Transmissible spongiform encephalopathies in non-domestic animals: origin,transmission and risk factors

The transmissible spongiform encephalopathies (TSEs), scrapie and bovine spongiform encephalopathy (BSE), are serious diseases of domestic animals. Although not as significant in terms of numbers of animals affected or geographical distribution, TSEs also affect non-domestic animals. Transmissible mink encephalopathy (TME) was the first TSE to be identified in non-domestic animals. This disease of captive mink (Mustela vison) is very rare and is associated with exposure through feed contaminated by a TSE agent. The second TSE to be identified in non-domestic animals was chronic wasting disease (CWD) of deer and elk. This disease is not known to be associated with feedstuffs contaminated with the agent of CWD, but the natural route of exposure appears to be oral, possibly through direct interaction between animals or through environmental contamination. Over the last five years, the known distribution of CWD across North America has expanded, increasing concerns over the impact of this disease on populations of free-ranging cervids and the viability of game farming industries. Concurrent with the epidemic of BSE, a variety of non-domestic ruminants and felid species were also affected in the United Kingdom, presumably through exposure to the agent in contaminated feed. These examples illustrate that when non-domestic animals are held in captivity, they depend upon feeds supplied by their caretakers and may show degrees of susceptibility to infectious agents in feeds which vary from those of domestic species. Although humans have less influence over exposure of free-ranging species to infectious agents, monitoring these populations for diseases may be important for managing the health of these animals. It is important to institute or continue surveillance for an entire range of infectious diseases, including TSEs, in free-ranging and captive non-domestic species. Study of diseases in these species may provide important information about infectious agents of concern for domestic animals and humans.     

The transmissible spongiform encephalopathies

Transmissible spongiform encephalopathies (TSEs) represent a group of neurodegenerative diseases characterised by a very long incubation period in regard to the life expectancy of the host species. The lesions are restricted to the central nervous system, although the pathogenesis of infection implies a primary replication step of TSE agents in the lymphoid organs followed by a neuroinvasive phase. The outcome is always fatal and today there is neither cure nor prophylaxis for these diseases. For years, the causative agents of TSEs have posed a conundrum in terms of current knowledge of microorganisms, and there are still open questions about their exact nature. They are usually called TSE agents or prions because they are thoughtto be primarily composed of a modified host protein, the prion protein (PrP). A pathological form of the prion protein, called PrPSc (for scrapie) or PrPRes, an operational definition referring to resistance to proteolytic digestion, accumulates in target organs. The aim of this introductory chapter is to presentthe general features of TSEs and a modern understanding of TSE agents and their mode of replication. Notwithstanding the plethora of unsolved questions on these diseases and their aetiology, knowledge of their pathogenesis and recent advances in understanding of the molecular basis of PrP accumulation, together with detection systems, provide the tools to conduct sound TSE risk management.     

Risk management of transmissible spongiform encephalopathies in Asia

A questionnaire-based survey was distributed to the Office International des Epizooties (OIE: World organisation for animal health) Member Countries in Asia to assess the use of risk management for transmissible spongiform encephalopathies. The author presents a summary of 16 responses received in July 2002. The survey revealed that import risk analysis on bovine spongiform encephalopathy (BSE) is not routinely carried out in ten countries, indicating an urgent need for further training courses. Although the number of ruminants imported from Europe is relatively small, significant quantities of feedstuffs of ruminant origin have been imported into Asia, which may mean that the BSE agent could have reached domestic cattle in most countries. The external challenge has been considerably reduced in recent years as most countries in Asia banned the importation of feedstuffs from countries with BSE, but a few weak spots which enable imports of risk materials still persist. Recycling of BSE through rendering plants is unlikely but cannot be totally excluded in some countries such as the People's Republic of China, India, Japan, Pakistan and Taipei China. Therefore, much more stringent management at slaughterhouses and rendering plants, as well as extensive surveillance programmes, are required in those countries. Bovine spongiform encephalopathy is not notifiable in six countries, indicating a total absence of risk management of BSE in those countries. Immediate actions by these governments to declare BSE a notifiable disease are considered necessary. Numbers of specimens tested for BSE are still very small in most countries in Asia, indicating a pressing need to upgrade surveillance programmes by introducing modern (economically affordable) diagnostic methods and by conducting practical training courses on epidemiological surveillance systems. With the exception of Japan, very little work has been performed on scrapie in Asia although the disease has been routinely monitored in the People's Republic of China, India, Myanmar, Pakistan and Taipei China.     

