Definition
Bovine spongiform encephalopathy (BSE), widely known as "mad
cow disease," is a chronic, afebrile, degenerative disease affecting the central
nervous system (CNS) of cattle.
Bovine spongiform encephalopathy belongs to the family of diseases
known as the transmissible spongiform encephalopathies (TSE's). These diseases are caused
by a transmissible agent that is yet to be fully characterized. They share the following
common characteristics:
- a prolonged incubation period of months or years;
- a progressive debilitating neurological illness that is always
fatal;
- when examined by electron microscopy, detergent-treated
extracts of brain tissue from animals or humans affected by these diseases reveal the
presence of scrapie-associated fibrils (SAF's);
- pathological changes appear to be confined to the CNS and
include vacuolation and astrocytosis;
- the transmissible agent elicits no detectable specific immune
response in the host.
Specific types of TSE's include scrapie, which affects sheep and
goats; transmissible mink encephalopathy; feline spongiform encephalopathy; chronic
wasting disease of deer and elk; and five rare diseases in humans: kuru, Creutzfeldt-Jakob
disease (CJD), Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia (FFI),
and new variant Creutzfeldt-Jakob disease (nvCJD).
Etiology
The clinical, pathological, and molecular genetic features of BSE,
as well as other transmissible spongiform encephalopathies, have led to speculation on the
nature of the etiologic agent and the pathogenic mechanisms of the disease. There are
three main theories on the nature of the scrapie agent:
1. The virus theory, in which the virus would have to have unusual
biochemical and biophysical characteristics that would help explain the remarkable
physicochemical properties (12, 24, 39, 40).
2. The prion theory, in which the agent is conceived of being
composed exclusively of a host-coded normal cellular protein (PrPc) that
becomes partially protease resistant (PrPBSE) — most likely through a
post-translational conformation change after infection. In this theory there is no nonhost
component of the agent. That is, a specific informational molecule (nucleic acid e.g., RNA
or DNA) is not present (5, 36).
3. The virino theory, which states that the agent consists of a
host-derived protein coat, (PrP being one of the candidates for this protective protein)
and a small noncoding regulatory nucleic acid (14, 21).
All of the proposed theories have some degree of validity.
Proponents of the virus and virino theories have concluded that the existence of different
scrapie strains unequivocally proves the presence of a nucleic acid component of the
infectious agent which, as in conventional viruses, may undergo mutations responsible for
phenotypic variations. The problem with these theories is that no agent-specific nucleic
acid has been convincingly identified to copurify with infectivity (15, 25, 28, 32, 42).
Moreover, chemical, enzymatic, or physical treatments that usually inactivate or degrade
nucleic acids have no effect on the transmissible properties of the infectious agent (3,
4, 27, 31). Possible reasons for this are that the amount of nucleic acid of the putative
agent is too small to be detected with available techniques and that its tight bond to the
protein protects it from chemical or physical inactivation. Also weakening the virus and
virino theories is the inability to identify any virus particles under the electron
microscope (6, 10), and the failure of an infected host to generate an immune response.
Recently small particles resembling virus structures have been observed by electron
microscopy (33).
The prion model involves propagation of a protein-only agent (PrPBSE)
whereby PrPc can assume various tertiary structures caused by a combination of
host genetics and the introduction of altered (infectious) PrP (PrPBSE). More
simply stated, the structure of the infecting PrPBSE imprints upon the normal
cellular precursor (PrPc) and results in a conformation change to the
protease-resistant form. It is suspected that "strain" differences result from
mutations in the PrP gene that may cause proteins "flip" and change shape.
Several explanations for scrapie strain genetics in the context of the prion theory have
been suggested but none have been proven (35, 41, 46).
It should be pointed out that the prion theory fails to explain a)
how the PrP of the infecting agent originally assumed the aberrant structure associated
with infectivity, and b) how the different structures originated as a function of the
different strains. Although numerous scrapie strains can be differentiated in a single
host (i.e., sheep), the PrP agents associated with these strains have not shown any
biochemical and molecular differences; thus, BSE seems to be caused by a single strain
type. This BSE strain is different from historical or contemporary isolates from sheep or
goats with natural scrapie, as determined by study of incubation periods and brain
"lesion profiles" in mice.
