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bovine spongiform encephalopathy

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Datasheet

bovine spongiform encephalopathy

Summary

  • Last modified
  • 22 April 2021
  • Datasheet Type(s)
  • Animal Disease
  • Preferred Scientific Name
  • bovine spongiform encephalopathy
  • Overview
  • Bovine spongiform encephalopathies (BSEs) are a group of three distinct prion diseases affecting cattle. Prion diseases, also named transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases that affect a large spectrum...

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Pictures

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PictureTitleCaptionCopyright
Clinical appearance of a Friesian cow with BSE; apprehensive, with ears directed back. Also, poor general bodily condition.
TitleSymptoms
CaptionClinical appearance of a Friesian cow with BSE; apprehensive, with ears directed back. Also, poor general bodily condition.
CopyrightCrown copyright 2004, Veterinary Laboratories Agency
Clinical appearance of a Friesian cow with BSE; apprehensive, with ears directed back. Also, poor general bodily condition.
SymptomsClinical appearance of a Friesian cow with BSE; apprehensive, with ears directed back. Also, poor general bodily condition.Crown copyright 2004, Veterinary Laboratories Agency
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)
TitleSigns
CaptionCattle 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)
CopyrightCenters for Disease Control and Prevention (CDC)/Atlanta, GA 30333, USA
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)
SignsCattle 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
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)
TitleSymptoms
CaptionCattle 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)
CopyrightCenters for Disease Control and Prevention (CDC)/Atlanta, GA 30333, USA
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)
SymptomsCattle 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
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.
TitleHistopathology - normal medulla oblongata
CaptionHistological 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.
CopyrightCrown copyright 2004, Veterinary Laboratories Agency
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.
Histopathology - normal medulla oblongataHistological 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
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.
TitleHistopathology - BSE medulla oblongata
CaptionHistological 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.
CopyrightCrown copyright 2004, Veterinary Laboratories Agency
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.
Histopathology - BSE medulla oblongataHistological 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
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).
TitleCross section through the medulla oblongata
CaptionCross 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).
CopyrightFelix Ehrensperger/Institute of Veterinary Pathology, University of Zürich, Switzerland
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).
Cross section through the medulla oblongataCross 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
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)
TitleInspected cattle
CaptionCattle 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)
CopyrightCenters for Disease Control and Prevention (CDC)/Atlanta, GA 30333, USA
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)
Inspected cattleCattle 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
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)
TitleCross section through the medulla oblongata
CaptionCross 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)
CopyrightFelix Ehrensperger/Institute of Veterinary Pathology, University of Zürich, Switzerland
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)
Cross section through the medulla oblongataCross 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
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).
TitleCross section through the medulla oblongata
CaptionCross 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).
CopyrightFelix Ehrensperger/Institute of Veterinary Pathology, University of Zürich, Switzerland
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).
Cross section through the medulla oblongataCross 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
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).
TitleCross section through the medulla oblongata
CaptionCross 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).
CopyrightFelix Ehrensperger/Institute of Veterinary Pathology, University of Zürich, Switzerland
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).
Cross section through the medulla oblongataCross 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
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.
TitleHistopathology
CaptionImmunohistochemical 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.
CopyrightCrown copyright 2004, Veterinary Laboratories Agency
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.
HistopathologyImmunohistochemical 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

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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
  • c-BSE
  • H-BSE
  • L-BSE
  • TSE

French acronym

  • ESB

Overview

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Bovine spongiform encephalopathies (BSEs) are a group of three distinct prion diseases affecting cattle. Prion diseases, also named transmissible spongiform encephalopathies (TSEs), are fatal neurodegenerative diseases that affect a large spectrum of mammalian species. These diseases are caused by the conversion of the normal form of the host prion protein PrPC into an abnormal isoform termed PrPSc. During an on-going prion disease, PrPSc has the capacity to recruit and convert PrPC into more PrPSc leading to its progressive accumulation in the peripheral tissues and the central nervous system (CNS). PrPSc accumulation in the CNS results in a progressive and fatal neurodegenerative process (Prusiner, 1982).

Classical BSE (c-BSE) was first recognized in 1984-85 as novel prion disease affecting cattle in the UK (Wells et al., 1987). The origin of c-BSE has still not been clearly established but the number of cases was amplified by the recycling of infected carcasses into cattle feed in the form of meat and bone meal (MBM) (Wilesmith et al., 1988). c-BSE was disseminated to at least 28 countries, mostly in Europe but also the USA, Canada, and Japan, through the export of infected live animals and/or contaminated MBM and livestock feed.

In 2001 the EU implemented an active TSE surveillance system in ruminant livestock. The system relied on the targeted testing of healthy slaughtered and rendered cattle for the presence of PrPSc in the brain. It led in 2004 to the identification of two atypical forms of BSE cases: bovine amyloidotic spongiform encephalopathy (BASE) or L-BSE, and H-BSE. L-BSE and H-BSE were categorized on the basis of low and high apparent molecular masses, respectively, of un-glycosylated protease-resistant PrPSc on western blots (Biacabe et al., 2004; Casalone et al., 2004). A low number of cases were identified in over 15 countries worldwide, including those where no c-BSE has been identified.

Atypical BSE cases identified so far were generally not associated with overt neurological abnormalities/disease. In c-BSE, the clinical disease is characterized by progressive neurological signs, which ultimately lead to death. The 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 hyperesthesia to sound and touch are the most prominent clinical signs.

Legislation prohibiting the inclusion of MBM and other animal proteins in livestock feed in the UK (1988, 1996), the EU (2001) and numerous other countries led to the rapid decline of c-BSE contamination and subsequent progressive reduction in the number of clinical cases. Since 2001 and the implementation of the active TSE surveillance system, the vast majority of c-BSE cases have been identified in asymptomatic animals. The incidence of c-BSE has now declined to very low incidence levels, with no cases or a single-digit number of cases reported each year since 2011.

However, it has been estimated that globally over 1 million BSE-infected cattle entered the human food chain, resulting in potential dietary exposure to c-BSE for millions of consumers. Even if the number of c-BSE cases that occurred in the UK exceeded by several orders of magnitude those observed in other affected countries, international trade of food commodities could have resulted in exposure of people even in regions that did not experience autochthonous c-BSE cases.

In 1996, a new form of Creutzfeldt-Jakob disease (CJD), termed variant CJD (vCJD) was identified in the UK, which is believed to result from zoonotic transmission of the BSE agent, probably as a consequence of dietary exposure to BSE-contaminated meat products (Collinge et al., 1996; Bruce et al., 1997). The total number of clinical cases of vCJD identified thus far is limited (230 patients worldwide at the time of writing). However, in the UK the prevalence of asymptomatic vCJD infection in populations exposed to c-BSE (born between 1941 and 1985) was estimated to range between 1 in 3,500 and 1 in 1,250 (Gill et al., 2013).

So far, there is no evidence of H-BSE and L-BSE transmission to humans. However, data obtained in experimental systems used to model the zoonotic ability of TSE agents converge on the view that L-BSE may have a higher ability to propagate in humans than c-BSE.

