National CJD Surveillance Unit Research Articles

Sporadic Creutzfeldt-Jakob disease in adults over 80years: a 10-year review of United Kingdom surveillance.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly progressive neurodegenerative disease with public health implications. Mean age of onset is 68years. Age-specific incidence declines after 80years. This may arise from under-ascertainment or other biological features of the disease. Accurate characterisation of late-onset sCJD is important for early diagnosis, avoiding unnecessary investigations and improving ascertainment for public health purposes. To phenotype the clinical features and investigation profile of sCJD in adults >80years. We analysed all probable and definite sCJD cases identified by the UK National CJD Research & Surveillance Unit over a 10-year period (2011-2021). Individuals were grouped by age of onset. Clinical features and investigation profiles were compared. 10.3% (123/1196) had an age of onset over 80. Median survival was shorter (3.2 vs 4.3months; P < 0.001). Pyramidal signs (48.3% vs 34.2%; P = 0.008) and akinetic mutism (55.1% vs 33.2%; P < 0.001) were more frequent. Psychiatric symptoms (26.3% vs 39.6%; P = 0.01) and cerebellar signs (65.4% vs 78.6%, P = 0.007) were less frequent. Cognitive impairment and myoclonus were highly prevalent regardless of age. Between age groups, the diagnostic sensitivity of cerebrospinal fluid real-time quaking-induced conversion (CSF RT-QuIC) (92.9% vs 91.9%, P = 0.74) was comparable, electroencephalography was superior (41.5% vs 25.4%; P = 0.006) and MRI was inferior (67.8% vs 91.4%; P < 0.001). Late-onset sCJD has distinct clinical features, shorter survival and a different profile of investigation sensitivity. CSF RT-QuIC, MRI brain and specialist CJD review is recommended in older adults with a rapidly progressive neurological disorder. Autopsy is valuable when the cause remains elusive.

Characterisation of RT-QuIC negative cases from the UK National CJD Research and Surveillance programme

IntroductionIncorporation of the real-time quaking-induced conversion (RT-QuIC) assays for diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) has transformed diagnosis largely related to its extremely high specificity. However, the test has a c.10% false-negative result and we aim to characterize the clinical features, investigation profile, and molecular subtype in this cohort of patients.Methods250 individuals diagnosed with definite sporadic CJD were identified from the UK National CJD Research and Surveillance Unit from 2012 to 2023. We compared the clinical features and investigation profile in those with a negative CSF RT-QuIC to those with a positive RT-QuIC.Results27 individuals (10.8%) were CSF RT-QuIC negative. Median age of onset was younger (62 years vs 68 years, p = 0.002), median disease duration was longer (4.4 months vs 10.5 months, p < 0.001), and these individuals were less likely to present with gait difficulties (73% vs 93%, p = 0.003) or motor symptoms (62% vs 80%, p = 0.04). The sensitivity of electroencephalography and diffusion-weighted MRI were similar in both groups. In those who were RT-QuIC negative, there was an overrepresentation of the VV1 (32% vs 1%) and MM2 molecular subtypes (21% vs 3%). Co-occurring neurodegenerative disease was found in 33% (9/27) of those who were RT-QuIC negative.ConclusionsIndividuals with sporadic CJD and a negative CSF RT-QuIC present with younger age of onset, different clinical features and are over-represented with the VV1 and MM2 subtypes of sporadic CJD. Further work is required to better understand the biochemical properties contributing to RT-QuIC negative results in these cases.

Magnetic resonance imaging arterial spin labeling hypoperfusion with diffusion-weighted image hyperintensity is useful for diagnostic imaging of Creutzfeldt-Jakob disease.

