Control Measures

The risk to human health from BSE was always recognized. The principal protective measure was the November 1989 ban on the use of certain specified bovine offal in human food. As with scraple, the tissues banned were those likely to contain the highest concentrations of the transmissible agent (brain, spinal cord, tonsil, spleen, thymus, and intestine of cattle older than 6 months of age). The intestine and thymus of calves was added to the list in 1994 when a long-term pathogenesis study in cattle by the Ministry of Agriculture, Fisheries and Food indicated that the transmissible agent could be found in the terminal ileum (it is assumed that the agent was present in Peyer's patches). In 1996 the whole head, other than the tongue, was formally banned because of concern about possible contamination with brain. Since the banned tissues now contain more than offal, the tissues are referred to as specified bovine material. During 1995, it became clear that spinal cord was not being completely removed from a small number of carcasses that were subsequently certified as fit for human consumption. Consequently, in December 1995 the U.K. government banned the use of bovine vertebral column for the production of mechanically recovered meat. In March 1996, when it became clear that human disease related to BSE was "probable" rather than "theoretical," the U.K. government introduced the over-30-month scheme, which allowed only animals under the age of 30 months to be used for human food, provided that all the banned specified bovine material had been removed. This added an extra margin of safety because cattle can be reasonably accurately aged by their dentition at 30 months and because BSE is relatively rare under the age of 30 months. Only 265 cases occurred in cattle younger than 30 months, and during 1997, the youngest animal with BSE was 37 months of age (Ministry of Agriculture, Fisheries and Food, pers. comm.). In the second half of 1997, the long-term pathogenesis experiment indicated that the transmissible agent of BSE could be recovered from the dorsal root ganglia of experimentally infected animals toward the end of the incubation period. Also, in one animal the agent was transmitted by intracerebral inoculation of mice with bovine bone marrow. Accordingly, in December 1997 the U.K. government introduced legislation to ban the sale of beef on the bone, even from animals under 30 months of age. Many in the United Kingdom thought that this regulation to prevent an extremely small risk of transmitting BSE in T-bone steaks and rib of beef was unnecessary. Nevertheless, the introduction of the specified bovine offal ban in 1989 and its subsequent refinements have ensured the safety of beef and beef products that now enter the human food chain in the United Kingdom. Even so, as a consequence of the emergence of new variant CJD, a worldwide ban on the sale of U.K. beef and beef products was introduced by the European Union in March 1996 and is still in force with the exception of a recent (March 1998) relaxation for certain herds in Northern Ireland.

New Variant CJD

Clearly, the first measures to protect human health were introduced before any human disease could be related to BSE. To guard against the possible emergence of such disease (or diseases), the U.K. Department of Health set up a CJD Surveillance Unit in 1990. The purpose of the unit was to monitor the trends in incidence of CJD and any unusual features among cases. Concern was first focused on the 1995 cases of the third and fourth U.K. farmer since 1990 to be confirmed as having CJD. Statistically, the chances of four such cases occurring in 6 years in the United Kingdom were very small. However, the clinical features of the disease were typical of classical CJD, and collaboration between the CJD Surveillance Unit and other European countries indicated that farmers were overrepresented compared with CJD cases in countries with no BSE. Subsequently, classic CJD was confirmed in these farmers; no further cases have been diagnosed in U.K. farmers, and the significance of the high incidence in 1995 is diminishing.

The death in May 1995 of the first adolescent ever to be diagnosed with CJD in the United Kingdom was followed in October 1995 by the death of a second adolescent; by January 1996, three other young (29 years of age) persons became ill. Atypical pathologic results were beginning to be defined in these patients; and on March 8, 1996, eight cases of what came to be known as new variant CJD or variant CJD (vCJD) were reported to the Spongiform Encephalopathy Advisory Committee. The cases were distinguished by the relatively young age at which the symptoms started (10,11). That age range is now 16 years to 52 years. The duration of the illness is relatively long, averaging approximately 14 months as opposed to the 4 to 5 months in classic CJD. The early symptoms are often psychiatric, and it may be 6 or 7 months before any neurologic signs appear. The characteristic electroencephalogram pattern of sporadic CJD is not seen in vCJD, and pathologic results show florid plaques and extensive cerebellar involvement with multiple PrP deposits. As with BSE and FSE, the neuropathologic appearances are the mainstay of laboratory confirmation. Magnetic resonance imaging scanning and detection of 14-3-3 protein can be helpful. Early evidence indicates that the diagnosis can often be made from tonsil biopsies (12). Otherwise, diagnosis must depend upon brain biopsy or postmortem examination.

When on March 20, 1996, the U.K. government announced the existence of 10 cases of vCJD and the opinion of the Spongiform Encephalopathy Advisory Committee that these were probably related to BSE, three questions immediately arose. The first was, "Is there really any link with BSE?" Additional evidence emerged from the work of Collinge and his colleagues (13) on the analysis of the PrP fragments after protease digestion. The position of the three fragments and the relatively high concentrations of the di-glycosylated form indicated that vCJD was distinct from the previously recognized forms of CJD and that similarities existed between the cases of vCJD and BSE and FSE. In 1997, the first results were published from the classic strain typing experiments initiated during 1996 (14). The characteristics of material from cases of vCJD, in terms of incubation period and lesion profile in RIII mice, were identical to those from cases of BSE and FSE. These observations are confirmed now in C57 black mice. Thus, vCJD can now be regarded as human BSE in the same way that FSE is regarded as feline BSE. The second question was, "What is the route of transmission from cattle to humans?" So far we have no evidence, only a working hypothesis, that transmission was likely from inclusion in the human food chain of tissues that contain the highest concentration of the transmissible agent. The major differences in human exposure to these tissues would have occurred first when sick animals were banned from the human food chain in 1988 and again in 1989 when the specified bovine offals of otherwise healthy animals were removed from the human food chain.

Studies continue in an attempt to answer the third question, "How many vCJD cases will there be in the future?" So far, 26 cases have been diagnosed in the United Kingdom (Table 4) and 1 in France. Incidence has not increased since vCJD was first diagnosed in 1995. If instead of looking at the date of death one looks at the date of onset of the symptoms in the 26 patients, two new cases occurred on average every quarter since 1994. All cases have been methionine homozygotes at codon 129 of the PrP gene. In the general population approximately 40% have such a genotype; 10% are valine homozygotes, and 50% are heterozygotes. An analysis of classic sporadic CJD indicates that 80% of those cases are methionine homozygotes, 10% valine homozygotes, and 10% heterozygotes. It is perhaps not surprising, therefore, that the first cases of vCJD to be seen are methionine homozygotes.

Only one published analysis has predicted the number of future nvCJD cases after constraining the models used to the known and surmised facts at the time (15). The total number of future cases will depend critically on the average incubation period of vCJD. At present, we have no way of determining that; therefore, it remains too early to predict with any accuracy the total number of future cases. It remains possible that the outbreak of vCJD cannot be regarded as a single curve and that the small number of cases have occurred in persons who are extremely susceptible for unknown reasons.