Two-year mortality and seizure recurrence following status epilepticus in Auckland, New Zealand: A prospective cohort study.

PURPOSE: To document the 2-year mortality and seizure recurrence rate of a prospective cohort of patients identified with status epilepticus (SE). METHODS: Patients presenting to any hospital in the Auckland region between April 6 2015, and April 5 2016, with a seizure lasting 10 min or longer were identified. Follow up was at 2 years post index SE episode via telephone calls and detailed review of clinical notes. RESULTS: We identified 367 patients with SE over the course of one year. 335/367 (91.3 %) were successfully followed up at the 2-year mark. Two-year all-cause mortality was 50/335 (14.9 %), and 49/267 (18.4 %) when febrile SE was excluded. Two-year seizure recurrence was 197/335 (58.8 %). On univariate analyses, children (preschoolers 2 to < 5 years and children 5 to < 15 years), Asian ethnicity, SE duration <30 mins and acute (febrile) aetiology were associated with lower mortality, while older age >60 and progressive causes were associated with higher mortality on both univariate and multivariate analyses. Age < 2 years and acute aetiology were associated with lower seizure recurrence, while non convulsive status epilepticus (NCSE) with coma and a history of epilepsy were associated with higher seizure recurrence. On multivariate analyses, a history of epilepsy, as well as having both acute and remote causes were associated with higher seizure recurrence. CONCLUSIONS: All-cause mortality in both the paediatric and adult populations at 2 years was lower than most previous reports. Older age, SE duration ≥30 mins and progressive aetiologies were associated with the highest 2-year mortality, while febrile SE had the lowest mortality. A history of epilepsy, NCSE with coma, and having both acute and remote causes were associated with higher seizure recurrence at 2 years. Future studies should focus on functional measures of outcome and long-term quality of life.

Early Use of Aspirin for Coronary Allograft Prophylaxis in Heart Transplant Recipients.

BACKGROUND: Coronary allograft vasculopathy (CAV) remains a significant cause of morbidity and mortality after heart transplantation. The use of aspirin for CAV prophylaxis has recently garnered interest as a possible therapeutic adjunct in this setting. METHODS: This 2-center retrospective cohort study included 372 patients who underwent heart transplantation between January 2009 and March 2018 and were stratified according to the commencement of aspirin during their index transplant admission. The primary outcome was the development of moderate or severe CAV (International Society for Heart and Lung Transplantation grade ≥2) at surveillance coronary angiography. Secondary endpoints included mortality at follow-up. RESULTS: There were no differences in age, sex, and cause of heart failure. In the early aspirin group, the preponderant risk factors included use of ventricular assist devices, pretransplant smoking, and mild or moderate rejection. Multivariable analyses to assess for independent predictors of CAV development and mortality demonstrated that aspirin was associated with reduced mortality (adjusted hazard ratio = 0.19; 95% confidence interval, 0.08-0.47, P < 0.01) and a trend toward a protective effect against the development of moderate or severe CAV (adjusted hazard ratio = 0.24; 95% confidence interval, 0.54-1.19; P = 0.08). CONCLUSIONS: In this retrospective risk-adjusted 2-center cohort study, early aspirin administration was associated with reduced risk of death and a trend toward a protective effect against CAV development. These findings warrant validation in prospective randomized trials.

Status epilepticus in Auckland, New Zealand: Treatment patterns and determinants of outcome in a prospective population-based cohort.

