BMJ 2001;323:858-861 ( 13 October )

Education and debate

New variant Creutzfeldt-Jakob disease: the epidemic that never was

George A Venters, consultant in public health medicine. 

Lanarkshire Health Board, Hamilton ML3 OTA

george.venters{at}lanarkshirehb.scot.nhs.uk

In 1996 a new variant of Creutzfeldt-Jakob disease was described and tentatively linked to bovine spongiform encephalopathy as a possible cause.1 Since then a number of studies have been undertaken in an attempt to confirm ingestion of the prion that causes bovine spongiform encephalopathy as the cause of new variant Creutzfeldt-Jakob disease. What was initially a speculation has now evolved into orthodoxy among the medical profession in the United Kingdom if not the whole of Europe, although in the United States the question of causality remains more open.2

Epidemiologists use certain criteria to assess the likelihood of a link between cause and effect for disease. When these criteria are applied to the case for new variant Creutzfeldt-Jakob disease being caused by the bovine spongiform encephalopathy prion the evidence seems weak. Such study also raises the question of whether this is a new disease, as the hypothesis of the infectivity of the bovine spongiform encephalopathy prion to humans and the novelty of the condition are inextricably linked. In this paper I examine the evidence for a causal link between new variant Creutzfeldt-Jakob disease and the bovine spongiform encephalopathy prion and argue in favour of the alternative hypotheses that the variant is not caused by the prion and is not new.


Summary points

The causal link between the bovine spongiform encephalopathy prion and new variant Creutzfeldt-Jakob disease is open to question
Assessment of the evidence against relevant epidemiological criteria reveals the weakness of the case for a link
The rate of growth in the number of cases is very much less than would be expected from a foodborne source
The rate of growth is consistent with a previously misdiagnosed but extremely rare disease being found---this could have resulted from the improved ascertainment of all possible cases of Creutzfeldt-Jakob disease that has been achieved in recent years by the United Kingdom Creutzfeldt-Jakob Disease Surveillance Unit




    Criteria to assess causality

A link between cause and disease can be self evident, but often it can be established or refuted only by a process of extensive observation, hypothesis testing, and experiment. In such cases systematic application of criteria that illuminate different aspects of causation can give an indication of the robustness of the hypothesis. Such criteria are

  • Biological plausibility---how much accord there is between the current understanding of biological and pathological processes and the likelihood of the cause producing the effect

  • Strength of association---how often exposure to the cause leads to the disease

  • Consistency---how consistent the findings are with other studies in different populations and at different times

  • Temporality of association---whether exposure to the cause precedes the development of disease

  • Specificity---whether the putative cause produces only the given disease and the given disease results only from that cause

  • Dose-response relation

  • Quality of evidence---how robust and pertinent is the evidence provided?

  • Reversibility---whether removal of the cause prevents occurrence of the disease.

These criteria are applied below to the case for the bovine spongiform encephalopathy prion being the cause of new variant Creutzfeldt-Jakob disease. The results are summarised in the table.


                              
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Criteria by which to judge likelihood of causality, and their application to the possibility of bovine spongiform encephalopathy prion causing new variant Creutzfeldt-Jakob disease

Biological plausibility
The bovine spongiform encephalopathy prion is known to produce prion encephalopathies when ingested by other species, and by analogy such infection may be possible in humans. However, there is no direct evidence that this prion is infectious to humans. To be infectious it would have to survive cooking, digestion, and the human immune system.

There is evidence for a robust species barrier between humans and prions from ungulate species. Prions produced in ungulates and humans have different sequences of amino acids. People do not get scrapie, and intracerebral injection of the bovine spongiform encephalopathy prion does not cause transmissable prion encephalopathy in mice genetically engineered to carry the gene for the human prion protein.3 Also, ingestion is an inefficient route of transmission of prions other than by cannibalism. Infection of humans from eating the bovine spongiform encephalopathy prion is therefore unlikely.

Strength of association
Details of individuals' exposures to the prion and the occurrence of subsequent disease are unknown.

Consistency of findings
A single unit is both the original proponent and the ultimate arbiter of this diagnosis, and the uniqueness of the circumstances in the United Kingdom makes comparative study difficult. There are, however, inconsistencies in findings. It is presumed that the general British population has been exposed to the bovine spongiform encephalopathy prion, but the disease is found predominantly in young people. Also, cases have been reported in France despite a much lower level of possible exposure of the population to the prion.

