Cases Of Iatrogenic Creutzfeldt-Jakob Disease Research Articles

Prion diseases, always a threat?

Prion diseases are caused by prions, which are proteinaceous infectious particles that have been identified as causative factors of transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD). Prion diseases are devastating neurodegenerative disorders in humans and many animals, including sheep, cows, deer, cats, and camels. Prion diseases are classified into sporadic and genetic forms. Additionally, a third, environmentally acquired category exists. This type includes kuru, iatrogenic CJD caused by human dura mater grafts or human pituitary-derived hormones, and variant CJD transmitted through food contaminated with bovine spongiform encephalopathy prions. Bovine spongiform encephalopathy and variant CJD have nearly been controlled, but chronic wasting disease, a prion disease affecting deer, is spreading widely in North America and South Korea and recently in Northern Europe. Recently, amyloid-beta, alpha-synuclein, and other proteins related to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases were reported to have prion features such as transmission to animals. Amyloid-beta transmission to humans has been suggested in iatrogenic CJD cases and in cerebral amyloid angiopathy cases with cerebral bleeding occurring long after childhood neurosurgery with or without cadaveric dura mater transplantation. These findings indicate that diseases caused by various prions, namely various transmissible proteins, appear to be a threat, particularly in the current longevity society. Prion disease represented by CJD has obvious transmissibility and is considered to be an “archetype of various neurodegenerative diseases”. Overcoming prion diseases is a top priority currently in our society, and this strategy will certainly contribute to elucidating pathomechanism of other neurodegenerative diseases and developing new therapies for them.

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.

Application of PMCA to screen for prion infection in a human cell line used to produce biological therapeutics

Advances in biotechnology have led to the development of a number of biological therapies for the treatment of diverse human diseases. Since these products may contain or are made using human or animal (e.g. cattle) derived materials, it is crucial to test their safety by ensuring the absence of infectious agents; specifically prions, which are highly resilient to elimination and produce fatal diseases in humans. Many cases of iatrogenic Creutzfeldt-Jakob disease have been caused by the use of biological materials (e.g. human growth hormone) contaminated with prions. For this reason, it is important to screen cells and biological materials for the presence of prions. Here we show the utility of the Protein Misfolding Cyclic Amplification (PMCA) technology as a screening tool for the presence of human (vCJD) and bovine (BSE) prions in a human cell therapy product candidate. First, we demonstrated the sensitivity of PMCA to detect a single cell infected with prions. For these experiments, we used RKM7 cells chronically infected with murine RML prions. Serial dilutions of an infected cell culture showed that PMCA enabled prion amplification from a sample comprised of only one cell. Next, we determined that PMCA performance was robust and uncompromised by the spiking of large quantities of uninfected cells into the reaction. Finally, to demonstrate the practical application of this technology, we analyzed a human cell line being developed for therapeutic use and found it to be PMCA-negative for vCJD and BSE prions. Our findings demonstrate that the PMCA technology has unparalleled sensitivity and specificity for the detection of prions, making it an ideal quality control procedure in the production of biological therapeutics.

Creutzfeldt-Jakob disease mortality in Canada, 1998 to 2013.

Human prion diseases, known collectively as Creutzfeldt-Jakob disease (CJD), are fatal, infectious neurodegenerative disorders that occur in all human populations. To summarize national surveillance data for CJD in Canada between January 1, 1998, and December 31, 2013. Detailed investigations were conducted of individual suspected CJD cases, with collaboration between Canadian health professionals and investigators affiliated with a central CJD surveillance registry operated by the Public Health Agency of Canada. Data were collected on the clinical profile, family history, and results of paraclinical and laboratory investigations, including post-mortem neuropathological examination. A total of 662 deaths from definite and probable CJD were identified in Canadian residents during the study period, comprising 613 cases of sporadic CJD (92.6%), 43 cases of genetic prion disease (6.5%), 4 cases of iatrogenic CJD (0.6%), and 2 cases of variant CJD disease (0.3%). The overall crude mortality rate for sporadic CJD was 1.18 per million per year [95% confidence interval (CI): 1.08,1.27]. Age-specific rates ranged from 0.05 [95% CI: 0.03,0.08] in persons under 50 years of age to 7.11 [95% CI: 6.20,8.11] in those aged 70 to 79. A significant net upward trend in age-adjusted rates was observed over the study period. Standardized mortality ratios, calculated for 10 individual Canadian provinces with reference to national average mortality rates, did not differ significantly from 1.0. Creutzfeldt-Jakob disease remains rare in Canada, although mortality rates vary by two orders of magnitude between older and younger age groups. The upward trend in age-standardized sporadic CJD mortality rate over the study period can be better accounted for by gradually improving case ascertainment than by a real increase in incidence.

