NR ANPM
AU Capek,I.; Vaillant,V.
AK French national Network for the surveillance of Creutzfeldt-Jakob disease and related diseases.
TI Creutzfeldt-Jakob disease and related diseases in France from 1998 to 2000
QU Euro Surveillance : Bulletin Europeen sur les Maladies Transmissibles = European Communicable Disease Bulletin 2003 Jan; 8(1): 14-8
IA http://www.eurosurveillance.org/em/v08n01/0801-223.asp
PT journal article
AB In France, the number of reports of suspected CJD increased from 1998 to 2000, probably due to the increase in the requests for biological tests: respectively 459 in 1998, 590 in 1999, and 823 in 2000. For all three years, the distribution by sex is similar, with a sex ratio (M/F) of 1.05. The proportion of suspected cases aged under 50 remained stable (16% of all reports in 1998-2000). The number of sporadic CJD, confirmed or probable, was stable, with a mortality ratio of 1.38 per one million in 1998, 1.56 in 1999, and 1.41 in 2000.
VT
The French national network for the surveillance of Creutzfeldt-Jakob disease (CJD) and related diseases (Gerstmann-Sträussler- Scheinker disease (GSS), and fatal familial insomnia (FFI)) is aimed at detecting all human cases of transmissible spongiform subacute encephalopathies (TSE), and, more specifically, cases of variant CJD (vCJD) linked to bovine spongiform encephalopathy (BSE). The objectives also include the classification of these diseases by their aetiology, the description of their epidemiological characteristics, and the identification of potential risk factors.
Network partners
Established in 1992, the network of neurologists and neuropathologists is coordinated by Unit 360 of the National Institute for Health and Medical Research, (Institut national de la santé et de la recherche médicale, INSERM U360), and has been boosted by the collaboration of additional partners: - the InVS (Institut national de veille sanitaire) has been sending on the mandatory notifications made by local health departments (Directions départementales des affaires sanitaires et sociales DDASS) since 1996;
- the network of neuropathologists, coordinated by the neuropathology laboratory of the Salpétrière Hospital -Paris public health hospital, AP-HP (hôpital de la Salpétrière de l'Assistance publique - Hôpitaux de Paris (AP-HP)) standardises neuropathological methods, sends on the results of autopsies and samples, and organises autopsies carried out according to ethical and safety regulations;
- the biology and genetics laboratories (department of biochemistry and molecular biology, Lariboisière Hospital, AP-HP; biochemistry department, Neurological Hospital, Civil Hospital of Lyons; and the virology laboratory of Bordeaux University Hospital (service de biochimie et de biologie moléculaire de l'hôpital Lariboisière, AP-HP, service de biochimie de l'hôpital Neurologique, Hospices civils de Lyon et laboratoire de virologie du CHU de Bordeaux)) undertake the search for markers in cerebrospinal fluid (CSF) (14-3-3 protein) and the study of the prion protein (PrP) gene;
- the national reference centre for non-conventional communicable agents, neurovirology laboratory of the atomic energy Commission (Centre national de référence des Agents transmissibles non conventionnel (CNR des ATNC : laboratoire de neurovirologie du Commissariat à l'énergie atomique)) ensures the molecular characterisation of the strains, and also animal inoculations;
- the National Reference Centre for iatrogenic CJD (Centre national de référence des MCJ iatrogènes) monitors the occurrence of new CJD cases associated with human derived growth hormone treatment.
Network functioning
Each neurologist and network partner sends all available information on CJD cases to U360. U360 validates and completes the data, then classifies each case according to the clinical, biological, anatomical and genetic characteristics gathered.
The classification criteria are detailed in appendix 1.