Temporality
There are two main components of temporality. The first component is the novelty of the disease as an entity, and the second one is the relation of detected cases to patterns of population exposure to the bovine spongiform encephalopathy prion.

Novelty of the disease
To prove that a disease is new it is necessary to review and legitimately reject other possibilities. Discovery of new variant Creutzfeldt-Jakob disease followed the epidemic of bovine spongiform encephalopathy in cattle and occurred within an incubation period compatible with that observed for kuru, the only previous foodborne epidemic in humans known to be caused by a prion.4 Kuru is a prion encephalopathy found in the Fore people in Papua New Guinea and spread by cannibalism.

The spectrum of clinical and neuropathological features found in kuru includes those found in new variant Creutzfeldt-Jakob disease, and both diseases involve the lymphoreticular system. Neuropathological differences between them may be more of degree than of kind, in that survival of patients with new variant Creutzfeldt-Jakob disease is likely to be longer because they will generally have received better health care than was available to people with kuru. Also, Creutzfeldt's original case died in Breslau aged 23 with clinical features and gross neuropathology entirely consistent with new variant Creutzfeldt-Jakob disease. 5 6 The novelty of the disease is therefore open to question.

Pattern of infection relative to exposure
The pattern of distribution of cases in a foodborne epidemic from a time limited source has a characteristic shape (fig 1). Initial small numbers of cases are followed by a rapidly accelerating rise to a peak. The rate of the rise to the peak is proportional to the rate at which susceptible people are exposed and infected, and the height of the peak depends on how many people are exposed and infected. The duration of the curve reflects the length of time the infectious agent persists as a threat.



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  		Fig 1.   Epidemic curve for the outbreak of Escherichia coli 0157 in Lanarkshire in 1996, all cases

The shape of this curve holds for foodborne infections no matter whether the incubation period is days, as for Escherichia coli 0157, or years, as is the case for prions.7-10 The curve has guided estimation of the rate of bovine spongiform encephalopathy infection in cattle, which is considered to have risen exponentially between 1983 and 1988, peaking at around 350 000 in 1988.9

As these cattle entered the food chain they became a potential source of infection for humans. Consequently, the rate at which humans were likely to have been exposed to infection should have paralleled that curve. As susceptible individuals were exposed and then incubated the disease, we would expect the rate of increase in the number of cases similarly to follow this curve. Cases have been appearing since 1994. Their rate of increase since then falls far short of what would be expected if this was a foodborne infection (fig 2). Temporality of association between cause and effect is therefore at best uncertain.



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  		Fig 2.   Number of referrals and deaths from Creutzfeldt-Jakob disease in the United Kingdom to 2000

Specificity
Interspecies prion infection differs from the conventional understanding of the infectious process, in which an infective agent reproduces itself in the infected cell or animal. Cells can only produce prion specific to the species they belong to, so the bovine spongiform encephalopathy prion can only induce production in the host species of prion with similar physicochemical characteristics to the bovine prion. Bovine spongiform encephalopathy prion itself can never be detected in human brains or in any species other than cattle. Arguments in favour of specificity of the agent are based on strong similarities between the prions for bovine spongiform encephalopathy and new variant Creutzfeldt-Jakob disease in physicochemical properties and strain typing in laboratory experiments with other species. 3 11-13 Consequently, the specificity of the link between the prion and the disease can only be inferred and remains an open question.

Dose-response relation
The dose-response relation is not known for humans.

Quality of evidence
Given that it is impossible to prove that the bovine spongiform encephalopathy prion is infectious to humans, evidence for the case has to be indirect. The evidence that has been amassed is directed towards confirming the hypothesis rather than testing it. Salient contrary information has been either played down or ignored.

Creutzfeldt's eponymous case was not cited in the original paper, nor was kuru considered as a possibility.1 Similarities between kuru and new variant Creutzfeldt-Jakob disease were used to justify the likelihood of ingestion as a route of infection, yet the possibility of them being the same disease was not raised.14

Despite the obvious improvement in detection and reporting of all prion encephalopathies after the establishment of the UK Creutzfeldt-Jakob Disease Surveillance Unit in 1990 (fig 2), better ascertainment does not seem to have been adequately considered as an explanation for the appearance of what was claimed to be a new disease. In the original paper, it was noted that the 10 index cases "would not ordinarily have been referred to the Unit."1 That they were was a result of the widespread concern about the potential infectiousness of the bovine spongiform encephalopathy prion. This resulted in a qualitative change in the type of patients referred to the unit, and among those referred were the index cases.