Review: Laboratory diagnosis and surveillance of Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) is a representative human transmissible spongiform encephalopathy associated with central nervous system degeneration. Prions, the causative agents of CJD, are composed of misfolded prion proteins and are able to self-replicate. While CJD is a rare disease affecting only 1-1.5 people per million worldwide annually, it has attracted both scientific and public attention as a threatening disease since an epidemic of variant CJD (vCJD) cases appeared in the mid-1990s. Due to its unconventional transmission and invariable fatality, CJD poses a serious risk to public health. The hundreds of sporadic, genetic, and iatrogenic CJD cases as well as potential zoonotic transmission suggest that CJD is an ongoing concern for the field of medicine. Nevertheless, treatment aimed at clinical prevention and treatment that reverses the course of disease does not exist currently. Active surveillance and effective laboratory diagnosis of CJD are, therefore, critical. In this report, the surveillance systems and laboratory tests used currently to diagnose CJD in different countries are reviewed. The current efforts to improve surveillance and diagnosis for CJD using molecular and biochemical findings are also described.

The French surveillance network of Creutzfeldt–Jakob disease. Epidemiological data in France and worldwide

France, involved for a long time in the epidemiological surveillance of transmissible spongiform encephalopathy (TSE), created a national network of surveillance in 1991, because of the description of the first cases of Creutzfeldt–Jakob disease (CJD) linked to a treatment by growth hormone of human origin and the observation of cases of cats infected with the agent of the bovine spongiform encephalopathy in the United Kingdom (UK). The French surveillance network is integrated into the European network of surveillance since its creation in 1993. As in other countries, sporadic CJD is the most frequent form of TSE in France with an annual mortality rate of 1.44 per million. Genetic forms are most often associated with a mutation at codon 200. Among the cases of iatrogenic CJD, 13 cases of CJD after duramater grafts were observed and 119 related to treatment with growth hormone. France is the country worst affected in Europe and the world by this latter form, before the USA and UK. Since 1996, 27 cases of variant of CJD (vCJD) has been observed, making France the second country in the world most affected after the UK. No cases of transfusion-associated vCJD have been observed.

52 Paediatric Neurological Diseases: What Does Active Canadian Surveillance Tell Us?

BackgroundPaediatric neurological diseases individually are rare; however, collectively affect thousands of children and have life-long impacts. The incidence of many of these is not readily available, and yet essential for...

Creutzfeldt-Jakob disease with unusually extensive neuropathology in a child treated with native human growth hormone

We report a case of iatrogenic Creutzfeldt-Jakob disease(iCJD) in a child with a neonatal growth hormone (GH) deficiency that was treated with native human growth hormone (hGH) between the ages of 9 months and 7 years. Three years after the end of treatment a progressive neurological syndrome consistent with Creutzfeldt-Jakob disease (CJD) developed, leading to death within a year, at age 11. Neuropathological examination showed an unusual widespread form of CJD, notably characterized by (i) involvement of the cerebellar white matter, (ii) cortico-spinal degeneration and (iii) ballooned neurons. A transitional form of the disease between common iatrogenic and panencephalopathic CJD is suggested.