Magnetic resonance imaging with arterial spin labeling (ASL) perfusion imaging is a noninvasive method for quantifying cerebral blood flow (CBF). We aimed to evaluate the clinical utility of ASL perfusion imaging to aid in the diagnosis of Creutzfeldt-Jakob disease (CJD). This retrospective study enrolled 10 clinically diagnosed with probable sporadic CJD (sCJD) based on the National CJD Research & Surveillance Unit and EuroCJD criteria and 18 healthy controls (HCs). Diffusion-weighted images (DWIs), CBF images obtained from ASL, N-isopropyl-(123I)-p-iodoamphetamine (123IMP)-single-photon emission computed tomography (SPECT) images, and 18F-fluorodeoxyglucose (18FDG)-positron emission tomography (PET) images were analyzed. First, the cortical values obtained using volume-of-interest (VOI) analysis were normalized using the global mean in each modality. The cortical regions were classified into DWI-High (≥ +1 SD) and DWI-Normal (< +1 SD) regions according to the DWI-intensity values. The normalized cortical values were compared between the two regions for each modality. Second, each modality value was defined as ASL hypoperfusion (< -1 SD), SPECT hypoperfusion (< -1 SD), and PET low accumulation (< -1 SD). The overall agreement rate of DWIs with ASL-CBF, SPECT, and PET was calculated. Third, regression analyses between the normalized ASL-CBF values and normalized SPECT or PET values derived from the VOIs were performed using a scatter plot. The mean values of ASL-CBF (N = 10), 123IMP-SPECT (N = 8), and 18FDG-PET (N = 3) in DWI-High regions were significantly lower than those in the DWI-Normal regions (p < 0.001 for all); however, HCs (N = 18) showed no significant differences in ASL-CBF between the two regions. The overall agreement rate of DWI (high or normal) with ASL-CBF (hypoperfusion or normal) (81.8%) was similar to that of SPECT (85.2%) and PET (78.5%) in CJD. The regression analysis showed that the normalized ASL-CBF values significantly correlated with the normalized SPECT (r = 0.44, p < 0.001) and PET values (r = 0.46, p < 0.001) in CJD. Patients with CJD showed ASL hypoperfusion in lesions with DWI hyperintensity, suggesting that ASL-CBF could be beneficial for the diagnostic aid of CJD.

Establishing a committee for antemortem reviews of suspect Creutzfeldt-Jakob disease cases in Ireland

BackgroundCreutzfeldt-Jakob disease (CJD) is a rapidly progressive, neurodegenerative disease. In Ireland, clinical diagnostics and laboratory testing remain the responsibility of the managing clinician and the Neuropathology Department at the Beaumont Hospital, respectively. Centralized review of individual cases is not undertaken.AimsTo determine how diagnostic processes for CJD could be improved in Ireland and to outline the structure and referral process for a new CJD review panel at the Beaumont Hospital.MethodsWe surveyed Irish neurologists’ experiences on the management of CJD in Ireland. We measured turnaround times (TAT) for CSF samples referred for diagnostic CJD testing. Finally, we retrospectively reviewed imaging of autopsy-proven CJD cases to compare with initial reports.ResultsNinety-three percent of neurologists supported a national central review of suspect CJD cases. A second clinical opinion was considered to be of likely benefit by 79%. Additionally, 93% reported that a centralized review of neuroradiology would be useful. All respondents felt that expediting turnaround of CSF analysis would be of benefit. The average TAT for CSF testing was 35.4 days. In retrospective review of imaging, all patients demonstrated MRI findings consistent with CJD. However, in only one of these cases were the initial pre-autopsy radiological findings reported as being consistent with CJD.ConclusionsThese findings support the need for improvements to the Irish National CJD Surveillance Unit to maximize antemortem diagnostic accuracy. On foot of this, a clinical CJD Multidisciplinary Team (CJD MDT) has been established to provide a second opinion on (i) the patient’s clinical history, (ii) neuroradiology and (iii) and neurophysiology reports (where available).

Impact of the COVID-19 pandemic on Creutzfeldt-Jakob disease surveillance and patient care in the United Kingdom.

Background and purposeCreutzfeldt–Jakob disease (CJD) is lethal and transmissible. We assessed the impact of the COVID‐19 pandemic on UK CJD surveillance. We hypothesized that (i) disruptions prolonged diagnostic latency; (ii) autopsy rates declined; and (iii) COVID‐19 infection negatively affected diagnosis, care, and survival.MethodsWe retrospectively investigated the first year of the pandemic, using the preceding year as a comparator, quantifying numbers of individuals assessed by the UK National CJD Research & Surveillance Unit for suspected CJD, time to diagnosis, disease duration, and autopsy rates. We evaluated the impact of COVID‐19 status on diagnosis, care, and survival in CJD.ResultsA total of 148 individuals were diagnosed with CJD in the pandemic (from a total of 166 individuals assessed) compared to 141 in the comparator (from 145 assessed). No differences were identified in disease duration or time to diagnosis. Autopsy rates were unchanged. Twenty individuals had COVID‐19; 60% were symptomatic, and 10% had severe disease. Disruptions in diagnosis and care were frequently identified. Forty percent of COVID‐19‐positive individuals died; however, COVID‐19 status did not significantly alter survival duration in CJD.ConclusionsThe COVID‐19 pandemic has not impacted UK CJD case ascertainment or survival, but diagnostic evaluation and clinical care of individuals have been affected.

