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From: TSS ()
Human transmissible spongiform encephalopathies in eleven countries: diagnostic pattern across time, 1993- 2002 Mellina4, Maria Puopolo4, Mauricio Pocchiari4, Inga Zerr5, Hans A Kretszchmar6, Jean- Philippe Brandel7, Nicole Delasnerie-Lauprętre7, Annick Alpérovitch7, Cornelia Van Duijn8, Pascual Sanchez-Juan8, Steven Collins9, Victoria Lewis9, Gerard H. Jansen10, Michael B. Coulthart10, Ellen Gelpi11, Herbert Budka11, Eva Mitrova12 . 1 Instituto de Salud Carlos III, Centro Nacional de Epidemiologia, Departamento de Epidemiologia Aplicada, Calle Sinesio Delgado 6, 28029, Madrid, Spain. 2Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany 3Institute of Neuropathology, University Hospital Zurich, Switzerland. 4Registry of Creutzfeldt-Jakob disease, –Department of Cell.Biology and Neurosciences, Istituto Superiore di Sanita, Viale Regina Elena 299, 00161 Rome, Italy. 5Department of Neurology, Georg-August-Universität Göttingen, Robert-Koch Strasse 40, 37075 Gottingen, Germany. 6Department. of Neuropathology, Ludwig-Maximilian University, Munich, Germany 7U.708 INSERM, Hopital de la Salpetriere, 75651 Paris, Cedex 13, France. 8Department of Epidemiology and Biostatistics, Erasmus MC, PO Box 1738, 3000 DR Rotterdam, The Netherlands 9Australian National Creutzfeldt-Jakob disease Registry, Department of Pathology, The University of Melbourne, Parkville, Australia. 10CJD Surveillance System, Division of Host Genetics and Prion Diseases, Public Health Agency of Canada, LCDC Building, AL 0601E2, Tunney's Pasture, Ottawa, Ontario, K1A 0L2, Canada. 11Institute of Neurology, Medical University of Vienna, and Austrian Reference Centre for Human Prion Diseases, AKH 4J, A-1097 Vienna, Austria. 12Research base of Slovak Medical University, Bratislava, Slovakia. § Corresponding author Abstract Background The objective of this study was to describe the diagnostic panorama of human transmissible spongiform encephalopathies across 11 countries. Methods From data collected for surveillance purposes, we describe annual proportions of deaths due to different human transmissible spongiform encephalopathies in eleven EUROCJD-consortium countries over the period 1993-2002, as well as variations in the use of diagnostic tests. Using logistic models we quantified international differences and changes across time. Results In general, pre-mortem use of diagnostic investigations increased with time. International differences in pathological confirmation of sporadic Creutzfeldt-Jakob disease, stable over time, were evident. Compared to their counterparts, some countries displayed remarkable patterns, such as: 1) the high proportion, increasing with time, of variant Creutzfeldt-Jakob disease in the United Kingdom, (OR 607.99 95%CI 84.72- 4363.40), and France (OR 18.35, 95%CI 2.20-152.83); 2) high, decreasing proportions of iatrogenic Creutzfeldt-Jakob disease in France, (OR 5.81 95%CI 4.09-8.24), and the United Kingdom, (OR 1.54 95%CI 1.03-2.30); and, 3) high and stable ratios of genetic forms in Slovakia (OR 21.82 95%CI 12.42-38.33) and Italy (OR 2.12 95%CI 1.69- 2.68). Conclusions Considerable international variation in aetiological subtypes of human transmissible spongiform encephalopathies was evident over the observation period. With the exception of variant Creutzfeldt-Jakob disease and iatrogenic Creutzfeldt-Jakob disease in France and the United Kingdom , these differences persisted across time. SNIP... Discussion In terms of case numbers, this study constitutes the largest-scale observation of HTSE ever conducted. Prior reports on this clinical population are sparse [10]. Taking into account that neither mortality of HTSE nor population denominators are considered in this study, the results suggest that: 1) the panorama of HTSE, as seen from deaths for all or part of the 1993-2002 period in 11 countries, varies within and between countries, sometimes exhibiting characteristic features; 2) there is an expected, overall rising time trend in annual deaths and proportions of patients studied using ancillary tests other than EEG; 3) characteristic national patterns, as seen from the magnitude of and time-trends for proportions of specific entities, were particularly relevant in the UK and France for vCJD and iCJD, and in Slovakia and Italy for gHTSE; 4) pathological confirmation of sCJD varied but international differences persisted across time; and, 5) the additional contribution of ancillary tests to sCJD diagnosis decreased to almost nil for EEG, increased to stable figures for the 14.3.3 test, and was high and stable across time for genetic assay insofar as gHTSE was concerned. The interpretation of these results is complicated by several parameters, due to the fact that use of methods for diagnosing HTSE, particularly CSF 14.3.3 test and MRI, improved significantly over the course of the study period. The eligibility of cases for this study based on vital status after death proved most appropriate, since diagnostic criteria for probable sCJD may require measurement of disease duration, <2 