BSE is on the list of diseases notifiable to the World Organisation for Animal Health (OIE). For further information on this disease from OIE, see the website: www.oie.int

Host Animals

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Animal nameContextLife stageSystem
Bos indicus (zebu)Domesticated hostCattle & Buffaloes|Bull; Cattle & Buffaloes|Cow; Cattle & Buffaloes|Ox; Cattle & Buffaloes|Steer
Bos taurus (cattle)Domesticated hostCattle & Buffaloes|Bull; Cattle & Buffaloes|Cow; Cattle & Buffaloes|Ox; Cattle & Buffaloes|Steer
Capra hircus (goats)Domesticated host
Cervus elaphus (red deer)Experimental settings
Homo sapiens
Macaca mulatta (rhesus macaque)Experimental settings
Mus musculus (house mouse)Experimental settings
Ovis aries (sheep)Experimental settings
Sus scrofa (pigs)Experimental settings

Hosts/Species Affected

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[Note that the ‘Host Animals’ table above relates to classical BSE]

c-BSE

Classical BSE (c-BSE) was first recognized in 1984-85 as a novel prion disease affecting cattle in the UK (Wells et al., 1987). The origin of c-BSE has still not been clearly established, but the number of cases was amplified by the recycling of infected carcasses into cattle feed in the form of meat and bone meal (MBM) (Wilesmith et al., 1988).

In the 1990s, c-BSE cases were observed in captive animals belonging to a variety of species such as kudu, nyala, Arabian onynx, Scimitar horned oryx, eland, gemsbok, bison, tiger, cheetah, ocelot and puma. c-BSE transmission was also observed in domestic cats. These cases were the probable consequence of a dietary exposure to c-BSE contaminated feed material (processed animal proteins or c-BSE infected carcasses) (Collinge, 2001).

The expansion of the c-BSE epizootic led to the consideration that this disease was a potential threat to small ruminants. To date, only two natural c-BSE cases have been officially identified in farmed small ruminants. Both cases occurred in goats. The first one was detected in 2002 by the active surveillance system in France (Eloit et al., 2005). The second case was initially reported as a scrapie case in 1990 in the UK but confirmed to be a c-BSE case in 2011 (Spiropoulos et al., 2011).

Successful experimental transmission of c-BSE has been reported in a large number of host species: cattle, pig (transmission by the intracerebral route but not by the oral route), sheep, goats, cervids, various rodent species, mink and primates (Dagleish et al., 2008; Hedman et al., 2018Houston and Andreoletti, 2019). These observations indicate the high capacity of c-BSE to cross the species barrier that naturally limits the capacity of TSE to propagate between species.

Exposure of fish (Sparus aurata, guilt head bream, by the oral route) or chicken (by the intracerebral route) to the c-BSE agent failed to cause transmission of the disease or the accumulation of detectable levels of PrPSc or prion infectivity (Salta et al., 2009; Moore et al., 2011).

Atypical BSEs

H-BSE- and L-BSE have only been identified in domestic cattle. Both L-BSE and H-BSE are transmissible by the intracerebral route to cattle (Balkema-Buschmann et al., 2011b, Suardi et al., 2012; Konold et al., 2014; Vallino Costassa et al., 2018). Oral transmission of L-BSE to cattle was also demonstrated (Okada et al., 2017a). The abilities of L- and H-BSE to propagate in farmed animal species remains to be established. So far, L-BSE has been successfully transmitted to mice, sheep, bank voles, primates and hamsters by the intracerebral route. H-BSE has not yet proven transmissible to sheep or primates (Comoy et al., 2008; Nicot et al., 2014; Gielbert et al., 2018).

Systems Affected

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nervous system diseases of large ruminants

Distribution

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c-BSE

In the UK, after its identification in 1985, the c-BSE epizootic peaked in 1992 with about 180,000 clinical cases in total (Wells et al., 1987). c-BSE was disseminated to at least 28 countries (including the USA, Canada, Japan and countries in Europe) through the export of infected live animals and/or contaminated MBM and livestock feed. After the UK, the European Union was the second most c-BSE-affected geographical area with a total of 6,193 cases recorded between 1989 and 2016 (European Food Safety Authority, 2019).

The OIE provides the list of BSE cases reported by its member states and an updated map of countries according to their c-BSE risk status.

Atypical BSE cases

L-BSE cases were reported in France, Italy, Germany, Great Britain, Romania and Poland. H-BSE has been reported in France, Great Britain, Germany, the Netherlands, Norway and Sweden. Outside the EU, atypical BSE has also been reported in Japan, the USA, Canada, Brazil and Switzerland (in a zebu). Interestingly, atypical BSE cases were identified in countries where no c-BSE cases have been observed (such as Brazil and Norway) (European Food Safety Authority, 2019). Considering the characteristics of atypical BSEs (low prevalence, cases detected in aged animals by active surveillance), the detection of these conditions in cattle populations remains difficult and the final geographical distribution of these two forms of bovine prion disease remains uncertain.

Distribution Table

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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.

Last updated: 10 Jan 2020
Continent/Country/Region Distribution Last Reported Origin First Reported Invasive Reference Notes

Africa

AlgeriaAbsent, No presence record(s)
AngolaAbsent, No presence record(s)
BotswanaAbsent, No presence record(s)
BurundiAbsent, No presence record(s)
Cabo VerdeAbsent, No presence record(s)
CameroonAbsent, No presence record(s)
Central African RepublicAbsent, No presence record(s)
Congo, Democratic Republic of theAbsent, No presence record(s)
Côte d'IvoireAbsent, No presence record(s)
DjiboutiAbsent, No presence record(s)
EgyptAbsent, No presence record(s)
EritreaAbsent, No presence record(s)
EswatiniAbsent, No presence record(s)
EthiopiaAbsent, No presence record(s)
KenyaAbsent, No presence record(s)
LesothoAbsent, No presence record(s)
LibyaAbsent, No presence record(s)
MadagascarAbsent, No presence record(s)
MalawiAbsent, No presence record(s)
MauritiusAbsent, No presence record(s)
MoroccoAbsent, No presence record(s)
MozambiqueAbsent, No presence record(s)
NamibiaAbsent, No presence record(s)
NigeriaAbsent, No presence record(s)
RéunionAbsent, No presence record(s)
RwandaAbsent, No presence record(s)
São Tomé and PríncipeAbsent, No presence record(s)
SeychellesAbsent, No presence record(s)
South AfricaAbsent, No presence record(s)
SudanAbsent, No presence record(s)
TanzaniaAbsent, No presence record(s)
TunisiaAbsent, No presence record(s)
UgandaAbsent, No presence record(s)
ZambiaAbsent, No presence record(s)
ZimbabweAbsent, No presence record(s)

Asia

ArmeniaAbsent, No presence record(s)
AzerbaijanAbsent, No presence record(s)
BahrainAbsent, No presence record(s)
BangladeshAbsent, No presence record(s)
BhutanAbsent, No presence record(s)
BruneiAbsent, No presence record(s)
ChinaAbsent, No presence record(s)
GeorgiaAbsent, No presence record(s)
Hong KongAbsent, No presence record(s)
IndiaAbsent, No presence record(s)
IndonesiaAbsent, No presence record(s)
IranAbsent, No presence record(s)
IraqAbsent, No presence record(s)
IsraelAbsent, No presence record(s)
JapanAbsent, No presence record(s)
JordanAbsent, No presence record(s)
KazakhstanAbsent, No presence record(s)
KuwaitAbsent, No presence record(s)
KyrgyzstanAbsent, No presence record(s)
LaosAbsent, No presence record(s)
LebanonAbsent, No presence record(s)
MalaysiaAbsent, No presence record(s)
-Peninsular MalaysiaAbsent, No presence record(s)
-SabahAbsent, No presence record(s)
-SarawakAbsent, No presence record(s)
MongoliaAbsent, No presence record(s)
MyanmarAbsent, No presence record(s)
North KoreaAbsent, No presence record(s)
PakistanAbsent, No presence record(s)
PhilippinesAbsent, No presence record(s)
SingaporeAbsent, No presence record(s)
South KoreaAbsent, No presence record(s)
Sri LankaAbsent, No presence record(s)
SyriaAbsent, No presence record(s)
TaiwanAbsent, No presence record(s)
TajikistanAbsent, No presence record(s)
TurkeyAbsent, No presence record(s)
TurkmenistanAbsent, No presence record(s)
UzbekistanAbsent, No presence record(s)
VietnamAbsent, No presence record(s)

