Enhanced Creutzfeldt-Jakob disease surveillance in the older population: Assessment of a protocol for screening brain tissue donations for prion disease.

Human prion diseases, including Creutzfeldt-Jakob disease (CJD), occur in sporadic, genetic, and acquired forms. Variant Creutzfeldt-Jakob disease (vCJD) first reported in 1996 in the United Kingdom (UK), resulted from contamination of food with bovine spongiform encephalopathy. There is a concern that UK national surveillance mechanisms might miss some CJD cases (including vCJD), particularly in the older population where other neurodegenerative disorders are more prevalent. We developed a highly sensitive protocol for analysing autopsy brain tissue for the misfolded prion protein (PrPSc ) associated with prion disease, which could be used to screen for prion disease in the elderly. Brain tissue samples from 331 donors to the Edinburgh Brain and Tissue Bank (EBTB), from 2005 to 2022, were analysed, using immunohistochemical analysis on fixed tissue, and five biochemical tests on frozen specimens from six brain regions, based on different principles for detecting PrPSc . An algorithm was established for classifying the biochemical results. To test the effectiveness of the protocol, several neuropathologically confirmed prion disease controls, including vCJD, were included and blinded in the study cohort. On unblinding, all the positive control cases had been correctly identified. No other cases tested positive; our analysis uncovered no overlooked prion disease cases. Our algorithm for classifying cases was effective for handling anomalous biochemical results. An overall analysis suggested that a reduced biochemical protocol employing only three of the five tests on only two brain tissue regions gave sufficient sensitivity and specificity. We conclude that this protocol may be useful as a UK-wide screening programme for human prion disease in selected brains from autopsies in the elderly. Further improvements to the protocol were suggested by enhancements of the in vitro conversion assays made during the course of this study.

Progressive multifocal leukoencephalopathy and Creutzfeldt-Jakob disease: population-wide incidences, comorbidities, costs of care, and outcomes.

Neurological disorders associated with chronic infections are often progressive as well as challenging to diagnose and manage. Among 4.4 million persons from 2004 to 2019 receiving universal health, progressive multifocal leukoencephalopathy (PML, n = 58) and Creutzfeldt-Jakob disease (CJD, n = 93) cases were identified, revealing stable yearly incidence rates with divergent comorbidities: HIV/AIDS affected 37.8% of PML cases while cerebrovascular disease affected 26.9% of CJD cases. Most CJD cases died within 1 year (73%) although PML cases lived beyond 5 years (34.1%) despite higher initial costs of care. PML and CJD represent important neurological disorders with evolving risk variables and impact on health care.

Assessment of the Sensitivity and Specificity of the Established Real-time Quaking-induced Conversion (RT-QuIC) Technique in Chinese CJD Surveillance.

Real-time quaking-induced conversion (RT-QuIC) assay is a newly established PrP Sc-detecting method. The development of RT-QuIC improves the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), showing good sensitivity and specificity in many countries when the method was used in cerebrospinal fluid (CSF) samples. However, in China, the sensitivity and specificity of RT-QuIC has yet to be determined due to the lack of definitive diagnosis samples. Recently, 30 definitive sCJD and 30 non-CJD diagnoses were evaluated by RT-QuIC assay. In the 30 sCJD CSF samples, 29 showed positive results. By contrast, all the non-CJD samples were negative. The sensitivity and specificity of our RT-QuIC assay were 96.67% and 100%, respectively, and are comparable to other published data. Results can provide a fundamental basis for the usage of RT-QuIC assay in CJD surveillance in China.

Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2019.