years, and quality of diagnosis is frequently determined by postmortem examination. Diagnosis classification for probable cases is therefore neither conditional to a specific disease course nor provisory. A rising time-trend in sCJD incidence or mortality has been observed over the last decade in Austria, France, Germany, Italy, Switzerland, the UK, and other countries [9,23-25] and has mainly been attributed to progressive, persistent, improvement in sCJD diagnostic ascertainment [26,27] or has gone unexplained [9]. This large dataset makes the EUROCJD countries the most stable reference population for comparing HTSE incidence, e.g., that of sCJD in specific age-groups. Nonetheless, undercounts due to poor reporting or case ascertainment before 1998, likely due to different awareness and clinical management of dementia prior to 14.3.3 CSF test, and incomplete case-finding after 2001 by observation at death, suggest that the optimal time interval for incidence measurements using this material should be carefully selected, e.g., 2000-2001 for sCJD. With regard to changes across time, differences due to the presence of vCJD in the UK and France are most remarkable. Abrupt changes in 1997 and 1998 for sCJD suggest a strong impact of the first vCJD report [4] on diagnostic practices and the updating of diagnostic criteria. Yet, interpretation of comparative linear time trends can sometimes prove problematic. For instance, changes in average age at death might reflect improved ascertainment for sCJD and an exposure-related cohort effect with increasing duration of incubation period for iCJD. Changes across time reported here may, among other things, reflect clinical management and reporting, and variations in pre- and post-mortem laboratory diagnostic practices and diagnostic criteria updates. The increasing use of MRI might explain rising trends for CJD since specific patterns of abnormality on diffusionweighted and fluid-attenuated inversion recovery images are highly sensitive and specific for CJD [28]. In EUROCJD countries, the use by clinicians of the 14.3.3 protein test in sCJD diagnosis first became significant in 1997. Accordingly, the 14.3.3 protein in CSF, identified for the not inconsiderable annual proportions of HTSE patients who died from 1993 to 1996 (Figure 1, bottom right) -with test results shown for definite and probable sCJD (Figure 4, centre) and probable sCJD (Table 2)- should have been determined post-mortem, in most cases on frozen CSF stored for research purposes. This policy might have had: a) positive effects, in terms of increasing the average amount of information per registered HTSE case, something that is particularly interesting for definite sCJD cases with date of death prior to 1998; and b) bias in research, due to inclusion of 14.3.3-test results in the database for probable sCJD being made conditional upon the presence of PSWCs in EEG, a requisite for such diagnosis before 1998. The study of associations similar to those reported [29-31] using this large database may benefit from stratification by period of death or diagnostic criteria for probable sCJD. Identifying a time-related increase in sCJD incidence in populations with valine in PRNP codon 129 which have been considerably exposed to BSE has been a key goal of EUROCJD-sponsored public health HTSE surveillance, reinforced by results of recent laboratory research [15,16]. The frequent lack of PRNP codon 129 data for age-specific national populations makes it impossible to calculate the incidence figures required as denominators for such analyses. Hence, a surrogate index is currently used, comparing proportions of sCJD with a valine allele in the UK versus those in other countries and their changes across time [31]. Our study results for the general population suggest that there have been no changes over time in this proportion since 1996 (Figure 4, bottom right). Due to frequent atypical clinical features [32], probable sCJD is particularly liable to being misdiagnosed in patients with valine in codon 129, and as a result expected improvement in sCJD diagnosis internationally is not reflected as a trend. Monitoring international changes across time in clinical-geno-phenotype with this extensive and unique material might require stratification by variables potentially associated with misdiagnosis and codon 129 structure, e.g., EEG pattern. Conclusions This study reveals remarkable international differences in the HTSE panorama that change with time, as seen from deaths in eleven countries in the period 1993-2002. Knowledge of possible biases in the study cohort is vital for future applications of this dataset, both in clinical/epidemiological research and in public health surveillance. snip... FULL TEXT 19 PAGES ; http://www.biomedcentral.com/content/pdf/1471-2458-6-278.pdf SEE STEADY INCREASE IN SPORADIC CJD IN THE USA FROM He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins. http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htm Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734. TSS
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