OBJECTIVE: Determination of the real-world performance of a health care system in the treatment of status epilepticus (SE). METHODS: Prospective, multicenter population-based study of SE in Auckland, New Zealand (NZ) over 1 year, with data recorded in the EpiNet database. Focus on treatment patterns and determinants of SE duration and 30-day mortality. The incidence, etiology, ethnic discrepancies, and seizure characteristics of this cohort have been published previously. RESULTS: A total of 365 patients were included in this treatment cohort; 326 patients (89.3%) were brought to hospital because of SE, whereas 39 patients (10.7%) developed SE during a hospital admission for another reason. Overall, 190 (52.1%) had a known history of epilepsy and 254 (70.0%) presented with SE with prominent motor activity. The mean Status Epilepticus Severity Score (STESS) was 2.15 and the mean SE duration of all patients was 44 min. SE self-terminated without any treatment in 84 patients (22.7%). Earlier administration of appropriately dosed benzodiazepine in the pre-hospital setting was a major determinant of SE duration. Univariate analysis demonstrated that mortality was significantly higher in older patients, patients with longer durations of SE, higher STESS, and patients who developed SE in hospital, but these did not maintain significance with multivariate analysis. There was no difference in the performance of the health care system in the treatment of SE across ethnic groups. SIGNIFICANCE: When SE was defined as 10 continuous minutes of seizure, overall mortality was lower than expected and many patients had self-limited presentations for which no treatment was required. Although there were disparities in the incidence of SE across ethnic groups there was no difference in treatment or outcome. The finding highlights the benefit of a health care system designed to deliver universal health care.

HeartMate 3 implantation with an emphasis on the biventricular configuration.

OBJECTIVES: Right ventricular failure following implantation of a durable left ventricular assist device (LVAD) is a major driver of mortality. Reported survival following biventricular (BiVAD) or total artificial heart (TAH) implantation remains substantially inferior to LVAD alone. We report our outcomes with LVAD and BiVAD HeartMate 3 (HM3). METHODS: Consecutive patients undergoing implantation of an HM3 LVAD between November 2014 and December 2021, at The Alfred, Australia were included in the study. Comparison was made between the BiVAD and LVAD alone groups. RESULTS: A total of 86 patients, 65 patients with LVAD alone and 21 in a BiVAD configuration underwent implantation. The median age of the LVAD and BiVAD groups was 56 years (Interquartile range 46-62) and 49 years (Interquartile range 37-55), respectively. By 4 years after implantation, 54% of LVAD patients and 43% of BiVAD patients had undergone cardiac transplantation. The incidence of stroke in the entire experience was 3.5% and pump thrombosis 5% (all in the RVAD). There were 14 deaths in the LVAD group and 1 in the BiVAD group. The actuarial survival for LVAD patients at 1 year was 85% and BiVAD patients at 1 year was 95%. CONCLUSIONS: The application of HM 3 BiVAD support in selected patients appears to offer a satisfactory solution to patients requiring biventricular support.

Female sex steroids and epilepsy: Part 2. A practical and human focus on catamenial epilepsy.

Catamenial epilepsy is the best described and most researched sex steroid-specific seizure exacerbation. Yet despite this there are no current evidence-based treatments, nor an accepted diagnostic tool. The best tool we currently have is tracking seizures over menstrual cycles; however, the reality of tracking seizures and menstrual cycles is fraught with challenges. In Part 1 of this two-part review, we outlined the often complex and reciprocal relationship between seizures and sex steroids. An adaptable means of tracking is required. In this review, we outline the extent and limitations of current knowledge on catamenial epilepsy. We use sample data to show how seizure exacerbations can be tracked in short/long and even irregular menstrual cycles. We describe how seizure severity, an often overlooked and underresearched form of catamenial seizure exacerbation, can also be tracked. Finally, given the lack of treatment options for females profoundly affected by catamenial epilepsy, Section 3 focuses on current methods and models for researching sex steroids and seizures as well as limitations and future directions. To permit more informative, mechanism-focused research in humans, the need for both a consistent classification of catamenial epilepsy and an objective biomarker is highlighted.

Female sex steroids and epilepsy: Part 1. A review of reciprocal changes in reproductive systems, cycles, and seizures.

Seizures, antiseizure medications, and the reproductive systems are reciprocally entwined. In Section 2 of this review, we outline how seizures may affect the hypothalamic-pituitary-gonadal axis, thereby altering sex steroids, and changes in sex steroids across the menstrual cycle and changes in pharmacokinetics during pregnancy may alter seizure susceptibility. The literature indicates that females with epilepsy experience increased rates of menstrual disturbances and reproductive endocrine disorders. The latter include polycystic ovary syndrome, especially for females on valproate. Studies of fertility have yielded mixed results. We aim to summarize and attempt to detangle the existing knowledge on these reciprocal interactions. The menstrual cycle causes changes in seizure intensity and frequency for many females. When this occurs perimenstrually, during ovulation, or in association with an inadequate luteal phase, it is termed catamenial epilepsy. There is a clear biophysiological rationale for how the key female reproductive neurosteroids interact with the brain to alter the seizure threshold, and Section 3 outlines this important relationship. Critically, what remains unknown is the specific pathophysiology of catamenial epilepsy that describes why not all females are affected. There is a need for mechanism-focused investigations in humans to uncover the complexity of the relationship between reproductive hormones, menstrual cycles, and the brain.