Developmental regression: Always a worrying signal

An 11-month old girl is presented to you for developmental delay. The child started to roll over at four months of age and sit independently at approximately seven months of age. Afterwards, she gradually regressed and could no longer achieve these motor milestones. In the past few weeks, she lost the ability to hold her head straight or bear weight on her legs. Her babbling and smiling have decreased, and she does not seem to be interested in her surroundings. The pregnancy and delivery were uneventful, and there is no history of neonatal complications, febrile illnesses or head injuries. The family reports that she received her first three pentavalent immunizations. An analysis of family history was negative for developmental delay; however, the parents are distant cousins. On examination, the child was unable to sit, roll or bear weight on her legs. Her eyes fixed poorly on objects and she did not reach for them. Her trunk and limb muscular tone was poor, while the muscle bulk remained normal. Deep tendon reflexes were hard to obtain. In view of the developmental deterioration and abnormal neurological examination, the patient was referred to a paediatric neurologist. LEARNING POINTS Primary health care providers treating children with progressive intellectual and neurological deterioration (PIND) are facing a challenging task, because a myriad of neurodegenerative disorders can present in a similar fashion. Regression of developmental milestones or PIND should alert primary health care providers of the need to conduct a detailed history and physical examination. ○ When clinically indicated, investigations such as magnetic resonance imaging, electroencephalogram, evoked potentials, biochemical studies, genetic investigations (cytogenetic studies and molecular testing) and biochemical evaluations should be considered. ○ A definitive diagnosis may require further investigations and more invasive testing (1,2). The two-year surveillance study (3) on PIND was used to enhance monitoring for the possibility of Creutzfeldt-Jakob disease (CJD) and variant-CJD. While CJD is rare, the occurrence of variant-CJD in Canada would signal an important change in its epidemiology. Canadian Paediatric Surveillance Program participants reported 99 possible PIND cases; 59 of these were confirmed. The three most frequent diagnoses were mitochondrial disorders, ceroid lipofuscinosis and mucopolysaccharidosis. One case of iatrogenic CJD was confirmed; however, no cases of the variant form were reported. Of note, there were no cases with toxic etiologies (4,5). A definitive etiological diagnosis could not be attained in eight cases, even after exhaustive investigations and review by an expert panel consisting of four paediatric neurologists, a medical geneticist and a paediatric neuropathologist. Support for ongoing research and surveillance on PIND disorders is essential to advance knowledge and provide useful public health information about trends occurring in rare neurological disorders.

Halting the spread of human prion disease – exceptional measures for an exceptional problem

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are uniformly fatal neurodegenerative diseases and include Transmissible Mink Encephalopathy in mink, scrapie in sheep, Bovine Spongiform Encephalopathy (BSE) in cattle and large cats, Chronic Wasting Disease (CWD) in deer and Creutzfeldt Jakob disease (CJD) in humans. They are characterised by a long incubation period, normally several months or years, but without evidence of an infecting agent or an immune response to one.1 The exact mode of transmission of TSEs is a matter of debate, but it is known that a host protein, the prion protein (PrP), plays a central role in these diseases. The prion protein adopts two main conformations: a normal, cellular form (PrPc) expressed in most cells, and a disease-associated form (PrPsc), usually found in brain, spleen and lymph node follicular dendritic cells, especially in tonsils. The altered structure of PrPsc is characterised by its lower alpha-helical and higher beta-sheet content, and by its partial resistance to proteinase K digestion. It is thought that PrPsc replicates by acting as a conformational template, causing the host PrPc to adopt the PrPsc conformation. As disease develops, large protein fibrils (called scrapieassociated fibrils, which contain aggregated PrPsc molecules) are seen in neuronal and lymphoid tissues.2 In the absence of a unique nucleic acid or an immune response, detection of the agent and diagnosis of the disease is difficult. Moreover, it has been known for some time that some TSE strains are resistant to steam sterilisation and most other common disinfection procedures. Consequently, a number of cases of iatrogenic CJD have been attributed to the failure of cleaning and sterilising procedures to effectively decontaminate medical and surgical instruments.3 The BSE agent is especially resistant to steam sterilisation and recent work has shown that the variant CJD (vCJD) agent is similarly resistant, with the standard autoclave cycle currently in use in the UK’s national health Service (NHS) reducing titres in infected brain with an estimated titre of 109 infectious units/gram by only 2 or 3 orders of magnitude. As the disease-forming characteristics of the agent rely on its secondary structure and not on the integrity of a nucleic acid sequence, many sterilisation processes such as UV irradiation are ineffective. Moreover, other inactivation processes such as fixation with formalin and other aldehydes preserve the infectious nature of the agent as they cross-link proteins and thus lock in their secondary structure. This is unlike conventional infectious agents such as viruses which require structural fluidity in their proteins to enter the host and replicate. Furthermore, inadequate heating may accelerate dehydration, forming a protective layer which inhibits further inactivation.