Europe

AndorraAbsent, No presence record(s)
AustriaAbsent, No presence record(s)
BelarusAbsent, No presence record(s)
BelgiumAbsent, No presence record(s)2006Last reported: 200610
Bosnia and HerzegovinaAbsent, No presence record(s)
BulgariaAbsent, No presence record(s)
CroatiaAbsent, No presence record(s)
CyprusAbsent, No presence record(s)
CzechiaAbsent, No presence record(s)
DenmarkAbsent, No presence record(s)
EstoniaAbsent, No presence record(s)
FinlandAbsent, No presence record(s)
FrancePresent, Localized
GermanyPresent
GreeceAbsent, No presence record(s)
HungaryAbsent, No presence record(s)
IcelandAbsent, No presence record(s)
IrelandPresent
ItalyPresent, Localized
LatviaAbsent, No presence record(s)
LiechtensteinAbsent, No presence record(s)
LithuaniaAbsent, No presence record(s)
LuxembourgAbsent, No presence record(s)
MaltaAbsent, No presence record(s)
MoldovaAbsent, No presence record(s)
MontenegroAbsent, No presence record(s)
NetherlandsAbsent, No presence record(s)
North MacedoniaAbsent, No presence record(s)
NorwayAbsent, No presence record(s)
PolandPresent
PortugalPresent
RomaniaAbsent, No presence record(s)
RussiaAbsent, No presence record(s)
SerbiaAbsent, No presence record(s)
Serbia and MontenegroAbsent, No presence record(s)
SlovakiaAbsent, No presence record(s)
SloveniaAbsent, No presence record(s)
SpainPresent, Localized
SwedenAbsent, No presence record(s)
SwitzerlandAbsent, No presence record(s)
UkraineAbsent, No presence record(s)
United KingdomPresent
-Northern IrelandPresent

North America

BarbadosAbsent, No presence record(s)
BelizeAbsent, No presence record(s)
BermudaAbsent, No presence record(s)
British Virgin IslandsAbsent, No presence record(s)
CanadaPresent, Localized
Cayman IslandsAbsent, No presence record(s)
Costa RicaAbsent, No presence record(s)
CubaAbsent, No presence record(s)
CuraçaoAbsent, No presence record(s)
DominicaAbsent, No presence record(s)
Dominican RepublicAbsent, No presence record(s)
El SalvadorAbsent, No presence record(s)
GreenlandAbsent, No presence record(s)
GuatemalaAbsent, No presence record(s)
HaitiAbsent, No presence record(s)
HondurasAbsent, No presence record(s)
JamaicaAbsent, No presence record(s)
MartiniqueAbsent, No presence record(s)
MexicoAbsent, No presence record(s)
NicaraguaAbsent, No presence record(s)
PanamaAbsent, No presence record(s)
Saint Kitts and NevisAbsent, No presence record(s)
Saint Vincent and the GrenadinesAbsent, No presence record(s)
Trinidad and TobagoAbsent, No presence record(s)
United StatesAbsent, No presence record(s)2006Last reported: 200603

Oceania

AustraliaAbsent, No presence record(s)
French PolynesiaAbsent, No presence record(s)
New CaledoniaAbsent, No presence record(s)
New ZealandAbsent, No presence record(s)
SamoaAbsent, No presence record(s)
VanuatuAbsent, No presence record(s)

South America

ArgentinaAbsent, No presence record(s)
BoliviaAbsent, No presence record(s)
BrazilAbsent, No presence record(s)
ChileAbsent, No presence record(s)
ColombiaAbsent, No presence record(s)
EcuadorAbsent, No presence record(s)
French GuianaAbsent, No presence record(s)
GuyanaAbsent, No presence record(s)
ParaguayAbsent, No presence record(s)
PeruAbsent, No presence record(s)
UruguayAbsent, No presence record(s)
VenezuelaAbsent, No presence record(s)

Pathology

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Post-mortem findings

c-BSE affected cattle may show loss of condition and reduced body weight.

Histopathology

In BSEs affected animals, histopathological changes are confined to the central nervous system (CNS).

c-BSE

Histological changes in c-BSE affected cattle consist of bilaterally symmetrical vacuolation of the grey matter neuropil in the brain stem. The 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. 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, in the thalamus and in the septal area. The neuropil vacuolation of the target nuclei is considered to be pathognomonic for c-BSE. Astrocytosis and microglial activation are also commonly observed. In about 5% of c-BSE cases, cerebral amyloidosis has been observed (Wells et al., 1991).

Atypical BSE

In natural L-type BSE cases (asymptomatic animals identified by a PrPSc detection screening test), spongiosis is not consistently found in the brainstem (obex, or more rostral areas). The frontal, parietal and occipital cortices are apparently spared, and vacuolation is absent in the olfactory bulb, piriform cortex and hippocampus (Casalone et al., 2004).

In experimental L-type BSE cases (clinical stage), the central grey matter (periaqueductal area) and the colliculus are more severely affected by vacuolar changes. These changes may also be seen in the amygdalae, the hippocampal area and in the dorsal horns of the spinal cord (Lombardi et al., 2008).

In experimental H-BSE cases, vacuolar changes can generally be observed in all areas of the brain. Severe vacuolation is found in the thalamic nuclei and neuropil of the central grey matter of the midbrain. Milder vacuolar changes are observed in the caudal cerebral and cerebellar cortex (Balkema-Buschmann et al., 2011b; Okada et al., 2011a; Okada et al., 2011b).

Diagnosis

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Clinical Diagnosis

c-BSE

Under natural conditions, clinical c-BSE cases have been observed in animals aged between 20 months and 22 years old. In the UK, during the early phase of the c-BSE epizootic (1986 to 1996) most cases occurred in cattle aged between 3 and 5 years old but over the following 15 years, the average age of cattle with confirmed signs of disease has gradually increased to over 12 years (European Food Safety Authority, 2019). This evolution was likely a consequence of a decline in the level of exposure of cattle to the c-BSE agent. End-point oral titration in cattle with decreasing amounts of c-BSE-affected cattle brain homogenate confirmed the progressive increase of the incubation period. In cattle that received very low amounts of infectious material (1 mg of brain equivalent material), disease was observed in some animals after more than 75 months of incubation (Arnold et al., 2009).

In natural c-BSE cases, early clinical signs include changes in anxiety/aggressiveness, and discrete gait/locomotion disturbance. As the disease progresses, the animals display increasing hyperaesthesia (to light, sound and touch), and stimulus-induced myoclonic jerks (to touch and sound), ataxia and loss of weight. The duration of the clinical phase can range from a few weeks to over 6 months (Konold et al., 2004). A video illustrating symptoms that can be found in c-BSE affected cattle can be found on the website of the APHA, Weybridge, UK, the former European TSE Reference Laboratory (https://science.vla.gov.uk/tseglobalnet/training.html)

Atypical-BSEs

To date, no natural cases of H- or L-type BSE have been identified on the basis of their clinical signs. The available clinical data for these types of BSE are all derived from experimental transmission in cattle inoculated by the intracerebral route. These data might inaccurately reflect the course/symptoms of natural disease.

