Prion-related peripheral neuropathy in sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: To assess whether the involvement of the peripheral nervous system (PNS) belongs to the phenotypic spectrum of sporadic Creutzfeldt-Jakob disease (sCJD). METHODS: We examined medical records of 117 sCJDVV2 (ataxic type), 65 sCJDMV2K (kuru-plaque type) and 121 sCJDMM(V)1 (myoclonic type) subjects for clinical symptoms, objective signs and neurophysiological data. We reviewed two diagnostic nerve biopsies and looked for abnormal prion protein (PrPSc) by western blotting and real-time quaking-induced conversion (RT-QuIC) in postmortem PNS samples from 14 subjects. RESULTS: Seventy-five (41.2%) VV2-MV2K patients, but only 11 (9.1%) MM(V)1, had symptoms or signs suggestive of PNS involvement occurring at onset in 18 cases (17 VV2-MV2K, 9.3%; and 1 MM(V)1, 0.8%) and isolated in 6. Nerve biopsy showed a mixed predominantly axonal and demyelinating neuropathy in two sCJDMV2K. Electromyography showed signs of neuropathy in half of the examined VV2-MV2K patients. Prion RT-QuIC was positive in all CJD PNS samples, whereas western blotting detected PrPSc in the sciatic nerve in one VV2 and one MV2K. CONCLUSIONS: Peripheral neuropathy, likely related to PrPSc deposition, belongs to the phenotypic spectrum of sCJDMV2K and VV2 and may mark the clinical onset. The significantly lower prevalence of PNS involvement in typical sCJDMM(V)1 suggests that the PNS tropism of sCJD prions is strain dependent.

Prion Disease in Dromedary Camels, Algeria.

Prions cause fatal and transmissible neurodegenerative diseases, including Creutzfeldt-Jakob disease in humans, scrapie in small ruminants, and bovine spongiform encephalopathy (BSE). After the BSE epidemic, and the associated human infections, began in 1996 in the United Kingdom, general concerns have been raised about animal prions. We detected a prion disease in dromedary camels (Camelus dromedarius) in Algeria. Symptoms suggesting prion disease occurred in 3.1% of dromedaries brought for slaughter to the Ouargla abattoir in 2015-2016. We confirmed diagnosis by detecting pathognomonic neurodegeneration and disease-specific prion protein (PrPSc) in brain tissues from 3 symptomatic animals. Prion detection in lymphoid tissues is suggestive of the infectious nature of the disease. PrPSc biochemical characterization showed differences with BSE and scrapie. Our identification of this prion disease in a geographically widespread livestock species requires urgent enforcement of surveillance and assessment of the potential risks to human and animal health.

A pilot study for targeted surveillance of bovine spongiform encephalopathy in Nigeria.

Bovine spongiform encephalopathy (BSE), popularly known as 'mad cow disease', led to an epidemic in Europe that peaked in the mid-1990s. Its impact on developing countries, such as Nigeria, has not been fully established as information on livestock and surveillance has eluded those in charge of this task. The BSE risk to Nigeria's cattle population currently remains undetermined, which has resulted in international trade restrictions on commodities from the cattle population. This is mainly because of a lack of updated BSE risk assessments and disease surveillance data. To evaluate the feasibility of BSE surveillance in Nigeria, we carried out a pilot study targeting cattle that were presented for emergency or casualty slaughter. In total, 1551 cattle of local breeds, aged 24 months and above were clinically examined. Ataxia, recumbency and other neurological signs were topmost on our list of criteria. A total of 96 cattle, which correspond to 6.2%, presented clinical signs that supported a suspect of BSE. The caudal brainstem tissues of these animals were collected post-mortem and analysed for the disease-specific form of the prion protein using a rapid test approved by the International Animal Health Organization (OIE). None of the samples were positive for BSE. Although our findings do not exclude the presence of BSE in Nigeria, they do demonstrate that targeted sampling of clinically suspected cases of BSE is feasible in developing countries. In addition, these findings point to the possibility of implementing clinical monitoring schemes for BSE and potentially other diseases with grave economic and public health consequences.

