Bovine spongiform encephalopathy – a forgotten disease?

If you were a practising cattle or official veterinarian in the UK in the 1990s, it is likely that you encountered a case of bovine spongiform encephalopathy (BSE). This neurological disease, first described in 1987 by the veterinary neuropathologist Gerald Wells (Wells et al., 1987), caused an epidemic with more than 180,000 cases in the UK alone and had its peak in 1992 with more than 36,000 cases. Like scrapie in sheep and goats, BSE is a transmissible spongiform encephalopathy caused by a proteinaceous infectious particle, the prion. While the former is not believed to be zoonotic, the BSE infectious agent is more transmissible to other species and is the cause of variant Creutzfeldt-Jakob disease in humans (Bruce et al., 1997).

The BSE epidemic resulted in many legislative changes, namely the ban on feeding of meat and bone meal (MBM) to ruminants, later extended to any farm animal to accelerate the slow decline of cases due to cross-contamination of feed or offering feed to ruminants not intended for this species, and the disposal of “specified risk material” at slaughter, which contained the highest amount of prions, such as tonsil, intestines and mesentery as well as skull with brain and eyes and spinal cord or spinal column with adjacent dorsal root ganglia, dependent on age. BSE was later detected in many other countries, which led to the Regulation (EC) No 999/2001 of the European Parliament and of the Council of 22 May 2001 laying down rules for the prevention, control and eradication of certain transmissible spongiform encephalopathies.

While [scrapie in sheep and goats] is not believed to be zoonotic, the BSE infectious agent is more transmissible to other species and is the cause of variant Creutzfeldt-Jakob disease in humans (Bruce et al., 1997)

The regulation, adopting some of the legislation already in place in the UK to eradicate BSE, applied to all EU member states and has been incorporated into the UK’s domestic legislation. It outlines an extensive surveillance programme to detect cases of BSE, initially targeting both adult healthy slaughter cattle and fallen stock. These legislative changes were extremely successful, significantly reducing the number of cases to the point of eradication. However, as the most recent case diagnosed in England in September 2021 has demonstrated, BSE is not completely eradicated, and it is important not to forget this notifiable disease and its clinical presentation.

Why is BSE important and why should suspect cases be reported?

It is currently mandatory to test all fallen stock over the age of 48 months for BSE by examination of a part of the brainstem, the obex, which is one of the areas where prions are first detected. There are some exceptions for specific countries where younger cattle have to be tested. The probability of detecting BSE is higher in fallen stock compared to healthy slaughter cattle, which is why testing of healthy slaughter cattle was dropped as the cases declined, but the highest BSE risk group is cattle with neurological conditions where BSE may be suspected.

Between 1988 and 2006 when the annual number of reported suspect cases in the UK exceeded 100, the percentage of suspect but BSE-negative cases ranged from 8 percent (192) in 1988 to 89 percent (103) in 2006. The reporting of suspect cases, where financial compensation provides some degree of incentive, has dramatically declined since and has stood at 2 or fewer suspects since 2013, even though it is unlikely that other neurological conditions in cattle with signs similar to BSE have disappeared. It may be because of the continuing testing of fallen stock which ensures some detection of BSE, the loss of reputation and subsequent cull of cattle epidemiologically linked to a case or the assumption that BSE has been eradicated.

Although some studies to investigate these negative cases found no significant brain lesions in the majority of cases (Jeffrey, 1992; Wells et al., 1995) which suggests the presence of metabolic diseases or other organ diseases that may cause some supposedly neurological signs, listeriosis was the most frequently diagnosed brain disease. Listeriosis is zoonotic but treatable and usually detectable during the statutory diagnosis for BSE, so diagnosis can be helpful for the farmer to prevent similar cases.

The World Organisation for Animal Health (OIE) has established a BSE risk status for countries or compartments within a country: negligible, controlled or undetermined. It is desirable for any country to achieve a negligible BSE risk status because of favourable trade conditions with other countries

The World Organisation for Animal Health (OIE) has established a BSE risk status for countries or compartments within a country: negligible, controlled or undetermined. It is desirable for any country to achieve a negligible BSE risk status because of favourable trade conditions with other countries, but within the UK currently only Northern Ireland has obtained this status. To obtain negligible status, certain conditions have to be met, which are outlined in chapter 11.4 of the OIE Terrestrial Animal Health Code. These include an assessment of the risk of entry of the BSE agent, exposure of animals to the BSE agent (which requires adequate feed controls and surveillance activities), an ongoing BSE awareness programme for people working with cattle, notification of suspect cases and the ability to diagnose the disease. In addition, indigenous cases of BSE must not occur or – if present – have to be born more than 11 years prior to the status application. To meet the required surveillance target, the OIE uses a points system which allocates more points to animals tested in the “clinical suspect” subpopulation compared to casualty slaughter, fallen stock or healthy slaughter cattle. Thus, by testing clinical suspects fewer animals have to be tested overall to fulfil the surveillance requirements, which will save costs.

