bovine spongiform encephalopathy

Pictures

Picture	Title	Caption	Copyright
Title Symptoms Caption Clinical appearance of a Friesian cow with BSE; apprehensive, with ears directed back. Also, poor general bodily condition. Copyright Crown copyright 2004, Veterinary Laboratories Agency	Symptoms	Clinical appearance of a Friesian cow with BSE; apprehensive, with ears directed back. Also, poor general bodily condition.	Crown copyright 2004, Veterinary Laboratories Agency
Title Signs Caption Cattle affected by BSE have progressive degeneration of the nervous system. Behavioural changes in temperament (e.g., nervousness or aggression), abnormal posture, incoordination and difficulty in rising, decreased milk production, and/or loss of weight despite continued appetite are followed by death in cattle affected by BSE. (Picture by CDC/Art Davis) Copyright Centers for Disease Control and Prevention (CDC)/Atlanta, GA 30333, USA	Signs	Cattle affected by BSE have progressive degeneration of the nervous system. Behavioural changes in temperament (e.g., nervousness or aggression), abnormal posture, incoordination and difficulty in rising, decreased milk production, and/or loss of weight despite continued appetite are followed by death in cattle affected by BSE. (Picture by CDC/Art Davis)	Centers for Disease Control and Prevention (CDC)/Atlanta, GA 30333, USA
Title Symptoms Caption Cattle affected by BSE experience progressive degeneration of the nervous system. Behavioral changes in temperament (e.g., nervousness or aggression), abnormal posture, incoordination and difficulty in rising, decreased milk production, and/or loss of weight despite continued appetite are followed by death in cattle affected by BSE. (Picture by CDC/Art Davis) Copyright Centers for Disease Control and Prevention (CDC)/Atlanta, GA 30333, USA	Symptoms	Cattle affected by BSE experience progressive degeneration of the nervous system. Behavioral changes in temperament (e.g., nervousness or aggression), abnormal posture, incoordination and difficulty in rising, decreased milk production, and/or loss of weight despite continued appetite are followed by death in cattle affected by BSE. (Picture by CDC/Art Davis)	Centers for Disease Control and Prevention (CDC)/Atlanta, GA 30333, USA
Title Histopathology - normal medulla oblongata Caption Histological section of part of the nucleus of the solitary tract in the medulla oblongata (obex region) from a normal cow (haematoxylin and eosin stain). Compare with the corresponding section from a cow with BSE. Copyright Crown copyright 2004, Veterinary Laboratories Agency	Histopathology - normal medulla oblongata	Histological section of part of the nucleus of the solitary tract in the medulla oblongata (obex region) from a normal cow (haematoxylin and eosin stain). Compare with the corresponding section from a cow with BSE.	Crown copyright 2004, Veterinary Laboratories Agency
Title Histopathology - BSE medulla oblongata Caption Histological section of part of the nucleus of the solitary tract in the medulla oblongata (obex region) from a cow with BSE. Marked vacuolation of the neurophil (haematoxylin and eosin stain). Compare with corresponding section from a normal cow. Copyright Crown copyright 2004, Veterinary Laboratories Agency	Histopathology - BSE medulla oblongata	Histological section of part of the nucleus of the solitary tract in the medulla oblongata (obex region) from a cow with BSE. Marked vacuolation of the neurophil (haematoxylin and eosin stain). Compare with corresponding section from a normal cow.	Crown copyright 2004, Veterinary Laboratories Agency
Title Cross section through the medulla oblongata Caption Cross section through the medulla oblongata (solitary tract nucleus) of a cow with BSE: spongiform lesions (numerous microvacuoles in the neuropil, arrowed) in the grey matter. Histopathology: haemalum-eosin stain, low magnification (lens 10x). Copyright Felix Ehrensperger/Institute of Veterinary Pathology, University of Zürich, Switzerland	Cross section through the medulla oblongata	Cross section through the medulla oblongata (solitary tract nucleus) of a cow with BSE: spongiform lesions (numerous microvacuoles in the neuropil, arrowed) in the grey matter. Histopathology: haemalum-eosin stain, low magnification (lens 10x).	Felix Ehrensperger/Institute of Veterinary Pathology, University of Zürich, Switzerland
Title Inspected cattle Caption Cattle which have been inspected by the Food Safety Inspection Service, (FSIS) before slaughter. All cattle presented for slaughter in the USA are inspected before slaughter by the Food Safety Inspection Service, (FSIS) for signs of central nervous system disorders. (Picture by CDC/Norman Watkins)|Cattle which have been inspected by the Food Safety Inspection Service, (FSIS) before slaughter. All cattle presented for slaughter in the USA are inspected before slaughter by the Food Safety Inspection Service, (FSIS) for signs of central nervous system disorders. (Picture by CDC/Norman Watkins) Copyright Centers for Disease Control and Prevention (CDC)/Atlanta, GA 30333, USA	Inspected cattle	Cattle which have been inspected by the Food Safety Inspection Service, (FSIS) before slaughter. All cattle presented for slaughter in the USA are inspected before slaughter by the Food Safety Inspection Service, (FSIS) for signs of central nervous system disorders. (Picture by CDC/Norman Watkins)|Cattle which have been inspected by the Food Safety Inspection Service, (FSIS) before slaughter. All cattle presented for slaughter in the USA are inspected before slaughter by the Food Safety Inspection Service, (FSIS) for signs of central nervous system disorders. (Picture by CDC/Norman Watkins)	Centers for Disease Control and Prevention (CDC)/Atlanta, GA 30333, USA
Title Cross section through the medulla oblongata Caption Cross section through the medulla oblongata (dorsal vagal nucleus) of a cow with BSE: spongiform lesions (arrows) in the grey matter, besides intact neurons (larger arrow). Histopathology: haemalum-eosin stain, high magnification (lens 40x) Copyright Felix Ehrensperger/Institute of Veterinary Pathology, University of Zürich, Switzerland	Cross section through the medulla oblongata	Cross section through the medulla oblongata (dorsal vagal nucleus) of a cow with BSE: spongiform lesions (arrows) in the grey matter, besides intact neurons (larger arrow). Histopathology: haemalum-eosin stain, high magnification (lens 40x)	Felix Ehrensperger/Institute of Veterinary Pathology, University of Zürich, Switzerland
Title Cross section through the medulla oblongata Caption Cross section through the medulla oblongata (vestibular nuclei) of a cow with BSE: vacuolar degeneration of a large neuron (arrowed). Histopathology: haemalum-eosin stain, high magnification (lens 40x). Copyright Felix Ehrensperger/Institute of Veterinary Pathology, University of Zürich, Switzerland	Cross section through the medulla oblongata	Cross section through the medulla oblongata (vestibular nuclei) of a cow with BSE: vacuolar degeneration of a large neuron (arrowed). Histopathology: haemalum-eosin stain, high magnification (lens 40x).	Felix Ehrensperger/Institute of Veterinary Pathology, University of Zürich, Switzerland
Title Cross section through the medulla oblongata Caption Cross section through the medulla oblongata (vestibular nuclei) of a cow with BSE: immunohistochemical demonstration of PrP accumulation (brown) in axons and neuronal cytoplasm. Histopathology: PrP immunohistochemistry, high magnification (lens 40x). Copyright Felix Ehrensperger/Institute of Veterinary Pathology, University of Zürich, Switzerland	Cross section through the medulla oblongata	Cross section through the medulla oblongata (vestibular nuclei) of a cow with BSE: immunohistochemical demonstration of PrP accumulation (brown) in axons and neuronal cytoplasm. Histopathology: PrP immunohistochemistry, high magnification (lens 40x).	Felix Ehrensperger/Institute of Veterinary Pathology, University of Zürich, Switzerland
Title Histopathology Caption Immunohistochemical preparation of the nucleus of the spinal tract of the trigeminal nerve (medulla oblongata) from a cow with BSE: diffuse particulate immunostaining of disease-specific prion protein in association with vacuolation of neuropil. Copyright Crown copyright 2004, Veterinary Laboratories Agency	Histopathology	Immunohistochemical preparation of the nucleus of the spinal tract of the trigeminal nerve (medulla oblongata) from a cow with BSE: diffuse particulate immunostaining of disease-specific prion protein in association with vacuolation of neuropil.	Crown copyright 2004, Veterinary Laboratories Agency