Main epidemiological characteristics
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Table 1
Number of CJD suspicion reports in France, by year and by notification category sources, 1998-2000
1998 1999 2000
Origin of the first notification Number % Number % Number %
Neurologists 28 6.1 26 4.4 7 0.9
Mandatory notifications 13 2.8 8 1.4 14 1.7
Neuropathologists 7 1.5 12 2.0 6 0.7
Biology / Genetics Laboratories 385 83.9 526 89.1 767 93.2
NRC for iatrogenic CJDs 22 4.8 8 1.4 9 1.1
Other 4 0.9 10 1.7 20 2.4
Total 459 590 823
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Reporting
The surveillance network received 459 reports of suspected CJD in 1998, 590 in 1999, and 823 in 2000 (Table 1). The number of reports of suspected cases has increased since 1998, probably due to the considerable increase of requests for biological tests, namely the dosage of the 14-3-3 protein. The biological laboratories that carry out these tests are thus the main source of preliminary reports of suspected CJD cases. In 1998, only 13 cases were initially reported by the mandatory notification system. There were 8 in 1999, and 14 in 2000. Meanwhile, in 1998, 90 suspected cases were subject to mandatory notification (19% of all suspected cases), 87 in 1999 (14%), and 98 in 2000 (12%).
The positive predictive value (PPV) of the preliminary reports varied according to different sources, and progressed over time[1]. The laboratories' PPV was the lowest, and decreased regularly. Furthermore, in 2000, the PPV given by neurologists increased while the mandatory notification PPV decreased (Table 2).
The distribution by sex of CJD reports is similar for all three years studied: sex ratio (male/female) was 1.05. The proportion of reports of suspected cases in those aged under 50 remained stable (16% of all reports from 1998 to 2000).
The geographical distribution of suspected CJD reports according to the district of the reporting physician was very heterogeneous (from 0 to 346 depending on the districts over the three successive years studied).
Notifications came mainly from districts which have a university hospital, such as Paris, Bordeaux, Marseilles or Strasbourg, but those with a regional hospital also actively participated in the reporting of suspected cases.
Main characteristics of CJD deaths from 1998 to 2000
These data concern CJD cases classified by year of death and according to the criteria detailed in appendix 1.
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Table 2
Positive predictive value of the first reports by the different sources, France, 1998-2000
1998 1999 2000
Origin of the first notification
Neurologists 0.57 0.46 0.63
Mandatory notifications 0.46 0.63 0.29
Biology / genetics laboratories 0.21 0.17 0.14
NRC for iatrogenic CJDs 0.64 1.00 0.78
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Table 3
Classification of CJD cases by year of death, France, 1998-2000
Number of deaths 1998 1999 2000
Sporadic confirmed or probable CJDs 81 92 83
vCDJ 0 0 1
Genetic CJDs 13 5 6
Iatrogen CJD exccept growth hormone 1 0 0
Extractive iatrogen CJD
linked to human growth hormone 8 8 9
TOTAL 103 105 99
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Classification of cases
The number of sporadic CJD cases, confirmed or probable, was stable, with a mortality rate of 1.38 cases per one million population in 1998, 1.56 in 1999, and 1.41 in 2000. In 2000, a second vCJD case died in France (the first case died in 1996, the third in 2001, and two other probable cases were still alive on 1 December 2001). The number of CJD deaths caused by human growth hormone was stable (Table 3).
Distribution by sex and age
During the period studied, the distribution by sex was stable with a sex ratio (M/F) of 0.82 for all forms of CJD. This is the same when we consider only sporadic CJD for which the sex ratio was 0.75. Regardless of the form of CJD, the rate of persons aged under 50 was stable over the studied period and represents 2% of deaths caused by sporadic CJD, 25% of deaths caused by familial CJD and 100% of deaths caused by iatrogenic CJD.
Geographic distribution (by district of residence at the time of death)
The mean incidence from 1998 to 2000 by district is quite heterogeneous. The map shows that 20 districts reported no CJD deaths during the three years studied, and in 36 of the districts which reported deaths, the yearly incidence was lower than the mean national incidence (1.44/1 million). In 44 districts, the yearly incidence was higher than the mean national incidence, and in four of them (Meuse, Haute-Saône, Orne, Lozère) it was three times higher.
Anatomopathological tests
The annual number of autopsies (CJD and other diagnoses) carried out was stable: 101 in 1998, 94 in 1999, and 105 in 2000. The geographical distribution of the autopsies conducted according to the reporting physicians' district varied considerably. The highest number of autopsies was undertaken in Paris (26 in three years), followed by the Bouches du Rhône and the Rhône (16 to 20 in three years). In 15 districts, between 6 and 15 autopsies were carried out over the same period. In 31 districts, there were no autopsies during those three years, but 24 of these 31 reported at least one suspected case.
