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.

Decreasing incidence of stroke, ischaemic heart disease and dementia in Norway, 1990-2019, a Global Burden of Disease study: an opportunity.

BACKGROUND AND PURPOSE: The declining incidence of stroke, ischaemic heart disease (IHD) and dementia (the 'triple threat') in Norway encourages further investigation. The risks and trends of the three conditions were analysed using data from the Global Burden of Disease study. METHODS: Global Burden of Disease 2019 estimations were used for age-, sex- and risk-factor-specific incidence and prevalence of the 'triple threat', their risk-factor-attributed deaths and disability combined, their age-standardized rates per 100,000 population in 2019 and their changes during 1990-2019. Data are presented as means and 95% uncertainty intervals. RESULTS: In 2019, 71.1 thousand Norwegians were living with dementia, 157.2 thousand with IHD and 95.2 thousand with stroke. In 2019, there were 9.9 thousand (8.5 to 11.3) new cases of dementia (35.0% increase since 1990), 17.0 thousand (14.6 to 19.6) with IHD (3.6% decrease) and 8.0 thousand (7.0 to 9.1) with stroke (12.9% decrease) in Norway. During 1990-2019, their age-standardized incidence rates decreased significantly-dementia by -5.4% (-8.4% to -3.2%), IHD by -30.0% (-31.4% to -28.6%) and stroke by -35.3% (-38.3% to -32.2%). There were significant declines in the attributable risks to both environmental and behavioural factors in Norway, but contradictory trends for metabolic risk factors during 1990-2019. CONCLUSIONS: The risk of the 'triple threat' conditions is declining in Norway, despite the increased prevalence. This offers the opportunity to find out why and how and to accelerate their joint prevention through new approaches and the promotion of the National Brain Health Strategy.

Global synergistic actions to improve brain health for human development.

The global burden of neurological disorders is substantial and increasing, especially in low-resource settings. The current increased global interest in brain health and its impact on population wellbeing and economic growth, highlighted in the World Health Organization's new Intersectoral Global Action Plan on Epilepsy and other Neurological Disorders 2022-2031, presents an opportunity to rethink the delivery of neurological services. In this Perspective, we highlight the global burden of neurological disorders and propose pragmatic solutions to enhance neurological health, with an emphasis on building global synergies and fostering a 'neurological revolution' across four key pillars - surveillance, prevention, acute care and rehabilitation - termed the neurological quadrangle. Innovative strategies for achieving this transformation include the recognition and promotion of holistic, spiritual and planetary health. These strategies can be deployed through co-design and co-implementation to create equitable and inclusive access to services for the promotion, protection and recovery of neurological health in all human populations across the life course.

Epilepsy-Related Direct Medical and Direct Non-Medical Cost in Adult Patients Living with Epilepsy at a Tertiary Neurology Center in Rwanda.

Objective: Up to one in four patients living with epilepsy (PwE) mentions financial constraints as a reason for loss to follow-up at the Ndera tertiary neuropsychiatry hospital. Therefore, we evaluated the annual direct medical cost (DMC) and direct non-medical cost (DnMC) of epilepsy and calculated costs assuming different follow-up frequency. Materials and Methods: DMC data were obtained from a descriptive retrospective study of medical records, pharmacy dispensation and hospital logs of PwE, following their initial consultation in 2018 and who adhered to the normal clinical practice of monthly consultations for one year. DnMC data were collected through structured interviews of PwE in a cross-sectional cohort in August 2020. DnMC included biomedical care costs (eg, transportation, hospitality) and non-biomedical costs (traditional healer visits). We report weighted means for total costs, health insurance costs, and out-of-pocket costs (OoP). Results: Mean annual total cost was 389.4 US$, of which 226.2 US$ was covered by the Rwandan Health Insurance co-payment for DMC and 163.2 US$ was OoP paid by patients. Mean weighted annual DMC (n = 55) was 248.9 US$. Mean weighted annual DMC for medical consultations and antiseizure medication accounted for 30.7 US$ and 161.7 US$, respectively. Based on structured interviews (n = 69), mean weighted annual DnMC for biomedical care was 73.0 US$. Mean DnMC for traditional healer care was 67.6 US$. Weighted annual total OoP was 163.2 US$ or 20% of the GDP per capita. OoP consisted of 14% DMC co-payment, 45% biomedical DnMC, and 41% traditional healer DnMC. Conclusion: Epilepsy-related costs at a tertiary center are an important economic burden for PwE and Rwandan Health Insurance. Biomedical and traditional healer DnMC constitute 86% of total OoP. Future prospective studies should evaluate outcomes and costs of reduced visit frequency, indirect costs, and costs of comorbidities.

