—from Epidemiological Bulletin, Vol. 22 No. 1, March 2001—

The Public Health Importance of Transmissible Spongiform
Encephalopathies: The "Mad Cow" Disease

• Introduction
• The TSEs
• Creutzfeldt-Jakob Disease (CJD)
  • Variant of Creutzfeldt-Jakod Disease (vCJD)
  • The first findings of vCJD
  • The new variant
  • Transmission
  • Diagnosis
• Bovine Spongiform Encephalopathy (BSE)
  • Distribution
  • Etiology
  • Transmission
  • Diagnosis
• Prevention and control of TSEs
• Non-food related modes of transmission
• The future of TSEs

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In March 1996, the Spongiform Encephalopathies Advisory Committee (SEAC) reported to the British Government that 10 cases of Creutzfeldt-Jakob Disease (CJD), recently evaluated in patients less than 42 years of age, presented a different pattern from the classical form of this disease. The Committee concluded that the most probable explanation was that of a possible exposure to Bovine Spongiform Encephalopathy (BSE), also known as “mad cow disease.”

To date, this new form of the human disease, called variant Creutzfeldt-Jakob disease (vCJD), has claimed a total of 95 victims in the United Kingdom (UK), three in France and one in Ireland. In the UK in particular, the figures show a clear rising trend, although no one ventures to predict the future incidence of this neuropathy (Table 1).

The association between vCJD and BSE, which both belong to the group of Transmissible Spongiform Encephalopathies (TSE), initiated a confidence crisis regarding the consumption of beef. In Europe in particular, the trade and consumption of this basic food have been destabilized. At the same time, the increase, at the end of 2000 and beginning of 2001, of the animal disease in herds of countries such as France, Germany, Spain, Portugal, Ireland, and Italy has caused panic among consumers around the world.

In the Americas, no existence of BSE has been found in livestock. After its detection in 1986 in the UK, countries such as the United States, Canada, Argentina and Uruguay, among others, have carefully assessed the risk of entry of the disease in their territories. To this day there has been no evidence of the disease in those countries.

The TSEs
The neurodegenerative phenomenon known in general terms as TSE has been recognized for some time. The name comes from observations of microscopic pores in the infected brain that make it look like a sponge. These diseases are characterized by a long incubation period and a progressive course causing degeneration of the central nervous system, affecting motor control, generally causing dementia and sometimes paralysis, and finally, death. There currently exists no cure for TSEs.

The group of TSEs includes encephalopathies that affect animals such as sheep and goat (Scrapie); mink (TME); mule, deer, and elk (CWD); cattle (BSE) and cat (FSE). Those that affect humans are known as Kuru, Creutzfeldt-Jakob Disease (CJD), and the Syndrome of Gerstman-Sträussler (GSS). BSE, which affects cattle, was described for the first time in the UK in 1986 and since then, nearly 180,000 cases have been recorded in this country.

With regards to the etiology of the disease, the most accepted theory to date is that the disease is caused by an agent known as proteinaceous infectious particles, or Prions. Lacking DNA and yet capable of replicating themselves without genes, prions are outside all known laws of traditional biology. They are resistant to inactivation by methods used to modify nucleic acids, and they have no identified background.

Although all forms of TSEs are considered important, those that affect humans (CJD) and cattle (BSE), are without a doubt the ones of greatest importance for public and animal health.

Creutzfeldt-Jakob Disease (CJD)
Of the TSEs known in humans, CJD is considered of greatest interest to science. It occurs in two forms, one associated with genetic predisposition (approximately 5-10% of the cases) and another more common form, known as sporadic, that accounts for 85-90% of the cases. A small percentage of cases (less than the 5%) is of the iatrogenic type and results from accidental transmission of the causative agent by means of contaminated surgical equipment or by cornea or dura mater transplantation. It has also been demonstrated that CJD can be transmitted to humans as a result of treatment with human growth hormones, a risk that has been reduced by the replacement of this natural hormone with a recombinant hormone.

The incidence of CJD is estimated to be 1 case per million population per year, with a broad geographical distribution in all continents.

Variant of Creutzfeldt-Jakob Disease (vCJD)
When the first case of BSE in the UK was identified, concern about the risk for humans triggered a series of measures in an attempt to eradicate BSE and avoid potentially infected tissues from entering the human food chain. One of the earliest measures taken in the UK was the establishment of a surveillance unit for CJD in May 1990. Three or four years later this unit was extended to several European countries, through the European Union, in the hope that change in the epidemiology of CJD in the UK would be detected at an early stage, and the significance of this change could be estimated by comparing it with the epidemiology of the disease in the European continent.

