"Untold Distress" - How did the COVID-19 pandemic affect those who had previously experienced an epilepsy-related bereavement?

PURPOSE: This study explores the impact of the COVID-19 pandemic and lockdown on people with lived experience of sudden bereavement as a consequence of an epilepsy-related death. METHOD: We developed an online survey with fixed choice and open-ended response formats to collect data on grief symptoms and well-being during the pandemic. A total of 275 people bereaved by epilepsy-related deaths between 1980-2020 participated in this study: with 79 participants providing free-text responses for inductive thematic analysis. RESULTS: In total, 84% of participants reported a bereavement following a sudden death of a person aged under 40, with 22% aged 19 and under. The majority (77% of participants) reported they had been thinking more about the person who died compared to before the COVID-19 outbreak and 54% had experienced more distressing flashbacks to the time of death. Additionally, 61% reported more difficulties falling asleep and staying asleep and 88% of participants reported that the outbreak and response measures had negatively impacted upon their mental health. Medication was being taken for a diagnosed mental health condition by 33% of participants at the time of the study. We categorized these negative experiences during COVID in to four main-themes - 'Family', 'Lifestyle', 'Personal Well-being' and 'Health Services and Shielding Populations'. The 'Personal Well-being' theme was inextricably linked to grief symptoms including 'reflection on the death', 're-exposure to feeling', 'grief', 'salience of sudden deaths in the media' and 'inability to commemorate anniversaries and rituals'. These findings were consistent for bereaved people irrespective of the recency of the death. CONCLUSION: This study highlights the impact of the disruption caused by the pandemic on the grief-management of those bereaved by epilepsy-related death. Grief is not static and its management is connected to the psychosocial and formal support structures that were disrupted during the pandemic. The removal of these supports had an adverse effect upon the mental health and well-being of many bereaved. There is an urgent need for a system-wide transformation of epilepsy and mental health services to be inclusive of the needs and experiences of people impacted by sudden deaths in epilepsy and the contribution of the specialist service developed by families and clinicians to meet this gap.

Impact of the COVID-19 pandemic on people with epilepsy: findings from the US arm of the COV-E study.

OBJECTIVES: As part of the COVID-19 and Epilepsy (COV-E) global study, we aimed to understand the impact of COVID-19 on the medical care and well-being of people with epilepsy (PWE) in the United States, based on their perspectives and those of their caregivers. METHODS: Separate surveys designed for PWE and their caregivers were circulated from April 2020 to July 2021; modifications in March 2021 included a question about COVID-19 vaccination status. RESULTS: We received 788 responses, 71% from PWE (n = 559) and 29% (n=229) from caregivers of persons with epilepsy. A third (n = 308) of respondents reported a change in their health or in the health of the person they care for. Twenty-seven percent (n = 210) reported issues related to worsening mental health. Of respondents taking ASMs (n = 769), 10% (n= 78) reported difficulty taking medications on time, mostly due to stress causing forgetfulness. Less than half of respondents received counseling on mental health and stress. Less than half of the PWE reported having discussions with their healthcare providers about sleep, ASMs and potential side effects, while a larger proportion of caregivers (81%) reported having had discussions with their healthcare providers on the same topics. More PWE and caregivers reported that COVID-19 related measures caused adverse impact on their health in the post-vaccine period than during the pre-vaccine period, citing mental health issues as the primary reason. SIGNIFICANCE: Our findings indicate that the impact of the COVID-19 pandemic in the US on PWE is multifaceted. Apart from the increased risk of poor COVID-19 outcomes, the pandemic has also had negative effects on mental health and self-management. Healthcare providers must be vigilant for increased emotional distress in PWE during the pandemic and consider the importance of effective counseling to diminish risks related to exacerbated treatment gaps.

Evidence that nuclear receptors are related to terpene synthases.