Investigation of a Possible Iatrogenic Case of Creutzfeldt-Jakob Disease After a Neurosurgical Procedure

To investigate a case of Creutzfeldt-Jakob disease (CJD) possibly acquired from contaminated neurosurgical instruments. Retrospective review of medical records, hospital databases, service log books, and state vital statistics. A tertiary care hospital (hospital A) in Missouri. The case patient was a 38-year-old African American woman with a 9-month history of progressive memory loss, visual disturbances, and dementia. She underwent neurosurgery in November 1996. CJD was confirmed in April 2004 by immunodiagnostic testing of brain biopsy samples. All patients who underwent neurosurgery at the same hospital within 6 months before or after the case patient's procedure were identified and investigated for preoperative or postoperative evidence of CJD. We reviewed data on 268 neurosurgical procedures, 84 pathology log entries, and 60 death certificates for neurosurgical patients at hospital A and identified 2 suspected cases of CJD. Clinical features and definitive prion testing of stored brain biopsy samples excluded a diagnosis of CJD. Standard operating room procedures were in place, but specific protocols for handling instruments potentially contaminated with prions were not used. Neurosurgical instruments were not implicated as the source exposure for CJD in the case patient. The 2 patients with suspected CJD were identified from different data sources, suggesting good internal consistency in data collection. The key elements of this investigation are suggested for use in future investigations into potential cases of iatrogenic CJD.

Human Growth Hormone–Related Iatrogenic Creutzfeldt-Jakob Disease With Abnormal Imaging

Although more than 160 cases of iatrogenic Creutzfeldt-Jakob disease (iCJD) from human growth hormone (hGH) treatment have been documented, to our knowledge abnormal cerebellar findings on magnetic resonance imaging (MRI) have not been reported. To report a case of hGH-related iCJD with abnormal cerebellar MRI findings on fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted MRI (DWI). Case report. Outpatient neurology clinic at a university medical center. A 33-year old man who had subacute gait ataxia and blurred vision. Beginning 19 years prior, this patient had received cadaveric pituitary-derived hGH treatment for at least 5 years. Magnetic resonance imaging revealed FLAIR and DWI abnormalities, particularly in the cerebellum. He died 7 months after disease onset of autopsy-confirmed iCJD. Pathological changes corresponded largely to MRI findings. To our knowledge, this is the first case of hGH-related iCJD with FLAIR and DWI abnormalities within the cerebellum. As symptoms referable to the cerebellum occur early in iCJD, it suggests that these MRI sequences may allow earlier diagnosis of this form of prion disease.