Identity

Preferred Scientific Name

• bovine spongiform encephalopathy

International Common Names

• English: bovine encephalopathy; bovine spongiform encephalopathy, bse; encephalopathy, bovine spongiform; mad cow disease; spongiform encephalopathies; spongiform encephalopathy in cattle; spongiform encephalopathy, bovine; transmissible spongiform encephalopathies
• French: vache folle

English acronym

• BSE
• TSE

Overview

Bovine spongiform encephalopathy (BSE) is a disease of cattle, which mainly occurs in animals aged 4-6 years old. The disease was first recognized in the United Kingdom in 1986 and is characterized by progressive neurological signs, which ultimately lead to death. The disease, also called ‘mad cow disease’, may last several months. BSE-affected cattle show behavioural changes, abnormalities of posture and movement, and changes in sensation. Nervousness, hind-limb ataxia, tremors, falling and hyperaesthesia to sound and touch are the most prominent clinical signs. Histological changes are confined to the central nervous system. Typically, bilateral symmetrical vacuolation in the grey matter of the brain, gliosis and hypertrophy of astrocytes, neuronal degeneration, and cerebral amyloidosis can be found.

The BSE epidemic occurred after oral exposure of cattle to a scrapie-like agent in the ruminant-derived protein of meat-and-bone meal, which was included in cattle feed. In many cases BSE-affected cases are manifested as solitary cases in a herd. Horizontal transmission under natural circumstances has not been demonstrated and there is no evidence that it occurs. Under experimental circumstances transmission of BSE between cattle has been demonstrated, after ingestion of brain-tissue from BSE-infected cattle.

Today, BSE can still only be diagnosed after the death of the affected animal, by histopathological examination of the brain, and by Western blot and ELISAs to identify the prion protein. This, together with the very long incubation period, severely hampers the control of the disease, and explains the need for very stringent preventive measures. The most important of these measures has been the ban on feeding ruminants with mammalian-derived protein in the European Union and some other countries. After a huge epidemic in the UK, involving more than 100,000 diseased cattle, BSE cases were identified in Ireland, Switzerland and other European countries, as well as in Japan and North America. BSE now also occurs outside Europe, and is thought to be linked to feeding meat and bone meal to cattle. Stringent control measures were imposed when the severity of BSE for both animals and man was recognised. This has resulted in a significant decrease in the number of BSE cases in the UK and other affected countries. Currently, the number of cases in the UK is decreasing.

Low numbers of clinical cases of BSE are found in many areas around the world. The BSE agent is particularly resistant. Insufficient inactivation of the agent during the rendering process is believed to have allowed survival of the BSE agent and subsequent ingestion by other cattle. The disease is thought to occur due to conversion of the natural prion protein into a pathogenic form in the brain of infected cattle. The pathogenic prion protein differs in structure from the naturally occurring prion protein. BSE belongs to the transmissible spongiform encephalopathies (TSEs) that occur in many mammalian species. In man, a variant form of human TSE, Creutzfeldt-Jakob disease, which is distinct from the classical form of Creutzfeldt-Jakob has been linked with BSE in cattle, since 1996. As a consequence, BSE is now considered a zoonosis and has been categorized as a notifiable disease in the European Union since 1990 and as a list B disease according to the OIE. Stringent preventive and surveillance measures, involving bans on inclusion of ruminant derived meat-and-bone meal (MBM) in ruminant feed, massive post-mortem testing schemes and culling of infected cohort animals, have been put in place. The aim of these measures is to prevent cattle and human exposure, and to eradicate BSE from the animal population.

This disease is on the list of diseases notifiable to the World Organisation for Animal Health (OIE). The distribution section contains data from OIE's WAHID database on disease occurrence. Please see the AHPC library for further information on this disease from OIE, including the International Animal Health Code and the Manual of Standards for Diagnostic Tests and Vaccines. Also see the website: www.oie.int.

