NR ASFM
AU anonym
AK WHO - World Health Organization
TI Excerpts from report of WHO Consultation on Clinical and Neuropathological Characteristics of the New Variant of CJD and Other Human and Animal Transmissible Spongiform Encephalopathies, Geneva, Switzerland 14 to 16 May 1996 (with the participation of OIE)
QU Internet
IA http://www.who.int/emc/diseases/bse/may14rep.html
PT Tagungsbericht
VT
1. INTRODUCTION
During a consultation on the newly reported variant of Creutzfeldt-Jakob disease (CJD) and other human and animal Transmissible Spongiform Encephalopathies (TSE), which was convened in Geneva from 14 to16 May 1996, a group of international experts reviewed the clinical and neuropathological characteristics of these diseases. The consultation was opened by Dr H. Nakajima, Director-General of WHO, who stressed the importance of the subject in view of the putative association of the emergence of the new variant of CJD with the satisfying of nutrition, an essential need of people.
This consultation was the second to be organized by WHO on TSE in 1996. The first was held on 2 and 3 April 1996 and issued conclusions and recommendations on certain cattle products and by-products in order to protect the health of the consumer.
As a follow-up to the April 1996 consultation, WHO decided to convene the present scientific meeting, the objectives of which were:
(a) to examine in detail the clinical, neurological and neuropathological findings associated with the new variant of CJD;
(b) to compare these findings to those in other TSE and further examine the putative relationship of human TSE to animal spongiform encephalopathies;
(c) to propose a protocol for diagnosis and surveillance of CJD and related diseases and promote international collaboration in surveillance activities;
(d) to review the tests developed for early TSE diagnosis and make recommendations on further research.
Dr J. Gibbs was elected chairman and Drs C. Weissmann and A.L.Taratuto were elected vice-chairpersons. Drs K. Kenney, C. Keohane and J. Ironside were rapporteurs. The list of participants is attached as Annex 1.
2. NEUROPATHOLOGICAL ASPECTS OF THE NEW VARIANT OF CJD: EVIDENCE TO SUPPORT THAT IT IS A VARIANT
A new variant form of CJD, with a characteristic clinical and pathological phenotype, has been identified in the UK in a series of 10 young patients. The characteristic neuropathological features are:
the presence of large numbers of kuru-type prion protein amyloid plaques surrounded by a halo of spongiform change in the cerebral cortex (particularly the occipital lobe); spongiform changes are most evident in the basal ganglia; thalamic gliosis; extensive deposition of prion protein (PrP) in all grey matter regions, particularly the cerebellum (including the molecular layer).
These cases share an early age at onset of symptoms, an unusual clinical course, with early psychiatric features and a prolonged duration of illness, all characteristics which had not been previously reported in the UK.
One similar case has recently been confirmed in France. Comparison of these cases with over 200 CJD cases in the UK Surveillance Project, with historical CJD cases in UK, and with CJD cases in other European surveillance projects, has failed to identify any similar cases in the past.
3. BOVINE SPONGIFORM ENCEPHALOPATHY (BSE) DISTRIBUTION AND UPDATE ON SOME TRANSMISSION STUDIES
The epidemic of BSE in the UK is progressively declining in response to the control measures being taken. Other countries with indigenous cases of BSE are Ireland (126 cases), Switzerland (210), France (18) and Portugal (35). Seven species of captive wild Bovidae and 18 animals in all have succumbed to SE probably via the same feed source as cattle. Domestic cats (71), puma (3), ocelot (2) and cheetah (4) have developed feline SE. The wild cats were probably infected after consuming BSE-infected tissues from the central nervous system of cattle. BSE has been transmitted to cattle, sheep, goats, pigs, marmosets, mink, mice and squirrel monkeys by parenteral inoculation. Unsuccessful attempts have been made to transmit BSE to hamsters and chickens.
Experimental oral transmission has been attempted in all the above species except marmosets; it has been successful except in the case of pigs. In all these species incubation periods were longer than after parenteral challenge, despite the use of much larger doses. Pigs remain healthy for nearly 6 years post-challenge, and tissues from a 2 year interim kill which did not show clinical or pathological evidence of SE, did not transmit BSE to mice. The BSE agent is different from any known strains of historical or contemporary scrapie and retains its biological characteristics following natural or experimental passage through six species, despite differences in PrP gene sequences. The BSE agent sampled from nine different cattle sources are biologically identical. The only tissues from confirmed cases of BSE that have shown infectivity are the brain, retina, cervical and terminal spinal cord, and, in experiments involving orally challenged cattle, the distal ileum, which consistently carry infectivity during the incubation period of the disease from 6-18 months after the oral challenge. No infectivity has been found in muscle (meat), milk, mammary gland, placenta, bone marrow or peripheral nerve from clinical cases and over 40 other tissues obtained from clinical cases.
