Iatrogenic Creutzfeldt-Jakob Disease Research Articles

Iatrogenic Alzheimer’s disease in recipients of cadaveric pituitary-derived growth hormone

Alzheimer’s disease (AD) is characterized pathologically by amyloid-beta (Aβ) deposition in brain parenchyma and blood vessels (as cerebral amyloid angiopathy (CAA)) and by neurofibrillary tangles of hyperphosphorylated tau. Compelling genetic and biomarker evidence supports Aβ as the root cause of AD. We previously reported human transmission of Aβ pathology and CAA in relatively young adults who had died of iatrogenic Creutzfeldt–Jakob disease (iCJD) after childhood treatment with cadaver-derived pituitary growth hormone (c-hGH) contaminated with both CJD prions and Aβ seeds. This raised the possibility that c-hGH recipients who did not die from iCJD may eventually develop AD. Here we describe recipients who developed dementia and biomarker changes within the phenotypic spectrum of AD, suggesting that AD, like CJD, has environmentally acquired (iatrogenic) forms as well as late-onset sporadic and early-onset inherited forms. Although iatrogenic AD may be rare, and there is no suggestion that Aβ can be transmitted between individuals in activities of daily life, its recognition emphasizes the need to review measures to prevent accidental transmissions via other medical and surgical procedures. As propagating Aβ assemblies may exhibit structural diversity akin to conventional prions, it is possible that therapeutic strategies targeting disease-related assemblies may lead to selection of minor components and development of resistance.

Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2022.

Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) 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 2022. 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 2022, a total of 599 domestic CSF specimens were referred for diagnostic testing and 79 persons with suspected human prion disease were formally added to the national register. As of 31 December 2022, just under half of the 79 suspect case notifications (36/79) remain classified as 'incomplete'; 15 cases were classified as 'definite' and 23 as 'probable' prion disease; five cases were excluded through neuropathological examination. For 2022, fifty-five percent of all suspected human-prion-disease-related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. The SARS-CoV-2 pandemic did not affect prion disease surveillance outcomes in Australia during 2022.

Teaching Neuro Images : Extensive cortical involvement in Creutzfeldt-Jakob disease

A 53-year-old alcoholic man presented with a 2-day history of worsening confusion. Initial examination showed appendicular hypertonia with multifocal arrhythmic asynchronous myoclonic jerks suggestive of cortical myoclonus occurring spontaneously intermittently and stimulus sensitive, with exaggerated deep tendon reflexes and extensor plantars. MRI brain demonstrated low-grade restricted diffusion affecting the entire cerebral cortex (figure 1), sparing the subcortical gray matter and cerebellum.1 T1-weighted imaging and fluid-attenuated inversion recovery sequences showed mild cerebral atrophy. 14-3-3 protein testing was positive and generalized slowing was demonstrated on EEG.2 Changes consistent with Creutzfeldt-Jakob disease (CJD) were found on histopathology (figure 2). The patient had no risk factors for familial, new variant, or iatrogenic CJD. Sporadic CJD was the final diagnosis.

Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease.

Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here, we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC) and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied 648 CSF and plasma samples, including 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) ('converters'; range from 9.9 prior to, and 7.4 years after onset). Symptomatic IPD CSF samples were screened by RT-QuIC assay variations, before testing the entire collection of at-risk samples using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and UCH-L1 levels were measured in plasma and CSF. Second generation (IQ-CSF) RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (CJD), iatrogenic and familial CJD phenotypes, and subsequently detected seeding activity in four presymptomatic CSF samples from three E200K carriers; one converted in under 2 months while two remain asymptomatic after at least 3 years' follow-up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease. No compatible RT-QuIC assay was discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in the typically slow IPDs (e.g. P102L), with significant differences in mean values segregating healthy control from IPD carriers (within 2 years to onset) and symptomatic IPD cohorts; plasma GFAP appears to change before NfL, and before clinical conversion. In conclusion, we show distinct biomarker trajectories in fast and slow IPDs. Specifically, we identify several years of presymptomatic seeding positivity in E200K, a new proximity marker (plasma GFAP) and sequential neurodegenerative marker evolution (plasma GFAP followed by NfL) in slow IPDs. We suggest a new preclinical staging system featuring clinical, seeding and neurodegeneration aspects, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies.