The number of autopsies may seem low compared to the number of suspected cases reported. Many of the patients reported as suspected CJD cases are still alive, and the clinical condition of some of these patients has already ruled out a diagnosis of CJD.
In 1998, 57 (51.4%) of the 111 possible and probable clinical diagnoses of CJD were confirmed by neuropathological tests conducted after the patients' death. In 1999 this number was 66 (54.5%) out of 121 diagnoses, and in 2000, 62 (57.9%) out of 107 diagnoses.
During the three years studied, 14 cerebral biopsies were carried out which allowed the confirmation of four CJD cases without an autopsy, and two positive biopsies were confirmed by autopsy2. Eight of those cerebral biopsies, however, led to a diagnosis other than CJD, and these results have been confirmed for at least two cases.
Genetics: mutation and codon 129
Familial CJD was confirmed by PRNP gene tests: 24 mutations were identified (one in codon 102, three in codon 178, 13 in codon 200, one in codon 203, five in codon 210 and one on codon 211). Codon 129 was studied for 57% of CJD cases, regardless of the form. Out of the 130 confirmed or probable CJD cases studied, 103 (79%) were homozygous, with 78 cases (76%) of the Met-Met type. Among the 24 cases of iatrogenic CJD caused by human growth hormone for which the study of codon 129 was carried out, 70% were homozygous (77% Met-Met and 23% Val-Val).
vCJD cases in France from 1996 to 1 December 2001
The five cases of vCJD reported in France as of 1 December 2001 presented the following characteristics: three confirmed cases of vCJD (patients who died in 1996, 2000 and 2001), and two probable cases of vCJD (reported alive in 2001). Three cases were male and two were female (reported alive in 2001). The median age at which they died or were reported was 27 years (between 18 and 36 years old). Three of them live or lived in the Ile de France district and two in other districts. All were homozygous for codon 129 and presented no known risk factor.
Discussion
Since 1992, when CJD surveillance by Unit 360 of INSERM began, the ratio between the number of cases of CJD diagnosed and the number of reports has changed considerably, from 85% in 1993 to 16% in 2000 (1-3). Since 1996, when vCJD was first identified in the United Kingdom, the number of reports has increased considerably, while the number of CJD diagnoses has increased very slowly. To make a comparison, the number of reports of suspected cases increased in the United Kingdom by a much smaller degree than in France, while the cumulative number of vCJD cases is 20 times higher (4). The current French surveillance system favours the sensitivity of the reporting: as the disease progresses, follow up of the cases allows other diagnoses to be ruled out, so that the system ends up with a strict classification of CJD cases. The analysis of the origin of the first notification shows that the increase in reporting reflects the increase in the dosages of the 14-3-3 protein in CSF. As the positive predictive value of this test is weak, however, the indications for prescribing this dosage should be better specified, keeping in mind the conditions of its specificity for the diagnosis of CJD, and its limitations.
Following an increase between 1993 and 1996, the progression of CJD mortality in France appears to be stable. The surveillance system is probably as exhaustive as it can be made. The results of the geographical distribution of mortality should be considered with caution, as the heterogeneous distribution observed could result from a stochastic effect, given the small group numbers studied.
The proportion of requests for an autopsy of a suspected CJD case decreased between 1998 and 2000, with a yearly mean of 16%. This was due to the significant increase in reports of suspected cases which eventually led to diagnoses other than CJD, and to the high number of patients reported as suspected CJD cases who have not yet died. Nevertheless, the number of autopsies remains stable, and 51% to 58% of CJD cases clinically classified as probable or possible have been confirmed by a postmortem neuropathological examination. However, this number is still insufficient: families who refuse consent, and the difficulties in transporting bodies to an appropriate autopsy site considerably limit this examination despite its vital importance.
The search for mutations of the PRNP gene over this period confirms that the most frequent mutation involves codon 200. Among sporadic CJD cases which were examined for codon 129, the majority were homozygous, particularly for Met-Met. This is similar for patients who have developed CJD after treatment with human growth hormone.
