National CJD Surveillance Unit Research Articles

Variant Creutzfeldt‐Jakob disease and exposure to fractionated plasma products

The risk to public health of onward transmission of variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion and plasma product administration is of on-going concern, particularly with the recent reported detection of abnormal prion protein in a person with haemophilia. To describe the history of fractionated plasma product exposure in clinical cases of vCJD in the UK. Through examination of records held at the National CJD Surveillance Unit (from relatives, general practices and hospitals). Nine out of 168 UK vCJD cases had a history of receipt of fractionated plasma products on 12 different occasions (1 pre-vCJD risk in 1970, the remaining between 1989-1998). According to the UK CJD Incident Panel risk assessment criteria, 11 were low-risk products and one was low or medium risk. It is unlikely that any of the UK vCJD clinical cases to date were infected through exposure to fractionated plasma products. However, the possibility that such transmission may result in vCJD cases in the future cannot be excluded.

Straight talk with...James Ironside

Would you entrust your brain to a bank? Well, many people do after they die, and such brain banks-often funded by government agencies or disease charities-are essential for neuroscience research. They collect and store the healthy and diseased brain specimens that neuroscientists need to explore neurological disorders such as Alzheimer's disease, schizophrenia and autism. Each brain bank typically has a limited supply of samples and tends to operate fairly independently. This means that researchers often have to trawl through numerous brain banks to find their desired specimens. Furthermore, there is a general shortage of brain samples. To help resolve these issues in the UK, James Ironside, professor of clinical neuropathology at the University of Edinburgh, was appointed in June as the director of the new UK Brain Banks Network. An expert in human prion diseases, particularly Creutzfeldt-Jakob disease (CJD), Ironside knows all about brain banks. He established the Brain and Tissue Bank at the UK's National CJD Surveillance Unit and is involved in the Sudden Death Brain and Tissue Bank at the University of Edinburgh. Jon Evans recently caught up with Ironside to discuss his new leadership position and how the brain network will benefit neuroscience research.

Pathological investigation of the first blood donor and recipient pair linked by transfusion‐associated variant Creutzfeldt–Jakob disease transmission

Neuropathology and Applied NeurobiologyVolume 35, Issue 4 p. 433-436 Pathological investigation of the first blood donor and recipient pair linked by transfusion-associated variant Creutzfeldt–Jakob disease transmission M. W. Head, M. W. Head National CJD Surveillance Unit, School of Molecular & Clinical Medicine (Pathology), University of Edinburgh, Edinburgh, UKSearch for more papers by this authorH. M. Yull, H. M. Yull National CJD Surveillance Unit, School of Molecular & Clinical Medicine (Pathology), University of Edinburgh, Edinburgh, UKSearch for more papers by this authorD. L. Ritchie, D. L. Ritchie National CJD Surveillance Unit, School of Molecular & Clinical Medicine (Pathology), University of Edinburgh, Edinburgh, UKSearch for more papers by this authorM. T. Bishop, M. T. Bishop National CJD Surveillance Unit, School of Molecular & Clinical Medicine (Pathology), University of Edinburgh, Edinburgh, UKSearch for more papers by this authorJ. W. Ironside, J. W. Ironside National CJD Surveillance Unit, School of Molecular & Clinical Medicine (Pathology), University of Edinburgh, Edinburgh, UKSearch for more papers by this author M. W. Head, M. W. Head National CJD Surveillance Unit, School of Molecular & Clinical Medicine (Pathology), University of Edinburgh, Edinburgh, UKSearch for more papers by this authorH. M. Yull, H. M. Yull National CJD Surveillance Unit, School of Molecular & Clinical Medicine (Pathology), University of Edinburgh, Edinburgh, UKSearch for more papers by this authorD. L. Ritchie, D. L. Ritchie National CJD Surveillance Unit, School of Molecular & Clinical Medicine (Pathology), University of Edinburgh, Edinburgh, UKSearch for more papers by this authorM. T. Bishop, M. T. Bishop National CJD Surveillance Unit, School of Molecular & Clinical Medicine (Pathology), University of Edinburgh, Edinburgh, UKSearch for more papers by this authorJ. W. Ironside, J. W. Ironside National CJD Surveillance Unit, School of Molecular & Clinical Medicine (Pathology), University of Edinburgh, Edinburgh, UKSearch for more papers by this author First published: 30 June 2009 https://doi.org/10.1111/j.1365-2990.2009.01025.xCitations: 14Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume35, Issue4August 2009Pages 433-436 RelatedInformation

Is there evidence of vertical transmission of variant Creutzfeldt–Jakob disease?