In experimental L-BSE cattle inoculated by the intracerebral route, early clinical signs involved muscular fasciculation (of the hind limbs), dullness and postural changes (such as low head carriage and mild kyphosis). As the disease progressed, muscle atrophy starting in the gluteal area and progressing to the paravertebral region became apparent. Hyper-reactivity to facial touch was also commonly observed. Progressive ataxia associated with difficulties in rising appeared as the disease progressed. The duration of the clinical phase in L-BSE challenged cattle was on average 2 months (10 and 105 days, n=2) (Konold et al., 2012).

In experimental H-BSE cases, symptoms and clinical phase duration (on average 2 months) were very similar to those observed in L-BSE experimental cases. The first clinical sign was a loss of weight that led to a deteriorating body condition. Animals displayed dullness and non-physiologically low head positions. H-BSE inoculated cattle showed hyper-responsiveness to acoustic and visual stimuli, and to tactile stimuli on their heads. As the disease progressed, the animals developed a progressive hind-limb ataxia that led rapidly to decumbency (downer-cow syndrome) (Konold et al., 2012).

Although some differences might be observed between the clinical signs displayed in experimental cases of atypical BSE and classical BSE in cattle, it is not possible to differentiate between the three forms of BSE using clinical presentation alone.

Differential Diagnosis

Non-infectious differential diagnosis should include the nervous form of ketosis, lead toxicity, CNS tumours and hypomagnesaemia. Infectious differential diagnoses should include listeriosis, rabies and Aujeszky’s disease.

Laboratory Diagnosis

Currently, there is no method capable of confirming the presence of any type of BSE in live cattle.

All post mortem samples intended to be examined for the presence of TSE shall in general be collected using the methods and guidelines laid down in the latest edition of the Manual for Diagnostic Tests and Vaccines for Terrestrial Animals of the World Organisation for Animal Health (OIE).

Histopathology

Historically, c-BSE confirmation in clinically suspect animals (identified by passive surveillance) has relied on the identification of vacuolar changes in the brain by histopathologic examination of formalin-fixed/paraffin embedded brain sections (Wells et al., 1989). The discovery of the central role of PrPSc in prion diseases followed by the development of antibodies against the prion protein that allowed immuno-detection of the Proteinase K (PK)-resistant moiety of the PrPSc opened the way for the development of various methodologies for c-BSE diagnosis (Merz et al., 1981; Merz et al., 1983; Somerville et al., 1986; Grassi et al., 2000). Vacuolar changes appear at a very late stage of the incubation period in c-BSE infected cattle. In contrast, PrPSc accumulation can be detected in the brains of c-BSE infected animals several months before clinical onset (Arnold et al., 2009). As a consequence, PrPSc immuno-detection is now the standard approach applied in BSE surveillance and confirmatory testing in suspected animals.

Detection of disease-associated PrP by immunohistochemistry

PrPSc detection in the brain by immunohistochemistry (IHC) is one of the two main confirmatory methods that are used for BSE diagnosis in cattle. IHC is performed on the same material (formalin-fixed paraffin-embedded tissue) that is used for the conventional histopathological examination. The combination of vacuolar changes and PrPSc deposition in certain neuroanatomical areas of the bovine brain provides a high level of reliability for c-BSE diagnosis. When performing IHC for disease-associated PrP detection a pre-treatment of the slides is necessary to reduce/eliminate PrPC and enhance PrPSc immunoreactivity. Numerous PrPSc IHC detection protocols are available in the literature. Their performances can vary significantly according to the protocol for slide pre-treatment and the nature of the anti-PrP antibody. PrPSc detection by IHC can be performed on formalin-fixed autolysed tissues (Monleón et al., 2003). However, when autolysis precludes the recognition of the anatomical structures in the brain, the reliability of the IHC diagnosis can be affected and, in this context, use of the western blot technique is suitable for BSE diagnosis.

Detection of disease-associated PrP by western blot

Western blot (WB) detection of PK-digested disease-associated PrP constitutes the second main reference method for the confirmation of BSE diagnosis. This method is highly specific and reliable. The SAF-immunoblot was the first WB protocol used for c-BSE diagnosis. This protocol requires a large amount of starting material (2-4 g) and is labour/time consuming due to the requirement of precipitation of disease-associated PrP by ultracentrifugation. Modern PrPSc extraction methods require lower amounts of brain material (about 100-fold less) than SAF immunoblots and only 2 hours of benchwork. Detection of PK-resistant PrPSc by WB can now be executed in less than 6 hours. WB can be applied to autolysed tissues without impairing the specificity/sensitivity of PrPSc detection (Hayashi et al., 2004).

The analytical sensitivity of different PK-resistant PrPSc WB detection protocols varies significantly and is highly dependent upon the extraction method used to prepare disease-associated PrP and the particular anti-PrP antibody used (Morel et al., 2004Féraudet et al., 2005). Periodic ring trial testing of a common set of reference samples plays a key role in maintaining the quality and consistency of BSE detection by WB in reference laboratories. WB is the most straightforward approach to discriminate between H-BSE, L-BSE and c-BSE cases. Discrimination is based on distinct N-terminal PK cleavage, antibody binding and glycosylation pattern of PK-resistant PrPSc (Jacobs et al., 2007).

Rapid PrPSc detection assays

The c-BSE epizootic stimulated development of commercial kits for the detection of disease-associated PrP for the diagnosis of c-BSE. These so-called rapid tests were designed with the objective of an accelerated test time (diagnostic results in less than 24h) and large-scale screening of healthy slaughtered and rendered cattle (Grassi et al., 2008). These rapid tests rely on the detection of disease-associated PrP by different immuno-detection methodologies such as WB, ELISA or immuno-chromatographic assays.

The European union established a standard procedure to validate and periodically assess the performances of rapid tests proposed for the detection of BSE. The EU approval process has been accepted as the gold standard by the OIE. However, certain countries, such as the USA, Canada and Japan, have established their own evaluation mechanisms. Since 2001, there has been a continual evolution of the list of cattle TSE rapid tests. At the time of writing, the following assays are approved and marketed for BSE testing in the European Union (European Food Safety Authority, 2019):

  • Prionics-Check Western
  • Bio-Rad TeSeE SAP
  • Prionics-Check LIA
  • IDEXX HerdChek BSE Antigen,
  • IDEXX HerdChek BSE-Scrapie EIA Antigen
  • Prionics-Check PrioSTRIP
  • Roboscreen Beta Prion BSE EIA

The distribution and use of TSE rapid tests are restricted to government-approved laboratories in charge of prion disease surveillance programs. 

