Q J Med 2000; 93: 617-631
© 2000 Association of Physicians
Commentary papers |
Is there evidence for exogenous risk factors in the aetiology and spread of Creutzfeldt-Jakob disease?
From the Welsh Combined Centres for Public Health, University of Wales College of Medicine, Cardiff, UK
Introduction
The transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases of unknown aetiology, and affect both animals and man. As a group, they have several unique features that separate them from other neurodegenerative conditions, notably characteristic neuropathology and the ability to be transmitted to experimental laboratory animals by inoculation.
Creutzfeldt-Jakob disease is a rapidly progressive dementia and is uniformly fatal. There appears to be a genetic basis in 10–15% cases, termed familial, and a small number of cases are associated with medical interventions and are termed iatrogenic. The majority of cases appear to arise spontaneously and are, thus, termed sporadic Creutzfeldt-Jakob disease (spCJD). Recently, a number of atypical cases of CJD have arisen, almost exclusively in young people in the UK. This new disease has been termed variant CJD (vCJD) and there is mounting evidence that it is the same disease as the animal TSE, bovine spongiform encephalopathy (BSE).
Aetiology
The cause of TSEs remains an area of considerable scientific uncertainty and debate. However, the neurodegeneration observed in the brains of affected animals and humans is accompanied by the pathological accumulation of an aberrant form of a normal ubiquitous cell surface glycoprotein, prion protein (PrP). The hypothesis that the aberrant PrP is the transmissible agent, known as the ‘prion’ theory, is fully described elsewhere,1–4 and is currently the most widely accepted explanation for the transmissibility of these diseases.
What might cause the transformation from the normal prion protein (PrP) to the pathogenic PrP is also the subject of intense debate. There are two contending hypotheses. The first is that the normal PrP spontaneously undergoes a conformational change to an aberrant form of the PrP. This aberrant PrP, resistant to enzyme degradation, accumulates in brain tissue and causes cell death. Thus, the sporadic form of CJD (spCJD) represents the spontaneous mutation of the ‘normal’ prion protein,5 and there is, by extension, no exogenous risk factor.
The second hypothesis suggests that disease is caused by the introduction of an aberrant form of the prion protein from some exogenous source which acts as a template for conversion of normal host prion protein to the abnormal form, resulting in neuronal cell damage and, eventually, cell death. Both hypotheses have problems in explaining the facts as observed.
It is, of course, possible that the two hypotheses are not mutually exclusive. It may be that a proportion of spCJD cases are truly sporadic (idiopathic), while others are the result of unidentified transmission events. Even invoking this more complex explanation, however, still requires us to consider the balance of idiopathic to exogenously acquired cases, not least because the two hypotheses suggest different approaches to the prevention of disease.
In this article we review existing epidemiological observations for each of these hypotheses, consider critically the handful of case-controlled studies and suggest methods of improving epidemiological surveillance. In asking how does man develop spCJD, we also consider whether vCJD is a helpful analogy, and whether what we know of transmission of BSE could help explain the source and spread of spCJD in at least some cases.
Methods
There are now over 67 000 citations listed on MEDLINE (OVID) under the heading of prion disease/transmissible spongiform encephalopathy. We conducted a MEDLINE (OVID) search from 1959–99 using the term ‘prion disease’ and ‘epidemiology’ and combined the two. This resulted in 2189 citations. A further search was performed using ‘CJD’ and ‘epidemiology’. Combining these terms resulted in a further 45 citations, 34 of which were in English only. The abstract of each citation from both searches was obtained and if the paper described a case report, case series, case cluster, case-control study or review, the full paper was requested. Further articles of possible relevance were selected by reading the titles of the references of these papers and obtaining case reports, case series, case clusters, case-control studies or articles containing epidemiological terms. In addition, the seven annual reports of the UK National CJD Surveillance Unit were reviewed.
Definitions
The terms used in this text regarding definite, probable and possible cases of CJD are based on the diagnostic criteria of Masters6 and are given below. Although these criteria have been superseded by WHO guidelines,7 it is important to realize that the modern techniques of immunocytochemistry were unavailable at the time that many of the articles in this paper were published, and it is for this reason that we quote the Masters criteria in full.