Nationwide surveillance of Creutzfeldt-Jakob disease and other human prion diseases is performed by the Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR). National surveillance encompasses the period since 1 January 1970, with prospective surveillance occurring from 1 October 1993. Over this prospective surveillance period, considerable developments have occurred in pre-mortem diagnostics; in the delineation of new disease subtypes; and in a heightened awareness of prion diseases in healthcare settings. Surveillance practices of the ANCJDR have evolved and adapted accordingly. This report summarises the activities of the ANCJDR during 2019. Since the ANCJDR began offering diagnostic cerebrospinal fluid (CSF) 14-3-3 protein testing in Australia in September 1997, the annual number of referrals has steadily increased. In 2019, 513 domestic CSF specimens were referred for 14-3-3 protein testing and 85 persons with suspected human prion disease were formally added to the national register. As of 31 December 2019, just under half (42 cases) of the 85 suspect case notifications remain classified as 'incomplete'; 16 cases were excluded through either detailed clinical follow-up (3 cases) or neuropathological examination (13 cases); 20 cases were classified as 'definite' and seven as 'probable' prion disease. For 2019, sixty-three percent of all suspected human prion disease related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. Two possibly causal novel prion protein gene (PRNP) sequence variations were identified.

BAMBI and CHGA in Prion Diseases: Neuropathological Assessment and Potential Role as Disease Biomarkers.

Prion diseases affect both animals and humans. Research in the natural animal model of the disease could help in the understanding of neuropathological mechanisms and in the development of biomarkers for human pathologies. For this purpose, we studied the expression of 10 genes involved in prion propagation in vitro in the central nervous system of scrapie-infected sheep. Dysregulated genes (BAMBI and CHGA) were further analysed in a transgenic murine model (Tg338) of scrapie, and their protein distribution was determined using immunohistochemistry and Western blot. Their potential as biomarkers was finally assessed using enzyme-linked immunosorbent assay (ELISA) in cerebrospinal fluid (CSF) of scrapie sheep and Creutzfeldt-Jakob disease (CJD) patients. Protein BAMBI was upregulated in highly affected brain areas and CHGA was overexpressed along the brain in both models. Moreover, BAMBI and CHGA immunostaining scores strongly correlated with spongiosis and microgliosis in mice. Finally, levels of BAMBI were significantly higher in the CSF of clinical sheep and CJD patients. In addition to their potential as biomarkers, our work confirms the role of BAMBI and CHGA in prion neuropathology in vivo, but besides prion replication, they seem to be involved in the characteristic neuroinflammatory response associated to prion infection.

Assessment of risk of variant creutzfeldt-Jakob disease (vCJD) from use of bovine heparin.

PURPOSE: In the late1990s, reacting to the outbreak of bovine spongiform encephalopathy (BSE) in the United Kingdom that caused a new variant of Creutzfeldt-Jakob disease (vCJD) in humans, manufacturers withdrew bovine heparin from the market in the United States. There have been growing concerns about the adequate supply and safety of porcine heparin. Since the BSE epidemic has been declining markedly, the US Food and Drug Administration reevaluates the vCJD risk via use of bovine heparin. METHODS: We developed a computational model to estimate the vCJD risk to patients receiving bovine heparin injections. The model incorporated information including BSE prevalence, infectivity levels in the intestines, manufacturing batch size, yield of heparin, reduction in infectivity by manufacturing process, and the dose-response relationship. RESULTS: The model estimates a median risk of vCJD infection from a single intravenous dose (10 000 USP units) of heparin made from US-sourced bovine intestines to be 6.9 × 10-9 (2.5-97.fifth percentile: 1.5 × 10-9 -4.3 × 10-8 ), a risk of 1 in 145 million, and 4.6 × 10-8 (2.5-97.fifth percentile: 1.1 × 10-8 -2.6 × 10-7 ), a risk of 1 in 22 million for Canada-sourced products. The model estimates a median risk of 1.4 × 10-7 (2.5-97.fifth percentile: 2.9 × 10-8 -9.3 × 10-7 ) and 9.6 × 10-7 (2.5-97.fifth percentile: 2.1 × 10-7 -5.6 × 10-6 ) for a typical treatment for venous thromboembolism (infusion of 2-4 doses daily per week) using US-sourced and Canada-sourced bovine heparin, respectively. CONCLUSIONS: The model estimates the vCJD risk from use of heparin when appropriately manufactured from US or Canadian cattle is likely small. The model and conclusions should not be applied to other medicinal products manufactured using bovine-derived materials.

Interventions to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease: a cost-effective modelling review.