Public Action for Prevention of Iatrogenic Transmission Of CJD

Creutzfeldt-Jakob Disease (CJD) is a rare and a rapidly progressive, invariably fatal neurodegenerative disorder believed to be caused by an abnormal isoform of a cellular glycoprotein known as the prion protein. The disease develops in very different ways, such as sporadic, familial, and iatrogenic. Although there is no means to prevent sporadic and familial CJD outbreaks, iatrogenic CJD can be prevented since the iatrogenic transmission pathway to human is mostly identified. However, despite its public health importance, there is no practical laboratory method for diagnosing this disease in an asymptomatic state. Therefore, it is very important to track the infection route one by one and act public preventive measure. However, there are no manual for prevention of iatrogenic transmission of this disease in Korea. Accordingly, this review summarizes on how to evaluate and act on surgical incidents that occurred in patients with CJD or high-risk patients. However, this is not an easy task for public health management teams as this field continues to require new scientific or specialized clinical knowledge. Therefore, a group or organization of expert panels is needed to manage and make decisions in general. Finally, this review was made with reference to the management regulations of countries with widespread exposure to CJD, including variant CJD. In other words, it is a very conservative and strict safety-oriented guideline. However, since the surveillance of diseases must take into each national medical situation and economic burden, some readjustments are necessary to the situation of the Republic of Korea.

Creutzfeldt-Jakob disease surveillance in Australia: update to 31 December 2021.

Nationwide surveillance of Creutzfeldt-Jakob disease (CJD) 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 2021. 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 2021, a total of 548 domestic CSF specimens were referred for 14-3-3 protein testing; 73 persons with suspected human prion disease were formally added to the national register. As of 31 December 2021, just over half of the 73 suspect case notifications (37/73) remain classified as 'incomplete'; 17 cases were classified as 'definite' and 13 as 'probable' prion disease; six cases were excluded through either detailed clinical follow-up (two cases) or neuropathological examination (four cases). For 2021, sixty-four percent of all suspected human-prion-disease-related deaths in Australia underwent neuropathological examination. No cases of variant or iatrogenic CJD were identified. The SARS-CoV-2 pandemic did not affect prion disease surveillance outcomes in Australia.

Prion protein monoclonal antibody (PRN100) therapy for Creutzfeldt–Jakob disease: evaluation of a first-in-human treatment programme

Human prion diseases, including Creutzfeldt-Jakob disease (CJD), are rapidly progressive, invariably fatal neurodegenerative conditions with no effective therapies. Their pathogenesis involves the obligate recruitment of cellular prion protein (PrPC) into self-propagating multimeric assemblies or prions. Preclinical studies have firmly validated the targeting of PrPC as a therapeutic strategy. We aimed to evaluate a first-in-human treatment programme using an anti-PrPC monoclonal antibody under a Specials Licence. We generated a fully humanised anti-PrPC monoclonal antibody (an IgG4κ isotype; PRN100) for human use. We offered treatment with PRN100 to six patients with a clinical diagnosis of probable CJD who were not in the terminal disease stages at the point of first assessment and who were able to readily travel to the University College London Hospital (UCLH) Clinical Research Facility, London, UK, for treatment. After titration (1 mg/kg and 10 mg/kg at 48-h intervals), patients were treated with 80-120 mg/kg of intravenous PRN100 every 2 weeks until death or withdrawal from the programme, or until the supply of PRN100 was exhausted, and closely monitored for evidence of adverse effects. Disease progression was assessed by use of the Medical Research Council (MRC) Prion Disease Rating Scale, Motor Scale, and Cognitive Scale, and compared with that of untreated natural history controls (matched for disease severity, subtype, and PRNP codon 129 genotype) recruited between Oct 1, 2008, and July 31, 2018, from the National Prion Monitoring Cohort study. Autopsies were done in two patients and findings were compared with those from untreated natural history controls. We treated six patients (two men; four women) with CJD for 7-260 days at UCLH between Oct 9, 2018, and July 31, 2019. Repeated intravenous dosing of PRN100 was well tolerated and reached the target CSF drug concentration (50 nM) in four patients after 22-70 days; no clinically significant adverse reactions were seen. All patients showed progressive neurological decline on serial assessments with the MRC Scales. Neuropathological examination was done in two patients (patients 2 and 3) and showed no evidence of cytotoxicity. Patient 2, who was treated for 140 days, had the longest clinical duration we have yet documented for iatrogenic CJD and showed patterns of disease-associated PrP that differed from untreated patients with CJD, consistent with drug effects. Patient 3, who had sporadic CJD and only received one therapeutic dose of 80 mg/kg, had weak PrP synaptic labelling in the periventricular regions, which was not a feature of untreated patients with sporadic CJD. Brain tissue-bound drug concentrations across multiple regions in patient 2 ranged from 9·9 μg per g of tissue (SD 0·3) in the thalamus to 27·4 μg per g of tissue (1·5) in the basal ganglia (equivalent to 66-182 nM). Our academic-led programme delivered what is, to our knowledge, the first rationally designed experimental treatment for human prion disease to a small number of patients with CJD. The treatment appeared to be safe and reached encouraging CSF and brain tissue concentrations. These findings justify the need for formal efficacy trials in patients with CJD at the earliest possible clinical stages and as prophylaxis in those at risk of prion disease due to PRNP mutations or prion exposure. The Cure CJD Campaign, the National Institute for Health Research UCLH Biomedical Research Centre, the Jon Moulton Charitable Trust, and the UK MRC.

