NR ALXX
AU van Duijn,C.M.; Delasnerie-Laupretre,N.; Masullo,C.; Zerr,I.; de Silva,R.N.; Wientjens,D.P.W.M.; Brandel,J.P.; Weber,T.; Bonavita,V.; Zeidler,M.; Alperovitch,A.; Poser,S.; Granieri,E.; Hofman,A.; Will,R.G.
TI Case-control study of risk factors of Creutzfeldt-Jakob disease in Europe during 1993-95. European Union (EU) Collaborative Study Group of Creutzfeldt-Jakob disease (CJD).
QU Lancet 1998 Apr 11; 351(9109): 1081-5
PT journal article
AB
BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy. Genetic and iatrogenic forms have been recognised but most are sporadic and of unknown cause. We have studied risk factors for CJD as part of the 1993-95 European Union collaborative studies of CJD in Europe.
METHODS: The 405 patients with definite or probable CJD who took part in our study had taken part in population-based studies done between 1993 and 1995 in Belgium, France, Germany, Italy, the Netherlands, and the UK. Data on putative risk factors from these patients were compared with data from 405 controls.
FINDINGS: We found evidence for familial aggregation of CJD with dementia due to causes other than CJD (relative risk [RR] 2.26, 95% CI 1.31-3.90). No significant increased risk of CJD in relation to a history of surgery and blood transfusion was shown. There was no evidence for an association between the risk of CJD and the consumption of beef, veal, lamb, cheese, or milk. No association was found with occupational exposure to animals or leather. The few positive findings of the study include increased risk in relation to consumption of raw meat (RR 1.63 [95% CI 1.18-2.23]) and brain (1.68 [1.18-2.39]), frequent exposure to leather products (1.94 [1.13-3.33]), and exposure to fertiliser consisting of hoofs and horns (2.32 [1.38-2.91]). Additional analyses, for example stratification by country and of exposures pre-1985 and post-1985, suggest that these results should be interpreted with great caution.
INTERPRETATION: Within the limits of the retrospective design of the study, our findings suggest that genetic factors other than the known CJD mutations may play an important part in CJD. Iatrogenic transmission of disease seems rare in this large population-based sample of patients with CJD. There is little evidence for an association between the risk of CJD and either animal exposure, or consumption of processed bovine meat or milk products for the period studied.
VT
Members of the EU Collaborative Study Group of CJD are listed at end of paper
Correspondence to: Dr C M van Duijn
Summary
Background
Creutzfeldt-Jakob disease (CJD) is a transmissible spongiform encephalopathy. Genetic and iatrogenic forms have been recognised but most are sporadic and of unknown cause. We have studied risk factors for CJD as part of the 1993-95 European Union collaborative studies of CJD in Europe.
Methods
The 405 patients with definite or probable CJD who took part in our study had taken part in population-based studies done between 1993 and 1995 in Belgium, France, Germany, Italy, the Netherlands, and the UK. Data on putative risk factors from these patients were compared with data from 405 controls.
Findings
We found evidence for familial aggregation of CJD with dementia due to causes other than CJD (relative risk [RR] 2.26, 95% CI 1.31-3.90). No significant increased risk of CJD in relation to a history of surgery and blood tranfusion was shown. There was no evidence for an association between the risk of CJD and the consumption of beef, veal, lamb, cheese, or milk. No association was found with occupational exposure to animals or leather. The few positive findings of the study include increased risk in relation to consumption of raw meat (RR 1.63 [95% CI 1.18-2.23]) and brain (1.68 [1.18-2.39]), frequent exposure to leather products (1.94 [1.13-3.33]), and exposure to fertiliser consisting of hoofs and horns (2.32 [1.38-2.91]). Additional analyses, for example stratification by country and of exposures pre-1985 and post-1985, suggest that these results should be interpreted with great caution.
Interpretation
Within the limits of the retrospective design of the study, our findings suggest that genetic factors other than the known CJD mutations may play an important part in CJD. Iatrogenic transmission of disease seems rare in this large population-based sample of patients with CJD. There is little evidence for an association between the risk of CJD and either animal exposure, or consumption of processed bovine meat or milk products for the period studied.
Introduction
Creutzfeldt-Jakob disease (CJD) is the most clinically significant spongiform encephalopathy in man.[1,2] Although the disease is rare,[3] the rapid development of bovine spongiform encephalopathy (BSE) from a sporadic to an endemic disease in cattle in the UK[4] underscores the potential transmissibility of these diseases. The discovery of a new variant (nv) of CJD in the UK following the BSE[5] epidemic has re-opened discussion on whether spongiform encephalopathies may be transmitted from animals to man. Also, the potential of iatrogenic transmission of CJD remains a matter of concern.