Regardless of whether the prion (PrPBSE) is or is not
the etiologic agent, the partially protease-resistant form of the prion protein is a
marker of infection.
Host Range
Bovine spongiform encephalopathy has been experimentally
transmitted to the following species via intracerebral (IC) inoculation: cattle, sheep,
and goats (17), mink (38), pigs (13), marmosets (1), macaques (22), and mice (16).
Intracerebral transmission was attempted in hamsters but was not successful. Via the oral
route, BSE has been successfully transmitted to cattle, sheep, and goats (17); mice (2);
and mink (38). Oral transmission has not been successful in swine. Parenteral and oral
transmission has also been attempted in chickens with no evidence of disease thus far.
A transmissible spongiform encephalopathy has been diagnosed in
eight species of captive wild ruminants as well as exotic (cheetahs, pumas, a tiger, and
an ocelot) and domestic cats. There have been about 81 domestic cat cases of feline
spongiform encephalopathy (FSE) in Great Britain and in 1 domestic cat each in Norway,
Northern Ireland, and Liechtenstein. The agent isolated from several of these cases using
strain typing in mice is indistinguishable from BSE in cattle, which suggests that FSE is
actually BSE in exotic and domestic cats. This also appears to be true for the other
ruminants. Epidemiological evidence suggests BSE-contaminated feed to be the primary
source of infection in these species (30).
Other cases of spongiform encephalopathy have been reported in
kudu, eland, nyala, gemsbok, and a few exotic cats. These too are thought to be linked to
contaminated feed.
It has also been suggested that 23 cases (as of January 31, 1998)
of a variant form of CJD (nvCJD) (a human disease) in Great Britain (U.K. Department of
Health, March 2, 1998) and 1 case in France may be linked to exposure to BSE before the
introduction of a specified bovine offal (SBO) ban at slaughter in 1989. The SBO ban
excludes from human consumption brain, spinal cord, and other tissues with potential BSE
infectivity.
Geographic Distribution
Worldwide there have been more than 170,000 cases since the
disease was first diagnosed in 1986 in Great Britain. Over 95 percent of these cases have
occurred in the United Kingdom. The disease has also been confirmed in native-born cattle
in Belgium, France, Ireland, Luxembourg, the Netherlands, Northern Ireland, Portugal, and
Switzerland but is not known to exist in the United States.
Transmission
Different scientific hypotheses have been advanced concerning the
origins of BSE. The epidemiologic data suggest that BSE in Great Britain is an extended
common source epidemic involving feed containing TSE-contaminated meat and bone meal as a
protein source. The causative agent is suspected to be from either scrapie-affected sheep
or cattle with a previously unidentified TSE.
Changes in rendering operations in the early 1980's —
particularly the removal of a solvent-extraction process that included a steam-heat
treatment — may have played a part in the appearance of the disease and the
subsequent amplification of the agent in the food chain. A ban on feeding animal protein
of ruminant origin to ruminants was enacted in Great Britain in July 1988(50).
In Great Britain the epidemic peaked in 1992-93, when
approximately 1,000 cases were being reported per week. In 1998 it remains on the decline
with approximately 100 cases reported per week. Cases that have been detected in other
countries appear be a result of importations of live cattle or, more significantly,
contaminated feed from Great Britain.
There is no evidence that BSE spreads horizontally; that is, by
contact between unrelated adult cattle or from cattle to other species.
New evidence suggests that maternal transmission may occur at an
extremely low level. Results of British research show low levels of transmission of BSE
from affected cows to their offspring. These results demonstrated that there is
approximately a 9 percent increase in the occurrence of BSE in offspring of BSE-affected
dams as compared with calves born to dams where BSE was not detected. The study did not
ascertain if this was the result of genetic factors or true transmission. The research
did, however, point out that, at this level, if maternal transmission does occur, it alone
will not sustain the epidemic (51).
In the naturally infected animals, the agent has been identified
by mouse bioassay in the brain, spinal cord, and retina. The route of inoculation into the
mice was intracranial. The naturally infected animals were adult cattle exhibiting
clinical signs of disease (16).