ObjectivesThe possibility of vertical transmission of variant Creutzfeldt–Jakob disease (vCJD) has been raised because of the widespread distribution of infectivity in vCJD and the demonstration that this condition can be...

Acquired human prion diseases - the past and the present issues

Transmissible spongiform encephalopathies, or prion diseases, are fatal neurodegenerative disorders. In aetiological viewpoint, human prion diseases are classified into 1) sporadic Creutzfeldt-Jakob disease (CJD) which comprises 80-90% of the total population of human prion disaeses, 2) inherited forms, and 3) acquired types by prion-contaminated surgical instruments, biopharmaceuticals or foodstuffs. The diseases cause an accumulation of the disease-associated form(s) of prion protein (PrP(Sc)) in the central nervous system. PrP(Sc) is regarded as the entity of prion agents and generally exerts infectivity, irrespective of its origin being from the sporadic cases or the inherited cases. Variant CJD (vCJD), first identified in the United Kingdom (UK) in 1996, is an acquired type of human CJD by oral intake of BSE prion. Cumulative numbers of 215 patients in the world have been reported for definite or probable vCJD cases according to the UK National Creutzfeldt-Jakob Disease Surveillance Unit by September, 2009. Different from sporadic CJD cases, vCJD patients show an accumulation of PrP(Sc) in spleen and tonsils. Such distribution of PrP(Sc) in lymphoid tissues raised clinical concern about the potential infectivity in the blood or blood components used for blood transfusion. To date, five instances of probable transfusion-mediated transmission of vCJD prion have been found in UK. Here we review the past and the present issues about the acquired human prion diseases.

SI08 Protein Misfolding Cyclic Amplification of Disease‐Associated Prion Protein Using Human Autopsy Tissues

The protein misfolding cyclic amplification (PMCA) technique allows for the in vitro production of protease‐resistant prion protein (PrPres) using a seed of disease‐associated prion protein (PrPsc) to convert normal cellular prion protein (PrPc). This system has been developed using brain tissue from scrapie infected hamsters to provide the seed and normal uninfected hamster brain to provide PrPc substrate and the required conversion factors. These are mixed and subjected to repeated rounds of sonication and incubation. Extremely low concentrations of PrPsc, such as those present in blood, have been detectable. In order to adapt this method for use in CJD research and in the development of diagnostic tests for human prion diseases it will be necessary to identify a source of human PrPc and co‐factors that support amplification of human PrPsc. We have tested whether human autopsy tissues held at the National CJD Surveillance Unit support PMCA. Using a seed extract from variant CJD brain mixed with homogenates of nonCJD neurological control brain we have been able to effect a >600‐fold increase in the detection limit of PrPres, as determined by Western Blotting. Further development of this technique in concert with high sensitivity PrPsc detection methods, such as conformation dependent immunoassay, may result in a method capable of acting as a confirmatory assay for disease‐associated prion protein in human tissues and biological fluids such as blood.

Creutzfeldt–Jakob disease and blood transfusion: results of the UK Transfusion Medicine Epidemiological Review study

This paper reports the results to 1 March 2006 of an ongoing UK study, the Transfusion Medicine Epidemiological Review (TMER), by the National CJD Surveillance Unit (NCJDSU) and the UK Blood Services (UKBS) to determine whether there is any evidence that Creutzfeldt-Jakob disease (CJD), including sporadic CJD (sCJD), familial CJD (fCJD), and variant CJD (vCJD) is transmissible via blood transfusion. Sporadic CJD and fCJD cases with a history of blood donation or transfusion are notified to UKBS. All vCJD cases aged > 17 years are notified to UKBS on diagnosis. A search for donation records is instigated and the fate of all donations is identified by lookback. For cases with a history of blood transfusion, hospital and UKBS records are searched to identify blood donors. Details of identified recipients and donors are checked against the NCJDSU register to establish if there are any matches. CJD cases with donation history: 18/31 vCJD, 3/93 sCJD, and 3/5 fCJD cases reported as blood donors were confirmed to have donated labile components transfused to 66, 20, and 11 recipients respectively. Two vCJD recipients have appeared on the NCJDSU register as confirmed and probable vCJD cases. The latter developed symptoms of vCJD 6.5 years and 7.8 years respectively after receiving non-leucodepleted red blood cells (RBCs) from two different donors who developed clinical symptoms approximately 40 and 21 months after donating. A third recipient, given RBC donated by a further vCJD case approximately 18 months before onset of clinical symptoms, had abnormal prion protein in lymphoid tissue at post-mortem (5-years post-transfusion) but had no clinical symptoms of vCJD. CJD cases with history of transfusion: Hospital records for 7/11 vCJD and 7/52 sCJD cases included a history of transfusion of labile blood components donated by 125 and 24 donors respectively. Two recipients who developed vCJD were linked to donors who had already appeared on the NCJDSU register as vCJD cases (see above). No further links were established. This study has identified three instances of probable transfusion transmission of vCJD infection, including two confirmed clinical cases and one pre- or sub-clinical infection. This study has not provided evidence, to date, of transmission of sCJD or fCJD by blood transfusion, but data on these forms of diseases are limited.