Circannual seizure provocation as the day lengthens in the northern and southern hemispheres.

Circannual status epilepticus (SE) patterns in communities near Earth's poles best test the hypothesis that SE susceptibility varies with light exposure because these communities are routinely subject to large changes in annual light exposure, which may result in changes to daily sleep time. We compared northern hemispheric circannual SE occurrence in Kivalliq, Canada (latitude-62.8° N) to southern hemispheric Auckland, New Zealand (latitude-36.9° S). Instead of peaking at a similar calendar time, SE peaked at a similar solar time during the increasing daylight phase after each region's respective winter solstice. This demonstrates that cumulative effects of increasing light exposure can mediate SE susceptibility.

Distinct characteristics of microglia from neurogenic and non-neurogenic regions of the human brain in patients with Mesial Temporal Lobe Epilepsy.

The study of microglia isolated from adult human brain tissue provides unique insight into the physiology of these brain immune cells and their role in adult human brain disorders. Reports of microglia in post-mortem adult human brain tissue show regional differences in microglial populations, however, these differences have not been fully explored in living microglia. In this study biopsy tissue was obtained from epileptic patients undergoing surgery and consisted of both cortical areas and neurogenic ventricular and hippocampal (Hp) areas. Microglia were concurrently isolated from both regions and compared by immunochemistry. Our initial observation was that a greater number of microglia resulted from isolation and culture of ventricular/Hp tissue than cortical tissue. This was found to be due to a greater proliferative capacity of microglia from ventricular/Hp regions compared to the cortex. Additionally, ventricular/Hp microglia had a greater proliferative response to the microglial mitogen Macrophage Colony-Stimulating Factor (M-CSF). This enhanced response was found to be associated with higher M-CSF receptor expression and higher expression of proteins involved in M-CSF signalling DAP12 and C/EBPß. Microglia from the ventricular/Hp region also displayed higher expression of the receptor for Insulin-like Growth Factor-1, a molecule with some functional similarity to M-CSF. Compared to microglia isolated from the cortex, ventricular/Hp microglia showed increased HLA-DP, DQ, DR antigen presentation protein expression and a rounded morphology. These findings show that microglia from adult human brain neurogenic regions are more proliferative than cortical microglia and have a distinct protein expression profile. The data present a case for differential microglial phenotype and function in different regions of the adult human brain and suggest that microglia in adult neurogenic regions are "primed" to an activated state by their unique tissue environment.

Spontaneous Coronary Artery Dissection in an Orthotopic Heart Transplant Recipient.

We present the case of acute myocardial infarction secondary to spontaneous coronary artery dissection in a patient 2 weeks post orthotopic heart transplantation. (Level of Difficulty: Advanced.).

Incidence and Predictors of Eosinophilic Myocardial Hypersensitivity in Patients Receiving Home Dobutamine.

