A strategic neurological research agenda for Europe: Towards clinically relevant and patient-centred neurological research priorities.

BACKGROUND AND PURPOSE: Neurological disorders constitute a significant portion of the global disease burden, affecting >30% of the world's population. This prevalence poses a substantial threat to global health in the foreseeable future. A lack of awareness regarding this high burden of neurological diseases has led to their underrecognition, underappreciation, and insufficient funding. Establishing a strategic and comprehensive research agenda for brain-related studies is a crucial step towards aligning research objectives among all pertinent stakeholders and fostering greater societal awareness. METHODS: A scoping literature review was undertaken by a working group from the European Academy of Neurology (EAN) to identify any existing research agendas relevant to neurology. Additionally, a specialized survey was conducted among all EAN scientific panels, including neurologists and patients, inquiring about their perspectives on the current research priorities and gaps in neurology. RESULTS: The review revealed the absence of a unified, overarching brain research agenda. Existing research agendas predominantly focus on specialized topics within neurology, resulting in an imbalance in the number of agendas across subspecialties. The survey indicated a prioritization of neurological disorders and research gaps. CONCLUSIONS: Building upon the findings from the review and survey, key components for a strategic and comprehensive neurological research agenda in Europe were delineated. This research agenda serves as a valuable prioritization tool for neuroscientific researchers, as well as for clinicians, donors, and funding agencies in the field of neurology. It offers essential guidance for creating a roadmap for research and clinical advancement, ultimately leading to heightened awareness and reduced burden of neurological disorders.

Statins as an antiepileptogenic or disease-modifying treatment? A survey of what UK patients and significant others think about repurposing and trialing them for epilepsy.

OBJECTIVE: To identify the views of people with epilepsy (PWE), and their significant others, on the repurposing and trialing of statins as a potential antiepileptogenic or disease-modifying treatment for those who have had the first seizure. METHODS: Online questionnaire. Participants needed to be aged ≥ 16 years, UK residents, and able to independently complete a questionnaire in English. User groups distributed study adverts. Embedded infographics explained repurposing, why anti-seizure treatment is not typically started after a first seizure and the nature of randomized placebo-controlled trials (RCTs). The questionnaire asked participants to reflect and rate their expected willingness to have started an unspecified treatment after their first seizure/s (or that of the person with epilepsy they knew). They also rated willingness if the treatment were a statin, views of statins, the importance of an RCT of statins to their community, the outcomes it should assess, and their willingness to have taken part in it. The estimated number needed for the survey was 324. RESULTS: Responses from 213 persons were analyzed; 111 (52.1%) were PWE and 102 (47.9%) significant others. The median years diagnosed was 10 and PWE suffered from relatively severe epilepsy. One hundred and seventeen (54.9%) said they would have started an unspecified treatment after their first seizure/s (or supported the person with epilepsy they knew to have). A similar proportion (55.4%) said they would have started the treatment if it were a statin. Participants' main concern about statins, expressed by 79%, was their possible side effects. Repurposing was a concern for only 25%. Most (85.8%) rated an RCT of statins as of extreme or high importance; 54.4% said they would have participated. CONCLUSION: The PWE and significant others (SOs) responding to our survey expressed views towards repurposing statins that were generally positive and indicate a trial in those who have had a first seizure might be feasible. Concerns regarding side effects are common. Our findings could help optimize a future trial's design and the case for funding. Limitations include that we did not survey persons who had experienced a first seizure and did not go on to develop epilepsy. Also, persons with uncontrolled epilepsy were overrepresented.

The prevalence of comorbidity in rheumatoid arthritis: a systematic review and meta-analysis.