Notes
1 Proportion of confirmed or probable CJD diagnoses among the first reports according to the source.
2 Cerebral biopsy should not be a confirmation examination to diagnose CJD: in addition to the risks it presents and the absence of benefit for the patient, a negative result does not allow a diagnosis of CJD to be ruled out because of the heterogeneity of lesions and the limited power of the sample.
References
1. N. Delasnerie-Lauprêtre , D. Salomon, J.P. Brandel, A. Alpérovitch, Etude épidémiologique de la maladie de Creutzfeldt-Jakob en France. BEH 2. Institut de veille sanitaire. Avril 1999.
2. I. Capek, Les suspicions de maladie de Creutzfeldt-Jakob et autres encéphalopathies subaiguës spongiformes humaines en 1996 et 1997. BEH 2. Institut de veille sanitaire. Avril 1999.
3. Institut de veille sanitaire : http://www.invs.sante.fr
4. Department of Health, United Kindom : http://www.doh.gov.uk/cjd/cjd_stat.htm
Acknowlegdments
We wish to thank all the network participants without whom this report would not have been possible and the INSERM Unit 36 who runs all the data on a daily basis : Annick Alpérovitch (Directeur de l'Unité 360 de l'INSERM), Jean-Philippe Brandel (CNR de la MCJ iatrogène et Unité 360 de l'INSERM), Isabelle Capek (InVS), Emmanuelle Cotto (Laboratoire de virologie du CHU de Bordeaux), Nicole Delasnerie-Lauprêtre (Unité 360 de l'INSERM), Jean-Claude Desenclos (InVS), Dominique Dormont (CNR des ATNC - Service de neurovirologie du CEA), Hervé Fleury (Laboratoire de virologie du CHU de Bordeaux), Jean-Jacques Hauw (Coordonnateur du réseau de neuropathologie, Laboratoire de neuropathologie de l'hôpital de la Salpétrière, AP-HP), Jean-Louis Laplanche (Service de biochimie et de biologie moléculaire de l'hôpital Lariboisière, AP-HP), Armand Perret-Liaudet (Service de biochimie de l'hôpital Neurologique, HCL), Dominique Salomon (Unité 360 de l'INSERM), Véronique Vaillant (InVS), Marta Valenciano (InVS).
Appendix 1
Definition of the various forms of CJD, Surveillance Network for CJD and related diseases, France, 2001
Sporadic Creutzfeldt-Jakob disease
Confirmed: neuropathological confirmation, and/or presence of PrPres in immuno-histochemistry or Western blot, and/or presence of SAF (scrapie associated fibrils).
Probable: progressive dementia, and typical EEG or presence of 14-3-3 protein in the CSF, and at least 2 of the following 4 clinical symptoms:
- myoclonias - pyramidal or extrapyramidal signs
- visual or cerebellar signs - akinetic mutism
Iatrogen Creutzfeldt-Jakob disease linked to extractive growth hormone
Confirmed or probable Creutzfeldt-Jakob disease occurring in a patient treated with extractive growth hormone before 1988.
Iatrogen Creutzfeldt-Jakob disease other than the one linked to extractive growth hormone
Confirmed or probable Creutzfeldt-Jakob disease occurring in a patient who had a treatment for which the epidemiological investigation allows to confirm the possibility of the disease being transmitted.
Familial Creutzfeldt-Jakob disease
Confirmed or probable Creutzfeldt-Jakob disease and confirmed or probable Creutzfeldt-Jakob disease in a direct relative, or neuropsychatric trouble with mutation of PRNP gene
Variant Creutzfeldt-Jakob disease (vMCJ)
1 - progressive neuropsychiatric trouble
2 - length of the disease longer than 6 months
3 - no other diagnosis after routine examinations
4 - no history of potential iatrogen
5 - absence of evidence in favour of a genetic form of ESST
6 - at least 4 of the following symptoms:
a) early psychiatric trouble *
b) persistent sensitive and painful symptoms **
c) ataxia
d) myoclona or chorea or dystonia
e) dementia
7 - no anomaly for typical EEG of sporadic CJD ***
8 - bilateral characteristic hypersignals in the pulvinars on the MRI
9 - presence of PrPres by immunocytochemistry and Western-Blot for tonsils biopsy
Probable vCJD
1) In the absence of positive tonsils biopsy, all criteria from 1 to 8 must be present
2) In case of positive tonsils biopsy (criterion 9), only characteristics 1 to 5 are required.
