vCJD and the gut: implications for endoscopy.
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Creutzfeldt-Jakob Syndrome↗
Biomedical subjects
J W Ironside
Publications and source records attributed to J W Ironside.
Dura mater-associated Creutzfeldt-Jakob disease: experience from surveillance in the UK.
Between 1970 and 2003, seven cases of human dura mater-associated Creutzfeldt-Jakob disease (CJD) were identified in the UK. Furthermore, we identified a case of CJD in a porcine dura graft recipient. The mean incubation period of the human dura mater cases was 93 (range 45-177) months. The clinico-pathological features of the cases are described and compared with cases previously reported in the world literature.
Adult↗
Size frequency distributions of the florid prion protein aggregates in variant Creutzfeldt-Jakob disease follow a power-law function.
The objective was to test the hypothesis that the size frequency distributions of the prion protein (PrP) plaques in cases of variant Creutzfeldt-Jakob disease (vCJD) follow a power-law function. The design was a retrospective neuropathological study. The patients were 11 cases of clinically and neuropathologically verified vCJD. Size distributions of the diffuse and florid-type plaques were measured in several areas of the cerebral cortex and hippocampus from each case and a power-law function fitted to each distribution. The size distributions of the florid and diffuse plaques were fitted successfully by a powerlaw function in 100% and 42% of brain areas investigated respectively. Processes of aggregation/disaggregation may be more important than surface diffusion in the pathogenesis of the florid plaques. By contrast, surface diffusion may be a more significant factor in the development of the diffuse plaques.
Adolescent↗
Predicting susceptibility and incubation time of human-to-human transmission of vCJD.
BACKGROUND: Identification of possible transmission of variant Creutzfeldt-Jakob disease (vCJD) via blood transfusion has caused concern over spread of the disease within the human population. We aimed to model iatrogenic spread to enable a comparison of transmission efficiencies of vCJD and bovine spongiform encephalopathy (BSE) and an assessment of the effect of the codon-129 polymorphism on human susceptibility. METHODS: Mice were produced to express human or bovine prion protein (PrP) by direct replacement of the mouse PrP gene. Since the human PrP gene has variation at codon 129, with MM, VV, and MV genotypes, three inbred lines with an identical genetic background were produced to express human PrP with the codon-129 MM, MV, and VV genotypes. Mice were inoculated with BSE or vCJD and assessed for clinical and pathological signs of disease. FINDINGS: BSE was transmitted to the bovine line but did not transmit to the human lines. By contrast, vCJD was transmitted to all three human lines with different pathological characteristics for each genotype and a gradation of transmission efficiency from MM to MV to VV. INTERPRETATION: Transmission of BSE to human beings is probably restricted by the presence of a significant species barrier. However, there seems to be a substantially reduced barrier for human-to-human transmission of vCJD. Moreover, all individuals, irrespective of codon-129 genotype, could be susceptible to secondary transmission of vCJD through routes such as blood transfusion. A lengthy preclinical disease is predicted by these models, which may represent a risk for further disease transmission and thus a significant public-health issue.
Amyloid↗
An intramedullary vascular malformation mimicking intrinsic spinal cord tumour.
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Aged↗
Variant Creutzfeldt-Jakob disease: risk of transmission by blood transfusion and blood therapies.
In the last decade, a new variant of the human prion disease Creutzfeldt-Jakob disease (now known as variant CJD or vCJD) was identified and causally linked to dietary exposure to bovine spongiform encephalopathy (BSE) during the 1980s and early 1990s. Preliminary studies in animal models suggest that prions can be transmitted by blood. Based on two recent reports of iatrogenic vCJD transmission by blood transfusion in humans, a Department of Health-sponsored risk assessment warned that recipients of plasma therapies are now at risk of contracting vCJD from potentially infected donors. It is believed that all the population may be susceptible to vCJD infection, although clinical cases have so far occurred only in methionine homozygotes at codon 129 in the human prion protein gene. A non-invasive blood-based diagnostic assay is urgently needed. Because the incubation period may be upwards of 40 years and there is no reliable screening test, it is currently unknown how many people may be in an asymptomatic phase of vCJD infection in the UK. However, there remains a distinct possibility that some infected patients may never develop clinical symptoms but will remain asymptomatic carriers who can potentially transmit the disease to other individuals. Therefore, screening of infectious individuals will be a critical component for individuals who rely on blood transfusions and/or blood therapies. In the absence of screening tests or effective therapies to treat this disease, a formidable worldwide public health challenge lies ahead to prevent new infections, accurately assess infection rates and treat infected patients.