A total of nine different studies (6 experimental and 3 epidemiological) have examined the possibility of maternal transmission. The conclusions to date are that maternal transmission cannot be excluded but that, if it is occurring, it is at a level so low as to be undetectable.
An attack rate study in cattle has revealed that 1 gram of BSE-infected cow brain is sufficient to cause BSE in the cow by the oral route. A comparative bioassay in cattle and mice provisionally shows that the infectivity titre of cow brain tissue measured in mice is 100 to 1000 times lower than that measured in cattle. Spleen and lymph node pools have not transmitted BSE to mice, and cows inoculated with such pools remain alive for twice the incubation period of those inoculated with a 1/10 dilution of brain tissue.
4. IMMUNOCYTOCHEMICAL DETECTION OF PRION PROTEIN IN CJD
Sporadic CJD has been confirmed in 179 cases by immunocytochemical detection of prion protein (PrP) with both monoclonal and polyclonal antibodies on paraffin sections of various brain regions pretreated by hydrated autoclaving. PrP deposition patterns include fine granular labeling of synaptic type (in about 90% of cerebral and cerebellar cortical specimens), patchy/perivacuolar deposits (mostly in cerebrum -38%) and plaque deposits (mostly in cerebellum -25%). Types of deposition and amount of immunoreactive PrP vary between cases but remain relatively constant between different regions of the individual brain. The brain stem is only involved infrequently (21% with PrP deposits). It is concluded that PrP immunocytochemistry is a very reliable diagnostic tool and detects a limited range of characteristic types of PrP deposition that has a relatively uniform distribution in the individual brain. Presence of Alzheimer-type brain amyloid may modify PrP deposition.
5. PHYLOGENETIC ANALYSIS OF PRION GENES
A study of the prion protein from the perspective of evolutionary theory, has attempted to identify major trends in the evolution of the prion protein by means of a comparative analysis of healthy prion genes. Genetic differences among species, as well as genetic polymorphisms within species, may prove valuable in understanding the nature of the species barrier, and the more likely routes of transmission of the TSE.
6. CSF PROTEIN MARKER DETECTION TEST
A recently developed simple and rapid test using cerebrospinal fluid (CSF) should prove a useful aid in confirming the clinical diagnosis of spongiform encephalopathy in humans or animals. To date, the test has shown high sensitivity and specificity, and further validation studies are in progress. Studies are underway to assess the test's reliability in BSE-affected cattle and in patients with the newly recognized variant form of CJD, and to clarify the association of proteins with these diseases.
7. NATIONAL REPORTS ON CJD AND RELATED DISORDERS (refer to full report)
8. CONCLUSIONS AND RECOMMENDATIONS
8.1 Clinical and neuropathological criteria for the diagnosis of clinical CJD and other human TSE
CJD classically occurs as a rare disorder worldwide (estimated worldwide incidence one case per million population per year) in adults (approximate average age 64 years) with rapidly progressive dementia, myoclonus, ataxia, and a characteristic EEG with a triphasic wave pattern. A broad spectrum of clinical features is recognized in this disorder, and patterns of onset may vary from case to case. The duration of illness is around 5 months on average, but cases with a prolonged clinical history have been encountered in many countries. The neuropathological features of CJD include spongiform change, neuronal loss and astrocytosis, with amyloid plaques in a minority of cases; neuropathology at present provides the only means of establishing a diagnosis of CJD. Most cases of CJD occur sporadically, but familial and iatrogenic cases are also recognized.
(a) Clinical diagnostic criteria
The following diagnostic criteria should be utilised:
Definite CJD is diagnosed by standard neuropathological techniques and/or, in reference laboratories, by additional methods [PrP immunocytochemistry, Western blot and/or preparation of scrapie-associated fibrils (SAF)].
Probable or possible CJD is diagnosed according to the following scheme:
Sporadic CJD
A probable CJD case shows:
progressive dementia;
typical EEG - Approximately 70% of cases of CJD exhibit the typical EEG pattern which consists of generalized triphasic periodic complexes occurring at a frequency of approximately one per second. There is, however, variation in the duration of the periodic complexes and the proportion of any record with such suggestive appearances.