Extensive experimentation in other species has been undertaken. A theoretically key experiment was the inoculation of human prion protein transgenic mice with bovine spongiform encephalopathy prion. Although the experiment was initially thought to have been successful,13 it failed.3 Therefore, another experiment infecting bovine prion protein transgenic mice with human new variant Creutzfeldt-Jakob disease prion was performed.3 The similarity of lesions produced by this and by bovine spongiform encephalopathy prion in bovine prion protein transgenic mice was used as an argument for the bovine spongiform encephalopathy prion being the cause of new variant Creutzfeldt-Jakob disease. However, it is the wrong experiment---we do not feed human brain to cattle.

Evidence for the case is of variable quality. It seems to have been selectively developed along the lines of the "faggot fallacy."15 (The faggot fallacy is a belief that multiple pieces of suspect or weak evidence provide strong evidence when bundled together.)

Reversibility
The hypothesis will be falsified as and when the disease occurs in people born after the bovine spongiform encephalopathy prion has been eliminated from the human food chain in the United Kingdom.


    Discussion

The quest for precision in medical diagnosis is a perennial and evolutionary process. Over the 80 years since Creutzfeldt's report many attempts have been made to define the boundaries of Creutzfeldt-Jakob disease and identify subtypes within it. Jakob's series became the diagnostic benchmark, and the attributes of his cases prevailed to define what we now call sporadic Creutzfeldt-Jakob disease. Creutzfeldt's case was ignored or forgotten.

In the 1960s British neurologists and neuropathologists were supporting the definition of a condition---subacute spongiform encephalopathy---as different from Creutzfeldt-Jakob disease, partly because they believed it to have a vascular aetiology.16 Other European neurologists were more inclusive, considering that what was being observed were differences in degree within one disease rather than fundamental distinctions between two, and time has proved them right. 17 18 However, new variant Creutzfeldt-Jakob disease is clearly a different disease from sporadic Creutzfeldt-Jakob disease. Whether it is different from kuru or from Creutzfeldt's case will also be clarified with the passage of time.

The final arbiters of the diagnosis of new variant Creutzfeldt-Jakob disease are those who first described it. Diagnostic criteria are already evolving,19 and the age range in which the disease is being sought has been considerably extended. This means that more cases are likely to be diagnosed, giving the appearance of an increase in frequency that is spurious and derives from widening the sampling frame from which cases are drawn. The rate of growth in the observed curve is entirely consistent with the view that improved ascertainment of a previously misdiagnosed disease has occurred.

Failure to refute that either Creutzfeldt's original case or kuru is a previous example of new variant Creutzfeldt-Jakob disease justifies an open verdict on the novelty of the disease and hence the causal link with the bovine spongiform encephalopathy prion. The epidemiological evidence weighs heavily against such a link.

There is a case to be made for the recategorisation of human prion encephalopathies. Apart from inherited and perhaps iatrogenic disorders, they seem to fall into two main groups---one familiar "sporadic" disease (that is, Jakob's disease) and another affecting a younger age group, as in Creutzfeldt's case. The differing features between the groups may reflect infection with a differently conformed prion with a particular pattern of spread throughout the central nervous system. Lymphoreticular system origins of, or infection by, this prion may contribute to the different clinical picture.

Creutzfeldt took seven years and considerable pains to determine the originality of the disease he described. We should emulate his rigour and acknowledge his primacy.


    Conclusion

Without doubt, general anxiety about so dreadful a possibility as bovine spongiform encephalopathy causing a similar disease in humans resulted in many workers involved with bovine spongiform encephalopathy and Creutzfeldt-Jakob disease having to reach precipitate conclusions in which public safety was rightly the prime consideration. I believe that the evidence now available casts serious doubts on the case for a causal link between bovine spongiform encephalopathy and "new" variant Creutzfeldt-Jakob disease. The medical profession should, at least, be publicly debating this as an issue. The purpose of this paper is to start that process.