Animals↗
Primary intracranial angiosarcoma of the Pineal gland: an unusual cause of recurrent intraventricular haemorrhage and superficial haemosiderosis.
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Cerebral Ventricles↗
Raised CSF phospho-tau concentrations in variant Creutzfeldt-Jakob disease: diagnostic and pathological implications.
OBJECTIVE: To investigate whether phosphorylated tau protein (tau-pT181) is increased in variant Creutzfeldt-Jakob disease (vCJD) and if the tau-pT181/tau protein ratio is useful for distinguishing between patients with and without CJD. METHODS: CSF tau protein and tau-pT181 were measured in 50 patients with sporadic CJD (sCJD), 51 patients with vCJD, 46 sCJD controls, and 37 vCJD controls, using Innotest hTau and Innotest P-Thr181, Innogenetics. RESULTS: Concentrations of CSF tau protein were increased in sCJD (5120 v 367 pg/ml in controls, p < 0.001) and vCJD (952 v 106 pg/ml, p < 0.001); tau-pT181 was also raised in sCJD (61 v 35 pg/ml in controls, p = 0.002) and vCJD (114 v 33 pg/ml, p < 0.001). Median concentrations of tau-pT181 were higher in vCJD than in sCJD (p < 0.001). The tau-pT181/tau protein ratio was lower than in controls in both sCJD (12 v 128 (p < 0.001)) and vCJD (119 v 279 (p < 0.001)). Mean tau-pT181/tau protein ratio was 10-fold higher in vCJD than in sCJD. Raised CSF tau protein had the highest efficiency for distinguishing sCJD and vCJD from controls. CONCLUSIONS: CSF tau-pT181 concentrations are raised in vCJD and are higher than in sCJD. Measurement of CSF tau-pT181/tau protein ratio does not improve the diagnostic efficiency of CSF tau protein alone for either vCJD or sCJD. The higher concentration of CSF tau-pT181 found in vCJD suggests that unexplained pathogenic factors influence the phosphorylation of tau protein in vCJD patients.
Adult↗
Size frequency distribution of prion protein (PrP) aggregates in variant Creutzfeldt-Jakob disease (vCJD).
The frequency distribution of aggregate size of the diffuse and florid-type prion protein (PrP) plaques was studied in various brain regions in cases of variant Creutzfeldt-Jakob disease (vCJD). The size distributions were unimodal and positively skewed and resembled those of beta-amyloid (A beta) deposits in Alzheimer's disease (AD) and Down's syndrome (DS). The frequency distributions of the PrP aggregates were log-normal in shape, but there were deviations from the expected number of plaques in specific size classes. More diffuse plaques were observed in the modal size class and fewer in the larger size classes than expected and more florid plaques were present in the larger size classes compared with the log-normal model. It was concluded that the growth of the PrP aggregates in vCJD does not strictly follow a log-normal model, diffuse plaques growing to within a more restricted size range and florid plaques to larger sizes than predicted.
Adolescent↗
The accuracy of meningioma grading: a 10-year retrospective audit.
Although descriptive classifications of meningioma subtypes are well established, there has been inconsistency in the categorization of meningiomas into benign, atypical and anaplastic groups. The aim of this study was to reassess the incidence of atypical (grade II) meningiomas over a 10-year period by applying the World Health Organization (WHO) 2000 classification system. A secondary aim was to determine if grade II and III tumours were becoming more common. Sections of 314 meningiomas resected between 1994 and 2003 were retrieved from the archives of the Western General Hospital's neuropathology unit in Edinburgh. They were reassessed and graded by using the WHO 2000 classification system. The reviewers were blind to the original classification and grading. There was a gradual increase in the numbers of meningiomas being resected annually over the 10-year period. On reclassification, 78% of the meningiomas were classified as grade I, 20.4% as grade II and 1.6% as grade III. With regard to grade II meningiomas classified by using the WHO 2000 classification system, 38.1% had originally been classified as grade I prior to 2000, whereas 13.6% had originally been classified as grade I after 2000. In most cases, reclassification was due to formal counts of mitotic figures. Atypical meningiomas are diagnosed more frequently under the current WHO classification system than they were under the previous classification systems. Although the current WHO (2000) classification is more prescriptive than its predecessors, interobserver variability is likely to remain because of the subjective nature of some of the criteria.
Adolescent↗
Third ventricular chordoid glioma: clinicopathological study of two cases with evidence for a poor clinical outcome despite low grade histological features.
