Bovine Spongiform Encephalopathy

In the 1990s, there was intensive debate about the nature of the BSE pathogen. To date, the most widely accepted hypothesis is that a proteinaceous infectious particle (prion) causes the disease. Prions are misfolded conformational isoforms of host-encoded proteins that induce protein misfolding, protein aggregation, and disease upon transmission to other organisms. This hypothesis is supported by the agent’s apparent resistance to heat, freezing, ultraviolet light, and chemical disinfectant procedures effective against bacteria and viruses. In addition, the inoculation of purified prions in animals is able to transmit the disease, confirming that the agent is only a protein.

Prions are also the cause of scrapie of sheep and goats; chronic wasting disease of deer; transmissible mink encephalopathy; and kuru, Creutzfeldt-Jakob disease, fatal familial insomnia, and similar disorders of humans. All of these conditions are also termed prion diseases, and the related protein is the prion protein PrP^Sc (in which Sc stands for "scrapie ", the first described prion disease).

On the basis of the anticipated mechanisms that trigger initial PrP^Sc misfolding, prion diseases are classified as infectious, sporadic, or genetic. Classical BSE is caused by infectious prions; however, intensive active surveillance of BSE in Europe, along with improved diagnostic methods, led to the identification, in the early 2000s, of two new forms of BSE in cattle (L-type and H-type), which were termed atypical BSE. Prions that cause classical and atypical BSE show differences in their biochemical characteristics, epidemiology, and neuropathologic lesions.

Classical BSE develops as a result of foodborne exposure to prions via contaminated animal-source proteins (meat and bone meal) in cattle rations. Calves born to infected cows are at greater risk of acquiring BSE than are calves born to noninfected cows; however, this mode of transmission is of minor importance relative to infections acquired through contaminated feed sources. BSE is not transmitted horizontally by contact or aerosols. There is no sex or breed predisposition.

Most cases of classical BSE are diagnosed in cattle 3–6 years old. The incubation period after exposure is ~2–8 years, and animals as young as 22 months have been diagnosed with BSE. During the BSE outbreak in Europe, dairy cows were affected three times more often than beef cattle; this is believed to be because dairy cows were more likely to be fed animal-source protein supplements.1 After oral exposure, the pathologic agent replicates in the Peyer's patches of the ileum and then migrates via peripheral nerves to the CNS, where it accumulates and disrupts normal neuronal function.

Atypical BSE cases have been described even from countries with no apparent classical BSE epidemic. Moreover, animals affected with atypical BSE are relatively old, and the incidence rates do not follow the trends observed for classical BSE. Together, these findings led to the hypothesis that atypical BSE results from spontaneous prion protein misfolding and is not related to the ingestion of prion-contaminated feed. The mechanisms that induce the spontaneous prion formation remain obscure. It has been postulated that atypical BSE was at the origin of the BSE epidemic in the UK. However, a study published in 2019 suggested that contamination of feed by prions that cause the atypical form of scrapie (Nor98) could also have been the origin of the BSE epidemic in cattle.2

BSE has been transmitted experimentally to many animal species by intracerebral inoculation. During the epidemic of BSE in the UK and other European countries, a few cases were reported in several species of captive-bred wild ungulates and in domestic companion cats, as well as in big cats in zoologic gardens. BSE has also been confirmed in two goats, one from France and another from Scotland; however, there is no evidence that BSE infected the small-ruminant population on a broader scale.

Initial clinical signs of BSE are subtle and behavioral; signs progress over weeks to months to include hyperesthesia, nervousness, difficulty negotiating obstacles, reluctance to be milked, aggression toward either farm personnel or other animals, low head carriage, hypermetria, ataxia, and tremors. Weight loss and decreased milk production are common. However, clinical signs may be nonspecific, and involvement of the nervous system is not obvious in every case. Most animals reach a terminal state by 3 months after clinical onset.

• Detection of the causative agent (PrP^Sc) in brain samples by:   

  • ELISA

  • Western immunoblot techniques

  • immunohistochemical techniques

  • ultrasensitive in vitro amplification techniques

Clinical examinations do not provide a definitive diagnosis of BSE. In case of clinical suspicion of the disease, the animal should be euthanized and the brain subjected to neuropathologic examination.

Differential diagnoses include nervous ketosis, hypomagnesemia, polioencephalomalacia, lead poisoning, ingestion of toxic plants or fungi, rabies, listeriosis, and other viral and bacterial infectious neurologic diseases. In contrast to these differential diagnoses, BSE typically has a slow onset of clinical signs, with an extended and progressive clinical course. Veterinarians considering BSE as a likely differential diagnosis should contact national veterinary authorities and ensure that definitive postmortem diagnostic tests are performed.

Spongiosis in bovine spongiform encephalopathy

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Courtesy of Centro de Encefalopatías y Enfermedades Transmisibles Emergentes, Universidad de Zaragoza.