CJD has been transmitted from person to person through human pituitary derived growth and gonadotropin hormones,[6-9] neurosurgery and electroencephalography electrode implantation,[10-13] and corneal transplantation.[14] Up until now there has been no epidemiological evidence of transmission through blood transfusion,[15] but research in animal models indicates that this possibility cannot be excluded.[16,17] Here, we present the findings of a collaborative study of risk factors for CJD in Europe, in which genetic factors, medical history, occupational history, animal exposure, and diet were studied.
Patients and methods
The study was embedded within the European Union (EU) collaborative studies monitoring the incidence of CJD in Belgium (Flanders only), France, Germany, Italy, the Netherlands, and the UK.[3] The registers aimed to ascertain all patients diagnosed with definite or probable CJD living in a defined geographical area, mainly at the national level. A standardised diagnostic protocol was used according to the criteria of Masters and colleagues.[18] The pooled data set of 613 cases of CJD described earlier and 11 additional cases identified in Belgium.[3] Of these patients, 405 (199 definite and 206 probable CJD) were included in the studies of risk factors, 43 patients from Flanders and/or the Netherlands, 75 patients from France, 136 patients from Germany, 63 from Italy, and 88 from the UK. Reasons for exclusion in the case-control study included failure to obtain permission to approach relatives of patients, refusal to participate in the study, lack of appropriate controls, and late referral of suspect cases. The patient series consisted of 154 men and 251 women.
Nine patients were younger than 40 years, 190 were between 40 years and 64 years, and 206 were age 65 years or older at the time of onset of CJD. Patients with and without a family history of CJD were included in the study. In 14 patients with CJD a mutation in the prion protein gene (PRNP) was found.[20-24]
The cases were matched to 405 controls according to age (SD 5 years) and sex. Control participants were recruited from the hospital where the patient who had CJD had been diagnosed. Patients diagnosed with dementia were not included in the control group. A standardised core questionnaire for risk-factor exposure was used. Data were collected by a structured interview done by a research assistant or physician. For cases, the data were obtained from a next-of-kin. For controls, a next-of-kin was interviewed whenever possible.
The raw data of the five participating centres were centralised and analysed. The strength of association between CJD and putative risk factors was assessed by computing the odds ratio as an estimate of the relative risk (RR).19 RRs were estimated by maximum likelihood, and the 95% CIs were based on the asymptotic standard errors. To achieve maximum statistical power, all analyses were done with an unconditional logistic-regression model, adjusted for the matching variable age, sex, and study centre. Significant findings were re-analysed with conditional logistic regression, in accordance with the matched design of the study. Because exposures may differ considerably between countries, we tested for heterogeneity by including an interaction term with a risk factor into the logistic-regression model. Also, a stratified analysis was done for exposures pre-1985 and post-1985, the year marking the start of the BSE epidemic in the UK.[4]
We also analysed the data stratified by sex, age at onset, diagnosis (probable versus definitive), family history of CJD, PRNP mutations, and the PRNP polymorphism at codon 129.[20-24] Despite the pooling of case-control studies, the sample size has limited power when testing for differences between risks in subgroups.[25] We therefore report here all significant findings within any of the subgroups studied, although tests for heterogeneity were not significant.
Results
54 cases and 22 controls had a positive family history of dementia other than CJD. In the cases of CJD the frequency of dementia in first degree relatives proved to be 2.26 (95% CI 1.31-3.90) that of the controls. Table 1 shows the medical history in patients and controls. Surgery of the vertebral column was found less often among cases, whereas there was a non-significant increase in the risk of CJD associated with surgery of the brain. A history of blood transfusion, electromyography, and lumbar puncture was seen less often in cases than controls. A history of blood transfusion more than 10 years before the interview (a period aetiologically relevant because of the long incubation period of CJD), did not increase the risk of subsequent development of CJD.
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History Exposure frequency Relative risk Relative risk
(at CJD diagnosis) (95% CI) at (95% CI) 10 years
Cases Controls diagnosis before onset
Surgery
Brain 12/400 7/405 1.77 (0.68-4.61) 1.76 (0.69-4.51)
Vertebral column 17/400 31/405 0.53 (0.23-0.98) 0.54 (0.29-0.98)
Other CNS surgery 2/400 2/405 1.03 (0.14-7.40) 1.01 (0.14-7.22)
Eye 33/401 34/406 0.96 (0.57-1.59) 0.98 (0.59-1.62)
Medical treatment/tests
Blood transfusion 38/341 71/378 0.56 (0.37-0.97) 0.74 (0.40-1.37)
Electromyography 9/162 26/176 0.32 (0.14-0.72) 0.25 (0.03-2.22)
Lumbar puncture 38/188 40/144 0.49 (0.28-0.87) 1.00 (0.41-2.43)
Vaccination 109/379 114/385 0.95 (0.68-1.32) 0.93 (0.18-4.90)
Hormone supplements41/313 30/320 1.50 (0.89-2.54) 0.98 (0.20-4.90)
CNS=central nervous system.