This systematic review and meta-analysis estimates the prevalence of common comorbid health disorders in adults with rheumatoid arthritis (RA). A multi-database search strategy was undertaken. Screening, data extraction and quality assessment were carried out by two independent reviewers. A meta-analysis and meta-regression were used to generate a pooled prevalence estimate and identify relevant moderators. After study selection, 33 studies (74633 participants) were included in the meta-analysis. Some 31 studies were judged to be of low risk of bias, and two studies were judged to be at moderate risk of bias. The three most common comorbidities in RA were anxiety disorders (62.1%, 95% Cl: 43.6%; 80.6%), hypertension (37.7%, 95% Cl: 29.2%; 46.2%) and depression (32.1%, 95% Cl: 21.6%; 42.7%). There was substantial statistically significant heterogeneity for all comorbidities (I2 ≥77%). Meta-regression identified that the covariate of mean age (unit increase) had a statistically significant effect on the prevalence of hypertension (+2.3%, 95% Cl: 0.4%; 4.2%), depression (-0.5%, 95% Cl: -0.6%; -0.4%) and cancer (0.5%, 95% Cl: 0.2%; 0.8%) in adults with RA. A country's income was identified to have a statistically significant effect on the prevalence of depression, with low-to moderate-income countries having 40% (95% Cl: 14.0%; 66.6%) higher prevalence than high-income countries. No studies consider health inequalities. It is concluded that comorbidities are prevalent among people with RA, particularly those associated with mental health and circulatory conditions. Provision of health services should reflect the importance of such multimorbidity and the consequences for quality and length of life.

Measuring patient experience: a systematic review to evaluate psychometric properties of patient reported experience measures (PREMs) for emergency care service provision.

PURPOSE: Knowledge about patient experience within emergency departments (EDs) allows services to develop and improve in line with patient needs. There is no standardized instrument to measure patient experience. The aim of this study is to identify patient reported experience measures (PREMs) for EDs, examine the rigour by which they were developed and their psychometric properties when judged against standard criteria. DATA SOURCES: Medline, Scopus, CINAHL, PsycINFO, PubMed and Web of Science were searched from inception to May 2015. STUDY SELECTION: Studies were identified using specific search terms and inclusion criteria. A total of eight articles, reporting on four PREMs, were included. DATA EXTRACTION: Data on the development and performance of the four PREMs were extracted from the articles. The measures were critiqued according to quality criteria previously described by Pesudovs K, Burr JM, Harley C, et al. (The development, assessment, and selection of questionnaires. Optom Vis Sci 2007;84:663-74.). RESULTS: There was significant variation in the quality of development and reporting of psychometric properties. For all four PREMs, initial development work included the ascertainment of patient experiences using qualitative interviews. However, instrument performance was poorly assessed. Validity and reliability were measured in some studies; however responsiveness, an important aspect on survey development, was not measured in any of the included studies. CONCLUSION: PREMS currently available for use in the ED have uncertain validity, reliability and responsiveness. Further validation work is required to assess their acceptability to patients and their usefulness in clinical practice.

HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.

BACKGROUND: Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations. METHODS: We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. RESULTS: The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). CONCLUSIONS: The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).

Valuations of epilepsy-specific health states: a comparison of patients with epilepsy and the general population.

AIMS: Utility values that can be used in the economic evaluation of treatments for epilepsy can be elicited from the general population and the patient population, but it is unclear how the health state values differ. The aim of this study is to compare the preferences of the general population and a sample of people with epilepsy for health states described by the NEWQOL-6D QALY measure. METHODS: The Time Trade Off preference elicitation technique was used to value eight NEWQOL-6D health states. The general population sample was recruited and interviewed in their homes, and the sample with epilepsy was recruited and interviewed in an epilepsy service in North West England. Descriptive analysis and regression modeling were used to compare health state values across the populations. RESULTS: A sample of 70 people with epilepsy and a sample of 60 members of the general population were included. The populations differed across a range of background characteristics, but there were limited differences between the health state values. Patients provided significantly higher (better) values for the most severe health state described by the NEWQOL-6D (p<0.01) and nonsignificant higher values for states with intermediate severity. The general population health state value was only higher for the best health state described by the NEWQOL-6D. CONCLUSIONS: The similarities in the patient and general population values for NEWQOL-6D health states suggest that the use of the general population utility weights for the estimation of QALYs in the economic evaluation of epilepsy interventions is appropriate and largely representative of patient preferences.

Acceptability of virtual psychiatric consultations for routine follow-ups post COVID-19 pandemic for people with intellectual disabilities: cross-sectional study.