Hosts/Species Affected

BSE originated in 1986 in cattle, the natural host species. Cattle are naturally infected after oral exposure. Following the occurrence of the BSE epidemic in cattle during the 1980s, spongiform encephalopathies also occurred in new species such as the greater kudu, nyala, Arabian onynx, Scimitar horned oryx, eland, gemsbok, bison, ankole, tiger, cheetah, ocelot, puma, and domestic cats, during the 1990s (Benbow, 1990; Collinge, 2001; Prusiner, 1997). Feline spongiform encephalopathy has been found in approximately 30 domestic cats in the UK. Brain extracts from BSE-infected cattle have transmitted disease to cattle, sheep and pigs after intracerebral inoculation, and also to goats, mice, mink, marmosets and macaque monkeys (Prusiner, 1997; OIE, 2000). The possible transmission of BSE to the marmoset, a non-human primate, is of particular importance (Whitaker, 1992).

BSE occurs in different dairy breeds and their crosses, in the proportion expected from the composition of the national herd. The genetic aspects of BSE have received great attention, in particular because the incidence of the homologous disease in sheep, scrapie, differs between different breeds of sheep. Several studies have been undertaken to see if certain cattle breeds are more susceptible to BSE than others. However, in the course of the UK epidemic, cattle were affected irrespective of their breed, and with similar incubation periods between breeds (Schreuder, 1998). Other studies involving the polymorphism of the bovine PrP gene, have investigated whether correlations can be made between gene organization and the susceptibility to BSE. There are two known polymorphisms of the coding region of the bovine PrP gene, a silent Hind II restriction site polymorphism, and a difference in the number of an octapeptide repeated sequence (either five or six copies). However, an analysis of 370 cattle in Scotland revealed no difference between the frequencies of these PrP genotypes in healthy cattle and cattle with BSE (Hunter et al., 1994). Therefore, both sexes and all cattle breeds are considered equally susceptible to BSE, although a genetically based difference in susceptibility is still not completely excluded.

In 2005 it was cofirmed that a goat from the Ardeche region in southwest France, which tested positive after slaughter for a TSE in 2002, did, in fact, have BSE. The goat was originally found positive in an EU testing system, and BSE was confirmed at the Community Reference Laboratory for TSEs in Weybridge, UK.

To date there is no scientific evidence that experimental oral BSE challenge of pigs and poultry with brain material from cattle with BSE results in disease, and there is no evidence for residual infectivity present in tissues. In addition, there are no reports of a naturally occurring TSE in these species. In the case of ostriches, naturally occurring spongiform encephalopathy in red-necked ostriches occurs. However, the disease has not been transmitted experimentally.

Distribution

BSE was recognized for the first time in the UK in 1986. The first case of BSE in continental Europe was reported in 1990 in Switzerland. Subsequently, BSE has been reported in many European countries, with significant epidemics reported in Switzerland (Perler et al., 2000), Ireland and Portugal (Collinge, 2001). An important distinction must be made between indigenous (local scrapie spread to local cattle population) and imported BSE (by importation of live animals or contaminated meat-and-bone meal (MBM)). The possibility of the importation of BSE in live animals has been demonstrated by cases of BSE in Oman (Carolan et al., 1990), the Falkland Islands, Denmark, Canada, Germany, Portugal, Italy and the Republic of Ireland. The contribution of contaminated MBM to the spread of BSE is difficult to assess, but also seems relevant, for example in the BSE cases in Switzerland (Schreuder, 1998). In 2000-2001, BSE was reported outside the UK in Belgium, the Czech Republic, Denmark, France, Greece, Italy, Japan, Kuwait, the Netherlands, Portugal, Slovakia, Slovenia and Spain (OIE, 2004a).  Since mid-2001, the European Union has required member states to undertake surveillance programmes for TSEs in cattle, sheep and goats. As at March 2004, no BSE had been reported in Sweden. Only in the UK, has the epidemic involved thousands of animals. In most other countries, except for France and Portugal, the number of infected animals has been low, and disease has probably been due to imported BSE, through exposure to feed contaminated by meat-and-bone meal originating in the UK (see table)(Schreuder, 1998; Donnelly et al., 1999; European Commission, 2001).

DNA analysis completed by the USA and Canada confirms investigatory findings that the index case of BSE reported in December 2003 was an animal of Canadian origin. This result makes the only BSE case in the USA an imported case (OIE, 2004b).

The table below is based on data from the Office International des Epizooties (OIE, 2004a), up to 1 March 2004. Data for the UK is up to September 2003.

Distribution Table

The distribution in this summary table is based on all the information available. When several references are cited, they may give conflicting information on the status. Further details may be available for individual references in the Distribution Table Details section which can be selected by going to Generate Report.

Pathology

Post-mortem findings

Affected cattle may show loss of condition and reduced body weight.

Histopathology

Histopathological changes are confined to the central nervous system (CNS). The most characteristic histological change in BSE consists of bilaterally symmetrical vacuolation of the gray matter neuropil. In cattle, areas most consistently and severely affected are the solitary tract nucleus, the spinal tract nucleus of the trigeminal nerve and the central grey matter of the midbrain. The neuropil vacuolation of the target nuclei is considered to be pathognomonic for BSE (Gavier-Widen et al., 2005). Degeneration and loss of neurons can be observed. Intraneuronal vacuoles resulting in the spongiform appearance mainly occur in the medulla oblongata, in the central grey matter of the mid-brain, in the paraventricular area of the hypothalamus, the thalamus and the septal area. The typical pattern of lesions is remarkably uniform, suggesting uniformity in pathogenesis, in terms of the route of infection and the causative agent (Schreuder, 1998). Astrocytes may show gliosis and hypertrophy. In about 5% of BSE cases cerebral amyloidosis has been observed. In extracts of brains from BSE-infected cattle, characteristic fibrils, similar to scrapie-associated-fibrils (SAF) can be found (Schreuder, 1998).

