Background: Improvements in daytime functioning ideally accompany improvements in insomnia. Scores on the Insomnia Severity Index (ISI) daytime-related items were analyzed following treatment with lemborexant (LEM), a dual orexin receptor antagonist, or placebo (PBO), based on baseline severity. Methods: Participants (≥18 y) with insomnia disorder in E2006-G000-303, a 12-month, randomized, double-blind, PBO-controlled study (first 6 months: Treatment Period 1 [TP1]), were randomized to PBO or LEM 5 mg (LEM5) or 10 mg (LEM10) for 6 months. ISI items are rated 0 (no problem) to 4 (very severe problem); daytime-related ISI items have a maximum score of 16. Results: Of 949 participants, 749 (78.9%) completed the ISI at baseline and end of TP1. Baseline daytime ISI total score distributions were similar between groups. More participants with baseline scores of 9-12 and 13-16 shifted to 0-4 with LEM5 (49.7% and 39.1%, respectively) and LEM10 (46.2% and 46.3%) versus PBO (26.6% and 29.6%). Overall shift distributions were significantly different, favoring both LEM groups (P<0.01). LEM was well tolerated. Conclusions: More LEM-treated participants had improved daytime functioning, evidenced by the significantly larger number of participants whose scores moved into lower categories (ie, better sleep) versus PBO-treated participants, demonstrating additional value beyond improved sleep parameters.

Background: Traditional insomnia drugs enhance gamma-aminobutyric acid and are associated with abuse/dependence. Dual orexin-receptor antagonists (DORAs) represent an alternate mechanism promoting wakefulness, rather than inhibition. Nonclinical studies indicate DORAs do not demonstrate abuse potential. Nonetheless, based on human abuse potential (HAP) studies and lack of postmarketing data at approval, DORAs are Schedule 4 controlled substances. However, HAP studies may not predict real-world abuse-potential risk. Methods: Adverse events with preferred terms (PTs) of drug-withdrawal-syndrome, drug-abuse, and drug-dependence were evaluated from Eisai’s ongoing global postmarketing safety surveillance system in the US, Canada, and Japan (20/Dec/2019–30/Sep/2023) and the FDA Adverse Event Reporting System (FAERS; 01/Jan/2015–30/Jun/2023). In FAERS, reports of those PTs from DORAs (lemborexant/suvorexant/daridorexant) were compared with zolpidem and with benzodiazepines approved for patients with insomnia (estazolam/temazepam/triazolam). Results: Since lemborexant’s approval, few of the 3 PTs were reported in Eisai’s surveillance system (~0.15 cases per million patient-days of global exposure). Reports in FAERS for PTs of drug-withdrawal-syndrome, drug-abuse, and drug-dependence for DORAs (10,202 reports) were <0.1%/<0.1%/0.1%, respectively. Reports for benzodiazepines (5534 reports) were 0.8%/12.9%/3.7%, respectively, and 1.0%/9.1%/5.3% for zolpidem (18,330 reports), respectively. Conclusions: Abuse potential may be better represented by nonclinical studies and national surveillance systems, suggesting DORAs may not pose meaningful abuse potential and related risks.

Background: Despite efforts to advance equity, women face gender-based barriers in research, including fewer senior authorship and grant opportunities. We examined gender disparities in Canadian Institutes of Health Research (CIHR) funding for Canadian neurology divisions and departments. Methods: Data on CIHR grant recipients and metrics (duration, quantity, and contribution) within Canadian neurology divisions and departments (2008-2022) were acquired from the CIHR Funding Decisions Database. Gender-based differences in grant prevalence, duration, and contribution amount within neurology were calculated with subgroup analysis for Canadian neurologists and Project Grant awards. Results: 1604 grants were awarded to Canadian neurology divisions and departments between 2008-2022. Women received fewer grants (41.46%), less funding (p<0.0001), and shorter grant durations (p<0.0001) than men annually. Women comprised the minority of recipients (45.47%) and were less likely to be awarded grants (p<0.001) annually relative to men. Differences were consistent in subgroup analyses, except grant durations were equal across genders in Project Grant awards. Conclusions: Gender disparities persist in CIHR grant funding to Canadian neurology divisions and departments. Women receive fewer grants, lower contribution amounts, and are less likely to be recipients compared to men. Future work includes addressing gender differences and continuing to evaluate CIHR funding to provide equitable opportunities for women.