List of Symptoms/Signs

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SignLife StagesType
Cardiovascular Signs / Bradycardia, slow heart beat or pulse Sign
Cardiovascular Signs / Tachycardia, rapid pulse, high heart rate Sign
Digestive Signs / Anorexia, loss or decreased appetite, not nursing, off feed Sign
Digestive Signs / Difficulty in prehending or chewing food Sign
Digestive Signs / Excessive salivation, frothing at the mouth, ptyalism Sign
Digestive Signs / Grinding teeth, bruxism, odontoprisis Sign
Digestive Signs / Inability to open (trismus) and / or close jaw, mouth Sign
Digestive Signs / Rumen hypomotility or atony, decreased rate, motility, strength Sign
General Signs / Abnormal proprioceptive positioning, knuckling Sign
General Signs / Ataxia, incoordination, staggering, falling Sign
General Signs / Dysmetria, hypermetria, hypometria Sign
General Signs / Forelimb weakness, paresis, paralysis front leg Sign
General Signs / Generalized lameness or stiffness, limping Sign
General Signs / Generalized weakness, paresis, paralysis Sign
General Signs / Head, face, ears, jaw weakness, droop, paresis, paralysis Sign
General Signs / Inability to stand, downer, prostration Sign
General Signs / Kyphosis, arched back Sign
General Signs / Paraparesis, weakness, paralysis both hind limbs Sign
General Signs / Sudden death, found dead Sign
General Signs / Tetraparesis, weakness, paralysis all four limbs Sign
General Signs / Trembling, shivering, fasciculations, chilling Sign
General Signs / Underweight, poor condition, thin, emaciated, unthriftiness, ill thrift Cattle & Buffaloes|Bull; Cattle & Buffaloes|Cow; Cattle & Buffaloes|Ox; Cattle & Buffaloes|Steer Sign
General Signs / Weight loss Sign
Musculoskeletal Signs / Forelimb spasms, myoclonus Sign
Musculoskeletal Signs / Hindlimb spasms, myoclonus Cattle & Buffaloes|Bull; Cattle & Buffaloes|Cow; Cattle & Buffaloes|Ox; Cattle & Buffaloes|Steer Diagnosis
Nervous Signs / Abnormal behavior, aggression, changing habits Cattle & Buffaloes|Bull; Cattle & Buffaloes|Cow; Cattle & Buffaloes|Ox; Cattle & Buffaloes|Steer Diagnosis
Nervous Signs / Abnormal hindlimb reflexes, increased or decreased Cattle & Buffaloes|Bull; Cattle & Buffaloes|Cow; Cattle & Buffaloes|Ox; Cattle & Buffaloes|Steer Diagnosis
Nervous Signs / Circling Sign
Nervous Signs / Constant or increased vocalization Sign
Nervous Signs / Disoriented, memory loss Sign
Nervous Signs / Excitement, delirium, mania Sign
Nervous Signs / Head pressing Sign
Nervous Signs / Head shaking, headshaking Sign
Nervous Signs / Head tilt Sign
Nervous Signs / Hyperesthesia, irritable, hyperactive Cattle & Buffaloes|Bull; Cattle & Buffaloes|Cow; Cattle & Buffaloes|Ox; Cattle & Buffaloes|Steer Diagnosis
Nervous Signs / Seizures or syncope, convulsions, fits, collapse Sign
Nervous Signs / Tremor Sign
Ophthalmology Signs / Blindness Sign
Ophthalmology Signs / Decreased or absent menace response but not blind Sign
Ophthalmology Signs / Enophthalmos, sunken eyes Sign
Ophthalmology Signs / Exophthalmos, eyes protruding, proptosis Sign
Ophthalmology Signs / Lacrimation, tearing, serous ocular discharge, watery eyes Sign
Ophthalmology Signs / Prolapsed third eyelid, protrusion nictitating membrane Sign
Ophthalmology Signs / Ptosis, lid droop Sign
Reproductive Signs / Agalactia, decreased, absent milk production Cattle & Buffaloes|Cow Sign
Respiratory Signs / Increased respiratory rate, polypnea, tachypnea, hyperpnea Sign
Skin / Integumentary Signs / Pruritus, itching skin Sign
Skin / Integumentary Signs / Rough hair coat, dull, standing on end Sign

Disease Course

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c-BSE

The pathogenesis of c-BSE in cattle has been extensively studied in animals experimentally challenged by the oral route. The attack rate and incubation periods in such animals is dependent on the exposure dose. 100% of the animals that received the equivalent of 100 g of brain material developed clinical disease in 34 to 45 months after inoculation. In contrast, only 1 out of 15 cattle that received 1 mg of the same inoculum developed c-BSE and did so 70 months after inoculation (Wells et al., 2007).

Irrespective of the challenge dose, accumulation of PrPSc in experimentally inoculated cattle occurred in the same tissues to that seen in natural cases of c-BSE. Following oral inoculation, PrPSc accumulation was detected at 4-6 months post-inoculation (mpi) in gut-associated lymphoid tissue (GALT) at the ileocecal junction and the jejunum. A few months later, PrPSc became detectable in caecal and duodenal Peyer’s patches (Buschmann et al., 2006; Hoffmann et al., 2007; Balkema-Buschmann et al., 2011a; Hoffmann et al., 2011). It is commonly accepted that in GALT, PrPSc can come in contact with the autonomic nervous fibres of the enteric nervous system (ENS) where it progressively accumulates. From there, PrPSc spreads to the coeliac-mesenteric nervous ganglions, before reaching the spinal cord (sympathetic nervous system) and the brainstem (parasympathetic nervous system) where it progressively accumulates. At the late stage of clinical c-BSE disease, PrPSc can centrifugally propagate through peripheral nerves to various muscles such as the masseter, intercostal muscles, semitendinosus, where it can be found at very low levels (Balkema-Buschmann et al., 2011b; Hoffmann et al., 2011).

Strikingly, while c-BSE prions have the ability to replicate in GALT, no consistent accumulation of PrPSc is observed in other lymphoid organs of TSE-infected cattle. Extensive investigations have failed to identify the c-BSE agent in the spleen, the thymus (cervical) and in most lymph nodes of TSE-infected cattle. However, the presence of the c-BSE agent was occasionally identified in the lingual tonsils of orally challenged cattle at the pre-clinical stage of the disease (20 to 33 mpi) and in the nictitating membrane in natural cases of c-BSE (Wells et al., 2005). Similarly, very low levels of the c-BSE agent were identified in the mesenteric lymph node (ileal and jejunal) collected in one orally challenged cow (36 mpi) (Franz et al., 2012).

Atypical BSEs

The origin of H-BSE and L-BSE is unknown. The low prevalence and the advanced age of cattle with these prion diseases has been suggested to be evidence for a spontaneous origin of atypical BSE, although an infectious aetiology cannot be definitively ruled out. No clinical case of cattle with natural atypical BSE has been identified so far and only a very limited panel of tissues are available from L-BSE and H-BSE cases identified through active surveillance (asymptomatic cases). Therefore, experimental transmission studies in cattle are the main source of information concerning the pathogenesis of atypical BSE agents.

In intracerebrally (IC) challenged cattle, PrPSc accumulation was identified in the CNS (in the brain, spinal cord and retina), the peripheral nervous system (autonomic and motor) and at lower levels in the skeletal muscle of affected animals. No consistent accumulation of PrPSc was reported in the lymphoid organs or in the intestines (Balkema-Buschmann et al., 2011b; Okada et al., 2011a; Konold et al., 2012; Suardi et al., 2012).

Following oral challenge of cattle with a range of doses of L-BSE infected cattle brain homogenate, only one animal that received the highest dose of 50 g developed neurological clinical signs and did so after an incubation time of 88 months. This animal showed a similar tissue distribution of PrPSc in the central and peripheral nervous system to that observed in IC challenged animals, although there were subtle differences in the distribution of PrPSc within the brain regions (Okada et al., 2017b). Tissues collected in some asymptomatic L-BSE cases in Italy confirmed the apparent restriction of the prion to the central and peripheral nervous system (Suardi et al., 2012).