Diagnosis

Clinical Diagnosis

A preliminary clinical diagnosis of BSE in cattle can be made by observation of both:

• general disease signs: including loss of condition and reduced milk yield
  
• neurological signs: including behavioural changes, abnormalities of posture and movement, and changes in sensation in an adult cow.

BSE has been demonstrated in cattle between 22 months and 17 years of age (Schreuder, 1998). Remarkably, the frequency of various clinical signs has not changed during the course of the epidemic, which suggests that the BSE agent and the host response have not changed. About 87% of the BSE cases in the UK exhibited signs of all three neurological categories: behavioural changes, abnormalities of posture and movement, and changes in sensation (Van Keulen et al., 2000).

The BSE Homepage website (www.bse.unizh.ch) of the Clinic for Cattle, Sheep and Goats, University of Zurich contains publications and illustrations on clinical diagnosis and downloadable video sequences to demonstrate behavioural clinical signs of BSE. Also, BSE information from the USDA Animal Plant Health Inspection Service can be found at the following websites (http://www.aphis.usda.gov/lpa/issues/bse/bse.html) and (http://www.aphis.usda.gov/lpa/issues/bse_testing/).

Differential Diagnosis

Non-infectious differential diagnosis should include the nervous form of ketosis, mummification of the white skin, lead toxicity, intra-cranial tumours and hypomagnesaemia. Infectious differential diagnoses should include encephalic listeriosis, rabies, Aujeszky’s disease and cerebro-cortical-necrosis (CCN) (Schreuder, 1998; OIE, 2000).

Laboratory Diagnosis

Thus far, there is no laboratory diagnosis available for BSE in the living animal. For obvious economical and procedural reasons brain biopsies on clinical BSE suspects cannot be performed. The absence of detectable immune responses in BSE precludes any serological test for detection of antibodies, and the agent cannot be detected in any body material before death. Therefore, the diagnosis of BSE is dependent on the evaluation of central nervous system samples during post-mortem examination. The agent can be identified and isolated by a bioassay involving the inoculation of mice with brain tissue from suspected cases. However, this bioassay may last nearly 300 days before the mice will die, due to the long incubation period. Confirmation of the clinical diagnosis may follow histopathological examination of the brain from clinically affected cases, for characteristic bilaterally symmetrical spongiform changes in grey matter and subsequent immunohistochemical demonstration of accumulations of the disease specific PrP^sc. It has been documented that 99.6% of positive BSE cases can be confirmed by examination of a single section of the medulla, for spongiform changes, at the level of the obex (Van Keulen, 2000). A presumptive clinical or inconclusive histological diagnosis can be confirmed electron-microscopically, by demonstration of fibrils similar to scrapie-associated fibrils (SAF), or by immunochemical and immunocytochemical detection of the constituent PrP^sc protein. SAF can only be purified satisfactorily from fresh or frozen brain material, not from fixed brain material (Schreuder, 1998; OIE, 2000).

For surveillance, a number of rapid tests have been developed and approved by the European Union. These include:

1. Western blot test for the detection of the protease-resistant fragment PrPRes (Prionics Check Western test, see www.prionics.ch).

2. Luminescence immunoassay allowing detection of disease-specific prion proteins (Prionics Check LIA, see www.prionics.ch).

3. Chemiluminescent ELISA test involving an extraction method and an ELISA technique, using an enhanced chemiluminescent reagent (Enfer BSE test, see www.abbottdiagnostics.com).

4. Sandwich immunoassay for PrPRes carried out following denaturation and concentration steps (Bio-Rad TsSeE test, see www.biorad.com).

5. Conformation-dependent immunoassay that detects abnormal folding of infectious prions and uses denaturing to expose an epitope buried in the folded protein (InPro CDI-5, see www.inprobiotech.com).

Tests have also been approved by the USDA for screening of cattle in the USA.

1. The Bio-Rad TsSeE test mentioned above.

2. Enzyme immunoassay for BSE antigen (HerdCheck BSE Antigen Test produced by Idexx, see www.idexx.com).

List of Symptoms/Signs

Disease Course

BSE is a prion disease. Prion diseases are manifested as infectious or genetic disorders. It is now widely accepted that BSE is an infectious disorder, and that a modified isoform of the natural prion protein, is essential for infectivity. According to the prion hypothesis, the disease starts when the natural PrP changes in conformation to the pathogenic isoform PrP^sc. This process involves a change of the host cellular prion protein, which acts as a template, into a disease specific isoform. As a result, the PrP^c, composed primarily as a alpha-helical structure, changes into a disease specific isoform PrP^sc that is rich in beta-sheets. In genetic prion diseases, this may be caused by a somatic mutation in the PrP^c gene. In infectious BSE, exposure to a foreign PrP^sc may start this conformation, leading to a progressive cascade of conformational change of the natural PrP^c into PrP^sc (Prusiner, 1997). In contrast to the natural PrP^c, PrP^sc is not digested by proteinase K. Enzymatic digestion of brain matter is therefore used in laboratory assays to distinguish natural and abnormal prion proteins.

BSE has an incubation period of approximately 4-5 years. In cattle, the incubation period is approximately 18 months, using brain homogenates from natural terminal cases. Common general signs include loss of weight and condition, and reduced milk yield. Most animals maintain a good appetite. BSE-affected cattle always show neurological signs. They may show behavioural changes, abnormalities of posture and movement, and changes in sensation. The first neurological sign is usually separation from the herd. The animals may also be reluctant to move into the milking parlour and may respond to milking with vigorous kicking. The earliest locomotory signs are subtle changes in the hind-limb gate and a difficulty in turning. Staring eyes, abnormal head posture and teeth grinding can also be observed. Over a period of weeks to months, the clinical signs worsen until death occurs. Ataxia of the hind-limbs may be severe and animals will easily fall when forced to move. Muscle fasciculation’s, tremor and myoclonus may occur. Rumination may be reduced, and bradycardia and altered heart rhythm can be present. Hyperaesthesia to sound and touch may be observed (Schreuder, 1998; OIE, 2000). Pruritis, frequently seen in sheep with scrapie, occurs infrequently in BSE-infected cattle. BSE is a fatal disease and euthanasia on welfare grounds is necessary.