ABSTRACT: We sought to examine incidence and predictors of eosinophilic myocardial hypersensitivity (EMH) in a cohort of patients in the home inotrope program of a quaternary cardiac transplant center. Patients on home inotropes with progression to heart transplantation or ventricular assist device (VAD) between January 2000 and May 2020 were included. EMH was diagnosed by the presence of an interstitial predominate eosinophilic infiltrate within the myocardium by experienced cardiac pathologists. From a cohort of 74 patients, 58% (43) were on dobutamine and 42% (31) were on milrinone. Dobutamine was associated with EMH incidence of 14% (6/43), with zero cases in the milrinone cohort. Mean age was 52 ± 12 years, 22% were female. More than half (62%) were nonischemic dilated cardiomyopathies, the remainder were ischemic cardiomyopathy. Dobutamine dose [250 (200-282) vs. 225 (200-291) µg/min] and duration of therapy [41 (23-79) vs. 53 (24-91) days] was similar between those with and without EMH. Median change in eosinophil count was 0.31 × 10 9 /L in the EMH group compared with only 0.03 × 10 9 /L in the non-EMH cohort, P = 0.02. Increase in peripheral eosinophil count of >0.20 × 10 9 /L demonstrated good discrimination between those with and without EMH, c-statistic 0.83 (95% CI 0.66-1.0). Heart failure hospitalization occurred in 83% of the EMH group versus 59% in the non-EMH group, P = 0.26. Requirement for VAD was significantly higher in the EMH group (83% vs. 41%, P = 0.05). In conclusion, EMH occurred in 14% of patients receiving home dobutamine. Rising eosinophil count should prompt physicians to consider EMH and switch to milrinone to avoid possible escalation to VAD.

Vasoplegia Following Orthotopic Heart Transplantation: Prevalence, Predictors and Clinical Outcomes.

BACKGROUND: Patients undergoing heart transplant are at high risk for postoperative vasoplegia. Despite its frequency and association with poor clinical outcomes, there remains no consensus definition for vasoplegia, and the predisposing risk factors for vasoplegia remain unclear. Accordingly, the aim of this study was to evaluate the prevalence, predictors, and clinical outcomes associated with vasoplegia in a contemporary cohort of patients undergoing heart transplantation. METHODS: This was a retrospective cohort study of patients undergoing heart transplantation from January 2015 to December 2019. A binary definition of vasoplegia of a cardiac index of 2.5 L/min/m2 or greater and requirement for norepinephrine (≥5 µg/min), epinephrine (≥4 µg/min), or vasopressin (≥1 unit/h) to maintain a mean arterial blood pressure of 65 mm Hg, for 6 consecutive hours during the first 48 hours postoperatively, was used in determining prevalence. Given the relatively low threshold for the binary definition of vasoplegia, patients were divided into tertiles based on their cumulative vasopressor requirement in the 48 hours following transplant. Outcomes included all-cause mortality, intubation time, intensive care unit length of stay, and length of total hospitalization. RESULTS: After exclusion of patients with primary cardiogenic shock, major bleeding, or overt sepsis, data were collected on 95 eligible patients. By binary definition, vasoplegia incidence was 66.3%. We separately stratified by actual vasopressor requirement tertile (high, intermediate, low). Stratified by tertile, patients with vasoplegia were older (52.7 ± 10.2 vs 46.8 ± 12.7 vs 44.4 ± 11.3 years, P = .02), with higher rates of chronic kidney disease (18.8% vs 32.3% vs 3.1%, P = .01) and were more likely to have been transplanted from left ventricular assist device support (n = 42) (62.5% vs 32.3% vs 37.5%, P = .03). Cardiopulmonary bypass time was prolonged in those that developed vasoplegia (155 min [interquartile range 135-193] vs 131 min [interquartile range 117-152] vs 116 min [interquartile range 102-155], P = .003). Intubation time and length of intensive care unit and hospital stay were significantly increased in those that developed vasoplegia; however, this difference did not translate to a significant increase in all-cause mortality at 30 days or 1 year. CONCLUSIONS: Vasoplegia occurs at a high rate after heart transplantation. Older age, chronic kidney disease, mechanical circulatory support, and prolonged bypass time are all associated with vasoplegia; however, this study did not demonstrate an associated increase in all-cause mortality LAY SUMMARY: Patients undergoing heart transplantation are at high risk of vasoplegia, a condition defined by low blood pressure despite normal heart function. We found that vasoplegia was common after heart transplant, occurring in 60%-70% of patients after heart transplant after excluding those with other causes for low blood pressure. Factors implicated included age, poor kidney function, prolonged cardiopulmonary bypass time and preoperative left ventricular assist device support. We found no increased risk of death in patients with vasoplegia despite longer lengths of stay in intensive care and in hospital.

Levosimendan and Continuous Outpatient Support With Inotropes in Patients With Advanced Heart Failure: A Single-Centre Descriptive Study.