S1-03-01: vCJD and blood transfusion

Variant Creutzfeldt–Jakob disease (vCJD) is a novel human prion disease, which is causally linked to bovine spongifom encephalopathy (BSE), with human infection probably due to past exposure to high titre bovine tissues in the human food chain. The pathogenesis of vCJD includes significant levels of disease–associated prion protein deposition and infectivity in peripheral lymphoreticular tissues, raising the possibility of secondary transmission through blood transfusion. To identify whether blood transfusion is a mechanism of transmission of vCJD from person to person. A look–back study of blood transfusion in vCJD (the TMER) has been undertaken in the UK since 1997 and is a collaborative study between the National Blood Services, the National CJD Surveillance Unit and the Office of National Statistics. In December 2003 a case of vCJD was identified with a prior history of a blood transfusion derived from an individual who died of vCJD, raising the possibility that the disease was transfusion transmitted. In 2004 an individual who had previously received blood donated by a vCJD donor died of intercurrent illness but was found to have positive immunostaining for prion protein in spleen and a lymph node, suggesting sub–clinical or pre–clinical infection. This individual was a PRNP codon 129 heterozygote in contrast to all tested clinical cases of vCJD, in which the genotype has been uniformly methionine homozygous. A further case of probable transfusion–transmission of vCJD was identified in 2006. The probability of transfusion transmission of vCJD has important implications for public health and a range of measures have been taken in a number of countries to minimise the risk, most initiated prior to the identification of the cases described above. With the identification of vCJD cases with a history of blood donation in a number of other countries, it is important to consider what measures may be necessary to protect public health in relation to blood and blood derived components.

Evaluation of urinary PrP Sc as a diagnostic test for sporadic, variant, and familial CJD

Previously collected urine specimens from 100 patients referred to the UK National CJD Surveillance Unit as suspected cases of Creutzfeldt-Jakob disease (CJD) were analyzed, testing for abnormal prion protein (PrP(Sc)). In this context, the test had a low sensitivity and was not completely specific for CJD. Additionally, the proteins detected by this assay were not PrP(Sc) but appeared to be immunoglobulins.

Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion

Variant Creutzfeldt-Jakob disease (vCJD) is a novel human prion disease caused by infection with the agent of bovine spongiform encephalopathy (BSE). Epidemiological evidence does not suggest that sporadic CJD is transmitted from person to person via blood transfusion, but this evidence may not apply to vCJD. We aimed to identify whether vCJD is transmissible through blood transfusion. The national CJD surveillance unit reported all cases of probable or definite vCJD to the UK blood services, which searched for donation records at blood centres and hospitals. Information on named recipients and donors was provided to the surveillance unit to establish if any matches existed between recipients or donors and the database of cases of vCJD. Recipients were also flagged at the UK Office of National Statistics to establish date and cause of death. 48 individuals were identified as having received a labile blood component from a total of 15 donors who later became vCJD cases and appeared on the surveillance unit's register. One of these recipients was identified as developing symptoms of vCJD 6.5 years after receiving a transfusion of red cells donated by an individual 3.5 years before the donor developed symptoms of vCJD. Our findings raise the possibility that this infection was transfusion transmitted. Infection in the recipient could have been due to past dietary exposure to the BSE agent. However, the age of the patient was well beyond that of most vCJD cases, and the chance of observing a case of vCJD in a recipient in the absence of transfusion transmitted infection is about 1 in 15000 to 1 in 30000.