Non-white cases of sporadic Creutzfeldt-Jakob disease: A 28 year review of United Kingdom National Surveillance Data

AimsDescriptions of sporadic Creutzfeldt-Jakob disease (sCJD) in non-White populations are limited. Improved understanding may aid diagnoses and case ascertainment within surveillance programmes. We aimed to: 1) Ascertain the proportion of sCJD cases with non-White ethnicity in the United Kingdom (UK); 2) Compare clinical and investigation findings between non-White and White cases. MethodsWe analysed records of probable and definite sCJD cases assessed by the UK National CJD Research and Surveillance Unit over 28 years (1990–2017). Cases were stratified into White and non-White groups. Demographics, clinical features, investigation findings, and post-mortem numbers were compared. Results1697 sCJD cases were included: 1642 (97%) White, 55 (3%) non-White (Asian/Asian British, Black/African/Caribbean). The proportion of non-Whites among sCJD cases is 7% lower than the proportion the non-White population make up in the UK (p < 0.001). This was not statistically significant when age-matched by ≥60 years (p = 0.071). Age at symptom onset was 4 years lower in the non-White population (p = 0.007). Clinical and investigation characteristics were otherwise similar between ethnic groupings. The proportion of non-Whites undergoing autopsy and classification as definite was 30% and 24% lower (p < 0.001) respectively in comparison to those for White cases. ConclusionsApproximately 3% of sCJD cases in the UK are non-White, despite non-Whites representing approximately 10% of the UK population. This difference was not statistically significant when age-matched at ≥60 years. Non-White cases tend to be younger and likelihood of autopsy is lower; relevant considerations for surveillance programmes. Reasons for these differences in non-White populations are unclear and merit further evaluation.

Report of a Case of Creutzfeldt-Jakob Disease With an Unusual Clinical Presentation.

We describe the clinical features, neuropsychological tests, laboratory, electroencephalography (EEG), magnetic resonance imaging (MRI) and positron emission tomography (PET) findings of a 59-year-old woman who presented to our Centre for cognitive impairment since few months, with language disturbances, particularly anomia, dyscalculia, and memory loss. The clinical and neuropsychological features were non-specific and overlapping with those of other rapidly progressing neurodegenerative disorders. However, brain MRI played a pivotal role in the diagnosis, showing cortical diffusion restriction, particularly in the parietal lobes and posterior cingulum, with sparing of the perirolandic cortex, typical of Creutzfeldt-Jakob disease (CJD). Brain MRI abnormalities were visible since the first evaluation and remained stable at 2 and 6 weeks follow up. Basal ganglia and thalami were never involved. PET showed left lateralized reduced glucose metabolism, with partial overlap with MRI signal abnormalities. Despite MRI were strongly indicative of CJD, clinical, laboratory and EEG findings did not fulfill the diagnostic criteria for CJD which applied at the time of clinical assessment. Indeed, neither myoclonus, visual or cerebellar signs or akinetic mutism were present. Also, the characteristic periodic sharp wave complexes were absent at baseline EEG, and the CSF assay for 14–3–3 was negative. We, therefore, performed a real-time quaking-induced conversion (RT-QuIC) assay on a frozen sample of corticospinal fluid (CSF), which showed a positive result. RT-QuIC is a prion protein conversion assay that has shown high diagnostic sensitivity and specificity for the diagnosis of CJD. RT-QuIC has been recently incorporated in the National CJD Research and Surveillance Unit and Center for Disease Control and Prevention (CDC) diagnostic criteria for CJD. The fatal evolution of the disease brought the patient to death 13 months after symptoms onset. Pathology proved the diagnosis of sporadic CJD, subtype MM/MV 2C.