Epidemiology

BSE occurred as a large-scale epidemic in the UK only (Collee and Bradley, 1997a, b; Donnelly et al., 1997; Ferguson et al., 1997). In 1986, several cases of BSE occurred simultaneously, mostly in dairy herds in different parts of the UK. The disease had probably already occurred, unrecognized, since April 1985 in the UK (Schreuder, 1998). On the basis of the only common factor found in all cases, feeding of concentrate feeds, the food-borne hypothesis was developed. A case-control study showed that the inclusion of meat-and-bone meal (MBM) was a statistically significant risk factor, associated with the incidence of BSE (Schreuder, 1998). The practice of including MBM in the diet of calves during their first 12 weeks of their lives began in the mid-1970s in the UK. Beef suckler herd calves were much less likely to have received MBM, and the incidence of BSE in beef suckler herds is much lower than that in dairy herds. It appears that changes made in the rendering process of the MBM increased the survival of scrapie-like material. Although the rendering processes before the 1970s were completely effective in inactivating the prions, it is conceivable that the threshold of infectivity has been breached. The changes in the rendering procedures therefore may have allowed sufficient infectivity to survive the process, to initiate and sustain an epidemic.

Originally, sheep and goat offal was prepared by a process involving steam treatment and hydrocarbon extraction. In the late 1970s, rendering plants in the UK altered their processing. Batch production of MBM, was gradually replaced by a continuous process. Also, the more effective solvent extraction process was replaced during the period 1980-1983, by a dry extraction process. The use of solvents was greatly decreased to increase the yield of tallow from carcasses. Simulation models predicting that exposure to a scrapie-like agent must have started during this period further substantiated the food-borne hypothesis (Prusiner, 1997; Schreuder, 1998). It is currently believed that a cattle-adapted scrapie-agent has initiated the events, and was facilitated by the recycling of infected bovine material within the cattle population through the use of MBM. It is known that cattle are susceptible to scrapie following parenteral administration of brains from scrapie-infected sheep. Experimentally, oral transmission has not been demonstrated (Schreuder, 1998). An alternative hypothesis is that epidemic BSE resulted from the recycling of sporadic BSE cases, as cattle were also rendered to produce MBM for cattle feed (Collinge, 2001).

In 1988, feeding cattle with protein derived from rendered sheep or cattle offal was forbidden. The numbers of BSE infected cattle rose dramatically from 1986 onwards, and reached its peak in the UK in 1993. This is indicative of the long incubation period of BSE. Typically, the incidence within herds during the course of the epidemic has remained low. Within affected herds the maximum annual incidence has been 3% (OIE, 2004a).

There is some evidence of a risk of vertical transmission for calves born to infected cows, but this is at best a rare event. The contribution of vertical transmission to the total UK epidemic was estimated as an additional 1%. A cohort study estimated the maximum level of maternal transmission as approximately 10%, but this was related to calves born from mothers that were in the last phase of the incubation period, about 1-4 months before the onset of clinical signs. The biological mechanisms involved are unknown (Wilesmith and Ryan, 1997; Donnelly, 1998; Fatzer et al., 1998; Schreuder, 1998; OIE, 2000). There is no evidence for horizontal transmission of BSE between cattle.

Species barrier

According to the current hypothesis, sheep-derived scrapie-proteins have crossed the sheep-to-cattle species barrier. Due to changes in rendering processes, an increasing concentration of surviving infectious material initiated a high level of incidence and the detection of hitherto unnoticed cases. During the course of the epidemic, recycling of bovine material further increased the titre of the BSE agent in the MBM, explaining the rapidly rising number of clinical cases (Prusiner, 1997, Schreuder, 1998). The bovine prion protein (PrP) and the sheep PrP differ at only 7-8 residues, depending on the breed of sheep. Presumably, the higher homology between the PrP of the donor and the host, the more easily the species barrier can be crossed. Scrapie is not considered a zoonosis, because long-term studies have failed to establish a correlation between scrapie in sheep and Creutzfeldt-Jakob disease in humans, not even when humans were exposed to risk material, such as sheep brains and eyeballs. Therefore, the barrier between sheep and human PrPs seems large. However, evidence that BSE from cattle can infect cats, indicates that a large genetic diversity does not exclude the possibility of a crossover. Evidently, the recent link of BSE with the new variant Creutzfeldt-Jakob disease (vCJD) in humans further substantiates this (Bruce et al., 1997; Prusiner, 1997; Collinge, 2001). Recent reports that sheep can contract BSE after oral exposure (Foster et al., 2001; Jeffrey et al., 2001), have again raised concerns.

Impact: Economic

The BSE epidemic, was probably the animal disease with the most important economic and social consequences during the twentieth century. The economic impact was enormous, due to the massive numbers of affected cattle in the UK, and the fear among consumers of meat, which resulted in dramatic drops in meat consumption. This caused huge problems in dealing with the perceived risks for the companies involved (Tacke, 2001). More than 183,000 BSE cases have been detected in the UK alone (September 2003) and the number of infected animals has been estimated at approximately 1,000,000 (Anderson et al., 1996). In other European countries, about 3000 BSE cases have thus far been reported, and a few BSE cases have been reported outside Europe. The explanation that recycling of animal protein facilitated the disease further boosted the public antipathy against modern intensive farming methods and its products. Upon confirmation of the first cases of BSE in several countries, sales of meat and meat products suddenly dropped, although this effect was generally of short duration. The BSE-related expenditure of the European Commission, including direct income support payments, selective culling and culling of cattle over 30 months of age in the UK during 1996, cost a total of 4696 Million EUR between 1996-2000 (European Commision, 2001). The amount does not include the costs borne by Member States, nor do they include lost earnings due to a drop in consumption, or lost markets, which are also very significant. Recent cases of BSE in the USA and Canada have had a smaller effect on domestic consumer reaction, but have resulted in closure of export markets.

