J. W. Wilesmith

The Neuropathology and Epidemiology of Bovine Spongiform Encephalopathy

Bovine spongiform encephalopathy (BSE), defined originally from its characteristic neuropathology, retains a place of particular interest in the scrapie‐like or prion disease group, presenting uniquely an example of such diseases occurring as a nationwide food‐borne epidemic in Great Britain. Comprehensive monitoring of the epidemic, both pathologically and epidemiologically, has facilitated our present understanding of the disease. BSE presents the classical neuropathological features of the transmissible spongiform encephalopathies. Although particularly similar to natural scrapie of sheep, BSE has, unlike scrapie, a stereotypic lesion profile from which it has been concluded that host and agent factors, including probably the strain of agent, which influence the profile, are constant in this disease. Neuronal loss in BSE may make an important but hitherto inapparent contribution to functional deficits. Preliminary ultrastructural studies have confirmed light microscopic features of brain changes in BSE but have as yet not established significant new findings.

A cohort study to examine maternally-associated risk factors for bovine spongiform encephalopathy

This long-term cohort study, initiated in July 1989, was designed to examine maternally-associated risk factors for bovine spongiform encephalopathy (BSE), forming part of the epidemiological research programme to assess the risks of non-feedborne transmission of BSE. In this study, the incidence of BSE in offspring of cows which developed clinical signs of BSE is compared with that in offspring, born in the same calving season and herd, of cows which had reached at least six years of age and had not developed BSE. All offspring were allowed to live to seven years of age. The results indicate a statistically significant risk difference between the two cohorts of 9.7 per cent and a relative risk of 3.2 for offspring of cows which developed clinical BSE. However, there is some evidence that this enhanced risk for offspring of BSE cases declined the later the offspring was born, but was increased the later the offspring was born in relation to the stage of the incubation period of the dam. The results presented cannot distinguish between a genetic component and true maternal transmission or a combination of both risks, but they do not indicate either that the BSE epidemic will be unduly prolonged or that the future incidence of BSE in Great Britain will increase significantly.

Temporal and geographical distribution of cases of foot-and-mouth disease during the early weeks of the 2001 epidemic in Great Britain

Estimates of the likely dates of infection of the early cases of the 2001 foot-and-mouth disease (FMD) epidemic indicate that at least 57 premises in 16 counties in Great Britain were infected before the first case was disclosed. Nationwide animal movement controls were imposed within three days of the first case being confirmed on February 20, when FMD was only known to be in two counties, and these controls limited its geographical spread. After the first few cases were confirmed, new cases were rapidly discovered, and the epidemic curve for the daily number of confirmed cases peaked five weeks later, 11 days later than the peak of the curve based on the estimated dates of infection. In the peak week, both curves showed an average daily number of 43 new cases. The estimated dates of infection are believed to be relatively unbiased for the early cases, for which they were derived from a known contact with infection. However, for the later cases they were estimated mainly from the age of the clinical signs of the disease, and were biased by species and other factors, a bias which would probably have made the estimated dates later than was in fact the case.

Bovine Spongiform Encephalopathy

The emergence in domestic cattle of a spongiform encephalopathy homologous with scrapie of sheep and goats (Wells et al. 1987; Hope et al. 1988; Fraser et al. 1988) has renewed interest in many aspects of the unconventional slow virus diseases of man and other mammals, none more so than their methods of transmission. From early clinical descriptions it is clear that scrapie, the exemplar of this disease group, occurred in Europe from 1700 onwards and has remained, or since become, endemic in many countries, including the UK (Parry 1983a). Although “calamitous epidemics” featured in the scrapie occurrences in Northwest Europe during the latter part of the 18th century (Parry 1983a), the magnitude of the present epidemic of bovine spongiform encephalopathy (BSE) is, among animal populations, without precedent in the recorded history of this group of neurodegenerative diseases. The origin of BSE is therefore fundamental to our knowledge of the properties of their unusual, if not unique, causal agents. The chronology of recognition of the naturally occurring transmissible spongiform encephalopathies and their geographic distribution is summarised in Table 1. Prior to the occurrence of BSE, the only ruminant species, apart from domestic sheep and goats, known to be affected by such diseases Table 1 Chronology of recognition of naturally occurring transmissible spongiform encephalopathies Host Disease Geographic distribution Original clinical observation Initial report Sheep Scrapie Widely distributed except Australia, New Zealand, some European countries ca. 1730, possibly much earlier Comber (1772) (cited by Parry 1983a) Goat Scrapie ? ? Eisenmayer and Gobel (1872) (cited by Parry 1983a) Man Kuru Papua New Guinea ca. 1900 Zigas and Gajdusek (1957) Gajdusek and Zigas (1957) Creutzfeldt-Jakob disease Worldwide 1920 Jakob (1921a-c) Gerstmann-Straussler-Scheinker syndrome Worldwide 1926 Gerstmann, Straussler, Scheinker (1936) Farmed mink (Mustela vison) Transmissible mink encephalopathy North America, Europe 1947 Burger and Hartsough (1964) Mule deer (Odocoileus hemionus hemionus) Chronic wasting disease North America, Europe 1967 Williams and Young (1980) Elk (Cervus elaphus nelsoni) Williams and Young (1982) Cattle Bovine spongiform encephalopathy UK, Republic of Ireland 1985 Wells et al. (1987) Bassett and Sheridan(1989) Nyala (Tragelaphus angasi) Gemsbok (Oryx gazella) a a UK UK \(\left. \begin{gathered} 1986 \hfill \\ 1987 \hfill \\ \end{gathered} \right\}\) Jeffrey and Wells (1988) Eland (Taurotragus oryx) a UK 1989 Fleetwood and Furley (1990) Arabian oryx (Oryx leucoryx) Greater kudu (Tragelaphus strepsiceros) a a UK UK \(\left. \begin{gathered} 1989 \hfill \\ \hfill \\ 1989 \hfill \\ \end{gathered} \right\}\) Kirkwood et al. (1990) Cat (Felis domesticus) a UK 1990 Wyatt et al. (1990) were captive groups of the North American cervids: mule deer (Odocoileus hemionus hemionus) and elk (Cervus elaphus nelsoni) (Williams and Young 1980; Williams and Young 1982).

