Sporadic Creutzfeldt Jakob Disease, Genetic Transmissible Spongiform Encephalopathy, Accidentally Transmitted Transmissible Spongiform Encephalopathy (or iatrogenic) and Variant Creutzfeldt-Jakob disease.
Following the identification in UK cattle of bovine spongiform encephalopathy (BSE) as one of the transmissible spongiform encephalopathies, the Southwood Report recommended that Creutzfeldt-Jakob Disease (CJD) should be monitored. The National CJD Research & Surveillance Unit (NCJDRSU) was established in 1990 with the primary aim of identifying any changes in the characteristics of CJD that might be linked to BSE. In 1996 a new variant of CJD (vCJD) was identified and evidence has since gathered that links vCJD causally to BSE. The exact mechanism of transmission of the BSE agent to the human population has not been identified, but dietary exposure to BSE contaminated beef products remains the most likely hypothesis.
The primary aim of CJD surveillance in the UK is to inform the scientific community, policy makers and, ultimately, the general public of changes in the epidemiology of CJD and vCJD and of potential risk factors, in order to plan for and to reduce the potential consequences of this disease.
The main objective of the NCJDRSU is to identify all cases of CJD in the UK and to investigate each case further by clinical examination, clinical investigations, neuropathological examination, genetic analysis, molecular biological studies, collecting basic epidemiological data and carrying out a case-control study in order to:
provide accurate data on the incidence of CJD, including vCJD;
investigate risk factors for CJD, including vCJD;
identify the mechanism of transmission of BSE to the human population;
provide estimates of short-term and long-term trends in the rate of occurrence of vCJD;
evaluate the potential risks of onward transmission of vCJD, including through iatrogenic routes;
identify any novel forms of human spongiform encephalopathy;
evaluate case definitions of CJD, including vCJD; and
evaluate diagnostic tests for CJD, including vCJD.
Referral of suspect cases to the NCJDRSU occurs in three ways:
Clinical - passive ascertainment: neurologists, neuropathologists and neurophysiologists are reminded twice yearly of the need to refer any individuals in whom CJD or vCJD is considered a possible diagnosis to the NCJDRSU
Death certificates - passive ascertainment: the Office for National Statistics for England and Wales and the General Register Offices for Scotland and Northern Ireland supply all death certificates coded under rubrics A81.0 and F02.1 (10th ICD revision).
Other sources - passive ascertainment: psychiatrists, paediatricians (also active surveillance - see below), geriatricians, other health professionals and members of the general public may refer cases to the NCJDRSU.
From July 2004, a new national reporting system was announced by the Chief Medical Officer. This is centred on the National CJD Reporting Form to be faxed, by the notifying clinician, to the National Creutzfeldt-Jakob Disease Research & Surveillance Unit (NCJDRSU), the National Prion Clinic (NPC) and the local CCDC. The National CJD Reporting Form and associated documents are available at the links shown below.
This system does not preclude the possibility of a clinician informally discussing a suspect or doubtful case with the NCJDRSU or the NPC. The NCJDRSU are very happy to discuss cases and provide clinical and other advice concerning potential cases of CJD. The NCJDRSU continues to provide a national CSF 14-3-3 service and will arrange courier collection of CSF samples and prompt results.
Suspect cases are classified according to published criteria. This is an on-going process, being constantly up-dated as more information is obtained. The date of any change of classification and the reason for that change is recorded on the Change in Classification Form. In addition, the classification is recorded at the following key stages:
Whenever possible all referrals to the NCJDRSU categorised as ‘definite CJD’, ‘probable CJD’, ‘possible CJD’, and ‘diagnosis unclear’ are visited in life in order to carry out a physical examination, to take specimen samples and to gather systematic clinical information from the suspect case and their relatives. During such visits, a NCJDRSU neurologist completes a copy of the Patient Review and Examination Form and where possible makes a copy of the relevant sections of the hospital records and relevant investigation results, including EEGs. A request is also made for copies of any relevant MRI scans to be sent to the NCJDRSU. At the same visit, as part of the case control study (see below) to investigate risk factors for CJD, a close relative or nominated spokesperson is interviewed by a nurse practitioner/research nurse, or deputy, from the NCJDRSU, who completes a copy of the Risk Factor Questionnaire and Beef Purchasing Questionnaire (variant cases only).
