Supporting the ambulance service to safely convey fewer patients to hospital by developing a risk prediction tool: Risk of Adverse Outcomes after a Suspected Seizure (RADOSS)-protocol for the mixed-methods observational RADOSS project.

INTRODUCTION: Ambulances services are asked to further reduce avoidable conveyances to emergency departments (EDs). Risk of Adverse Outcomes after a Suspected Seizure seeks to support this by: (1) clarifying the risks of conveyance and non-conveyance, and (2) developing a risk prediction tool for clinicians to use 'on scene' to estimate the benefits an individual would receive if conveyed to ED and risks if not. METHODS AND ANALYSIS: Mixed-methods, multi-work package (WP) project. For WP1 and WP2 we shall use an existing linked data set that tracks urgent and emergency care (UEC) use of persons served by one English regional ambulance service. Risk tools are specific to clinical scenarios. We shall use suspected seizures in adults as an exemplar.WP1: Form a cohort of patients cared for a seizure by the service during 2019/2020. It, and nested Knowledge Exchange workshops with clinicians and service users, will allow us to: determine the proportions following conveyance and non-conveyance that die and/or recontact UEC system within 3 (/30) days; quantify the proportion of conveyed incidents resulting in 'avoidable ED attendances' (AA); optimise risk tool development; and develop statistical models that, using information available 'on scene', predict the risk of death/recontact with the UEC system within 3 (/30) days and the likelihood of an attendance at ED resulting in an AA.WP2: Form a cohort of patients cared for a seizure during 2021/2022 to 'temporally' validate the WP1 predictive models.WP3: Complete the 'next steps' workshops with stakeholders. Using nominal group techniques, finalise plans to develop the risk tool for clinical use and its evaluation. ETHICS AND DISSEMINATION: WP1a and WP2 will be conducted under database ethical approval (IRAS 307353) and Confidentiality Advisory Group (22/CAG/0019) approval. WP1b and WP3 have approval from the University of Liverpool Central Research Ethics Committee (11450). We shall engage in proactive dissemination and knowledge mobilisation to share findings with stakeholders and maximise evidence usage.

Acute seizure risk in patients with encephalitis: development and validation of clinical prediction models from two independent prospective multicentre cohorts.

Objective: In patients with encephalitis, the development of acute symptomatic seizures is highly variable, but when present is associated with a worse outcome. We aimed to determine the factors associated with seizures in encephalitis and develop a clinical prediction model. Methods: We analysed 203 patients from 24 English hospitals (2005-2008) (Cohort 1). Outcome measures were seizures prior to and during admission, inpatient seizures and status epilepticus. A binary logistic regression risk model was converted to a clinical score and independently validated on an additional 233 patients from 31 UK hospitals (2013-2016) (Cohort 2). Results: In Cohort 1, 121 (60%) patients had a seizure including 103 (51%) with inpatient seizures. Admission Glasgow Coma Scale (GCS) ≤8/15 was predictive of subsequent inpatient seizures (OR (95% CI) 5.55 (2.10 to 14.64), p<0.001), including in those without a history of prior seizures at presentation (OR 6.57 (95% CI 1.37 to 31.5), p=0.025).A clinical model of overall seizure risk identified admission GCS along with aetiology (autoantibody-associated OR 11.99 (95% CI 2.09 to 68.86) and Herpes simplex virus 3.58 (95% CI 1.06 to 12.12)) (area under receiver operating characteristics curve (AUROC) =0.75 (95% CI 0.701 to 0.848), p<0.001). The same model was externally validated in Cohort 2 (AUROC=0.744 (95% CI 0.677 to 0.811), p<0.001). A clinical scoring system for stratifying inpatient seizure risk by decile demonstrated good discrimination using variables available on admission; age, GCS and fever (AUROC=0.716 (95% CI 0.634 to 0.798), p<0.001) and once probable aetiology established (AUROC=0.761 (95% CI 0.6840.839), p<0.001). Conclusion: Age, GCS, fever and aetiology can effectively stratify acute seizure risk in patients with encephalitis. These findings can support the development of targeted interventions and aid clinical trial design for antiseizure medication prophylaxis.

Socioeconomic and health factors related to polypharmacy and medication management: analysis of a Household Health Survey in North West Coast England.