Risk management of transmissible spongiform encephalopathies in Europe

Bovine spongiform encephalopathy (BSE) was first described in the United Kingdom (UK) in November 1986. After the introduction of an active surveillance system, most countries in Europe have reported BSE cases in the cattle population. This indicates that the use of active surveillance in addition to passive surveillance is important to assess the true BSE status in a country. Scrapie, a transmissible spongiform encephalopathy (TSE) in sheep and goats, has been reported in countries throughout the world with a few notable exceptions. Concern was expressed that BSE could have been introduced into sheep and goats. Currently, distinguishing between scrapie and BSE in small ruminants is only possible through lengthy experiments in mice. Preliminary results of active surveillance, introduced in 2002, show that significant under-reporting occurred. The history of BSE in cattle shows that risk assessments concerning the risk in a given country were often ignored and subsequent risk management decisions were inaccurate, i.e. although the risk was probable, no measures were taken in terms of either animal or human health. Furthermore, the effect of the measures taken was often overestimated and these had to be amended several times. The most important action to prevent new cases of TSEs occurring is by banning the feeding meat-and-bone meal (MBM) to ruminants. Further measures to be considered are the exclusion of specified risk material and carcasses from rendering, the process parameters for rendering of animal waste and the prevention of cross-contamination of feed with MBM. The most important measures to protect the consumer are the ban on specified risk material, such as brain and spinal cord, which may contain particularly high concentrations of the BSE agent, and the ban on mechanically recovered meat. The most important measures taken in Europe and the scientific background thereof are described and discussed.     

Risk communication of the transmissible spongiform encephalopathies

Previous chapters of this review have dealt with the scientific basis of assessing the risks from transmissible spongiform encephalopathies and how those risks should be managed. The author explores the theory and practice of risk communication and sets out the basic principles for good risk communication when dealing with uncertainty.     

Atypical transmissible spongiform encephalopathies (TSEs) in ruminants

Transmissible spongiform encephalopathies (TSEs) are associated with the accumulation in infected tissues of a disease-associated form of a host-encoded protein, the prion protein (PrP). Contrary to the normal form of the protein, this form of PrP is partially resistant to protease digestion (PrP(res)). Detailed characterisation of PrP(res) has been intensively investigated in recent years to try and decipher the diversity of TSEs in human and animals. This considerably and unexpectedly enlarged our knowledge about such diseases in ruminants. Previously, such a diversity was essentially shown by the demonstration that scrapie from sheep and goats could have different biological behaviours following transmission of the disease in mice, unlike bovine spongiform encephalopathy from cattle (BSE) which showed a distinct and unique behaviour. The properties of the BSE agent were also demonstrated to be very stable, following transmission to a variety of different species. Molecular studies of PrP(res), followed by transmission studies to mice, gave the first evidence for the accidental transmission of the BSE agent to humans where it induced a variant form of the fatal Creutzfeldt-Jakob disease (CJD) and also to different animal species including a goat in France. This last case was found among a few unusual cases of TSEs in small ruminants that showed some molecular similarities with BSE and which are currently under investigation by transmission studies in mice. The application of the molecular methods to characterise PrP(res) has most recently led to the unexpected discovery of deviant BSE forms in a few affected cattle in Europe and in the United States, which raises the question of a possible different origin at least of some cases of BSE in cattle. Finally, considerable numbers of a new TSE form in small ruminants, referred to as "atypical scrapie" or "Nor98", have meanwhile been identified in most European countries by TSE rapid testing using an assay which recognizes also comparatively less PK resistant PrP(res).     

Sub-acute, transmissible spongiform encephalopathies: current concepts and future needs.

The first diagnosis of bovine spongiform encephalopathy (BSE) in the United Kingdom in 1986 was to stimulate the most intensive epidemiological study of any animal disease of all time in that country. It led also to the initiation of a broad-based research programme with an international flavour. This principally involved scientists and veterinarians in Europe (especially the United Kingdom) and the United States of America, especially those with experience of slow infections in general and experimental scrapie in particular. This final chapter highlights some of the significant discoveries made in the study of BSE and related diseases of this group but also emphasises the deficits in knowledge which need to be corrected before such diseases as scrapie in sheep and goats can be brought under control. The benefits resultant upon effective disease control will be manifest as improvement in animal production, welfare and, importantly, the removal of trading barriers currently in place to protect countries in which diseases such as BSE and scrapie do not exist. Of key importance is the development of a simple, cheap and effective diagnostic test for use in the live animal before the onset of clinical signs. This will be difficult since the nature of the causal agents is uncertain and none provokes either a detectable immune response or inflammatory reaction in the host. The earlier chapters, written by acknowledged specialists from around the world, deal with the specific diseases in detail and all present some of the most recent knowledge available. Here the authors emphasise the important role that major national and international agencies have in effecting the highest level of control possible in the absence of key information. International collaboration with countries in which these diseases exist, and as well as those where they are absent, is of paramount importance. It is essential that the BSE epidemic which has severely affected the cattle industry of the United Kingdom is not allowed to happen in developing countries. Whereas the former has implemented stringent control measures based on scientific knowledge and is well on the way to eradicating the disease, the latter could have much greater difficulty in establishing control. The answer is clear. BSE must be prevented from occurring elsewhere. To do that, knowledge of BSE and other members of the group should be widely dispersed and it is the purpose of this issue to do just that.     