Background: Cancer survival rates in Canada have been improving, leading to a steady increase in the number of survivors entering the typical ages of dementia onset. Yet, some cancer treatments (e.g. chemotherapy) are neurotoxic and adversely affect normal brain functioning. We conducted a review to examine changes observed in brain imaging and cognitive measures in survivorship, and long-term risk of dementia among cancer survivors. Methods: 91 Primary studies were selected from PubMed. Inclusion criteria were studies investigating the changes in brain imaging, cognition, and future dementia risk among adult survivors who received chemotherapy. Study quality was assessed based on 1) prospective, controlled design, 2) sample size, and 3) validated imaging and cognitive metrics. Results: Imaging studies identified MRI-based structural grey and white matter changes and functional network changes among survivors. Cognitive studies reported heterogeneous impairments in attention, memory, and executive function. In studies that examined dementia risk among cancer survivors, 67% reported lower risk of dementia, while 33% reported no association or a higher risk. Conclusions: While short-term cognitive impairment with associated changes on brain imaging is widely reported, findings concerning future or long-term cognitive impairment are mixed. Studies are warranted to identify potential connections between short-term and long-term cognitive function after cancer treatment.

Background: Sex and gender are related but distinct determinants of disease, treatment response, and research reproducibility whose consideration is increasingly required for research funding. Nevertheless, the quality of sex and gender reporting in neurological randomized controlled trials (RCTs) remains unknown. Methods: This ongoing study of RCTs associated with Food and Drug Administration neurological drug approvals aims to determine the frequency of accurate reporting of RCT participants’ sex and gender. Secondary outcomes include changes in reporting over time and RCT design characteristics. Results: Preliminary analysis included 145 RCTs (153,410 participants) associated with 77 medications approved in 1985-2023, most commonly for epilepsy (19%), migraine (16%), and multiple sclerosis (16%). Sixty-six RCTs (45.5%) used sex-related terms appropriately. Nine RCTs (6.2%) reported gender accurately. Fifty-three RCTs (37%) used sex- or gender-related terms interchangeably. There are no statistically significant differences in the proportions of studies reporting sex and/or gender accurately when comparing those published until versus after 2017. No RCT reported sex or gender collection methods, definitions of sex or gender, or including sex or gender minority participants. Conclusions: Preliminary results suggest shortcomings in reporting sex and, especially, gender accurately and inclusively among neurological drug RCTs and no significant improvement thereof in recent years.

Background: We evaluated the accuracy of code strokes activations at two comprehensive stroke centres in Toronto, Canada. Methods: We conducted a multi-centre, retrospective cohort study of all adult patients seen as code stroke in emergency rooms (ER) of two comprehensive stroke centres (CSC) in Toronto, Canada between January 1, 2022 and Dec 31, 2022. We included cases where the code stroke was activated in the field by paramedics and where it was activated in the ER by a physician. We reported off-criteria code stroke activations as the proportion of code stroke activations that did not meet all criteria for activation, and described the criteria that were not met. Results: A total of 677 (61.9% paramedic) code strokes were seen at CSC1 and 439 (80.6% paramedic) at CSC2. At CSC1, 21.2% paramedic-activated and 38.6% ER-activated were off-criteria, and at CSC2, 14.2% paramedic-activated and 48.1% ER-activated code stroke were off-criteria. Most of these were due to incorrect assessment of the last seen normal time. Conclusions: One in five code strokes did not meet criteria for activation. Improving the accuracy of paramedic and ER assessment of last seen normal time may be an avenue to reduce off-criteria code stroke activations.