Ligand-activated nuclear receptors (NRs) orchestrate development, growth, and reproduction across all animal lifeforms - the Metazoa - but how NRs evolved remains mysterious. Given the NR ligands including steroids and retinoids are predominantly terpenoids, we asked whether NRs might have evolved from enzymes that catalyze terpene synthesis and metabolism. We provide evidence suggesting that NRs may be related to the terpene synthase (TS) enzyme superfamily. Based on over 10,000 3D structural comparisons, we report that the NR ligand-binding domain and TS enzymes share a conserved core of seven α-helical segments. In addition, the 3D locations of the major ligand-contacting residues are also conserved between the two protein classes. Primary sequence comparisons reveal suggestive similarities specifically between NRs and the subfamily of cis-isoprene transferases, notably with dehydrodolichyl pyrophosphate synthase and its obligate partner, NUS1/NOGOB receptor. Pharmacological overlaps between NRs and TS enzymes add weight to the contention that they share a distant evolutionary origin, and the combined data raise the possibility that a ligand-gated receptor may have arisen from an enzyme antecedent. However, our findings do not formally exclude other interpretations such as convergent evolution, and further analysis will be necessary to confirm the inferred relationship between the two protein classes.

Impact of the COVID-19 pandemic on people with epilepsy: Findings from the Brazilian arm of the COV-E study.

The COVID-19 pandemic has had an unprecedented impact on people and healthcare services. The disruption to chronic illnesses, such as epilepsy, may relate to several factors ranging from direct infection to secondary effects from healthcare reorganization and social distancing measures. OBJECTIVES: As part of the COVID-19 and Epilepsy (COV-E) global study, we ascertained the effects of COVID-19 on people with epilepsy in Brazil, based on their perspectives and those of their caregivers. We also evaluated the impact of COVID-19 on the care delivered to people with epilepsy by healthcare workers. METHODS: We designed separate online surveys for people with epilepsy and their caregivers. A further survey for healthcare workers contained additional assessments of changes to working patterns, productivity, and concerns for those with epilepsy under their care. The Brazilian arm of COV-E initially collected data from May to November 2020 during the country's first wave. We also examined national data to identify the Brazilian states with the highest COVID-19 incidence and related mortality. Lastly, we applied this geographic grouping to our data to explore whether local disease burden played a direct role in difficulties faced by people with epilepsy. RESULTS: Two hundred and forty-one people returned the survey, 20% were individuals with epilepsy (n = 48); 22% were caregivers (n = 53), and 58% were healthcare workers (n = 140). Just under half (43%) of people with epilepsy reported health changes during the pandemic, including worsening seizure control, with specific issues related to stress and impaired mental health. Of respondents prescribed antiseizure medication, 11% reported difficulty taking medication on time due to problems acquiring prescriptions and delayed or canceled medical appointments. Only a small proportion of respondents reported discussing significant epilepsy-related risks in the previous 12 months. Analysis of national COVID-19 data showed a higher disease burden in the states of Sao Paulo and Rio de Janeiro compared to Brazil as a whole. There were, however, no geographic differences observed in survey responses despite variability in the incidence of COVID-19. CONCLUSION: Our findings suggest that Brazilians with epilepsy have been adversely affected by COVID-19 by factors beyond infection or mortality. Mental health issues and the importance of optimal communication are critical during these difficult times. Healthcare services need to find nuanced approaches and learn from shared international experiences to provide optimal care for people with epilepsy as the direct burden of COVID-19 improves in some countries. In contrast, others face resurgent waves of the pandemic.

Correction: Bypassing the requirement for aminoacyl-tRNA by a cyclodipeptide synthase enzyme.

[This corrects the article DOI: 10.1039/D0CB00142B.].

Bypassing the requirement for aminoacyl-tRNA by a cyclodipeptide synthase enzyme.

Cyclodipeptide synthases (CDPSs) produce a variety of cyclic dipeptide products by utilising two aminoacylated tRNA substrates. We sought to investigate the minimal requirements for substrate usage in this class of enzymes as the relationship between CDPSs and their substrates remains elusive. Here, we investigated the Bacillus thermoamylovorans enzyme, BtCDPS, which synthesises cyclo(l-Leu-l-Leu). We systematically tested where specificity arises and, in the process, uncovered small molecules (activated amino esters) that will suffice as substrates, although catalytically poor. We solved the structure of BtCDPS to 1.7 Å and combining crystallography, enzymatic assays and substrate docking experiments propose a model for how the minimal substrates interact with the enzyme. This work is the first report of a CDPS enzyme utilizing a molecule other than aa-tRNA as a substrate; providing insights into substrate requirements and setting the stage for the design of improved simpler substrates.

Evaluating risk to people with epilepsy during the COVID-19 pandemic: Preliminary findings from the COV-E study.