Chordoid glioma of the third ventricle is a rare glial tumour whose precise histogenesis remains uncertain. We describe two cases that presented recently to our department and review the background literature. The neoplasm tends to occur in women and its clinical presentation is variable, resulting from acute hydrocephalus or impingement upon local structures. However, the radiological appearance is distinct, with an ovoid shape, hyperdensity and uniform contrast enhancement on computerized tomography and magnetic resonance imaging. Intraoperative smear diagnosis is difficult because of the lack of specific features, although the presence of metachromatic extracellular mucin may be useful. The characteristic histological appearance is that of cords and clusters of cohesive, oval-to-polygonal epithelioid cells with abundant eosinophilic cytoplasm and a mucinous background. There is often a mixed chronic inflammatory infiltrate with lymphocytes and plasma cells with Russell bodies. The main differentials for histological diagnosis include chordoid meningiomas, pilocytic astrocytomas and ependymomas. An immunohistochemical panel including antibodies to glial fibrillary acidic protein, CD 34, epithelial membrane antigen, pan cytokeratin, S100 and vimentin can be used to distinguish between these possibilities. Ultrastructurally the tumour cells have basal lamina and microvilli, reminiscent of ependymomas. The clinical outcome in our cases was poor because of the location of the lesion and its close relation to the hypothalamus. Limited follow-up after surgery with or without radiotherapy suggests that as-full-as-possible resection favours a better outcome, although surgery in this area carries significant operative risks.
Adult↗
Phenotypic variability in human prion diseases.
Human prion diseases are rare neurodegenerative disorders that can occur as sporadic, familial or acquired disorders. Within each of these categories there is a wide range of phenotypic variation that is not encountered in other neurodegenerative disorders. The identification of the prion protein and its key role in the pathogenesis of this diverse group of diseases has allowed a fuller understanding of factors that influence disease phenotype. In particular, the naturally occurring polymorphism at codon 129 in the prion protein gene has a major influence on the disease phenotype in sporadic, familial and acquired prion diseases, although the underlying mechanisms remain unclear. Recent technical advances have improved our ability to study the isoforms of the abnormal prion protein in the brain and in other tissues. This has lead to the concept of molecular strain typing, in which different isoforms of the prion protein are proposed to correspond to individual strains of the transmissible agent, each with specific biological properties. In sporadic Creutzfeldt-Jakob disease there are at least six major combinations of codon 129 genotype and prion protein isotype, which appear to relate to distinctive clinical subgroups of this disease. However, these relationships are proving to be more complex than first considered, particularly in cases with more than a single prion protein isotype in the brain. Further work is required to clarify these relationships and to explain the mechanism of neuropathological targeting of specific brain regions, which accounts for the diversity of clinical features within human prion diseases.
Creutzfeldt-Jakob Syndrome↗
Variant Creutzfeldt-Jakob disease transmission by plasma products: assessing and communicating risk in an era of scientific uncertainty.
A substantial body of animal data indicates that transmissible spongiform encephalopathies (TSEs) are transmitted through blood. These data have been augmented in the past year by reports that two recipients of red cells from donors with variant Creutzfeldt-Jakob disease (vCJD) in the United Kingdom have acquired this infection. Most of the blood donations collected in countries affected by bovine spongiform encephalopathy (BSE) and vCJD also contribute plasma to fractionation pools. Thus, a number of batches of fractionated products have included plasma from donors who developed vCJD. On the basis of public health strategies influenced, in part, by risk assessments, the UK and the French authorities have instituted measures for recalling products and informing patients of the estimated risks. It is therefore relevant to review the principles used by authorities in generating risk assessments for the transmission of TSEs by blood and blood products. While the general principles are fairly straightforward, the final assessments are very dependent on the magnitude of several key parameters, which are, largely, still unknown. A critical determinant of final product risk is the extent to which the plasma fractionation process will contribute to eliminating the infectious prion agent. Therefore, regulatory and industry measures to characterize fractionation processes for their capacity to eliminate prions are to be strongly encouraged. In the interim, an understanding of the principles used to generate risk assessments should contribute to an enhanced ability to address this threat to patient safety. Authorities should recognize that adequate communication is an integral part of good risk-management practices.
Animals↗
Abnormal prion protein in the retina of the most commonly occurring subtype of sporadic Creutzfeldt-Jakob disease.
