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. 2002 Jul 13;325(7355):102.

vCJD: the epidemic that never was

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

R G Will 1, R S G Knight 1, H J T Ward 1, J W Ironside 1
PMCID: PMC1123598  PMID: 12114248

Editor—Venter's article on new variant Creutzfeldt-Jakob disease (vCJD) is intended to stimulate debate, which we hope will be better informed than the article itself.1

Is variant Creutzfeldt-Jakob disease a new disease? Venters places great emphasis on Creutzfeldt's case, but this patient did not have Creutzfeldt-Jakob disease. The illness was characterised by gait disturbance, a relapsing and remitting course, nystagmus, and status epilepticus. These are not the clinical features of variant Creutzfeldt-Jakob disease and, crucially, the neuropathological appearances were “not characterisitic of Creutzfeldt-Jakob disease.”2

In 1996 confidence in the novelty of variant Creutzfeldt-Jakob disease was based largely on the identification of a neuropathological phenotype that was distinct from that experienced in the United Kingdom from 1970. Since then archival tissues have been reviewed in many countries and no past cases with a similar neuropathological pattern have been found.3 Retrospective epidemiological surveys in England and Wales have not identified any missed cases of variant Creutzfeldt-Jakob disease from 1979-96.4 Current evidence strongly supports the hypothesis that variant Creutzfeldt-Jakob disease is indeed a new disease.

Was variant Creutzfeldt-Jakob disease identified solely because of improved surveillance? There was a doubling in the annual death rates for sporadic Creutzfeldt-Jakob disease in the United Kingdom between the 1980s and the 1990s, but similar increases in the apparent death rates for sporadic Creutzfeldt-Jakob disease had occurred in other European countries.5 These countries have been subject to similar potential improvements in case identification, but variant Creutzfeldt-Jakob disease remains a disease occurring predominantly in the United Kingdom, despite significant numbers of young suspect cases being investigated in each country (figure).

Venters argues correctly that the curve for the epidemic of variant Creutzfeldt-Jakob disease does not parallel the number of cattle with bovine spongiform encephalopathy (BSE) between 1983 and 1988. However, human exposure to the BSE agent almost certainly extended to 1996 and depended on a range of variables not addressed by his model. These include the species barrier between cattle and humans, the numbers of cattle in the final year of the incubation period, the load of bovine central nervous tissue entering the human food chain, the efficiency of legislative measures, and temporal changes in food production. Extrapolation from conventional foodborne epidemics to epidemics of variant Creutzfeldt-Jakob disease and BSE is clearly too simplistic.

A wealth of laboratory evidence supports the hypothesis that the BSE agent is the cause of variant Creutzfeldt-Jakob disease.6 Venters states correctly that there is no direct evidence that the BSE prion is infectious to humans, but obtaining such evidence would be difficult to justify ethically as this would involve inoculating humans with the agent. A judgment on the link between BSE and variant Creutzfeldt-Jakob disease inevitably depends on an assessment of a range of clinical, pathological, epidemiological and laboratory based evidence. There is now overwhelming evidence that BSE is the cause of variant Creutzfeldt-Jakob disease, although there remain uncertainties about the future number of cases and the mechanism of transmission of BSE to humans.

Figure.

Figure

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Death rates for sporadic Creutzfeldt-Jakob disease and total numbers of deaths from variant Creutzfeldt-Jakob disease by country