When to suspect BSE?

BSE is a slowly progressive neurological disease with insidious onset. During the height of the epidemic, BSE was a disease of adult cattle between four and six years of age, which affected single animals or several animals of the same cohort, but due to the feed controls, multiple cases on one farm are now unlikely to occur. Incubation period depends on the amount of oral intake of feedstuffs contaminated with the BSE agent, which is the main route of exposure and still believed to be the main cause in cattle born long after the extended MBM feed ban. The higher the amount, the shorter the incubation period and even 1mg of BSE brainstem homogenate administered orally can cause disease (Konold et al., 2012a). In the UK, the youngest animal with BSE was 21 months of age and the oldest over 22 years old.

In general, BSE causes progressive changes in behaviour, sensation and locomotion (Wilesmith et al., 1991). Affected animals become more apprehensive, particularly evident when entering a milking parlour, when walking through doorways or when they have to cross a drain or other minor obstacle (Figure 1). Previously familiar objects or noise may suddenly cause hesitation or startle responses. In fact, startle responses or general over-reactivity to external stimuli are so characteristic in BSE that they have been used to aid in the clinical diagnosis: flashlight (“flash test”), hand clapping, banging against an object (“bang test”) or waving a hand or clipboard towards the animal from a distance (“clipboard test”, Figure 2) may elicit a startle response that is repeatable (Konold et al., 2004). Touching the hindlimbs with a (flexible) stick may cause the animal to kick out forcefully (“stick test”), which makes milking dangerous. The animal may be averse to approach from the front while restrained and to touching its head or neck (Figure 3) and may jump backwards, struggle or head toss while salivating or roaring in extreme cases. In some cases, this may turn into aggressive behaviour, such as violent head butting, pawing the ground or attacking. Head or body tremors are also frequently observed. Locomotion becomes impaired, usually first in the hindlimbs, characterised by ataxia or dysmetria, which may cause the animal to stumble, knuckle over in the fetlocks and eventually fall.

Clinical suspicion in downer cows

With the reduction of BSE cases, this disease is often not considered in the differential diagnosis of downer cows. A neurological examination may be limited, nervousness may not be as prominent depending on the duration of recumbency and other concurrent diseases may mask signs usually associated with BSE although startle responses to external stimuli may still be elicited (Konold et al., 2006). A lack of response to treatment in combination with the clinical history (changed behaviour, gait abnormalities) are important indicators of BSE in the list of suspect diagnoses. The three most recent cases (in 2015 in Wales, 2018 in Scotland and 2021 in England) were all recumbent or had a history of falling, had clinical signs suggestive of a nervous disease (eg nervousness or aggressiveness) and/or failed to respond to treatment (hypomagnesaemia or milk fever). BSE is a fatal disease, and cattle will end up recumbent if left to progress to the terminal stage of disease.

A lack of response to treatment in combination with the clinical history (changed behaviour, gait abnormalities) are important indicators of BSE in the list of suspect diagnoses

The discovery of atypical forms

Two other prion diseases in cattle were reported almost simultaneously in 2004, which differed from BSE in the migration pattern of proteinase-resistant prion protein in a Western blot and the formation of amyloid plaques in the brain: L-type, also named bovine amyloidotic spongiform encephalopathy, and H-type BSE. Respectively, these had protein bands lower and higher than the “classical” form of BSE (Biacabe et al., 2004; Casalone et al., 2004). These cases were usually in cattle aged eight years and above and found in approximately 1 in 1,000,000 tested cattle, a similar prevalence rate as sporadic Creutzfeldt-Jakob disease in humans.

It is currently assumed that these cases are sporadic and not linked to consumption of MBM but questions remain about their pathogenesis and link to classical BSE. Most of the information about these diseases is derived from experimental (intracerebral) inoculations, including the clinical presentation, which could be similar to classical BSE (nervous syndrome) or unlike classical BSE (dull syndrome) (Konold et al., 2012b; Konold et al., 2014). However, difficulty getting up appears to be a common feature (Figure 4).

As these cases may not have a clinical history of changed behaviour or locomotor changes, diagnosis will be more challenging if presented with a downer cow. Atypical BSE has been exclusively detected in brains from cattle presented as fallen stock or healthy slaughter cattle, which is why there is so little information available about the pathogenesis in naturally occurring disease. Only if suspects are reported and subject to a more detailed necropsy so that a range of peripheral tissues can be collected are we able to assess whether our experimental production of atypical BSE accurately mimics natural disease. It is thus very desirable to report clinical suspects to allow good-quality sample collection and not to rely merely on testing fallen stock.