Background: Previous research demonstrates that for acute ischemic stroke (AIS) cases, rapid endovascular therapy (EVT) performance improves outcomes. This study provides updated metrics summarizing estimates for modified Rankin Scale (mRS) gains accrued by streamlining time to EVT. Methods: A systematic review and meta-analysis (MA) was conducted using electronic databases. Eligible studies reported time-benefit slope with times from AIS onset (or time last-seen-normal) to EVT commencement; the predictor was onset-to-groin (OTG) time. Primary and secondary outcomes were 90-day functional independence (mRS 0-2) and 90-day excellent function (mRS 0-1), respectively. Results: The five included studies showed increased chance of good outcome with each hour of pre-EVT time savings for mRS 0-2 for 0-270’ (OR 1.25, 95% CI 1.16-1.35, I2 40%) and 271-360’ time frame (1.22, 95% CI 1.12-1.33, I2 58%). For studies assessing mRS 0-1, pooled effect estimates were appropriate for the 0-270’ time frame (OR 1.34, 95% CI 1.19-1.51, I2 27%) and the 271-360’ time frame (OR 1.20, 95% CI 1.03-1.38, I2 60%). Conclusions: Each hour saved from AIS onset to EVT start is associated with a 22-25% increased odds of functional independence, a useful metric to inform patient-specific and systems planning decisions.

Background: Stroke incidence is rising among younger adults (≤65yrs). Modifiable and behavioural risk factors are linked to stroke; however, limited understanding of knowledge and behaviour exists around preventative/lifestyle medicine (LSM) among this patient population. Study aim was to assess younger adult stroke patients’ lifestyle knowledge, habits, and barriers. Methods: A cross-sectional design was employed. Data were collected through an online, self-reported survey following a routine stroke prevention clinic visit and analyzed using descriptive and inferential statistics. Results: Sample included 103 participants (56.3% women, 60% white, mean age 47.6, 54.5% prior stroke). Majority (63%) understood current healthy lifestyle recommendations around blood pressure, sleep, and alcohol use, but fewer (<24.3%) around exercise and diet. Almost 70% ate processed food weekly, with emotions and social/family situations influencing eating habits. Interestingly, despite not understanding the current recommendations, >80% exercised moderately (3.5d/wk) with work and family responsibilities as main barriers. Over 50% slept <7hrs/night, had moderate to high stress levels, and implemented different coping strategies (food, TV, video games, and exercise). Majority (82.4%) reported willingness to change habits. Conclusions: Our findings provide valuable insight on young adult stroke patients’ preventative/LSM-related knowledge, habits, and barriers and provide new opportunities for the development of brain care-related initiatives.

Background: Over the past decade, worldwide stroke incidence has been increasing among young adults (≤65years), which has implications during the most dynamic period of their life. There is a dearth of research exploring young adults stroke patients’ experiences, healthy lifestyle habits, preferences, and recommendations for brain care-related initiatives. The study aimed to gain knowledge and a deeper understanding of young adult stroke patients’ experiences, lifestyle habits, and support needs for brain care-related education and interventions. Methods: A descriptive qualitative study was used. Participants who took part in the quantitative phase of a larger mixed methods study (n=103 that expressed an interest in the qualitative phase, were invited to take part in semi-structured focus groups. Simultaneous data collection and analysis are being conducted. Data are being analyzed using inductive thematic analysis outlined by Braun and Clarke (2006). Results: Findings will be available by May 20, 2024. Conclusions: Study findings will be essential to 1) mobilize an understanding of young adult stroke patients’ lived experience; 2) reconceptualize the current model of stroke care and services that is traditionally geared towards older adults; and 3) inform the development of brain care-related education and interventions to meet the unique needs, priorities, and preferences of young adult stroke patients.

Background: Cerebral venous thrombosis (CVT) is a rare cause of stroke, with 10–15% of patients experiencing dependence or death. The role of endovascular therapy (EVT) in the management of CVT remains controversial and practice patterns are not well-known. Methods: We distributed a comprehensive 53-question survey to neurologists, neuro-interventionalists, neurosurgeons and other relevant clinicians globally from May 2023 to October 2023. The survey asked about practice patterns and perspectives on EVT for CVT and assessed opinions regarding future clinical trials. Results: The overall response rate was 31% (863 respondents from 2744 invited participants) across 61 countries. A majority (74%) supported use of EVT for certain CVT cases. Key considerations for EVT included worsening level of consciousness (86%) and other clinical deficits (76%). Mechanical thrombectomy with aspiration (22%) and stent retriever (19%) were the most utilized techniques, with regional variations. Post-procedurally, low molecular weight heparin was the predominant anticoagulant administered (40%), although North American respondents favored unfractionated heparin. Most respondents supported future trials of EVT (90%). Conclusions: Our survey reveals significant heterogeneity in approaches to EVT for CVT, highlighting the necessity for adequately powered clinical trials to guide standard-of-care practices.