Transmissible virus dementia (synonymous with definite CJD)
Cases experimentally transmitted to nonhuman primates and/ or other animals, producing an experimental spongiform encephalopathy
Definite or probable CJD
Definite CJD
Neuropathologically confirmed spongiform encephalopathy in a case of progressive dementia with at least one of the following features: (i) myoclonus; (ii) pyramidal signs; (iii) characteristic electroencephalogram; (iv) cerebellar signs; (v) extrapyramidal signs.
Probable CJD
Neuropathologically unconfirmed cases with the same clinical features as above.
Possible CJD
History, without medical records allowing confirmation, of progressive dementia with: (i) myoclonus and a course of <3 years; or (ii) a member of the family having transmissible definite or probable CJD (Groups I, IIA, IIB); or (iii) at least two of the clinical features listed for IIA together with the appearance of prominent and early signs of lower motor neuron involvement (the amyotrophic form of CJD).
Animal studies
Studies in animals defined this group of neurodegenerative diseases in animals and man, demonstrated them to be transmissible but with a variable ‘species barrier’ and provided evidence that different routes of transmission (intracerebral, intraperitoneal, intramuscular, subcutaneous and oral, in decreasing order of efficiency of transmission) can spread these diseases. Susceptible experimental primate and non-primate hosts to various TSEs are shown in Table 1
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The cause of CJD: findings of case reports, series and surveys
National and regional surveys
From the large number of national and regional surveys (Table 2) of spCJD, certain statements can be made. Sporadic CJD occurs world-wide. The reported male to female ratio is approximately 1:1. There has been a reported incidence per million population varying from 0.06, in an early Italian study, to 1.60 in a recent study from Canada. Overall reported incidence is increasing world-wide. The reason for this is unclear but is usually attributed to better case ascertainment.
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The median age of death is 65 years. Below the age of 40, the incidence is extremely low, but increases steadily, reaching a peak of approximately 2/million/year in the 60–69 group. Most retrospective studies have demonstrated that disease incidence drops steadily after the age of 70. However, the most recent UK CJD Surveillance Report11 and a study in Italy12 both show that the greatest relative increase in mortality has occurred in those aged 70 years and above.
Clusters of cases
Something which is difficult to reconcile with the hypothesis that the initial event in spCJD is a spontaneous conformational change in PrP, in the absence of exogenous factors, is the existence of apparent clusters of cases. There have been at least eight of these reported19,25,36–39 and one for vCJD.
Libyan Jews
A countrywide search for CJD in Israel uncovered 29 cases with onset between 1963–72.25 The incidence in various ethnic groups varied from 0.4 to 1.9 per million, except among Jewish immigrants from Libya, among whom the incidence was 31.3 per million. The eating of lightly cooked sheep brain, a delicacy amongst Mediterranean Jews, was at first postulated to be responsible, but the incidence of CJD amongst other ethnic groups with the same dietary habits was only 1–2 cases per million of the population. Subsequently a genetic mutation at codon 200 of the prion protein gene (PRNP) has been discovered in this ethnic group40 and would explain this increased rate of disease seen. The accepted view is that this mutation predisposes an individual to spontaneous transformation of the normal soluble prion protein into the abnormal insoluble isoform. This hypothesis is supported by the experimental observation that transgenic mice carrying one of the mutations associated with Gerstmann-Straussler-Scheinker disease (GSS), a rare hereditable human prion disease, also spontaneously develop a spongiform encephalopathy.41 However, could this mutation have its effect by predisposing to susceptibility to an environmental cofactor? A more recent study by Zilber42 attempted to answer this question. They argue that a direct answer could be obtained by studying, either the incidence of CJD among the non-Jewish population in Libya (same environment as the Libyan immigrants to Israel but different ethnic group) or the incidence of CJD among Israeli born Jewish population of Libyan ancestry (different environment but same ethnic origin). Unfortunately little epidemiological data exist about the incidence of CJD in Libya, and most of the cases, who emigrated to Israel in 1949 and their children, born in Israel, are still too young for epidemiological study. Instead, they tested their environmental hypothesis indirectly. They made the assumption that the probability of becoming infected would increase with length of stay in Libya if there were an environmental risk factor. They found no indication of any difference in probability of CJD by age at immigration.