RT-QuIC: a new test for sporadic CJD

The diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) can be difficult, but the real-time quaking-induced conversion (RT-QuIC) assays have made a considerable impact on its clinical diagnosis. This technique exploits the...

Post-mortem magnetic resonance imaging in patients with suspected prion disease: Pathological confirmation, sensitivity, specificity and observer reliability. A national registry.

The relationship between magnetic resonance imaging (MRI) and clinical variables in patients suspected to have Creutzfeldt-Jakob Disease (CJD) is uncertain. We aimed to determine which MRI features of CJD (positive or negative), previously described in vivo, accurately identify CJD, are most reliably detected, vary with disease duration, and whether combined clinical and imaging features increase diagnostic accuracy for CJD. Prospective patients suspected of having CJD were referred to the National CJD Research and Surveillance Unit between 1994–2004; post-mortem, brains were sent for MRI and histopathology. Two neuroradiologists independently assessed MRI for atrophy, white matter hyperintensities, and caudate, lentiform and pulvinar signals, blind to histopathological diagnosis and clinical details. We examined differences in variable frequencies using Fisher’s exact tests, and associations between variables and CJD in logistic regression models. Amongst 200 cases, 118 (59%) with a histopathological diagnosis of CJD and 82 (41%) with histopathological diagnoses other than CJD, a logistic regression model including age, disease duration at death, atrophy, white matter hyperintensities, bright or possibly bright caudate, and present pulvinar sign correctly classified 81% of cases as CJD versus not CJD. Pulvinar sign alone was not independently associated with an increased likelihood of histopathologically-confirmed CJD (of any subtype) or sporadic CJD after adjustment for age at death, disease duration, atrophy, white matter hyperintensities or caudate signal; despite the large sample, data sparsity precluded investigation of the association of pulvinar sign with variant CJD. No imaging feature varied significantly with disease duration. Of the positive CJD signs, neuroradiologists most frequently agreed on the presence or absence of atrophy (agreements in 169/200 cases [84.5%]). Combining patient age, and disease duration, with absence of atrophy and white matter hyperintensities and presence of increased caudate signal and pulvinar sign predicts CJD with good accuracy. Autopsy remains essential.

Brain biopsies requiring Creutzfeldt-Jakob disease precautions in the Republic of Ireland 2005-2016.

Creutzfeldt-Jakob disease (CJD) risk precautions are required when performing brain biopsies on patients with a dementing illness and in 'risk' groups. The impact on a diagnostic neuropathology service is considerable. We sought to determine if better case selection might reduce the necessity for application of CJD risk precautions. We reviewed the clinical information, contributory investigations and final neuropathologic diagnosis in a cohort of patients (n=21), referred to the National CJD Surveillance Centre between January 1, 2005, and December 31, 2016. Of this 21-patient cohort, five were positive for CJD, four belonged to the 'at risk of CJD' category requiring brain surgery, while the remaining 12 were referred to the National CJD Surveillance Unit with CJD as part of their differential diagnosis. CJD was confirmed in 5/21 (three sporadic [s]CJD, one variant [v]CJD and one iatrogenic [i] CJD). CJD was clinically probable in 4/5 proven CJD patients (80%). The patients (n=4) in the 'at risk of CJD' group were diagnosed with tumour (n=2), inflammation (n=1) and non-specific changes (n=1). Of the remaining 12 patients (in whom CJD was included in the differential diagnosis), the final neuropathologic diagnoses included tumour (n=2), neurodegenerative (n=2), inflammatory (n=1), metabolic (n=2), vascular (n=2) and non-specific gliosis (n=3). More often than not, the clinical suspicion of CJD was not borne out by the final neuropathological diagnosis. Failure by clinicians to adhere to the recommended CJD investigation algorithm impacts adversely on the neuropathology workload and causes unnecessary concern among operating theatre, laboratory and nursing personnel.

Postmortem findings in a case of variant Creutzfeldt-Jakob disease treated with intraventricular pentosan polysulfate

BackgroundA small number of patients with variant Creutzfeldt-Jakob disease (vCJD) have been treated with intraventicular pentosan polysulfate (iPPS) and extended survival has been reported in some cases. To date, there...