Transmission of Cerebral β-Amyloidosis Among Individuals.

Deposition of amyloid β protein (Aβ) in the brain (cerebral β-amyloidosis) is a hallmark of Alzheimer's disease (AD). So far, there have been increasing number of experimental studies using AD mouse model that cerebral β-amyloidosis could be transmitted among individuals as prion-like mechanism. Furthermore, several pathological studies using autopsied patients with iatrogenic Creutzfeldt-Jakob disease (CJD) showed that cerebral β-amyloidosis in addition to the CJD pathology could be transmitted among humans via medical procedures, such as human growth hormone derived from cadaver injection and cadaveric dura mater graft. In addition, although cerebral amyloid angiopathy (CAA), which is Aβ deposition in the cerebral vessels, related cerebral hemorrhage rarely develops in young people, several patients with CAA-related cerebral hemorrhage under the age of 55 with histories of neurosurgeries with and without dura mater graft in early childhood have been reported. These patients might show that Aβ pathology is often recognized as Aβ-CAA rather than parenchymal Aβ deposition in the transmission of cerebral β-amyloidosis in humans, and we proposed an emerging concept, "acquired CAA". Considering that there have been several patients with acquired CAA with an incubation period from neurosurgery and the onset of CAA related cerebral hemorrhage of longer than 40years, the number of cases is likely to increase in the future, and detailed epidemiological investigation is required. It is necessary to continue to elucidate the pathomechanisms of acquired CAA and urgently establish a method for preventing the transmission of cerebral β-amyloidosis among individuals.

Human prion disease

AbstractHuman prion diseases (HPDs) are progressive and fatal neurodegenerative diseases caused by abnormal prion protein (PrPSc). They can be sporadic, genetic or acquired. Sporadic HPDs include sporadic Creutzfeldt–Jakob disease (CJD) and sporadic fatal insomnia. Genetic HPDs include genetic CJD, Gerstman–Sträussler–Scheinker disease and fatal familial insomnia. Acquired HPDs include Kuru, variant CJD and iatrogenic CJD. The World Health Organization clinical diagnostic criteria for HPDs include clinical findings, cerebrospinal fluid protein markers and electroencephalography, and the UK and European clinical diagnostic criteria include a combination of clinical findings, 14‐3‐3 protein in the cerebrospinal fluid, magnetic resonance imaging diffusion‐weighted imaging and electroencephalography. Recently, the development and clinical application of real‐time quaking‐induced conversion has allowed pre‐mortem diagnosis of sporadic CJD. The real‐time quaking‐induced conversion assay allows detection of >1 fg of PrPSc in diluted CJD brain homogenate, as well as a variety of biological tissues and cerebrospinal fluid. However, the real‐time quaking‐induced conversion assay does not provide prognostic data and has lower diagnostic accuracy for some rarer, atypical prion diseases. Furthermore, recent advancements in laboratory testing and magnetic resonance imaging diffusion‐weighted imaging have shown improved diagnostic accuracy for prion diseases. Clinical trials of prion disease treatments have recently begun in many countries. The therapeutic window consists mainly of the early stage of disease, and few clinical studies have examined the role of biomarkers at this stage. Therefore, biomarkers, imaging and clinical symptoms might be extremely important for the diagnosis of prion diseases.Clinical trials of prion disease treatments have recently begun in many countries. The therapeutic window mainly consists of the early stage of disease, and few clinical studies have examined the role of biomarkers at this stage. Therefore, biomarkers, imaging and clinical symptoms might be extremely important for the diagnosis of prion diseases.

