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From: TSS ()
Subject: Human transmissible spongiform encephalopathies in eleven countries: diagnostic pattern across time, 1993-2002
Date: November 18, 2006 at 9:22 am PST

Human transmissible spongiform encephalopathies in

eleven countries: diagnostic pattern across time, 1993-

2002


Jesús de Pedro-Cuesta1§, Markus Glatzel2, Javier Almazán1, Katharina Stoeck3, Vittorio

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
1997 TO 2006. SPORADIC CJD CASES TRIPLED, with phenotype
of 'UNKNOWN' strain growing. ...


http://www.cjdsurveillance.com/resources-casereport.html


There is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.

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


http://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdf


Full Text

Diagnosis and Reporting of Creutzfeldt-Jakob Disease

Singeltary, Sr et al. JAMA.2001; 285: 733-734.


http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=dignosing+and+reporting+creutzfeldt+jakob+disease&searchid=1048865596978_1528&stored_search=&FIRSTINDEX=0&journalcode=jama


http://www.neurology.org/cgi/eletters/60/2/176#535


BRITISH MEDICAL JOURNAL


BMJ


http://www.bmj.com/cgi/eletters/319/7220/1312/b#EL2

TSS




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