Table 1: Medical history and the risk of CJD
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The medical history of the controls may not be representative of the general population. If neurological inpatient controls were excluded, there was no significant difference between cases and controls for surgery of the vertebral column, electromyography, or lumbar puncture, which suggests the inverse associations in table 1 may be explained by selection of the controls. There was no evidence for an association between CJD and any of the disorders studied in the medical history including neurological and psychiatric disease, infectious disorders, allergies and atopy, head trauma and for ophthalmological examination or dental treatment (not in table).
With regard to occupational history, medical or allied professions, and occupations that involve contact with animals or animal products were assessed (table 2). None of the professions studied was significantly associated with increased risk of CJD in the pooled analysis. Occupational exposure to cows was associated with an increased risk of CJD in the small subset of Italy only (RR 11.14 [95% CI 1.11-112.02]). However, when compared with the risk observed at the other sites, no significant difference could be found. With regard to domestic animals, associations were found at single sites: to cats in the UK (2.48 [1.35-4.55], significantly [p=0.01] different from the other sites) and to birds in France (7.57 [1.54-37.24], not significantly different from the other sites). In the overall analyses, contact with leather products other than through clothes was associated with a 1.94-fold (1.13-3.33; table 2) increase in the risk of CJD. This association was absent in the Italian population. Exposure to fertiliser that contained hoofs and horns was reported significantly more often for patients than controls (2.32 [1.38-2.91]). However, this risk was not apparent in analyses after 1985 in the Netherlands/Belgium, Italy, or the UK.
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Exposure Exposure frequency Relative risk
* Cases Controls (95% CI)
Occupational exposures
Health professional* 32/397 35/404 0.92 (0.69-1.32)
Butcher 7/392 5/401 1.43 (0.45-4.60)
Slaughterhouse worker 2/347 2/354 1.05 (0.14-7.29)
Meat/food processor 9/347 9/354 1.01 (0.39-2.61)
Leather worker 2/347 2/354 1.01 (0.14-7.33)
Animals/animal products 73/395 75/402 0.99 (0.68-1.42)
Husbandry 57/393 51/400 1.17 (0.77-1.77)
Farm worker
Cows 43/344 38/354 1.20 (0.75-1.93)
Sheep 23/343 23/354 1.05 (0.57-1.96)
General exposure to animals and animal products
Lived on farm 153/395 142/399 1.14 (0.86-1.54)
Used artificial fertiliser 24/302 32/318 0.76 (0.43-1.36)
Used fertiliser containing 48/366 24/382 2.32 (1.38-2.91)
hoofs and horns
Contact with bone meal 57/358 46/374 1.42 (0.90-2.22)
Contact with fur/leather other 42/391 24/397 1.94 (1.13-3.33)
than through clothes
*Occupations included physician, neuropathologist, nurse, laboratory technician, dentist, and ambulance worker.
Table 2: Occupational history and animal exposure and the risk of CJD
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Table 3 shows that the consumption of raw meat products is significantly associated overall with an increased risk of CJD. Although risks did not differ significantly between countries, risks were found to be significantly increased in Netherlands/Belgium (RR 3.35 [1.35-8.31]) and Germany (2.30 [1.39-3.79]) but not in other countries. The association was found for the periods before and after 1985 (start of the BSE epidemic). Compared with those who never consumed raw meat, participants for whom a consumption pattern after 1985 was described as less than monthly the RR was 1.70 (0.98-2.95), while the RR for consumption monthly was 1.51 (0.82-2.78) and weekly was 2.87 (1.19-6.93). In the stratified analysis, the increase in risk was found to be limited to those homozygote for valine at codon 129 of PRNP (cases 13 of 24, controls four of 24, RR 5.91 [1.55-22.58]; p for interaction=0.02).
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Consumption animal products Exposure frequency Relative risk
. Cases Controls (95% CI)
Meat and milk products
Sausage 382/400 381/403 1.22 (0.64-2.34)
Raw meat 143/390 106/393 1.63 (1.18-2.23)
Raw fish 24/131 20/143 1.53 (0.72-3.23)
Animal blood products 206/269 190/262 1.24 (0.80-1.92)
Milk 292/307 290/313 1.57 (0.79-3.12)
Cheese 321/332 329/339 0.89 (0.37-2.14)
Organ meat
Tripe 152/387 155/393 1.00 (0.70-1.42)
Kidney 176/383 175/398 1.10 (0.80-1.51)
Liver 317/391 310/395 1.18 (0.83-1.69)
Brain 49/115 37/118 1.68 (1.18-2.39)
Eye 4/316 2/332 2.12 (0.38-11.90)
Table 3: Consumption of organ, meat, and milk products and the risk of CJD
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Brain consumption (animal source unspecified) was associated with an increased risk of CJD (RR 1.68 [1.18-2.39]; table 3) but this increase was not, by conditional regression analysis, significant (p=0.18). The number of exposures at each site was too small for interpretation, but the association was found consistently in each subgroup analysis. None of the dairy, organ, or meat products such as sausage or black pudding was associated with increased CJD risk in an analysis testing for a trend with increasing frequency of consumption. Finally, there was no evidence for a significant association of CJD with the consumption of beef, veal, lamb, or pork (table 4). The only evidence for an increase in risk of CJD with increasing consumption was found for pork consumption (p for trend 0.02).