At least two out of the following clinical features must be met :
myoclonus;
visual or cerebellar disturbance (ataxia);
pyramidal/extrapyramidal dysfunction;
akinetic mutism.
A possible CJD case shows:
Same clinical criteria as probable CJD but no EEG available or without a typical EEG (as described above) and a duration of illness of less than two years.
Accidentally transmitted CJD
progressive cerebellar syndrome in a pituitary hormone recipient;
sporadic CJD with a recognized exposure risk (e.g. dura mater transplant).
Familial CJD
definite or probable CJD plus definite or probable CJD in a first degree relative;
neuropsychiatric disorder plus disease-specific PrP gene ( PRNP) mutation.
(b) Neuropathological diagnostic criteria
The definite diagnosis of (CJD) and other human transmissible spongiform encephalopathies requires neuropathological confirmation on brain at autopsy or, in carefully selected cases, cerebral biopsy. This is of paramount importance in view of the steadily growing spectrum of clinical and pathological phenotypes. The many historically described CJD variants with different names have been shown to be parts of this spectrum. The considerable morphological variation may be influenced by length of the disease, by the PrP genotype, and by as yet unidentified factors including strains of the infectious agent.
Extensive sampling from various brain areas (at least the frontal, temporal, and occipital lobes, from the basal ganglia, and from the cerebellum) is mandatory in every autopsy of suspected spongiform encephalopathy. The comparison of cerebral and cerebellar involvement is especially important.
When handling tissues and other materials from suspected CJD, specific safety precautions are mandatory to avoid accidental transmission and to eliminate any infectivity H. Budka et al. Tissue handling in suspected CJD and other human spongiform encephalopathies, Brain pathology, 5: 319-322 (1995). , Committee on Health Care Issues, American Neurological Association, Precautions in handling tissues, fluids and other contaminated materials from patients with documented or suspected CJD, Annals of Neurology, Vol.19 No.1.
Neuropathological diagnostic criteria for CJD and other human transmissible spongiform encephalopathies are summarised as follows:
CJD - sporadic, iatrogenic (recognized risk) or familial (same disease in first degree relative):
Spongiform encephalopathy in cerebral and/or cerebellar cortex and/or subcortical grey matter; and/or
Encephalopathy with PrP immuno-reactivity (plaque and / or diffuse synaptic and / or patchy/perivacuolar types).
Gerstmann-Sträussler-Scheinker disease (GSS) (in family with dominantly inherited progressive ataxia and/or dementia and one of a variety of PrP gene mutations):
Encephalo(myelo)pathy with multicentric PrP plaques.
Familial fatal insomnia (FFI) (in member of a family with PrP178 mutation):
Thalamic degeneration, variable spongiform change in cerebrum.
Kuru (in the Fore population of Papua New Guinea):
While most neurological features correspond to those of CJD with plaques, it should be diagnosed only in members of the Fore population in Papua New Guinea.
In the absence of PrP immunocytochemistry the crucial feature is the spongiform change accompanied by neuronal loss and gliosis. This spongiform change is characterised by diffuse or focally clustered small round or oval vacuoles in the neuropil of the deep cortical layers, cerebellar cortex or subcortical grey matter, which may become confluent. Spongiform change (status spongiosus) should not be confused with non-specific spongiosis. Status spongiosus comprises irregular cavities in gliotic neuropil following extensive neuronal loss (including also lesions of "burnt-out" CJD), "spongy" changes in brain oedema and metabolic encephalopathies, and artefacts such as superficial cortical, perineuronal, or perivascular vacuolation disease. Focal changes indistinguishable from spongiform change may occur in some cases of Alzheimer's and diffuse Lewy body disease.
Recently, immunocytochemistry for PrP has been added to classical histological techniques and has rapidly evolved into a most useful diagnostic tool (see section 4). However, it is at present a rather delicate procedure that should be used for diagnostic purposes only by an experienced laboratory. In CJD, immunoreactivity for PrP is seen mainly in three patterns which frequently overlap: plaque, diffuse synaptic and patchy/perivacuolar types.
Very rare cases might not be diagnosed by the criteria outlined above. Confirmation must then be sought by additional techniques such as immunoblotting, preparations for electron microscopic examination of scrapie associated fibrils (SAF), molecular biologic studies, or experimental transmission.
8.2 Clinical and neuropathological criteria for the diagnosis of the newly recognized variant of CJD
Eleven patients have recently been identified in the UK and one in France with a newly recognized variant form of CJD; 9 of these 12 patients have since died. All patients were aged 41 years or less at death.