Neurological diseases of ruminant livestock in Australia. I: general neurological examination, necropsy procedures and neurological manifestations of systemic disease, trauma and neoplasia.

Disease surveillance is an integral part of most veterinary practices in Australia. The aim of this series of invited reviews is to facilitate the differential and ultimately definitive diagnosis of some of the previously known, as well as the novel and emerging, neurological disorders of ruminant livestock, which is of particular importance in the surveillance for transmissible spongiform encephalopathies. General principles of a systematic neurological examination, necropsy procedures and the neurological manifestations of systemic disease, trauma and neoplasia are described here.

Encefalopatías espongiformes transmisibles:biología del prion y estado actual de la vigilanciaepidemiológica en Colombia / Encefalopatias espongiformes transmissíveis: biologia do prião e estado atual davigilância epidemiológica na Colômbia / Transmissible spongiform encephalopathies: biology of the Prion and current state of the epidemiologic surveillance in Colombia

Las Encefalopatías Espongiformes Transmisibles, también llamadas enfermedades priónicas, sonun grupo de enfermedades neurodegenerativas, que afectan una gran variedad de mamíferos. El agenteresponsable de estas patologías se ha identificado como una isoforma anormal de una proteína celular, lacual luego de sufrir un cambio conformacional (prion), adquiere la capacidad de comportarse como unagente infeccioso. Se ha demostrado la capacidad de los priones para cruzar la barrera de especies entreel ganado y los seres humanos; lo cual se ha reflejado en un problema de salud pública que ha afectadogravemente a los países donde se han presentado brotes de estas enfermedades. Las EncefalopatíasEspongiformes Transmisibles se han reportado en una gran cantidad de países y Colombia no ha sido ajenaa la presencia de casos esporádicos humanos, no relacionados con el consumo de material contaminadoprocedente de animales enfermos. Con el presente artículo se pretende dar una visión de la historia y elestado actual de Colombia frente a estas enfermedades, las cuales representan una grave amenaza para lasalud pública y la agrocadena ganadera del país.

Transmissible Spongiform Encephalopaties, also called prion diseases, are a group of neurodegenerativediseases affecting a variety of mammals. The responsible agent consists of an abnormal isoform of a cellularprotein that suffers a conformational change (prion), acquiring the ability of being transmissible. It hasbeen demonstrated prions capacity to cross the species barrier between the cattle and humans; affectingpublic health in countries with reported cases of bovine spongiform encephalopathy. The transmissiblespongiform encephalitis have been reported in a number of countries and Colombia is not the exceptionwith some human sporadic cases, not related with the intake of contaminated material from sick animals.With this manuscript we pretend to give a view of the history and the current state of prion diseases inColombia, which represent a serious threat for the public health and the cattle industry of the country.

As doenças encefalopatias espongiformes transmissíveis, são do grupo de doenças neurodegenerativas,que afetam uma grande variedade de mamíferos. O agente responsável de estas patologias estáidentificado como uma isoforma anormal de uma proteína celular, a qual logo de apresentar umamudança de conformação (prião), adquire a capacidade de comportar-se como um agente infeccioso.Tem-se demonstrado a capacidade que tem o prião para ultrapassar a barreira de espécies entre o gadoe o ser humano; o qual está refletido gravemente aos países onde tem-se apresentado estas doenças.As encefalopatias espongiformes transmissíveis estão reportadas em uma grande quantidade de países.Na Colômbia tem-se apresentado casos esporádicos em humanos, não relacionados com o consumo dematerial contaminado procedente de animais doentes. O presente artigo, busca dar uma visão da historiae o estado atual da Colômbia frente as doenças, as quais representam uma grave ameaça para a saúdepública e da pecuária do pais.

