldt-Jakob disease

New variant Creutzfeldt-Jakob disease (nvCJD) is a novel human transmissible spongiform encephalopathy which was first identified in 1996 in the United Kingdom (UK). Subsequent scientific studies have revealed that the strain of the transmissible agent responsible for nvCJD is identical to that of the bovine spongiform encephalopathy (BSE) agent, and the disease has been considered as 'human BSE'. By 31 December 1999, 52 cases of nvCJD had been reported (49 cases in the UK, two cases in France and one case in the Republic of Ireland). All these individuals were under 53 years of age and all those tested were methionine homozygotes at codon 129 of the prion protein gene. The number of cases of nvCJD likely to occur in the future is impossible to estimate because of multiple uncertainties, in particular the disease incubation period, the degree of exposure to the infective agent and the susceptibility of other genetic subtypes. Continued surveillance of both BSE and CJD is required in the UK and in other countries, to ensure that the scale of this potential epidemic is adequately monitored and that all possible steps are taken to prevent further human exposure to the BSE agent.     

Tubulovesicular structures in human and experimental Creutzfeldt-Jakob disease

Tubulovesicular structures (TVS) have been consistently observed in brain tissue of animals with transmissible spongiform encephalopathies such as natural and experimental scrapie, bovine spongiform encephalopathy, and experimental Creutzfeldt-Jakob disease (CJD). In this communication we demonstrate for the first time the presence of TVS in natural CJD. TVS were detected in all 3 CJD specimens. However, they were rare and were found only in one or two locations per grid. They were seen in distended pre- and postsynaptic terminals and measured approximately 35 nm in diameter, and they were smaller and of higher electron density than synaptic vesicles. Their occurrence in all types of spongiform encephalopathies irrespective of the affected host and the strain of infectious agent emphasizes their biological significance.Corresponding author.     

The risk of accidental transmission of transmissible spongiform encephalopathy: identification of emerging issues

The transmissible spongiform encephalopathies (TSEs), thought to be caused by prions, are fatal neurodegenerative disorders of humans and animals. Despite their rarity, human prion diseases have received prominence because the consumption of prion-contaminated meat from cattle with bovine spongiform encephalopathy (BSE) is thought to be responsible for the emergence of variant Creutzfeldt-Jakob disease (vCJD) in humans. Clinical criteria for the diagnosis of vCJD is now available. Recent, more startling evidence suggests that the clinical presentation of vCJD may vary and that patients may present as classical (sporadic) CJD or may have subclinical infection and be apparently healthy. These patients may still pose a risk of iatrogenic transmission through surgical or medical (blood transfusion) procedures. The aim of future work is to develop preclinical screening tests for the identification of infected but still healthy individuals. The future course of vCJD is still uncertain. Modelling studies to predict the cases of vCJD depend on the date of origin of BSE and time of infection, which is, at best, only approximated. As the number of cases of BSE in the UK declines, the risk of BSE in other countries from imported cattle or meat and bone meal from the UK has been increasing. It is also recognized that other animal species (farmed, domestic and wild animals) other than cows are susceptible to TSEs. The possibility of interspecies transmission of TSEs and the global presence of the disease suggests a need for a co-ordinated worldwide risk management approach to eradicate TSEs.     

The phenotypic expression of different mutations in transmissible familial Creutzfeldt-Jakob disease

Cases of familial Creutzfeldt-Jakob disease (CJD) with mutations in the PRNP gene were analyzed for distinctive clinico-pathological and experimental transmission characteristics. An insert mutation within the region of codons 51 to 91 was associated with a markedly early age at onset and prolonged course of illness. Point mutations at codons 178 and 200 were also associated with ages at onset, durations of illness, and clinical symptom profiles that differed from sporadic CJD. The age at onset of illness in each group was correlated with the length of incubation periods in primates inoculated with their brain tissue, suggesting that the early onset of familial CJD results not from a time shift of the initiating event, but from an accelerated pre-clinical (incubation) phase of disease, perhaps due to a more rapid formation of amyloid induced by a mutationally-altered precursor protein template.     

Comparison of Lyme Disease in the United States and Europe

Lyme disease, or Lyme borreliosis, is the most common tickborne disease in the United States and Europe. In both locations, Ixodes species ticks transmit the Borrelia burgdorferi sensu lato bacteria species responsible for causing the infection. The diversity of Borrelia species that cause human infection is greater in Europe; the 2 B. burgdorferi s.l. species collectively responsible for most infections in Europe, B. afzelii and B. garinii, are not found in the United States, where most infections are caused by B. burgdorferi sensu stricto. Strain differences seem to explain some of the variation in the clinical manifestations of Lyme disease, which are both minor and substantive, between the United States and Europe. Future studies should attempt to delineate the specific virulence factors of the different species of B. burgdorferi s.l. responsible for these variations in clinical features.     