ABSTRACT: To describe the use of levosimendan in a quaternary referral center with a dedicated heart failure service and compare its efficacy and safety to continuous outpatient support with inotropes (COSI) among patients with advanced heart failure (AHF) who require bridge-to-decision (BTD) or bridge-to-transplant (BTT) therapy. This study was a retrospective, single-center, descriptive study of patients with AHF who received either a single levosimendan infusion or COSI between 2018 and 2021. A total of 23 patients received a levosimendan infusion, and 14 were started on COSI. Three indications for levosimendan were identified: (1) to facilitate weaning of continuous inotropes, (2) to augment diuresis in cardiorenal syndrome, and (3) as first-line therapy for cardiogenic shock in selected patients. Eighty-three percent (19 of 23) of patients who received levosimendan survived to discharge, and there were few clinically significant adverse events. Overall survival at 12 months among patients who received levosimendan was 74%. No statistically significant difference in survival was observed at 12 months (P = 0.68) or beyond (P = 0.63) between patients who received levosimendan and were discharged with a plan for BTD or BTT and those who received COSI. Levosimendan is a safe and effective short-term therapy in AHF and offers comparable long-term survival to COSI in patients who require BTD or BTT therapy.

Identifying Neural Progenitor Cells in the Adult Human Brain.

The discovery, in 1998, that the adult human brain contains at least two populations of progenitor cells and that progenitor cells are upregulated in response to a range of degenerative brain diseases has raised hopes for their use in replacing dying brain cells. Since these early findings, the race has been on to understand the biology of progenitor cells in the human brain, and they have now been isolated and studied in many major neurodegenerative diseases. Before these cells can be exploited for cell replacement purposes, it is important to understand how to (1) locate them, (2) label them, (3) determine what receptors they express, (4) isolate them, and (5) examine their electrophysiological properties when differentiated. In this chapter we have described the methods we use for studying progenitor cells in the adult human brain and in particular the tissue processing, immunohistochemistry, autoradiography, progenitor cell culture, and electrophysiology on brain cells. The Neurological Foundation of New Zealand Human Brain Bank has been receiving human tissue for approximately 25 years during which time we have developed a number of unique ways to examine and isolate progenitor cells from resected surgical specimens as well as from postmortem brain tissue. There are ethical and technical considerations that are unique to working with human brain tissue, and these, as well as the processing of this tissue and the culturing of it for the purpose of studying progenitor cells, are the topic of this chapter.

Postdischarge Functional Capacity, Health-Related Quality of Life, Depression, Anxiety, and Post-traumatic Stress Disorder in Patients Receiving a Long-term Left Ventricular Assist Device.

BACKGROUND: There is a paucity of data on depression, anxiety and post-traumatic stress disorder after left ventricular assist device (LVAD) implantation. We designed an observational study to integrate these with functional capacity and health-related quality of life (HR-QOL) in surviving LVAD patients. METHODS AND RESULTS: Consenting patients between 1 month and 9 years after LVAD implantation (n = 121) were screened for functional capacity (World Health Organization Disability Assessment Schedule 2.0 [WHODAS 2.0)]); HR-QOL (European Quality of Life [EQ-5D] and Visual Assessment Scales [EQ-VAS]), depression (Patient Health Questionnaire [PHQ-9], anxiety (Generalized Anxiety Disorder Scale [GAD-7]) and post-traumatic stress disorder (Impact of Event Scale Revised [IES-R]). Of the 94% of patients who consented, 34.7% reported impaired functional capacity (WHODAS 2.0 score of ≥25%), 23.1%-34.7% HR-QOL problems (domain EQ-5D of ≥3), 10.7% "poor health" (EQ-VAS of ≤40), 14.9% depression (PHQ-9 of >14), 11.7% suicidal ideation and 17.5% anxiety (GAD-7 of >10). Among these patients, 23.5% had a positive screen for post-traumatic stress disorder (IES-R of ≥24). An EQ-VAS of 80 or greater predicted good functional capacity (P < .001). CONCLUSIONS: One-third of discharged LVAD patients reported impaired function, HR-QOL, and psychological issues. A standardized evaluation before and after LVAD implantation could facilitate psychologic prehabilitation, inform decision-making, and identify indications for mental health intervention.