Evaluación de riesgos aplicado a la prevención y la vigilancia de la encefalopatía espongiforme bovina (EEB) en los países de la región de las Américas / Risk assessment applied to the prevention and surveillance of bovine spongiform encephalopathy (BSE) in the countries of the Americas region

Se desarrolló un modelo bayesiano para evaluación de riesgos de EEB. Conjuga registros y opinión experta con datos de muestreo. Se compararon percentiles de probabilidad de EEB obtenidos con la evaluación de riesgo, muestreo y Bayes a partir de datos de Argentina y de escenarios hipotéticos. Bajo un escenario hipotético de incertidumbre, la importancia del muestreo y de la estimación bayesiana fue evidente. Los resultados ratifican la coherencia del Código de OIE y la condición de Argentina de riesgo insignificante y muestran la conveniencia de aplicar regularmente modelos similares.(AU)

A Bayesian model for BSE risk evaluation was developed. It conjugates records and expert opinion with sampling data. EEB probability percentiles by sampling, risk evaluation and Bayes were compared using data from Argentina and from hypothetical scenarios. Under a scenario of uncertainty, sampling and Bayesian estimation importance was evident. Results ratify coherence of the OIE Code and Argentinean condition of insignificant risk and show the convenience of applying similar models regularly.(AU)

Time trends in exposure of cattle to bovine spongiform encephalopathy and cohort effect in France and Italy: value of the classical Age-Period-Cohort approach.

BACKGROUND: The Age-Period-Cohort (APC) analysis is routinely used for time trend analysis of cancer incidence or mortality rates, but in veterinary epidemiology, there are still only a few examples of this application. APC models were recently used to model the French epidemic assuming that the time trend for BSE was mainly due to a cohort effect in relation to the control measures that may have modified the BSE exposure of cohorts over time. We used a categorical APC analysis which did not require any functional form for the effect of the variables, and examined second differences to estimate the variation of the BSE trend. We also reanalysed the French epidemic and performed a simultaneous analysis of Italian data using more appropriate birth cohort categories for comparison. RESULTS: We used data from the exhaustive surveillance carried out in France and Italy between 2001 and 2007, and comparatively described the trend of the epidemic in both countries. At the end, the shape and irregularities of the trends were discussed in light of the main control measures adopted to control the disease. In Italy a decrease in the epidemic became apparent from 1996, following the application of rendering standards for the processing of specific risk material (SRM). For the French epidemic, the pattern of second differences in the birth cohorts confirmed the beginning of the decrease from 1995, just after the implementation of the meat and bone meal (MBM) ban for all ruminants (1994). CONCLUSION: The APC analysis proved to be highly suitable for the study of the trend in BSE epidemics and was helpful in understanding the effects of management and control of the disease. Additionally, such an approach may help in the implementation of changes in BSE regulations.

Impact of potential changes to the current bovine spongiform encephalopathy surveillance programs for slaughter cattle and fallen stock in Japan.

Cattle slaughtered in Japan for human consumption, regardless of their age, have been tested for bovine spongiform encephalopathy (BSE) since October 2001. Beginning in April 2004, all fallen stock from 24 months of age also have been tested. We evaluated the impact of potential changes to the current BSE surveillance programs for both slaughter cattle and fallen stock using a simple stochastic model. We calculated the probability that a BSE-infected dairy cow, Wagyu beef animal, Wagyu-Holstein cross steer or heifer, or Holstein steer slaughtered for human consumption or arising as fallen stock would be tested and detected. Four surveillance strategies were explored for cattle slaughtered for human consumption, with the minimum age at testing set at 0, 21, 31, or 41 months. Three surveillance strategies were explored for fallen stock, with the minimum age at testing set at 24, 31, or 41 months. Increasing the minimum age of testing from 0 to 21 months for both dairy cattle and Wagyu beef cattle had very little impact on the probability that a BSE-infected animal slaughtered for human consumption would be detected. Although increasing the minimum age at testing from 21 to 31 or 41 months would lead to fewer slaughtered animals being tested, the impact on the probability of detecting infected animals would be insignificant. The probability of infected Wagyu-Holstein crosses and Holstein steers being detected at slaughter or as fallen stock would be very low under all surveillance strategies.