Interest in the disease was enhanced by the discovery of infection in some ungulate animals as well as in domestic cats and wild felines in captivity. In these studies, the ungulate animals and domestic cats received meat and bone-based food, whereas the wild cats consumed raw tissues, including tissue from parts of the central nervous systems of livestock. Findings of infection forced scientists to face the possibility that the disease could cross the inter-species barrier to humans, through the consumption of meat and milk products or possibly by contact with livestock by certain occupational groups such as milkers, livestock and slaughterhouse workers.

What initially silenced the concern for human infection was the fact that BSE had its origin in scrapie, which is not pathogenic for humans. Another consideration was that if BSE had originated from a spontaneous mutation in livestock, experimental studies on the susceptibility of some species to the new TSE were not sufficiently advanced to rule out the same phenomenon in humans. In spite of that, during the 10 years following identification of the first BSE case, cases of CJD did not increase in high-risk groups and continued to occur in the general population, showing the same clinical and neuropathological characteristics as before the appearance of BSE.

The First Findings of vCJD
Between May and October 1995, the UK CJD Surveillance Unit received reports of three cases of CJD in patients of only 16, 19 and 29 years of age, who presented amyloid plates in their neuropathological examinations, an unexpected condition since it occurs in only 5 to 10% of the sporadic cases of CJD. Additionally, taking into account the fact that this disease generally affects elderly people, the young age of the patients and the pathology findings from their brain samples led investigators to search for similar cases in patients whose deaths could have been associated with another diagnosis. In particular, they searched for cases of Subacute Sclerosing Panencephalitis (SSPE), based on the fact that the three young patients with CJD had been previously identified by SSPE surveillance, but no case of that disease appeared in the UK records.

In December 1995, the CJD Surveillance Unit was informed of 10 suspected cases CJD, all in patients younger than 50 years old. In two of these patients, who were 29 and 30 years old respectively, the disease had been confirmed by neuropathology. Similar to the three previously mentioned patients, they presented abundant amyloid plates in their central nervous system tissue. This led scientists to suspect an association between those cases and BSE, which could be explained by exposure of the patients to diseased cattle. At this point however, much evidence was still needed to confirm an association.

In January 1996, two more confirmed cases of CJD were reported in young patients. These two cases were eventually confirmed by neuropathology, and a clinically distinctive syndrome began to emerge. This syndrome was associated with the formation of amyloid plates and characterized by its appearance in young individuals, with psychiatric amnesia-like symptoms, marked ataxia, periodic absence of electroencephalographic activity and a prolonged duration of illness compared to what was previously known about CJD. Some of those characteristics, alone or combined, had been seen in sporadic or classic cases of CJD.

Review of the histories of the patients with CJD registered before 1980 in the UK revealed that three young patients shared some of the aforementioned characteristics, and an inquiry concerning young patients with CJD in other European countries revealed an average age similar to that of the patients in the UK. Because of these findings, precautions were enhanced. The greatest concern was that those seven, apparently similar cases, could represent a heterogeneous group of patients with genetic or classic forms of CJD. Complete comparative pathological neuro-examinations of both the pre- and post-1980 patients were carried out, in addition to genetic sequencing analysis of the cases, whenever possible.

Image 1: Young people are the principal victims of the human version of "Mad Cow Disease"

In February 1996, the Surveillance Unit received the report of another case with a similar clinical evolution to that of the seven previous patients. Analyses of the neuropathology of the patient revealed, as in his predecessors, the characteristic morphology of amyloid plates with an amyloid center surrounded by “petals” showing spongiform changes.

By March 4, genetic analyses were completed for six of the cases. Mutations had not been encountered in any of the results, which made it possible to rule out genetic causes of the syndrome. The information received on March 20 from the European CJD surveillance system indicated that none of the young patients in other countries showed the clinical or pathological characteristics of the cases from the UK.

The new variant
Two confirmed cases of the variant were added to the list. A report on the group of 10 cases concluded that a variant of CJD, unrecognized before and affecting people under 45 years of age, could be due to exposure to BSE. This association has recently been convincingly established through laboratory studies demonstrating identical, biological and distinctive molecular properties in the pathogen isolated from livestock infected with BSE and in the human cases of vCJD.

Transmission
The source of contamination is still unknown, but it is generally accepted that the most probable means of exposure is through food containing bovine tissues, particularly meat products contaminated with tissues from the central nervous systems of clinically sick animals more than two years old.

