Sporadic, familial, iatrogenic and variant Creutzfeldt Jakob Disease (CJD), including Gerstmann-Straussler-Scheinker Syndrome (GSS) and Fatal Famial Insomnia (FFI).

Following the identification in UK cattle of bovine spongiform encephalopathy (BSE) as one of the transmissible spongiform encephalopathies, the Southwood Report recommended that CJD should be monitored. The National CJD Surveillance Unit (CJDSU) 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 CJDSU 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 CJDSU occurs in three ways:

• Clinical- passive ascertainment: neurologists, neuropathologists and neurophysiologists are reminded annually of the need to refer any individuals in whom CJD or vCJD is considered a possible diagnosis to the CJDSU.
• 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 the rubrics 046.1 and 331.9 (9th ICD revision).  
• Other sources- passive ascertainment: pyschiatrists, paediatricians, geriatricians, other health professionals and members of the general public may refer cases to the CJDSU.

Suspect cases are classified according to the criteria below by a neurologist from the CJDSU. This is an on-going process, being constantly up-dated as more information is ascertained. The date of any change of classification and the reason for that change is recorded. In addition, the classification is recorded at the following key stages:

• At notification;
• When the suspect case was first seen in life by a neurologist from the CJDSU;
• The highest classification on the basis of clinical information alone (ie. not including neuropathological information); and
• When review by the CJDSU is complete (ie. when the case-file is 'closed').

• Diagnosis unclear- when the diagnostic criteria for possible, probable or definite CJD are not met nor is there a reasonable alternative diagnosis and, therefore, CJD remains a possibility;  
• CJD thought unlikely- when information indicates that a clinical diagnosis of CJD is very unlikely because of atypical disease features, and/or an atypical course, and/or atypical clinical investigation results, and/or a reasonable alternative diagnosis is made, but is not confirmed. This category includes cases which improve clinically without another firm diagnosis being made; and  
• Definitely not CJD- when information indicates that CJD is not the diagnosis and there is another definite diagnosis proven by clinical examination, clinical investigations or pathology.

Whenever possible all referrals to the CJDSU 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 CJDSU 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 CJDSU. At the same visit, as part of the case control study to investigate risk factors for CJD, a close relative or nominated spokesperson is interviewed by a nurse practitioner/ research nurse, or deputy, from the CJDSU, who completes a copy of the risk factor "Questionnaire".

Following this visit a "Final Review Form" is opened for each suspect case and held in their file at the CJDSU. Incoming clinical, pathological and laboratory data are recorded on this form as they arrive at the CJDSU. 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 CJDSU 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 CJDSU neurologist. At the same visit, a close relative or nominated spokesperson is interviewed by a nurse practitioner/ research nurse, or deputy, from the CJDSU, who completes a copy of the risk factor "Questionnaire" . 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 familial CJD, Gertsmann- Straussler- Scheinker Syndrome (GSS), Fatal Familial Insomnia (FFI) and iatrogenic CJD are not followed up, unless the diagnosis is unclear or a specific request is made by the local clinician for a visit by a neurologist from the CJDSU.

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 three-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.

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 the patient by CJDSU 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 (PrP^RES) typing is performed where possible on the CNS and other tissues in cases in which frozen tissues are stored at post mortem.

Once relatives and local clinicians have been informed of the diagnosis of definite vCJD and in those cases that have a final classification of probable vCJD, the CJDSU informs the following:

• The Chief Medical Officer is notified by fax of the gender, date of death and vCJD classification. The DOH informs other government departments and the Spongiform Encephalopathy Advisory Committee (SEAC) Secretariat; 
• The Public Health Laboratory Service Communicable Disease Surveillance Centre are notified of the CJDSU identification number, age at death, gender, date of onset, date of notification to the CJDSU, date of birth, date of death and date confirmed as 'definite/probable' vCJD.  
• Colleagues in the EU Surveillance System, WHO Headquarters, CDC Atlanta, European Commission, Alzheimer's Disease Society, Human BSE Foundation, BSE Enquiry and other interested parties are sent the gender, date of death, vCJD classification and the current total number of definite (and those with a final classification of probable) vCJD cases.

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.

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 CJDSU web-site and in the SCIEH weekly report.

The CJDSU annual report contains the following minimum information:

• Deaths from sporadic CJD by region (England and Wales, Scotland and Northern Ireland) by year;
• Cases of sporadic CJD by year of death and by age;
• Age- and sex- specific mortality rates from sporadic CJD;
• Trends in mortality rates from sporadic CJD by time;
• Standardised mortality ratios by Region; and
• Analysis of risk factors, depending on available information.

• Cases of vCJD by date of onset;
• Geographical distribution of places of residence (UK only) at onset of vCJD; and
• Analysis of risk factors, depending on available information.

• Table of referrals and deaths from definite and probable sporadic, iatrogenic, familial and variant CJD and GSS by year.
• Latest annual report of CJDSU.
• CJD in Europe

• Deaths (absolute numbers and annual mortality rates per million population) from definite and probable cases of sporadic, familial, GSS and iatrogenic CJD by country by year;
• Total number of cases of sporadic CJD (definite and probable cases and deaths) by country by year;
• Annual mortality rates from sporadic CJD by country by year;
• Total number of cases (deaths) of familial/genetic CJD and iatrogenic CJD by country; and
• Referrals of suspected CJD < 50 years old (from 1996 onwards) and number of cases of vCJD by country.

As requested.

• Develop and test hypotheses about novel forms of spongiform encephalopathy;
• Track trends over time;
• Detect clusters;
• Detection of risk factors and mechanisms of transmission;
• Determine magnitude of public health problem;
• Inform prevention strategies; and
• Development and evaluation of diagnostic tests.

 Special aspects

 Collaboration with surveillance units within the EU and world-wide.

 Reference section

1. Budka et al. Tissue handling in suspected Creutzfeldt-Jakob Disease (CJD) and other human spongiform encephalopathies (prion diseases). Brain Pathology 1995; 5: 319-322.
2. Will RG, Stewart G, Zeidler M, Macleod MA, Knight RSG. Psychiatric features of new variant Creutzfeldt-Jakob disease. Psychiatric Bulletin 1999; 23: 264- 267.
3. Ironside JW, Sutherland K, Bell JE et al. A new variant of Creutzfeldt-Jakob disease: neuropathological and clinical features. Cold Harbour Symposia on Qualitative Biology 1996; 61: 523- 530.