BACKGROUND: Creutzfeldt-Jakob disease is a fatal neurological disease caused by abnormal infectious proteins called prions. Prions that are present on surgical instruments cannot be completely deactivated; therefore, patients who are subsequently operated on using these instruments may become infected. This can result in surgically transmitted Creutzfeldt-Jakob disease. OBJECTIVE: To update literature reviews, consultation with experts and economic modelling published in 2006, and to provide the cost-effectiveness of strategies to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease. METHODS: Eight systematic reviews were undertaken for clinical parameters. One review of cost-effectiveness was undertaken. Electronic databases including MEDLINE and EMBASE were searched from 2005 to 2017. Expert elicitation sessions were undertaken. An advisory committee, convened by the National Institute for Health and Care Excellence to produce guidance, provided an additional source of information. A mathematical model was updated focusing on brain and posterior eye surgery and neuroendoscopy. The model simulated both patients and instrument sets. Assuming that there were potentially 15 cases of surgically transmitted Creutzfeldt-Jakob disease between 2005 and 2018, approximate Bayesian computation was used to obtain samples from the posterior distribution of the model parameters to generate results. Heuristics were used to improve computational efficiency. The modelling conformed to the National Institute for Health and Care Excellence reference case. The strategies evaluated included neither keeping instruments moist nor prohibiting set migration; ensuring that instruments were kept moist; prohibiting instrument migration between sets; and employing single-use instruments. Threshold analyses were undertaken to establish prices at which single-use sets or completely effective decontamination solutions would be cost-effective. RESULTS: A total of 169 papers were identified for the clinical review. The evidence from published literature was not deemed sufficiently strong to take precedence over the distributions obtained from expert elicitation. Forty-eight papers were identified in the review of cost-effectiveness. The previous modelling structure was revised to add the possibility of misclassifying surgically transmitted Creutzfeldt-Jakob disease as another neurodegenerative disease, and assuming that all patients were susceptible to infection. Keeping instruments moist was estimated to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease cases and associated costs. Based on probabilistic sensitivity analyses, keeping instruments moist was estimated to on average result in 2.36 (range 0-47) surgically transmitted Creutzfeldt-Jakob disease cases (across England) caused by infection occurring between 2019 and 2023. Prohibiting set migration or employing single-use instruments reduced the estimated risk of surgically transmitted Creutzfeldt-Jakob disease cases further, but at considerable cost. The estimated costs per quality-adjusted life-year gained of these strategies in addition to keeping instruments moist were in excess of £1M. It was estimated that single-use instrument sets (currently £350-500) or completely effective cleaning solutions would need to cost approximately £12 per patient to be cost-effective using a £30,000 per quality-adjusted life-year gained value. LIMITATIONS: As no direct published evidence to implicate surgery as a cause of Creutzfeldt-Jakob disease has been found since 2005, the estimations of potential cases from elicitation are still speculative. A particular source of uncertainty was in the number of potential surgically transmitted Creutzfeldt-Jakob disease cases that may have occurred between 2005 and 2018. CONCLUSIONS: Keeping instruments moist is estimated to reduce the risk of surgically transmitted Creutzfeldt-Jakob disease cases and associated costs. Further surgical management strategies can reduce the risks of surgically transmitted Creutzfeldt-Jakob disease but have considerable associated costs. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017071807. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 11. See the NIHR Journals Library website for further project information.

The aims of this report were to summarise evidence relating to surgically transmitted Creutzfeldt­Jakob disease and to explore the value for money of strategies to reduce the chance of any future surgically transmitted Creutzfeldt­Jakob disease cases. Current recommendations include keeping sets of surgical instruments together for high-risk operations and using separate instruments for people born after 1996. The project involved reviewing published papers, speaking with experts and building a computer model. The literature reviews found that Creutzfeldt­Jakob disease occurs in around 1­2 per million people and that no definite cases of surgically transmitted Creutzfeldt­Jakob disease have been observed since the 1970s. The reviews also looked for information on the possibility of patients being infected with Creutzfeldt­Jakob disease after having surgery on high-risk tissues, such as the brain and the back of the eye. They found that there was a great deal of uncertainty regarding who might have Creutzfeldt­Jakob disease, but not yet have symptoms, as well as the risk of transmission and the ability of strategies to reduce this risk. The computer model aimed to estimate value for money of different strategies to reduce the risks of surgically transmitted Creutzfeldt­Jakob disease. However, the reviews found that some of the numbers needed for the model were not known, so experts were asked to estimate this information instead along with the range of possible values. This information included the effectiveness of different cleaning practices and the chances of infected tissue being transmitted between patients undergoing high-risk surgery. The model found that keeping surgical instruments moist prior to cleaning was likely to save money and reduce the chance of future surgically transmitted Creutzfeldt­Jakob disease cases. However, additional measures, such as using only sets of single-use instruments, ensuring that instruments were kept together in their sets or using separate instruments for those born after 1996, appeared to be poor value for money.

