The most problematic symptoms of prion disease - an analysis of carer experiences

Objectives: Prion diseases are rare dementias that most commonly occur sporadically, but can be inherited or acquired, and for which there is no cure. We sought to understand which prion disease symptoms are most problematic for carers, to inform the development of outcome measures. Design: Self-completed questionnaire with follow-up of a subset of participants by structured interview. Setting: A nested study in the UK National Prion Monitoring Cohort, a longitudinal observational study. Participants and measurements: 71 carers, of people with different prion diseases with a wide range of disease severity, identified 236 of their four most problematic symptoms by questionnaire which were grouped into ten domains. Structured interviews were then done to qualitatively explore these experiences. Eleven family carers of people with prion disease were selected, including those representative of a range of demographics and disease subtypes and those who cared for people with prion disease, living or recently deceased. Interviews were transcribed and formally studied. Results: The six most problematic symptom domains were: mobility and coordination; mood and behavior; personal care and continence; eating and swallowing; communication; and cognition and memory. The prevalence of these symptoms varied significantly by disease stage and type. A formal analysis of structured interviews to explore these domains is reported. Conclusions: We make suggestions about how healthcare professionals can focus their support for people with prion disease. Clinical trials that aim to generate evidence regarding therapies that might confer meaningful benefits to carers should consider including outcome measures that monitor the symptomatic domains we have identified as problematic

Developing the Screen Industries in North Staffordshire

This report was produced for the North Staffordshire Regeneration Partnership to examine the state of the sector in the region and suggest a strategic way forward

The Untrodden Route to Resilience for Small Island Developing States

This paper examines the broad practical and theoretical research behind a book due for publication in early 2021 entitled ‘Beyond the Blue Economy: Creative Economies and Sustainable Development in Small island developing States’. It highlights some of the challenges of delivering the blue economy in the real world and the role that the digital-creative industries can play in supporting that goal, broadening the economic bases of island nations and thereby building resilience to the kind of external shocks we are now experiencing. This paper seek to make a clear argument for the digital-creative industries being central to a more sustainable economy for small island developing states (SIDS), both in terms of the specifics of developing creative, knowledge-based economies but also understanding the impact that a strong creative sector has on innovation and entrepreneurship across all sections of industry, society and culture

Investigation into use of double-layer grid structures as frequency selective surfaces for buildings

A simple Double–Layer Grid plane wave filter structure is proposed that can provide multiple transmission bands for cellular phone frequencies but with a reflection band for WLAN signals. The approach offers ease of construction making it applicable to building applications. A parametric study using simulation supported by simple experimental data investigates the proposed, novel desig

Estimation of the number of inherited prion disease mutation carriers in the UK

Inherited prion diseases (IPD) are a set of rare neurodegenerative diseases that are always caused by mutation of the prion protein gene (PRNP). These are highly heterogeneous in clinical presentation and best described by the specific gene mutation, but traditionally include the canonical syndromes familial Creutzfeldt-Jakob disease, Gerstamann-Straussler-Scheinker syndrome, and fatal familial insomnia. In the UK, care of IPD patients and clinical PRNP sequencing have been carried out almost exclusively by the National Prion Clinic and affiliated laboratories since the disease gene was discovered in 1989. Using data obtained over 30 years (1990-2019), this study aimed to provide a greater understanding of the genetic prevalence of IPD using multiple complementary methods. A key source of bias in rare disorders is ascertainment, so we included an analysis based on capture-recapture techniques that may help to minimise ascertainment bias. 225 patients, with 21 different IPD mutations were identified, varying in frequency (with 8/21 mutations comprising over 90% observed cases), derived from 116 kindreds and 151 3-generation families. We estimated a total of 303 UK families (95% CI = 222, 384) segregate IPD mutations, 1091 (95% CI = 720, 1461) UK mutation carriers and a lifetime risk of approximately 1 in 60,000. Simpler methods of measuring prevalence based on extrapolation from the annual incidence of disease, and large scale genomic studies, result in similar estimates of prevalence. These estimates may be of value for planning preventive trials of therapeutics in IPD mutation carriers, prevention of prion disease transmission and provision of specialist services

Prevalence and Treatments of Movement Disorders in Prion Diseases: A Longitudinal Cohort Study