BACKGROUND: Involvement of the eye has been reported in patients with variant Creutzfeldt-Jakob disease (vCJD), but there is disagreement on whether retinal involvement occurs in sporadic Creutzfeldt-Jakob disease (sCJD). METHODS: Western blotting, paraffin embedded tissue blotting, and immunohistochemistry were used to test whether the abnormal form of the prion protein (PrPSc) accumulates to detectable levels in the eye in a case of the most common subtype of sCJD (MM1). RESULTS: Low levels of PrPSc were detectable in the retina, localised to the plexiform layers of the central retina. PrPSc was not detectable in other ocular tissues. CONCLUSIONS: The abnormal form of the prion protein is present in the retina in the most common sCJD subtype (MM1), albeit at levels lower than those found previously in vCJD and in sCJD of the VV2 subtype.
Aged↗
Presentation of a case of variant CJD in general dental practice.
This case report describes the initial presentation of variant CJD to a general dental practitioner. The case highlights the importance of prompt referral of patients presenting with a history of atypical facial symptoms.
Adult↗
Neuropathology and molecular biology of variant Creutzfeldt-Jakob disease.
The neuropathological features of human prion diseases are spongiform change, neuronal loss, astrocytic proliferation and the accumulation of PrP(Sc), the abnormal isoform of prion protein (PrP). The pattern of brain involvement is remarkably variable and is substantially influenced by the host PrP genotype and PrP(Sc) isotype. Variant Creutzfeldt-Jakob disease (vCJD) is a novel human prion disease which results from exposure to the bovine spongiform encephalopathy (BSE) agent. The neuropathology of vCJD shows consistent characteristics, with abundant florid and cluster plaques in the cerebrum and cerebellum, and widespread accumulation of PrP(res) on immunocytochemistry. These features are distinct from all other types of human prion disease. Spongiform change is most marked in the basal ganglia, while the thalamus exhibits severe neuronal loss and gliosis in the posterior nuclei. These areas of thalamic pathology correlate with the areas of high signal seen in the thalamus on magnetic resonance imaging (MRI) examination of the brain. Western blot analysis of PrP(Sc) in the brain in vCJD tissue shows a uniform isotype, with a glycoform ratio characterized by predominance of the diglycosylated band, distinct from sporadic CJD. PrP(Sc) accumulation in vCJD is readily detectable outside the brain, in contrast with other forms of human prion disease, particularly in the lymphoid system and in parts of the peripheral nervous system. This has raised concern about the possible iatrogenic transmission of vCJD by contaminated surgical instruments, or blood. All cases of vCJD are methionine homozygotes at codon 129 of the prion protein gene (PRNP). Continued surveillance is required to investigate cases of vCJD in the UK and other countries where BSE has been reported, particularly as cases of 'human BSE' in individuals who are MV or VV at codon 129 of the PrP gene have not yet been identified. Histological, genetic and biochemical techniques are essential tools for the adequate diagnosis and investigation of human prion diseases.
Brain↗
Isolated cervical intramedullary sarcoidosis--a histological surprise.
We present a case of cervical intramedullary sarcoidosis. A 56 year old woman presented with progressive paraesthesia affecting the lower limbs. MRI revealed an intramedullar lesion from C4-C7. A laminectomy and subtotal resection was carried out for this presumed intramedullary tumour. Pathology revealed this to be a granulomatous lesion with features indicative of sarcoidosis. Postoperatively, there was no change in her neurological function and her symptoms improved with steroid therapy.
Cervical Vertebrae↗
Variant Creutzfeldt-Jakob disease: risk of transmission by blood and blood products.
Variant Creutzfeldt-Jakob disease (CJD) is a novel acquired human prion disease apparently resulting from exposure to the bovine spongiform encephalopathy (BSE) agent. Variant CJD differs from other human prion diseases in that the disease-associated form of the prion protein and infectivity are readily detectable in lymphoid tissues throughout the body. Lymphoid tissues and lymphocytes are implicated in the peripheral pathogenesis of prion diseases (where infectivity may be detected during the preclinical phase of the illness), giving rise to concerns that blood and blood products may also contain infectious particles, representing a possible source of iatrogenic spread of variant CJD. This concern has been reinforced following the experimental transmission of BSE in a sheep model by transfusion of blood and buffy coat from animals in the preclinical phase of the illness, and the recent identification of a UK case of variant CJD in a patient who had received packed red blood cells that had been donated by an individual who subsequently died from variant CJD. Studies in animal models suggest that most prion infectivity in blood may be cell-associated, with lower levels in the plasma, and there is evidence to suggest that any infectivity present may be reduced during the process of plasma fractionation. However, the possibility that plasma or blood products could transmit the disease cannot be excluded. Further studies are required to develop more sensitive means to detect disease-associated prion protein in blood; such techniques could be employed for screening purposes to reduce exposure to contaminated products and to assist with risk management in potentially exposed individuals.
Blood Coagulation Factors↗