BACKGROUND: After the rapid implementation of digital health services during the COVID-19 pandemic, a paucity of research exists about the suitability of remote consulting in people with intellectual disabilities and their carers, particularly for neuropsychiatric reviews. AIM: This study examines when remote neuropsychiatric routine consulting is suitable for this population. METHOD: A survey was conducted of people with intellectual disabilities and their carers, examining their preference between face-to-face and video consultations for ongoing neuropsychiatric reviews within a rural countywide intellectual disability service in Cornwall, England (population: 538 000). The survey was sent to all adults with intellectual disabilities open to the service on 30 July 2022, closing on 30 September 2022. Participants were asked to provide responses on 11 items predesigned and co-produced between clinicians and experts by experience. The entire service caseload of people had White ethnicity, reflecting the ethnic demographics of Cornwall. Responses received without consent were excluded from the study dataset. RESULTS: Of 271 eligible participants, 119 responses were received, 104 of whom consented to having their anonymised data used for research analysis. There were no significant differences between preferences and age and gender variables. There was no statistically significant difference regarding preference for the reintroduction of face-to-face appointments (52.0%) compared with video consultations (48.0%). Travel distance (>10 miles) to the clinical setting was important but did not outweigh benefits for those preferring a face-to-face appointment. CONCLUSIONS: This study offers insights into the factors that influence preferences about what type of neuropsychiatric appointment is most suitable for people with intellectual disabilities.

The development of a QALY measure for epilepsy: NEWQOL-6D.

Cost-utility analysis is used to inform the allocation of healthcare resources, using the quality-adjusted life year (QALY) as the outcome measure. We report the development of an epilepsy-specific QALY measure (NEWQOL-6D) derived from the NEWQOL measure of health-related quality of life. Firstly, psychometric and Rasch analyses established the dimension structure of NEWQOL and generated a reduced health state classification system including one item per dimension. Secondly, health states generated by the classification system were valued using Time Trade Off, and the results were modeled to generate a utility score for every health state. A classification system with 6 dimensions (worry about attacks; depression; memory; concentration; stigma; control) was produced, and generalized least squares regression was used to generate utility scores for every health state. This study is the first attempt to derive an epilepsy-specific QALY measure, and the utility values can be used in the economic evaluation of emerging technologies for epilepsy.

Protocol for an observational cohort study investigating biomarkers predicting seizure recurrence following a first unprovoked seizure in adults.

INTRODUCTION: A first unprovoked seizure is a common presentation, reliably identifying those that will have recurrent seizures is a challenge. This study will be the first to explore the combined utility of serum biomarkers, quantitative electroencephalogram (EEG) and quantitative MRI to predict seizure recurrence. This will inform patient stratification for counselling and the inclusion of high-risk patients in clinical trials of disease-modifying agents in early epilepsy. METHODS AND ANALYSIS: 100 patients with first unprovoked seizure will be recruited from a tertiary neuroscience centre and baseline assessments will include structural MRI, EEG and a blood sample. As part of a nested pilot study, a subset of 40 patients will have advanced MRI sequences performed that are usually reserved for patients with refractory chronic epilepsy. The remaining 60 patients will have standard clinical MRI sequences. Patients will be followed up every 6 months for a 24-month period to assess seizure recurrence. Connectivity and network-based analyses of EEG and MRI data will be carried out and examined in relation to seizure recurrence. Patient outcomes will also be investigated with respect to analysis of high-mobility group box-1 from blood serum samples. ETHICS AND DISSEMINATION: This study was approved by North East-Tyne & Wear South Research Ethics Committee (20/NE/0078) and funded by an Association of British Neurologists and Guarantors of Brain clinical research training fellowship. Findings will be presented at national and international meetings published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NIHR Clinical Research Network's (CRN) Central Portfolio Management System (CPMS)-44976.

Protocol for the development of an international Core Outcome Set for treatment trials in adults with epilepsy: the EPilepsy outcome Set for Effectiveness Trials Project (EPSET).

BACKGROUND: A Core Outcome Set (COS) is a standardised list of outcomes that should be reported as a minimum in all clinical trials. In epilepsy, the choice of outcomes varies widely among existing studies, particularly in clinical trials. This diminishes opportunities for informed decision-making, contributes to research waste and is a barrier to integrating findings in systematic reviews and meta-analyses. Furthermore, the outcomes currently being measured may not reflect what is important to people with epilepsy. Therefore, we aim to develop a COS specific to clinical effectiveness research for adults with epilepsy using Delphi consensus methodology. METHODS: The EPSET Study will comprise of three phases and follow the core methodological principles as outlined by the Core Outcome Measures in Effectiveness Trials (COMET) Initiative. Phase 1 will include two focused literature reviews to identify candidate outcomes from the qualitative literature and current outcome measurement practice in phase III and phase IV clinical trials. Phase 2 aims to achieve international consensus to define which outcomes should be measured as a minimum in future trials, using a Delphi process including an online consensus meeting involving key stakeholders. Phase 3 will involve dissemination of the ratified COS to facilitate uptake in future trials and the planning of further research to identify the most appropriate measurement instruments to use to capture the COS in research practice. DISCUSSION: Harmonising outcome measurement across future clinical trials should ensure that the outcomes measured are relevant to patients and health services, and allow for more meaningful results to be obtained. CORE OUTCOME SET REGISTRATION: COMET Initiative as study 118 .