Zoonoses and Food Safety

In humans, prion disease has traditionally been classified into Creutzfeldt-Jakob disease, (CJD), Gerstmann-Sträussler-Scheinker disease (GSS) and Kuru. The diseases can further be categorized into three etiological categories of sporadic, acquired, and inherited. Acquired prion diseases include iatrogenic CJD and may arise from corneal transplants, injections with human pituitary growth hormone, dura mater grafts, or from cannibalism. Sporadic CJD occurs with a random incidence of 1 case per million people. The similarities between BSE, scrapie in sheep and TSE disease in man raised concerns from the start of the epidemic, about the risk of BSE for humans (Rossor, 1996; Bekkum and Heidt, 1996). Since BSE has been regarded as a putative zoonosis, minimising the risk of human exposure to the BSE agent became necessary. The UK government has taken several measures to prevent exposure of humans to BSE-contaminated material. Various cattle-derived tissues are used for human consumption (see table 1). Several studies have shown that PrP^sc is present in various tissues in varying concentrations during the incubation period, long before the disease has reached its clinical state. Based on the available information, the Scientific Steering Committee (SSC) from the European Union issued a list of estimated human risk exposures from various tissues, characterized as specified risk materials (SRMs), for which BSE infectivity for cattle has been demonstrated. These include brain, eyes (retina), trigeminal ganglia, the spinal cord, the dorsal root ganglia and the distal ileum in various degrees of infectivity (see table 2). When the link between BSE and vCJD was definitively established in 1996, cattle of 30 months and older, representing the major risk group, were promptly eliminated in the UK from the human food and animal feed chains by the so-called ‘over thirty months scheme’ (OTMS). Subsequently, removal of SRM was recommended by the SSC from the food and feed chain in countries with a risk of BSE. Restrictive measures were implemented for SRMs, in which the presence of BSE had been demonstrated: brain, spinal cord, thymus, spleen, tonsils, large lymph nodes, nerves and intestines.

Patients suffering from the vCJD may show behavioural and psychiatric disturbances, sometimes with dysaesthesia or pain in the limbs or face. The clinical presentation of vCJD is relatively constant, with similar symptoms being present in all cases. This suggests that vCJD is caused by a single prion strain. Another characteristic is that PrP^sc in vCJD is only detectable in the tonsils and other lymphoreticular tissues, which is not the case in other forms of human prion diseases. This is indicative of a distinctive pathogenesis (Collinge, 2001). Epidemiological surveys have pointed towards a link with BSE and this was further supported by molecular typing studies. All cases of vCJD are associated with type 4 PrP^sc,whereas classical CJD is caused by PrP types 1-3. Also, vCJD and BSE show similar transmission properties in mice. This, together with the evidence that vCJD patients to date are invariably homozygous for methionine at codon 129, suggests that a relatively homogenous, genetically susceptible subgroup of the human population, with a short incubation period for BSE, have contracted BSE to date (Collinge, 2001). The risk for humans to contract vCJD seems to depend on internal factors such as genetic susceptibility and age, and external factors such as the route of infection, the quantity, nature, and the source of the infective material. Importantly, the oral route seems to be relative insufficient, based on many transmission studies. The conclusion that cattle were mainly infected during early life, may be attributable by a relatively incomplete gut-barrier. The fact that quantity is important has arisen from numerous infectivity assays, with tissues harbouring varying concentrations of infective material. However, animal models have their limitations for extrapolation of the results to man (Schreuder, 1998). Up to April 2001, nearly 100 confirmed or suspected cases of vCJD had been reported, mainly in the UK, with only 3 cases in France, and 1 in Ireland (OIE, 2004a).

Laboratory workers handling the tissues of BSE-suspect animals should wear appropriate protective clothing and observe a strict code of practice to avoid exposure to the agent, which is highly resistant to many physical and chemical treatments. Use of laminar flow cabinet, special protective clothing, a mouth cap and gloves is strongly recommended. Because BSE is not contagious, laboratory precautions should primarily aim to avoid accidental iatrogenic, ocular or oronasal exposures (OIE et al., 2001).

Table 1: Bovine tissues and materials used for human consumption

Table 2: Scientific Steering Committee estimate of cattle infectivity dose (ID)₅₀

Source: Human Exposure Risk (HER) via food with respect to BSE. Opinion of the European Union Scientific Steering Committee (SSC), 10 December 1999

Disease Treatment

There is no treatment possible for BSE. Failure of common therapy against the suspected diseases mentioned under the differential diagnosis may indicate that BSE is involved.

Prevention and Control

Prevention, monitoring, surveillance and eradication

Based on the fact that data to date indicates BSE is not horizontally (contact) transmitted, and that the primary, if not exclusive route of transmission is ingestion of contaminated feed, a ban on feeding cattle and other ruminants most mammalian protein is the primary preventative measure. For BSE or other TSEs, no vaccines are available. Prevention strategies of BSE should therefore be aimed at prevention of oral exposure of cattle to PrP^sc. In countries considered free of BSE, preventative measures are ruminant to ruminant feed ban, import controls and surveillance (Cohen.et al., 2001, 2003). In countries with cases in cattle, measures are targeted at slaughter and compensation of farmers for definite cases, controls on recycling of mammalian protein, and effective identification and tracing of cattle (Tyrrell, 1992; Ammendrup, 1999; OIE, 2000; Vossen, 2001).

In 1990, BSE became a notifiable disease, to ensure reporting of suspected cases and subsequent laboratory diagnosis. This was helped by an increased awareness among veterinary practitioners, who increasingly sent in cattle for confirmation of the diagnosis. In July 1989, the European Commission restricted the importation of live animals from the UK into EU Member States. First, an import ban was issued involving cattle born before 1988, because those cattle might have been fed with MBM. In February 1990 the ban was extended to a ban on all live cattle except those under six months of age, which would be slaughtered before they reached that age. The risk of importation of BSE into countries of the EU is related to the number and age of the cattle, whether they were beef or dairy, and to the import of MBM. It was shown that the predicted occurrence of BSE was in close agreement with the observed incidence, but the number of expected BSE cases was higher than the number of reported cases. An important consequence is the possibility that secondary BSE cases might occur in countries where recycling of bovine protein is practised analogous to the early UK situation, with insufficient inactivation of the PrP^sc in the rendering process (Schreuder et al., 1997).