Levels of abnormal prion protein in dental tissue

Objective To study the distribution of disease-associated prion protein (PrP) in oral and dental tissues in variant CJD. Design Prospective single centre autopsy based study. Setting Within the National CJD Surveillance Unit, UK, 2000–2002. Materials and methods Patients with suspected variant CJD undergoing autopsy where permission to remove tissues for research purposes had been obtained from the relatives. Fixed and frozen autopsy tissues from the brain, trigeminal ganglion, alveolar nerve, dental pulp, gingiva, salivary gland, tongue and tonsils were studied by Western blot, PET blot and immunocytochemistry to detect disease-associated PrP. Results Disease-associated PrP was only detected in the brain, trigeminal ganglia and tonsils. Conclusions The failure to detect disease-associated PrP in most dental and oral tissues will help inform ongoing risk assessments for dental surgery in relation to the possible iatrogenic transmission of variant CJD via dental instruments.

Investigation of PrPres in dental tissues in variant CJD.

To study the distribution of disease-associated prion protein (PrP) in oral and dental tissues in variant CJD. Prospective single centre autopsy based study. Within the National CJD Surveillance Unit, UK, 2000-2002. Patients with suspected variant CJD undergoing autopsy where permission to remove tissues for research purposes had been obtained from the relatives. Fixed and frozen autopsy tissues from the brain, trigeminal ganglion, alveolar nerve, dental pulp, gingiva, salivary gland, tongue and tonsils were studied by Western blot, PET blot and immunocytochemistry to detect disease-associated PrP. Disease-associated PrP was only detected in the brain, trigeminal ganglia and tonsils. The failure to detect disease-associated PrP in most dental and oral tissues will help inform ongoing risk assessments for dental surgery in relation to the possible iatrogenic transmission of variant CJD via dental instruments.

Sensory features of variant Creutzfeldt-Jakob disease.

Sensory symptoms are a prominent feature of variant Creutzfeldt-Jakob disease (vCJD), occurring at an early stage of the illness. They are persistent and can be troublesome. Here, they are described in detail and a possible anatomical basis is discussed. The first 50 cases of vCJD confirmed by the National CJD Surveillance Unit (NCJDSU) were reviewed. Where possible the patients and their relatives were interviewed and case notes were examined. The presence and nature of sensory symptoms and signs were noted. Results of investigation and types of treatment offered were also reviewed. Of 50 definite cases, 64 % had persistent sensory symptoms, 16 % had no sensory symptoms and 18 % were uncertain. In 2 % there was insufficient information. Of the 32 with definite symptoms, 31 % were symptomatic from the onset of the illness. The symptoms were varied and some patients complained of more than one type of symptom. Limb pain was described in 63 % cases. This was the most common symptom and was often non-specific and poorly localised, usually occurring in the lower limbs. Other symptoms included cold feelings (25 % patients), dysaesthesia (28 % patients), paraesthesia (31 % patients) and numbness (25 % patients). The symptoms were lateralised in 31 % of patients. Sensory symptoms are a prominent feature of vCJD, occurring in nearly two thirds of cases. They may help distinguish variant from sporadic CJD. They are likely to be of thalamic origin but the recognised MRI changes in vCJD do not correlate with the presence or absence of sensory symptoms. Neuropathological changes in the thalamus, however, show marked astrocytosis and neuronal loss.

Geographical distribution of variant Creutzfeldt-Jakob disease in Great Britain, 1994–2000

Geographical variation in the distribution of variant Creutzfeldt-Jakob disease (vCJD) might indicate the transmission route of the infectious agent to man. We investigated whether regional incidences of vCJD were correlated with regional dietary data. The National CJD Surveillance Unit prospectively identified 84 people with vCJD up to Nov 10, 2000, in Great Britain. Their lifetime residential histories were obtained by interviews with a close relative. Cumulative incidences of vCJD by standard region were calculated. Grid references for places of residence in 1991 were identified and evidence of geographical clusters were sought. Data on diet in the 1980s were analysed for regional correlations with vCJD incidence. The socioeconomic status of the places of residence of people with vCJD was compared with that of the general population. vCJD incidence was higher in the north of Great Britain than the south. The rate ratio (north vs south) was 1.94 (95% CI 1.27-2.98). The mean Carstairs' deprivation score for areas of residence of people with vCJD was -0.09 (-0.73 to 0.55), which is close to the national average of zero. Regional rates of vCJD were correlated with consumption of other meat or meat products as classified and recorded by the Household Food Consumption and Expenditure Survey (r=0.72), but not with data from the Dietary and Nutritional Survey of British Adults. Five people with vCJD in Leicestershire formed a cluster (p=0.004). Regional differences in vCJD incidence are unlikely to be due to ascertainment bias. We had difficulty determining whether regional variations in diet might cause these differences, since the results of dietary analyses were inconsistent.

