Biomedical subjects
R G Will
Publications and source records attributed to R G Will.
Variations in neurodegenerative disease across the UK: findings from the national study of Progressive Intellectual and Neurological Deterioration (PIND).
AIMS: To identify any UK children with variant Creutzfeldt-Jakob disease (vCJD) and obtain information about the causes of progressive intellectual and neurological deterioration (PIND) and the geographical distribution of cases. METHODS: The PIND Study uses the monthly surveillance card that is sent to all UK paediatricians by the British Paediatric Surveillance Unit. Case details are obtained from the reporting paediatricians by telephone interview, site visit, or self completion of a questionnaire. A paediatric neurology expert group then classifies the anonymised cases. The Communicable Disease Surveillance Centre (CDSC) provides mapping support. RESULTS: After five years and five months of surveillance, 1400 children had been reported. In the UK the majority of PIND cases had a confirmed diagnosis (comprising 99 different conditions); 505 "no cases" and 97 "outstanding" cases were excluded. A total of 798 PIND cases were included as follows: 577 with a confirmed underlying diagnosis; six with definite or probable vCJD, 51 who had undiagnosed PIND but were not thought to have vCJD, and 164 cases who were still under investigation. In some districts there were unexpectedly high numbers of PIND cases with a heterogeneous mixture of underlying diagnoses. In the five districts with the largest numbers of resident cases the majority not only came from a particular ethnic group but also had high reported rates of consanguinity. CONCLUSIONS: In districts with large numbers of PIND cases there are major resource implications. These children and their families have complex problems and they need access to diagnostic facilities and appropriate service provision.
The neuropsychological profile associated with variant Creutzfeldt-Jakob disease.
We report the neuropsychological profile associated with variant Creutzfeldt-Jakob disease (vCJD). A retrospective study was carried out of data from neuropsychological reports prepared on 24 patients with vCJD. While there was some variability in neuropsychological profiles, the overall pattern was one of a combined cortical and subcortical dementia, with impaired performance being particularly prominent on tests of memory, executive function, speed of attention, and visuoperceptual reasoning. Across 16 cases where Wechsler Adult Intelligence Scale-Revised intelligence quotient (IQ) scores were available, this profile was in part reflected by an invariably low performance IQ (<90 in all patients). All patients who received tests of verbal fluency, digit-symbol substitution and faces recognition memory showed deficits on these tests. Basic vocabulary, digit span and verbal reasoning skills were relatively preserved in most patients. In four cases who underwent more detailed cognitive testing, additional observations were made of relatively intact long-term autobiographical memory and faces perception. Cognitive impairment may represent one of the earliest features of vCJD and it is possible that, at least in some cases, neuropsychological deficits precede the onset of psychiatric or neurological symptoms. Our findings may help in the early detection and management of patients with vCJD.
Deaths from variant Creutzfeldt-Jakob disease in the UK.
In 2002, 17 people died from variant CJD (vCJD) in the UK, compared with 20 in 2001 and 28 in 2000. We analysed data for deaths from vCJD since 1995 and estimated the underlying trend in mortality. The trend had a quadratic component (p=0.005), suggesting that the increase was not exponential, and that the previously increasing trend is slowing down. The death rate peaked in 2000. These findings are encouraging, but mortality might increase again in the future.
Variant Creutzfeldt-Jakob disease.
Variant CJD is a novel human prion disease that represents the first known occasion in which animal prion diseases have been transmitted to humans. There are many uncertainties concerning vCJD, including the mechanism of transmission between species, the extent of human exposure to the BSE agent, the infectious dose for humans, and the future burden of human disease. It is hoped that continuing scientific research may lead to answers to some of these questions and that further understanding of the mechanism of prion replication may lead to the development of effective treatment. Indeed a recent publication has suggested that the drugs quinacrine or chloropromazine may be candidates for the treatment of human prion diseases [42].
Prions and the oral cavity.
Prion diseases have recently emerged as a significant challenge to health-care workers, including those involved in dentistry. Abnormal prion proteins are resistant to complete inactivation by conventional sterilization techniques. In the last decade, a new form of prion disease emerged in the UK, termed "variant CJD", thought to be acquired by consumption of bovine spongiform encephalopathy-contaminated food products. At present, CJD is an invariably fatal disease with no immediate prospect of treatment or vaccination. Of concern with the variant form of CJD, unlike the more classic forms of the disease, is the appearance of significant levels of infectivity outside the central nervous system. This raises concerns for the potential transmission of prion proteins via surgical procedures from individuals in the asymptomatic stage of the disease. This article reviews the existing knowledge base on the nature of prions, their distribution in oral tissues, and the implications for dental treatment.
The biology and epidemiology of variant Creutzfeldt-Jakob disease.
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The pulvinar sign and diagnosis of Creutzfeldt-Jakob disease.
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vCJD: the epidemic that never was. New variant Creutzfeldt-Jakob disease: the critique that never was.
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Variant Creutzfeldt-Jakob disease.
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Detection of variant Creutzfeldt-Jakob disease infectivity in extraneural tissues.
Abnormal accumulations of prion protein (PrP) can be detected in the spleen, lymph nodes, and tonsils of patients with variant Creutzfeldt-Jakob disease (vCJD). Therefore, it has been assumed, but not shown, that these tissues harbour infectivity, which in turn presents the potential for iatrogenic spread through surgery. Here, we show and measure levels of infectivity in spleen and tonsil from two patients with vCJD, by bioassay in intracerebrally inoculated RIII mice. Similar bioassays failed to detect infectivity in buffy coat and plasma.