The following clinical features are characteristic:
a psychiatric presentation with anxiety, depression, withdrawal and other behavioural changes with progression to neurological abnormalities;
onset of a progressive cerebellar syndrome within weeks or months of presentation;
forgetfulness and other memory impairment, with dementia in the late stages;
myoclonus or chorea in the late stages;
the EEG does not show the changes normally observed in classical CJD.
Less common features include early onset of dysaesthesia in limbs and face at presentation, and extrapyramidal and pyramidal signs later in the illness.
The diagnosis of the newly recognized variant form of CJD can only be made on neuropathological examination, which is mandatory for confirmation of suspected clinical cases. The neuropathological diagnostic criteria are:
abundant kuru-type amyloid plaques surrounded by vacuoles (clearly visible in H&E and PAS stains);
spongiform change most prominent in the basal ganglia;
marked thalamic astrocytosis;
abundant PrP deposits on immuno-cytochemistry, including prominent "pericellular" deposition in cerebral and cerebellar cortex (especially in the molecular layer) .
Genetic analysis is required in every suspected case to exclude familial CJD; patients should have no history of exposure to human pituitary-derived products or any other source of iatrogenic CJD.
The present meeting considered that this recently described disorder is part of the CJD spectrum; it is a new variant form of CJD on grounds of its unique clinical and pathological features. BSE has been transmitted naturally and experimentally to a range of other animal species by the oral route, and it has been suggested that the emergent cluster of the new variant form of CJD may be a consequence of exposure of the human population to the BSE agent. It should be emphasised that such a link has not been proven.
After a thorough review of the characteristics of natural and experimental TSE, the consultation concluded that the type of lesions and the clinical presentation of the new variant form of CJD do not provide information on the possible origins of this disorder.
8.3 Surveillance of CJD and related disorders
The initiation of disease surveillance systems should help in establishing the geographic distribution of the newly described variant of CJD, and establishing the true incidence of CJD - all types and subtypes. It should also help to investigate the possible relationship of CJD to spongiform encephalopathies in animals and to establish epidemiological parameters and risk factors for CJD. It should finally provide the public with accurate information; this is especially important because of great public concern.
It is accepted that with any surveillance programme reported cases will increase. There are different ways of approaching surveillance, and methods depend on available resources. Mechanisms of surveillance can be active or passive and various methods are already in use in some countries (see section 7).
(a) Mechanisms for data collection
All methods of disease surveillance have advantages and disadvantages, and it was agreed that for maximum comparability of data, a single method of surveillance should be promoted by WHO. After obtaining permission from the EU and making any necessary modifications, the questionnaire-based method elaborated by the EU for CJD Surveillance should be used by WHO to develop a standard protocol for global surveillance of CJD and its variants. In a given country, this protocol should be made available to health institutions for further adaptation to prevalent conditions. The adapted protocol should then be used by targets goups for the identification of suspect (possible and probable) cases.
The following mechanisms for data collection should be used:
reports with individual examination of each case from the specific groups involved in surveillance, e.g., neurologists, neuropathologists and health care workers especially those involved in the surveillance of flaccid paralysis within the framework of the poliomyelitis eradication programme;
specialized referral centres for screening and reviewing individual cases referred to by target groups;
central registration via death certification and postal register surveillance.
The questionnaire developed by the EU surveillance project comprises four sections (A, B, F and R); A and R are further divided into subsections (A1 to 10, R1 to R9 ). A list of titles of the sections and subsections is attached as Annex 2. Section A of the EU questionnnaire (including for 'cases only' data on clinical presentation, further investigations including EEG, neuropathological and genetic tests ) could be used after adaptation to the techniques usually available in the targeted regions and countries. In section R, subsections R7 to R9 dealing with identification of risk factors by interviewing cases and controls on their occupation, diet and animal contacts, should be simplified and used only within the context of special research projects. The person completing the questionnaire will differ in each country, but it was considered that the final WHO questionnaire should be applicable to any country. When reporting to WHO, each country should specify the mechanisms of data collection used.
Central registration via death certification and postal register surveillance or country-wide investigation via neurologists and neuropathologists could be used where appropriate and feasible. All centres may not be able to complete all aspects of the surveillance. If they do not have resources at the outset, they could concentrate on identifying cases of the newly-described variant of CJD, which are likely to occur in younger subjects .
(b) International collaboration
There is a need to plan international collaborative studies, including appropriate controls to identify possible risk factors in the newly described variant of CJD. Collaboration has already started and should continue between various institutions and the UK. Suspected cases should initially be checked with the CJD Surveillance Unit in Edinburgh.