* depression, anxiety, apathy, withdrawn behaviour, delirium
** this includes frank pain and/or tough dysesthesias
*** generalised triphasic complexes at around 1 cycle per second
IN
In Frankreich gibt es seit 1992 ein von der Einheit U360 im nationalen Institut für Gesundheit und medizinische Forschung (INSERM) koordiniertes Netzwerk von Neurologen und Neuropathologen für die Entdeckung, Klassifizierung und epidemiologischen Untersuchung möglichst vieler Fälle menschlicher Prion-Krankheiten. Diesem übermittelt das nationale Institut für die Gesundheitsüberwachung (InVS) seit 1996 die vorgeschriebenen Meldungen der lokalen Gesundheitsämter (DDASS) über Fälle von Creutzfeldt-Jakob-Krankheit (CJK), Gerstmann-Sträussler-Scheinker-Syndrom (GSS) und tödlicher erblicher Schlaflosigkeit (FFI). Das vom neuropathologischen Labor des Pariser Krankenhauses Hôpital de la Salpétrière de l'Assistance publique - Hôpitaux de Paris (AP-HP) koordinierte Neuropathologen-Netzwerk übermittelt die Ergebnisse und Proben von Autopsien. Biochemische, molekularbiologische und virologische Laboratorien in Lyon und Bordeaux suchen nach spezifischen Markern in der Cerebrospinalflüssigkeit und untersuchen das Prionproteingen. Als nationales Referenzzentrum für unkonventionelle Krankheitserreger (Centre national de référence des Agents transmissibles non conventionnel) führt das neurovirologische Labor der Atomenergiekommission (Laboratoire de neurovirologie du Commissariat à l'énergie atomique) die Erregerstamm-Charakterisierung und Tierversuche durch. Das nationale Referenzzentrum für iatrogene CJK-Fälle (Centre national de référence des MCJ iatrogènes) beobachtet (vorwiegend) die Entwicklung bei den durch kontaminiertes menschliches Wachstumshormon verursachten CJK-Fällen. Alle Partner des Netzwerkes und insbesondere alle Neurologen übermitteln ihre Informationen an die Netzwerkzentrale, wo die U360 die Daten überprüft und komplettiert und jeden Fall klassifiziert. Die Verdachtsmeldungen nahmen von 459 im Jahr 1998 über 590 (1999) auf 823 im Jahr 2000 zu und kommen meistens zunächst von den biologisch-genetischen Laboratorien.
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Tabelle 3
Klassifizierung der französischen CJK-Fälle
Jahr der Feststellung 1998 1999 2000
bestätigte oder wahrscheinliche 81 92 83
Fälle "sporadischer" CJK
neue Variante der CJK 0 0 1
CJK-Fälle mit pathogenen Mutationen 13 5 6
Iatrogene CJK-Fälle bei Kleinwüchsigen 8 8 9
andere iatrogene CJK-Fälle 1 0 0
Summen 103 105 99
CJK-Mortalitätsrate/Million Einwohner 1,38 1,56 1,41
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Die erkannte CJK-Mortalitätsrate stieg in Frankreich von 1993 bis 1996 deutlich an, blieb danach aber mit 1,38 im Jahr 1998, 1,56 in 1999 und 1,41 Fällen pro Million Einwohner im Jahr 2000 insgesamt annähernd konstant. Sie war aber in verschiedenen Distrikten extrem unterschiedlich. Immerhin 20 Distrikte meldeten in den 3 Jahren keinen einzigen Fall, während die gemeldete CJK-Inzidenz in den Distrikten Meuse, Haute-Saône, Orne, Lozère dreifach über dem nationalen Durchschnitt lag. Dazu passt die unglaublich geringe Zahl von Autopsien (101 in 1998, 94 in 1999 und 105 in 2000), mit denen man CJK hätte diagnostizieren können. In 31 Distrikten wurde in diesem Zeitraum keine einzige Autopsie im Hinblick auf eine mögliche CJK durchgeführt. Von den aufgrund klinischer Symptome möglichen oder wahrscheinlichen CJK-Verdachtsfällen wurden im Jahr 1998 nur 57 von 111 (51,4%), 1999 nur 66 von 121 (54.5%) und in 2000 nur 62 von 107 (57.9%) durch neuropathologische Untersuchungen bestätigt. Dies lässt auf Mängel bei der klinischen Diagnose und eine geringe Bereitschaft zur Durchführung von Autopsien und dementsprechend auf eine erhebliche Dunkelziffer schließen, auch wenn Zufall als alleinige Ursache für die sehr ungleiche Verteilung der Fälle nicht ganz ausgeschlossen werden kann.