References

  • 1.Venters GA. New variant Creutzfeldt-Jakob disease: the epidemic that never was. BMJ. 2001;323:858–861. doi: 10.1136/bmj.323.7317.858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Richardson EP, Masters CL. The nosology of Creutzfeldt-Jakob disease and conditions related to the accumulation of PrPCJD in the nervous system. Brain Pathology. 1995;5:33–41. doi: 10.1111/j.1750-3639.1995.tb00575.x. [DOI] [PubMed] [Google Scholar]
  • 3.Budka H, Dormont D, Kretzschmar H, Pocchiari M, van Duijn C. BSE and variant Creutzfeldt-Jakob disease: never say never. Acta Neuropathol. 2002;103:627–628. doi: 10.1007/s00401-002-0538-4. [DOI] [PubMed] [Google Scholar]
  • 4.Majeed A, Lehmann P, Kirby L, Knight R, Coleman M. Extent of misclassification of death from Creutzfeldt-Jakob disease in England 1979-96: retrospective examination of clinical records. BMJ. 2000;320:145–147. doi: 10.1136/bmj.320.7228.145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Will RG, Alperovitch A, Poser S, Pocchiari M, Hofman A, Mitrova E, et al. Descriptive epidemiology of Creutzfeldt-Jakob disease in six European countries, 1993-1995. Ann Neurol. 1998;43:763–767. doi: 10.1002/ana.410430611. [DOI] [PubMed] [Google Scholar]
  • 6.Zeidler M, Ironside JW. The new variant of Creutzfeldt-Jakob disease. Rev Sci Tech Off Int Epiz. 2000;19:98–120. doi: 10.20506/rst.19.1.1206. [DOI] [PubMed] [Google Scholar]
BMJ. 2002 Jul 13;325(7355):102.

Creutzfeldt's patient did not have Creutzfeldt-Jakob disease

Markus Reuber 1

Editor—Venters uses Creutzfeldt's original case report of 1921 as an argument against the existence of a “new” variant of Creutzfeldt-Jakob disease (CJD).1-1 Creutzfeldt described a patient who presented to his department aged 23.

She was the youngest of five children, two of whom had mental retardation. The patient's parents were both dead, the cause or date of the father's death was not known, the mother had died of a “non-neurological” disease when the patient was 14. In her late adolescence, the patient was thought to be odd, as she continued to play with dolls and exhibit other childlike behaviour. Aged 21, she refused to eat, claiming that she wanted to lose weight. At the same time, her gait was noted to be “heavy.” Aged 22 she developed a symmetrical rash affecting her face, later also both hands, her groin, and both feet. She was found to have spastic legs and tremor in all limbs. While on a dermatology ward she had a “hysterical seizure” with arc de cercle. It is not clear how she was treated, but all of her symptoms, including the gait disorder, improved.

One year later the gait deteriorated again. At the same time the patient refused to eat or wash, complained about chest pains, and exhibited agitated and paranoid behaviour or inappropriate laughter. On admission to the neurology department she was pyrexic at 38.9°C, incoherent and not oriented in time or space. Her speech had a staccato quality. She had myoclonic limb jerks, intention tremor, nystagmus, increased limb tone, brisk tendon jerks, hyperaesthesia, and hyperalgesia. She gradually deteriorated over three months and died in status epilepticus characterised by tonic seizures, seizures with Jacksonian march, and clonic jerks.

From a clinical point of view, family history, relapsing course, and skin rash would argue against a diagnosis of “variant” or sporadic Creutzfeldt-Jakob disease. More importantly perhaps, Creutzfeldt's meticulous histopathological report does not mention spongiform change (conspicuous in almost all known cases of Creutzfeldt-Jakob disease) or florid plaques (one of the hallmarks of variant Creutzfeldt-Jakob disease).1-2 Creutzfeldt's original pathology slides were reviewed by Jakob who thought the changes were identical to those seen in two of his own patients.1-3,1-4

The tissue from Jakob's two patients was reviewed by the neuropathologist C L Masters in 1982, who found that these patients of Jakob's did not have any evidence of a spongiform encephalopathy. Only his later patients had changes typical of Creutzfeldt-Jakob disease.1-5 The first two patients certainly did not have new variant Creutzfeldt-Jakob disease. Perhaps we should drop the “C” from Creutzfeldt-Jakob disease.

References

  • 1-1.Venters GA. New variant Creutzfeldt-Jakob disease: the epidemic that never was. BMJ. 2001;323:858–861. doi: 10.1136/bmj.323.7317.858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 1-2.Creutzfeld HG. Ueber eine eigenartige Erkrankung des Zentralnervensystems. Z ges Neurol Psychiat. 1920;57:1–18. [Google Scholar]
  • 1-3.Jakob A. Ueber eigenartige Erkrankungen des Zentralnervensystems mit bemerkenswertem anatomischem Befunde (Spastische Pseudosklerose-Encephalomyelopathie mit disseminierten Degenerationsherden) Z ges Neurol Psychiat. 1921;64:147–228. [Google Scholar]
  • 1-4.Richardson EP, Masters CL. The nosology of Creutzfeldt-Jakob Disease and conditions related to the accumulation of PrPcjd in the nervous system. Brain Pathol. 1995;5:33–41. doi: 10.1111/j.1750-3639.1995.tb00575.x. [DOI] [PubMed] [Google Scholar]
  • 1-5.Masters CL, Gajdusek DC. The spectrum of Creutzfeldt-Jakob disease and the virus-induced subacute spongiform encephalopathies. In: Smith WT, Cavanagh JB, editors. Recent advances in neuropathology. Edinburgh: Churchill Livingstone; 1982. pp. 139–163. [Google Scholar]
BMJ. 2002 Jul 13;325(7355):102.