Background: We tested the hypothesis that delivering remote ischemic conditioning (RIC) with an adjunct tissue reflectance sensor (TRS) device may be feasible in patients with acute ischemic stroke (AIS) and cerebral small vessel disease (cSVD). Methods: AIS patients with neurological deficits within 7 days of symptom onset were screened for moderate to severe cSVD. Eligible patients were randomized 2:1 to receive intervention RIC or sham RIC (7 days). The primary outcome measure was intervention feasibility. It was assessed as an intervention-related comfort by a 5-point Likert scale during each session (1-very uncomfortable, 5-very comfortable). The secondary outcome measure was assessment of TRS derived dermal blood concentration and blood oxygenation changes during RIC. Results: Forty-seven (32 intervention, 15 sham) patients were enrolled at a median (IQR) 39.7 (25-64) hours after symptom onset, with mean±SD age of 75±12 years, 22 (46.8%) were females and median baseline NIHSS of 5(3-7). The Likert scale was 3.5 (3-4) in the intervention group and 4 (4-5) in the sham group. The TRS derived blood concentration and blood oxygenation changes were proportionate in the intervention arm and absent in the sham arm. Conclusions: RIC treatment with TRS is feasible in patients with AIS+cSVD. The efficacy of RIC needs further assessment.

Background: Hyperacute stroke care demands rapid, coordinated care. Traditional metrics like Door-to-Needle time are pivotal but insufficient for capturing the complexity of endovascular stroke interventions. The SMILES collaboration aims to standardize and optimize protocols for door-to-intervention times, incorporating Crew Resource Management (CRM). Methods: The multidisciplinary initiative integrates both hospitals, ED, neurology, and QI teams. We employed a comprehensive approach: stakeholder engagement, simulation-based learning, process mapping, and literature review. Emphasis was placed on enhancing situational awareness, triage and prioritization, cognitive load management, role clarity, effective communication, and debriefing. Results: The collaboration led to PDSA cycles and development of refined stroke protocols. Interventions included: 1) A ’zero point survey’ for team pre-arrival briefings, enhancing situational awareness and role clarity; 2) Streamlined patient registration to reduce cognitive load and improve triage efficiency; 3) Direct transfer of patients to imaging. Additionally, digital tools were implemented to facilitate communication. Simulation sessions reinforced CRM principles, leading to improved team cohesion and operational performance. Conclusions: The SMILES initiative is grounded in CRM principles by standardizing protocols and emphasizing non-technical skills crucial for high-stakes environments. This improves outcomes but also fosters a culture of safety and efficiency. Future directions include an evaluation of these protocols’ impact on patient factors.

Background: Research consistently shows that adolescents transitioning from pediatric to adult care struggle. Although data looking at young adults with epilepsy is limited, research suggests that these adults tend to have higher rates of depression and anxiety, lower rates of medication compliance, and lower education. Methods: To better understand this population and their struggles, a retrospective chart review of 58 patients transferred from pediatric to adult care was done. Results: 39.7% of participants were lost to follow-up; 12 were temporarily lost (average 1.3 years) and 11 were permanently lost. Twenty-three participants admitted to medication non-compliance, with fifteen having break-through seizures. Of the 45 patients that filled out mental health assessments at initial visit, 28.9% met the threshold for major depressive disorder, and 56.6% of patients had symptoms of anxiety. Data found that at one-year follow-up, 60% of these patients had similar or worsened depression scores, and 64% had similar or worsened anxiety scores. Conclusions: The findings of this study are concerning and highlight the need for greater education and support for these adolescents. Specifically, patients need more education on the importance of consistent follow-ups and consistently taking medication. Findings also suggest the importance of assessing and addressing mental health concerns.