Preventive health behavior and adaptive accuracy of risk perceptions.

This study examined the relation between health behavior and risk perceptions in the context of an acute livestock epidemic. Participants in a longitudinal web-based survey (N= 195) were asked to report their meat consumption and their perceived risk in relation to bovine spongiform encephalopathy (BSE) and other related livestock diseases. Cross-sectional analyses at both measurement points (T1 and T2) showed that participants with low levels of preventive nutrition (high meat consumption) felt more at risk for BSE-related diseases than those reporting comparable higher levels of preventive behavior (low meat consumption), indicating relative accuracy. These results suggest that people recognize when their behavior is risky. More importantly, perceived risk also showed adaptive accuracy from a change perspective: increases in preventive nutrition from T1 to T2 were significantly associated with decreases in perceived risk between T1 and T2. Possible foundations and implications of an adaptive accuracy of risk perceptions are discussed.

The impact of Creutzfeldt-Jakob disease on surgical practice.

Creutzfeldt-Jakob disease (CJD) is characterised by abnormal prion protein that can replicate and replace nervous tissue, with rapid lethal neurodegenerative consequences. The transmissible nature of CJD has been known for half a century and transmission has occurred through neurosurgical procedures. Variant Creutzfeldt-Jakob disease (vCJD) emerged in 1996, and the presence of abnormal prion in lymphatic tissue extended the number of surgical specialties dealing with infected material; transmission through blood transfusion raised the possibilities of a large carrier pool and spread of epidemic proportion. The abnormal prion is difficult to remove and this could influence future decontamination programmes. Contaminated instruments must be withdrawn from surgical practice, and this can interfere with the efficient running of a surgical unit and optimal patient care. There is an urgent need for reliable methods for the detection of abnormal prion, within and outside the body. These will help to clarify the epidemiology of CJD, and to reduce its transmission via blood and tissue. They will also allow determination of the efficacy of new decontamination products in surgical practice, and the value of any treatment of sufferers and carriers of CJD. In the meantime, continued vigilance and informed regulation of all aspects of CJD must remain.

Analyzing BSE surveillance in low prevalence countries.

If the prevalence of bovine spongiform encephalopathy (BSE) varies among cohorts within a population, stratified analysis of BSE surveillance data may allow identification of differences in BSE exposure that are important with respect to the design and evaluation of disease prevention and control measures. In low BSE prevalence populations, however, surveillance at levels that meet or exceed international guidelines may provide insufficient statistical power to distinguish prevalence levels among cohorts. Furthermore, overstratification to account for hypothetical variability in the population may inflate uncertainty in BSE risk estimates.

BSE risk assessment as a basis for updating French screening policy.

The current French bovine spongiform encephalopathy (BSE) surveillance system, based on rapid testing of all cattle over 24 months of age and on clinical diagnosis, detects all clinical cases and some preclinical cases of BSE. Several indicators point to a marked shrinkage of the French BSE epidemic in recent years, owing to risk reduction measures. Meat and bone meal, the only known vector of the BSE agent, was banned in feed for all farmed species in November 2000. Thus the surveillance system may be relaxed. The objective of this risk assessment study was to provide information for decisionmakers on the minimum age at which healthy and high-risk cattle now need to be screened with rapid tests. For this purpose, we used the back-calculation method to project the course of the BSE epidemic. We examined the predicted patterns of the number and age distribution of cases of BSE that would be detected by the different existing surveillance streams. Various theoretical sensitivities of rapid tests were explored. Assuming that feed-borne sources of infection no longer exist, and that BSE does not occur spontaneously, our models suggest that it would have been possible to raise the minimum age for rapid tests to 66 months in early 2006, whereas theoretical reasoning, based on the assumption that the total meat and bone meal ban was effective in November 2001, suggests that this age cutoff could only be raised to 48 months in early 2006. These results only apply to cattle born and bred in France. If the situation remains unchanged, the age cutoff could be raised incrementally each year.