----------------------------------------------------------------------
Frequency of Beef Veal Lamb Pork
consumption Cases Contr RR (95% CI) Cases Contr RR (95% CI) Cases Contr RR (95% CI) Cases Contr RR (95% CI)
Never 7 12 Reference 102 121 Reference 117 117 Reference 7 9 Reference
Once/month 154 175 1.53 97 97 1.13 93 75 1.40 128 145 1.13
(0.58-4.06) (0.66-1.95) (0.87-2.25) (0.41-3.14)
>=once/week 186 174 1.86 45 36 1.51 30 30 1.14 218 190 1.51
(0.71-4.90) (0.65-3.54) (0.60-2.14) (0.55-4.18)
RR=relative risk.
Table 4: Consumption of meat and the risk of CJD
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Discussion
In our collaborative study of risk factors of CJD, we found evidence for familial aggregation of CJD with dementia due to causes other than CJD. We did not find significant evidence for iatrogenic transmission of CJD. With regard to the exposures to animals and animal products studied, a significant increase in risk of CJD was found for cases exposed to leather products and fertiliser containing hoofs and horns. Of the dietary factors studied, the consumption of brain and raw meat were associated with an increased risk of CJD. No association was found with the consumption of beef, veal, lamb, cheese, or milk in these analyses.
Although the study aimed to be population based, the inclusion rate, when known, of patients at the participating centres varied from 39% to 88%. Response rates in controls are not known. Thus, findings may have been distorted if the response rate in either cases or controls, or both, was associated with the factor or factors studied. With regard to information bias, it is important to note that data collection was standardised and done by trained physicians. All data on risk factor exposures were collected after disease onset from a surrogate informant for cases. The delay and use of informants may have reduced the validity of the information. In some instances, the control was interviewed in person, which may have introduced a systematic difference between the cases and controls. To check the validity of the findings, the data were re-analysed including only patients and matched controls for whom the data were obtained from a next-of-kin with comparable results.
Another source of information bias may have been recall bias: because of the devastating effects of the disease informants of patients may have been more likely to report past exposures than informants of controls. Important determinants of this type of bias are the time between the onset of CJD and the interview and the vital status of the patient at the time of the interview. Data were therefore stratified according to the vital status of the patient and the time between onset of CJD and the interview. None of these analyses changed the conclusions of this study. However, these analyses cannot exclude the possibility that some of the positive findings in this study may largely or entirely reflect respondent bias; evidence for such bias in a case-control study of CJD has been reported.[26]
In light of the interpretation of the negative findings, the statistical power of the studies is of importance. Given an exposure frequency in controls of 10%, a significance level of 5% (two-sided), and statistical power of 80%, the smallest detectable RR in a study of 405 cases and 405 controls is 1.5.[19] For more rare exposures of 1%, the smallest detectable RR is 4.2,[18] which is a strong association in epidemiological terms.[19] Thus, although the case-series is by far the largest up-to-date study, the power to address rare exposures, to give RRs of less than 1.2, may still have been limited. The power of the study has also been low when testing for heterogeneity between countries and interactions, specifically, with rare factors such as PRNP mutations. [25,27]
Our study confirms earlier findings of familial aggregation of CJD with other dementias.[15] Although PRNP mutations have been found in patients with familial forms of dementia initially not recognised as CJD or patients with CJD may not be known to informants, it is unlikely that the presense of dementia in the families of the 54 cases can be explained by the rare PRNP mutations. In control selection, patients with dementia were excluded, which may have resulted in an underestimate of the frequency of a positive family history of dementia in our control group, particularly in the controls with neurological disorders. However, the frequency of a family history of dementia was similar in controls in hospital because of neurological disease and non-neurological disease, which argues against the possibility that ascertainment of controls may explain the findings. Further, the frequency of a family history of dementia in our controls was similar to other hospital-based studies.[27] It is of note that this frequency in our and other hospital-based studies is lower than that seen in population studies. In agreement with earlier findings,[15] iatrogenic transmission of disease seems to be rare because no significant increased risk of CJD related to the medical history could be shown in this large population-based sample of patients with CJD. The inverse association of risk of CJD from surgery, electromyography, and blood transfusion could be explained largely by the use of hospital controls. Further studies on iatrogenic transmission with population-based controls and well defined incubation periods are necessary.