Iatrogenic Creutzfeldt–Jakob disease at the millennium

The causes and geographic distribution of 267 cases of iatrogenic Creutzfeldt-Jakob disease (CJD) are here updated at the millennium. Small numbers of still-occurring cases result from disease onsets after longer and longer incubation periods following infection by cadaveric human growth hormone or dura mater grafts manufactured and distributed before the mid-1980s. The proportion of recipients acquiring CJD from growth hormone varies from 0.3 to 4.4% in different countries, and acquisition from dura mater varies between 0.02 and 0.05% in Japan (where most cases occurred). Incubation periods can extend up to 30 years, and cerebellar onsets predominate in both hormone and graft recipients (in whom the site of graft placement had no effect on the clinical presentation). Homozygosity at codon 129 of the PRNP gene is over-represented in both forms of disease; it has no effect on the incubation period of graft recipients, but may promote shorter incubation periods in hormone cases. Knowledge about potential high-risk sources of contamination gained during the last quarter century, and the implementation of methods to circumvent them, should minimize the potential for iatrogenic contributions to the current spectrum of CJD.

Iatrogenic Creutzfeldt-Jakob disease at the millennium.

The causes and geographic distribution of 267 cases of iatrogenic Creutzfeldt-Jakob disease (CJD) are here updated at the millennium. Small numbers of still-occurring cases result from disease onsets after longer and longer incubation periods following infection by cadaveric human growth hormone or dura mater grafts manufactured and distributed before the mid-1980s. The proportion of recipients acquiring CJD from growth hormone varies from 0.3 to 4.4% in different countries, and acquisition from dura mater varies between 0.02 and 0.05% in Japan (where most cases occurred). Incubation periods can extend up to 30 years, and cerebellar onsets predominate in both hormone and graft recipients (in whom the site of graft placement had no effect on the clinical presentation). Homozygosity at codon 129 of the PRNP gene is over-represented in both forms of disease; it has no effect on the incubation period of graft recipients, but may promote shorter incubation periods in hormone cases. Knowledge about potential high-risk sources of contamination gained during the last quarter century, and the implementation of methods to circumvent them, should minimize the potential for iatrogenic contributions to the current spectrum of CJD.

PrP expression in B lymphocytes is not required for prion neuroinvasion.

Prion diseases are typically initiated by infection of peripheral sites, as in the case of bovine spongiform encephalopathy, new variant Creutzfeldt-Jakob disease, kuru and most cases of iatrogenic Creutzfeldt-Jakob disease. In mouse scrapie, prion infectivity accumulates in lymphoid organs, and the absence of mature B lymphocytes prevents peripherally administered prions from inducing central nervous system disease. We have now assessed whether expression of the cellular prion protein, PrPc, is required for B lymphocytes to mediate neuroinvasion. We found that repopulation of SCID and Rag-1(-/-) mice with fetal liver cells from either PrP-expressing or PrP-deficient mice and from T-cell deficient mice, but not from B-cell deficient mice, is equally efficient in restoring neuroinvasion after intraperitoneal inoculation of scrapie prions. These results indicate that cells whose maturation depends on B cells or their products, such as follicular dendritic cells, may enhance neuroinvasion. Alternatively, B cells may transport prions to the nervous system by a PrP-independent mechanism.

Detection of 14-3-3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt-Jakob disease.

The analysis of 14-3-3 protein in cerebrospinal fluid (CSF) was shown to be highly sensitive and specific for the diagnosis of Creutzfeldt-Jakob disease (CJD). However, the predictive value of this test in the clinical diagnosis of, and its relation to, sporadic, genetic, and iatrogenic CJD cases have yet to be established. CSF samples of suspect CJD cases seen in the prospective German surveillance study were tested for the presence of 14-3-3 protein by using a modified western blot (WB) technique. WB detected 14-3-3 protein in 95.4% of definite and 92.8% of probable cases. In two patients classified initially as not having CJD the test was positive, and both were later proved to have definite CJD. The positive predictive value is 94.7% and the negative predictive value is 92.4%. False-positive results in a single CSF analysis were seen in patients with herpes simplex encephalitis, hypoxic brain damage, atypical encephalitis, intracerebral metastases of a bronchial carcinoma, metabolic encephalopathy, and progressive dementia of unknown cause. WB analysis for 14-3-3 protein was positive in only 5 of 10 cases of familial forms of spongiform encephalopathies. CSF analysis for 14-3-3 protein should thus be performed in any case suspect for CJD.