Variant Creutzfeldt-Jakob disease in an elderly patient.
We report a case of variant Creutzfeldt-Jakob disease(vCJD) in a 74-year old man in whom diagnosis was made at necropsy. The occurrence of vCJD in an individual in this age group is unlikely to be an isolated event. Doctors need to be aware that vCJD can arise in elderly patients so that appropriate investigations (including magnetic resonance imaging) can be done, and permission for neuropathological necropsy requested, in suspected cases. This case could also have important implications for public health policy decisions and surveillance programmes that target the younger age range of vCJD cases.
Misleading results with the 14-3-3 assay for the diagnosis of Creutzfeldt-Jakob disease.
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Geographical distribution of variant Creutzfeldt-Jakob disease in Great Britain, 1994-2000.
BACKGROUND: Geographical variation in the distribution of variant Creutzfeldt-Jakob disease (vCJD) might indicate the transmission route of the infectious agent to man. We investigated whether regional incidences of vCJD were correlated with regional dietary data. METHODS: The National CJD Surveillance Unit prospectively identified 84 people with vCJD up to Nov 10, 2000, in Great Britain. Their lifetime residential histories were obtained by interviews with a close relative. Cumulative incidences of vCJD by standard region were calculated. Grid references for places of residence in 1991 were identified and evidence of geographical clusters were sought. Data on diet in the 1980s were analysed for regional correlations with vCJD incidence. The socioeconomic status of the places of residence of people with vCJD was compared with that of the general population. FINDINGS: vCJD incidence was higher in the north of Great Britain than the south. The rate ratio (north vs south) was 1.94 (95% CI 1.27-2.98). The mean Carstairs' deprivation score for areas of residence of people with vCJD was -0.09 (-0.73 to 0.55), which is close to the national average of zero. Regional rates of vCJD were correlated with consumption of other meat or meat products as classified and recorded by the Household Food Consumption and Expenditure Survey (r=0.72), but not with data from the Dietary and Nutritional Survey of British Adults. Five people with vCJD in Leicestershire formed a cluster (p=0.004). INTERPRETATION: Regional differences in vCJD incidence are unlikely to be due to ascertainment bias. We had difficulty determining whether regional variations in diet might cause these differences, since the results of dietary analyses were inconsistent.
MRI of Creutzfeldt-Jakob disease: imaging features and recommended MRI protocol.
Creutzfeldt-Jakob Disease (CJD) is a rare, progressive and invariably fatal neurodegenerative disease characterized by specific histopathological features. Of the four subtypes of CJD described, the commonest is sporadic CJD (sCJD). More recently, a new clinically distinct form of the disease affecting younger patients, known as variant CJD (vCJD), has been identified, and this has been causally linked to the bovine spongiform encephalopathy (BSE) agent in cattle. Characteristic appearances on magnetic resonance imaging (MRI) have been identified in several forms of CJD; sCJD may be associated with high signal changes in the putamen and caudate head and vCJD is usually associated with hyperintensity of the pulvinar (posterior nuclei) of the thalamus. These appearances and other imaging features are described in this article. Using appropriate clinical and radiological criteria and tailored imaging protocols, MRI plays an important part in the in vivodiagnosis of this disease.
Use of 14-3-3 and other brain-specific proteins in CSF in the diagnosis of variant Creutzfeldt-Jakob disease.
OBJECTIVES: The detection of the protein 14-3-3 in the CSF has been shown to be a reliable and sensitive marker for sporadic Creutzfeldt-Jakob disease (CJD). Other brain-specific proteins such as neuron specific enolase (NSE), S-100b, and tau protein have also been reported to be increased in the CSF of patients with sporadic CJD. In 1996 a variant of CJD (vCJD) was described which is likely to be causally linked to the bovine spongiform encephalopathy agent. This study reports and compares the findings of CSF brain specific protein analysis in 45 patients with vCJD and in 34 control patients. METHODS: The CSF from 45 patients with vCJD and 34 controls were investigated for the presence of 14-3-3 by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting with chemiluminescent detection. Tau protein, S-100b, and NSE concentrations in CSF were measured using enzyme immunoassays. RESULTS: Protein 14-3-3 was detected in the CSF of 22/45 patients with vCJD and in 3/34 controls. The mean concentrations of NSE, S-100b, and tau protein in CSF were significantly raised in patients with vCJD compared with controls. The positive predictive value of CSF 14-3-3 was 86% and the negative predictive value was 63%. These values are lower than those reported for sporadic CJD. An increased CSF tau had a positive predictive value of 93% and a negative predictive value of 81%. The combination of CSF 14-3-3 and/or increased CSF tau had a positive predictive value of 91% and a negative predictive value of 84%. CONCLUSIONS: CSF protein 14-3-3 is not as useful a marker for vCJD as it is for sporadic CJD. Increased concentration of CSF tau was found to be a sensitive marker of vCJD but as concentrations may be increased in many forms of non-CJD dementia, this may limit its usefulness as a diagnostic test.
Variant Creutzfeldt-Jakob disease is not associated with individual abilities to metabolise organophosphates.
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