The codon 200 mutation is not confined to Libyan Jews. It has been found in families affected by familial CJD in Slovakia,43 Chile,44 America and Japan,45 countries with very different cultures. This suggests that an environmental cofactor would have to be ubiquitous. Also the codon 200 mutation does not automatically predict development of clinical disease. Low degrees of disease penetrance (as low as 56% carrying the mutation44) also suggest that other genes or environmental factors may contribute to the expression of disease in these mutation positive families.
The English clusters
Matthews described three geographical clusters in England. The first concerned a small rural community in the Midlands and involved three cases. Case 1, a woman of 46, died in 1964 and 4 years later, case 2, a woman of 34, died of CJD. Case 2 had regularly spent time at her sister's residence 2 km from the first case. Case 1 probably met case 2, but this remains unconfirmed. In 1971, case 3, a 54-year-old man died of CJD. He had lived in the same village as the sister of case 2 during the 1960s.
The second cluster involved five cases with onsets between 1969 and 1973 in four towns/villages in eastern England (separated by no more than 20 km), of whom at least three had lived locally since 1960. No definite contact between cases could be established.
The third cluster described a patient who died of confirmed CJD in 1965. In 1968, a patient who lived within 250 m also died of the disease. Although they shared the same General Practitioner, their medical records had been destroyed, and no further information was available. In 1980, a patient who lived midway between the two previous patients and within sight of both houses died of pathologically-proven CJD. This last patient had been a dentist from 1950–77, and used his house as a surgery. Although the dental records have been examined, they were incomplete and did not include records of either of the previous two patients.39
An Italian cluster
Eleven cases of CJD occurred in and around Parma, Italy, between 1975 and 1979. Of the 11 cases, five were farmers. Case 1 was a man aged 50 who had been born into a farming family. From 1936–9, he had lived in Ethiopia, and from 1940 to 1946 in Libya. Since then he had been a lorry driver. He had been otherwise fit, except for contracting malaria at age 30, and having surgery in Libya for a strangulated hernia. Case 2 was a miller who lived in the country 10 km from Parma. Cases 3, 4 and 5 were described as small landowners and farmers. Case 4 had a gastrectomy in 1960. Case 6 was a blacksmith, and had previous surgery for carcinoma of the lip. No details are given for case 7. Case 8 lived permanently in Parma but had spent two short holidays in the same village where case 3 had lived. Case 9 had been a farmer, and cases 10 and 11 had both been housewives, although the latter had at one time been a cook.38 No spatio-temporal analysis was attempted and no conclusions can be drawn.
The Chilean cluster
A cluster in Chile, involving four cases of histologically-proven CJD in three farmers and one housewife, occurred in 1982–3. The four lived in small rural communities situated within a 20-km radius of the town of Chillian. They were unrelated and did not know each other. Their life long dietary habits are of interest, but uncertain relevance. They all consumed uncooked sheep blood and poorly-cooked sheep blood and brain.
Although the existence of clusters might be said to constitute persuasive evidence for an exogenous environmental factor in the aetiology of CJD, it must be remembered that some clustering may occur by chance and that ascertainment of a first case may predispose to ascertainment of further cases.46
Case-to-case transmission in humans: case reports and series in which spread through everyday human contact is suggested
There are six reports in which this possible mode of transmission is considered. The most recent is that of a couple from the USA who had been married for 30 years.47 The husband died at age 53. He had no relevant family history, but had had a rotator cuff repair one year before disease onset. His wife developed symptoms four and half years after her husband's death. She was morbidly obese and had had a previous hysterectomy, hernia repair and cholecystectomy. Both occasionally ate brains in the form of ‘kizka’, a type of sausage.
Immunocytochemistry confirmed pathogenic prion protein deposition in brain tissue from both husband and wife. Full sequencing of the open reading frame of the PRNP failed to demonstrate any pathogenic mutations. Another suspected conjugal case has recently been shown not to be CJD. The histopathological specimens did not stain for prion protein despite the microscopic appearance of spongiform change.48
Sporadic CJD has been described in two co-workers who shared a school wing for 9 months.49 The first was a 48-year-old Californian-born man of Hispanic American descent who had had a traumatic leg amputation at age 23, but was otherwise well. The second was a 48-year-old Chilean-born male who had a blood transfusion 6 months before onset of symptoms, and was known to eat lambs' brains. The first patient developed symptoms 5 months after the last contact with his colleague and was confirmed to have spCJD 2 months after this. The second patient developed symptoms months later and died 9 months after the last contact with his colleague.