Prion diseases, always a threat?

Prion disease is caused by prion which was identified as a causative factor of transmissible spongiform encephalopathy such as Creutzfeldt-Jakob disease (CJD) and means proteineaceous infectious particle. Prion diseases are devastating neurodegenerative disorders of human and many animals including sheep, cows, deer, cats and camels. CJD presents usually as a rapidly progressive dementia with other symptoms inevitably resulting in death often in months with no available therapy. Like other neurodegenerative diseases, prion diseases are classified into sporadic and genetic forms. In addition, there is the third category of environmentally acquired form. This type includes kuru and iatrogenic CJD due to human dura mater grafts or human pituitary derived hormones as well as variant CJD transmitted through food contaminated with prion of bovine spongiform encephalopathy (BSE). BSE and variant CJD has been almost controlled but chronic wasting disease, prion disease of deer, is spreading widely in North America and South Korea and recently in northern Europe. Recently Aß, α-synuclein and other proteins related to Alzheimer's, Parkinson's and other diseases were reported to have prion features such as transmission to animals. Aß transmission to human was suggested in iatrogenic CJD cases as well as in cerebral amyloid angiopathy cases with cerebral bleeding long after childhood neurosurgery with or without cadaveric dura. These findings indicate prion diseases due to various prions, namely various transmissible proteins appear to be a threat particularly in this longevity society. To overcome prion diseases is one of the top priority in our society.

Potential for transmission of sporadic Creutzfeldt–Jakob disease through peripheral routes

Five sporadic Creutzfeldt–Jakob disease (CJD) strains have been identified to date, based on differences in clinicopathological features of the patients, the biochemical properties of abnormal prion proteins, and transmission properties. Recent advances in our knowledge about iatrogenic transmission of sporadic CJD have raised the possibility that the infectivity of sporadic CJD strains through peripheral routes is different from that of intracranial infection. To test this possibility, here we assessed systematically the infectivity of sporadic CJD strains through the peripheral route for the first time using a mouse model expressing human prion protein. Although the infectivity of the V2 and M1 sporadic CJD strains is almost the same in intracerebral transmission studies, the V2 strain infected more efficiently than the M1 strain through the peripheral route. The other sporadic CJD strains examined lacked infectivity. Of note, both the V2 and M1 strains showed preference for mice with the valine homozygosity at the PRNP polymorphic codon. These results indicate that the V2 strain is the most infectious sporadic CJD strain for infection through peripheral routes. In addition, these findings raise the possibility that individuals with the valine homozygosity at the PRNP polymorphic codon might have higher risks of infection through peripheral routes compared with the methionine homozygotes. Thus, preventive measures against the transmission of the V2 sporadic CJD strain will be important for the eradication of iatrogenic CJD transmission through peripheral routes.The authors sought to determine whether the infectivity of sporadic Creutzfeldt–Jakob disease prion strains through peripheral routes is different from that from intracranial infection. They found that among the strains, V2 is the most infectious through peripheral routes. Thus, preventive measures against transmission of this strain will be important for the eradication of iatrogenic transmission of Creutzfeldt–Jakob disease.