South-East Asia Bovine Populations and The Japanese Cattle Breeds do not Harbour The E211K Variant of The PRNP

An important outcome of intensive worldwide Bovine spongiform encephalopathy (BSE) obtained with the surveillance by The National Creutzfeldt-Jakob Disease Surveillance Unit (http://www.cjd.ed.ac.uk/figures.htm), has been the detection of atypical BSE in cattle. The discovery of a prion protein gene (PRNP) E211K variant in an atypical BSE case is particularly remarkable because it is analogous to the most common pathogenic mutation in humans (E200K), which causes hereditary Creutzfeldt-Jakob disease (CJD). Knowledge of the distribution and frequency of PRNP E211K variants in cattle populations is critical for understanding and managing atypical BSE. This study was carried out to investigate the prevalence of the E211K variant in the South-East Asia bovine populations and in the Japanese cattle breeds. It was discovered that E211K variant was monomorphic for a G allele and the GG genotype in the 745 animals analyzed in this study. Therefore, neither the Bos indicus nor the Bos taurus animals analyzed are presently known to harbor the 211K variant predicting that the number of carriers for this variant will also be vanishingly low.

Prion diseases remain a mystery

In the 1980s and 1990s, the UK outbreak of bovine spongiform encephalopathy (BSE) in cattle, and the subsequent human cases of a then novel variant of Cruetzfeldt-Jakob disease (vCJD) linked to the bovine disease, led to some of the defining political moments of the time and large-scale reassessment of agricultural practices and food safety. From the then Agriculture Minister, John Gummer, giving his daughter a hamburger to reassure the nation that British beef was safe in 1990, to the mass slaughter of over 4 million cattle to contain the BSE epidemic, images from the period still resonate in the country's consciousness. Given the lingering shadow of the BSE and vCJD outbreaks, the news, as reported by David Holmes in this month's Newsdesk, that so far in 2012 not a single case of the human disease has been reported in the UK is particularly welcome. 2012 looks like being the first year since 1995 without a reported case. One could easily think that this news should be cause for celebration, a sign that the outbreak of this devastating, rapidly progressive, and invariably fatal disease is coming to an end. Indeed, since a peak in 2000 when 28 people died from vCJD, the number of deaths seemed to tail off, with no more than five deaths a year since 2005. But, as suggested several times since the start of the outbreak, serious concern exists that these early cases could be just the tip of the iceberg. All confirmed patients so far have had a particular prion-protein genotype (methionine homozygotes at codon 129), but people who are either homozygous for valine or heterozygous at this codon might have a longer incubation time, so a second wave of vCJD related to consumption of contaminated meat remains a possibility. Moreover, there is evidence that as many as one in 2000 people of all genotypes are asymptomatic carriers of the defective prions that cause the disease. Not only might these people go on to develop vCJD, but also they might pass on the infection to susceptible individuals through tissue donations and transplants. These concerns highlight the real problem with vCJD and other prion diseases that affect human beings: the dearth of knowledge. So little is known about the role of normal prion proteins, how pathogenic prions replicate without genetic information, the pathogenic mechanisms, and why different prion diseases have different presentations. True of familial, sporadic, and iatrogenic CJD, fatal familial insomnia, and kuru, our limited understanding of these diseases prohibits attempts to develop sensitive diagnostic tests let alone effective treatments. As such, prion diseases remain a death sentence. Thankfully, these diseases are rare. The total number of cases of vCJD in the UK in 1995–2011 was 176, with another 49 being recorded in 11 other countries. The UK has done detailed surveillance of CJD since the height of the BSE crisis in 1990. The latest report (published on Oct 8, 2012) from the National CJD Research and Surveillance Unit in Edinburgh shows that although the cases of vCJD have declined, the number of cases of sporadic CJD have remained fairly constant for the past 15 years, hovering around 70 per year, although in 2008, 2009, and 2011, the number of deaths was 85 or higher. Alongside the detailed surveillance from the National Surveillance Unit, research done at the Medical Research Council Prion Unit (University College London Institute of Neurology, UK) has begun to elucidate possible mechanisms for human prion diseases and last year reported the first reliable blood assay to detect vCJD prions. This ongoing research and surveillance will be essential to further our understanding of these diseases in the hope of better assessing future risks and developing approaches to disease management. In a research Article published online in The Lancet Infectious Diseases, Michael Head (University College London) and colleagues have estimated UK investments in global infectious diseases research from 1997 to 2010; they found that more than £30 million had been spent on research into prion disease, around £20 million of which came from the Department of Health. When compared with research investments in HIV (£461 million), hepatitis B (£12 million), hepatits C (£60 million), and malaria (£346 million), the spending may seem disproportionate to the burden of disease. However, given the incurable nature of these diseases, the potential for prions to cross the species barrier, and the potential for future outbreaks among asymptomatic carriers of pathogenic prions, continued surveillance and research is essential to fill in the many gaps in our knowledge.