The COVID-19 pandemic has caused global anguish unparalleled in recent times. As cases rise, increased pressure on health services, combined with severe disruption to people's everyday lives, can adversely affect individuals living with chronic illnesses, including people with epilepsy. Stressors related to disruption to healthcare, finances, mental well-being, relationships, schooling, physical activity, and increased isolation could increase seizures and impair epilepsy self-management. We aim to understand the impact that COVID-19 has had on the health and well-being of people with epilepsy focusing on exposure to increased risk of seizures, associated comorbidity, and mortality. We designed two online surveys with one addressing people with epilepsy directly and the second for caregivers to report on behalf of a person with epilepsy. The survey is ongoing and has yielded 463 UK-based responses by the end of September 2020. Forty percent of respondents reported health changes during the pandemic (n = 185). Respondents cited a change in seizures (19%, n = 88), mental health difficulties (34%, n = 161), and sleep disruption (26%, n = 121) as the main reasons. Thirteen percent found it difficult to take medication on time. A third had difficulty accessing medical services (n = 154), with 8% having had an appointment canceled (n = 39). Only a small proportion reported having had discussions about epilepsy-related risks, such as safety precautions (16%, n = 74); mental health (29%, n = 134); sleep (30%, n = 140); and Sudden Unexpected Death in Epilepsy (SUDEP; 15%, n = 69) in the previous 12 months. These findings suggest that people with epilepsy are currently experiencing health changes, coupled with inadequate access to services. Also, there seems to be a history of poor risk communication in the months preceding the pandemic. As the UK witnesses a second COVID-19 wave, those involved in healthcare delivery must ensure optimal care is provided for people with chronic conditions, such as epilepsy, to ensure that avoidable morbidity and mortality is prevented during the pandemic, and beyond.

Paediatric sudden unexpected death in epilepsy: A parental report cohort.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) accounts for a large percentage of deaths in children with epilepsy. Contributing factors to paediatric SUDEP are incompletely understood. AIMS OF STUDY: The Epilepsy Deaths Register (EDR) is an anonymized register that compiles information on deaths related to epilepsy, across all ages and epilepsy classifications. Using the EDR, we sought to identify key risk factors for SUDEP in children to assist the development of preventive measures. METHODS: All registrations between the ages of 1 and 16 years were reviewed to identify definite or probable SUDEP. These cases were analysed to identify common demographics, comorbidities, monitoring, treatments and circumstances near to the deaths. RESULTS: We identified forty-six cases (27 males) of definite or probable SUDEP. Paediatric SUDEP is more common in a 12- to 16-year age group and in those with neuro-disability. Most paediatric SUDEP occurs during apparent sleep. There were four cases with a vagus nerve stimulator. SUDEP can occur early after the onset of seizures. CONCLUSIONS: This is the largest single cohort of SUDEP reported in children. Reports from caregivers can augment population data. Surveillance in sleep is a priority area of development.

Has the Time Come to Stratify and Score SUDEP Risk to Inform People With Epilepsy of Their Changes in Safety?

Recent publication of the American Academy of Neurology SUDEP guidance highlighted the importance to American clinicians of making people with epilepsy aware of SUDEP risk. It is the first guideline to do this in the United States. It follows precedent set out in the UK by National Institute of Clinical Excellence in 2004. While a significant achievement, the lack of clarity of how to deliver this guidance in an enduring and person-centered manner, raises concerns on how its long-term effectiveness in risk mitigation. Shared decision-making with an emphasis on delivering person-centered communication to foster self-management strategies is increasingly recognized as the ideal model of patient-clinician communication in chronic diseases such as epilepsy. The tension between delivering evidence-based risk information, yet, tailoring it to the individual is complex. It needs to incorporate the potential for change not only in seizure factors but also other health and social factors. Safety advice needs to be dynamic and situation sensitive as opposed to a "one off" discussion. As a significant minority of people with epilepsy have drug-resistant seizures, the importance of keeping the advice contextual at different intervals of the person's life cannot be overstated as many of them are managed in primary care. We present some exploratory work, which identifies the need to improve communication at a primary care level and to review risks regularly. Regular reviews using a structured risk factor checklist as a screening tool could identify, sooner, people who's health issues are worsening and justify referrals to specialists.

Digital Care in Epilepsy: A Conceptual Framework for Technological Therapies.