Prion strains associated with iatrogenic CJD in French and UK human growth hormone recipients

Treatment with human pituitary-derived growth hormone (hGH) was responsible for a significant proportion of iatrogenic Creutzfeldt–Jakob disease (iCJD) cases. France and the UK experienced the largest case numbers of hGH-iCJD, with 122 and 81 cases respectively. Differences in the frequency of the three PRNP codon 129 polymorphisms (MM, MV and VV) and the estimated incubation periods associated with each of these genotypes in the French and the UK hGH-iCJD cohorts led to the suggestion that the prion strains responsible for these two hGH-iCJD cohorts were different. In this study, we characterized the prion strains responsible for hGH-iCJD cases originating from UK (n = 11) and France (n = 11) using human PrP expressing mouse models. The cases included PRNP MM, MV and VV genotypes from both countries. UK and French sporadic CJD (sCJD) cases were included as controls. The prion strains identified following inoculation with hGH-iCJD homogenates corresponded to the two most frequently observed sCJD prion strains (M1CJD and V2CJD). However, in clear contradiction to the initial hypothesis, the prion strains that were identified in the UK and the French hGH-iCJD cases were not radically different. In the vast majority of the cases originating from both countries, the V2CJD strain or a mixture of M1CJD + V2CJD strains were identified. These data strongly support the contention that the differences in the epidemiological and genetic profiles observed in the UK and France hGH-iCJD cohorts cannot be attributed only to the transmission of different prion strains.

The Origins of the Protein Spread in Parkinson's Disease.

The Origins of the Protein Spread in Parkinson's Disease.

Les maladies à prions ou encéphalopathies spongiformes transmissibles

Prion diseases or transmissible spongiform encephalopathies (TSEs) are human and animal diseases naturally or experimentally transmissible with a long incubation period and a fatal course without remission. The nature of the transmissible agent remains debated but the absence of a structure evoking a conventional microorganism led Stanley B. Prusiner to hypothesize that it could be an infectious protein (proteinaceous infectious particle or prion). The prion would be the abnormal form of a normal protein, cellular PrP (PrPc) which will change its spatial conformation and be converted into scrapie prion protein (PrPsc) with properties of partial resistance to proteases, aggregation and insolubility in detergents. No inflammatory or immune response are detected in TSEs which are characterized by brain damage combining spongiosis, neuronal loss, astrocytic gliosis, and deposits of PrPsc that may appear as amyloid plaques. Although the link between the accumulation of PrPsc and the appearance of lesions remains debated, the presence of PrPsc is constant during TSE and necessary for a definitive diagnosis. Even if they remain rare diseases (2 cases per million), the identification of kuru, at the end of the 1950s, of iatrogenic cases in the course of the 1970s and of the variant of Creutzfeldt-Jakob disease (CJD) in the mid-1990s explain the interest in these diseases but also the fears they can raise for public health. They remain an exciting research model because they belong both to the group of neurodegenerative diseases with protein accumulation (sporadic CJD), to the group of communicable diseases (iatrogenic CJD, variant of CJD) but also to the group of genetic diseases with a transmission Mendelian dominant (genetic CJD, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia).

Prionopathies and Prionlike Protein Aberrations in Neurodegenerative Diseases

Protein misfolding has been an area of intense research and is implicated in a number of neurodegenerative diseases. Key proteins in the brain lose their native ability to fold and instead assume abnormal conformations. Misfolded proteins cluster to form pathologic aggregates, which cause cellular dysfunction, neuronal death, and neurodegeneration. The prionopathies are best known among the neurodegenerative diseases for their ability to misfold, self-propagate, and infect other organisms. There is increasing evidence of a rationale for a prionlike mechanism of spread of other neurodegenerative diseases through a similar seeding mechanism. In this review, we detail the role of a key protein aberration known to the various prion diseases, including sporadic, variant, and iatrogenic Creutzfeldt-Jakob disease; variably protease-sensitive prionopathy; Gerstmann-Straussler-Scheinker disease; fatal familial insomnia; and kuru. We also discuss the clinical presentation, the available, and emerging imaging options for these diseases. In the second part of this review, we delineate how a prionlike seeding process may be driving the progression of other neurodegenerative diseases, including Parkinson disease, Alzheimer disease, and Huntington disease. A discussion of clinical presentation and imaging features of these example diseases follows to make a case for a common approach to developing imaging biomarkers and therapies of these diseases.Learning Objective: Upon completion of this article, one should be able to describe the various types of prion diseases, recognize and identify the common the neuro-imaging findings in prion diseases, describe seeding mechanism of prion disease, list the common amyloid PET tracers used for Alzheimer’s disease, and list common imaging biomarkers in neurodegenerative diseases.