Mice fed milk, mammary gland, placenta, lymph nodes, or spleen
have failed to develop the disease or to establish subclinical infection of the
lymphoreticular system within their natural lifespan (29).
Another study was conducted to examine the pathogenesis of BSE in
cattle; that is the replication (tissue distribution) of the agent during the incubation
period. This study, which has not yet been completed, has identified the agent via mouse
bioassay in the distal ileum of the experimentally infected calves. It is thought that the
agent may be associated with the lymphoid tissue of the intestines. The calves were 4
months of age at the time of oral dosing. First isolation of the agent in the distal ileum
was made at 6 months after oral dosing. Subsequent isolations from the distal ileum were
made at 10, 14, and 18 months after dosing (47). Recently this study has also identified
infectivity in bone marrow, trigeminal ganglion, dorsal root ganglion, brain, and spinal
cord (48).
No infectivity has been found by parenteral or oral challenge, or
both, in over 40 other tissues from clinically ill cattle using the mouse bioassay. It
appears as if the distribution of the BSE agent is not as diverse as the scrapie agent in
sheep. However, there is a possibility that the agent is present but is at such low levels
that the bioassay is not sensitive enough to detect it (30).
Incubation Period
The incubation period usually ranges from 2 to 8 years. Following
the onset of clinical signs, the animal's condition gradually deteriorates until the
animal becomes recumbent, dies, or is destroyed. This usually takes from 2 weeks to 6
months. Most cases in Great Britain have occurred in dairy cows (Friesians) between 3 and
6 years of age (50). The youngest confirmed case occurred in a 20-month-old heifer, and
the oldest case was found in a cow 18 years of age.
Clincial Signs
Cattle affected by BSE develop a progressive degeneration of the
nervous system. Affected animals may display changes in temperament, abnormalities of
posture and movement, and changes in sensation. More specifically, the signs include
apprehension, nervousness or aggression, incoordination, especially hind-limb ataxia,
tremor, difficulty in rising, and hyperaesthesia to sound and touch. In addition, many
animals have decreased milk production or loss of body condition, or both, despite
continued appetite.
Gross Lesions
There is no gross lesion associated with BSE.
Morbidity and Mortality
In Great Britain, 19 percent of the dairy herds and 1.6 percent of
the beef herds have had one or more cases of BSE. This difference is believed to result
from the fact that dairy calves were fed a higher level of protein supplement. The average
incidence in herds in Great Britian has been 1.75 cases. However, there have been a few
herds with over 30 cases. Affected animals die.
Diagnosis
Field Diagnosis
A field diagnosis of BSE is based on the occurrence of clinical
signs of the disease. A bovine animal that has signs of a CNS disturbance should be
observed over time (at least 2 weeks) to determine whether the signs become progressively
more severe. If, after this interval, improvement or recovery has not taken place, BSE
should be suspected and the animal humanely euthanized.
Specimens for Laboratory
Because the BSE agent is considered a human pathogen, protective
clothing, gloves, and face protection should be worn when performing the necropsy. The
entire brain should be removed intact with a portion of the cranial cervical spinal cord
attached. Portions should be placed in a plastic bag and submitted unfixed. The remainder
of the brain should be fixed in 10 percent buffered formalin solution. One cerebral
hemisphere is removed by cutting the brain stem through the space between the cerebellum
and cerebrum with a longitudinal cut between the cerebral hemispheres.
Laboratory Diagnosis
Bovine spongiform encephalopathy currently must be confirmed by
histopathological examination of brain tissue. Bilaterally symmetrical degenerative
changes are usually seen in the gray matter of the brain stem. These changes are
characterized by vacuolation or microcavitation of nerve cells in the brain stem nuclei.
The neural perikarya and axons of certain brain stem nuclei contain intracytoplasmic
vacuoles of various sizes, that give the impression of a spongy brain. Hypertrophy of
astrocytes often accompanies the vacuolation (49). A diagnosis may also be made by the
detection of SAF's using electron microscopy.