WHO should further expand and coordinate international collaboration, including surveillance, through its Division of Emerging and other Communicable Diseases Surveillance and Control (EMC). WHO should identify specific reference centres, with due regard to geographic balance, where various specific aspects of collaboration and standardization could be undertaken: EEG interpretation, immunostaining, genetic analysis, CSF tests, epidemiology, transmission experiments, etc. EMC, in collaboration with the Neurosciences unit of the Division of Mental Health and Substance Abuse (MSA) should assist in this by facilitating the transfer of material and personnel to reference centres, and in training as appropriate.
TSE should be further investigated in other species, and WHO should facilitate international collaboration in these studies with OIE, FAO, EU, and other international bodies dealing with veterinary medicine and veterinary public health.
(c) Handling of information
Because of the great media interest in these diseases, and the sensitive nature of the cases, it is essential that the incoming data be handled carefully.
Initially, at least 3-monthly reports of diagnosed cases should be released, with publication of any additional cases of the newly described variant form of CJD, as reported by a country, in the Weekly Epidemiological Record.
WHO should be informed as early as possible if any such cases occur. Because of media interest and economic consequences, participating key figures in each country should be alerted so that they are able to deal accurately with media interest and further disseminate the information within their own country.
8.4 Evaluation of ongoing research and definition of future research needs
The group reviewed current TSE research and recommended this be continued and extended as indicated below for the following six categories: basic science, transmission studies, diagnostic methods, biosafety studies, genetic studies and treatment methods.
(a) Basic science
Because the precise nature of the causative agent and the mechanism of development of disease are not yet known, further basic science research is essential. The studies should include the following:
clarification of the nature of the agent;
determination of the function of PrP;
determination of the mechanism of pathogenic PrP production;
pathogenesis.
(b) Transmission studies
There is a need to seek evidence for the natural transmission of spongiform encephalopathies of animals to man in order to determine the distribution of BSE infectivity in tissues and derived products from infected cattle that enter the human food or animal feed chain during the incubation period. It is also necessary to expand current studies on the CJD infectivity of human non-CNS tissues such as those used for transplantation and, in particular, blood and blood products (although there is no proven risk of CJD transmission from these sources).
To this end, the following studies are recommended:
neuropathological and epidemiological surveillance of human and animal TSE worldwide;
transmission of the agent of the newly described variant form of CJD in the UK and France (V-CJD), as well as agents of all other distinct human TSE (Kuru, GSS and FFI) and previously described CJD variants into:
conventional inbred strains of mice for strain-typing by lesion profile/ incubation time bioassay (work on this is already in progress);
PrP-null transgenic mice carrying multicopies of the human PrP gene to determine if this assay can distinguish agent strains and, if so, if the system is quicker for strain typing than using conventional inbred strain of mice; and cattle.
Inoculation, although this is of lower priority, of brain tissue from the various human variants of spongiform encephalopathies into non-human primates for comparative purposes.
Although there is no evidence of infectivity (using the mouse bioassay) in tissues from cattle infected with the BSE agent, other than the CNS and distal ileum, transmission studies are recommended using tissues and derived products from BSE-infected cattle into:
- PrP-null transgenic mice carrying multiple copies of the bovine PrP gene;
cattle (testing infectivity of products and tissues such as milk, muscle, gelatin);
- (The purpose of these two types of transmission studies is to improve sensitivity by eliminating the species barrier.)
non-human primates (CNS tissues only by the oral and intra cerebral routes).
Transmission of scrapie (from sheep and goats in the UK and other countries with and without BSE) to:
- non-human primates (by the oral and intra cerebral routes) as a control for the study above involving the BSE agent.
Studies of distribution of infectivity within various tissues of TSE-affected animals at different times of the illness (preclinical, early and late clinical stages) by:
- expanding the pathogenesis studies in BSE-infected cattle already in progress or near completion, should any infectivity be found in cattle tissues other than the CNS and distal ileum;
- considering re-evaluating the distribution of tissue infectivity of the scrapie agent in sheep with newer methods (e.g. the use of transgenic mice).
Studies to further investigate horizontal and vertical (maternal) transmission of BSE in cattle.
Studies to determine the tissue distribution of infectivity for CJD and other human TSE using PrP-null transgenic mice carrying multiple copies of the human PrP gene (from whole blood, buffy coat and plasma).
