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1. Introduction to bovine spongiform encephalopathy (BSE)
2. Diseases related to BSE

1. Introduction to bovine spongiform encephalopathy (BSE)

BSE is a new disease of cattle. It was first recognized and defined in the United Kingdom in November 1986 by histopathological examination of affected brains (Wells et al., 1987). Over the next four years, the disease developed into a large-scale epidemic in most of the country, with serious economic consequences.

BSE occurs in adult animals of both sexes, typically in four- and five year olds. It is a neurological disease involving pronounced changes in mental state, abnormalities of posture and movement and of sensation. The clinical disease usually lasts for several weeks and it is characteristically progressive and fatal (Wilesmith et al., 1988).

The pathology of BSE immediately suggested the nature of the disease and its probable cause. Microscopic lesions in the central nervous system consist of a bilaterally symmetrical, non-inflammatory vacuolation of neuronal perikarya end grey-matter neuropil (Wells et al., 1987). This is the classical picture of the scrapie family of diseases and, on this evidence alone, it seemed highly likely that BSE was a new member of the family.

BSE was subsequently shown to be experimentally transmissible to other cattle, after very long incubation periods (one to two years) by the injection of brain homogenates from clinical cases (Dawson, Wells and Parker, 1990a). This left no doubt that BSE is caused by a scrapie-like infectious agent.

Epidemiological studies showed the vehicle of infection to be meat and bone meal that had been incorporated into concentrated feedstuffs as a protein-rich supplement. The outbreak was probably started by scrapie infection of cattle, but the subsequent course of the epidemic was driven by the recycling of infected cattle material within the cattle population (Wilesmith, Ryan and Atkinson, 1991; Wilesmith and Wells, 1991).

The average level of infection to which cattle were exposed was very low. The reason why this led to such a large number of BSE cases is that much of the United Kingdom dairy cattle population was exposed for many years. There is no firm evidence for the direct transmission of infection from cattle to cattle.

In July 1988 the British Government introduced a ban on the feeding of ruminant protein to ruminants to stop the occurrence of new infections (HMSO, 1988a). However, the average incubation period of BSE is around four to five years and, as of July 1991, there had been insufficient time for the feed ban to affect the incidence of clinical disease.

Long incubation periods are a characteristic feature of all scrapie-like diseases. There is no laboratory diagnostic test for the infectious agent in live animals, mainly because of the absence of any known immune response to infection. Infected animals can only be identified when they develop the clinical disease.

The fact that BSE belongs to the scrapie family is of the greatest importance. The biochemical nature of the scrapie/BSE agent has yet to be established but many of the biological properties of these infectious agents are well understood. There are precedents among members of the scrapie family to indicate the possible future directions of the BSE epidemic and the additional measures that might be needed to eradicate it (Wilesmith and Wells, 1991).

The epidemiological relationships between the various members of the scrapie family clearly define the circumstances under which BSE might, in theory, present a risk to public health. Knowledge of the pathogenesis of these diseases shows precisely the preemptive action that can be taken to minimize this risk (Kimberlin, 1990b; 1990c).

The advent of BSE has made a sizeable impact throughout much of the world even though few countries, other than the United Kingdom, have experienced cases. Trade has been disrupted, sometimes unnecessarily, and great fears have been aroused about the possible occurrence of BSE elsewhere in the world. However a rapid increase in the understanding of the disease over the last four years leaves few unanswered questions of major practical importance. BSE can be prevented controlled and eradicated.

TABLE 1. Spongiform encephalopathies related to BSE in chronological order of demonstrated transmissibility

Disease and occurrence Host species Date
Common in several countries throughout the world
Sheep, goats 1936
Transmissible mink encephalopathy (TME)
Very rare, but adult mortality nearly 100% in some outbreaks
Mink 1965
Once common among the Fore-speaking people of
Papua New Guinea, now rare
Humans 1966
Creutzfeldt-Jakob disease(CJD)
Uniform worldwide incidence of one per million per annum
Humans 1968
Gerstmann-Straussler syndrome (GSS)
A familial form of CJD; less than 0.1 per million per annum
Humans 1981
Chronic wasting disease (CWD)*
Colorado and Wyoming, USA
Mule deer,

*Experimental transmission not demonstrated

2. Diseases related to BSE

2.1. Scrapie
2.2. Transmissible mink encephalopathy (TME)
2.3. Kuru
2.4. Creutzfeldt-jakob disease (CJD)

To understand BSE requires an appreciation of some of the other diseases in the scrapie family listed in Table 1. A detailed review has recently been published (Kimberlin, 1990a). The main features of those diseases that are particularly important in the context of BSE are summarized below. Other related diseases are discussed on pages 28-30.

2.1. Scrapie

Scrapie in sheep (and goats) is the best understood member of the family. It has been endemic in the United Kingdom for over two centuries and is present in many other countries of the world.

Scrapie occurs as a natural infection of adult sheep which is transmitted maternally, from ewe to lamb. Some of this maternal transmission occurs before or at the time of parturition. But it can also occur afterwards because the incidence of scrapie in offspring increases the longer that lambs run with their ewes. Scrapie infection can also spread horizontally between unrelated sheep. With both types of transmission, the oral route of infection is one of those implicated and the placenta is one tissue known to be a source of infection. This information provides a basis for the control of scrapie using two complementary approaches.