An English woman, who died of CJD, histologically confirmed at post mortem, was known to have contact with several affected members of a family with familial CJD and was related to them by marriage.39 She had known one of the family, who later died of CJD and had afternoon tea with her at family gatherings, twice a year, for 20 years, as well as visiting in her final illness. The woman herself died 12 years later. There is another similar case of probable CJD, reported in a Chilean woman who died 13 years after contact with a family with familial CJD. No details of contact are given. A third case of death from CJD in someone related in marriage to a family with familial CJD has been reported in France, in a Tunisian family. No details are given with regards to family history or contact.21 What is notable about these last three incidents of supposed infection by social contact is that all have occurred in association with familial CJD. Although these patients were not known to have been genetically related to their spouses, the possibility that they came from the same gene pool cannot be dismissed.
Iatrogenic case-to-case transmission in humans: case reports and series in which iatrogenic transmission has been proposed
It is clear that CJD can be transmitted from person to person by injecting or implanting CJD infected instruments, tissue extracts and organs.50–52 Several points relevant to a wider understanding of the epidemiology arise. (i) The time from inoculation to disease onset is dependent on the route of entry, the shortest incubation being approximately 16 months, in the case of implantation of cerebral electrodes and recipients of corneal grafts. By contrast, the longest incubation time is 30 years following subcutaneous and intramuscular injection of growth hormone extract and of gonadotrophins. These incubation times call into question some of the proposed case-to-case transmission scenarios (above). (ii) The route of transmission predicts the clinical appearance. Those infected directly into the central nervous system develop a global dementia, whereas those infected peripherally develop a progressive cerebellar syndrome. The genotype of the prion gene does not explain this difference. That the peripheral route of infection presents as a cerebellar syndrome would support the view that vCJD is acquired peripherally by, for example, diet, as cerebellar signs are an early prominent feature of vCJD but not of spCJD.
Blood transfusion
The infectivity of blood for TSEs in animals is well described.53,54 In experimental scrapie, serum from infected sheep has transmitted the disease to mice following intracerebral inoculation. Rat-to-rat transmission has been demonstrated, also following inoculation of serum intracerebrally. Infected mouse whole blood has been used to infect previously healthy mice via the intracerebral route. Experimental CJD in a guinea pig has transmitted to other guinea pigs by inoculation of buffy coat (leukocytes and platelets) by the intracerebral, intramuscular, intraperitoneal and subcutaneous routes, and inoculation of infected mouse buffy coat by the intraperitoneal route has caused disease in healthy mice.
Nevertheless, attempts to transmit CJD by infusing units of blood from patients with CJD to the chimpanzee have failed.55 Although experimentally difficult, transmission of spCJD and human growth-hormone-related iatrogenic CJD to mouse, hamster and guinea pig, by buffy coat and whole blood, has been demonstrated on four separate occasions,53 but only after intracerebral injection. This suggests that transmission from human to human, via blood and blood products, is difficult but theoretically possible. A number of case reports have suggested that transmission by the transfusion of blood or a blood product has occurred in humans.
In Australia,56 Klein reported on four patients who had died of CJD in the early 1990s. None had a history of familial CJD or had received human pituitary growth hormone (hGH) or gonadotropin (hPG), but each had received a blood transfusion 5 years before onset of symptoms. Unlike other reported cases of blood-transfusion-related CJD cases, all presented with symptoms of CJD suggestive of infection by the peripheral route—a cerebellar syndrome in the absence of early dementia. Concern was raised that these patients may have received blood from 1500 women who had received pituitary gonadtrophin for infertility, three of whom have already died of CJD ascribed to CJD-contaminated hPG. Of these three women, two are known to have been regular blood donors.
There is only a single confirmed case of spCJD who is known to have received albumin from a donor with confirmed CJD.57 This was a 69-year-old Canadian man who received 3 units of albumin during surgery for a triple-coronary-artery bypass graft. The patient became symptomatic 8 to 10 months post transfusion, and died one year later.