A model (BSurvE) for evaluating national surveillance programs for bovine spongiform encephalopathy.

Our BSurvE spreadsheet model estimates the BSE prevalence in a national cattle population, and can be used to evaluate and compare alternative strategies for a national surveillance program. Each individual surveillance test has a point value (based on demographic and epidemiological information) that reflects the likelihood of detecting BSE in an animal of a given age leaving the population via the stated surveillance stream. A target sum point value for the country is calculated according to a user-defined design prevalence and confidence level, the number of cases detected in animals born after the selected starting date and the national adult-herd size. Surveillance tests carried out on different sub-populations of animals are ranked according to the number of points gained per unit cost, and the results can be used in designing alternative surveillance programs.

Quantifying the risk from ovine BSE and the impact of control strategies.

Although no naturally infected sheep with bovine spongiform encephalopathy (BSE) has ever been discovered, it remains possible that BSE once infected the UK sheep population, has been transmitted between sheep, and is still present today. We constructed a mathematical model to assess the current maximum theoretical exposure to consumers from BSE-infected ovine material and to estimate the risk reduction that could be achieved by abattoir-based control options if BSE-infected sheep were ever found in the national flock. We predict that, if present, the exposure to consumers from a single BSE-infected sheep would be high: one sheep, close to the end of its incubation period, is likely to contribute 10-1000 times more infectious material than a fully infectious cow. Furthermore, 30% of this exposure comes from infectivity residing in lymphatic and peripheral tissue that cannot be completely removed from a carcass. We are 95% confident that throughout Great Britain, no more than four sheep flocks currently harbour an ongoing BSE epidemic. However, since the exposure from a single infected sheep is high, the annual human exposure from four 'typical' BSE-infected flocks could be considerable. Small reductions in exposure could be achieved by strategies based on tissue testing, a 12-month age restriction or expanded definitions of high-risk tissues. A six-month age restriction is likely to be more effective and genotype-based strategies the most effective.

An abattoir survey on bovine spongiform encephalopathy (BSE) in Turkey.

The aim of this study was to investigate Bovine Spongiform Encephalopathy (BSE) in Turkish cattle in the Marmara region which borders the European Union (EU). For this, cattle brought to abattoirs in Istanbul were analysed. The high risk group were selected and therefore 384 cattle above 2 years old were included in the study. They were primarily examined for the presence of any clinical signs of nervous system and also other clinical disorders. The whole brains were taken and analysed for the presence of vacuolar degeneration and prion protein by PLATELIA BSE test kit. Only 5 cattle were found to be nervous and showed aggressive behaviour. There were no cattle showing incoordination or other neurological disorders. Cysts were observed in 3 brains. Histopathologically, no vacuolar degeneration indicative of BSE was found in any cattle examined. However, in 8 brains, few vacuoles were observed in neurons in sections taken from the brain, cerebellum, medulla oblongata and medulla spinalis. Slight mononuclear cell infiltration in 9 brain, intensed mononuclear cell infiltration in 1 brain, haemorrhages in 5 brains and gliosis in 11 brains were also found. No infective prion was detected by ELISA in samples taken from 384 cattle brain.

Development of a monoclonal antibody-based immunohistochemistry method for BSE surveillance in China.

Five hybridoma cell lines secreting anti-PrP antibodies were established from the fusion between mouse myeloma Sp2/0 and spleen cells from mice immunized with recombinant Chinese Luxi yellow cattle (Bos taurus, Luxi) PrP (24-234) or recombinant Chinese small-tailed Han sheep PrP (94-227). According to their Western blot reactivity, five monoclonal antibodies (mAbs) could be divided into two groups. Group A, mAbs 1H2, 4C6, and 4C11 recognized re-PrP, PrP(C), and PrP(Sc) from both bovine and sheep. Group B, mAbs 2H3 and 4H10 only recognized re-PrP and PrP(Sc) of sheep, and especially, these two mAbs could not recognize PrP(C) from both bovine and sheep. In immunohistochemistry (IHC) test, mAb 4C11 immunostained the PrP(Sc) accumulation in tissue sections from BSE cattle and Scrapie sheep, and compared with mAb 6H4, it had the same immunohistochemical pattern. An IHC method based on mAb 4C11 for the detection of BSE was established and had been applied for the long-term surveillance of BSE in China. From 2001 to 2004, 12,692 samples from the whole country had been tested and all had negative results.