The effects of vitamin E supplementation on malondialdehyde as a biomarker of oxidative stress in haemodialysis patients: a systematic review and meta-analysis.

BACKGROUND: Haemodialysis (HD) patients tend to have higher levels of oxidative stress (OS), associated with increased morbidity and premature mortality, compared to the general population. Levels of malondialdehyde (MDA), a biomarker of OS, are reduced by the antioxidant properties of vitamin E (VE) but outcomes from randomised control trials of VE supplementation on MDA in HD patients have been inconsistent. METHODS: We undertook a systematic review and meta-analysis of adult HD patients from VE supplementation studies with measures of MDA. The following search criteria of MEDLINE and EMBASE were considered from inception to January 2020: 'dialysis' AND 'Vitamin E OR tocopherol' AND 'malondialdehyde OR MDA'. Two reviewers independently extracted study data and assessed risk of bias. Mean MDA levels and standard deviation were determined before and after VE supplementation. Standardised mean difference (SMD) and standard error were calculated as the within person difference and units of measure were not consistently recorded across all studies. The SMD were pooled using random effects meta-analysis. RESULTS: The SMD of MDA levels from 18 comparisons was significantly lower in HD patients following VE supplementation (- 1.55; confidence interval: - 2.17 to - 0.94, P < 0.00001). There were significant levels of heterogeneity between studies (I2 value = 91%; P < 0.00001) with evidence of potential publication bias toward smaller studies. CONCLUSIONS: Our findings support the use of VE to reduce the effects of OS in HD patients although high levels of heterogeneity and variation in the methodological approaches used by some studies highlight the need for further investigation.

Part 1: The Wider Considerations in Translating Heart Failure Guidelines.

Congestive Heart Failure (CHF) is an emerging epidemic. Within one generation, the medical community has learned much of CHF syndromes. It has two distinct mechanisms, systolic and diastolic abnormalities, to account for the common CHF presentation. It is complex as it challenges the available health care services, resource, and funding models in providing an equitable service across the health continuum. Despite the improvement in many cardiovascular diseases, some CHF outcomes like readmissions and costs have increased. The reinvigoration of evidence- based medicine, the development of health services models of care, and standardisation of disease processes with taxonomies have also occurred within the same time span. These processes, however, need to be linked with health policy as presented in white papers. In this paper, we explore achieving optimal CHF guideline-recommended outcomes as the science approaches realworld translation.

The results of a single-center experience with HeartMate 3 in a biventricular configuration.

BACKGROUND: Right ventricular (RV) failure after left ventricular assist device (VAD) implantation is a difficult problem. One solution is the implantation of continuous-flow VADs in a biventricular configuration. Disappointing survival and a concerning incidence of right-sided pump thrombosis have been previously reported. METHODS: From May 2017 to April 2020, a total of 12 patients underwent implantation of HeartMate 3 (HM3) biventricular VADs (BiVADs) as a bridge to cardiac transplantation. The right-sided pump was implanted in the right atrium in all cases. Adverse events and patient outcomes were determined. RESULTS: Patients were male, and the mean age was 44 years. The etiology was dilated cardiomyopathy (6 patients), sarcoid heart disease (2 patients), ischemic cardiomyopathy (1 patient), anthracycline cardiomyopathy (1 patient), non-compaction cardiomyopathy (1 patient), and arrhythmogenic RV cardiomyopathy with biventricular involvement (1 patient). There was 1 death from multisystem failure. There were 3 episodes of right VAD thrombus (thrombosis or clot ingestion); 1 managed medically, 1 recognized intraoperatively treated with clot retrieval, and 1 requiring pump exchange. There were 3 driveline infections. At 18 months after the procedure, 5 patients (41.7%) had undergone cardiac transplantation, 5 patients (41.7%) were alive and on biventricular support, 1 patient had died (8.3%), and 1 patient had VAD explantation for myocardial recovery (8.3%). Actuarial survival at 18 months was 91.7%. CONCLUSIONS: In this small study, HM3 BiVAD in these critically ill patients was used with low mortality. This suggests that the timely deployment of biventricular support with HM3 can be associated with favorable outcomes.