Epilepsy care in the COVID-19 era.

The COVID-19 pandemic will impact on how care for chronic conditions is delivered. We use epilepsy to exemplify how care for patients will be affected, and suggest ways in which healthcare systems can respond to deliver the most effective care. Where face-to-face outpatient appointments have been cancelled, telemedicine can facilitate remote clinical consultations for new and follow-up epilepsy clinic patients while reducing the risk of infection to both patients and healthcare staff. First-seizure patients will need investigation pathways rationalised, while those with chronic epilepsy will need to have reliable alternative avenues to access clinical advice. At the same time, neurologists should support emergency departments and acute medical units, advising on appropriate management of seizures and other acute neurological presentations. Ultimately, the revolution in our clinical practice is unlikely to cease after this pandemic, with reconfiguration of services likely to bring improvements in efficiency and convenience, and a reduced environmental impact.

Cauda Equina Syndrome Core Outcome Set (CESCOS): An international patient and healthcare professional consensus for research studies.

BACKGROUND: Cauda Equina Syndrome (CES) is an emergency condition that requires acute intervention and can lead to permanent neurological deficit in working age adults. A Core Outcome Set (COS) is the minimum set of outcomes that should be reported by a research study within a specific disease area. There is significant heterogeneity in outcome reporting for CES, which does not allow data synthesis between studies. The hypothesis is that a COS for CES can be developed for future research studies using patients and healthcare professionals (HCPs) as key stakeholders. METHODS AND FINDINGS: Qualitative semi-structured interviews with CES patients were audio-recorded, transcribed and analysed using NVivo to identify the outcomes of importance. These were combined with the outcomes obtained from a published systematic literature review of CES patients. The outcomes were grouped into a list of 37, for rating through two rounds of an international Delphi survey according to pre-set criteria. The Delphi survey had an overall response rate of 63% and included 172 participants (104 patients, 68 HCPs) from 14 countries who completed both rounds. Thirteen outcomes reached consensus at the end of the Delphi survey and there was no attrition bias detected. The results were discussed at an international consensus meeting attended by 34 key stakeholders (16 patients and 18 HCPs) from 8 countries. A further three outcomes were agreed to be included. There was no selection bias detected at the consensus meeting. There are 16 outcomes in total in the CESCOS. DISCUSSION: This is the first study in the literature that has determined the core outcomes in CES using a transparent international consensus process involving healthcare professionals and CES patients as key stakeholders. This COS is recommended as the most important outcomes to be reported in any research study investigating CES outcomes and will allow evidence synthesis in CES.

Understanding routine antiepileptic drug decisions: a qualitative analysis of patients' accounts of hospital consultations.

OBJECTIVE: We sought to understand how antiepileptic drug (AED) decisions, similar to those that occur in observational studies on AEDs, were made between doctors and patients in the hospital clinic. We could find no previous research that focused specifically on understanding AED decision making in epilepsy. METHODS: In-depth interviews were conducted with patients who carried a secure diagnosis of epilepsy and who had recently attended a follow-up appointment with a consultant with a special interest in epilepsy. Interviews were digitally recorded and professionally transcribed. A "grounded theory" approach was used for analysis; the Nvivo (QRS release 2.0) computer package was used to manage the data effectively and transparently. No new important themes emerged by the final 10 transcripts, suggesting theoretical data saturation had been reached. RESULTS: Five major themes emerged: preappointment treatment considerations; preconsultation feelings and hopes; acceptance of prognosis and disillusionment; hypothetical change; and decisional ownership. Our interviewees appeared highly susceptible to the doctor's suggestions. All those with active epilepsy and seizures that impacted their life appeared happy to follow the doctor's advice-whatever that may be. This highlights both the desperation many patients have to be free of epilepsy and also the doctor's authority; the perceived authority of the doctor seemed to explain why even patients who were seizure free said they would follow the advice to change treatment, were it suggested. CONCLUSION: Our findings describe decision making from the patients' perspective and support a dominant role for the doctor in the decision making process. There may be factors specific to intractable epilepsy that may be disempowering to involvement in decision making. However, whether patients wish for greater involvement in decision making remains unanswered as stated by one patient "But you're there to take their [the doctor's] advice, that's what you go for don't you?".