Two supplemental tests are available to enhance the diagnostic
capabilities for BSE. These are immunohistochemistry and the Western blot technique. In
the past, if the brain tissue was not harvested shortly after the animal's death,
autolysis often made it very difficult to confirm a diagnosis by histopathology. These
tests allow for the possibility of confirming a diagnosis of BSE by detecting PrPBSE even if the brain has been frozen or autolytozed .
Differential Diagnosis
Differentials for BSE include rabies, listeriosis, nervous
ketosis, milk fever, grass tetany, lead poisoning, and other toxicities or etiological
agents affecting the nervous or musculoskeletal system of adult cattle.
Treatment
There is no known treatment for BSE or any of the TSE's.
Vaccination
There is no preventative vaccine.
Control and Eradication
Bovine spongiform encephalopathy from foreign sources may be
prevented by the implementation of import regulations prohibiting live ruminants and
ruminant products (especially meat, bone meal, and offal) from countries where BSE may
exist. Because the origin of BSE remains unknown, preventing an epidemic of BSE would
involve, at a minimum, the prohibition of feeding ruminant proteins to ruminants. The
prevention program of any country should also include an active surveillance effort
focused on high-risk cattle for the early detection of BSE. Most countries of the world
have prohibited the importation of cattle and bovine products from countries known to have
BSE. In addition many countries have taken steps to enact regulations prohibiting the
feeding of ruminant proteins to ruminants. This is true even in countries such as
Australia and New Zealand with no known animal TSE's.
Agricultural officials in countries known to have BSE have taken a
series of actions to control and, it is to be hoped, eradicate BSE. These include making
BSE a notifiable disease, prohibiting the inclusion of certain animal proteins in
ruminants' rations (the feed bans vary depending on the amount of BSE detected), and
depopulating certain populations of cattle thought to be of higher risk because of
epidemiological findings.
To prevent human exposure to the BSE agent numerous countries have
established prohibitions on the inclusion of high risk material in foods, pharmaceuticals,
cosmetics, and so forth.
U.S. Actions
With an active surveillance program in place for 8 years, BSE has
not been detected in the United States. The United States Department of Agriculture
(USDA), Food and Drug Administration (FDA), and industry groups are actively working to
maintain this status. The measures USDA, Animal and Plant Health Inspection Service
(APHIS), has taken in this regard include prohibitions or restrictions, or both, on
certain animal and product imports, ongoing surveillance for the disease in the United
States, preparation of an emergency response plan in the unlikely event an introduction
were to occur, and continuing educational efforts. The Animal and Plant Health Inspection
Service actively shares information and coordinates closely with other Federal agencies,
as well as the States, livestock and affiliated industries, veterinary and research
communities, and consumer groups, to ensure that the United States has a uniform approach
to transmissible spongiform encephalopathies based on sound scientific information.
A comprehensive surveillance program has been implemented by APHIS
in the United States to ensure timely detection and swift response in the unlikely event
that an introduction of BSE were to occur. This surveillance program entails the location
of imports from countries known to have BSE and targeted active and passive surveillance
for either BSE or any other TSE in cattle.
To locate each of the 496 British cattle that were imported into
this country between January 1, 1981, and July 1989, APHIS has conducted a traceback
effort. In July 1989, the United States prohibited the importation of ruminants from
countries affected with BSE. As of March 1998, only 17 of these animals are known to be
alive in the United States, and these are being carefully monitored by APHIS personnel on
an ongoing basis. In addition, five head of cattle imported from Belgium in 1996 are now
under quarantine. In cooperation with the states and industry, APHIS continues to purchase
these animals for diagnostic purposes. No evidence of BSE has been found in any of these
imported animals.
The United States has had an aggressive, active surveillance
program for BSE since May 1990. Bovine spongiform encephalopathy is a notifiable disease,
and there are more than 250 Federal and State regulatory veterinarians specially trained
to diagnose foreign animal diseases, including BSE. The Animal and Plant Health Inspection
Service leads an interagency surveillance program, which includes the Food Safety
Inspection Service (FSIS) and the Centers for Disease Control (CDC). The surveillance
samples include field cases of cattle exhibiting signs of neurological disease, cattle
condemned at slaughter for neurological reasons, rabies-negative cattle submitted to
public health laboratories, neurological cases submitted to veterinary diagnostic
laboratories and teaching hospitals, and random sampling of cattle that are nonambulatory
at slaughter. As of February 21, 1998, over 6,600 brains had been examined for BSE or
another form of a transmissible spongiform encephalopathy in cattle. No evidence of either
condition has been detected by histopathology or immunohistochemistry.
