Climate change and the brain

Heatwaves are becoming more common as a result of climate change. Sanjay Sisodiya discusses some of the potential impacts of climate change on the nervous system, particularly in individuals with neurological disorders, and emphasizes the need to take action now to help mitigate these effects

Hot brain: practical climate change advice for neurologists.

'We are called to be architects of the future, not its victims'-Buckminster FullerPeople with chronic neurological conditions may be vulnerable to change and less able to manage its demands: neurological diseases are among the most burdensome. Whether climate change has particular effects on specific neurological diseases or not, the known impaired resilience to change affecting people with neurological diseases requires neurologists to have awareness of potential climate impacts and their management. Preparedness should include understanding of general national and local alerts and action systems, and the ability to advise patients about managing extreme weather events, particularly heatwaves, but also floods and cold snaps. At the same time, we need more research into the particular consequences of climate change on specific neurological diseases. Climate change is a serious healthcare issue, requiring the neurological community to respond as it would, or did, to other serious challenges, such as COVID-19. As disease experts, we all have a role to play

Innovating Marketing Undergraduate Curriculum: How Integrating Courses at the Undergraduate Level Enhance Skills and Competencies for New Hires Entering the Workplace

[EN] The marketing field continues to evolve as the functions within organizations are constantly changing.  New hires are finding that along with the evolving landscape they need to be able to master their field of expertise to work well with others both inside and outside their respective organizations.  This dynamic environment is increasing pressure on how universities prepare undergraduate students for careers in marketing. The purpose of this study is to investigate how revisions to marketing undergraduate curriculum better prepares student career readiness.  Based on field interviews, managers note that gaps exist in undergraduate curriculum as it is intended to prepare students for the workplace, more importantly as students advance their careers.  While there have been many proposed changes to curriculum (e.g., Bridges 2020; McCollough and Shook 2017), we take a broader look at how curriculum can be adapted and be made adaptable to the dynamic environment. Our study focuses on two areas.  First, we explore the knowledge new hires need to be successful in their roles in marketing.  For domain knowledge, we investigate specific marketing expertise and how marketing topics integrate (thus bolstering cross-functional expertise) from a marketing knowledge standpoint.  Second, we study how integrative curriculum better provides new hires the skills and competencies essential for when working with others in the workplace.  Similar to previous research considering skills and competencies of undergraduate students (e.g., Zekeri 2004), we use the The Tailored Design Method to administer a survey to gather data in order to investigate these research questions further.Larson, E.; Sanjay R., S. (2022). Innovating Marketing Undergraduate Curriculum: How Integrating Courses at the Undergraduate Level Enhance Skills and Competencies for New Hires Entering the Workplace. En Proceedings INNODOCT/21. International Conference on Innovation, Documentation and Education. Editorial Universitat Politècnica de València. 49-55. https://doi.org/10.4995/INN2021.2021.13336495

Case report: Dravet syndrome, feeding difficulties and gastrostomy

Dravet syndrome (DS) is a developmental and epileptic encephalopathy associated with variants in the voltage-gated sodium channel alpha 1 subunit (SCN1A) gene in around 90% of individuals. The core phenotype is well-recognized, and is characterized by seizure onset in infancy, typically with prolonged febrile seizures, followed by the emergence of multiple seizure types that are frequently drug-resistant, developmental delay, and intellectual disability. Comorbidities are common and include autism spectrum disorder, gait impairment, scoliosis, and sleep disorder. Feeding difficulties and weight loss are frequently reported by DS caregivers, and negatively impact quality of life, yet have received little attention. Here we report an adult with DS who developed reduced food and fluid intake in adolescence, resulting in weight loss and malnutrition. No underlying cause for her feeding difficulties was identified, and she subsequently required insertion of a percutaneous endoscopic gastrostomy. We review the occurrence of feeding difficulties in people with DS and discuss potential mechanisms