With regard to the exposure to animals and animal products, the consumption of brain as well as raw meat was associated with an increased risk of CJD, although the association with brain consumption was not significant with conditional regression analysis. For consumption of brain and raw meat, the lack of a unique or more pronounced association in the UK, where by far the most cases of BSE have occurred and human BSE exposure must have been highest, argues against a specific association with BSE. The observation of an association between raw meat consumption and risk of CJD in those homozygote for valine at codon 129 of PRNP may be an artifact of subgroup analysis. However, because recall bias is expected to be independent of the PRNP genotype, this observation might indicate increased susceptibility to raw meat consumption in a genetic subgroup of classic CJD - ie, valine homzygotes. Up until now, cases with nvCJD have all been homozygous for methionine at codon 129 of PRNP and no cases with the typical pathological signs have yet been identified in valine homozygotes.[5] However, homozygosity for valine is a risk factor for iatrogenic CJD and we therefore cannot exclude that this genetic subgroup may be susceptible for other novel exogenic risk factors. A significant increase in risk of CJD was found for individuals exposed to fertiliser that contained hoofs and horns, but interpretation of this finding regarding BSE is difficult because of the small number of exposures after 1985 and the absence of an apparent risk in the UK in that period. Although no association was found with occupational exposure to leather, frequent exposure to leather products was reported significantly more often for CJD cases. Further, in the analysis for trend, the frequency of consumption of pork was found to be associated to the risk of CJD, despite the lack of evidence for an increased frequency of spongiform encephalopathy in pigs. Each of these three findings lack a plausible biological explanation and need to be confirmed.
From a public-health perspective several of the negative findings are especially relevant. In the overall analyses, no evidence was found for an increase in risk of CJD associated with occupational exposure to cows. There was no association of CJD with the consumption of beef, veal, lamb, or milk products. Although these findings are compatible with an absence of risk of transmission of spongiform encephalopathies from cows to man through the consumption of meat, our study is limited to patients diagnosed at or before 1995. Because the first patients with nvCJD, an atypical form of CJD that has been associated with BSE, were described in 1995, any definitive conclusions must await future research in nvCJD.
EU Collaborative Study Group for CJD
R G Will, R de Silva, M Zeidler, J Mackenzie (Western General Hospital, Edinburgh, UK); A Hofman, C M van Duijn, D Wientjens (Erasmus University Medical School, Rotterdam, The Netherlands); A Alpérovitch, J-P Brandel, L Delasnerie-Lauprêtre (Hopital de La Salpetriere, Paris, France); C Masullo, G Macchi, S Almonti, V Filippini (Catholic University of Sacred Heart, Rome, Italy); S Poser, I Zerr, A Giese, H Kretzschmar (Georg-August University Göttingen, Germany); T Weber (Hamburg, Germany); M Pocchiari, M D'Alessandro, R Petraroli, F Cardone (Instituto Superiore di Sanita, Rome Italy); E Granieri, G Lauria, R Pascarella (University of Ferrera, Ferrera, Italy); V Bonavita, S Sanpaolo (Federico II University, Naples, Italy); G Trabattoni (University of Parma, Parma, Italy); E Mitrova (Institute of Preventative and Clinical Medicine, Bratislava, Slovakia).
Contributors
R G Will and A Hofman co-ordinated the study. J Mackenzie was the study administrator. C M van Duijin supervised data management, analysis, and interpretation of the collaborative analysis. N Delasnerie-Lauprêtre and A Alpérovitch were responsible for data analysis of familial factors in the collaborative analysis. C Masullo was responsible for data analysis of nutritional factors in the collborative analysis. I Zerr and S Poser were responsible for data analysis of medical history in the collborative analysis. R de Silva and M Ziedler collaborated in data collection and analysis of the UK study. D P W M Wientjens collaborated in data collection and analysis of the Belgian/Dutch study. J-P Brandel collaborated in data collection and analysis of the French study. T Weber collaborated in data collection and analysis of the German study. V Bonavita and E Granieri collaborated in data collection and analysis of the Italian study.
Acknowledgments
This research was done under the auspices of the EU Concerted Action on the Epidemiology of CJD funded through the BIOMED1 programme. We thank Hanneke de Breeijen and Michael Koenders for their help in data management and data analysis and H Diringer and Paul Brown for advice. We also thank Jean-Philippe Deslys, Dominique Dormont, Jean-Jacques Hauw, Jean-Louis Laplanche, and Véronique Sazdovitch for co-operation in the French study, which was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Direction Générale de la Santé (DGS). The German study was supported by the Bundesministerium für Gesundheit (grant number 324-4473-05/3). We also thank Maurice Pocchiari and the National Registry of CJD in Italy. The studies done in Italy were partially supported by the National Research Council, Targeting Project on Aging (contract number 95.01005.PF40) and by MURST. The studies done in the Netherlands were supported by The Netherlands Institute for Health Sciences and the Netherlands Organisation of Scientific Research. The study in the UK was funded by the Department of Health and Scottish Home and Health Department. We thank J Ironside and J Bell for their co-operation in the UK study.
