Bovine spongiform encephalopathy



Bovine spongiform encephalopathy (BSE), commonly known as mad cow disease, is a transmissible spongiform encephalopathy and fatal neurodegenerative disease in cattle that causes a spongiform degeneration of the brain and spinal cord. BSE has a long incubation period, of 2.5 to 5 years, usually affecting adult cattle at a peak age onset of four to five years. BSE is caused by a misfolded protein—a prion. In the United Kingdom, the country worst affected by an epidemic in 1986–1998, more than 180,000 cattle were infected and 4.4 million slaughtered during the eradication program.

The disease may be most frequently transmitted to humans by eating food contaminated with the brain, spinal cord, or digestive tract of infected carcasses. However, the infectious agent, although most highly concentrated in nervous tissue, can be found in virtually all tissues throughout the body, including blood. When it has been transmitted to humans, it is known as new variant Creutzfeldt–Jakob disease (vCJD or nvCJD), and by June 2014 it had killed 177 people in the United Kingdom, and 52 elsewhere, primarily in western Europe in countries supplied with beef or beef products from the UK. Between 460,000 and 482,000 BSE-infected animals had entered the human food chain before controls on high-risk offal were introduced in 1989.

A British and Irish inquiry into BSE concluded the epizootic was caused by cattle, which are normally herbivores, being fed the remains of other cattle in the form of meat and bone meal (MBM), a protein supplement in concentrated feeds. Since dairy calves are generally fed concentrated feed after they are weaned, they usually develop this disease more often than beef cattle

The cause of BSE may be from the contamination of MBM from sheep with scrapie that were processed in the same slaughterhouse. The epidemic was probably accelerated by the recycling of infected bovine tissues prior to the recognition of BSE. The origin of the disease itself remains unknown. The infectious agent is distinctive for the high temperatures at which it remains viable, over 600 C. This contributed to the spread of the disease in the United Kingdom, which had reduced the temperatures used during its rendering process. Another contributory factor was the feeding of infected protein supplements to very young calves.

Classification
BSE is a transmissible disease that primarily affects the central nervous system; it is a form of transmissible spongiform encephalopathy, like Creutzfeldt–Jakob disease and kuru in humans and scrapie in sheep, and chronic wasting disease in cervids.

Signs and symptoms
Symptoms are not seen immediately in cattle due to the diseases’ extremely long incubation period. Some cattle have been observed to have an abnormal gait, changes in behavior, tremors and hyper-responsiveness to certain stimuli. Hindlimb ataxia affects the animal’s gait and occurs when muscle control is lost. This results in poor balance and coordination. Behavioural changes may include aggression, anxiety relating to certain situations, nervousness, frenzy or an overall change in temperament. Some rare but previously observed symptoms also include persistent pacing, rubbing or licking. Additionally, nonspecific symptoms have also been observed which include weight loss, decreased milk production, lameness, ear infections and teeth grinding due to pain. Some animals may show a combination of these symptoms, while others may only be observed demonstrating one of the many reported. Once clinical symptoms arise, they typically get worse over the upcoming weeks and months, eventually leading to recumbency, coma and death.

Cause
The infectious agent in BSE is a specific type of misfolded protein called a prion.

Prions can be transmitted to humans by eating food contaminated with them.

Prions are not destroyed even if the beef or material containing them is cooked or heat-treated. Prion proteins carry the disease between individuals and cause deterioration of the brain. Transmissible spongiform encephalopathy (TSE)s like BSE can arise in animals that carry an allele which causes previously normal protein molecules to contort by themselves from an alpha helical arrangement to a beta pleated sheet, which is the disease-causing shape for the particular protein. Transmission can occur when healthy animals come in contact with tainted tissues from others with the disease. In the brain, these proteins cause native cellular prion protein to deform into the infectious state, which then goes on to deform further prion protein in an exponential cascade. This results in protein aggregates, which then form dense plaque fibers leading to the microscopic appearance of "holes" in the brain, degeneration of physical and mental abilities, and ultimately death.