Perceptions of emergency care using a seizure care pathway for patients presenting to emergency departments in the North West of England following a seizure: a qualitative study.

OBJECTIVES: To establish the appropriateness of a previously developed seizure care pathway by exploring to what extent patients valued the intervention and perceived it as being helpful or not. DESIGN: Qualitative descriptive study, using semistructured, in-depth interviews and thematic template analysis, theoretically informed by critical realism. SETTING: In North West England, a seizure care pathway has been developed in collaboration with a specialist neurology hospital to support clinical management of seizure patients on initial presentation to the emergency department (ED), as well as access to follow-up services on discharge, with the aim of improving patient experience. Three National Health Service (NHS) EDs and a specialist neurology hospital provided the setting for participant recruitment to this study. PARTICIPANTS: 181 patients fulfilled the inclusion criterion with 27 participants taking part following their experience of an ED attendance and outpatient follow-up appointment after a seizure. RESULTS: Five main themes emerged from the data: decision to seek care, responsiveness of services, waiting and efficiency, information and support, and care continuity. Two integrative themes spanned the whole study: lived experience and communication. This paper reports on two of the main themes: care continuity, and waiting and efficiency. The average time between ED presentation and interview completion was 100 days. CONCLUSIONS: Implementation of a care pathway is a complex intervention, requiring long-term follow-up to assess its integration into practice and effectiveness in service improvement. The seizure care pathway has the potential to enhance the care of seizure patients in the ED and at follow-up by improving continuity and management of care. The study demonstrates good aspects of the seizure care pathway as observed by patients and also recognises shortcomings within current service provision and questions what the NHS should and should not be delivering. Our study suggests various ways to enhance the pathway at service level to potentially drive improved patient experience.

Outcomes Reported After Surgery for Cauda Equina Syndrome: A Systematic Literature Review.

STUDY DESIGN: This is a systematic literature review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. OBJECTIVE: To assess the outcomes reported in trials and observational studies of surgery for cauda equina syndrome (CES), and to inform the development of a core outcome set. SUMMARY OF BACKGROUND DATA: Scoping searches revealed that there were inconsistencies in which outcomes were reported and how they were measured in research studies for patients who had undergone surgery for CES. METHODS: Ovid Medline, Embase, CINAHL Plus, and trial registries were searched from January 1, 1990 to September 30, 2016 with the term "cauda equina syndrome." Inclusion and exclusion criteria were applied according to study design, diagnosis, procedure, publication date, language, and patient age. Data extracted included demographics, study design, the outcomes reported, and their definition. We also assessed variation in the use of terminology for each outcome domain. RESULTS: A total of 1873 articles were identified, of which 61 met the inclusion criteria. Of these, 737 outcomes reported verbatim were categorized into 20 core outcome domains and 12 subdomains with a range of 1 to 141 outcomes per outcome domain or subdomain. The most commonly reported outcomes were bladder function (70.5%), motor function (63.9%), and sensation (50.8%). Significant variation in the terms used for each outcome was documented, for example, bladder function outcome domain had 141 different terms. CONCLUSION: There is significant heterogeneity in outcomes reported for studies after surgery for CES patients. This indicates a clear need for the development of a core outcome set, which has been registered as number 824 on the COMET (Core Outcome Measure in Effectiveness Trials) database. LEVEL OF EVIDENCE: 1.

Comparing drug treatments in epilepsy.

The great majority of randomised controlled trials (RCTs) that compare antiepileptic drugs are industry sponsored and have the objective of obtaining a monotherapy license for a drug. Such trials do not inform everyday clinical practice as they tend to be too short and to depart from clinical practice by restricting clinicians in their choice of actions. The data that exists provides evidence that drugs with actions on voltage-gated sodium channels provide best seizure control for localised onset seizures and epilepsy syndromes, while valproate provides best seizure control for generalised epilepsy and unclassified syndromes. Drugs do, however, vary in their tolerability over the short term and in their risk for rare serious idiosyncratic adverse events, chronic toxicity and teratogenicity; issues that cannot be examined within the scope of RCTs.