One case-control study has examined blood transfusion in spCJD. Esmonde58 identified 202 definite and probable UK cases of spCJD between 1980–4 and 1990–2. Twenty-one patients had received blood, and 29 had donated blood. This frequency of blood transfusion or donation did not differ from that in age- and sex-matched controls. The clinical features in patients with a history of blood transfusion were similar to those with a history of classical spCJD and clearly distinct from CJD in recipients of human growth hormone. However since spCJD is a rare disease and the number of potentially infected units of blood is small, any difference in the rate of receipt of transfusions between cases and controls will be small. Thus a case-control study would have to be very large to detect such a small difference.
Dietary factors: case reports and series compatible with the dietary route of infection
Several case reports and series have reported an apparent increase in the prevalence of CJD in populations of people who eat sheep or wild animal brains. There has been one case report of definite CJD in a Dutch man who ate occasional sheep brain and an annual feast of hog brain,59 and a case series of four patients from North America who all ate squirrel and other animal brains, including goat.60 A more recent case series obtained a history of eating squirrel brains in all five patients with probable or definite CJD seen over 3.5 years in a neurocognitive clinic in Western Kentucky, USA.61 There are, however, two reports of CJD in vegetarians. Matthews described a case in a 62-year-old lifelong vegetarian.62 Although she had never eaten meat, meat products or offal, she had handled raw meat, preparing food for her husband. A study of seen patients from India63 revealed that two cases had been vegetarians, but no further details are given.
Zoonotic transmission: case reports and series compatible with infection from animals
CJD and scrapie exist together in many countries, but the incidence of CJD in countries where there is no scrapie, such as Australia, New Zealand and Chile, (Table 2
) is no different from that in scrapie-endemic countries.
In France, a detailed study looking at regional distribution of CJD and scrapie infected flocks found no relationship.64 Nevertheless as CJD is rare, the incubation period may be very long, and both human and animal populations may be very mobile, thus any reassurance would have to be qualified.
A recent case of an Italian man and his cat65 is of interest. A 60-year-old man developed CJD in November 1993 and died 3 months later. His cat developed a neurological disease at the same time, and was killed at the time of her owner's death. Strain typing suggested that the man was a case of sporadic CJD. The cat had the same strain, distinct from the feline spongiform encephalopathy (FSE) strain, described in the UK in the early 1990s.66 Zoonotic transmission would require that the cat had infected her owner whilst pre-symptomatic. A common source for both cat and man would seem more probable. The circumstances would be hard to explain without an exogenous source of disease.
Matthews67 described definite or probable CJD in four patients all of whom kept ferrets for pets. One of the cases, who had also kept ferrets 30 years previously, had definitely been bitten by a ferret 2 years before disease onset. After his death, the ferret was killed and examined histologically but no spongiform change was found. In addition the brain of the ferret was inoculated into four species of monkey and one cat, all of whom remained well. No such studies were performed with the other cases.
Finally, Brown68 mentions two cases of CJD in patients who, a year before diagnosis, had hip replacements from goats as well as a case who had been a member of the French Foreign Legion and had had sexual relations with a goat.
Occupational exposure: observations from case reports and series
Case reports and series focus on two main occupational groups; health professionals and those who are exposed to farm animals, in particular sheep and cattle.
There are at least 26 reports of sporadic CJD in health-care workers world-wide.69–71 These include seven physicians, including a neurologist and head of an intensive care unit, two neurosurgeons, an orthopaedic surgeon and a pathologist, three dentists, a dental surgeon, nine nurses, three nursing assistants and two histopathology technicians. Clinical details are available for six of the cases.
Berger70 describes a 58-year-old physician who died of definite CJD and who, 20 years previously, had frequently performed autopsies. Weber71 described a case in a 55-year-old orthopaedic surgeon who died of definite CJD. The clinical picture was suggestive of a peripheral route of infection. Twenty years previously, he had handled both sheep and human dura mater. The specimens of dura mater were later sent to a company that sold dura mater preparations that subsequently transmitted CJD on six occasions. His wife did not remember any definite injury during the time he was working with dura mater. Schoene72 reported a case with an atypical clinical presentation including necrotizing cutaneous lesions with vasculitis in a 54-year-old neurosurgeon, which was later confirmed, as CJD, by experimental transmission. There was no definite history of exposure to any case of CJD. In a case in a pathologist,73 he is known to have performed over 14 000 autopsies, but it is not known if any of them were cases of CJD. There is no information on the dentists or nurses. One of the two histopathology technicians had been a neuropathology technician for 22 years74 and had come into contact with two cases of CJD, 16 and 11 years before the onset of her disease. The other technician75 had been exposed to animal and human brain.