Different hypotheses exist for the origin of prion proteins in cattle. Two leading hypotheses suggest it may have jumped species from the disease scrapie in sheep, or that it evolved from a spontaneous form of "mad cow disease" that has been seen occasionally in cattle for many centuries. In the 5th century BC, Hippocrates described a similar illness in cattle and sheep, which he believed also occurred in man. Publius Flavius Vegetius Renatus recorded cases of a disease with similar characteristics in the fourth and fifth centuries AD. The British Government enquiry took the view the cause was not scrapie, as had originally been postulated, but was some event in the 1970s that was not possible to identify.

Other theories state that the agent is a virus, virino, Spiroplasma species, or Acinetobacter species.

Pathogenesis
The pathogenesis of BSE is not well understood or documented like other diseases of this nature. Even though BSE is a disease that results in neurological defects, its pathogenesis occurs in areas that reside outside of the nervous system. There was a strong deposition of PrPSc initially located in the Ileal Peyer’s patches of the small intestine. The lymphatic system has been identified in the pathogenesis of scrapies, it has not, however, been determined to be an essential part of the pathogenesis of BSE. The Ileal Peyer’s patches have been the only organ from this system that has been found to play a major role in the pathogenesis. Infectivity of the Ileal Peyer's patches has been observed as early as 4 months after inoculation. PrPSc accumulation was found to occur mostly in tangible body macrophages of the Ileal Peyer’s patches. Tangible body macrophages involved in PrPSc clearance are thought to play a role in PrPSc accumulation in the Peyer’s patches. Accumulation of PrPSc was also found in follicular dendritic cells; however, it was of a lesser degree. Six months after inoculation, there was no infectivity in any tissues, only that of the ileum. This led researchers to believe that the disease agent replicates here. In naturally confirmed cases, there have been no reports of infectivity in the Ileal Peyer’s patches. Generally, in clinical experiments, high doses of the disease are administered. In natural cases, it was hypothesized that low doses of the agent were present, and therefore, infectivity could not be observed.

Diagnosis
Diagnosis of BSE continues to be a practical problem. It has an incubation period of months to years, during which no symptoms are noticed, though the pathway of converting the normal brain prion protein (PrP) into the toxic, disease-related PrPSc form has started. At present, virtually no way is known to detect PrPSc reliably except by examining post mortem brain tissue using neuropathological and immunohistochemical methods. Accumulation of the abnormally folded PrPSc form of PrP is a characteristic of the disease, but it is present at very low levels in easily accessible body fluids such as blood or urine. Researchers have tried to develop methods to measure PrPSc, but no methods for use in materials such as blood have been accepted fully.

The traditional method of diagnosis relies on histopathological examination of the medulla oblongata of the brain, and other tissues, post mortem. Immunohistochemistry can be used to demonstrate prion protein accumulation.

In 2010, a team from New York described detection of PrPSc even when initially present at only one part in a hundred billion (10−11) in brain tissue. The method combines amplification with a novel technology called surround optical fiber immunoassay and some specific antibodies against PrPSc. After amplifying and then concentrating any PrPSc, the samples are labelled with a fluorescent dye using an antibody for specificity and then finally loaded into a microcapillary tube. This tube is placed in a specially constructed apparatus so it is totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique allowed detection of PrPSc after many fewer cycles of conversion than others have achieved, substantially reducing the possibility of artifacts, as well as speeding up the assay. The researchers also tested their method on blood samples from apparently healthy sheep that went on to develop scrapie. The animals’ brains were analysed once any symptoms became apparent. The researchers could, therefore, compare results from brain tissue and blood taken once the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals’ lives, and from uninfected animals. The results showed very clearly that PrPSc could be detected in the blood of animals long before the symptoms appeared. After further development and testing, this method could be of great value in surveillance as a blood- or urine-based screening test for BSE.

Prevention
A ban on feeding meat and bone meal to cattle has resulted in a strong reduction in cases in countries where the disease was present. In disease-free countries, control relies on import control, feeding regulations, and surveillance measures.

In UK and US slaughterhouses, the brain, spinal cord, trigeminal ganglia, intestines, eyes, and tonsils from cattle are classified as specified risk materials, and must be disposed of appropriately.