Die variante Creutzfeldt-Jakob-Krankheit (vCJK)

In the wake of the bovine spongiform encephalopathy (BSE) epidemic, variant Creutzfeldt-Jakob disease (vCJD) has emerged as a previously unknown prion disease of humans. The initial occurrence of vCJD was observed in 1995/1996, and, so far, a total of 219 vCJD cases have been reported worldwide from seven European and four non-European countries. Of these, 172 cases were observed in the United Kingdom. The exact prevalence of sub- or pre-clinical vCJD infections is unclear. Despite effective measures that have been implemented against both BSE in ruminants and its transmission to humans, there is now a theoretical risk of secondary vCJD transmissions from human to human, for example via blood and blood products, organs and tissues, or contaminated surgical instruments and medical devices. Four cases of probable vCJD transmissions via blood have been described, as well as one case of secondary infection via a plasma product. This article provides an overview of the surveillance and epidemiology of vCJD and outlines public health strategies for the risk assessment and risk management of this novel BSE-associated prion disease in humans.     

Transmissible spongiform encephalopathies in Australia.

The Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR) commenced surveillance in September 1993 as part of the Commonwealth's response to 4 cases of pituitary hormone (gonadotrophin)-associated Creutzfeldt-Jakob disease (CJD). With the passage of time, the Registry has become responsible for ascertaining all human transmissible spongiform encephalopathies (TSE; also known as prion diseases) within Australia since 1970. Included in the spectrum of diseases monitored are classical (sporadic, genetic, and health care acquired) CJD, and variant CJD (vCJD), first reported in 1996 in the United Kingdom. Variant CJD has not yet been diagnosed in Australia. Final classification of persons with suspected human prion disease is based upon all available clinical, investigational and pathological information. Ascertainment methods are diverse and include prompted, half-yearly personal communications from neurologists and neuropathologists, death certificate searches, and morbidity separation coding searches of major hospital, and State and Territory databases. More recently, referral for diagnostic CSF 14-3-3 protein testing (performed by the ANCJDR) has considerably increased prospective notifications of suspect cases. As at September 2001 there were 460 cases on the register; 237 definite cases, 168 probable and 55 incomplete cases awaiting final classification.     

Protease-resistant prion protein in lymphoreticular tumors of variant Creutzfeldt-Jakob disease mice

We report protease-resistant prion protein (PrPres) in spontaneous lymphoreticular tumors of mice infected with the agent of variant Creutzfeldt-Jakob disease (vCJD). PrPres may accumulate in lymphoreticular system tumors of asymptomatic persons with vCJD. The statistical power of estimates of vCJD prevalence might be increased by expanding screening to include samples of lymphoreticular neoplasms.     

Creutzfeldt-Jakob disease: diagnosis, incidence, prevention and treatment

Creutzfeldt-Jakob disease (CJD) is a rare, neurodegenerative disorder belonging to the spongiform encephalopathies. A variant form (vCJD) is most likely the result of infection with the agent that causes bovine spongiform encephalopathy (BSE). Diagnostic information can be obtained by EEG, testing cerebrospinal fluid for the presence of the 14-3-3 protein, MRI, brain biopsy, tonsil biopsy, and postmortem brain examination. Some tests, such as MRI and postmortem brain examination, can be used to distinguish between CJD and vCJD. Pathological prions in a tonsil biopsy are only found with vCJD. In the Netherlands, there are four known cases of iatrogenic CJD. On the basis of certain exposure to BSE via the food chain, cases of vCJD are also to be expected. Chloropromazine and mepacrine are known to inhibit the formation of pathological prion conformations, but clinical trials have not yet been carried out.     

Can a second wave of new variant of the CJD be discarded in absence of observation of clinical non Met-Met cases?

BACKGROUND: Presently, all patients with clinical variant Creutzfeldt-Jakob disease in the United Kingdom have been Met-Met at codon 129 of the PrP gene. There is much worry about the possibility of a second wave of the epidemic in the 60% of the United Kingdom population which are not Met-Met. METHODS: A mathematical model of a putative United Kingdom variant Creutzfeldt-Jakob disease epidemic that could occur in non Met-Met is derived. The risk of infection is assumed to parallel the Met-Met risk which has been previously modelled. The reason for the present absence of clinical non Met-Met cases is assumed to be a longer incubation period in these subjects than in others. The incubation period is assumed to be lognormally distributed. The means and coefficients of variation compatible with the present absence of clinical cases are systematically searched. RESULTS: We show that the present absence of clinical cases of variant Creutzfeldt-Jakob disease in the Met-Val or Val-Val population can be compatible with a second wave only if the mean incubation period is more than 25 years. The best estimates of the size of the second wave are always below 250. A fraction of these cases however will never be observed, as they will die from other causes before the onset of the new variant. CONCLUSION: The mean incubation period values compatible with the absence of non Met-Met clinical cases that we found are not implausible, and the possibility of a second wave cannot yet be ruled out. However, should this second wave occur, it would be below 250 in the worst hypothesis.     