Feasibility of Remote Assessment of Human Prion Diseases for Research and Surveillance.

BACKGROUND: Prion disease research and surveillance can be challenging due to the disease's difficulty to diagnose, rapid progression, and geographic dispersion. Improving accessibility through teleneurology could improve the ability to conduct these activities. OBJECTIVES: The aim of this study was to determine the feasibility of conducting teleneurology assessments for research and surveillance of prion diseases. METHOD: Participants were offered in-person visit, medical record review, or teleneurology assessment. Standardized histories and assessments evaluating cognition, functional ability, and neuropsychiatric symptoms were collected. Data regarding participants' satisfaction with teleneurology were collected. RESULTS: From April 2017 to July 2018, the study received 114 referrals. 45 and 5 participants consented for the teleneurology and medical record review arms of the study, respectively. 29 subjects participated in at least one teleneurology visit. Participants expressed satisfaction with teleneurology and found it easy to participate. Some aspects of the examination were hindered or interrupted due to technological reasons. CONCLUSIONS: We demonstrate the feasibility and preference of teleneurology as a modality in which subjects with prion disease can partake in clinical research. Technological aspects sometimes interfered with research assessments.

Renewed assessment of the risk of emergent advanced cell therapies to transmit neuroproteinopathies.

The inadvertent transmission of long incubating, untreatable and fatal neurodegenerative prionopathies, notably iatrogenic Creutzfeldt-Jakob disease, following transplantation of cadaver-derived corneas, pituitary growth, hormones and dura mater, constitutes a historical precedent which has underpinned the application of precautionary principles to modern day advanced cell therapies. To date these have been reflected by geographic or medical history risk-based deferral of tissue donors. Emergent understanding of other prion-like proteinopathies, their potential independence from prions as a transmissible agent and the variable capability of scalably manufacturable stem cells and derivatives to take up and clear or to propagate prions, substantiate further commitment to qualifying neurodegenerative proteinopathy transmission risks. This is especially so for those involving direct or facilitated access to a recipient's brain or connected visual or nervous system such as for the treatment of stroke, retinal and adult onset neurodegenerative diseases, treatments for which have already commenced. In this review, we assess the prospective global dissemination of advanced cell therapies founded on transplantation or exposure to allogeneic human cells, recap lessons learned from the historical precedents of CJD transmission and review recent advances and current limits in understanding of prion and other neurodegenerative disease prion-like susceptibility and transmission. From these we propose grounds for a reassessment of the risks of emergent advanced cell therapies to transmit neuroproteinopathies and suggestions to ACT developers and regulators for risk mitigation and extension of criteria for deferrals.

Reducing the risk of iatrogenic Creutzfeldt-Jakob disease by improving the cleaning of neurosurgical instruments.