Epidemiology

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c-BSE

While the UK c-BSE epizootic peaked in 1992, the 1988 ban on the inclusion of MBM in ruminant feed material was instrumental in controlling transmission of the disease in cattle. In EU countries such as Portugal, Ireland, Spain and France, several hundreds of c-BSE cases were observed. However, in most other countries the number of c-BSE cases that were identified remained insignificant when compared to the UK. These differences in the epidemiological profile of the c-BSE cases between countries was likely due to the consequence of the early implementation of preventive measures, such as the limitation of the use of PAP, before the establishment of sustainable re-circulation of c-BSE agent through the animal feed chain. Interestingly, in countries where autochthonous c-BSE cases have been detected and in which an incomplete feed ban was implemented, such as Canada before 2007, new c-BSE cases have continued to occur. The incidence of c-BSE has now declined to very low incidence levels, with no cases or a single-digit number of cases reported each year since 2011. No case of c-BSE has been found in the EU since 2018 with the last reported case identified in the UK.

While the over-whelming weight of evidence points at the role of the PAP in the spread and maintenance of c-BSE in cattle populations, the identification of c-BSE cases born after the reinforced feed ban implemented in 2001 in the EU (a total of 60 cases) raise new questions about the origin of c-BSE cases in cattle. Their occurrence also raises some concerns about the possible re-emergence of c-BSE in a scenario where the restriction on the use of PAP in the animal feed chain might be relaxed (EFSA Panel on Biological Hazards (BIOHAZ) et al., 2017).

Atypical BSEs

The L-BSE and H-BSE cases reported so far were mainly detected in asymptomatic cattle 8 years of age or older, in contrast to c-BSE where the majority of cases were 4-6 years old. Between 2001 and 2019, a total of 69 cases of L-BSE and 64 cases of H-BSE were reported worldwide. Epidemiological studies in the French cattle population indicated that the apparent prevalence of atypical BSE cases is very low (1.9 cases of H-BSE and 1.7 cases of L-BSE per million tested cattle over 8 years old) (Biacabe et al., 2008). The origin of H-BSE and L-BSE cases is unknown. It has been argued that the low prevalence and the advanced age of positive animals provide evidence for a spontaneous origin of atypical BSE although an infectious aetiology remains a possibility.

Species barrier

In the early 1960s seminal TSE infectivity experiments led to the recognition that passage of prions from one species to another are limited by a transmission barrier, which is also referred to as the species barrier. Transmission barriers often result in a lack of propagation of prions in the new host species. However, in some cases, inoculation of a prion into a new host species produces a low or inconsistent disease incidence characterised by prolonged incubation periods or subclinical infection. After one or more sub-passage of prion infectivity in the same host species the clinical incidence rate increases and incubation periods become shorter, and are ultimately very predictable for a defined dose of inoculum and specific route of infection (Béringue et al., 2008b). The molecular mechanisms that determine the permeability of transmission barriers by prions are still not fully understood. However, there is now a wealth of evidence that the important factors which influence cross-species transmission include the nature of the prion strain, the compatibility between the primary amino acid sequence of donor and host PrP, and the dose/exposure route of inoculum in the recipient host. Despite this progress in understanding the basis of the transmission barrier, it still remains impossible to predict a priori the capacity of a prion to propagate in a new host species.

Impact: Economic

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The c-BSE epidemic was probably the animal disease with the most important economic and social consequences during the twentieth century. The most obvious impact of the c-BSE epizootic was the massive numbers of affected cattle, and the fear among consumers over bovine meat consumption. In Europe, an audit of the 1996-2000 crisis caused by the spread of BSE in cattle and the identification of the link between c-BSE and vCJD in humans was estimated to have a direct cost of 4.5 billion Euros. In Canada, the c-BSE outbreak that occurred during the period 2003-2005 resulted in trade disruption with major economic partners. The direct economic cost for the cattle industry exceeded 6 billion Canadian dollars. Despite financial compensations and support, the long-term impact of the c-BSE epizootic on the cattle farming system and beef industry in the UK, and mainland Europe has been significant. The indirect costs associated with c-BSE control measures implemented across the world are extremely difficult to estimate, such as the disposal of hazardous materials (SRM), lost value of products to the rendering industry, and costs of substitutions to MBM within the feed market. c-BSE also had indirect and durable consequences on industries that might at first glance seem unrelated to the cattle industry, such as the cosmetics, or the pharmaceutical industry. Finally, beyond the economic consequences, the BSE epizootic triggered a major and durable confidence crisis in the food industry and in the capacity of the governmental and political authorities to protect public health.

Zoonoses and Food Safety

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Zoonotic properties of BSE agents

c-BSE

The occurrence of a large epizootic of a novel prion disease in UK cattle rapidly raised concerns about the risk that c-BSE might represent for humans. In 1990, the UK Department of Health set up the National CJD Surveillance Unit with a specific remit to monitor the incidence and study the epidemiology of human prion diseases.

In 1995, two cases of CJD were reported in teenagers in the UK, which was considered to be an unusually early onset for this neurodegenerative disease (Bateman et al., 1995; Britton et al., 1995). These patients also displayed atypical clinical symptoms and distinctly different neuropathological changes compared to known human prion diseases. The emergence of a new form of human prion disease, which was named variant CJD (vCJD), naturally pointed to c-BSE as the probable causative agent (Will et al., 1996).

Definitive evidence for the link between BSE and vCJD was provided by transmission studies in inbred mouse lines (Bruce et al., 1997). Mice injected with vCJD infected human brain material exhibited phenotypes (incubation periods and lesion profile) that were indistinguishable from those obtained following transmission of c-BSE infected cattle brain. This indicated that both diseases were caused by the same prion agent. Similarly, c-BSE isolates from individual affected cattle in different farms and locations displayed identical phenotypes following strain typing in mice, which confirmed that c-BSE was caused by a single prion strain (Bruce et al., 1997; Castilla et al., 2003).

To date, 230 cases of vCJD have been identified worldwide and of these 178 cases have occurred in UK residents, and a number of other cases have occurred in individuals with a history of residence in the UK during the high-risk period 1980-1996. All definite clinical cases of vCJD that have undergone PRNP genetic analysis are homozygous for methionine at codon 129 (129MM), apart from the latest UK case, who was heterozygous for methionine and valine (129MV) (Mok et al., 2017).

After a peak in 2001-2002, the number of clinical vCJD cases recorded in the UK has declined. While the limited number of cases is consistent with inefficient transmission of the c-BSE agent to humans, many uncertainties remain concerning the number of individuals incubating vCJD sub-clinically in the exposed population (Diack et al., 2014). To address this issue, several studies have been performed to estimate the prevalence of vCJD infection in the UK population. Since disease-associated PrP deposits can be detected in the lymphoid organs of vCJD patients during preclinical and clinical phases of the disease (Head et al., 2004; Peden et al., 2004), prevalence studies were based on anonymized surveys of more than 45,000 appendix and tonsil samples removed and archived following routine surgery. The targeted patients belonged to age cohorts most likely to have experienced dietary exposure to c-BSE and the lymphoid tissues were tested for the presence of disease-associated PrP by IHC. In two separate surveys, a total of 19 appendix samples were positive for disease-associated PrP accumulation (Hilton et al., 2004; Gill et al., 2013). Strikingly, positive samples were found to be amino acid codon 129MM, MV or VV, suggesting that the BSE agent may infect individuals of all human PRNP genotypes (Gill et al., 2013). These findings led to an estimated worst-case scenario of up to 1 in 2000 (95% confidence interval 1/3500-1/1250) of the UK population sub-clinically infected with vCJD (Gill et al., 2013). Whether this represents the true prevalence of vCJD infection in the UK is still a matter of debate, particularly since the prevalence estimates are not consistent with the small observed numbers of clinical vCJD cases. It is reasonable to assume that the populations of countries and regions that did not experience autochthonous c-BSE cases are likely to have experienced less exposure to the c-BSE agent. However, international trade of food commodities could have resulted in exposure of people in these areas to the c-BSE agent and it remains to be established what the prevalence is of vCJD infection in countries other than the UK.