Risk management of the transmissible spongiform encephalopathies in North America

As North American Free Trade Agreement partners, Canada, the United States of America (USA) and Mexico apply independent but harmonised transmissible spongiform encephalopathy (TSE) risk management strategies in observance of Office International des Epizooties guidelines. The divergence between bovine spongiform encephalopathy (BSE) risk management approaches in North American and Europe reflects comparatively reduced external and internal BSE risks in North America. The external quarantine and internal surveillance measures adopted for BSE respond to several iterations of national risk assessments initiated in the early 1990s and revised as recently as 2002. Feed bans applied since 1997 to preclude establishment of BSE also bear the potential to limit intra-species and inter-species exposure to scrapie, chronic wasting disease (CWD) and transmissible mink encephalopathy (TME). Surveillance continues for the four TSEs through collaborative efforts of national and sub-national veterinary infrastructures and accompanying laboratory networks. Mexico has never identified the presence of any TSE. The last diagnosed case of TME in North America dates back to 1985. Since the only recognised appearance in Canada through an import from Great Britain in 1993, BSE has not been detected in North America. Scrapie and CWD remain at generally low prevalence in Canada and the USA. Independent but harmonised eradication programmes target elimination of the latter two diseases.     

Some problems of diagnosis of the spongiform encephalopathies in ruminants

The difficulties of a positive diagnosis in the spongiform encephalopathies based only on epidemiological and clinical data are briefly reviewed. However, in B.S.E. as in scrapie, the epidemiology and the clinical data may frequently suggest these diseases. The main diseases which must be taken into account in the differential diagnosis of both spongiform encephalopathies are discussed and the criteria of the differential diagnosis are tabulated.     

The potential for transmissible spongiform encephalopathies in non-ruminant livestock and fish

Pigs and poultry in the United Kingdom have undeniably been exposed to the bovine spongiform encephalopathy (BSE) agent. They consumed the same ruminant protein that gave rise to the BSE epidemic in cattle, but there has been no evidence of an epidemic in these species. Experimental investigations have shown pigs to be susceptible to infection by multiple parenteral challenge, but resistant to oral exposure with BSE-infected cattle brain. Current but incomplete evidence suggests that they are also resistant to oral challenge with sheep scrapie. Studies in domestic chickens indicate that they are resistant to both parenteral and oral challenge. Unfortunately, no published data exists on the susceptibility of fish to infection. Incidental findings in the brains of unexposed pigs are described that could otherwise give rise to concerns aboutthe presence of a transmissible spongiform encephalopathy in pig populations around the world.     

Transmissible spongiform encephalopathies: assessment of exposure risk in the histological working environment using GC-MS detection of fatty acids as marker for central nervous tissues

To elucidate the risk of occupational exposure to the agent of transmissible spongiform encephalopathies (TSE) in the histological working environment, we assessed the principal suitability of three analytical methods for the detection of tissues of the central nervous system (CNT). We tested a neuron-specific enolase (NSE) Western blot, a glial fibrillary acidic protein (GFAP) ELISA and the GC-MS detection of some CNT typical fatty acids (FAs): omega9-tetracosenic acid, omega7-tetracosenic acid, lignoceric acid, and cerebronic acid. Histological sample processing (formalin fixation, dehydration, paraffin embedding) affected both of the immunochemical approaches considerably. The NSE Western blot produced negative results without exception. The results for the GFAP ELISA were better but still far too insensitive. Thus, both methods were judged to be unsuitable in their present form without major analytical adjustment. GC-MS sensitivity remained unaffected by the formalin fixation process. Sensitivity was reduced in the course of the final dehydration step using xylene in the histological sample processing. However, this reduction was found to be rather moderate (range 42-59%) when compared to the immunochemical methods. Overall, we judged GC-MS to be a promising analytical approach for the assessment of a potential TSE exposure risk via airborne CNT particles in the histological working environment. All the FAs we tested showed very low but detectable baseline contents. Thus, cut-off values must be used in the present GC-MS approach. The most suitable FA turned out to be omega9-tetracosenic acid due to the greatest difference between its content in histological CNT samples and the respective cut-off value (689:1). Preliminary results by GC-MS monitoring of CNT via omega9-tetracosenic acid (and other FAs) on filters of routinely used vacuum cleaners and on filters after air sampling indicate that the airborne CNT/TSE exposure risk in the histological laboratory is minor if existing at all. However, further in depth studies will have to validate our preliminary findings and assess these results in the light of possible future data on human oral and/or pulmonary TSE susceptibility.     