Current standards of neuropsychological assessment in epilepsy surgery centers across Europe.

We explored the current practice with respect to the neuropsychological assessment of surgical epilepsy patients in European epilepsy centers, with the aim of harmonizing and establishing common standards. Twenty-six epilepsy centers and members of "E-PILEPSY" (a European pilot network of reference centers in refractory epilepsy and epilepsy surgery), were asked to report the status of neuropsychological assessment in adults and children via two different surveys. There was a consensus among these centers regarding the role of neuropsychology in the presurgical workup. Strong agreement was found on indications (localization, epileptic dysfunctions, adverse drugs effects, and postoperative monitoring) and the domains to be evaluated (memory, attention, executive functions, language, visuospatial skills, intelligence, depression, anxiety, and quality of life). Although 186 different tests are in use throughout these European centers, a core group of tests reflecting a moderate level of agreement could be discerned. Variability exists with regard to indications, protocols, and paradigms for the assessment of hemispheric language dominance. For the tests in use, little published evidence of clinical validity in epilepsy was provided. Participants in the survey reported a need for improvement concerning the validity of the tests, tools for the assessment of everyday functioning and accelerated forgetting, national norms, and test co-normalization. Based on the present survey, we documented a consensus regarding the indications and principles of neuropsychological testing. Despite the variety of tests in use, the survey indicated that there may be a core set of tests chosen based on experience, as well as on published evidence. By combining these findings with the results of an ongoing systematic literature review, we aim for a battery that can be recommended for the use across epilepsy surgical centers in Europe.

Repeated assessment of larynx compound muscle action potentials using a self-sizing cuff electrode around the vagus nerve in experimental rats.

RATIONALE: Vagus nerve stimulation (VNS) is an adjunctive treatment for patients with refractory epilepsy. In more than 30% of the patients VNS has no therapeutic effect. The goal of this study was to find an objective parameter that can be used as an indicator of effective stimulation of the vagus nerve. METHODS: The electrophysiological response to VNS was recorded from the vagus nerve, recurrent laryngeal nerve and larynx muscles. Nerve lesions and muscle relaxing agent were used to find the source of the electrophysiological response. A cuff-electrode for chronic stimulation and recording was implanted for chronic recording of the VNS-induced electrophysiological response after implantation. Dose-response curves were determined daily during a follow-up period of 2 months. RESULTS: VNS induced an electrophysiological response around 3 ms after start of the stimulation. This response was identified as a larynx compound action potential (LCMAP) LCMAP could be recorded immediately after surgery in 11/21 rats, while in the other 10/21 rats, a recovery period with an average of 25 days was required. Once the LCAMP could be recorded, the latency and overall characteristics of the doses response curves of the LCMAP remained stable during the entire follow-up period. CONCLUSIONS: In this study, we provide an objective electrophysiological parameter for vagus nerve activation. LCAMP may indicate recovery of the vagus nerve after implantation, which may help to determine when uptitration of VNS therapy can be initiated. LCAMP could be of value in future experiments for objectification of VNS in animal models for epilepsy.

Improving decision-making in caring for people with epilepsy and intellectual disability: an action research project.

AIM: This paper is a report of an action research study aimed at improving decision-making concerning risks in people with epilepsy and intellectual disability and the empowerment of participants to sustain this improvement. BACKGROUND: Residents of long-stay units in specialized epilepsy centres suffer severe epilepsy and are often intellectually disabled. Professional caregivers have to find a balance between risk-taking and protection, as both can have a negative effect on quality of life. Clients, their representatives and caregivers are involved in this decision-making process. METHOD: A participative action research project was conducted. Data were gathered continuously over a 22-month period in 2004-2006 by interviews, observation, written reports of meetings and personal stories. FINDINGS: The action research resulted in an ongoing process of improvement. Problems in decision-making about risk were clarified. The importance of consensus about risks and commitment to risk management between all involved became apparent. Phases in risk management were discerned and used to adjust caregiving to clients' needs and capacities Assessment of client risk became more systematic and 'steps to an individual framework for decision-making' were developed as a tool for a systematic approach. CONCLUSION: Using an action research model to improve decision-making provided the preconditions for improving decision-making and risk management and suggesting a way to improve this process in this and other institutions.