Atypical BSEs

Due to the low apparent prevalence of atypical BSE and the design of cattle TSE surveillance programs it is unlikely that atypical BSE cases are efficiently detected. Therefore, it should be assumed that small numbers of cattle with atypical BSE do enter the human food chain. The many uncertainties related to the distribution of atypical BSE cases in cattle herds mean that epidemiological approaches are unlikely to be informative in their assessment of the zoonotic potential of H- and L-type BSE prions.

Intracerebral injection of L-BSE isolates from European and Japanese cattle into cynomolgus macaques resulted in disease transmission with shorter survival times than in c-BSE infected macaques (23-25 months for L-BSE versus 38-40 months C-BSE) (Comoy et al., 2008; Ono et al., 2011). In contrast, no positive transmission was reported in macaques that were inoculated with H-BSE (Comoy et al., 2015). Inoculation of L-BSE, H-BSE and c-BSE isolates into transgenic mice over-expressing human PrP (TgHu mice) demonstrated that L-BSE transmitted more efficiently than c-BSE on primary transmission, with 100% attack rates and no shortening of incubation periods on subsequent sub-passage. In contrast, H-BSE isolates failed to transmit in the same mouse model (Béringue et al., 2008a). Another study using a different human 129M PrP transgenic mouse model also showed efficient primary transmission of L-BSE (Kong et al., 2008). Biological strain typing of L-BSE and a panel of sporadic CJD (sCJD) subtypes in human PrP transgenic mice failed to find any evidence that L-BSE causes a recognised form of sCJD (Jaumain et al., 2016).

Collectively, these results support the view that the H-BSE agent has a low zoonotic potential. In contrast, L-BSE displays an equal or greater virulence than c-BSE in primate and TgHu mouse models, and may therefore pose a higher risk of zoonotic infection.

Food Safety

The SRM measures that are currently in place ensure a very high degree of safety towards c-BSE exposure for food consumers. Data related to H- and L-BSE remain incomplete. However, available information supports the view that the SRM measures as currently applied in the EU strongly mitigate the risk of exposure by consumers to atypical BSE agents.

Professional and occupational risks

Laboratory workers handling the tissues of BSE-suspect cattle should wear appropriate protective clothing and observe a strict code of practice to avoid exposure to the prion agent. Laboratory precautions should primarily aim to avoid accidental iatrogenic, ocular or oronasal exposure since BSE is not contagious. Work should be performed in adequate biocontainment (L2/L3) facilities and the laboratory must comply with national biocontainment and biosafety regulations to protect staff from exposure to the pathogen. Recommended physical inactivation is by porous load autoclaving at 134°C-138°C for 18 minutes at 2.2 bar. However, total inactivation may not be achieved under certain conditions, such as when the test material is in the form of a macerate, of high titre or when the agent is protected within dried organic matter. Disinfection of potential fomites is carried out using sodium hypochlorite containing 2% available chlorine, or 2 N sodium hydroxide, applied for more than 1 hour at 20°C for surfaces, or overnight for equipment.

Disease Treatment

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There is currently no efficient treatment for TSEs in cattle.

Prevention and Control

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Following its appearance in the UK, c-BSE was disseminated to numerous countries by the import of live cattle and/or contaminated animal products and feed material. In reaction, the OIE produced recommendations aimed at preventing the entry of c-BSE in disease-free countries and assisted to progressively control and eradicate the disease in countries where c-BSE was present. Over the last 30 years these recommendations have evolved to adapt to the changes in our understanding and knowledge of bovine TSE diseases. Numerous countries, in particular those where c-BSE epizootics had severe adverse consequences, including EU nations and Canada, have implemented surveillance, control and eradication measures that exceed the OIE recommendations. As occurs with other bovine diseases, individual cattle identification enables effective surveillance and tracing of suspected animals and plays a central role in the surveillance, the control and the eradication of c-BSE.

Prevention

In 2000 the OIE provided a methodology to assess the risk of c-BSE presence and circulation in countries/geographical areas (GBR: geographical BSE risk). The GBR methodology relies on the assessment of:

  • The risk of entry of c-BSE into a territory by the import of ruminants or animal products
  • The risk of cattle exposure to the c-BSE agent including rendering practices, production and use of processed animal proteins
  • The existence and level of BSE surveillance in cattle populations
  • Transparent and reliable reports of data on the BSE epidemiological situation

Based on these criteria the BSE risk in countries/geographical areas is regularly updated and classified as:

  • Negligible c-BSE risk countries
  • Controlled c-BSE risk countries
  • Countries without an OIE official c-BSE status

The OIE risk status only addresses the risk of c-BSE as it is considered that atypical BSE corresponds to a spontaneous disease in cattle.

Negligible BSE risk countries are defined as countries:

  • That have had a negligible risk with regards to c-BSE for at least 7 years
  • Where an adequate surveillance program has been implemented and is maintained for at least 7 years
  • Where no autochthonous c-BSE case has been observed in animals born less than 11 years ago
  • Where a documented ruminant-to-ruminant feed ban has been in place for at least 8 years

The OIE BSE status provides a basis for national import/export regulations applicable to live cattle, certain commodities and animal products between areas with different BSE status (OIE terrestrial animal health code Article 11.4.6 to 11.4.20)

Monitoring and surveillance

For more than 20 years passive surveillance, which refers to the clinical identification and testing of c-BSE suspect cases, has remained the only available approach for the monitoring and surveillance of the TSE in ruminants. In the early 1990s passive surveillance allowed the identification of c-BSE cases outside the UK in countries such as France, Ireland and Portugal. However, the characterization of c-BSE pathogenesis in cattle rapidly led to the consensus that passive surveillance has a limited value for the detection and epidemiological monitoring of the disease. At the end of the 1990s the development of rapid tests (immuno-detection of diseases-associated PrP in the brainstem), which allow an earlier and more sensitive detection than passive surveillance, provided a paradigm shift in BSE diagnosis. From 1998 the European Commission instigated a harmonized BSE surveillance program within its member states and from 2000 rapid tests have been used to implement large scale and systematic BSE surveillance programs in cattle populations. Since the start of these programmes, approximately 100 million animals have been tested by rapid tests in the framework of the EU TSE surveillance programs.

Currently, the BSE active surveillance program relies on the screening of targeted categories of cattle using rapid tests in approved laboratories. In the case of an initial positive reaction, the sample is submitted for confirmatory testing at a reference laboratory. When a positive BSE diagnosis is established, a discriminatory assay (generally WB) is performed to identify whether the bovine TSE is c-BSE, H-BSE or L-BSE (European Food Safety Authority, 2019).

The EU TSE surveillance follows EU Regulation (EC) 999/2001. This regulation was amended several times and from 2009, the age categories of the cattle to be tested were progressively narrowed as shown by the surveillance by period (year and age of cattle) in table 1 below. This evolution of the surveillance by period reflected the c-BSE epidemiological situation in the EU member states.

Period

Healthy slaughter

Fallen Stock
Emergency slaughter

2001 Jan–Jun

> 30 months*

> 30 months

2001 Jan–Jun

> 30 months

> 24 months

2002–2008

> 30 months

> 24 months

2009–2010

> 48 months

> 48 months

2011–2012

> 72 months

> 48 months

2013–2020

-

> 48 months

Table 1: Overview of the evolution of EU legislation on BSE surveillance by period (year and age of cattle*).