Risk factors and outcome of hyperammonaemia in people with epilepsy

BACKGROUND: Hyperammonaemia is a recognised complication of antiseizure treatment but risk factors leading to individual patient susceptibility and outcome remain unclear. OBJECTIVE: To identify risk factors for hyperammonaemia and investigate the impact of its management on clinical outcomes. METHODS: We carried out a retrospective observational study of adults with epilepsy who had ammonia tested over a 3-year period. Hyperammonaemia was defined as ammonia level > 35 μmol/L. Patients were classified into two groups: hyperammonaemic and non-hyperammonaemic. Association analyses and linear regression analysis were used to identify risk factors for hyperammonaemia. RESULTS: We reviewed 1002 ammonia requests in total and identified 76 people with epilepsy who had ammonia concentration measured, including 26 with repeated measurements. 59/76 (78%) were found to have hyperammonaemia. There was borderline statistical significance of hyperammonaemia being less common in patients with an established monogenic/metabolic condition than in those with structural or cryptogenic epilepsy (P = 0.05). Drug resistance, exposure to stiripentol and oxcarbazepine were identified as risk factors for hyperammonaemia. We found a dose-dependent association between valproate and hyperammonaemia (P = 0.033). Clinical symptoms were reported in 22/59 (37%) of the hyperammonaemic group. Improved clinical outcomes with concurrent decrease in ammonia concentration were seen in 60% of patients following treatment adjustment. CONCLUSIONS: Drug resistance and exposure to stiripentol, oxcarbazepine or high-dose valproate are associated with an increased risk of hyperammonaemia. Clinicians should consider symptoms related to hyperammonaemia in patients on high-dose valproate or multiple antiseizure treatments. Prompt identification of hyperammonaemia and subsequent treatment adjustments can lead to improved clinical outcomes

Mortality in Dravet syndrome: A review

AbstractIntroductionPremature mortality is a major issue in Dravet syndrome (DS). To improve understanding of DS premature mortality, we conducted a comprehensive literature search with a particular emphasis on SUDEP.MethodsWe searched PubMed, Embase, Web of Science, Cochrane, CENTRAL, CINAHL, PsycINFO, Academic Search Premier, and ScienceDirect on the following terms: “Dravet syndrome”, “severe myoclonic epilepsy”, “SMEI”, “mortality”, “survivors”, “prognosis”, and “death”. DS cases or cohorts studies reporting mortality were included.ResultsThe search yielded 676 articles and 86 meeting abstracts. After removing duplicates and screening titles and abstracts, full text of 73 articles was reviewed. Only 28 articles and six meeting abstracts met inclusion criteria. Five articles and four meeting abstracts were excluded, as the case(s) were also described elsewhere. After checking the references, five additional studies were included. The 30 items reported 177 unique cases. Sudden unexpected death in epilepsy was the likely cause in nearly half of the cases (n=87, 49%), followed by status epilepticus (n=56, 32%). Drowning or accidental death was reported in 14 cases (8%), infections in 9 (5%), other causes in six (3%), and unknown in five (3%). Age at death was reported for 142 of the 177 cases (80%), with a mean age of 8.7±9.8years (SD); 73% died before the age of 10years.DiscussionDravet syndrome is characterized by high epilepsy-related premature mortality and a marked young age at death. Sudden unexpected death in epilepsy is the leading reported cause of death in DS, accounting for nearly half of all deaths. The cause of this excess mortality remains elusive but may be explained by epilepsy severity, as well as genetic susceptibility to SUDEP

SCN1A: bioinformatically-informed revised boundaries for promoter and enhancer regions

Pathogenic variations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene are responsible for multiple epilepsy phenotypes, including Dravet syndrome (DS), febrile seizures (FS), and genetic epilepsy with febrile seizures plus (GEFS+). Phenotypic heterogeneity is a hallmark of SCN1A-related epilepsies, the causes of which are yet to be clarified. Genetic variation in the non-coding regulatory regions of SCN1A could be one potential causal factor. However, a comprehensive understanding of the SCN1A regulatory landscape is currently lacking. Here, we summarised the current state of knowledge of SCN1A regulation, providing details of its promoter and enhancer regions. We then integrated currently available data on SCN1A promoters by extracting information related to the SCN1A locus from genome-wide repositories, and clearly defined the promoter and enhancer regions of SCN1A. Further, we explored the cellular specificity of differential SCN1A promoter usage. We also reviewed and integrated the available human brain-derived enhancer databases and mouse-derived data to provide a comprehensive computationally-developed summary of SCN1A brain-active enhancers. By querying genome-wide data repositories, extracting SCN1A-specific data and integrating the different types of independent evidence, we created a comprehensive catalogue that better defines the regulatory landscape of SCN1A, which could be used to explore the role of SCN1A regulatory regions in disease

Distinct genetic basis of common epilepsies and structural magnetic resonance imaging measures