Possibility of BSE being cause of variant CJD is indeed biologically plausible

Steve Dealler 1

Editor—Venters argued against bovine spongiform encephalopathy (BSE) causing variant Creutzfeldt-Jakob disease.2-1 In fact, the biological plausibility of this being the cause, the strength of the epidemiological association, and the experiments indicating that the same prion is involved are all good.

Incubation periods for BSE are proportional to the life expectancy of the animal affected. The disease's incubation period is 18% of a cow's life expectancy and would be expected to about double when crossing to another species—that is, to 36% of 70 years in humans. Thus the incidence of a disease due to BSE in humans would be predicted to peak in 2014. A few human cases would be seen before 2000 and none early in the 1990s. Small outbreaks would be expected early in the epidemic before they become lost among a high background prevalence.2-2 The pattern of variant Creutzfeldt-Jakob disease cases fits this.

Everyone in the United Kingdom has eaten on average over 50 meals of the tissues of cattle infected with BSE; this figure would be lower in other countries. The novelty of variant Creutzfeldt-Jakob disease is not now questioned as it is different from kuru on histopathological grounds and scrapie prion (PrPsc) biochemistry. No similar cases before 1995 have been found.2-3

BSE infects a different range of animals from scrapie and infected all the species inoculated experimentally except chickens and hamsters. It is reasonable that it might infect humans. When fed BSE, 25% of sheep, 33% of goats, 50% of kudu, 100% of mice, and 100% of mink died. Calculating this percentage for humans is difficult as it is early in the epidemic.2-2

BSE prion doses to which humans may have been exposed might well cause large numbers to become infected despite the inefficiency of the oral route. Beef exported from the United Kingdom to France was mainly older animals, specific tissues, and calves. This means that there was a relatively high dose of prions per meal in France, and this fits the number of cases of variant Creutzfeldt-Jakob disease seen there.2-2 Why younger people are apparently becoming infected is not clear, but this does not mean that BSE is not the cause.

Identical pathology and PrPsc glycoforms are produced in mice when variant Creutzfeldt-Jakob disease, BSE, or feline spongiform encephalopathy is inoculated. This is exceptional evidence that the same prion is the cause.2-4 PrPsc associated with BSE will alter human normal prion protein to the abnormal form in vitro,2-5 but it is not surprising that transgenic mice expressing human prion protein did not become infected easily with BSE.

References

  • 2-1.Venters GA. New variant Creutzfeldt-Jakob disease: the epidemic that never was. BMJ. 2001;323:858–861. doi: 10.1136/bmj.323.7317.858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2-2.Dealler SF. Should young UK cattle be considered free of BSE or is it endemic? Br Food J. 2001;103:264–280. [Google Scholar]
  • 2-3.McLean CA, Ironside JW, Alpers MP, Brown PW, Cervenakova L, Anderson RM, et al. Comparative neuropathology of kuru with the new variant of Creutzfeldt-Jakob disease: evidence for strain of agent predominating over genotype of host. Brain Pathol. 1998;8:429–437. doi: 10.1111/j.1750-3639.1998.tb00165.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2-4.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. doi: 10.1038/39057. [DOI] [PubMed] [Google Scholar]
  • 2-5.Raymond GJ, Hope J, Kocisko DA, Priola SA, Raymond LD, Bossers A, et al. Molecular assessment of the potential transmissibilities of BSE and scrapie to humans. Nature. 1997;388:285–288. doi: 10.1038/40876. [DOI] [PubMed] [Google Scholar]
BMJ. 2002 Jul 13;325(7355):102.