OBJECTIVES: To examine the socioeconomic and demographic drivers associated with polypharmacy (5-9 medicines), extreme polypharmacy (9-20 medicines) and increased medication count. DESIGN, SETTING AND PARTICIPANTS: A total of 5509 participants, from two waves of the English North West Coast, Household Health Survey were analysed OUTCOME MEASURES: Logistic regression modelling was used to find associations with polypharmacy and extreme polypharmacy. A negative binomial regression identified associations with increased medication count. Descriptive statistics explored associations with medication management. RESULTS: Age and number of health conditions account for the greatest odds of polypharmacy. ORs (95% CI) were greatest for those aged 65+ (3.87, 2.45 to 6.13) and for those with ≥5 health conditions (10.87, 5.94 to 19.88). Smaller odds were seen, for example, in those prescribed cardiovascular medications (3.08, 2.36 to 4.03), or reporting >3 emergency attendances (1.97, 1.23 to 3.17). Extreme polypharmacy was associated with living in a deprived neighbourhood (1.54, 1.06 to 2.26). The greatest risk of increased medication count was associated with age, number of health conditions and use of primary care services. Relative risks (95% CI) were greatest for those aged 65+ (2.51, 2.23 to 2.82), those with ≥5 conditions (10.26, 8.86 to 11.88) or those reporting >18 primary care visits (2.53, 2.18 to 2.93). Smaller risks were seen in, for example, respondents with higher levels of income deprivation (1.35, 1.03 to 1.77). Polypharmic respondents were more likely to report medication management difficulties associated with taking more than one medicine at a time (p<0.001). Furthermore, individuals reporting a mental health condition, were significantly more likely to consistently report difficulties managing their medication (p<0.001). CONCLUSION: Age and number of health conditions are most associated with polypharmacy. Thus, delaying or preventing the onset of long-term conditions may help to reduce polypharmacy. Interventions to reduce income inequalities and health inequalities generally could support a reduction in polypharmacy, however, more research is needed in this area. Furthermore, increased prevention and support, particularly with medication management, for those with mental health conditions may reduce adverse medication effects.

High-mobility group box 1 as a predictive biomarker for drug-resistant epilepsy: A proof-of-concept study.

Currently no sensitive and specific biomarkers exist to predict drug-resistant epilepsy. We determined whether blood levels of high-mobility group box 1 (HMGB1), a mediator of neuroinflammation implicated in drug-resistant epilepsies, identifies patients with drug-resistant seizures. Patients with drug-resistant epilepsy express significantly higher levels of blood HMGB1 than those with drug-responsive, well-controlled seizures and healthy controls. No correlation existed between blood HMGB1 levels and total pretreatment seizure count or days since last seizure at new epilepsy diagnosis, indicating that blood HMGB1 does not solely reflect ongoing seizures. HMGB1 distinguishes with high specificity and selectivity drug-resistant versus drug-responsive patients. This protein therefore has potential clinical utility to act as a biomarker for predicting response to therapy, which should be addressed in prospective clinical studies.

Study protocol for a pragmatic randomised controlled trial comparing the effectiveness and cost-effectiveness of levetiracetam and zonisamide versus standard treatments for epilepsy: a comparison of standard and new antiepileptic drugs (SANAD-II).

INTRODUCTION: Antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment. Over the past 20 years, a number of new drugs have been approved for National Health Service (NHS) use on the basis of information from short-term trials that demonstrate efficacy. These trials do not provide information about the longer term outcomes, which inform treatment policy. This trial will assess the long-term clinical and cost-effectiveness of the newer treatment levetiracetam and zonisamide. METHODS AND ANALYSIS: This is a phase IV, multicentre, open-label, randomised, controlled clinical trial comparing new and standard treatments for patients with newly diagnosed epilepsy. Arm A of the trial randomised 990 patients with focal epilepsy to standard AED lamotrigine or new AED levetiracetam or zonisamide. Arm B randomised 520 patients with generalised epilepsy to standard AED sodium valproate or new AED levetiracetam. Patients are recruited from UK NHS outpatient epilepsy, general neurology and paediatric clinics. Included patients are aged 5 years or older with two or more spontaneous seizures requiring AED monotherapy, who are not previously treated with AEDs. Patients are followed up for a minimum of 2 years. The primary outcome is time to 12-month remission from seizures. Secondary outcomes include time to treatment failure (including due to inadequate seizure control or unacceptable adverse reactions); time to first seizure; time to 24-month remission; adverse reactions and quality of life. All primary analyses will be on an intention to treat basis. Separate analyses will be undertaken for each arm. Health economic analysis will be conducted from the perspective of the NHS to assess the cost-effectiveness of each AED. ETHICS AND DISSEMINATION: This trial has been approved by the North West-Liverpool East REC (Ref. 12/NW/0361). The trial team will disseminate the results through scientific meetings, peer-reviewed publications and patient and public involvement. TRIAL REGISTRATION NUMBERS: EudraCT 2012-001884-64; ISRCTN30294119.