The first control method relies on the fact that many of the lambs born to scrapie-infected ewes will themselves become infected regardless of the stage in the ewe's incubation period when they were born. With detailed breeding records, it becomes possible to cull selectively in the female line to reduce the number of sheep in the flock with a high probability of being infected.

The basis of the second approach is that a breeding ewe that is incubating scrapie will not only drop a lamb with a high risk of being infected, but an infected placenta as well. This will be a direct (through eating the placenta) and an indirect (through contamination of the lambing pasture) source of infection to other sheep that come into contact with it. The physicochemical stability of the scrapie agent means that infection can persist in the environment for a long time. Hence farmers are advised to destroy placentas as soon as possible and to keep the lambing premises clean.

Although scrapie is caused by an infectious agent, a single sheep gene (known as sip: scrapie incubation period) exerts a major influence on the length of incubation period. This gene has two alleles (sA and pA), producing three different sip genotypes of sheep. Sheep homozygous for sA are the most likely to develop the natural disease, but some heterozygotes (sApA) may succumb to the disease if the exposure to infection is high enough.

It seems highly probable that the sip gene is the same as the PrP gene which codes for the precursor of the fibril protein that forms scrapie associated fibrils (SAF) (see Evidence for infection, p. 13 and Molecular pathology, p. 35). Biochemical markers are being developed to identify the sA and pA alleles of the sip gene with a view to the possible use of selected sires (sip pApA) as an additional approach to the control of scrapie.

The relevance of scrapie to BSE is threefold. First, scrapie is the likely origin of the BSE epidemic (see p. 22). Second, scrapie provides one of the two main scenarios for the future course of BSE and indicates the type of control measures to be considered should BSE become an endemic infection of cattle (see Control and eradication, p. 55). Third, past exposure to scrapie, which has not been a risk for human beings, provides a baseline for assessing the public health risks caused by BSE (see Creutzfeldt-Jakob disease, p. 6).

2.2. Transmissible mink encephalopathy (TME)

TME is a very rare disease of ranch-reared mink, but it can have devastating consequences, sometimes eliminating an entire herd of adult breeding animals. The disease is caused by an exogenous source of infection to which mink become exposed via contaminated feed. It is not uncommon for mink ranchers to include untreated abattoir waste and dead stock in mink feed.

Since sheep (and perhaps goats) are the only known animal reservoirs of the scrapie-like agents in nature, a direct link between scrapie and TME is likely even though it has not been possible to document the feeding of sheep material in all outbreaks. The same assumption can be made for BSE. Indeed, TME provides a precedent for the origin of BSE, although the circumstances of infection are different. The main differences are that TME is associated with rare, geographically localized, comparatively high levels of exposure to infection in untreated abattoir waste, whereas BSE (at least in the United Kingdom) is due to widespread, prolonged exposure to a very low level of infection in processed animal waste (Kimberlin, 1990b).

An important aspect of TME is that it is a "dead-end" disease with no natural routes of transmission from mink to mink, unless there is cannibalism. In this respect it differs markedly from scrapie and provides a precedent for the alternative scenario for the future course of the BSE epidemic.

2.3. Kuru

Kuru is associated with the very small population of Fore-speaking people in Papua New Guinea and it occurred in rather special circumstances. It may have originated from a spontaneous case of Creutzfeldt-Jakob disease (CJD), but the practice of ritual cannibalism of dead relatives was certainly the means by which neuropathogenic strains of the agent were "passaged" within families. An equivalent situation occurred in BSE with the recycling of infected cattle material within the cattle population. This proved to be the main factor driving the BSE epidemic (see p. 25-26).

Kuru is also important because there appear to be no other routes for the transmission of infection and the cessation of cannibalism has led to the gradual disappearance of kuru. In other words, human beings are effectively a "dead-end" host for the disease. In this respect, kuru resembles TME.

2.4. Creutzfeldt-Jakob disease (CJD)

Two other scrapie-like diseases are known in human beings, although Gerstmann-Straussler syndrome (GSS) is usually regarded as a variant of CJD (see Table 1).

CJD can occur in a familial pattern (as do GSS and scrapie) but it is typically sporadic and has a remarkably uniform incidence worldwide of about one case per million of the population per annum. The epidemiological explanation for the sporadic occurrence of CJD is uncertain but one important possibility has been eliminated.

Because of the precedent set by TME, the possibility that CJD is caused by occasional exposure to scrapie has been intensively studied ever since the transmissibility of CJD was demonstrated in 1968. A large number of investigations have failed to show any epidemiological link between scrapie and CJD. For example, the occurrence of CJD throughout the world is largely independent of the distribution of scrapie and the consumption of sheep products. In addition, several studies have analysed the incidence of CJD in relation to eating habits (e.g. brain), environment (e.g. urban or rural) and various occupations such as those of shepherd, butcher and veterinarian. These studies have also failed to establish a link between scrapie and CJD. It is clear therefore that sheep and goats are not the major reservoir of CJD infection and no other animal reservoir has been identified.

These findings are important in assessing the public health consequences of BSE. Indeed, BSE will be no more of a threat to public health than scrapie unless it is different in the particular ways discussed under The problem (p. 50).

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