Author has overlooked several findings that support his argument

Gordon T Stewart 1

Editor—Venters's reappraisal of variant Creutzfeldt-Jakob disease (vCJD) is important3-1 because, even if new cases of the disease continue to be reported sporadically or in an occasional cluster, there is no evidence of an epidemic anywhere.3-2 But in dismissing the misfolded prion glycoprotein that “causes” bovine spongiform encephalopathy (BSE) as the cause of variant Creutzfeldt-Jakob disease in humans Venters overlooks other findings that support his argument.3-3

Firstly, BSE began in dairy herds in 1986, almost immediately after the Ministry of Agriculture, Fisheries and Food removed controls on foodstuffs for cattle and mandated supplementary feeding with proteinaceous offal, often containing scrapie material, to increase milk production.

Secondly, suckler-fed, grass-fed pedigree herds were virtually unaffected unless they were in contact with dairy cattle.

Thirdly, BSE subsided when supplementary feeding with proteinaceous offal was banned.

Fourthly, ascertainment of unprecedented intensity has shown an excess of all five forms of Creutzfeldt-Jakob disease in the United Kingdom since 1989 but no excess of variant Creutzfeldt-Jakob disease in those at high, continuous, and percutaneous risk of occupational exposure to actual BSE—namely, veterinarians, and people working on farms and in cattle markets, abattoirs, butchers' shops, and canteens.

Fifthly, the same ascertainment has identified variant Creutzfeldt-Jakob disease in younger people with questionable levels of presumed exposure from ingestion of cooked beef or beef products possibly containing BSE prion. An increase in incidence, from 0.8 confirmed cases per million in 1995 to 1.2 in 2000, is continuing, along with an overall increase in total (including iatrogenic) referrals but a decrease in all other forms of Creutzfeldt-Jakob disease. Surveillance of relevant neurological disease in children in the United Kingdom since 1997 has yielded only three cases, although suspect prion is present in tonsils.

Prusiner and his team give reasons for regarding scrapie prion as the common cause of BSE.3-4 But there are genetic and other reasons, as above, for questioning the hypothesis that BSE is directly transmissible to humans. Although published as a witness statement in the BSE enquiry,3-3 these reasons were not discussed in the ensuing (Phillips) report, which preferred to conclude that BSE originated as a mutant of scrapie prion in the 1970s.3-5 It was content to accept common causation on the basis of endpoint similarities in neuropathological features of variant Creutzfeldt-Jakob disease and BSE, as observed in cattle and in transgenic mice bred with the gene for BSE prion and then inoculated intracerebrally with brain material from cattle with BSE.

Factual evidence about the revolution in animal feeding and the nil incidence of variant Creutzfeldt-Jakob disease in close human contacts at highest risk is giving way to artefactual experimental results in mice supporting a hypothesis that BSE prion can cross a further species barrier to cause variant Creutzfeldt-Jakob disease in humans.3-2,3-3,3-5,3-6 This is the scientific hypothesis now used to maintain speculation that anyone who eats British beef or beef products has a lifetime risk—at present, 1.2-1.5 per million persons per annum3-2,3-6—of developing variant Creutzfeldt-Jakob disease and starting an epidemic.

References

  • 3-1.Venters GA. New variant Creutzfeldt-Jakob disease: the epidemic that never was. BMJ. 2001;323:858–861. doi: 10.1136/bmj.323.7317.858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3-2.Scottish Executive. Health Bulletin. 2001;59(6):70. [Google Scholar]
  • 3-3. Stewart GT. Witness statement to the BSE enquiry 2000. www.bse.org.uk refs 586 and 586 annex.
  • 3-4.Peretz D, Williamson RSA, Klotoshi K, Vergara J, Leclerc E, Schmit-Ulms G, et al. Antibodies inhibit prion propagation and clear cell cultures of prion infectivity. Nature. 2001;412:739–743. doi: 10.1038/35089090. [DOI] [PubMed] [Google Scholar]
  • 3-5.Following through on Phillips (report of the BSE inquiry) Nature. 2000;408:1. [Google Scholar]
  • 3-6.Stewart GT. More on BSE/CJD. J R Soc Med. 2002;95:112. doi: 10.1258/jrsm.95.2.112. [DOI] [PMC free article] [PubMed] [Google Scholar]

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