Consideration should be given to convening a future WHO meeting regarding the infectivity of human non-CNS tissues of CJD patients such as the tissues used for transplantation, in particular blood and blood products. The pathogenesis of CJD may differ with the route of exposure and strain of agent.
(c) Diagnostic methods
A recent investigation on CSF marker proteins (see section 6) appears to provide potential for a sensitive in vivo test for CJD and related disorders. However, further studies on cases of CJD, other neurological disorders and control cases are required to establish the diagnostic value of this test in human and animal TSE.
The group recommended:
The development of rapid, reliable tests with high sensitivity and specificity, particularly in the early or pre-clinical stages of illness, from easily obtained sources (e.g. body fluids). These are desperately needed to diagnose both human and animal TSE.
The start of further validation studies for existing diagnostic tests, as well as for those currently under development.
(d) Biosafety studies
Further studies should be performed on current physicochemical protocols, alone and in various combinations, and new protocols toward the complete inactivation of infectivity from:
contaminated surgical instruments, equipment and accommodation;
animal products and animal waste, using the most sensitive methods now available (e.g. the use of transgenic mice).
Research should be considered to examine any risks that may arise during conventional slaughter of TSE-infected but clinically healthy animals in abattoirs.
Investigations of the complete pathway of all tissues from food animals should be carried out to determine their fate, whether they are used in food, feed, medicinal products and devices, or in other products.
(e) Genetic studies
The studies outlined below should be carried out:
extension of the molecular genetic studies of the PrP gene (and other genes possibly associated with TSE) in humans and animals, especially cattle and sheep;
the extent of polymorphisms in the PrP gene of humans and animals, in order to identify genetic associations between distantly related species (in progress).
(f) Treatment methods
There is an urgent need to develop a strategy for the prevention and treatment of human TSE based on genetic, biological and chemical approaches. It is noted that some preventive strategies for some animal TSE are already in place.
(g) Use of in-vitro tests and animals for research
It is strongly recommended that every effort be made to develop in-vitro tests for diagnosis and research, and that studies requiring the use of laboratory and other animals should involve the smallest number of animals possible.
8.5 Proposed WHO monograph on TSE
There is already a wealth of scientific literature and books available on the current state of knowledge on TSE. However the publication by WHO of a short monograph on human and animal TSE for both practising medical and veterinary officers would be extremely useful within the framework of the surveillance system.
9. CONCLUDING REMARKS
Dr H. Nakajima closed the meeting by thanking all participants for their outstanding scientific contribution to the consultation and for the very productive and exemplary collaboration between the different domains of expertise involved, for example, clinical neurology, neuropathology and veterinary pathology and epidemiology. He expressed the willingness of WHO to continue to provide a forum for discussions on this and other subjects requiring the sharing of experience and knowledge from both the human and animal health sectors.
10. ACKNOWLEDGEMENTS
In its discussions and preparation of this report, the group took into consideration: (a) Consensus Report on Neuropathological Diagnostic Criteria for CJD and other Human Spongiform Encephalopathies by H. Budka et al, Brain Pathology, 5: 459-466 (1995), (b) Surveillance of prion diseases in humans by R. Will in method in molecular medicine: Prion diseases, edited by H. Baker & R.M. Ridley, Humana Press, Inc. Totawa, New Jersey, pp. 119-137 (1996) and (c) Questionnaire for the surveillance and clinical criteria for the diagnosis of CJD and related disorders prepared by the participants in the EU supported Biomed 1 concerted action for "CJD surveillance in the EU".