    Acknowledgments

I gratefully acknowledge the help of Dr David Doyle, Dr Jim Miller, and my sons Drs Angus and Gregor Venters for helping me to refine and focus my arguments. I also thank Dr David Ogilvie and Dr Sahaya Josephine for keeping me right on causality and Ralph Hoeninger and Dr Andreas Weser for their patience and generously given guidance through the German of Creutzfeldt's original paper.

    Footnotes

Competing interests: None declared.


    References

1. Will RG, Ironside JW, Zeidler M, Cousens SN, Estibeiro K, Alperovitch A, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996; 347: 921-925[CrossRef][Medline].
2. Creutzfeldt-Jakob disease. In: Chin J, ed. Control of communicable disease manual. Washington, DC: American Public Health Association, 2000:183-186.
3. Scott MR, Will R, Ironside J, Nguyen HO, Tremblay P, DeArmond SJ, et al. Compelling transgenetic evidence for transmission of bovine spongiform encephalopathy prions to humans. Proc Natl Acad Sci USA 1999; 96: 15137-15142[Abstract/Free Full Text].
4. Lindenbaum S. Kuru: sorcery, disease and danger in the New Guinea highlands. Palo Alto: Mayfield Publishing, 1979.
5. Creutzfeldt HG. Uber Eine Eigenartige Erkrankung des Zentralnervensystems. Zeitschrift f.d. gesamte Neurologie u Psychiatrie 1920; 57: 1-18.
6. Creutzfeldt HG. Ubereine Eigenartige Erkrankung des Zentralnervensystems. In: Nissl F, Alzheimer A, eds. Histologische and Histopathologische Arbeiten uber die Grosshirnrinde. , Vol 6 Jena: G Fischer, 1921:1-48.
7. Cornell J, Neal KR. Protracted outbreak of Salmonella typhimurium definitive phage type 170 food poisoning related to tripe, `pig bag', and chitterlings. Commun Dis Public Health 1998; 1: 28-30[Medline].
8. Patterson WJ, Painter MJ. Bovine spongiform encephalopathy and new variant Creutzfeldt-Jakob disease: an overview. Commun Dis Public Health 1999; 2: 5-13[Medline].
9. Anderson RM, Donnelly CA, Ferguson NM, Woolhouse MEJ, Watt CJ, Udy HJ, et al. Transmission dynamics and epidemiology of BSE in British cattle. Nature 1996; 382: 779-788[CrossRef][Medline].
10. Brown P. Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease. BMJ 2001; 322: 841-844[Free Full Text].
11. Collinge J. Variant Creutzfeldt-Jakob disease. Lancet 1999; 354: 317-323[CrossRef][Medline].
12. Collinge J, Sidle KCL, Meads J, Ironside J, Hill AF. Molecular analysis of prion strain variation and the aetiology of 'new variant' CJD. Nature 1996; 383: 685-690[CrossRef][Medline].
13. Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, et al. Transmissions to mice indicate that 'new variant' CJD is caused by the BSE agent. Nature 1997; 389: 498-501[CrossRef][Medline].
14. Lantos PL, Bhatia K, Doey LJ, al-Sarraj S, Doshi R, Beck J, et al. Is the neuropathology of new variant Creutzfeldt-Jakob disease and kuru similar? Lancet 1997; 350: 187-188[Medline].
15. Skrabanek P, McCromick J. Follies and fallacies in medicine. Glasgow: Tarragon Press, 1989:30.
16. Kirschbaum WR. Jakob Creutzfeldt disease. New York: Elsevier, 1968.
17. Garcia R, Nevin S, Alema G. Synthèse clinique. Report on a symposium on Creutzfeldt-Jakob disease held in Venice 4th - 9th June 1965. Acta Neuropathologica (Berlin) 1967; (suppl III): 145-147.
18. Jakob H, Van Bogaert L. Synthèse des apports histopathologique. Report on a symposium on Creutzfeldt-Jakob disease held in Venice 4th - 9th June 1965. Acta Neuropathologica (Berlin) 1967; (suppl III): 148-151.
19. Will RG, Zeidler M, Stewart GE, Macleod MA, Ironside JW, Cousens SN, et al. Diagnosis of new variant Creutzfeldt-Jakob disease. Ann Neurol 2000; 47: 575-582[CrossRef][Medline].

(Accepted 25 June 2001)

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