BACKGROUND: In all, there have been 178 variant Creutzfeldt-Jakob disease (vCJD) patients diagnosed in the UK, with an estimated maximum 1:2000 carriage rate based on archived appendix and tonsil tissue, implying that infection may be rare but carriage relatively frequent. Previous workers have identified that maintenance of surgical instruments in a humid atmosphere after use and prior to cleaning assists cleaning efficacy. Recently the Department of Health/Advisory Committee on Dangerous Pathogens UK have recommended a surgical instrument cleanliness threshold post cleaning of <5 µg protein per instrument side. AIM: To quantify cleanliness of neurosurgical instruments and to investigate cost-effective measures for improved cleaning. METHODS: Two instrument protein quantification methods were used: one based on the International Standard (15883 series) using sodium dodecyl sulphate elution and ortho-phthalaldehyde reaction, and a second in-situ protein fluorescence detection system (ProReveal) providing results per instrument side. In-vitro investigation of the efficacy of some commercial and in-house pre-clean wetting agents was undertaken using artificial test soil and stainless steel discs under standard conditions. In-vivo evaluation of best-performing in-vitro agents was undertaken on craniotomy sets. FINDINGS: ProReveal technology demonstrated that 163 out of 187 (87%) neurosurgical instruments had <5 µg residual protein per instrument side. The use of proprietary National Health Service plastic bags and sterile water-soaked wound pads were equivalent in efficacy to commercial pre-cleaning wetting products and significantly less expensive. CONCLUSION: Although we demonstrate low in-situ protein levels on neurosurgical instruments and the beneficial effects of keeping instruments moist, other cleaning critical-control points such as instrument loading patterns should also be monitored.

A direct assessment of human prion adhered to steel wire using real-time quaking-induced conversion.

Accidental transmission of prions during neurosurgery has been reported as a consequence of re-using contaminated surgical instruments. Several decontamination methods have been studied using the 263K-hamster prion; however, no studies have directly evaluated human prions. A newly developed in vitro amplification system, designated real-time quaking-induced conversion (RT-QuIC), has allowed the activity of abnormal prion proteins to be assessed within a few days. RT-QuIC using human recombinant prion protein (PrP) showed high sensitivity for prions as the detection limit of our assay was estimated as 0.12 fg of active prions. We applied this method to detect human prion activity on stainless steel wire. When we put wires contaminated with human Creutzfeldt-Jakob disease brain tissue directly into the test tube, typical PrP-amyloid formation was observed within 48 hours, and we could detect the activity of prions at 50% seeding dose on the wire from 10(2.8) to 10(5.8) SD50. Using this method, we also confirmed that the seeding activities on the wire were removed following treatment with NaOH. As seeding activity closely correlated with the infectivity of prions using the bioassay, this wire-QuIC assay will be useful for the direct evaluation of decontamination methods for human prions.

Caregiver burden in atypical dementias: comparing frontotemporal dementia, Creutzfeldt-Jakob disease, and Alzheimer's disease.

BACKGROUND: Caregiver burden is a significant issue in the treatment of dementia and a known contributor to institutionalization of patients with dementia. Published data have documented increased caregiver burden in behavioral variant frontotemporal dementia (bvFTD) compared to Alzheimer's disease (AD). Another atypical dementia with high-perceived caregiver burden is sporadic Creutzfeldt-Jakob disease (sCJD), but no formal studies have assessed this perception. The aim of this study was to compare caregiver burden across atypical dementia etiologies. METHODS: 76 adults with atypical dementia (young-onset AD [YOAD], bvFTD, language variant FTD [lvFTD], and sCJD) were administered an abbreviated version of the Zarit Burden Interview (ZBI), Neuropsychiatric Inventory (NPI-Q), and other assessment instruments during a five-year time period at Johns Hopkins Hospital (JHH). A Cox regression model examined differences between disease categories that impact mean ZBI scores. RESULTS: Mean ZBI scores were significantly different between dementia etiologies, with bvFTD and sCJD having the highest caregiver burden (p = 0.026). Mean NPI-Q caregiver distress scores were highest in bvFTD and sCJD (p = 0.002), with sCJD and bvFTD also having the highest number of endorsed symptom domains (p = 0.012). On regression analyses, an interactive variable combining final diagnosis category and NPI-Q total severity score demonstrated statistically significant differences in mean ZBI scores for sCJD and bvFTD. CONCLUSIONS: This study demonstrates that bvFTD and sCJD have increased levels of caregiver burden, NPI-Q caregiver distress, total severity scores, and number of endorsed symptom domains. These results suggest that higher caregiver burden in bvFTD and sCJD are disease specific and possibly related to neuropsychiatric symptoms.

Infections and exposures: reported incidents associated with unsuccessful decontamination of reusable surgical instruments.