PrP^Sc prion deposition in bovine spongiform encephalopat...

Image

Courtesy of Centro de Encefalopatías y Enfermedades Transmisibles Emergentes, Universidad de Zaragoza.

In most countries, BSE is a notifiable disease, and a suspect case must be reported to the veterinary authorities. The World Organisation for Animal Health, or WOAH (formerly the Office International des Épizooties, or OIE) has nominated Reference Laboratories to assist national authorities of WOAH member states in the diagnosis of BSE. The identification of characteristic vacuolar changes by histopathology in specific target structures of the CNS is indicative of BSE. Confirmatory diagnostic methods include PrP^Sc immunohistochemistry and Western immunoblot in brain tissue.

Testing of suspect cases (ie, animals that show clinical signs compatible with the disease) is referred to as “passive surveillance”, whereas “active surveillance” refers to the testing of animals not reported as suspected of being infected by BSE. This includes animals with clinical signs other than BSE and slaughtered healthy animals at epidemiological risk. In most countries with a BSE case history, active surveillance programs have been established.

Approximately a dozen commercial rapid BSE screening tests are available for active disease surveillance, in ELISA, Western immunoblot, and immunochromatographic test formats. All of these tests are based on the immunologic detection of PrP^Sc in medulla oblongata samples, and they enable the screening of a large number of samples in a short period of time. Ideally, however, confirmation of a positive diagnosis of BSE detected by a rapid test requires the use of immunohistochemistry or Western immunoblot. In vitro ultrasensitive techniques for detecting minute amounts of prions have been developed. These techniques include protein misfolding cyclic amplification (PMCA) and real-time quaking-induced conversion (RT-QuIC). However, they have not been evaluated for application within legal BSE surveillance programs.

• No effective treatment or vaccines are available

• Control measures: banning of meat and bone meal in cattle feeds, active and passive surveillance, and culling sick animals

There is no effective treatment or vaccine for BSE. Euthanasia is advisable as soon as there is some certainty of the clinical diagnosis, because animals become unmanageable as the disease progresses, compromising their welfare and handler safety.

The most effective control measure is to prohibit the feeding of meat and bone meal to cattle. Meat and bone meal supplements for cattle have been banned in many countries as a consequence of the BSE epidemic. Because of the risk of cross-contamination in feed mills, the UK and other European countries have implemented similar statutory prohibitions banning the use of meat and bone meal in all farm animal diets.

With the drastic decline of classical BSE cases since the epidemic of the 1990s, an ongoing discussion centers on possibly relaxing the complete ban of meat and bone meal in the feed of animals other than cattle—ie, pigs and poultry. Relevant to that discussion, it is important to remember that any reemergence of BSE will remain unrecognized for years because of the extraordinarily long incubation period of the disease. Moreover, the fact that atypical BSE persists in the cattle population means there is a constant risk of reintroduction of BSE. Therefore, a high level of disease awareness, as well as effective surveillance and control measures, must be maintained.

In accordance with WOAH's Terrestrial Animal Health Code, the efficient strategies for preventing BSE and decreasing the risk of human exposure include banning meat and bone meal in ruminant feed, diagnosing clinical suspects (passive surveillance), diagnosing animals subjected to emergency slaughtering or dead on the farm (active surveillance), removing specified risk materials (SRMs—eg, brain and spinal cord) from the human feed chain, prohibiting SRMs in animal feeds, destroying all animals suspected of being exposed to contaminated feed, restricting the importation of live cattle and their products, incineration of affected carcasses, and appropriately identifying cattle for efficient surveillance and case tracing.

A novel variant of Creutzfeldt-Jakob disease (vCJD) in the human population in Great Britain, initially observed in 1996, has been associated with the emergence of the BSE agent. Cases of vCJD have also occurred outside the UK. Some of the affected individuals in other countries formerly lived in the UK; however, cases have occurred in other European countries among people who have not visited the UK.

Humans became infected with the vCJD-causing agent by eating infected bovine tissues, and in fatal human cases, BSE prion was identified in brain tissue. Therefore, many countries have introduced the statutory removal of high-risk bovine tissues from the human food chain and/or banned human consumption of cattle > 24 months old. In addition, appropriate safety precautions for handling the BSE agent and conducting necropsies of cattle suspected of being infected are recommended. Safety precautions should be aimed primarily at avoiding accidental exposures.

• WOAH: Bovine Spongiform Encephalopathy

• BSE review: Bradley R. Bovine spongiform encephalopathy (BSE): the current situation and research. Eur J Epidemiol. 1991;7(5):532-544.

• vCJD review: Ward HJT, Head MW, Will RG, Ironside JW. Variant Creutzfeldt-Jakob disease. Clin Lab Med. 2003;23(1):87-108.

• Animal & Plant Health Agency video: Clinical Signs of Bovine Spongiform Encephalopathy in Cattle.