Andererseits wurden in den 3 Jahren auch 14 Hirnproben von noch lebenden Patienten entnommen, die in 4 Fällen auch ohne anschließende Autopsie zu einer eindeutigen CJK-Diagnose führten. Zu Recht kritisieren die Autoren diese Praxis, weil sie für den Patienten nur schädlich ist und außerdem bei negativem Befund CJK nicht ausschließen kann.
Der Anteil der schließlich bestätigten CJK-Verdachtsfälle hat von 1993 bis 2000 deutlich abgenommen. Während 1993 noch 85% der gemeldeten Verdachtsfälle bestätigt wurden, war dies im Jahr 2000 nur noch in 16% der Fälle so. Verantwortlich dafür ist aber zumindest nicht nur eine gesteigerte Aufmerksamkeit gegenüber CJK, sondern eine zunehmende Zahl von 14-3-3-Tests, die ziemlich unspezifisch sind und viele Fehlalarme auslösen. Besonders stark nahm die Zahl der Meldungen nach der Veröffentlichung der ersten britischen Fälle von nvCJK im Jahr 1996 zu.
Konstant blieb 1998-2000 auch die Zahl der CJK-Fälle bei Kleinwüchsigen, die auf eine oder mehrere infektiöse Präparationen menschlichen Wachstumshormons zurückgeführt werden. Es gab in den Jahren 1996, 2000 und 2001 jeweils einen bestätigten Fall von neuer Variante der CJK und am 1 Dezember 2001 lebten zwei wahrscheinliche Fälle von nvCJK noch. Das Durchschnittsalter dieser 5 Patienten lag bei ihrem Tod oder der Meldung bei nur 27 Jahren (18-36). Drei dieser 5 Patienten lebten im Distrikt Ile de France und alle 5 waren homozygot hinsichtlich des Codons 129. Die Autoren erwähnen es leider nicht, aber sie dürften alle Methionin-homozygot gewesen sein. Unter allen französischen CJK-Patienten liegt das Geschlechterverhältnis (Männer/Frauen) bei 0,82. Der Anteil der weniger als 50 Jahre alten CJK-Fälle betrug bei den sporadischen 2%, bei den erblichen 25% und bei den iatrogenen Fällen 100%.
Bei den erblichen Fällen von CJK wurden 24 Mutationen (1 in Codon 102, 3 in Codon 178, 13 in Codon 200, 1 in Codon 203, 5 in Codon 210 und 1 in Codon 211) identifiziert. Codon 129 wurde in nur 57% der CJD-Fälle untersucht. Von 130 bestätigten oder wahrscheinlichen Fällen waren 103 (79%) homozygot, davon 78 (76%) Met-Met. Von den 24 daraufhin untersuchten Fällen von iatrogener CJK bei Kleinwüchsigen waren 70% homozygot (77% Met-Met und 23% Val-Val).
MH Age Distribution; Codon; Creutzfeldt-Jakob Syndrome/*epidemiology/genetics/pathology; France/epidemiology; Human; Mutation; Population Surveillance; Risk Factors
AD Institut de Veille Sanitaire, Saint-Maurice, France.
SP englisch
PO Frankreich
ZF kritische Zusammenfassung von Roland Heynkes