ANNEX 1
LIST OF PARTICIPANTS
Dr M. Alpers, Institute of Medical Research, Post Office Box 60, Goroka, E.H.P., Papua New Guinea. (unable to attend)
Dr M. Ben Hamida, Consultant Neurologie, Institut National de Neurologie, La Rabta, 5 Avenue Haroun Errachid, 1002 Tunis, Tunisia
Dr R. Bradley, Central Veterinary Laboratory, New Haw, Addlestone KT15 3NB, UK
Dr H. Budka, Professor of Neuropathology, Institute of Neurology, University of Vienna, 1097 Vienna, Austria
Dr L. Cartier, Professor of Neurology, University of Chile, Santiago de Chile, Chile
Professor G. Collinge, Prion Disease Group, Department of Biochemistry and Molecular Genetics, St. Mary's Hospital Medical School, Norfolk Place, London W21 PG (unable to attend)
Dr D. Dormont, Direction des Sciences du Vivant, Département de Recherche Médicale, Service de Neurologie, Centre d'Etudes Nucléaires (CEA), BP6, 92265 Fontenay-aux-Roses, France (unable to attend)
Dr D.K. Dastur, Director, Department of Neuropathology and Applied Biology, Bombay Hospital, Marine Lines, Bombay 400-020, India
IN
Dr .H. Nakajima, Generaldirektor der WHO, Dr. M. Ben Hamida vom Institut National de Neurologie in Tunis, Dr. Ray Bradley vom Central Veterinary Laboratory im britischen Addlestone, Prof. Dr. H. Budka, vom Institut für Neurology der Universität Wien, Prof. Dr. L. Cartier von Chilenischen Universität in Santiago, Dr. D.K. Dastur, Direktor der Abteilung Neuropathologie und Angewandte Biologie im indischen Bombay Hospital sowie Prof. Dr. C. Weissmann, Dr. J. Gibbs, Dr. A.L.Taratuto, Dr. K. Kenney, Dr. C. Keohane und Dr. J. Ironside berieten im Auftrag der Weltgesundheitsorganisation vom 14. bis zum 17. Mai in Genf über die neue Variante der Creutzfeldt-Jakob-Krankheit und ihre mögliche Verbindung zu tierischen übertragbaren schwammförmigen Gehirnerkrankungen. Man legt bezeichnenderweise Wert auf die Feststellung, dass ein ursächlicher Zusammenhang mit BSE nicht bewiesen ist.
Als typisch für den einen französischen und die bis dahin 11 britischen Fälle beschreibt das Gremium in der Kleinhirnrinde, speziell im hinteren Lappen, eine große Anzahl Kuru-typischer amyloider Prionprotein-Plaques, welche von zerstörten Nervenzellen umgeben sind. Am markantesten waren die Löcher in den Basalganglien, die Gliazellenvermehrung im Thalamus und die Prionprotein-Ablagerungen in allen grauen, dass heißt zellulären Hirnregionen, jedoch besonders im Kleinhirn. Die Symptome setzten früh (vor dem 40. Lebensjahr) mit psychiatrischen Veränderungen wie Angst, Depression und Zurückgezogenheit ein, aber die Kranheitsphasen dauerten mit zunehmender Vergeßlichkeit und Demenz, später auch Muskelzucken und unwillkürlichen Bewegungen sehr lange. Die EEGs zeigten nicht die oft beobachteten Muster. Sensibilitätstörungen in Gesicht und Gliedern setzten ungewöhnlich früh ein. Ein Vergleich mit über 200 britischen CJD-Fällen und mit anderen untersuchten europäischen CJD-Fällen soll keine vergleichbaren Fälle geliefert haben.
Außerhalb von England soll es in Irland 126, in der Schweiz 210, in Frankreich 18 und in Portugal 35 BSE-Fälle gegeben haben. Die deutschen Fälle zählten wohl nicht. An BSE-artigen Erkrankungen starben 18 Individuen von 7 Huftierarten, 71 Hauskatzen, 3 Pumas, 2 Ozelots und 4 Geparde. Experimentell gelang die Übertragung von BSE unter Umgehung des Verdauungssystems auf Rinder, Schafe, Ziegen, Schweine, Krallenaffen, Nerze, Mäuse und Totenkopfäffchen (Saimiri sciureus, squirrel monkey), jedoch nicht auf Hamster und Hühner. Durch Verfüttern wurde BSE auf Rinder, Schafe, Ziegen, Nerze, Mäuse und Totenkopfäffchen (Saimiri sciureus, squirrel monkey) übertragen. Eine Handvoll Schweine blieb nach der Verfütterung von nur 12 kg Rinderhirn 6 Jahre lang gesund. Mit Krallenaffen hat man es nicht versucht. Die besonderen Eigenschaften von BSE sollen bei sage und schreibe 9 Rindern gleich gewesen sein und auch nach Übertragungen auf 6 andere Tierarten erhalten bleiben. Wie sieht es bei den übrigen Tierarten aus? Infektiosität wurde nach Angaben der WHO von 1996 bei Rindern nur in Hirn, Retina, im vorderen und hinteren Rückenmark und bereits 6 Monate nach der Aufnahme infektiösen Futters im von Lymphfollikeln durchsetzten äußeren, sich an den Magen anschließenden Dünndarmabschnitt gefunden. Keine Infektiosität wurde bei Rindern in Muskeln, Milch, Milchdrüsen, Plazenta, Knochenmark und peripheren Nerven und mehr als 40 anderen Geweben gefunden.