Epilepsy is associated with a significant increase in morbidity and mortality. The likelihood is significantly greater for those patients with specific risk factors. Identifying those at greatest risk of injury and providing expert management from the earliest opportunity is made more challenging by the circumstances in which many such patients present. Despite increasing recognition of the importance of earlier identification of those at risk, there is little or no improvement in outcomes over more than 30 years. Despite ever increasing sophistication of drug development and delivery, there has been no meaningful improvement in 1-year seizure freedom rates over this time. However, in the last few years, there has been an increase in patient-triggered interventions based on automated monitoring of indicators and risk factors facilitated by technological advances. The opportunities such approaches provide will only be realized if accompanied by current working practice changes. Replacing traditional follow-up appointments at arbitrary intervals with dynamic interventions, remotely and at the point and place of need provides a better chance of a substantial reduction in seizures for people with epilepsy. Properly implemented, electronic platforms can offer new opportunities to provide expert advice and management from first presentation thus improving outcomes. This perspective paper provides and proposes an informed critical opinion built on current evidence base of an outline techno-therapeutic approach to harnesses these technologies. This conceptual framework is generic, rather than tied to a specific product or solution, and the same generalized approach could be beneficially applied to other long-term conditions.

Sudden unexpected death in epilepsy: measures to reduce risk.

This review looks at the strategies that may help to reduce the risk of sudden unexpected death in epilepsy beyond that of trying to achieve seizure cessation, which is not possible for up to 30% of patients with epilepsy. These strategies include seizure safety checklists, mobile phone technology, telehealth and various devices currently available or in development. We highlight interventions where there is evidence of benefit, and draw attention for the need both to involve patients with epilepsy in risk reduction and to improve communication with those at risk.

Developing an Evidence-Based Epilepsy Risk Assessment eHealth Solution: From Concept to Market.

INTRODUCTION: Sudden unexpected death in epilepsy (SUDEP) is possibly the most common cause of death as a result of complications from epilepsy. The need to educate and regularly review risk for all patients with epilepsy is paramount, but rarely delivered in actual clinical practice. Evidence suggests that education around SUDEP and modifiable risk variables translate into better self-management of epilepsy. OBJECTIVE: We aimed to develop and implement an eHealth solution to support education and self-management of risks, in epilepsy. METHODS: We undertook an innovation pathways approach, including problem identification, feasibility assessment, design, implementation, and marketing. People with epilepsy were provided a smartphone-based app (Epilepsy Self-Monitor, EpSMon), which translates the clinical risk assessment tool into an educational and self-monitoring platform, for the self-management of epilepsy. RESULTS: Results include the success of the marketing campaign, and in what areas, with an estimated reach of approximately 38 million people. EpSMon has proved a success in academic and clinical circles, attracting awards and nominations for awards. The number of users of EpSMon, after 3 months, turned out to be lower than expected (N=221). A 4-month trial of the app in use in the United Kingdom, and the success of the marketing strategy, point to necessary changes to the model of delivery and marketing, summarized in this paper. These include the marketing message, user cost model, and need for the availability of an Android version. CONCLUSIONS: EpSMon has proven a success in respect to its reception by academics, clinicians, stakeholder groups, and the patients who use it. There is work needed to promote the model and increase its acceptability/attractiveness, including broadening the marketing message, increasing its availability, and reducing its cost. Future development and promotion of the tool will hopefully inform iterative design of its core features for a receptive audience and lead to increased uptake as it is launched worldwide in 2016.

Steps to prevent SUDEP: the validity of risk factors in the SUDEP and seizure safety checklist: a case control study.

Our objectives were to compare people with epilepsy (PWE) who died of sudden unexpected death in epilepsy (SUDEP) with live controls using the risk factor items of the SUDEP and Seizure Safety Checklist. All 48 SUDEPs of 93 epilepsy deaths which occurred in Cornwall UK 2004-2012 were compared to 220 live controls using the SUDEP and Seizure Safety Checklist, an evidenced based tool used to communicate person centered risk of SUDEP to PWE. The odds ratio for having a specific factor in those who died was compared to controls and ranked according to P value using a sequential Bonferroni correction for multiple comparisons. Of the 17 modifiable and non-modifiable risk factors analyzed 9 were statistically significant of which 7 are potentially modifiable. Well known modifiable factors such as nocturnal monitoring, compliance and sleeping position featured prominently in the risk association. This is the first case control study exploring the risk factors for SUDEP since 2009. The findings are compared to the current considered risk factors as identified in a major recent review. The study further validates certain SUDEP risk factors. It highlights that the majority of risk factors strongly associated with SUDEP are potentially modifiable. There is an emerging profile to rank the risk factors. It furthers the evidence to use structured risk assessment and communication tools such as the SUDEP and Seizure Safety Checklist in daily clinical practice. It highlights key areas for a person centered discussion to empower PWE to mitigate risk.