Different prion disease phenotypes result from inoculation of cattle with two temporally separated sources of sheep scrapie from Great Britain

BackgroundGiven the theoretical proposal that bovine spongiform encephalopathy (BSE) could have originated from sheep scrapie, this study investigated the pathogenicity for cattle, by intracerebral (i.c.) inoculation, of two pools of scrapie agents sourced in Great Britain before and during the BSE epidemic.Two groups of ten cattle were each inoculated with pools of brain material from sheep scrapie cases collected prior to 1975 and after 1990. Control groups comprised five cattle inoculated with sheep brain free from scrapie, five cattle inoculated with saline, and for comparison with BSE, naturally infected cattle and cattle i.c. inoculated with BSE brainstem homogenate from a parallel study. Phenotypic characterisation of the disease forms transmitted to cattle was conducted by morphological, immunohistochemical, biochemical and biological methods.ResultsDisease occurred in 16 cattle, nine inoculated with the pre-1975 inoculum and seven inoculated with the post-1990 inoculum, with four cattle still alive at 83 months post challenge (as at June 2006). The different inocula produced predominantly two different disease phenotypes as determined by histopathological, immunohistochemical and Western immunoblotting methods and biological characterisation on transmission to mice, neither of which was identical to BSE. Whilst the disease presentation was uniform in all scrapie-affected cattle of the pre-1975 group, the post-1990 inoculum produced a more variable disease, with two animals sharing immunohistochemical and molecular profile characteristics with animals in the pre-1975 group.ConclusionThe study has demonstrated that cattle inoculated with different pooled scrapie sources can develop different prion disease phenotypes, which were not consistent with the phenotype of BSE of cattle and whose isolates did not have the strain typing characteristics of the BSE agent on transmission to mice.

Descriptive spatial analysis of the epidemic of bovine spongiform encephalopathy in Great Britain to June 1997

This was a spatial analysis of the epidemic of bovine spongiform encephalopathy (BsE) in Great Britain, based on agricultural census data collected between 1986 and 1996 and BSE case data collected up to June 1997. Kemel smoothing techniques were used to plot the distribution of BSE-positive cattle holdings per 100 holdings per square kilometre and the distribution of confirmed BSE cases per 100 head of cattle per square kilometre. In the early stages of the epidemic reported BSE cases were scattered widely throughout Great Britain, with no clearly identifiable focus. By June 1997, a statistically significant cluster of BSE-positive holdings was identifiable in the eastern part of the South west region of England. During the epidemic the highest densities of confirmed BSE cases per 100 cattle per square kilometre occurred in the greater part of the South west region of England and within Dyfed in the south west of Wales. In Wales, a small number of holdings experienced large numbers of confirmed BSE cases. In the South west region of England a large number of holdings experienced small numbers of confirmed cases. By June 1997, the distribution of BsE-positive holdings across Great Britain was largely determined by factors that influenced the amount of recycled infectious material they were exposed to.

Temporal aspects of the epidemic of bovine spongiform encephalopathy in Great Britain: holding.associated risk factors for the disease