NMDA receptor autoantibodies in sporadic Creutzfeldt-Jakob disease

Sporadic Creutzfeldt-Jakob disease (sCJD) and N-methylD-aspartate receptor antibody (NMDAR-Ab) encephalitis [1], share similar clinical features including prominent psychiatric symptoms, memory problems, and seizures (Table 1). Previously, other forms of autoimmune encephalitis have been misdiagnosed as CJD, including Hashimoto’s and voltage-gated potassium channel complex antibody-associated encephalopathies [2, 3]. Here, conversely, we describe two patients presenting with progressive cognitive impairment and NMDAR-Abs with confirmed sCJD at post mortem. A retrospective review of 100 pathologically confirmed cases of sCJD seen by the UK National CJD surveillance unit [4] over the past 2 years identified six tested for NMDAR-Abs at presentation in whom results were available: four were negative and two positive. Both NMDAR-Ab positive cases presented with subacute cognitive decline and behavioral disturbance leading to serum testing for the antibodies. Patient A progressed to an akinetic mute state over 3 months and patient B over 9 months. Both had basal ganglia high signal on MRI brain imaging, a positive 14-3-3 immunoassay and elevated S100b level. Patient A twice had positive serum NMDARAb levels at dilutions up to 1:80. He was given 3 days of intravenous methylprednisolone and continued to deteriorate, dying 9 days later. Patient B deteriorated over 9 months. Some months after discharge to palliative care, his earlier positive serum NMDAR-Ab titre of 1:80 was discovered. Both had sporadic CJD confirmed at post mortem. CSFs were negative for NMDAR-Abs in all six cases. The presentation and clinical evolution in these two cases was consistent with sCJD and the positive NMDARAb results were surprising. Detecting NMDAR-Abs involves the demonstration of autoantibodies binding to a cell line expressing the NR1 and NR2B subunits [5]. All positive sera (tested at 1:20 initially) are checked against cells expressing other antigens, and the cells alone, to exclude any false-positive results [5, 6]. Positive results in healthy individuals or other disease controls are very rare; not found in 160 neurological disease controls [5]. The existence of these antibodies in two out of six patients with confirmed CJD is therefore intriguing. The titres were low, but at a level seen in patients with NMDAR-Ab encephalitis. One possibility is that these antibodies occurred as a secondary event resulting from an immune response to NMDARs released from damaged neurons. An altered composition of NMDAR has been implicated in cell death Electronic supplementary material The online version of this article (doi:10.1007/s00415-012-6489-3) contains supplementary material, which is available to authorized users.