Focal and generalized epilepsies are associated with robust differences in MRI measures of subcortical structures, grey matter and white matter. However, it is unknown whether such structural brain differences reflect the cause or consequence of epilepsy or its treatment. Analyses of common genetic variants underlying both common epilepsy and variability in structural brain measures can give further insights, since such inherited variants are not influenced by disease or treatment. Here, we performed genetic correlation analyses using data from the largest genome-wide association study (GWAS) on common epilepsy (n=27,559 cases and 42,436 controls) and GWAS on MRI measures of white (n=33,292) or grey matter (n=51,665). We did not detect any significant genetic correlation between any type of common epilepsy and any of 280 measures of grey matter, white matter or subcortical structures. These results suggest that there are distinct genetic bases underlying risk of common epilepsy and for structural brain measures. This would imply that the genetic basis of normal structural brain variation is unrelated to that of common epilepsy. Structural changes in epilepsy could rather be the consequence of epilepsy, its comorbidities or its treatment, offering a cumulative record of disease

Structural imaging biomarkers of sudden unexpected death in epilepsy.

Sudden unexpected death in epilepsy is a major cause of premature death in people with epilepsy. We aimed to assess whether structural changes potentially attributable to sudden death pathogenesis were present on magnetic resonance imaging in people who subsequently died of sudden unexpected death in epilepsy. In a retrospective, voxel-based analysis of T1 volume scans, we compared grey matter volumes in 12 cases of sudden unexpected death in epilepsy (two definite, 10 probable; eight males), acquired 2 years [median, interquartile range (IQR) 2.8] before death [median (IQR) age at scanning 33.5 (22) years], with 34 people at high risk [age 30.5 (12); 19 males], 19 at low risk [age 30 (7.5); 12 males] of sudden death, and 15 healthy controls [age 37 (16); seven males]. At-risk subjects were defined based on risk factors of sudden unexpected death in epilepsy identified in a recent combined risk factor analysis. We identified increased grey matter volume in the right anterior hippocampus/amygdala and parahippocampus in sudden death cases and people at high risk, when compared to those at low risk and controls. Compared to controls, posterior thalamic grey matter volume, an area mediating oxygen regulation, was reduced in cases of sudden unexpected death in epilepsy and subjects at high risk. The extent of reduction correlated with disease duration in all subjects with epilepsy. Increased amygdalo-hippocampal grey matter volume with right-sided changes is consistent with histo-pathological findings reported in sudden infant death syndrome. We speculate that the right-sided predominance reflects asymmetric central influences on autonomic outflow, contributing to cardiac arrhythmia. Pulvinar damage may impair hypoxia regulation. The imaging findings in sudden unexpected death in epilepsy and people at high risk may be useful as a biomarker for risk-stratification in future studies

Risk-conferring HLA variants in an epilepsy cohort: benefits of multifaceted use of whole genome sequencing in clinical practice

BACKGROUND: Whole genome sequencing is increasingly used in healthcare, particularly for diagnostics. However, its clinically multifaceted potential for individually customised diagnostic and therapeutic care remains largely unexploited. We used existing whole genome sequencing data to screen for pharmacogenomic risk factors related to antiseizure medication-induced cutaneous adverse drug reactions (cADRs), such as human leucocyte antigen HLA-B*15:02, HLA-A*31:01 variants. METHODS: Genotyping results, generated from the Genomics England UK 100 000 Genomes Project primarily for identification of disease-causing variants, were used to additionally screen for relevant HLA variants and other pharmacogenomic variants. Medical records were retrospectively reviewed for clinical and cADR phenotypes for HLA variant carriers. Descriptive statistics and the χ2 test were used to analyse phenotype/genotype data for HLA carriers and compare frequencies of additional pharmacogenomic variants between HLA carriers with and without cADRs, respectively. RESULTS: 1043 people with epilepsy were included. Four HLA-B*15:02 and 86 HLA-A*31:01 carriers were identified. One out of the four identified HLA-B*15:02 carriers had suffered antiseizure medication-induced cADRs; the point prevalence of cADRs was 16.9% for HLA-A*31:01 carriers of European origin (n=46) and 14.4% for HLA-A*31:01 carriers irrespective of ancestry (n=83). CONCLUSIONS: Comprehensive utilisation of genetic data spreads beyond the search for causal variants alone and can be extended to additional clinical benefits such as identifying pharmacogenomic biomarkers, which can guide pharmacotherapy for genetically-susceptible individuals