References
1 Prusiner SB, Hsiao KK. Human prion diseases. Ann Neurol 1994; 35: 385-95.
2 Brown P, Cazthala F, Raubertas RF, Gajdusek D, Vastaigne P. The epidemiology of Creutzfeldt-Jakob disease: conclusion of a 15-year investigation in France and review of the world literature. Neurology 1987; 37: 895-904.
3 Will RG, Alpérovitch A, Poser S, et al. Creutzfeldt-Jakob disease in Europe 1993-1995. Ann Neurol (in press).
4 Anderson RM, Donnelly CA, Ferguson NM, et al. Transmission dynamics and epidemiology of BSE in British Cattle. Nature 1996; 382: 779-88.
5 Will RG, Ironside JW, Zeidler M, et al. A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996; 347: 921-25.
6 Powell-Jackson J, Weller R, Kennedy P, et al. Creutzfeldt-Jakob disease following human growth hormone administration. Lancet 1985; 2: 244-46.
7 Gibbs C, Joy A, Heffner R, et al. Clinical and pathological features and laboratory confirmation of Creutzfeldt-Jakob disease in a recipient of pituitary-derived human growth hormone. N Engl J Med 1985; 313: 734-39.
8 Brown P, Gajdusek DG, Gibbs CJ, Asher DM. Potential epidemic of Creutzfeldt-Jakob disease from human growth hormone therapy. N Engl J Med 1985; 313: 728-31.
9 Cochius JI, Mack K, Burns RJ, Alderman CP, Blumbergs PC. Creutzfeldt-Jakob disease in a recipient of human pituitary gonadotrophin. Austr N Z J Med 1990; 20: 592-93.
10 Masters CL, Richardson EP Jr. Subacute spongiform encephalopathy Creutzfeldt-Jakob disease: the nature and progression of spongiform change. Brain 1978; 101: 333-44.
11 Will RG, Matthews WB. Evidence for case-to-case transmission of Creutzfeldt-Jakob disease. J Neurol Neurosurg Psychiatry 1982; 45: 235-38.
12 Thadani V, Penar PL, Partington J, et al. Creutzfeldt-Jakob disease probably acquired from a cadaveric dura mater graft. J Neurosurg 1988; 69: 766-69.
13 Bernouilli C, Siegfried J, Baumgartner G, et al. Danger of accidental person to person transmission of Creutzfeldt-Jakob disease by surgery. Lancet 1977; 1: 478-79.
14 Duffy P, Wolf J, Collins G, et al. Possible person to person transmission of Creutzfeldt-Jakob disease. N Engl J Med 1974; 290: 692-93.
15 Wientjens DPWM, Davanipour Z, Hofman A, et al. Risk factors for Creutzfeldt-Jakob disease: a re-analysis of case-control studies. Neurology 1996; 46: 1287-91.
16 Manuelidis E, Kim JH, Mericangas J, Manuelidis L. Transmission to animals of Creutzfeldt-Jakob disease from human blood. Lancet 1985; ii: 896-97.
17 Tateishi J. Transmission of Creutzfeldt-Jakob disease from human blood and urine into mice. Lancet 1985; ii: 1074.
18 Masters CL, Haoris JO, Gajdusek DC, et al. Creutzfeldt-Jakob disease: patterns of worldwide occurrence and the significance of familial and sporadic clustering. Ann Neurol 1979; 5: 177-88.
19 Schlesselman JL. Case-control studies. New York: Oxford University Press, 1982.
20 Collinge J, Palmer MS, Dryden AJ. Genetic prediposition to iatrogenic Creutzfeldt-Jakob disease. Lancet 1991; 337: 1441-42.
21 Palmer MS, Dryden AJ, Hughes JT, Collinge J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 1991; 352: 340-41.
22 Laplanche JL, Delasnerie-Lauprêtre N, Brandel JP, et al. Molecular genetics of prion disease in France. Neurology 1994; 44: 2347-51.
23 Salvatore M, Genuardi M, Petravoli R, et al. Polymorphisms of the prion protein gene in Italian patients with Creutzfeldt-Jakob disease. Hum Genet 1994; 94: 375-79.
24 Windl O, Dempster M, E Stibeiro JP, et al. Genetic basis of Creutzfeldt-Jakob disease in the United Kingdom: a systematic analysis of predisposing mutations and allelic variation in PRNP gene. Hum Genet 1996; 98: 259-64.
25 Smith PG, Day NE. The design of case-control studies: the influence of confounding and interaction effects. Int J Epidemiol 1984; 13: 356-65.