Background: Sedation in PICU masks physical exam findings, leading to diagnostic challenges. In adult models, electroencephalography can evaluate the brain’s response to sedation using feedforward connectivity and anteriorization of alpha hubs, proving useful for prognostication. Feasibility of model translation into pediatric population was assessed, with the hypothesis that the same markers of adaptive reconfiguration would correlate with a higher potential for recovering consciousness. Methods: Electroencephalograms from children undergoing sedation were analyzed for strength and direction of functional connectivity using the weighted and directed phase lag index. Target population was refined with an iterative inclusion criteria. We examined relationships between hub location reconfiguration, directed phase lag index, baseline Glasgow Coma Scale, and 3-month post-treatment Glasgow Outcome Scale-Extended. Results: Evaluation of 14 subjects showed promise in children aged 5-18 undergoing sedation with midazolam, dexmedetomidine, and propofol. Further analysis of five subjects revealed a correlation between adaptive reconfiguration during anesthesia and both higher baseline Glasgow Coma Scale and Glasgow Outcome Scale-Extended scores post-treatment. Conclusions: The findings indicate that the functional brain network connectivity model may have diagnostic and prognostic potential regarding children’s consciousness levels. While the initial data is promising, further analysis of six additional cases is pending and deemed essential to thoroughly evaluate the model’s efficacy.

Background: Medically refractory pediatric epilepsy is a disorder that can cause significant financial and physical burden. Although multiple treatments exist, cost-effectiveness remains unclear. We conducted a systematic review to assess cost-effectiveness of treatments for medically refractory pediatric epilepsy and to summarize key issues and areas for further inquiry. Methods: We searched MEDLINE and 6 other databases up to July 2022. We included partial and full economic evaluations (EEs) on treatments for medically refractory pediatric epilepsy. Pairs of reviewers independently screened the literature, extracted data, and assessed quality using the 24-item Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. We extracted data on study characteristics, health outcomes, model design, costs, and treatment characteristics. Results: We identified 37 eligible studies for analysis, 19 of which were partial EEs and 18 were full EEs. Study quality, outcomes reported, treatment comparators, and factors included in cost calculations were common influential factors in study results. Vagus nerve stimulation and cannabinoid oil were the most consistently cost-effective, in 6 of 7 and 1 of 2 studies, respectively. Other treatments were inconsistently cost-effective. Conclusions: The cost-effectiveness of treatments for medically refractory pediatric epilepsy was not definitive. Consistency in study design and inputs is necessary for future comparison of epilepsy treatment.

Background: People with epilepsy experience higher rates of cardiac arrhythmia and sudden death than the general population, with the highest risk in genetic epilepsies. Despite growing evidence of a possible cardiac contribution, routine cardiac screening for epilepsy patients is rarely performed. Methods: We performed a single center, retrospective review of patients with developmental epileptic encephalopathies caused by genetic variants expressed in the heart and brain. Clinical history, medications, age, and cardiac evaluation data were extracted. Results: Among 67 patients (56% female), 54 (81%) had at least one ECG. Twenty (37%) had an abnormal ECG. Forty-one had a repeat ECG: 8 showed persistent abnormalities, 7 resolution of abnormalities, and 7 a new abnormality. Five patients with an abnormality did not receive a follow up ECG. Two patients each had histories of cardiac arrest, syncope, and sudden death in a family member. Cardiac phenotypes differed in patients who experienced generalized tonic-clonic seizures and patients with epilepsy for 3+ years. Conclusions: Almost 1/3 of our high-risk epilepsy cohort had history of cardiac events or abnormalities on cardiac testing. Seizure type and epilepsy duration were associated with altered cardiac phenotypes. Since some findings were potentially clinically significant, routine cardiac screening of high-risk epilepsy patients may be warranted.

Background: Continuous spike and waves during slow-wave sleep (CSWS) is a childhood-onset epileptic encephalopathy that is characterized by clinical seizures, electrical status epilepticus during sleep (ESES), and neurocognitive regression. Early intervention can preserve neurocognitive development, and vagus nerve stimulator (VNS) therapy had positive outcomes in the few previously reported case reports. We present three patients with intractable CSWS unresponsive to medications, who had a positive response to VNS therapy. Methods: Review of clinical records of three pediatric patients diagnosed with CSWS were compared for selected clinical outcomes and electrographic data both prior to and in the years following the initiation of VNS therapy. Results: Three patients now aged 13, 16 and 20 years, were treated with VNS following intolerance and a lack of response to multiple medications (5-9) for CSWS. The ketogenic diet was not an option. The CSWS resolved in all three patients, resulting in improved cognitive function. Patient 3 had resurgence of CSWS on EEG when the VNS settings inadvertently reset to the factory settings and improved with adjustment in the cycling. Conclusions: In patients who are unresponsive to medication, VNS provides an alternative option for resolving CSWS to preserve and, in some cases, potentially restore neurocognitive function.