Monitoring and surveillance

In 1998, the introduction of yearly BSE monitoring was introduced in the EU. Initially, passive surveillance was required, where countries had to report the number of BSE cases, based on laboratory confirmation of suspected cases. However, this was considered insufficient and an active surveillance method was developed, using a ranking scheme of geographical risks of BSE (GBR). The GBR indicates the relative risk of a country to harbour BSE. This was adopted in 2000, and was followed by the introduction of an active surveillance programme for BSE using special tests, in order to detect and monitor BSE in member countries (Heim and Wilesmith, 2000; Urlings and van Zijderveld, 2001). For this purpose, the EU evaluated several rapid tests, of which three tests were approved (Moynagh and Schimmel, 1999). The number of approved BSE tests is expected to increase with further evaluation rounds. Currently, all slaughtered cattle of 30 months of age or older have to be tested for BSE (EU Regulation 309R0999).

Eradication

Control

In the BSE Chapter within the Terrestrial Animal Health Code, 2005, the World Organisation for Animal Health (OIE) provides recommendations to manage the human and animal health risks associated with the presence of BSE in cattle. This chapter provides recommendations for cattle associated commodity imports; BSE risk status assessment, and import recommendations from countries of undetermined BSE risk status (OIE, 2005).

Mammalian meat and bone meal (MBM) ban

When the food-borne hypothesis gained firm ground, measures were taken to prevent contaminated animal protein from entering the animal feed. Consequently, a number of regulations have been issued, keeping in pace with the growing knowledge about the transmission and risk assessment of BSE. In the UK, a feed ban was issued in 1988, two years after the onset of the BSE epidemic. This prohibited feeding of ruminant derived meat-and-bone meal (MBM) to ruminants (Hoinville, 1994). The EU adopted this ban in 1994. In countries where ruminant MBM is fed to food animal species other than ruminants, cross-contamination of ruminant rations with feed for non-ruminant species must be prevented. In particular, the total separation of production lines in feed mills for ruminants and other livestock must be ensured (Schreuder, 1998). If this cannot be guaranteed, MBM from any species should not be fed to ruminants. Avoidance of cross-contamination must be complete (OIE et al., 2001).

References

Ammendrup S, 1999. Summary review of the chronology of the major measures in relation to bovine spongiform encephalopathy (BSE) in the United Kingdom and the European Union. Acta Veterinaria Scandinavica, Supplementum, Supplement 91:19-20.

Anderson RM, Donnelly CA, Ferguson NM, Woolhouse MEJ, Watt CJ, Udy HJ, MaWhinney S, Dunstan SP, Southwood TRE, Wilesmith JW, Ryan JBM, Hoinville LJ, Hillerton JE, Austin AR, Wells GAH, 1996. Transmission dynamics and epidemiology of BSE in British cattle. Nature (London), 382(6594):779-788; 56 ref.

Anon, 2001. Regulation EC/999/2001 of the European Parliament and Council - laying down rules for the prevention, control and eradication of certain transmissible spongiform encephalopathies. Official Journal of the European Communities, L147:1-40.

Bekkum DWvan, Heidt PJ, 1996. BSE and risk to humans. Nature (London), 382(6592):574; 3 ref.

Benbow GM, 1990. Zoo animal BSE. Vet. Rec., 126:441.

Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, McCardle L, Chree A, Hope J, Birkett C, Cousens S, Fraser H, Bostock CJ, 1997. Transmissions to mice indicate that 'new variant' CJD is caused by the BSE agent. Nature (London), 389(6650):498-501; 28 ref.

Carolan DJP, Wells GAH, Wilesmith JW, 1990. BSE in Oman. Veterinary Record, 126(4):92; 2 ref.

Cohen JT, Duggar K, Gray GM, Kreindel S, Abdelrahman H, Habtemariam T, Oryang D, Tameru B, 2003. Evaluation of the potential for bovine spongiform encephalopathy in the United States. Harvard Center for Risk Analysis, Harvard School of Public Health and the Center for Computational Epidemiology, College of Veterinary Medicine, Tuskegee University, 150 pp. (http://www.aphis.usda.gov/lpa/issues/bse/madcow.pdf accessed on 4 April 2006).

Collee JG, Bradley R, 1997. BSE: a decade on - part 2. Lancet (British edition), 349(9053):715-721; 46 ref.

Collee JG, Bradley R, 1997. BSE: a decade on-part 1. Lancet (British edition), 349(9052):636-641; 45 ref.

Collinge J, 2001. Prion diseases of humans and animals: their causes and molecular basis. Ann. Rev. Neurosci., 24:519-550.

Donnelly CA, 1998. Maternal transmission of BSE: interpretation of the data on the offspring of BSE-affected pedigree suckler cows. Veterinary Record, 142(21):579-580; 9 ref.

Donnelly CA, Ferguson NM, Ghani AC, Woolhouse MEJ, Watt CJ, Anderson RM, 1997. The epidemiology of BSE in cattle herds in Great Britain. I. epidemiological processes, demography of cattle and approaches to control by culling. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 352(1355):781-801; 53 ref.

Donnelly CA, Santos R, Ramos M, Galo A, Simas JP, 1999. BSE in Portugal: anticipating the decline of an epidemic. J. Epidemiol. Biostat., 4:277-283.

European Commission, 2001. Special Report No 14/2001, 2001/C 324/0. Official Journal of the European Commission 20-11-2001.

Fatzer R, Ehrensperger F, Heim D, Schmidt J, Schmitt A, Braun U, Vandevelde M, 1998. Investigation of 182 offspring of cows with bovine spongiform encephalopathy (BSE) in Switzerland. Part 2. Epidemiological and neuropathological results. Schweizer Archiv für Tierheilkunde, 140(6):250-254; 14 ref.

Ferguson NM, Donnelly CA, Woolhouse MEJ, Anderson RM, 1997. The epidemiology of BSE in cattle herds in Great Britain. II. model construction and analysis of transmission dynamics. Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 352(1355):803-838; 38 ref.

Foster JD et al., 2001. Clinical signs, histopathology and genetics of experimental transmission of BSE and natural scrapie to sheep and goats. Vet. Rec., 148:165-171.