Atypical bovine spongiform encephalopathies, France, 2001-2007

In France, through exhaustive active surveillance, approximately 17.1 million adult cattle were tested for bovine spongiform encephalopathy from July 2001 through July 2007; approximately 3.6 million were >8 years of age. Our retrospective Western blot study of all 645 confirmed cases found that 7 were H-type and 6 were L-type.     

The use of antioxidants in transmissible spongiform encephalopathies: a case report

BACKGROUND: Transmissible spongiform encephalopathies (TSE), which include Creutzfeldt-Jakob disease and new variant Creutzfeldt-Jakob disease, are diseases characterized by progressive deterioration in the central nervous system with neuronal degeneration, vacuolatization of the neuropil, and gliosis. Little is known about the pathogenic mechanisms of infection, and controversy exits around the inciting infective agent. It has been shown that an important factor in pathogenesis is the immune system. CASE: The reported case points to beneficial effects when antioxidant therapies are used in transmissible spongiform encephalopathies. The case revealed an early reversal in cognitive decline and subsequent improvements in myoclonus, apnea and rigidity. Although death was the ultimate outcome, the patient succumbed to the illness over 22 months after the onset of symptoms when the early rapid decline predicted demise within a few months. CONCLUSION: It is possible that strategies blocking the effect of proinflammatory cytokines and the resulting oxidative damage may stem the progressive damage to the neuropil that occurs in spongiform encephalopathies. Further investigation into the use of antioxidants and other types of agents quelling inflammation needs to be undertaken. If antioxidants could be combined with treatments for the inciting infective agent, a new direction could be taken in the outcome of transmissible spongiform encephalopathies including CJD and vCJD.     

Candidate cell substrates, vaccine production, and transmissible spongiform encephalopathies

Transmissible spongiform encephalopathy (TSE) agents have contaminated human tissue-derived medical products, human blood components, and animal vaccines. The objective of this study was to determine the potential susceptibility to infection of 5 cell lines used or proposed for manufacture of biological products, as well as other lines. Cell lines were exposed to the infectious agents of sporadic and variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy (BSE). Exposed cultures were tested for TSE-associated prion protein (PrP(TSE)) and TSE infectivity by assay in rodents and nonhuman primates. No PrP(TSE) or infectivity has been detected in any exposed cell line under study so far. Animals inoculated with BSE brain homogenate developed typical spongiform encephalopathy. In contrast, animals inoculated with cells exposed to the BSE agent remained asymptomatic. All cell lines we studied resisted infection with 3 TSE agents, including the BSE agent.     

Brief review on the epidemiology of transmissible spongiform encephalopathies (TSE)

Transmissible spongiform encephalopathies (TSE) form a group of human and animal diseases that share common features such as (a) distinct pathological lesions in the central nervous system, (b) transmissibility at least in experimental settings, and (c) a long incubation period. Considerable differences exist in the host range of individual TSEs, their routes of transmission, and factors influencing the host susceptibility (such as genotype). The objective of this review was to briefly describe the main epidemiological features of TSEs with emphasis on small ruminant (sheep, goats) TSE, bovine spongiform encephalopathy (BSE) in cattle and chronic wasting disease (CWD) in deer and elk.     

Public health issues related to animal and human spongiform encephalopathies: memorandum from a WHO meeting.

The transmissible spongiform encephalopathies (TSE) include bovine spongiform encephalopathy (BSE), which was first described in 1986 in the United Kingdom but has occurred subsequently in several other countries. This Memorandum reviews the existing state of knowledge on all the known spongiform encephalopathies, and evaluates the pathways of transmission and associated hazards. The possible implications of the animal diseases, especially BSE, with regard to the use of animal tissues as animal feed, human food, and in the preparation of medicinal and other products for human use are discussed, with recommendations to national health authorities on appropriate measures to minimize the consequences of BSE to public and animal health.     

Risk of Creutzfeldt-Jakob disease in relation to animal spongiform encephalopathies: A collaborative study in Europe

This paper describes a study of the risk of Creutzfeldt-Jakob disease in various European countries. The objectives of the study are to investigate the frequency of Creutzfeldt-Jakob disease and other human spongiform encephalophaties in Europe in relation to animal spongiform encephalophaties, and to assess the risk of Creutzfeldt-Jakob disease in relation to genetic, occupational and nutritional factors. The study will consist of three parts: the establishment of registries of Creutzfeldt-Jakob disease on the basis of cases in the registries, and molecular genetic studies with material collected in the registries.