The objectives of this study were first to describe the pattern of the epidemic of bovine spongiform encephalopathy (BSE) in Great Britain in terms of the temporal change in the proportion of all cattle holdings that had experienced at least one confirmed case of BSE to June 30, 1997, and secondly to identify risk factors that influenced the date of onset of a holdings first confirmed BSE case. The analyses were based on the population of British cattle at risk, derived from agricultural census data collected between 1986 and 1996, and the BSE case data collected up to June 30, 1997. The unit of interest was the cattle holding and included all those recorded at least once on annual agricultural censuses conducted between June 30,1986, and June 30,1996. The outcome of interest was the date on which clinical signs were recorded in a holdings first confirmed case of BSE, termed the BSE onset date. Univariate and multivariate survival analysis techniques were used to describe the temporal pattern of the epidemic. The BSE epidemic in Great Britain started in November 1986, with the majority of affected holdings having their BSE onset date after February 1992. After adjusting for the effect of the size and type of holding, holdings in the south of England (specifically those in the Eastern, South east and South west regions) had 2.22 to 2.43 (95 per cent confidence interval [ci] 2.07 to 2.58) times as great a monthly hazard of having a BSE index case as holdings in Scotland. After adjusting for the effect of region and type of holding, holdings with more than 53 adult cattle had 5.91 (95 per cent ci 5.62 to 6.21) times as great a monthly hazard of having a BSE index case as holdings with seven to 21 adult cattle. Dairy holdings had 3.06 (95 per cent ci 2.96 to 3.16) times as great a monthly hazard of having a BSE index case as beef suckler holdings. These analyses show that there were different rates of onset in different regions and in holdings of different sizes and types, that the epidemic was propagated most strongly in the south of the country, and that the growth of the epidemic followed essentially the same pattern in each region of the country, with modest temporal lags between them. The control measures imposed in 1988 and 1990 brought the expansion of the epidemic under control, although the rate of progress was slowed by those regions where the effectiveness of the control methods took some time to take full effect.

Modelling studies on bovine spongiform encephalopathy occurrence to assist in the review of the over 30 months rule in Great Britain

The objective of this study was to contribute to a risk assessment to review the over 30 months (OTM) scheme in cattle, whereby all cattle aged over 30 months slaughtered in the UK are removed from the human food chain. We use back–calculation methods to estimate the impact of changes to the OTM rule, by using passive and active surveillance data collected between 1 July 2001 and 30 June 2002. There are two types of change considered: increasing the age limit and allowing animals born after a certain date into the food chain. Results indicate that under the OTM rule less than 1 animal in the last 12 months of the incubation period would enter the food chain in 2003. The birth date changes considered and small changes to the upper age limit would increase this number by a relatively small amount.

Temporal aspects of the epidemic of bovine spongiform encephalopathy in Great Britain: individual animal-associated risk factors for the disease

The objectives of this study were first to determine the cumulative incidence of bovine spongiform encephalopathy (BSE) in the British cattle population from July 1986 to June 1997, secondly, to identify individual animal-associated risk factors that influenced the age of onset of clinical signs in confirmed BSE cases, and, thirdly, to assess the effectiveness of the measures introduced to control BSE during the epidemic. The analyses were based on the population of British cattle at risk, derived from agricultural census data collected between 1986 and 1996, and BSE case data collected up to June 30,1997. The unit of interest was individual adult cattle recorded on annual agricultural censuses between June 1986 and June 1996. Univariate and multivariate survival analysis techniques were used to characterise the age of onset of clinical signs. In total 167,366 cases of BSE were diagnosed in Great Britain up to June 30,1997. The cumulative incidence of BSE between July 1986 and June 1997 was 1.10 (95 per cent confidence interval [ci] 1.09 to 1.10) cases per 100 adult cattle at risk. Cattle from the South east, South west and Eastern regions of England had 4.26 to 5.96 (95 per cent cl 4.15 to 6.14) times as great a monthly hazard of being confirmed with BSE as cattle from Scotland. Compared with cattle born before June 1985, those born between July 1987 and June 1988 had 22.5 (95 per cent cl 22.1 to 22.8) times the monthly hazard of being confirmed with BSE, whereas those born in the 12 months after July 1988 had only 7.39 (95 per cent cl 7.24 to 7.54) times the monthly hazard of being confirmed with BSE. This reduction in hazard was directly attributable to the ban on the use of ruminant protein as a feed instituted in July 1988. Successive cohorts from 1989 to 1991 experienced further reductions in the hazard of experiencing BSE. The additional decrease in hazard observed for the 1990 cohort may be attributed to the effect of the Specified Bovine Offal ban instituted in September 1990.

Scrapie surveillance in Great Britain: results of an abattoir survey, 1997/98

A randomised sample of 2809 apparently healthy sheep, 55 per cent of them less than 15 months of age, which were slaughtered for human consumption at abattoirs in Great Britain in 1997/98, was taken to establish the prevalence of scrapie infection. The medulla oblongata of each sheep was examined histopathologically at the level of the obex, and fresh brain tissue was examined for scrapie-associated fibrils (SAF) to establish whether there was evidence of scrapie. In addition, histological sections of the medulla from 500 of the sheep were immunostained with an antiserum to PrR and the same technique was also applied to any animal found positive or inconclusive by the histological or SAF examinations. Any sheep which was positive by any of these diagnostic methods was also examined by Western immunoblotting, for the detection of the disease-specific protein PrPsc. A total of 2798 sheep (99.6 per cent) were negative by all the methods applied. Ten animals were SAF-positive but negative by all the other methods, and in one animal there was immunohistochemical staining which could not be interpreted unequivocally as diseasespecific. A mathematical model was used to estimate the prevalence of scrapie infection in the national slaughtered sheep population which would be consistent with these results. By this model, the absence of unequivocally substantiated cases of scrapie in the sample was consistent with a prevalence of infection in the slaughter population of up to 11 per cent.