Gavier-Widen D, Stack MJ, Baron T, Balachandran A, Simmons M, 2005. Diagnosis of transmissible spongiform encephalopathies in animals: a review. J. Vet. Diagn. Invest., 17:509-527.

Heim D, Wilesmith JW, 2000. Surveillance of BSE. Arch. Virol. Suppl., 16:127-133.

Hochstrasser DF, Frutiger S, Wilkins MR, Hughes G, Sanchez JC, 1997. Elevation of apolipoprotein E in the CSF of cattle affected by BSE. FEBS Letters, 416(2):161-163; 17 ref.

Hoinville LJ, 1994. Decline in the incidence of BSE in cattle born after the introduction of the 'feed ban'. Veterinary Record, 134(11):274-275; 12 ref.

Hunter N, Goldmann W, Smith G, Hope J, 1994. Frequencies of PrP gene variants in healthy cattle and cattle with BSE in Scotland. Veterinary Record, 135(17):400-403; 25 ref.

Jeffrey M et al., 2001. Oral inoculation of sheep with the agent of bovine spongiform encephalopathy (BSE). 1. Onset and distribution of disease-specific PrP accumulation in brain and viscera. J. Comp. Pathol., 124:280-289.

Jones V, Martin TC, Keyes P, Dawson M, 1996. Protein markers in cerebrospinal fluid from BSE-affected cattle. Veterinary Record, 139(15):360-363; 21 ref.

Lasmézas CI, Deslys JP, Robain O, Jaegly A, Beringue V, Peyrin JM, Fournier JG, Hauw JJ, Rossier J, Dormont D, 1997. Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science (Washington), 275(5298):402-405; 31 ref.

Manuelidis L, Fritch W, Xi YouGen, 1997. Evolution of a strain of CJD that induces BSE-like plaques. Science (Washington), 277(5322):94-98; 40 ref.

Moynagh J, Schimmel H, 1999. Tests for BSE evaluated. Nature (London), 400(6740):105; 2 ref.

OIE Handistatus, 2003. World Animal Health Publication and Handistatus II (dataset for 2002). Paris, France: Office International des Epizooties.

OIE Handistatus, 2004. World Animal Health Publication and Handistatus II (data set for 2003). Paris, France: Office International des Epizooties.

OIE Handistatus, 2005. World Animal Health Publication and Handistatus II (data set for 2004). Paris, France: Office International des Epizooties.

OIE, 2000. Bovine spongiform encephalopathy. In: OIE Manual of Standards for diagnostic tests and vaccines. Office International des Epizooties, edition 4, 457-460.

OIE, 2004. Bovine Spongiform Encephalopathy (BSE). Paris, France: Office International des Epizooties. Online. http://www.oie.int/eng/info/en_esb.htm Accessed on 1 March 2004.

OIE, 2004. Bovine spongiform encephalopathy in the United States of America. Follow-up report no. 2 (the reported case was an imported animal). Disease Information. 9 January 2004. Vol. 17 - No. 2. Online. http://www.oie.int/eng/info/hebdo/AIS_63.HTM#Sec0.

OIE, 2005. Animal diseases data. Office International des Epizooties, http://www.oie.int/eng/maladies/en_OldClassification.htm#ListeA, Accessed 8 March 2005.

OIE, 2005. Bovine spongiform encephalopathy. In: Terrestrial Animal Health Code, 14th Edition. Paris, France: World Organisation for Animal Health, 173-180.

OIE, 2009. World Animal Health Information Database - Version: 1.4. World Animal Health Information Database. Paris, France: World Organisation for Animal Health. http://www.oie.int

OIE, FAO, WHO, 2001. BSE and its risks: Animal and Public health, International trade. A world wide web page at: http://www.oie.int/eng/manifestations/bse20010611.htm.

Perler L, Heim D, Geiser F, Muller HK, Kihm U, 2000. Ten years of BSE in Switzerland. The development of an extraordinary disease. Schweiz Arch Tierheilkd., 142:657-664.

Prusiner SB, 1997. Prion diseases. In: Viral pathogenesis. Nathanson, et al., eds. Philadelphia, USA: Lippin-Cott-Raven Publishers, 871-911.

Rossor MN, 1996. BSE and human disease. J R Coll. Physicians Lond., 30:494-495.

Schreuder BEC, 1998. Epidemiological aspects of scrapie and BSE including a risk assessment study. ISBN 90-393-1636-8. Thesis University of Utrecht.

Schreuder BEC, Wilesmith JW, Ryan JBM, Straub OC, 1997. Risk of BSE from the import of cattle from the United Kingdom into countries of the European Union. Veterinary Record, 141(8):187-190; 7 ref.

Schulz-Schaeffer WJ et al., 2000. Detection of PrP(Sc) in subclinical BSE with the paraffin-embedded tissue (PET) blot. Arch. Virol. Suppl., 16:173-180.

Tacke V, 2001. BSE as an organizational construction: a case study on the globalization of risk. Br. J. Sociol., 52:293-312.

Taylor DM, 1991. Inactivation of BSE agent. Dev. Biol. Stand., 75:97-102.

Tyrrell DA, 1992. An overview of bovine spongiform encephalopathy (BSE) in Britain. Dev. Biol. Stand., 76:275-284.

Urlings HA, van Zijderveld FG, 2001. Active surveillance of BSE in cattle in The Netherlands. Vet. Q., 23:134-138.

Van Keulen LJM et al., 2000. Diagnosis of bovine spongiform encephalopathy: a review. Vet. Quart., 22:197-200.

Vossen P, 2001. Scientific advice in support to risk management with regard to BSE. Verh. K. Acad. Geneeskd. Belg., 63:379-403.

Whitaker DA, 1992. Infection of a marmoset with the BSE agent. Vet. Rec., 130:251.

Wilesmith JW, Ryan JBM, 1997. Absence of BSE in the offspring of pedigree suckler cows affected by BSE in Great Britain. Veterinary Record, 141(10):250-251; 5 ref.

Links to Websites

Distribution Maps