Contamination can occur in several ways, such as: contact of muscle with infected brain or spinal cord tissue through contaminated equipment during slaughtering; inclusion of paraspinal nodes in cuts of meat that contain vertebrate tissue (T-bone steak, chops and others); cerebrovascular clots due to stunning instruments used before bleeding out; and perhaps most importantly, presence of the remains of spinal cord and paraspinal nodes in “mechanically recovered meat” (MRM), which is used in some countries as raw material for the preparation of cooked meat products.

The quantity of ingested infectious tissue could be a critical determinant in the transmission of BSE to humans in the form of vCJD, however there are numerous other factors not mentioned here, including genetic ones, may also influence susceptibility to the disease.

Diagnosis
Due to the characteristics of the prion, the usual analytical biochemical methods of detection cannot be applied directly. Diagnostic capabilities are further limited by the fact that there is no absolute certainty that the prion is the infectious agent. Additionally, infection by the prion does not seem to cause any immune reaction, making it impossible to detect antibodies, and there is no known genetic material that would enable the use of molecular biology techniques. Therefore, the diagnosis of vCJD can currently only be confirmed by histopathological examination of the brain, which makes it possible to see the “florid amyloid plates” characteristic of this new variant.

Bovine Spongiform Encephalopathy (BSE)
BSE is a form of TSE that affects cattle and the disease was described for the first time in the UK in 1986, although retrospective studies trace its possible presence as far back as 1985. Since then, more than 180,000 cases have been reported in that country, and the disease has been related to “lumbar pruritus” or Scrapie found in sheep and goats (a condition recognized in Europe since the middle of the 18th century).

Distribution
With nearly 180,000 cases of registered BSE coming from more than 35,000 herds in the UK, the disease is considered to be of sporadic occurrence. However, it is not restricted to the UK. Indeed, its presence has been detected in other countries as a result of animal importation (one case in Canada, another in the Falkland Islands and two cases in Oman), or importation of dietary supplements for livestock. Cases due to importation of animals or animal-tissue-based feed have also been registered in several countries of the world.

In some countries, such as the UK, the incidence of the disease shows a downward trend, while in others including Spain, France, Portugal, Germany and the Republic of Ireland, incidence is either showing an upward trend or the initial emergence of cases is being registered, a phenomenon that could be explained by improved sensitivity of the surveillance systems. Despite the fact that native cases of BSE have been identified in several countries, no authochthon case has been notified outside the UK. BSE has not been reported in countries that have been recognized importers of livestock, meat, meat products, or dietary supplements from the UK. The cattle epidemic seems to have emerged only in this country.

 

Number of cases of bovine spongiform encephalopathy (BSE) reported in the United Kingdom (1) As of 21.12.2000
Year	Great Britain	Northern Ireland	Isle of Man (2)	Jersey	Guernsey (3)	Total United Kingdom
Up to 1987	442	0	0	0	4	446
1988	2 469	4	6	1	34	2 514
1989	7 137	29	6	4	52	7 228
1990	14 181	113	22	8	83	14 407
1991	25 032	170	67	15	75	25 359
1992	36 682	374	109	23	92	37 280
1993	34 370	459	111	35	115	35 090
1994	23 945	345	55	22	69	24 436
1995	14 302	173	33	10	44	14 562
1996	8 016	74	11	12	36	8 149
1997	4 312	23	9	5	44	4 393
1998	3 179	18	5	8	25	3 235
1999	2 274	7	3	6	11	2 301
2000	1 076	14	0	0	11	1 101
(1) Cases are shown by year of restriction. (2) In the isle of Man BSE is confirmed on the basis of a laboratory examination of tissues for the first case on a farm and thereafter by clinical signs only. However, all cases in animals born after the introduction of the feed ban have been subjected to histopath/SAF analysis. To date, a total of 277 animals have been confirmed on clinical grounds only. (3) In Guernsey BSE is generally confirmed on the basis of clinical signs only. To date, a total of 597 animals have been confirmed without laboratory examination. (4) Cases prior to BSE being made notifiable are shown by year of report, apart from cases in Great Britain which are shown by year of clinical onset of disease. (5) As at 31 October 2000. Source: International Office of Epizootics (OIE)

 

Etiology
The origin of the disease in cows is still the subject of serious debate. One of the most accepted theories attributes the cause of the disease to an unconventional communicable agent, not well known in nature, that would cause a modification in the Prion. This modification would induce a neurodegenerative type of disease without inflammation or demyelinization, that is communicable and always fatal.

The Prion, a protein coded by a cellular gene, presents two isoforms: normal (PrPC) and abnormal (PrPSc) or infectious. It is accepted that the PrPC sequence determines the existence of an interspecies barrier for TSEs, which, in the case of BSE, could have been crossed by the causative agent of Scrapie. Indeed, the gene sequencing of ovine and bovine prions show a 98% homology between both proteins, which would explain the crossing of the interspecies barrier. Another theory considers a pathogenic mutation that occurred in livestock in the decade of the 1970s.