An enhanced BSE-related feed ban is in effect in both the United States and Canada to help improve prevention and elimination of BSE.

Treatment
As of 2015 there was no cure for BSE; some of the symptoms like twitching can be managed but otherwise treatment is palliative care.

Epidemiology


The table to the right summarizes reported cases of BSE and of vCJD by country. (The vCJD column is by country of residence of patient at time of diagnosis and not suspected origin of beef.) BSE is the disease in cattle, while vCJD is the disease in people.

The tests used for detecting BSE vary considerably, as do the regulations in various jurisdictions for when, and which cattle, must be tested. For instance in the EU, the cattle tested are older (30 months or older), while many cattle are slaughtered younger than that. At the opposite end of the scale, Japan tests all cattle at the time of slaughter. Tests are also difficult, as the altered prion protein has very low levels in blood or urine, and no other signal has been found. Newer tests are faster, more sensitive, and cheaper, so future figures possibly may be more comprehensive. Even so, currently the only reliable test is examination of tissues during a necropsy.

As for vCJD in humans, autopsy tests are not always done, so those figures, too, are likely to be too low, but probably by a lesser fraction. In the United Kingdom, anyone with possible vCJD symptoms must be reported to the Creutzfeldt–Jakob Disease Surveillance Unit. In the United States, the CDC has refused to impose a national requirement that physicians and hospitals report cases of the disease. Instead, the agency relies on other methods, including death certificates and urging physicians to send suspicious cases to the National Prion Disease Pathology Surveillance Center (NPDPSC) at Case Western Reserve University in Cleveland, which is funded by the CDC.

To control potential transmission of vCJD within the United States, the American Red Cross has established strict restrictions on individuals' eligibility to donate blood. Individuals who have spent a cumulative time of 3 months or more in the United Kingdom between 1980 and 1996, or a cumulative time of 5 years or more from 1980 to present in any combination of countries in Europe, are prohibited from donating blood.

North America
The first reported case in North America was in December 1993 from Alberta, Canada. Another Canadian case was reported in May 2003. The first known U.S. occurrence came in December of the same year, though it was later confirmed to be a cow of Canadian origin imported to the U.S. Canada announced two additional cases of BSE from Alberta in early 2005. In June 2005, John R. Clifford, chief veterinary officer for the United States Department of Agriculture animal health inspection service, confirmed a fully domestic case of BSE in Texas.

Practices in the United States relating to BSE
Soybean meal is cheap and plentiful in the United States. Cottonseed meal, 1.5 million tons of which are produced in the U.S. every year, none of which is suitable for humans or any other simple-stomach animals, is even cheaper than soybean meal. Historically, meat and bone meal, blood meal, and meat scraps have almost always commanded a higher price as a feed additive than oilseed meals in the U.S., so not much incentive existed to use animal products to feed ruminants. As a result, the use of animal byproduct feeds was never common, as it was in Europe. However, U.S. regulations only partially prohibited the use of animal byproducts in feed. In 1997, regulations prohibited the feeding of mammalian byproducts to ruminants such as cattle and goats. However, the byproducts of ruminants can still be legally fed to pets or other livestock, including pigs and poultry. In addition, it is legal for ruminants to be fed byproducts from some of these animals. Because of this, some authors have suggested that under certain conditions, it is still possible for BSE incidence to increase in U.S. cattle. A proposal to end the use of cattle blood, restaurant scraps, and poultry litter (fecal matter, feathers, bedding material) in January 2004 has yet to be implemented.

In February 2001, the US Government Accountability Office reported the FDA, which is responsible for regulating feed, had not adequately enforced the various bans. Compliance with the regulations was shown to be extremely poor before the discovery of a cow in Washington infected with BSE in 2003, but industry representatives report that compliance is now total. Even so, critics call the partial prohibitions insufficient. Indeed, US meat producer Creekstone Farms was forcibly prevented from conducting BSE testing by the USDA, which under an obscure 1913 law had the authority to restrict sales of BSE testing kits, allegedly to protect other producers from being forced to conduct the same tests to stay competitive.