A reply

We would like to thank Drs Willcox and Turner for their interest in our paper [1]. We are pleased that our publication raised a number of discussion points and we welcome the opportunity to comment. We agree that the risk of transmission of infection from endoscopes is probably low. However, current guidelines suggest that single-use devices should be used where possible (although only if the performance is equivalent) [2, 3]. In addition, the Department of Health bulletin states that endoscopes should be cleaned before and after each use [3]. Consequently, the single-use Ambu aScope is likely to have a shorter ready-to-use time than a re-usable device. This is especially relevant when delay in securing the airway increases the risk to patients, i.e. the Plan B of the Difficult Airway Society guidelines [4]. Furthermore, the single-use fibrescope may be useful in locations remote from the main theatre complex where the fibrescope is infrequently used and an endoscope reprocessing unit may not be readily available. Provision and maintenance of re-usable fibrescopes in such remote locations may be prohibitively expensive. Lastly, the National Creutzfeldt-Jakob Disease Surveillance Unit provides fibrescopes only for established cases of vCJD. The lack of a suction port of the aScope may impair the operator’s ability to clear secretions and blood in the airway. However, the suction channel of the LF-GP Olympus re-usable scope used in our study is only 1.5 mm. Cautious use of external suction, accessing the airway thorough the mouth with either a soft or rigid suction catheter, is likely to provide much better clearance than the limited suction force from the re-usable fibrescope. There are limitations to extrapolating data from any study into clinical practice. Manikin studies have an established place in the evaluation process of an airway device [5, 6]. This is recognised by the Airway Device Evaluation Project Team (ADEPT) [7]. There are number of reasons why no newly introduced device should be used on patients before manikin evaluation is completed. Firstly, the findings of a manikin study can exclude unsafe devices from being used on patients [8, 9] and highlight the design features that require further evaluation on patients [10]. Secondly, they allow for the device to be tested by a large number of clinicians and not only by a small number of researchers and experts. Thirdly, the manikin study design allows for levels of simulation that are likely to be considered unethical if conducted on patients (i.e. crossover study design and simulation of a difficult airway). Although, in our institution, manikin studies go through the same rigorous review as the patient studies (Research and Development and Ethics Committee review), they are still likely to be faster than patient studies in providing initial evidence regarding the safety and usefulness of an untested device. Furthermore, data on historical controls that are required for obtaining level 3b evidence stated in the ADEPT article [7] may not be available for every device currently on the market. Our study was designed to provide evidence on the ease of use and manoeuvrabity of the Ambu aScope when used by a large number of anaesthetists in a manikin set to simulate difficult fiberscope placement. Although this single-use device has a number of potential applications and advantages, the clinical usefulness of the aScope remains to be established.

RNA integrity in post mortem human variant Creutzfeldt-Jakob disease (vCJD) and control brain tissue

To determine premortem and post mortem factors affecting quality and yield of RNA isolated from the unique archived brain material in the UK National Creutzfeldt-Jakob Disease Surveillance Unit Brain and Tissue Bank and to compare this to control brain tissue with no neurological disease. In parallel and in replicate, RNA was prepared from the frontal parasagittal or subfrontal cortex of samples dissected from half brains (frozen intact) or from brain samples snap frozen or placed in RNALater. A total of 350 RNA samples from 78 human autopsy cases, 21 variant Creutzfeldt-Jakob disease, 26 other neurological diseases and 31 non-neurological diseases were studied. There was no difference in the quality or yield of RNA isolated from variant Creutzfeldt-Jakob disease, other neurological disease and non-neurological disease brains. RNA preparations from archived frozen half brains or snap frozen autopsy samples were generally of poor quality (RNA integrity number<5). There was a highly significant negative correlation between the number of times frozen half brains had been sampled and the quality of RNA. Samples stored in RNALater provided higher-quality RNA (RNA integrity number>5). Age at death, gender, post mortem interval and freezer storage time had no effect on RNA quality. Reasonable-quality RNA can be isolated from samples dissected from archived frozen human half brains but repeated sampling results in RNA degradation. Better-quality RNA is obtained from samples placed in RNALater than from snap frozen samples. The quality and yield of RNA are not affected by age at death, gender, post mortem interval of >6 h or freezer storage time.

The role of cerebrospinal fluid 14-3-3 and other proteins in the diagnosis of sporadic Creutzfeldt–Jakob disease in the UK: a 10-year review

BackgroundIt is 10 years since the detection of cerebrospinal fluid (CSF) 14-3-3 was included in the diagnostic criteria for sporadic Creutzfeldt–Jakob disease (sCJD) by the WHO. Since that time, other...