Safe and sound? A systematic literature review of seizure detection methods for personal use.

PURPOSE: The study aims to review systematically the quality of evidence supporting seizure detection devices. The unpredictable nature of seizures is distressing and disabling for sufferers and carers. If a seizure can be reliably detected then the patient or carer could be alerted. It could help prevent injury and death. METHODS: A literature search was completed. Forty three of 120 studies found using relevant search terms were suitable for systematic review which was done applying pre-agreed criteria using PRISMA guidelines. The papers identified and reviewed were those that could have potential for everyday use of patients in a domestic setting. Studies involving long term use of scalp electrodes to record EEG were excluded on the grounds of unacceptable restriction of daily activities. RESULTS: Most of the devices focused on changes in movement and/or physiological signs and were dependent on an algorithm to determine cut off points. No device was able to detect all seizures and there was an issue with both false positives and missed seizures. Many of the studies involved relatively small numbers of cases or report on only a few seizures. Reports of seizure alert dogs are also considered. CONCLUSION: Seizure detection devices are at a relatively early stage of development and as yet there are no large scale studies or studies that compare the effectiveness of one device against others. The issue of false positive detection rates is important as they are disruptive for both the patient and the carer. Nevertheless, the development of seizure detection devices offers great potential in the management of epilepsy.

Pancreaticoduodenectomy hospital resource utilization in octogenarians.

BACKGROUND: Although pancreaticoduodenectomy (PD) is feasible in patients greater than or equal to 80 years, little is known about the potential strain on resource utilization. METHODS: Outcomes and inpatient charges were compared across age cohorts (I: ≤70, II: 71 to 79, III: ≥80 years) in 99 patients who underwent PD (2005 to 2013) at our institution. The generalized linear modeling approach was used to estimate the impact of age. RESULTS: Perioperative complications were equivalent among cohorts. Increasing age was associated with intensive care unit use, increased length of stay (LOS), and the likelihood of discharge to a skilled facility. After controlling for covariates, hospital charges were significantly higher in Cohort III (P = .006) and Cohort II (P = .035) when compared with Cohort I. However, hospital charges between Cohorts II and III were equivalent (P = .374). Complications (P = .005) and LOS (P < .001) were associated with higher hospital charges. CONCLUSIONS: Increasing age was associated with increased intensive care unit, LOS, and discharge to skilled facilities. However, octogenarians had equivalent PD charges and outcome measures when compared with septuagenarians and future studies should validate these findings in larger national studies.

Keeping patients with epilepsy safe: a surmountable challenge?

This quality improvement project was inspired as an answer to a problem that intellectual disability teams have been struggling to manage whilst caring for people with epilepsy (PWE). The issue was that despite guidance to discuss the possibility of sudden unexpected death in epilepsy (SUDEP) be discussed with a newly diagnosed PWE this is rarely done. Additionally when, how, and what to discuss about SUDEP and reduce its risk is arbitrary, non-person centred, and with no structured evidence. Prior to initiating changes a discussion of SUDEP was recorded in just 10% of PWE. We introduced a check-list to help identify risk factors for SUDEP. We then modified the check-list, and then used it via telehealth, a way of contacting patients and their carers over the phone using the check-list approach. Following interventions, discussions of SUDEP are now recorded in 80% of PWE. Feedback from patients, carers and primary and secondary care professionals has been positive. We are now developing an app so that patients and carers can monitor their own risk factors, thus empowering them and increasing their knowledge and awareness of SUDEP.

Sudden unexpected death in epilepsy: addressing the challenges.

Epilepsy is associated with a higher rate of premature death than the general population, and the commonest cause of epilepsy mortality is sudden unexpected death in epilepsy (SUDEP). It is difficult to quantify because of the variable reporting of this cause of death. Death occurs due to autonomic deregulation of cardio-respiratory pathways as a result of seizures. Measures to reduce cardio-respiratory dysfunction are discussed together with the importance of seizure control in preventing SUDEP. The role of seizure detection devices, antiepileptic drugs and the importance of providing information about SUDEP to people with epilepsy are highlighted. There is increasing interest in SUDEP and some current initiatives are discussed.