Unter Hinweis auf 6 experimentelle und 3 epidemiologische Studien stellten die Experten Mitte Mai 1996 fest, dass eine mütterliche BSE-Übertragung aufgrund der zu diesem Zeitpunkt vorhandenen Daten nicht ausgeschlossen werden könne, dass sie jedoch höchstens unmeßbar selten vorkomme. Zu dumm, dass diese Einschätzung schon 1 Monat später durch das SEAC-Statement als unglaublich dreiste Lüge entlarvt wurde
Eine leider nicht zitierte Studie soll gezeigt haben, dass die Verfütterung von nur 1 Gramm infektiösen Rinderhirns ausreicht, um Rinder an BSE erkranken zu lassen. Ein Vergleich soll zeigen, dass Rinderhirn für Rinder 100-1000 fach infektiöser als für Mäuse ist.
Man hält es für erwähnenswert, dass mit Milz- und Lymphknoten-Pools infizierte Mäuse bereits doppelt so lange leben, wie mit 1:10 verdünntem Hirn infizierte.
179 Creutzfedt-Jakob-Fälle mit ungeklärter Ursache Sporadic wurden bestätigt, indem monoklonale und polyklonale Antikörper in autoklavierten Paraffinschnitten aus verschiedenen Hirnregionen Prionprotein-Ablagerungen markierten. Das Ausmaß der Ablagerungen variierte von Fall zu Fall, aber die Verteilungen innerhalb der einzelnen Gehirne war sehr konstant. Was zu erwarten war, wenn man die unter anderen namenbekannten Varianten der Creutzfeldt-Jakob-Krankheit ausschließt.
Die WHO-Fachleute halten die amerikanische Testmethode mit Rückenmarksflüssigkeit für einfach und schnell, hochempfindlich und spezifisch und erwarten sich davon künftig eine wertvolle Hilfe bei der Diagnose spongiformer Enzephalopathien bei Menschen und anderen Tieren. Die anderen, wesentlich aussichtsreicheren Testmethoden wurden ignoriert.
Die Experten geben zu, dass die Prionkrankheiten in ihrer Symptomatik sehr variabel sind und daß das Spektrum der beobachteten Variabilität ständig zunimmt. Sie zählen sogar Kuru, das Gerstmann-Sträußler-Scheinker-Syndrom und die tödliche erbliche Schlaflosigkeit zum Spektrum der Creutzfeldt-Jakob-Krankheit. Dennoch definieren sie bis zum Abwinken, was unter möglichen, wahrscheinlichen und sicheren Fällen zu verstehen sei. Erstaunlicherweise wird zwar vor Verwechslungsmöglichkeiten gewarnt, aber Creutzfeldt-Jakob-Diagnosen mit Löchern aber ohne Prionprotein-Ablagerungen werden zugelassen. Auch die Methoden der Datenerfassung sollen vereinheitlicht werden. Creutzfeldt-Jakob-Fälle sollen mindestens dreimonatlich, die neue Variante wöchentlich im Weekly Epidemiological Record veröffentlicht werden. Die Unterichtung der Öffentlichkeit soll wegen möglicher wirtschaftlicher Auswirkungen durch besonders geschulte Fachleute und sehr vorsichtig geschehen.
Natürlich liegt den Wissenschaftlern die Intensivierung der Forschung besonders am Herzen. Das infektiöse Agenz und seine Funktionsweisen sollen ebenso erforscht werden wie die Eigenschaften des normalen Prionproteins.
Außerdem sollen Übertragungsexperimente Gefahrenpotentiale in der menschlichen Nahrung und in der Medizin besser untersuchen. Die Sensibilität des biologischen Testverfahrens soll verbessert werden, indem transgene Mäuse mit nur menschlichen Prionproteinen sowie Kälber verwendet werden, um Speziesbarrieren abzubauen. Außerdem sollen Übertragungen auf Menschenaffen die Gefährdung besser einschätzen lassen. Diese Tierversuche sind völlig sinnlos, wenn man vorbeugenden Gesundheitsschutz betreibt.
Vorangetrieben werden soll nun plötzlich auch die Entwicklung von Lebendtests, wobei jedoch die wichtigsten nicht erwähnt werden. Die bisherigen Einschätzungen bezüglich der Sterilisierungsmaßnahmen sowie der Schlachtung nur scheinbar gesunder Tiere sollen mit empfindlicheren Nachweismethoden überprüft werden.
Man hält den Stand der Forschung bereits für ausreichend dargestellt, es fehle jedoch an kurzen Zusammenfassungen für Mediziner und Tierärzte.
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