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Glossary

Characterization of Sporadic Creutzfeldt-Jakob Disease and History of Neurosurgery to Identify Potential Iatrogenic Cases.

We previously reported a phenotype of Creutzfeldt-Jakob disease (CJD), CJD-MMiK, that could help identify iatrogenic CJD. To find cases mimicking CJD-MMiK, we investigated clinical features and pathology of 1,155 patients with diagnosed sporadic CJD or unclassified CJD with and without history of neurosurgery. Patients with history of neurosurgery more frequently had an absence of periodic sharp-wave complexes on electroencephalogram than patients without a history of neurosurgery. Among 27 patients with history of neurosurgery, 5 had no periodic sharp-wave complexes on electroencephalogram. We confirmed 1 case of CJD-MMiK and suspected another. Both had methionine homozygosity at codon 129 of the prion protein gene and hyperintensity lesions in the thalamus on magnetic resonance images of the brain, which might be a clinical marker of CJD-MMiK. A subgroup with a history of neurosurgery and clinical features mimicking dura mater graft-associated CJD might have been infected during neurosurgery and had symptoms develop after many years.

Update on Iatrogenic Creutzfeldt-Jakob Disease

Recent progress in understanding of iatrogenic Creutzfeldt-Jakob disease (CJD) has revealed pathological and biochemical features specific to patients with iatrogenic CJD Based on the pathological and biochemical characteristics, we have identified iatrogenic CJD cases among presumed sporadic cases; in a neurosurgeon and in a patient with a medical history of neurosurgery. In addition, incidents of suspected CJD exposure via contaminated neurosurgical instruments are occasionally noted. Therefore, improvement of CJD case recognition and tracking of neurosurgical instruments are necessary to prevent iatrogenic CJD transmission via neurosurgical instruments. Further, accumulating evidence suggests that certain misfolded proteins and amyloid proteins, as well as prion proteins, are transmissible between individuals. Evaluation of the potential risks of iatrogenic transmission and the development of preventative strategies for these infectious proteins are our future tasks.

Diagnostic Accuracy of Prion Disease Biomarkers in Iatrogenic Creutzfeldt-Jakob Disease.

Human prion diseases are classified into sporadic, genetic, and acquired forms. Within this last group, iatrogenic Creutzfeldt–Jakob disease (iCJD) is caused by human-to-human transmission through surgical and medical procedures. After reaching an incidence peak in the 1990s, it is believed that the iCJD historical period is probably coming to an end, thanks to lessons learnt from past infection sources that promoted new prion prevention and decontamination protocols. At this point, we sought to characterise the biomarker profile of iCJD and compare it to that of sporadic CJD (sCJD) for determining the value of available diagnostic tools in promptly recognising iCJD cases. To that end, we collected 23 iCJD samples from seven national CJD surveillance centres and analysed the electroencephalogram and neuroimaging data together with a panel of seven CSF biomarkers: 14-3-3, total tau, phosphorylated/total tau ratio, alpha-synuclein, neurofilament light, YKL-40, and real-time quaking induced conversion of prion protein. Using the cut-off values established for sCJD, we found the sensitivities of these biomarkers for iCJD to be similar to those described for sCJD. Given the limited relevant information on this issue to date, the present study validates the use of current sCJD biomarkers for the diagnosis of future iCJD cases.

Informing patient contacts about iatrogenic Creutzfeldt–Jakob disease

The unanticipated diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) in a patient after previous neurosurgery can lead to difficult decisions regarding informing contacts. A patient developed sCJD 3 years after neurosurgery. There were 29 potential contacts and 26 were contacted. Twelve completed a questionnaire. The majority of patients wished to know about the contact and to be seen face-to-face, and their main concern was developing the disease despite verbal and written reassurance that this was unlikely. Informing patients of sCJD contact is difficult and can lead to significant patient anxiety. Face-to-face meetings, a helpline and follow-up can help.