The Assessment of Pathogenic Prions in the Brains of Eye Tissue Donors: 2-Years Experience in the Czech Republic

The aim of this study was to assess the presence of pathogenic prions in the brain tissue of eye donors and to evaluate the benefits of 2-year obligatory testing in the Czech Republic. Brain tissue was retrieved during autopsies of eye donors of 3 tissue banks in the Czech Republic. The frozen specimens obtained from the frontal lobe were transported to the Czech National Reference Laboratory for the diagnosis of human prion disorders. The presence of pathogenic prions was tested using the Prionics-Check WESTERN kit. Confirmative Western blotting using 1 of 2 different clones of monoclonal anti-PrP antibody was performed as well. No pathogenic prions were found in any of the 1142 tested specimens. One specimen revealed weak positivity at initial screening; however, repeated examination of the specimen and other specimens from different locations in the brain of the same donor did not confirm the presence of pathogenic prions. The negative result was confirmed by the National CJD Surveillance Unit, University of Edinburgh, United Kingdom. The absence of pathogenic prions from all of the 1142 tested specimens corresponds to the presumed very low risk of transmission of Creutzfeldt-Jakob disease through corneal graft transplantation. As a result of this disorder's rarity, a larger series of tested samples should be evaluated to obtain statistically significant findings. Although such testing increases the safety of donor eye tissue, it also increases the expense, causes organizational difficulties, and may extend the time needed to release the tissue for grafting.

Validation of diagnostic criteria for variant Creutzfeldt-Jakob disease.

Variant Creutzfeldt-Jakob disease (vCJD), a novel form of human prion disease, was recognized in 1996. The disease affected a younger cohort than sporadic CJD, and the early clinical course was dominated by psychiatric and sensory symptoms. In an attempt to aid diagnosis and establish standardization between surveillance networks, diagnostic criteria were established. These were devised from the features of a small number of cases and modified in 2000 as the clinical phenotype was established. Since then, only minor changes have been introduced; revalidation of the criteria in the current format is overdue. Included in this study are autopsy/cerebral biopsy-proven cases of vCJD referred to the National CJD Surveillance Unit (NCJDSU) between 1995 and 2004 and suspect cases in which an alternative diagnosis was identified following autopsy/cerebral biopsy. Over the 10-year period, 106 definite cases of vCJD and 45 pathologically confirmed "noncases" were identified from the archives of the NCJDSU. The median age at onset of the cases was significantly younger than that of the noncases (27 years [range, 12-74 years] vs 43 years [range, 10-64 years]), and the median duration of illness was significantly shorter (14 months [range, 6-39 months] vs 22 months [range, 2-139 months]). The most commonly identified core clinical feature in cases was dementia; persistent painful sensory symptoms were the least frequent. Eighty-eight of 106 (83%) vCJD cases were retrospectively classified as probable in life, 6 cases were classified as possible. Most cases were classified as probable on the basis of core clinical features and brain magnetic resonance imaging. To date, the diagnostic criteria remain 100% specific, with no autopsy/cerebral biopsy-proven noncases classified as probable in life. This study confirms that the diagnostic criteria for vCJD are sensitive and specific and provide a useful standard framework for case classification in a surveillance setting.

Variant Creutzfeldt‐Jakob disease in a transfusion recipient: coincidence or cause?

To date there have been four instances of infection transmitted through blood transfusions derived from individuals who later developed variant Creutzfeldt-Jakob disease (vCJD). The identification of further transmission of vCJD through this route would have important implications for risk assessment and public health. Through the UK Transfusion Medicine Epidemiology Review (TMER) the fate of blood donations from individuals who develop vCJD is traced and recipients of labile components are identified. The details of recipients are cross-checked with the register of vCJD cases held at the National CJD Surveillance Unit (NCJDSU) to identify any linkage between donors and recipients. In the reverse study, when individuals with vCJD are found to have a history of blood transfusion the donors of the transfused blood components are traced and their details cross-checked with the vCJD register to identify any missed or unrecognized linkage between donors and recipients. A case of vCJD has been identified with a history of blood transfusion in infancy. The donors who provided the components transfused cannot be identified, but a blood donor known to have donated blood to another individual who subsequently developed vCJD could have been a donor to the index case. The at-risk donor is alive 20 years after the relevant donation and continued to donate for some years, until identified as at risk, with 27 other blood components issued for use in patients, none of whom are known to have developed vCJD. Circumstantial evidence has raised the possibility that the case in this report represents a further instance of transfusion transmission of vCJD. However, detailed investigation indicates that the pattern of events may have occurred by chance and disease in this individual may have been caused by transmission of bovine spongiform encephalopathy infection, as is the presumed cause in other primary cases of vCJD.