Investigating imaging network markers of cognitive dysfunction and pharmacoresistance in newly diagnosed epilepsy: a protocol for an observational cohort study in the UK.

INTRODUCTION: Epilepsy is one of the most common serious brain disorders, characterised by seizures that severely affect a person's quality of life and, frequently, their cognitive and mental health. Although most existing work has examined chronic epilepsy, newly diagnosed patients present a unique opportunity to understand the underlying biology of epilepsy and predict effective treatment pathways. The objective of this prospective cohort study is to examine whether cognitive dysfunction is associated with measurable brain architectural and connectivity impairments at diagnosis and whether the outcome of antiepileptic drug treatment can be predicted using these measures. METHODS AND ANALYSIS: 107 patients with newly diagnosed focal epilepsy from two National Health Service Trusts and 48 healthy controls (aged 16-65 years) will be recruited over a period of 30 months. Baseline assessments will include neuropsychological evaluation, structural and functional Magnetic Resonance Imaging (MRI), Electroencephalography (EEG), and a blood and saliva sample. Patients will be followed up every 6 months for a 24-month period to assess treatment outcomes. Connectivity- and network-based analyses of EEG and MRI data will be carried out and examined in relation to neuropsychological evaluation and patient treatment outcomes. Patient outcomes will also be investigated with respect to analysis of molecular isoforms of high mobility group box-1 from blood and saliva samples. ETHICS AND DISSEMINATION: This study was approved by the North West, Liverpool East Research Ethics Committee (19/NW/0384) through the Integrated Research Application System (Project ID 260623). Health Research Authority (HRA) approval was provided on 22 August 2019. The project is sponsored by the UoL (UoL001449) and funded by a UK Medical Research Council (MRC) research grant (MR/S00355X/1). Findings will be presented at national and international meetings and conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: IRAS Project ID 260623.

Protocol for the development of a core outcome set for cauda equina syndrome: systematic literature review, qualitative interviews, Delphi survey and consensus meeting.

INTRODUCTION: Cauda equina syndrome (CES) is a serious neurological condition most commonly due to compression of the lumbosacral nerve roots, which can result in significant disability. The evidence for acute intervention in CES is mainly from retrospective studies. There is heterogeneity in the outcomes chosen for analysis in these studies, which makes it difficult to synthesise the data across studies. This study will develop a core outcome set for use in future studies of CES, engaging with key stakeholders and using transparent methodology. This will help ensure that relevant outcomes are used in future and will facilitate attempts to summarise data across studies in systematic reviews. METHODS AND ANALYSIS: A systematic literature review will document all the outcomes for CES after surgery mentioned in the literature. The qualitative interviews with patients with CES will be semistructured, audio recorded, transcribed and thematically analysed with the use of NVivo V.10 to identify outcomes and determine the themes described. The outcomes from the literature review and patient interviews will be combined and prioritised to determine what the most important outcomes are in CES research studies to patients and healthcare professionals. The prioritisation will be done through a two-round iterative Delphi survey and a consensus meeting. This process will decide the core outcome set for patients with CES. ETHICS AND DISSEMINATION: REC and HRA approval was obtained on the 6/12/16 for the qualitative interviews from South Central-Hampshire A REC. REC reference 16/SC/0587. REC and HRA approval was obtained on 26/3/18 for the Delphi process and consensus meeting from North West-Greater Manchester Central REC. REC reference was 18/NW/0022. The final core outcome set will be published and freely available. TRIAL REGISTRATION NUMBER: This study is registered with the Core Outcome Measures in Effectiveness Trials database as study 824.