As of December 12, 1997, APHIS has prohibited the importation of
live ruminants and most ruminant products from all of Europe until a thorough assessment
of the risks can be made. The new restrictions apply to Albania, Austria,
Bosnia-Herzegovina, Bulgaria, Croatia, Czech Republic, Denmark, Federal Republic of
Yugoslavia, Finland, Germany, Greece, Hungary, Italy, Former Yugoslav Republic of
Macedonia, Norway, Poland, Romania, Slovak Republic, Slovenia, Spain, and Sweden.
This action was taken because, in the past year, the Netherlands,
Belgium, and Luxembourg have reported their first cases of BSE in native-born cattle.
There is evidence that European countries may have had high BSE risk factors for several
years and less than adequate surveillance. Additionally, Belgium reported that the cow
diagnosed with BSE was processed into the animal food chain.
The Food and Drug Administration (FDA) has recently established
regulations that prohibit the feeding of most mammalian proteins to ruminants. The
effective date of this regulation was August 4, 1997.
Public Health
BSE and CJD — Human Health Concerns
On March 20, 1996, the U.K.'s Spongiform Encephalopathy Advisory
Committee (SEAC) announced the identification of 10 cases of a new variant form of CJD
(nvCJD). All of the patients developed onset of illness in 1994 or 1995. The following
features describe how these 10 cases differed from the sporadic form of CJD:
- The affected individuals were much younger than the sporadic
CJD patient. Typically, sporadic CJD patients are over 63 years old. The average patient
age for the variant form of CJD is 27.5 (range of 16 to 42) years.
- The course of the disease in the nvCJD averaged 13 months.
Sporadic CJD cases average a 6-month duration.
- In the variant cases, electroencephalographic (EEG) electrical
activity was not typical of sporadic CJD.
- Although brain pathology was recognizable as CJD, the pattern
was different from normal CJD, and evidenced large aggregates of prion protein plaques.
Epidemiologic and case studies have not revealed a common risk
factor among the cases of nvCJD. According to the SEAC, all victims were reported to have
eaten beef or beef products in the last 10 years, but none had knowingly eaten brain
material. One of the affected individuals had been a vegetarian since 1991 (52).
The SEAC concluded that, although there was no direct scientific
evidence of a link between BSE and nvCJD, on the basis of current data and in the absence
of any credible alternative, the most likely explanation was that the cases were linked to
exposure to BSE before the introduction of control measures; namely, the specified bovine
offal (SBO) ban in 1989.
Research reported in later 1996 and 1997 has presented further
evidence to support a causal association between nvCJD and BSE. Two significant studies
published in the October 2, 1997, edition of Nature led the SEAC to conclude that the BSE
agent is very likely to be the cause of nvCJD. Dr. Moira Bruce and colleagues at the
Institute for Animal Health in Edinburgh, Scotland, inoculated three panels of inbred mice
and one panel of crossbred mice with BSE, nvCJD, and sporadic CJD. Interim results
indicate that mice inoculated with BSE show the same pattern of incubation time, clinical
signs, and brain lesions as mice inoculated with tissues from patients with nvCJD. This
provides evidence that BSE and nvCJD have the same signature or are the same
"strain." In addition classical CJD and known scrapie strains were not similar
to nvCJD or BSE (9).
Results from another study published by Dr. John Collinge and
colleagues of Imperial College School of Medicine, London, United Kingdom, strongly
support Bruce's results. Collinge's paper reports experimental transmission of BSE to
transgenic mice expressing only human PrP (20).
The Health and Safety Executive in the United Kingdom now advises
that BSE must be considered a biological agent (human pathogen) within the meaning of the
Control of Substances Hazardous to Health Regulations 1994 (45).
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L. A. Detwiler, D.V.M. , USDA, APHIS, VS, Robbinsville, NJ 08691
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