26 National CJD Surveillance Unit, Department of Epidemiology & Population Sciences. Creutzfeldt-Jakob disease surveillance in the United Kingdom. Fourth annual report, 1995.
27 van Duijn CM, Clayton D, Chandra V, et al. Familial aggregation of Alzheimer's disease and related disorders: a collaborative re-analysis of case-control studies. Int J Epidemiol 1991; 20: S13-S20.
ZR 27 Zitate
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Im Rahmen einer 1993-1995 in Belgien, Frankreich, Deutschland, Italien, den Niederlanden und dem vereinigten Königreich durchgeführten Studie wurden 405 sichere oder wahrscheinliche Creutzfeldt-Jakob-Patienten hinsichtlich möglicher Risikofaktoren mit 405 anscheinend nicht von der Creutzfeldt-Jakob-Krankheit betroffenen Menschen verglichen. Es ist aber zu beachten, dass die Kontrollpersonen jeweils zur selben Zeit wie der zu vergleichende Creutzfeldt-Jakob-Patient im selben Krankenhaus lagen. So praktisch diese Auswahl sein mag, sie hat auch ihre Nachteile. Insbesondere hat diese Kontrollgruppe selber mit erhöhter Wahrscheinlichkeit Behandlungen wie Blutransfusionen erhalten. Dadurch werden medizinische Risikofaktoren für die Creutzfeldt-Jakob-Krankheit systematisch verdeckt. Man fand eine Korrelation zwischen CJD und anderen in der Familie aufgetretenen Demenzen. Allerdings wurden Demenzkranke aus der Kontrollgruppe ausgeschlossen. Dies spricht nach Ansicht der Autoren für genetische Einflüsse außerhalb des Prionproteins. Dies könnte aber auch ein Hinweis auf Fehldiagnosen sein und außerdem muß wohl der Ausschluß von Demenzkranken aus der Kontrollgruppe zu einer künstlich erhöhten Korrelation zwischen Demenzen und der CJD-Gruppe führen. Kein signifikant erhöhtes Risiko konnte nach medizinischen Eingriffen festgestellt werden:
Gehirn 12/400(CJD-Gruppe) bzw. 7/405(Kontrollgruppe),
Wirbelsäule 17/400(CJD-Gruppe) bzw. 31/405(Kontrollgruppe),
andere Operationen am Zentralnervensystem 2/400(CJD-Gruppe) bzw. 2/405(Kontrollgruppe),
Auge 33/401(CJD-Gruppe) bzw. 34/406(Kontrollgruppe),
Bluttransfusionen 38/341(CJD-Gruppe) bzw. 71/378(Kontrollgruppe),
Elektromyographie 9/162(CJD-Gruppe) bzw. 26/176(Kontrollgruppe),
Lumbarpunktur 38/188(CJD-Gruppe) bzw. 40/144(Kontrollgruppe),
Impfung 109/379(CJD-Gruppe) bzw. 114/385(Kontrollgruppe),
Hormonbehandlung 41/313(CJD-Gruppe) bzw. 30/320(Kontrollgruppe).
Es wurde auch kein Zusammenhang zwischen CJD und neurologischen oder psychiatrischen Krankheiten, Infektionen, Allergien, Überempfindlichkeiten, Schädeltraumen, Augenuntersuchungen oder Zahnbehandlungen festgestellt.
Auch Zusammenhänge mit bestimmten Berufen waren nicht erkennbar:
Gesundheitsberufe 32/397(CJD-Gruppe) bzw. 35/404(Kontrollgruppe),
Metzger 7/392(CJD-Gruppe) bzw. 5/401(Kontrollgruppe),
Schlachthofarbeiter 2/347(CJD-Gruppe) bzw. 2/354(Kontrollgruppe),
Fleisch- und Futterverarbeiter 9/347(CJD-Gruppe) bzw. 9/354(Kontrollgruppe),
Lederverarbeiter 2/347(CJD-Gruppe) bzw. 2/354(Kontrollgruppe),
Umgang mit Tieren und Tierprodukten 73/395(CJD-Gruppe) bzw. 75/402(Kontrollgruppe),
Viehzüchter 57/393(CJD-Gruppe) bzw. 51/400(Kontrollgruppe),
Farmarbeiter mit Rindern 43/344(CJD-Gruppe) bzw. 38/354(Kontrollgruppe),
Farmarbeiter mit Schafen 23/343(CJD-Gruppe) bzw. 23/354(Kontrollgruppe).
Im Zusammenhang mit Kontakt zu Tieren und Tierprodukten gibt es allerdings Auffälligkeiten:
Wohnen auf Bauernhöfen 153/395(CJD-Gruppe) bzw. 142/399(Kontrollgruppe),
Gebrauch von Kunstdünger 24/302(CJD-Gruppe) bzw. 32/318(Kontrollgruppe),
Kontakt zu Dünger aus Huf- und Hornmehl 48/366(CJD-Gruppe) bzw. 24/382(Kontrollgruppe),
Kontakt mit Knochenmehl 57/358(CJD-Gruppe) bzw. 46/374(Kontrollgruppe),
Kontakt mit Pelzen und Leder außer Kleidung 42/391(CJD-Gruppe) bzw. 24/397(Kontrollgruppe).