Clinicopathological phenotype of codon 129 valine homozygote sporadic Creutzfeldt–Jakob disease

The naturally occurring polymorphism at codon 129 of the human prion protein gene (PRNP) influences susceptibility to sporadic Creutzfeldt-Jakob Disease (CJD); the majority of the patients are methionine homozygotes at this locus, while valine homozygotes represent only 10% of cases. The aim was to study the clinical and neuropathological phenotype of sporadic CJD in valine homozygotes, to estimate the reliability of current clinical diagnostic criteria, and to identify any consistent and distinct features. Twelve cases of sporadic CJD with a codon 129 valine homozygote genotype were identified at the National CJD Surveillance Unit in Edinburgh. In addition to a retrospective clinical analysis, tissue blocks were stained by conventional techniques and by immunocytochemistry for prion protein. Frozen brain tissue was available from five cases for Western blot analysis of PrPRES, which in all cases showed a type 2 mobility. The cases included four males and eight females, average age 63.6 years, with a mean duration of illness of 6 months. Eleven patients presented with ataxia, and none had the characteristic EEG changes found in sporadic CJD. The neuropathological phenotype comprised spongiform change and prion protein immunopositivity most marked in the subcortical grey matter and cerebellum, prion protein positive plaque-like deposits in all regions, laminar deposition of prion protein in the cerebral cortex, and hippocampal involvement (which is seldom reported in sporadic CJD). In conclusion, these cases exhibited a fairly uniform phenotype, which is relatively distinct from sporadic CJD in methionine homozygotes, and thus diagnosis may be difficult using existing clinical criteria.

Surveillance of Creutzfeldt Jakob disease in the United Kingdom.

By the end of May 2000, 54 definite cases and 13 probable cases of vCJD had been notified in the United Kingdom by the National CJD Surveillance Unit set up in 1990. All definite cases for whom data are available are methionine homozygous at codon 129 of

Extent of misclassification of death from Creutzfeldt-Jakob disease in England 1979-96: retrospective examination of clinical records

Objective: To investigate the extent to which deaths from Creutzfeldt-Jakob disease were misclassified during 1979-96.Design: Structured review of clinical records based on predetermined criteria to determine whether death could have...

Geographical distribution of variant CJD in the UK (excluding Northern Ireland)

The agent that causes variant Creutzfeldt-Jakob disease (variant CJD) is indistinguishable from the causative agent of bovine spongiform encephalopathy (BSE). The transmission route by which human beings are infected has not been established. One hypothesis is that cases of variant CJD have resulted from exposure to the BSE agent via rendering plants involved in the production of meat and bone meal, the main vehicle of the BSE epidemic. We identified cases of variant CJD through the National CJD Surveillance Unit, and obtained lifetime residential histories of cases by interviewing a relative. The addresses of all rendering plants in the UK (excluding Northern Ireland) in production in 1988 were available from a survey done in that year. We calculated the distance between each case's place of residence on Jan 1, 1988, and the nearest rendering plant from postcode data, and used data from the 1991 UK census to estimate the population living within various distances of rendering plants. We compared the observed number of cases of variant CJD within a particular distance of a rendering plant with the number expected if there is no association between residential proximity to a rendering plant and the risk of developing variant CJD. Up to Aug 31, 1998, 26 cases of variant CJD with onset in the UK (Northern Ireland not included) had been identified. The observed and expected numbers of variant CJD cases living within a specified distance of any rendering plant up to 50 km were almost the same. Two plants in the county of Kent each had four cases within 50 km in 1988, significantly more cases than expected (plant A, 1.04 expected; plant B, 0.74 expected). Multiple significance tests were done, so some tests would be expected to appear significant by chance alone. Computer simulations suggested that the observation of four cases of variant CJD living in an area with a population of 1.5 million (the size of Kent) is not unexpected. There is no evidence that people with variant CJD tended to live closer than the population as a whole to rendering plants in the 1980s. The reported cluster of variant CJD cases in Kent is most probably a chance finding.