Background: Aromatic l-amino acid decarboxylase (AADC) deficiency is a metabolic disorder that causes deficient serotonin, dopamine, and catecholamine synthesis. How children respond to neurological insult post intracranial gene therapy remains underreported. We present a 10 year old girl with profound neurological injury after a brief in-hospital cardiac arrest, secondary to viral infection-induced respiratory failure, 4 years after gene therapy. Methods: Patient’s chart review included brain imaging, clinical notes, laboratory results, and treatment. Results: MRI showed symmetric abnormalities in the basal ganglia, thalami, cortex, and cerebellar hemispheres. CSF analysis showed homovanillic acid 27 nmol/L (reference range 167-563) and 5-hydroxyindoleacetic acid 7 nmol/L (reference range 67-189). She developed generalized dystonia and oculogyric crises which were not seen since before gene therapy. There was poor catecholamine production causing refractory hypotension. She required a one-month stay in ICU for hypotension and status dystonicus. Dystonia was controlled with high doses of 6 agents. Conclusions: We describe a patient with AADC deficiency post gene therapy who experienced disproportionately severe neurological injury and decreased AADC activity after hypoxic neurological insult. There may be unique considerations of dopaminergic neuron integrity, AADC gene promoter sensitivity, and cerebrovascular autoregulation in children with AADC deficiency post gene therapy.

Background: Deep Brain Stimulation (DBS) has become increasingly prevalent in the management of paediatric movement disorders, with the globus pallidus interna (GPi) serving as the most utilized target. However, limitations exist, including variable responses in genetic versus acquired forms of movement disorder and structural damage in the GPi would preclude its use as a target. Given these limitations, there is a pressing need to explore alternative targets. We investigated the application of non-GPi targets in paediatrics through a systematic review. Methods: Individual data points were gathered from references identified through a systematic electronic search and analysed descriptively. We included paediatric patients (0-18 years) with movement disorders who underwent non-GPi-DBS. We excluded adults and other indications. Results: Preliminarily, 64 patients were identified from 40 references. Dystonia was the most common movement disorder type, followed by tremor and chorea. The subthalamic nucleus was the frequent DBS target for dystonia, yielding promising outcomes of improvement as measured on the Burke-Fahn-Marsden movement scale ranging from 43% to 95%. The ventral intermediate nucleus was the second most employed target, demonstrating favourable results. Conclusions: Non-pallidal DBS targets hold promise as potentially efficient and safe. However, to further validate their effectiveness and safety, larger multi-centre randomized studies are required.

Background: Children with neurological injuries/insults carry the highest risk of death and disability in Pediatric and Neonatal ICUs. These patients comprise 25-30% of admissions and have a myriad of diagnoses. Longitudinal outcome data is required to inform treatment effects and innovation strategies. NCC at the Alberta Children’s Hospital (ACH) participates in acute, subacute, and long-term/outpatient management with an aim to use comprehensive clinical data to improve outcomes. Methods: A prospective, longitudinal, population-based observational cohort study of NCC patients from local NICUs, PICU, and a NCC follow-up program, with comprehensive data from clinical records, development scores and QoL assessments. Results: Since 2019, 929 patients have been enrolled including: 407 neonates, 167 infants, 106 preschool-age and 100 school-age children, and 152 adolescents. The most common reasons for NCC consult were paroxysmal events (36%), encephalopathy (27%) and neonatal HIE (20%). Conclusions: Our database encapsulates the diverse nature of NCC patients and has enabled cohort-specific studies (e.g., neonatal HIE and ECLS outcomes). Program evolution will further facilitate higher powered research studies through large enrollment, comprehensive data capture (with a provincial EHR), and longitudinal outcomes. Engagement with staff and families will also inform treatment and afford evidence-based counseling to families.