Molecular isoforms of high-mobility group box 1 are mechanistic biomarkers for epilepsy.

Approximately 30% of epilepsy patients do not respond to antiepileptic drugs, representing an unmet medical need. There is evidence that neuroinflammation plays a pathogenic role in drug-resistant epilepsy. The high-mobility group box 1 (HMGB1)/TLR4 axis is a key initiator of neuroinflammation following epileptogenic injuries, and its activation contributes to seizure generation in animal models. However, further work is required to understand the role of HMGB1 and its isoforms in epileptogenesis and drug resistance. Using a combination of animal models and sera from clinically well-characterized patients, we have demonstrated that there are dynamic changes in HMGB1 isoforms in the brain and blood of animals undergoing epileptogenesis. The pathologic disulfide HMGB1 isoform progressively increased in blood before epilepsy onset and prospectively identified animals that developed the disease. Consistent with animal data, we observed early expression of disulfide HMGB1 in patients with newly diagnosed epilepsy, and its persistence was associated with subsequent seizures. In contrast with patients with well-controlled epilepsy, patients with chronic, drug-refractory epilepsy persistently expressed the acetylated, disulfide HMGB1 isoforms. Moreover, treatment of animals with antiinflammatory drugs during epileptogenesis prevented both disease progression and blood increase in HMGB1 isoforms. Our data suggest that HMGB1 isoforms are mechanistic biomarkers for epileptogenesis and drug-resistant epilepsy in humans, necessitating evaluation in larger-scale prospective studies.

A comparison of HMGB1 concentrations between cerebrospinal fluid and blood in patients with neurological disease.

AIMS: To determine whether a correlation exists between paired cerebrospinal fluid (CSF) and serum levels of a novel inflammatory biomarker, high-mobility group box 1 (HMGB1), in different neurological conditions. METHODS: HMGB1 was measured in the serum and CSF of 46 neurological patients (18 idiopathic intracranial hypertension [IIH], 18 neurological infection/inflammation [NII] and 10 Rasmussen's encephalitis [RE]). RESULTS: Mean serum (± SD) HMGB1 levels were 1.43 ± 0.54, 25.28 ± 27.9 and 1.89 ± 1.49 ng/ml for the patients with IIH, NII and RE, respectively. Corresponding mean (± SD) CSF levels were 0.35 ± 0.22, 4.48 ± 6.56 and 2.24 ± 2.35 ng/ml. Both CSF and serum HMGB1 was elevated in NII. Elevated CSF HMGB1 was demonstrated in RE. There was no direct correlation between CSF and serum levels of HMGB1. CONCLUSION: Serum HMGB1 cannot be used as a surrogate measure for CSF levels. CSF HMGB1 was elevated in NII and RE, its role as a prognostic/stratification biomarker needs further study.

Exploring the genomic basis of pharmacoresistance in epilepsy: an integrative analysis of large-scale gene expression profiling studies on brain tissue from epilepsy surgery.

Some patients with pharmacoresistant epilepsy undergo therapeutic resection of the epileptic focus. At least 12 large-scale microarray studies on brain tissue from epilepsy surgery have been published over the last 10 years, but they have failed to make a significant impact upon our understanding of pharmacoresistance, because (1) doubts have been raised about their reproducibility, (2) only a small number of the gene expression changes found in each microarray study have been independently validated and (3) the results of different studies have not been integrated to give a coherent picture of the genetic changes involved in epilepsy pharmacoresistance. To overcome these limitations, we (1) assessed the reproducibility of the microarray studies by calculating the overlap between lists of differentially regulated genes from pairs of microarray studies and determining if this was greater than would be expected by chance alone, (2) used an inter-study cross-validation technique to simultaneously verify the expression changes of large numbers of genes and (3) used the combined results of the different microarray studies to perform an integrative analysis based on enriched gene ontology terms, networks and pathways. Using this approach, we respectively (1) demonstrate that there are statistically significant overlaps between the gene expression changes in different publications, (2) verify the differential expression of 233 genes and (3) identify the biological processes, networks and genes likely to be most important in the development of pharmacoresistant epilepsy. Our analysis provides novel biologically plausible candidate genes and pathways which warrant further investigation to assess their causal relevance.