Following this visit a Final Review Form is opened for each suspect case and held in their file at the NCJDRSU. Incoming clinical, pathological and laboratory data are recorded on this form as they arrive at the NCJDRSU. Following the death of a suspect case, if a post-mortem is performed, every effort is made to obtain details of the report and review of any pathological material is organised. In addition, following the death of a definite or probable case of variant CJD, the general practice records are requested and used to update the Final Review Form. This form is closed when it is apparent that no further data are likely to be forthcoming.
If notification to the NCJDRSU is made after death or death occurs soon after notification and before a visit can be performed, for definite cases (and in cases that the final classification is probable) hospital records are requested. In addition, an attempt is made to visit the relatives of the case in order to gather further clinical information. Data extracted from the hospital records and obtained from relatives are recorded on a copy of the Late Referral Form by a NCJDRSU neurologist. At the same visit, a close relative or nominated spokesperson is interviewed by a nurse practitioner/research nurse, or deputy, from the NCJDRSU, who completes a copy of the Risk Factor Questionnaire and Beef Purchasing Questionnaire (variant cases only). The Late Referral Form is closed when it is apparent that no further clinical, pathological or other laboratory data are likely to be forthcoming.
Changes in diagnostic criteria that occur as data is accrued in relation to suspect cases of CJD are noted on the Change in Classification Form.
Notifications classified as probable or definite genetic CJD or accidentally transmitted TSE (also known as iatrogenic CJD) are not followed up by NCJDRSU, unless the diagnosis is unclear or a specific request is made by the local clinician for a visit by a neurologist from the NCJDRSU. Professor Michael Preece, Institute of Child Health, London, follows up cases of growth hormone related iatrogenic CJD and the investigation of cases of familial CJD is undertaken by staff at the National Prion Clinic, London.
In order to obtain as much complete data on each case as is possible, following the death of a suspect case (or following recovery) the files are reviewed twice yearly. When it is apparent that no further clinical, pathological or other laboratory data are likely to be forthcoming, the case file is closed.
This is carried out through prospective active surveillance in conjunction with the British Paediatric Surveillance Unit. The aim is to identify cases of progressive intellectual and neurological deterioration and to determine whether or not cases of CJD are occurring in children resident in the UK aged under 16 years at onset of symptoms.
This is a 3-year project involving all the neuropathology laboratories in the UK, which commenced in 1999. The aim is to review cases of CJD which have been identified in diagnostic files back to 1970 (the earliest point of prospective clinical surveillance data) and to review selected groups of atypical dementia cases in order to determine whether any cases of CJD have been misclassified or missed altogether.
Variant CJD: As soon as a suspect case is classified as ‘probable’, the Medical Director(s) of the relevant (according to residential history) Transfusion Service(s) is notified with the following information: forename, surname, maiden name, gender, date of birth, residential history, whether a donor, donation dates, places of donation, vCJD classification and country (England, Wales etc.) notified. An anonymised copy is sent to the appropriate Department of Health(s).
Aims - The aims of the study are to investigate the aetiology of sporadic and variant CJD and to identify routes by which the agent responsible for sporadic and variant CJD is transmitted.
Cases - Cases are identified through routine surveillance (as described above). Only those individuals classified as definite or probable cases of sporadic or variant CJD are included as cases in the case-control study.
Controls - As of November 2002, an additional two control groups will be recruited into the study and general practice recruited controls will cease to be recruited because of a poor response. This will provide four control groups in total, which will enable a comparison to be made between the findings from each group. This may provide some indication of the extent to which selection and recall bias have occurred.
Hospital controls - The clinician caring for a case of CJD will be asked to identify a control from their in-patients. A research nurse will visit the hospital and the first age- and sex-matched in-patient that is identified will be used.
Controls referred as 'suspect' cases of CJD who subsequently are thought unlikely/definitely do not have CJD: This group of controls are referred to the NCJDRSU as suspect cases and undergo the usual procedure for cases (see above).
General population controls: The National Centre for Social Research (the largest independent social and public policy research institute in Britain) will carry out this part of the study. The aim is to recruit 1000 people from the general population aged 10 years and over with an age distribution that matches the distribution of variant and sporadic CJD cases. A random sample of households will be selected from the Postcode Address File (PAF), with oversampling in the north of the Great Britain to take into account the increased incidence of variant CJD in the north.
Relative-nominated controls: At the initial interview with the research nurse, relatives of the case will be asked if they would be willing to nominate a friend who has a relative of preferably the same degree and approximately the same age as the case. Through the friend, the control will be approached.