A wide range of occupations have been reported among cases of sporadic CJD.6,21 Several case series quote an excess number of farmers and farmers' wives.24,30 In an Italian study,24 the incidence was three times the expected. An analysis of epidemiological surveillance data in the UK from 1970–9616 revealed a statistically significant excess of cases among dairy farm workers and their spouses and among people with greater degrees of contact with live cattle infected with BSE. No such excess was found in abattoir workers butchers or meat cutters.
Case-control studies
Case control studies are the time-honoured way of studying rare diseases. To date there have been seven case-control studies of spCJD in humans.
Methods
A synopsis of these, with their methods of case and control selection and how information was obtained is given in Table 3. Table 4 gives the significant findings from these case control studies.
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Selection of cases
Each study used series of cases referred to research or surveillance institutions with a particular interest in spCJD. In the Japanese, UK and Australian studies, the cases were anticipated to be most of the cases occurring in the geographical area over the period of the study. Selection criteria were based on ‘characteristic’ clinical presentations of spCJD (above). Less characteristic presentations, particularly if they resulted in atypical patterns of referral, may not have been included.
Selection of controls
Various control selection procedures were used with different inherent strengths and weaknesses. In the first American study,76 relatives were asked to select a friend of the patient, matched for age and sex. In the Japanese study,75 relatives were asked to select a neighbour and if this was not possible, public health personnel were allowed to serve as the control. Of the potential 75 eligible questionnaires, 15 were rejected, with the reason for rejection not being given. In the second American study,79–81 relatives were used as one control group and hospital in-patients as a second. For the hospital controls, an introductory letter was sent to the medical records department of each of the hospitals from which the cases had been reported. Identifying data was gathered on ten in-patients matched for sex and age who were admitted, as close as possible to the same date as their corresponding case. Potential controls with mental or neurological disease were excluded. A hospital control was selected from this pool of 10 patients using a random number table. In the England and Wales study of 1980–4,14 two control groups were again selected; hospital patients with neurological disease (one group) and those with non-neurological disease (the other). Suitable controls were selected by questioning ward staff and accepting the first offered patient. The selection criteria used by staff were not described. The 1993–5 European study82 simply states that control participants were recruited from the hospital where the patient who had spCJD had been diagnosed and, apart from the exclusion of patients with dementia, no further information is given on selection. Finally for the control group for the Australian study, the authors randomly selected three community controls for every case by using a random telephoning dialling survey, stratified by age, sex and urban or rural residence.
Respondent-nominated controls, such as used in the first American study, may have lead to an over-representation of controls with similar occupations and social backgrounds. Selecting controls from relatives may obscure inherited risk factors for disease. Selecting from hospitals has the potential to mask associations with other medical and health care procedures, through overmatching, even though individuals with mental or neurological disease were generally excluded.
Measurement
To turn from selection to measurement, a central difficulty with all the case-control studies in CJD is that the patient is invariably too demented to give any useful history by the time the diagnosis is suspected. Thus a spouse or close relative was approached to answer, on behalf of the patient, whereas, in many studies, the controls respond on their own behalf. The differences in case and control selection and in obtaining data would be sufficient for there to be observed differences in the risk factors for CJD even if they were truly the same.
Interpreting results
There are, of course, problems in interpreting statistically significant differences that emerge from multiple tests. The Davanipour study of diet, for example, investigated 45 items, and various categorizations of exposure were tested.
Given that the studies span Europe, Asia, Australia and North America, it is of note that similar categories of risk factors do emerge; consumption of undercooked meat and offal products, contacts with various small biting animals and working in, or receiving health care, notably surgical procedures. The re-analysis of pooled data from the two American, Japanese and early UK case-control studies offers little further by way of insights.85 The authors found that the risk of CJD was statistically significantly increased for patients with a family history of CJD. There was also an elevated, but non-significant, risk of CJD for subjects with a family history of dementia other than spCJD, a history of poliomyelitis, for subjects employed as health professionals and subjects ever exposed to cows and sheep. If the associations observed were due to recall bias, for example, it seems rather surprising that similarly differential recall occurs across different populations and cultures.
