Bovine spongiform encephalopathy

Bovine spongiform encephalopathy, commonly known as mad cow disease, is an incurable and always fatal neurodegenerative disease of cattle. Symptoms include abnormal behavior, trouble walking, and weight loss. Later in the course of the disease, the cow becomes unable to function normally. There is conflicting information about the time between infection and onset of symptoms. In 2002, the World Health Organization suggested it to be approximately four to five years. Time from onset of symptoms to death is generally weeks to months. Spread to humans is believed to result in variant Creutzfeldt–Jakob disease or Creutzfeldt–Jakob disease., a total of 233 cases of vCJD had been reported globally.
BSE is thought to occur due to an infection by a misfolded protein, known as a prion. Cattle are believed to have been infected by being fed meat-and-bone meal that contained either the remains of cattle who spontaneously developed the disease or scrapie-infected sheep products. The United Kingdom was afflicted with an outbreak of BSE and vCJD in the 1980s and 1990s. The outbreak increased throughout the UK due to the practice of feeding meat-and-bone meal to young calves of dairy cows. Cases are suspected based on symptoms and confirmed by examination of the brain. Cases are classified as classic or atypical, with the latter divided into H- and L types. It is a type of transmissible spongiform encephalopathy.
Efforts to prevent the disease in the UK include not allowing any animal older than 30 months to enter either the human food or animal feed supply. In continental Europe, cattle over 30 months must be tested if they are intended for human food. In North America, tissue of concern, known as specified risk material, may not be added to animal feed or pet food. About four million cows were killed during the eradication programme in the UK.
Four cases were reported globally in 2017, and the condition is considered to be nearly eradicated. In the United Kingdom, more than 184,000 cattle were diagnosed from 1986 to 2015, with the peak of new cases occurring in 1993. A few thousand additional cases have been reported in other regions of the world. In addition, it is believed that several million cattle with the condition likely entered the food supply during the outbreak.

Signs

Signs are not seen immediately in cattle, due to the disease's 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 and an overall change in temperament. Some rare but previously observed signs also include persistent pacing, rubbing and licking. Additionally, nonspecific signs 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 signs, while others may only be observed demonstrating one of the many reported. Once clinical signs arise, they typically get worse over the subsequent weeks and months, eventually leading to recumbency, coma and death.

Cause

BSE is an infectious disease believed to be due to a misfolded protein, known as a prion. Cattle are believed to have been infected from being fed meat and bone meal that contained the remains of other cattle who spontaneously developed the disease or scrapie-infected sheep products. The outbreak increased throughout the United Kingdom due to the practice of feeding meat-and-bone meal to young calves of dairy cows.
BSE prions are misfolded forms of the particular brain protein called prion protein. When this protein is misfolded, the normal alpha-helical structure is converted into a beta sheet. The prion induces normally-folded proteins to take on the misfolded phenotype in an exponential cascade. These sheets form small chains which aggregate and cause cell death. Massive cell death forms lesions in the brain which lead to degeneration of physical and mental abilities and ultimately death. The prion is not destroyed even if the beef or material containing it is cooked or heat-treated under normal conditions and pressures. Transmission can occur when healthy animals come in contact with tainted tissues from others with the disease, generally when their food source contains tainted meat.
The British Government enquiry took the view that the cause was not scrapie, as had originally been postulated, but was some event in the 1970s that could not be identified.

Spread to humans

Spread to humans is believed to result in variant Creutzfeldt–Jakob disease. The agent can be transmitted to humans by eating food contaminated with it. Though any tissue may be involved, the highest risk to humans is believed to be from eating food contaminated with the brain, spinal cord, or digestive tract.
Despite the lack of knowledge on potential factors triggering the misfolded protein forms, idiopathic prion disorders are the most prevalent, accounting for 85–90% of human cases.

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 PrP^Sc initially located in the ileal Peyer's patches of the small intestine. The lymphatic system has been identified in the pathogenesis of scrapie. 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 four months after inoculation. PrP^Sc accumulation was found to occur mostly in tangible body macrophages of the Ileal Peyer's patches. Tangible body macrophages involved in PrP^Sc clearance are thought to play a role in PrP^Sc accumulation in the Peyer's patches. Accumulation of PrP^Sc was also found in follicular dendritic cells, to 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 signs are noticed, though the pathway of converting the normal brain prion protein into the toxic, disease-related PrP^Sc form has started. At present, no way is known to detect PrP^Sc reliably except by examining post mortem brain tissue using neuropathological and immunohistochemical methods. Accumulation of the abnormally folded PrP^Sc 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 PrP^Sc, 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 PrP^Sc even when initially present at only one part in a hundred billion in brain tissue. The method combines amplification with a novel technology called surround optical fiber immunoassay and some specific antibodies against PrP^Sc. After amplifying and then concentrating any PrP^Sc, 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 PrP^Sc 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 signs became apparent. The researchers could, therefore, compare results from brain tissue and blood taken once the animals exhibited signs of the diseases, with blood obtained earlier in the animals' lives, and from uninfected animals. The results showed very clearly that PrP^Sc could be detected in the blood of animals long before the signs 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.

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, scrapie in sheep, and chronic wasting disease in deer.

Prevention

A ban on feeding meat and bone meal to cattle has resulted in a strong reduction in cases in countries where the disease has been 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 was enacted in both the United States and Canada to help improve prevention and elimination of BSE.