A retrospective study of Creutzfeldt-Jakob disease in Italy (1972–1986)

In a retrospective study of Creutzfeldt-Jakob disease (CJD) in Italy from 1972 to 1986, we found 79 cases which fulfilled the diagnostic criteria for CJD. The annual mortality rate was 0.09 cases per million inhabitants. In this series the female to male ratio was 2.59, a value significantly higher than that found in Italian population (1.05). The mean age at death was 62.1 ± 9.4 years and the mean duration of the disease was 5.3 ± 3.0 months. No familial cases of CJD were found in our series. Mental deterioration was present in all of our cases, myoclonus in 85% and the other clinical signs were present at a lower rate. Periodic EEG activity was found in 92% of the cases. Two patients had had neurological or ophthalmic surgery and 17% of our cases had undergone general surgery within 5 years prior to the clinical onset of CJD.     

Risk of variant Creutzfeldt-Jakob disease in France

BACKGROUND: France has the second highest number of variant Creutzfeldt-Jakob disease (vCJD) cases worldwide. Imports of bovine carcasses from the UK probably constituted the main source of exposure of the French population to the bovine spongiform encephalopathy (BSE) agent. Meat products consumed whilst visiting the UK have also been considered as a possible source of exposure. METHODS: We estimated the number of future vCJD cases in France using a simulation approach. Both the distribution of the vCJD incubation period and the age-dependent susceptibility to the BSE agent were estimated from UK data. The French epidemic was simulated by gender and birth-cohort from data on the infectivity of UK bovine tissues and simulations of the French consumption of infected beef products. We also used data on travel to the UK between 1980 and 1995. RESULTS: We predicted 33 future cases of vCJD: 12 in the 1940-69 birth-cohort and 21 in the post-1969 birth-cohort. No case was predicted in the pre-1940 cohort. Based on our model, simulated vCJD cases occurred later in the older (1940-69) than in the younger cohort (post-1969). Age at onset was stable in the post-1969 cohort and increased in the older cohort. The model predicted a small excess of male patients. No case was attributed to travels in the UK. CONCLUSIONS: This modelling confirms that a large vCJD epidemic in France is very unlikely. Since France (where 60% of the total British exports of bovine carcasses were exported) has been highly exposed to the BSE agent, our results are reassuring for most countries worldwide.     

Variant Creutzfeldt-Jakob disease: implications for the health care system

The recognition of the first cases of variant Creutzfeldt-Jakob Disease in the United Kingdom (UK) in 1996 and the realisation that this new disease represented the human form of the cattle disease BSE has prompted a considerable investment in research, particularly in the UK, Europe and the United States (US). Much has been learnt about this disease but much is still unknown. Infectivity is not destroyed by conventional sterilisation and disinfection treatment methods. This, combined with the widespread distribution throughout the lymphoid system as well as the central nervous system, raises the spectre of transmission through both surgical and ophthalmological procedures. Reports in 2004 of two likely transfusion-transmitted cases of vCJD suggest the probability of infection through blood transfusion and tissue transplantation. The risk of hospital-based and community-based transmission has not been quantified. To complicate matters even further, there is no suitable ante-mortem screening test or effective treatment for this fatal disease. The incubation period prior to onset of clinical disease is many years and there is good evidence for the existence of subclinical infection and infectivity during this stage. The extent of under-diagnosis and misdiagnosis is probably significant, adding to the risk of human-to-human transmission.     

Ovine scrapie: Follow-up of sheep belonging to an endemic scrapie-infected flock

There is a close similarity between the unconventional virus-induced ovine scrapie and human Creutzfeldt-Jakob disease. Since infection might be transmitted orally, the ovine production of an endemically scrapie-infected farm was studied. About 80% of the annual production are sold (50% as butcher-meat, 30% as breeding animals), and scrapie appears in 20% of the sheep kept on the farm. Was the same proportion of butcher-meat animals scrapie-infected? Since the scrapie agent has been detected in “clinically normal” lambs, the same problem occurs with breeding-sheep and “apparently healthy” animals: are they carriers of the pathogenic agent? Are they responsible for the spread of the ovine disease and/or of the human disease?