Variant Creutzfeldt-Jakob disease (vCJD)
Background
Variant CJD, the most recently described TSE in man, was first described in 1996 by Will and Ironside of the UK CJD Surveillance Unit.86 Several clinical characteristics distinguish it from spCJD: young age, predominance of sensory and psychiatric presenting symptoms, disease duration, lack of specific EEG changes and characteristic neuropathology, in particular large kuru-like plaques.86–88 Variant CJD has now been convincingly linked by laboratory studies to BSE.89–91 How the infection got from cattle to humans remains obscure, but is assumed to have occurred via the consumption of affected bovine material, especially brain and spinal cord.
By the end of 1999, there were 51 reported cases, 49 cases occurring in UK citizens and two suspected cases in French citizens. Up to 31 December 1998, the median age at onset of the disease was 28 years and the median age of death at 29 years (compared with 65 years for spCJD).
Cluster
A cluster of vCJD cases in East Kent has occurred.92 Four confirmed cases lived in Kent during the 1980s, and a fifth had been resident at a boarding school, a statistical excess of cases based on the assumption of a Poisson distribution.93 Subsequent re-analysis on a larger number of cases (34 by end of December 1998) suggested that the number of cases observed was not excessive, but this conclusion has been questioned.94
Case-control study
An on-going case-control study by the UK CJD Surveillance Unit has not consistently identified any medical, dietary or occupational exposure. However in the 1998 report,92 cases were reported to have consumed beef more frequently than controls (p=0.02)11 and consumption of venison was significantly associated in two earlier reports.95,83 There is also an excess of nurses and catering workers in the vCJD group, although the cases have outnumbered the controls (34 vs. 24) and these have been hospital-based.
Explaining the source and spread of CJD—hypotheses
If each case of CJD does not simply start all over again from nowhere, as the hypothesis that spCJD represents the spontaneous mutation of the ‘normal’ prion protein5 implies, then a central problem becomes how such a rare disease is sustained in a human population. We know case-to-case transmission can occur by injection or implantation of CJD-infected material,50–52 and it seems that surgical instruments, even following sterilization, can occasionally transmit the disease. The ‘dose response’ seen in the rise in risk in relation to the number of operative procedures in the Australian case control study84 would be consistent with such an explanation as would the slight excess of cases seen among health care workers. Nevertheless, as Matthews et al. observed, as long ago as 1979, ‘it is difficult to conceive that such a rare disease as spCJD could be maintained solely by case to case transmission and some reservoir of infection, animal or human is probable’. Thus, an animal reservoir, which clearly exists for vCJD, should, at least, be considered for spCJD. There is some evidence that would support the hypothesis that spCJD could be transmitted through zoonotic exposure both directly and by diet.
To consider first dietary exposures, in particular raw meats and offal, which emerge in both case studies and case-control studies, infection could be introduced in various ways, for example, inoculation via conjunctivae, oral mucosa or gut mucosa and even inoculation during food preparation.
Direct transmission from affected herd animals is at least plausible, and might explain the frequently observed excess of CJD in farmers. However, no such excess has been seen in other occupations that deal with animals, such as slaughterhousemen and veterinary surgeons. Could zoonotic transmission occur from small biting animals, particularly when there appears to be no naturally occurring TSE in many of the animals in question? There are several possible reasons for considering this, especially as they have been postulated as risk factors in a number of studies. First, TSEs may occur naturally in small biting animals but remain unrecognized. Thus, for example, TSEs in cats, of which there would appear to be more than one type, have only been recognized in the last 10 years. Secondly, small biting animals could inoculate material from other animals such as cattle or sheep. Thirdly, TSEs could occur, but with an incubation period longer than the natural life expectancy of the animal.