Enfermedad de Creutzfeldt-Jakob en Neurocirugía: una revisión de riesgos y medidas de prevención

From 1988 to 1996 there have been at least 17 reports on Creutzfeldt-Jakob disease (CJD) related to the placement of dura mater grafts of cadaveric origin during the course of neurosurgical procedures. The knowledge of means of transmission in the neurosurgical milieu, the changes introduced in the procurement and sterilization of grafts of human origin, and especially the widespread utilization of autologous tissues in dural repair, seems to have put to an end to this feared neurosurgical complication. Probably, we will see in the future only sporadic and infrequent cases of this entity. The authors review their personal experience, published and unpublished data on iatrogenic CJD cases, and the methods in use for eradication of this disease, in which the neurosurgeons have been involuntary protagonists and vectors. We also note the role played by neurosurgeons in the active investigation of most cases, and in contributing to halt CJD spread in the surgical environment.

How to Limit the Spread of Creutzfeldt-Jakob Disease

AbstractTransmissible spongiform encephalopathies are rare lethal diseases induced in humans and animals by unconventional agents called transmissible spongiform encephalopathy agents (TSEAs), virions, or prions. Several cases of iatrogenic Creutzfeldt-Jakob disease (CJD) have been reported in the literature after neuro-surgery, treatment with pituitary-derived hormones, corneal grafting, and use of dura mater lyophilisates. In a given infected individual, TSEA-associated infectiousness depends on the nature of the organ: the central nervous system has the highest infectiousness, spleen and lymph nodes a medium infectiousness, and organs such as bone, skin, or skeletal muscles do not harbor any detectable infectiousness in experimental models. Transmissible spongiform encephalopathy/prions have unconventional properties; in particular, they resist almost all the chemical and physical processes that inactivate conventional viruses. Therefore, prevention of CJD agent transmission must be taken into account in daily hospital practice. Efficient sterilization procedures should be determined. In tissue and blood donation, donors with a neurologic history must be excluded, and patients treated with pituitary-derived hormones should be considered potentially infected with TSEA and excluded.

How to limit the spread of Creutzfeldt-Jakob disease.

Transmissible spongiform encephalopathies are rare lethal diseases induced in humans and animals by unconventional agents called transmissible spongiform encephalopathy agents (TSEAs), virions, or prions. Several cases of iatrogenic Creutzfeldt-Jakob disease (CJD) have been reported in the literature after neurosurgery, treatment with pituitary-derived hormones, corneal grafting, and use of dura mater lyophilisates. In a given infected individual, TSEA-associated infectiousness depends on the nature of the organ: the central nervous system has the highest infectiousness, spleen and lymph nodes a medium infectiousness, and organs such as bone, skin, or skeletal muscles do not harbor any detectable infectiousness in experimental models. Transmissible spongiform encephalopathy/prions have unconventional properties; in particular, they resist almost all the chemical and physical processes that inactivate conventional viruses. Therefore, prevention of CJD agent transmission must be taken into account in daily hospital practice. Efficient sterilization procedures should be determined. In tissue and blood donation, donors with a neurologic history must be excluded, and patients treated with pituitary-derived hormones should be considered potentially infected with TSEA and excluded.

Iatrogenic and zoonotic Creutzfeldt-Jakob disease: the Australian perspective.

The transmissible brain diseases of humans and animals, the spongiform encephalopathies, continue to stimulate interest, and the announcement that exposure to "mad cow disease" (bovine spongiform encephalopathy [BSE]) is a possible explanation for more than 10 cases of a variant Creutzfeldt-Jakob disease in humans in the United Kingdom is a recent example. Cases of iatrogenic Creutzfeldt-Jakob disease (from previous use of human cadaveric tissues for pituitary hormone therapy and neurosurgical grafts) are still being identified, and the unique nosological status of this group of disorders-that they are both transmissible and inherited and that the only known component of their infectious agent is protein-alone makes these diseases remarkable.