Transmission
Epidemiological studies and the knowledge gathered to date make it possible to deduce that the appearance of BSE originated in the exposure of cattle to a common source: meat-and-bone meal provided for a balanced diet as a source of protein, and contaminated with the agent of sheep Scrapie. Changes in feed processing eliminated the use of solvents and stages that included heat treatments that inactivate the agent of Scrapie, which could have increased the levels of infectious agent found in the protein products. Despite the fact that animal dietary supplement production processes in other countries may have experienced similar modifications to those applied in the UK at the end of the 1970s, BSE seems to have emerged only in that country. The most apparent explanation is that the proportion of sheep remains in the input mixture to prepare those supplements and the proportion of infected sheep, was higher in that country that in any other.

Later, the recycling of tissues from livestock that had died from BSE contributed to strengthen the epidemic. In fact, it is estimated that the rapid increase of the disease in the mid- 90s (850 cases per week in 1994) was probably due to the inclusion of undiagnosed sick animals in the manufacture of feed for bovine consumption. Therefore, the most important measure taken in the UK was to prohibit the use of ruminant animal proteins for feed in 1988. There has been a clear decline of the epidemic in this country since 1992 (Figure 1).

Contrary to what is known about Scrapie and its frequent vertical transmission, neither vertical nor horizontal transmission has ever been demonstrated in BSE. In the UK, where intensive production systems prevail, the occurrence of the disease in herds remains sporadic.

Experimental transmission has been achieved through parenteral inoculation to livestock, sheep, goats, pigs, monkeys, mink, and mice. Oral inoculation has been attempted in these same species, (except monkeys) and was successful in sheep, goat, mink and mice.

The disease has an incubation period of 2 to 8 years, and induces changes in mental state that create nervous or aggressive behavior, difficulties in locomotion with loss of coordination and ataxia, and death after a clinical course that lasts from 2 weeks to 6 months.

Image 2: Mad cows, the origin of the scandal

Diagnosis
Because of the characteristics of the causative agent, the infection does not induce detectable immunological reaction in the host, which means that it is impossible to perform tests in live animals. The only sure diagnosis is done through histopathology and biochemical tests on nervous tissue from dead animals.

BSE is detectable through clinical examination when signs of the disorder are evident through changes in the Central Nervous System (CNS). Approximately 90% of cases are detected clinically by histopathology. The biochemical diagnosis is based on the identification of the infectious form of the Prion, the PrPBSE, achieved using the “Western Blotting” technique.

Prevention and control of TSEs
The principal measure used to prevent these diseases from spreading is the elimination of all livestock parts that are likely to be high-risk vehicles of contamination in the human and animal food chain. Today, these are known as Specific Risk Materials (SRM), and include the brain, spinal cord, eyes, tonsils and intestines. Recently, the Scientific Committee of the European Union decided to add specific meat cuts and mechanically recovered meat (MRM) to this list.

Viscera (kidneys, liver, lung, pancreas, lymph nodes and placenta) are considered tissues with some level of infectious risk. Low-risk tissues include milk and its derivatives, sebum and gelatin. Nevertheless, milk is not completely ruled out as a possible agent of transmission. British scientists have recently reopened closed research that was based on the supposition that contaminated cow’s milk did not transmit the causative agent to laboratory mice. Since species barriers were not taken into account in previous experiments, scientist are now attempting to inoculate infected milk directly to the female calves. The study is expected to last three years, which is the time required before the first symptoms of the disease manifest themselves.

The basic requirement for control of TSEs consists of eliminating the exposure of livestock to the agents of TSEs through feed. Affected countries are prohibiting the use of mammal remains or proteins derived from them, in ruminant feed. Tissues that contain the BSE agent should also be excluded from the human and animal food chains and countries should prohibit the use of ruminant tissues in animal feed. Other measures include prohibition of the use of ruminant meat and bone meal as fertilizer.

Since the first official report of BSE in Great Britain in 1986, the International Office of Epizootics (OIE) has coordinated the establishment of epidemiological surveillance in all the member countries, and is committed to report any case of the disease. In order to prevent the spread of BSE between countries, the OIE proposed directives for veterinary services of member countries, during the Expert Meeting held in 1994. Those directives are contained in the Reviewed Chapter 3.2.13 of the International Zoo-Sanitary Code.