The implementation of a TSE surveillance program and transparent data reporting is a key component of the OIE geographical BSE risk assessment. The OIE provides a methodology to design TSE surveillance programs in cattle. The methodology considers the size and age distribution of the adult cattle population in countries and proposes one of two types of surveillance programmes according to an estimated prevalence of the disease to be detected.

  • Type A surveillance was designed to allow the detection of BSE with an estimated prevalence of at least one case per 100,000 in the adult cattle population (confidence level of 95%).
  • Type B surveillance was designed to allow the detection of BSE with an estimated prevalence of at least one case per 50,000 in the adult cattle population (confidence level of 95%).

Type B surveillance may be carried out in countries with negligible BSE risk status. It may also be carried out by countries with controlled BSE risk status following the achievement of the target prevalence using Type A surveillance.

While the OIE methodology remains the international standard for designing BSE surveillance programs its current validity is debated. Indeed, the model that was used to design the methodology relied largely on data derived from the c-BSE epizootic (i.e. the age of cattle detected as BSE-positive in the brain) observed in the 1980s and 1990s in the UK. These data no longer reflect the epidemiological situation of c-BSE as may exist in cattle populations.

Control

Following the emergence of the c-BSE epizootic in the UK, processed animal proteins produced from ruminant carcasses were rapidly identified as the main vector responsible for the spread of the disease in cattle populations. In this context, preventing the dietary exposure of cattle to ruminant tissues known to be susceptible to contain significant amounts of c-BSE infectivity appeared as an effective means to:

  • prevent occurrence of new infection in cattle
  • reduce the risk of c-BSE transmission to other species (farmed animals and human)

In order to achieve these goals, two specific and complementary types of measure were implemented, namely specified risk materials measures and the mammalian meat and bone meal (MBM) ban.

Specified Risk Materials measures

Specified risk materials (SRMs) refers to cattle tissues that are known to be susceptible to contain significant amounts of c-BSE prion infectivity. Elimination of the SRMs allows the exclusion of over 99.9% of c-BSE prion infectivity associated with infected cattle that are likely to enter the food chain. The OIE provides a list of SRMs that is considered to be the minimum standard of cattle tissue to be excluded. It is possible for countries to adopt more stringent regulations depending upon a number of national and international factors. The OIE has more flexible standards in terms of SRMs than those implemented in controlled BSE risk countries. Table 2 below provides an overview of the SRM in various geographical areas and guidelines from the World Organisation for Animal Health (OIE).

Tissue

Canada

USA

Japan

OIE

European Union

Tonsils

≥ 30 months

All ages

Distal ileum

All ages

-

Last four metres of the small intestine, the caecum, mesentery including fat

-

All ages

Brain, eyes, skull and spinal cord

≥ 30 months

>30 months

>12 months

Vertebral column including the DRG

≥ 30 months

>30 months

Table 2. EU 2015/728 amended 999/2001 from May 2015 which excluded the intestines from duodenum to rectum in cattle of all ages.

Apart from in the USA, SRMs are banned from both human food and animal feed chains. In the USA, while the full list of SRMs is banned from human food, only a subset of these tissues is banned from animal feed (i.e. the brain and spinal cord from cattle 30 months of age and older, as well as the entire carcass of BSE-positive cattle).

Currently available data suggest that SRM measures designed to deal with the c-BSE exposure risk are probably also efficient for mitigating the exposure risk to the L-BSE and H-BSE agents. However, the uncertainties that still exist about the distribution of infectivity in the tissues of atypical BSE cases preclude any quantitative estimate of the SRM measures.

Mammalian meat and bone meal (MBM) ban

In the UK a ban on the use of processed ruminant proteins to feed ruminants was introduced as early as 1988. In 1994 this feed ban was reinforced by the exclusion of all mammalian proteins (with specific exceptions) from ruminant feed material. In 1996 mammalian meat and bone meal (mammalian MBM) was banned from the feed for any farmed livestock (including fish and horses).

In 1994 the European Union introduced a ban of mammalian processed animal proteins (PAP) to cattle, sheep and goats. In January 2001 this feed ban was expanded to prohibit the use of all PAPs being fed to any farmed animal (with certain limited exceptions). This total feed ban was implemented to ensure that there was no cross-contamination between feed containing PAP intended for species other than ruminants and feed intended for ruminants. Only certain animal proteins considered to be safe, such as fishmeal, could be used for feed purposes (under very strict conditions). Table 3 below summarises the feed ban rules in the EU as applicable from 1 July 2017.

Farmed animals other than fur animals

Pets and animals

Ruminants

Non-ruminants except fish

Fish

Ruminant PAP, including ruminant blood meal

NA

NA

NA

A

Non-ruminant PAP, including non-ruminant blood meal and insect PAP, but excluding fishmeal

NA

NA

A

A

Blood products from ruminants

NA

NA

NA

A

Gelatine and collagen from ruminants

NA

NA

NA

A

Fishmeal

NA

NA

NA

A

Blood products from non-ruminants

NA

NA

NA

A

Di and tricalcium phosphate of animal origin

NA

A

A

A

Hydrolysed proteins from non-ruminants or from ruminant hides and skins

A

A

A

A

Gelatine and collagen from non-ruminants

A

A

A

A

Egg, egg products, milk, milk products, colostrum

A

A

A

A

Animal proteins other than the above-mentioned ones

NA

A

A

A

NA: Not authorized – A: Authorized under conditions

Table 3: Current measures related to the use of processed animal proteins in the European Union.

The feed ban measures that are in place in the EU exceed the OIE recommendations and those currently in place in most of the countries that experienced autochthonous c-BSE cases, such as the USA and Canada where convergent feed ban measures are now implemented.

The current OIE recommendations on feed ban includes:

  • The removal of SRMs from the human food and the animal feed chains during slaughter and the processing of animal carcasses
  • The prohibition of the inclusion of SRMs in animal feeds
  • A ban on the use of PAP in ruminant feed (ruminant-to-ruminant feed ban, further reinforced by a mammalian-to-ruminant feed ban).

In 1997 Canada banned most mammalian proteins from ruminant feed. There were certain exceptions to this ban allowing porcine and equine meal to continue to be used in ruminant feed. In 2003 Canada enforced new measures that required the removal of the following cattle SRMs from the animal feed supply:

  • Skull and brain, the trigeminal ganglia, eyes, tonsils, spinal cord and dorsal root ganglia of cattle over thirty months of age
  • The distal ileum of cattle of all ages

Eradication

Historically when a c-BSE case was detected in the EU all the animals that belonged to the herd of origin of the index case were systematically destroyed. Numerous studies supported the contention that in the vast majority of the incidences, there were no other c-BSE cases present in the herd of origin, or in the same birth cohort as the index case. Current EU regulatory eradication measures consist of the culling, testing and elimination of:

  • birth cohorts (bovine animals born within the 12 months preceding or following the date of birth of the affected bovine animal in the same herd)
  • rearing cohorts (bovine animals that at any time during the first year of their lives were reared together with the affected bovine animal during the first year of its life)
  • the progeny of a diseased female animal born within a period of 2 years prior to or after the clinical onset of the disease

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Distribution References

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

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

OIE, 2004. Bovine Spongiform Encephalopathy (BSE)., Paris, France: World Organisation for Animal Health. https://www.oie.int/en/animal-health-in-the-world/animal-diseases/Bovine-spongiform-encephalopathy/

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

Links to Websites

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OIE Manual of Diagnostic Tests and Vaccines for Terrestrial Animalshttps://www.oie.int/standard-setting/terrestrial-manual/access-online/

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11/03/2021 Updated by:

Olivier Andréoletti, ENVT, France

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