If consent is obtained, a relative will be interviewed by a NCJDRSU research nurse (except for general population controls where NCSR trained interviewers will be used) using the Risk Factor Questionnaire and Beef Purchasing Questionnaire (controls for variant cases only). In addition, if consent is obtained, NCJDRSU research nurse will visit the relevant practice(s) and complete the General Practice Medical Records Form.
Data collection - Interviews cannot be performed with suspect cases of CJD themselves and must therefore be performed with a relative. In order to maximise the comparability of the information obtained for cases and controls, the information on controls is also obtained by interviewing a relative, wherever possible of the same “degree” as the relative giving information about the case.
The Nurse Practitioner/Research Nurse conducts a structured interview with the relative using the Risk Factor Questionnaire. When the Nurse Practitioner/Research Nurse has completed the interviews with the relatives of the case and their control(s), they visit the case’s general practice to complete copies of the General Practice Medical Records Form concerning the surgical and medication history of the case and control(s) using the medical notes held by the general practice.
The following minimum data sets are collected. Please note, the "Patient Review and Examination", "Late Referral" and "Final Review" forms are completed on those suspect cases outlined in the previous section "Follow-up of suspect cases".
Identification information, notification details, history, examination at notification, investigations, risk factors, classification at notification.
For each change in classification: classification, criteria for classification, date of change and reason for change.
Identification information, clinical history, state of patient at admission/first seen by a neurologist, previous medical history, examination of patient by NCJDRSU neurologist, history and examination related to current illness, investigations (including EEG, MRI and CSF), specimens collected and classification based on clinical information.
Identification information, clinical history, state of patient at admission/first seen by a neurologist, previous medical history, history and examination related to current illness, investigations (including EEG, MRI and CSF), clinical and neuropathological materials available, post mortem results and classification history.
Identification information, summary of clinical history and examination, investigations (including EEG, MRI and CSF), clinical and neuropathological materials available, post mortem results and classification history.
Post-mortem report with the referring pathologist's diagnosis, and any other relevant findings at autopsy. Review of the neuropathological material includes PrP immunocytochemistry and investigations on non-central nervous system (CNS) tissues, including lymphoid and peripheral nervous system tissues. All referring pathologists are encouraged to freeze CNS and other tissues for biochemical studies and (when necessary) DNA extraction.
Prion protein gene (PRNP) analysis is performed in cases in which consent for genetic analysis is obtained.
Prion protein (PrPres) typing is performed where possible on the CNS and other tissues in cases in which frozen tissues are stored at post mortem.
By case of variant CJD
Once relatives and local clinicians have been informed of the diagnosis of definite or probable vCJD, the NCJDRSU informs the following:
Transfusion Medicine
Transfusion Medicine Epidemiology Review (TMER)
The UK Transfusion services are informed six monthly of all definite and probable cases of sporadic and familial CJD who were reported as blood donors ("main TMER") and those that were reported as blood product recipients ("reverse TMER"). The basic information they are sent is the name, maiden name, gender and date of birth of the case. In addition, for blood donors, they are informed of the year of donation(s), the home address at the time of donation(s) and where the donation(s) was given and, for transfusion recipients, they are informed of the year of the transfusion(s), the home address at the time of transfusion(s), the hospital where the transfusion(s) occurred and the indication for the transfusion(s). Similar details for controls are also given. The information sent is 'blinded' with regards to whether it relates to cases or controls.
Variant CJD: As soon as a suspect case is classified as 'probable', the Medical Director(s) of the relevant (according to residential history) Transfusion Service(s) is notified with the following information (Appendix 8): forename, surname, maiden name, gender, date of birth, residential history, whether a donor, donation dates, places of donation, vCJD classification and country (England, Wales etc.) notified. An anonymised copy is sent to the appropriate Department of Health(s). Details on controls of probable vCJD cases are also sent to the relevant Transfusion Service(s), which are the forename, surname, maiden name, gender, date of birth, residential history, whether a blood donor and whether received a blood/ blood product transfusion. The information sent is not 'blinded' with regards to whether it relates to cases or controls.
Monthly
Numbers of referrals for investigation, numbers of sporadic, iatrogenic, familial, GSS and vCJD cases by year are published by the Department of Health (press release and web-site), on the NCJDRSU web-site and in the SCIEH weekly report.
Annually
The NCJDRSU annual report contains the following minimum information:
Sporadic CJD
Variant CJD
UK (www.cjd.ed.ac.uk)
Europe (www.eurocjd.ed.ac.uk)- tables of:
Ad hoc
As requested.
Principal uses of data for decision making
Special aspects
Collaboration with surveillance units within the EU and world-wide.
Reference section