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Creutzfeldt–Jakob disease (CJD) is one of the transmissible spongiform encephalopathies (TSEs), or Prion diseases, and exists in four forms, defined partly by clinico-pathological features but mainly by causation (Tables 1 and 2). It has the distinction of existing in sporadic, inherited and acquired forms.

TSEs are a group of rather disparate central nervous system (CNS) diseases of animals and humans but are all progressively fatal neurological illnesses characterized by the tissue deposition of a protein, PrP^Sc, which is an abnormal form of a normal cellular protein, the prion protein or PrP^C. Deposition of PrP^Sc is not entirely confined to nervous system tissue, but the pathological manifestations of TSEs are essentially neurological. In human disease, PrP^Sc is formed by a posttranslational conformational alteration of PrP^C that is transcribed from the PRNP gene on chromosome 20 [1].

In sporadic CJD (sCJD), this protein structural change may be a random, spontaneous event. However, two recent studies have found that prior surgical procedures are a risk factor for sCJD, suggesting that some cases may arise from hitherto unrecognized surgical contamination events [2, 3]. In genetic CJD, the gene mutation produces a PrP^C that is more likely to undergo change to PrP^Sc. In acquired forms of CJD, exposure to an infective agent causes the conversion of PrP^C to PrP^Sc [1, 4, 5].

All forms of TSE, including originally non-acquired forms such as genetic CJD, are potentially transmissible. Infectivity is of the highest titre in CNS tissues, but may be present in ophthalmological and other tissues. Direct exposure of the CNS to infectivity carries the greatest likelihood of transmission, but more peripheral routes (e.g. intramuscular, intravenous or oral) may be effective [1, 4, 5]. The nature of the infective agent is not completely clear, but the prion theory holds that PrP^Sc is either the agent itself or a major component of it [1].

Human-to-human transmission has occurred in the forms of iatrogenic CJD and kuru [5, 6]. Table 3 lists the present situation with respect to iatrogenic CJD. It is important to emphasize that to date, instances of such transmission, aside from those related to human growth hormone and dura mater grafts, are extremely rare. Whatever the precise nature of prion infectivity, it can be difficult to inactivate. Routinely used methods of disinfection such as standard autoclaving, glutaraldehyde, ionizing radiation and dry heat are all relatively ineffective. Exposure to sodium hypochlorite, sodium hydroxide and special autoclaving procedures are relatively effective, but such methods are not always practical when dealing with certain instruments. This unusual resistance of the agent to deactivation is one reason for particular concern concerning the potential for surgical transmission of CJD [4].

Variant CJD was first described in 1996 and the earliest case had an onset of the illness in 1994 [7]. It was believed to be due to BSE contamination of food [8]. One hundred and thirty-nine cases have been confirmed in the UK (as of August 2003), with six cases in France, one in the Republic of Ireland, one in Italy, one in the USA and one in Canada. It is important to note that cases are attributed to a country according to the person's country of normal residence at the time of the onset of illness. It is likely that the American and Canadian cases contracted vCJD while in the UK.

The agents that cause vCJD and BSE are identical, both in terms of protein analysis and, more compellingly, in terms of biological behaviour in animals [9, 10, 11]. The epidemiological evidence strongly supports the view that the agent passed from cattle to man and there is no reasonable alternative theory. The means of infection is highly likely to be food contamination and probably mostly by spinal cord remnants in mechanically recovered meat (MRM) added to cheaper pre-prepared products [8]. There is, however, no real proof of this at present. Current understanding suggests that the agent enters via gut-associated reticulo-endothelial tissue and then via nerves to the spinal cord, ascending to the brain. It is also possible that the agent travels to the brain stem along the trigeminal nerves. Again, there is no real proof of this at present. In vCJD, in contradiction to all other forms of CJD, PrP^Sc is found in reticulo-endothelial tissue (lymph nodes, spleen, appendix and tonsil). This PrP^Sc deposition has been shown to be associated with infectivity in these tissues [12].

There have been a number of papers attempting to predict the final number of cases of vCJD that will result from dietary contamination in the UK. However, the predictions are very uncertain, mainly because they have to make a number of assumptions on the basis of several unknowns, not least the incubation period of vCJD. It is possible that the minimum incubation period is around 5 years (in line with what is known of kuru and European human growth hormone-related cases); the mean and maximum remain unknown. At present, the numbers of cases in the UK are increasing on an exponential basis with a predicted doubling time of 4.2 years [13, 14].¹

Other countries are clearly at risk. As indicated above, vCJD is already not entirely confined to the UK. The UK exported animals, animal products and feeds to other countries in the period of potential risk. Other countries have reported BSE, albeit at substantially lower levels than in the UK [15].

In the UK, BSE is in sharp decline and there are many measures in place to protect against further dietary transmission. However, there is obviously concern about the possibility of secondary, iatrogenic spread of vCJD. While there is certain risk from CNS or ophthalmological procedures in symptomatic cases, such events are hopefully avoidable. The uncertainty centers on the possibility that there may be many preclinical cases in the UK who are potentially infective but unrecognized as such. In addition, the fact that PrP^Sc and infectivity is found in reticulo-endothelial tissues in vCJD raises the possibility that general surgical and ENT procedures may transmit disease. In two cases, such PrP^Sc deposition was found in appendices removed routinely 8 months and 2 years, respectively, prior to the onset of neurological disease ([16], personal communication NCJDSU). There is currently no proven case of preclinical involvement of the tonsil. A retrospective survey of routinely surgically removed appendices and tonsils has, to date, found no instance of PrP^Sc positivity [17]. Although this included over 3000 appendices (and 95 tonsils), the negative result does not exclude the possibility of a significantly sized epidemic. The study continues and further results will be available in the very near future. There are official guidelines in the UK for the prevention of infection with CJD [18].