The USDA has issued recalls of beef supplies that involved introduction of downer cows into the food supply. Hallmark/Westland Meat Packing Company was found to have used electric shocks to prod downer cows into the slaughtering system in 2007. Possibly due to pressure from large agribusiness, the United States has drastically cut back on the number of cows inspected for BSE.

Effect on the US beef industry
Japan was the top importer of US beef, buying 240,000 tons valued at $1.4 billion in 2003. After the discovery of the first case of BSE in the US on 23 December 2003, Japan halted US beef imports. In December 2005, Japan once again allowed imports of US beef, but reinstated its ban in January 2006 after a violation of the US-Japan beef import agreement: a vertebral column, which should have been removed prior to shipment, was included in a shipment of veal.

Tokyo yielded to US pressure to resume imports, ignoring consumer worries about the safety of US beef, said Japanese consumer groups. Michiko Kamiyama from Food Safety Citizen Watch and Yoko Tomiyama from Consumers Union of Japan said about this: "The government has put priority on the political schedule between the two countries, not on food safety or human health."

Sixty-five nations implemented full or partial restrictions on importing US beef products because of concerns that US testing lacked sufficient rigor. As a result, exports of US beef declined from 1,300,000 metric tons in 2003, (before the first mad cow was detected in the US) to 322,000 metric tons in 2004. This has increased since then to 771,000 metric tons in 2007.

On 31 December 2006, Hematech, Inc, a biotechnology company based in Sioux Falls, South Dakota, announced it had used genetic engineering and cloning technology to produce cattle that lacked a necessary gene for prion production – thus theoretically making them immune to BSE.

In April 2012, some South Korean retailers ceased importing beef from the United States after a case of BSE was reported. Indonesia also suspended imports of beef from the US after a dairy cow with mad cow disease was discovered in California.

Japan
With 36 confirmed cases, Japan experienced one of the largest number of cases of BSE outside Europe. It was the only country outside Europe and the Americas to report non-imported cases. Reformation of food safety in the light of the BSE cases resulted in the establishment of a governmental Food Safety Commission in 2003.

Britain
Cattle are naturally herbivores, eating grasses. In modern industrial cattle-farming, though, various commercial feeds are used, which may contain ingredients including antibiotics, hormones, pesticides, fertilizers, and protein supplements. The use of meat and bone meal, produced from the ground and cooked leftovers of the slaughtering process, as well as from the carcasses of sick and injured animals such as cattle or sheep, as a protein supplement in cattle feed was widespread in Europe prior to about 1987. Worldwide, soybean meal is the primary plant-based protein supplement fed to cattle. However, soybeans do not grow well in Europe, so cattle raisers throughout Europe turned to the cheaper animal byproduct feeds as an alternative. The British Inquiry dismissed suggestions that changes to processing might have increased the infectious agents in cattle feed, saying, "changes in process could not have been solely responsible for the emergence of BSE, and changes in regulation were not a factor at all." (The prion causing BSE is not destroyed by heat treatment.)



The first confirmed instance in which an animal fell ill with the disease occurred in 1986 in the United Kingdom, and lab tests the following year indicated the presence of BSE; by November 1987, the British Ministry of Agriculture accepted it had a new disease on its hands. Subsequently, 177 people (as of June 2014) contracted and died of a disease with similar neurological symptoms subsequently called (new) variant Creutzfeldt–Jakob disease (vCJD). This is a separate disease from 'classical' Creutzfeldt–Jakob disease, which is not related to BSE and has been known about since the early 1900s. Three cases of vCJD occurred in people who had lived in or visited the UK – one each in the Republic of Ireland, Canada, and the United States of America. Also, some concern existed about those who work with (and therefore inhale) cattle meat and bone meal, such as horticulturists, who use it as fertilizer. Up-to-date statistics on all types of CJD are published by the National Creutzfeldt–Jakob Disease Surveillance Unit in Edinburgh, Scotland.