In countries where BSE has not been reported, an analysis of the risk factors of BSE can provide an estimate of the potential risk of the emergence of the disease. Studies in Argentina and the United States have been pioneers in the Region.

• Contact with intact skin or mucous membranes does not carry a notable risk, although it is highly recommended that people working with infected material avoid direct contact with this material. Other types of contact, such as for example cornea transplantation, inoculations with injections and contact with contaminated surgical material, seem to carry a high potential risk.
• To date, no case of spongiform encephalopathy transmitted through blood transfusion has been detected in humans, although there exists a low theoretical risk. However, health authorities of some countries have adopted preventive measures for such transmission. This problem is assessed taking into account that a balance should be found between rejecting some sources of blood and maintaining sufficient blood reserves for patients in need of transfusion.
• The United States is not accepting blood donations from persons that have spent six months or more in the UK between 1980 and 1996. Canada has recently added to that restriction donors who have spent a total of six months or more in France during the same period. Though some consider these precautionary measures exaggerated, they can contribute to the reduction of the theoretical risk. It is important to note, however, that all the known risks are not necessarily managed, even in countries where blood donations are very well organized.
• To date, no case of human transmission by dental manipulation has been found. However, experiments in animals have shown that intraperitoneal inoculation of the infectious agent can contaminate the gums and dental pulps, and that these, in turn, can contaminate a healthy brain. As a result, the World Health Organization has recommended that in risky cases, disposable instruments be used and that they be destroyed by incineration. In cases where this is not possible, specific decontamination protocols should be followed. To allow for more extensive decontamination and cleaning, it is recommended that patients who need manipulation of neurovascular tissue be seen at the end of the day. Greater precautions are recommended for possibly contaminated patients needing a surgical process. Precautions such as these are designed to prevent contamination of hospital personnel, as well as of patients who are going to be treated using the same surgical instruments.
• It is not known whether encephalopathy is transmitted from a mother to her child during birth. Familial cases of Creutzfeldt-Jakob disease are mainly due to genetic mutation. For this reason, it may not be necessary to adopt special measures during birth by an infected mother, except in the case of invasive procedures that imply contact with tissues considered high-risk. The newborn should be handled using routine infection control procedures and special precautions should be taken to avoid exposure to the placenta and its associated liquids, which should be incinerated.

Ultimately, the safest method for guaranteeing no risk of residual infection by contaminated instruments and other materials is their destruction by incineration. When this is not possible, other less effective methods can be used. These include following a specific soda (sodium hydroxide) washing protocol and then sterilization, or washing the contact surfaces with disinfectant solutions.

Another possible risk is that of human or animal vaccines that contain ingredients based on bovine tissues. It has been recommended that the pharmaceutical industry avoid the use of those materials as well as materials from other animal species in which TSEs occur naturally. If its use is absolutely necessary, such materials should be obtained from countries that have been proven BSE-free. Cosmetics manufacturers should also follow this last precaution.

The future of TSEs
The recent death of at least two people considered “older” from a medical standpoint has not resolved another enigma surrounding vCJD: its period of incubation, a challenge that scientists have not been able to explain. To date, the quantity of prions necessary to produce transmission in humans is also unknown, and therefore, the hypothesis that young infected animals do not represent a risk due to their low prion levels remains untouched.

The difference between BSE and vCJD is that humans have not been subjected to the recycling of infected tissues that triggered the epidemic in cattle, and therefore it is expected that the vCJD epidemic will evolve slowly.

Due to the unknown incubation period and other elusive variables of vCJD, the scientific community is concerned that there may be a large number of people silently incubating the disease. This would imply a potential for iatrogenic spread of the disease between humans.

The most pressing need is to develop in vivo diagnostic tests in order to answer several questions regarding the disease. In the UK, the government has sponsored a research project aimed at analyzing tonsil samples from public hospitals, as a way to better evaluate the prevalence of the new variant.

There are many controversies on the subject of mad cow disease. Several of these are based on the fact that any disease that has caused less than 100 deaths in a population close to 300 million should not create panic. There are other diseases that cause a much higher mortality and morbidity that are latent risks in our countries. However, it is important to recognize that it is the effect of the disease that terrifies, and is rooted in the myths and the atavism of our diet, which cannot be ignored by anyone.

For further information on BSE and vCJD cases, please visit: http://www.oie.int and http://www.doh.gov.uk/cjd/cjd_stat.htm

Source: Prepared by Dr. Juan Cuellar of PAHO's Pan American Institute for Food Protection and Zoonoses (INPPAZ) Division of Disease Prevention and Control (HCP).

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Epidemiological Bulletin , Vol. 22 No. 1, March 2001