Reusable surgical instruments provide a potential route for the transmission of pathogenic agents between patients in healthcare facilities. As such, the decontamination process between uses is a vital component in the prevention of healthcare-associated infections. This article reviews reported outbreaks and incidents associated with inappropriate, inadequate, or unsuccessful decontamination of surgical instruments, indicating potential pitfalls of decontamination practices worldwide. To the author's knowledge, this is the first review of surgical instrument decontamination failures. Databases of medical literature, Medline and Embase, were searched systematically. Articles detailing incidents associated with unsuccessful decontamination of surgical instruments were identified. Twenty-one articles were identified reporting incidents associated with failures in decontamination. A large proportion of incidents involved the attempted disinfection, rather than sterilization, of surgical instruments (43% of articles), counter to a number of national guidelines. Instruments used in eye surgery were most frequently reported to be associated with decontamination failures (29% of articles). Of the few articles detailing potential or confirmed pathogenic transmission, Pseudomonas aeruginosa and Mycobacterium spp. were most represented. One incident of possible variant Creutzfeldt-Jakob disease transmission was also identified. Limitations of analysing only published incidents mean that the likelihood of under-reporting (including reluctance to publish failure) must be considered. Despite these limitations, the small number of articles identified suggests a relatively low risk of cross-infection through reusable surgical instruments when cleaning/sterilization procedures are adhered to. The diverse nature of reported incidents also suggests that failures are not systemic.

Special needs populations: perioperative care of the patient with creutzfeldt-jakob disease.

Creutzfeldt-Jakob disease (CJD) is a rare but lethal prion disease. The worldwide mortality rate of CJD is 1.67 per one million people, although 90% of cases will lead to death within one year of symptom onset. Rapid, progressive dementia is the cardinal sign of CJD. Other early symptoms include deterioration of muscle coordination, memory, judgment, and vision, as well as personality changes, insomnia, and depression. It occurs in two types, classic and new variant, and classic CJD can be further divided into three subtypes: sporadic, familial (ie, genetic), and iatrogenic (ie, health care associated). Surgery often requires using instruments that come in contact with high-infectivity tissue, especially during neurosurgical procedures and diagnostic biopsies. To reduce the risk of disease transmission, infection control practices should include identification of the risk of infection, implementation of safety protocols (eg, use of personal protective equipment), proper selection and use of instrumentation, and adequate disinfection and sterilization practices. Silent carriers, risks of iatrogenic infection, and the possibility of inadvertent exposure of healthy patients may carry great liability to public health and hospital stability.

Risk assessment for transmission of variant Creutzfeldt-Jakob disease by transfusion of red blood cells in the United States.

BACKGROUND: Variant Creutzfeldt-Jakob disease (vCJD) is transmitted by blood transfusion. To mitigate the risk of transfusion-transmitted vCJD (TTvCJD), the US Food and Drug Administration has recommended deferral of potential at-risk blood donors, but some risk remains. We describe a quantitative risk assessment to estimate residual, postdeferral TTvCJD risk in the United States. STUDY DESIGN AND METHODS: We assumed that certain US donors may have acquired vCJD infection through dietary exposure to the agent of bovine spongiform encephalopathy during time spent in the United Kingdom, France, and other countries in Europe. Because of uncertainties regarding the prevalence of vCJD in the United Kingdom, we used both low and high UK prevalence estimates as model inputs. The model estimated the risk of infection from a transfusion in year 2011 and the cumulative risk from 1980 through 2011. The model was validated by comparing the model predictions with reported cases of vCJD. RESULTS: Using the low UK prevalence estimate, the model predicted a mean risk of 1 in 134 million transfusions, zero TTvCJD infections acquired in the year 2011, and zero cumulative clinical TTvCJD cases for the period spanning 1980 to 2011. With the high UK prevalence estimate, the model predicted a mean risk of 1 in 480,000 transfusions, six infections for 2011, and nine cumulative clinical cases from 1980 to 2011. CONCLUSIONS: Model validation exercises indicated that predictions based on the low prevalence estimate are more consistent with clinical cases actually observed to date, implying that the risk, while highly uncertain, is likely very small.