For many of the vCJD patients, direct evidence exists that they had consumed tainted beef, and this is assumed to be the mechanism by which all affected individuals contracted it. Disease incidence also appears to correlate with slaughtering practices that led to the mixture of nervous system tissue with ground meat (mince) and other beef. An estimated 400,000 cattle infected with BSE entered the human food chain in the 1980s. Although the BSE epizootic was eventually brought under control by culling all suspect cattle populations, people are still being diagnosed with vCJD each year (though the number of new cases currently has dropped to fewer than five per year). This is attributed to the long incubation period for prion diseases, which is typically measured in years or decades. As a result, the full extent of the human vCJD outbreak is still not known.

The scientific consensus is that infectious BSE prion material is not destroyed through cooking procedures, meaning that even contaminated beef foodstuffs prepared "well done" may remain infectious. In fact the infectious agent remains viable over 600 C.

Alan Colchester, a professor of neurology at the University of Kent, and Nancy Colchester, writing in the 3 September 2005 issue of the medical journal The Lancet, proposed a theory that the most likely initial origin of BSE in the United Kingdom was the importation from the Indian Subcontinent of bone meal which contained CJD-infected human remains. The government of India vehemently responded to the research, calling it "misleading, highly mischievous; a figment of imagination; absurd," further adding that India maintained constant surveillance and had not had a single case of either BSE or vCJD. The authors responded in the 22 January 2006 issue of The Lancet that their theory is unprovable only in the same sense as all other BSE origin theories are and that the theory warrants further investigation.

During the course of the investigation into the BSE epizootic, an enquiry was also made into the activities of the Department of Health Medicines Control Agency (MCA). On 7 May 1999, David Osborne Hagger, a retired civil servant who worked in the Medicines Division of the Department of Health between 1984 and 1994, produced a written statement to the BSE Inquiry in which he gave an account of his professional experience of BSE.

In February 1989, the MCA had been asked to "identify relevant manufacturers and obtain information about the bovine material contained in children’s vaccines, the stocks of these vaccines and how long it would take to switch to other products." In July, "[the] use of bovine insulin in a small group of mainly elderly patients was noted and it was recognised that alternative products for this group were not considered satisfactory." In September, the BSE Working Party of the Committee on the Safety of Medicines (CSM) recommended that "no licensing action is required at present in regard to products produced from bovine material or using prepared bovine brain in nutrient media and sourced from outside the United Kingdom, the Channel Isles and the Republic of Ireland provided that the country of origin is known to be free of BSE, has competent veterinary advisers and is known to practise good animal husbandry."

In 1990, the British Diabetic Association became concerned regarding the safety of bovine insulin. The CSM assured them "[that] there was no insulin sourced from cattle in the UK or Ireland and that the situation in other countries was being monitored."

In 1991, the European Commission "[expressed] concerns about the possible transmission of the BSE/scrapie agent to man through use of certain cosmetic treatments."

In 1992, sources in France reported to the MCA "that BSE had now been reported in France and there were some licensed surgical sutures derived from French bovine material." Concerns were also raised at a CSM meeting "regarding a possible risk of transmission of the BSE agent in gelatin products."

The ban on British beef
The BSE crisis led to the European Union banning exports of British beef with effect from March 1996; the ban lasted for 10 years before it was finally lifted on 1 May 2006 despite attempts in May 1996 by British prime minister John Major to get the ban lifted. The ban resulted in trade controversies between the UK and other EU states, dubbed "beef war" by media. Restrictions remained for beef containing "vertebral material" and for beef sold on the bone.

Russia was proceeding to lift the ban sometime after November 2012 after 16 years; the announcement was made during a visit by the UK's chief veterinary officer Nigel Gibbens.

It was successfully negotiated that beef from Wales was allowed to be exported to the Dutch market, which had formerly been an important market for Northern Irish beef. Of two approved export establishments in the United Kingdom in 1999, one was in Scotland – an establishment to which live beef was supplied from Northern Ireland. As the incidence of BSE was very low in Northern Ireland – only six cases of BSE by 1999 – partly due to the early adoption of an advanced herd tagging and computerization system in the region, calls were made to remove the EU ban on exports with regard to Northern Irish beef.