BACKGROUND: Prion diseases cause a range of movement disorders involving the cortical, extrapyramidal, and cerebellar systems, and yet there are no large systematic studies of their prevalence, features, associations, and responses to commonly used treatments. OBJECTIVES: We sought to describe the natural history and pharmacological management of movement disorders in prion diseases. METHODS: We studied the serial examination findings, investigation results, and symptomatic treatment recorded for 700 patients with prion diseases and 51 mimics who had been enrolled onto the prospective longitudinal National Prion Monitoring Cohort study between 2008 and 2020. We performed an analysis to identify whether there were patterns of movement disorders associated with disease aetiology, PRNP codon 129 polymorphism, disease severity rating scales, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) findings. RESULTS: Gait disturbances, myoclonus, and increased tone are the most frequently observed movement disorders in patients with prion diseases. The typical pattern of early motor dysfunction involves gait disturbance, limb ataxia, impaired smooth pursuit, myoclonus, tremor, and increased limb tone. Disturbances of gait, increased tone, and myoclonus become more prevalent and severe as the disease progresses. Chorea, alien limb phenomenon, and nystagmus were the least frequently observed movement disorders, with these symptoms showing spontaneous resolution in approximately half of symptomatic patients. Disease severity and PRNP codon 129 polymorphism were associated with different movement disorder phenotypes. Antiepileptics and benzodiazepines were found to be effective in treating myoclonus. CONCLUSIONS: We describe the prevalence, severity, evolution, treatment, and associated features of movement disorders in prion diseases based on a prospective cohort study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Assessing initial MRI reports for suspected CJD patients

BACKGROUND: MRI is invaluable for the pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD), demonstrating characteristic diffusion abnormalities. Previous work showed these changes were often not reported (low sensitivity), leading to eventual diagnosis at a more advanced state. Here, we reviewed the situation a decade later, on the presumption of improved access and awareness over time. METHODS: We reviewed initial MRI scans of 102 consecutive suspected sCJD patients recruited to the National Prion Monitoring Cohort study between 2015 and 2019, assessing for characteristic signal changes in the striatum, thalamus and cortical ribbon. We compared our findings to formal reports from referring centres. Requesting indications were studied to assess if they were suggestive of CJD. Patients were examined and their MRC Prion Disease Rating Scale scores recorded. RESULTS: We identified characteristic MRI abnormalities in 101 cases (99% sensitivity), whilst referring centres reported changes in 70 cases (69% sensitivity), which was a significant improvement in reporting sensitivity from 2012. Reporting sensitivity was associated with signal change in the cerebral cortex, and with the number of regions involved, but not significantly affected by clinical information on request forms, or referring centres being regional neuroscience/non-neuroscience centres. Similar to a previous study, patients with missed abnormalities on initial reporting possessed lower MRC Scale scores when referred to the NPC than those correctly identified. CONCLUSIONS: Whilst local MRI reporting of sCJD has improved with time, characteristic abnormalities remain significantly under detected on initial scans. Sensitivity is better when the cerebral cortex and multiple regions are involved. We re-emphasize the utility of MRI and encourage further efforts to improve awareness and sensitivity in the assessment of patients with rapidly progressive dementia

Development of prognostic models for survival and care status in sporadic Creutzfeldt-Jakob disease

Sporadic Creutzfeldt-Jakob disease, the most common human prion disease, typically presents as a rapidly progressive dementia and has a highly variable prognosis. Despite this heterogeneity, clinicians need to give timely advice on likely prognosis and care needs. No prognostic models have been developed that predict survival or time to increased care status from the point of diagnosis. We aimed to develop clinically useful prognostic models with data from a large prospective observational cohort study. Five hundred and thirty-seven patients were visited by mobile teams of doctors and nurses from the National Health Service National Prion Clinic within 5 days of notification of a suspected diagnosis of sporadic Creutzfeldt-Jakob disease, enrolled to the study between October 2008 and March 2020, and followed up until November 2020. Prediction of survival over 10-, 30- and 100-day periods was the main outcome. Escalation of care status over the same time periods was a secondary outcome for a subsample of 113 patients with low care status at initial assessment. Two hundred and eighty (52.1%) patients were female and the median age was 67.2 (interquartile range 10.5) years. Median survival from initial assessment was 24 days (range 0-1633); 414 patients died within 100 days (77%). Ten variables were included in the final prediction models: sex; days since symptom onset; baseline care status; PRNP codon 129 genotype; Medical Research Council Prion Disease Rating Scale, Motor and Cognitive Examination Scales; count of MRI abnormalities; Mini-Mental State Examination score and categorical disease phenotype. The strongest predictor was PRNP codon 129 genotype (odds ratio 6.65 for methionine homozygous compared with methionine-valine heterozygous; 95% confidence interval 3.02-14.68 for 30-day mortality). Of 113 patients with lower care status at initial assessment, 88 (78%) had escalated care status within 100 days, with a median of 35 days. Area under the curve for models predicting outcomes within 10, 30 and 100 days was 0.94, 0.92 and 0.91 for survival, and 0.87, 0.87 and 0.95 for care status escalation, respectively. Models without PRNP codon 129 genotype, which is not immediately available at initial assessment, were also highly accurate. We have developed a model that can accurately predict survival and care status escalation in sporadic Creutzfeldt-Jakob disease patients using clinical, imaging and genetic data routinely available in a specialist national referral service. The utility and generalizability of these models to other settings could be prospectively evaluated when recruiting to clinical trials and providing clinical care