Impact of reimbursement restrictions on the choice of antiepileptic drugs: Belgian Study on Epilepsy Treatment (BESET).

BACKGROUND: In Belgium, new and costly antiepileptic drugs (AEDs) are only reimbursed as second-line treatment, after documented treatment with conventional and cheaper AEDs has failed. The objective of this study was to describe the treatment of epilepsy in Belgium and to analyze the impact of the reimbursement restrictions on the choice of AEDs. METHODS: Between May and June 2003, a sample of 100 neurologists, representative of the entire neurological community in teaching, academic, and regional hospitals in Belgium, were personally interviewed on the basis of a structured questionnaire (modified Rand method). The questionnaire contained questions on treatment choices and strategies in adult epilepsy. RESULTS: Unanimously, initial monotherapy was the preferred treatment strategy in all types of epilepsy. In the opinion of most neurologists, valproate was the first choice for idiopathic generalized and focal epilepsy with/without secondary generalization. Carbamazepine as their first choice for the treatment of focal epilepsy. New AEDs were most often prescribed as second-line therapy. Lamotrigine was the most frequently prescribed new AED and used for both generalized and focal epilepsy. It was followed by levetiracetam, topiramate and oxcarbazepine for focal epilepsy. In the absence of reimbursement restrictions, two new AEDs would be significantly more often prescribed as a first-line therapy: lamotrigine for idiopathic generalized epilepsy and oxcarbazepine for focal epilepsy. CONCLUSIONS: The neurologists reached a high level of consensus on many of the key treatment questions. Monotherapy with valproate and carbamazepine was the standard treatment strategy in Belgium. Lamotrigine and less so levetiracetam, topiramate and oxcarbazepine were commonly prescribed as second-line AEDs. In the absence of reimbursement restrictions, lamotrigine and oxcarbazepine would be more frequently prescribed.

Vagus nerve stimulation for refractory epilepsy.

Vagus nerve stimulation (VNS) is a neurophysiological treatment for patients with medically or surgically refractory epilepsy. Since the first human implant in 1989, more than 10,000 patients have been treated with VNS. Two randomized controlled studies have shown a statistically significant decrease in seizure frequency during a 12-week treatment period versus a baseline period when 'high stimulation' mode was compared with 'low stimulation' mode. The efficacy appears to increase over time. In general, one third of the patients show a > 50% reduction of seizure frequency; one third show a 30-50% seizure reduction, and one third of patients show no response. Few patients become seizure-free. Side effects during stimulation are mainly voice alteration, coughing, throat paraesthesia and discomfort. When studied on a long-term basis, VNS is an efficacious, safe and cost-effective treatment not only in adults but also in children and the elderly. The precise mechanism of action remains to be elucidated. In recent years much progress has been made through neurophysiological, neuroanatomical, neurochemical and cerebral blood flow studies in animals and patients treated with VNS. Further elucidation of the mechanism of action of VNS may increase its clinical efficacy and our general understanding of some physiopathological aspects of epilepsy. Finally, VNS may become an alternative treatment for other conditions such as depression and pain.

Comparison of performance of spherical and realistic head models in dipole localization from noisy EEG.

The performance of a three-shell spherical head model versus the performance of a realistic head model is investigated when solving the inverse problem with a single dipole, in the presence of noise. This is evaluated by calculating the average dipole location error for 1000 noisy scalp potential sets, originating from the same test dipole and having the same noise level. The average location errors are obtained utilizing a local linearization, which is validated with a Monte-Carlo simulation. When the difference between the average location error utilizing a spherical and a realistic head model, represented by deltaR, is large for a large number of test dipoles, then it is worth using the more computationally demanding realistic head model. However, if deltaR is small for a large number of test dipoles, then it does not matter which model is used. For 27 electrodes, an electroencephalogram (EEG) epoch of one time sample and spatially white Gaussian noise, we found that the importance of the realistic head model over the spherical head model reduces by increasing the noise level. We further found that increasing the number of scalp electrodes from 27 to 44 has limited impact on the importance of the realistic head model over the spherical head model in EEG dipole source analysis. By increasing the number of time samples to six, the performance of the realistic head model in the inverse calculation gains importance compared with the three-shell spherical head model. Finally, we used spatially and temporally correlated background EEG instead of Gaussian noise. The advantage of the realistic head model over the spherical head model is reduced when applying correlated noise compared to Gaussian noise.