In Italien wurde kein erhöhtes Risiko im Zusammenhang mit Lederprodukten beobachtet. Im Gegensatz zu anderen Ländern wurde in England bei Katzenbesitzern eine 2,5-fach erhöhte CJD-Häufigkeit gefunden.
Es ergaben sich auch keine statistisch signifikanten Zusammenhänge zwischen CJD und dem Konsum von Rindfleisch, Kalbfleisch, Lamm, Käse oder Milch. In einer Trendanalyse zeigte sich ein statistisch signifikanter Zusammenhang zwischen der Häufigkeit von Schweinefleisch im Essen und der Creutzfeldt-Jakob-Krankheit. Die wenigen übrigen positiven Korrelationen waren die zwischen CJD und einer Vorliebe für rohes Fleisch und Gehirn, häufige Berührung von Lederprodukten, sowie Kontakt zu Dünger aus Huf- und Hornmehl.
Im Hinblick auf Nahrungsmittel deutet sich ein erhöhtes CJD-Risiko bei verstärktem Konsum von Hirn und rohem Fleisch an:
Wurst 382/400(CJD-Gruppe) bzw. 381/403(Kontrollgruppe),
rohes Fleisch 143/390(CJD-Gruppe) bzw. 106/393(Kontrollgruppe),
roher Fisch 24/131(CJD-Gruppe) bzw. 20/143(Kontrollgruppe),
Produkte aus tierischem Blut 206/269(CJD-Gruppe) bzw. 190/262(Kontrollgruppe),
Milch 292/307(CJD-Gruppe) bzw. 290/313(Kontrollgruppe),
Käse 321/332(CJD-Gruppe) bzw. 329/339(Kontrollgruppe),
Eingeweide 152/387(CJD-Gruppe) bzw. 155/393(Kontrollgruppe),
Niere 176/383(CJD-Gruppe) bzw. 175/398(Kontrollgruppe),
Leber 317/391(CJD-Gruppe) bzw. 310/395(Kontrollgruppe),
Hirn 49/115(CJD-Gruppe) bzw. 37/118(Kontrollgruppe),
Auge 4/316(CJD-Gruppe) bzw. 2/332(Kontrollgruppe).
Allerdings beruht die erhöhte Fallzahl bei Konsumenten von rohem Fleisch hauptsächlich auf deutschen und vorallem belgisch-niederländischen Zahlen. Die erhöhte Inzidenz bei Hirnessern ist noch nicht signifikant. Generell gab es unter den CJD-Patienten weniger Vegetarier als in der Kontrollgruppe, während die mehr als einmal pro Woche Fleisch essenden unter den CJD-Patienten häufiger waren. Diese erkennbare Tendenz ist aber statistisch noch nicht signifikant.
Alle erhöhten Inzidenzien waren beschränkt auf bezüglich des Codons 129 homozygote Menschen.
Von 405 europäischen Creutzfeldt-Jakob-Patienten waren 9 jünger als 40, 190 zwischen 40 und 64 und die restlichen 206 waren 65 oder älter. Bei nur 14 von 405 Creutzfeldt-Jakob-Patienten wurden Mutationen im Prionprotein gefunden.
MH Adult; Aged; Case-Control Studies; Creutzfeldt-Jakob Syndrome/*epidemiology/genetics; Diet; Europe/epidemiology; Female; Human; Male; Middle Age; Risk Factors; Support, Non-U.S. Gov't
AD Department of Epidemiology & Biostatistics, Erasmus University Medical School, PO Box 1738, 3000 DR Rotterdam, The Netherlands (C M van Duijn PhD, D P W M Wientjens MD, A Hofman MD); U 360 INSERM, Hopital de la Salpetrire, Paris, France (N Delasnerie-Lauprêtre MD, J-P Brandel MD, A Alpérovitch MD); Department of Neurology, Catholic University of Sacred Heart, Rome, Italy (C Masullo MD); Neurologische Klinik, Georg-August University Göttingen, Göttingen, Germany (I Zerr MD, S Poser MD); CJD Surveillance Unit, Western General Hospital, Edinburgh, UK (R de Silva MRCP, M Zeidler MRCP, R G Will FRCP); Marienkrankenhaus, Alfred Strasse 9, Hamburg, Germany (T Weber MD); Department of Neurology, Federico II University, Naples, Italy (V Bonavita MD); Department of Neurology, University of Ferrara, Ferrara, Italy (E Granieri MD)
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ZF kritische Zusammenfassung von Roland Heynkes