Variant CJD (vCJD) and bovine spongiform encephalopathy (BSE): 10 and 20 years on: part 2.

Up until February 2006, variant CJD (vCJD), the human disease associated with transmission of BSE from cattle, has been confirmed in 160 patients resident in the UK and 28 elsewhere, some of whom have never visited the UK. Cases have been reported in France (16 cases), Ireland (3), USA (2), Canada, Italy, Japan, The Netherlands, Portugal, Saudi Arabia and Spain (1 each). The presumed main period of hazard for ingestion of the BSE agent in bovine products in the UK is 1984-89, or perhaps up to 1995-6 but at a reduced level. Debated incubation periods for vCJD are discussed, with special reference to the wide, but currently reducing, range of predicted further primary cases in the UK. The primary disease seems to be preferentially acquired by, and expressed in, relatively young people. All but one of the British cases examined so far were homozygous for methionine at the polymorphic codon 129 of the prion protein PRNP gene. Tests of appendix specimens from large numbers of otherwise normal subjects at the time of appendicectomy have revealed lymphoreticular accumulations of PrP(Sc) in a few samples. Furthermore, three patients who died of vCJD had appendices removed by appendicectomy whilst healthy. Two of these appendices were retrospectively shown to be positive for PrP(Sc) and one removed 10 years before clinical onset was negative. This has led to worries regarding the possibility of pre-clinical or sub-clinical prion-associated disease in an unknown proportion of the population. To date, there has been no known association of primary vCJD with occupation, medicines, immunising agents, gelatine, or surgery (including the use of catgut sutures), or exposure to bovine products other than by ingestion. There is much concern that human-to-human (secondary) vCJD infection is transferred by blood transfusion. A possible risk is also perceived from infected blood products, human organs and tissues, or via contaminated surgical instruments or devices though, so far as is known, no cases have yet arisen in this way. Steps have been taken to reduce the risks and much research is in hand in this field. Continued TSE surveillance, the maintenance of adequate preventive controls, attention to possible parenteral challenges, and further research studies are of paramount importance.

Clinical epidemiologic evaluation of BSE screening tests in Japan.

To address the public concerns provoked by the first incidence of bovine spongiform encephalopathy (BSE) in Japan, the BSE screening tests in Japan are evaluated in use of modeling analysis in evidence-based diagnosis. Under the assumptions based on epidemiological statistics such as the annual number of screened cattle with 1,227,385, the annual incidence of BSE infection with four, and the sensitivity of 99.0% for both primary and secondary tests, it was estimated that, the current threshold of cut-off for the BSE positive would have 0.119 false negatives per year. The decrease of the sensitivity of ELISA down to 90.0% resulted in the increase up to 0.792 false negatives per year. Even with the 90.0% sensitivity, shifting the cut-off point from the current level to the best one remarkably reduced the false negatives per year down to 0.0004. Regarding false positives, with 99.7% specificity for both ELISA and the confirmatory tests revealed the risk of 0.03 false positives per year, while the cut-off shifting that can best minimize false negatives largely increased the false positives up to 11,013. Although it is confirmed the possibility of false negatives is very low, the current method of screening can be further improved by shifting the decision level of cut-off to define the BSE "positive". Such an improvement, however, raises an issue of trade-off : the less false negatives, the more false positives. We believe our approach can help the public perception of an optimum decision-making for BSE screening, considering the trade-off.