Can we learn anything about spCJD from vCJD (which is now widely accepted to be BSE in humans)? What was the source of BSE in cattle and how did the disease get from cattle to man? That the origin of BSE was associated with consumption of ruminant-derived foodstuff by cattle is not in doubt. But what got into the cattle feed in the first place? There is reason to question the received view that it was scrapie-infected sheep. There appear to be over 20 different ‘strains’ of scrapie, but only one ‘major strain’ of agent causing BSE. So far, none of the scrapie ‘strains’ appear to match with this BSE ‘strain’.89,96 Secondly, scrapie has been known to be endemic in sheep for more than 200 years without apparent transmission to cattle. Thirdly, when BSE homogenate is injected or fed to sheep, it produces different clinical signs to classical scrapie. The sheep do not show signs of incoordination or rubbing, but rather a ‘progressive lethargy culminating in recumbency within one to two weeks’.97 Finally, the changes in the rendering processes, especially the decrease in the use of solvents, which are postulated to have allowed the scrapie agent to survive in sufficient amount to infect cattle by the oral route97 were not confined to the UK. It is worth considering whether it could be the rendering of other animals with TSEs which was the source of BSE and therefore vCJD. Were this the case then, by analogy, could a hitherto unrecognized animal reservoir exist for spCJD? To the untutored eye, the published strain phenotypes of spCJD appear rather more homogenous of those of scrapie. By way of an, admittedly speculative, illustrative possibility, consider deer. TSE occurs in wild deer (mule deer and elk) in Northern America, with a prevalence of 2.5% in northeastern Colorado and Wyoming. Elk will breed with red deer, a native of Britain, and consumption of venison has increased over the last 2–3 decades. To move from speculation, of which there has arguably been too much, to the scientific examination of hypotheses, a number of approaches could be taken. Records of rendering plants where cases of BSE occurred early in the epidemic could be reviewed to see if deer were rendered and in what numbers. Secondly, sequencing of deer prion genes could be performed and compared with cattle, sheep and human sequences. Thirdly, strain phenoytyping of CWD in mule deer and elk could be performed and compared with scrapie, BSE and CJD.
Future epidemiological studies
Even if the source of vCJD and BSE were unequivocally known and, for that matter, if there were a similar zoonotic source for spCJD, there would still be much to learn about how the diseases might spread. This, it could be argued, is mainly an epidemiological task and one where an active approach to vCJD might lead to knowledge applicable to spCJD. Such an active approach would, in effect, approach the emergence of vCJD using an outbreak investigation strategy. Components of this would include a specific, hypothesis-driven, case-control study and active field investigation of reported clusters, incidents where potential transmission has been proposed and of cases in relevant occupational groups. A case-control study would need four to five community controls per case. Ideally, blood would be obtained for genetic analysis so genetic susceptibility of controls would be known and could be controlled for in analysis. Exposure data would be obtained by face-to-face interviews with household companions of cases and controls. Questions would focus on very specific histories of ingestion of commonly eaten products known to contain specified bovine offal as well as more exotic offal. Details as to purchase and preparation preferences would also be obtained. Questions regarding inoculation injuries in the presence of raw beef, beef products, offal and preparation of venison would be asked. Cumulative measures of exposure would need to be made. Ophthalmic and dental histories would be sought. Histories of encounters with animals in domestic and occupational settings would be obtained with attention being given to recording the range of species, the extent of the exposure and the health of the animals to which the subjects were exposed.
At least some of these tasks might be addressed by repeating the recent Australian study, which used telephone controls, in a UK or American setting, which would also indicate if the results could be replicated.
Conclusions
The hypothesis that spCJD is caused solely by genetic abnormalities leading to a spontaneous mutation of prion protein, favoured in the 1980s, looks increasingly incomplete. As predicted by Matthews in 1979, reservoirs of infection, notably zoonotic, may well exist and a perhaps a smaller number of cases are caused through iatrogenic and person-to-person contact. It is possible at least some cases of what has been labelled spCJD are caused by a complex zoonotic cycle of the type familiar to us, for example, from Hydatid Disease, Lyme Disease or toxoplasmosis. Delineating this will unravel further the complex epidemiology of these diseases, and may assist critically in their prevention.
Notes
Address correspondence to Dr C.E.M. Hillier, Welsh Combined Centres for Public Health, University of Wales College of Medicine, Abton House, Wedal Road, Cardiff CF4 3QX. e-mail: charlie.hillier{at}cdsc.wales.nhs.uk1 
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