Background: The effect of remote ischemic conditioning on cognitive and radiological outcomes in patients with cerebrovascular disease is uncertain. We performed a systematic review to evaluate the effects of remote ischemic conditioning on cognitive and radiological outcomes in patients with cerebrovascular diseases. Methods: A systematic search using relevant keywords and database specific terms was conducted in MEDLINE, Embase, and Web of Science from inception to October 27 2022. Results: A total of 4269 articles were screened, of which 20 were included. Ten papers assessing cognitive outcomes were included, with 5/10 reporting improvements in cognitive scores relative to a control group. Sixteen papers reporting on radiologic outcomes were included, three reporting on changes in infarct volume, and four on lesion volume. Improvement in infarct and lesion volume was reported in 1/3 studies and 4/4 studies respectively, however there was considerable variation in the time between assessments (range 1-365 days). Nine papers assessing blood flow changes were found, of which 3/8 using transcranial doppler reported improved blood flow velocity post intervention. Conclusions: The articles identified suggest that remote ischemic conditioning may provide improvement for both cognitive and radiological outcomes in patients with cerebrovascular diseases, however future well-designed studies are needed to determine degree of benefit.

Background: Occult bacterial infection is a proposed etiology of low back pain (LBP). However, a causative link between LBP and bacteria remains unconfirmed. Herein, we determined the incidence of occult discitis in patients receiving surgery for LDH. Methods: Study Design: prospective cohort study. Inclusion criteria: consecutive adult patients undergoing discectomy for symptomatic LDH. Exclusion criteria: prior epidural steroid use, prior spinal surgery, and antibiotic use within 2 weeks of surgery. Tissue samples: Four nuclear tissue and ligamentum flavum (control) samples were obtained per patient using stringent aseptic protocol. Samples underwent 16S-PCR and culturing. Results: Eighty-one patients were enrolled (mean age 43.3±13.3 years). All (100%) of tissue samples were negative by 16S PCR and no virulent species were detected. Nuclear and ligament cultures were both negative in 51 (62.9%) cases. Cultures were positive for nuclear tissue only, ligament only, or both in 14.8%, 12.3%, and 9.9% of cases, respectively. Fifteen of 20 (75%) disc positive samples grew a single colony of an indolent species. Conclusions: The findings of this prospective cohort study of consecutive patients receiving surgery for LDH do not support the theory of occult discitis. All samples were 16S-PCR negative, and most cultures were negative or grew a single colony suggestive of contamination.

This is the first of two articles reviewing consent in those under the age of 18 (also referred to as ‘minors’ in UK law). This can be a complex issue in clinical practice because the law endows competent/capacitated minors with the absolute right to accept treatment, but a limited right to refuse. This first article summarises recent cases of refusal of treatment in minors. It uses them to ask two central questions: how do we, as clinicians, think about autonomous self-determination in minors and to what extent does the rights agenda support minors’ autonomous self-determination? Autonomy as one of the principles of biomedical ethics is explored. How the minors’ rights agenda supports the development of autonomy is considered. The amount of weight given in the domestic courts to the rights of minors with reference to the Human Rights Act 1998 and the United Nations Convention on the Rights of the Child is described. These considerations demonstrate the way that the courts are giving the views of the minor greater weight in decision-making in keeping with age and maturity. This article introduces the second article, which comprehensively reviews decision-making in minors, explores competence and capacity in minors and examines the differential treatment of acceptance and refusal.

Background: Endoscopic endonasal surgeries performed in areas involving the visual pathway are associated with postoperative visual dysfunction. We previously demonstrated that continued eye monitoring during surgery by flash visual evoked potential (FVEP) represents a good method to prevent/reduce visual deficit post-surgery. We wondered whether FVEP monitoring may be more beneficial in patients with meningioma, strongly associated with postoperative visual loss.

The aim was to explore the visual capacity in patients subjected to meningioma resection at The Ottawa Hospital. Methods: A retrospective chart review of patients who underwent minimally invasive endoscopic skull base surgery and FVEP monitoring for meningioma resection (July 2018 to present) was conducted. Only patients with available pre- (up to 3 months) and post-surgery (1-9 months) visual evaluation were analyzed. Results: 40 eyes were included (20 patients). The median age was 61 years (range:43-84) and 90% of patients were female. The LogMAR visual acuity was not significantly modified post-surgery (from +0.25 to +0.21; p=0.7). Color vision (# errors reading Ishihara/16-plates) was not modified post-surgery (from 2.6 to 3.2; p=0.6). Visual field (Humphrey, 32-2) was not significantly modified post-surgery (from 78.1% to 81.9%; p=0.7). Conclusions: The prevention of visual pathway injury during surgery by FVEP monitoring prevents visual deficits after endoscopic meningioma resection.

Early adolescence is characterized by rapid changes in executive function and increased vulnerability to internalizing difficulties. The aim of this study was to explore whether internalizing symptoms are stable across early adolescence and to identify possible links with executive function. Using data from the Adolescent Brain and Cognitive Development Study (ABCD), we identified four dimensions of internalizing symptoms from item-level ratings on the Child Behavior Checklist at ages 10 (n = 10,841) and 12 (n = 5,846), with an invariant factor structure across time. These dimensions corresponded to anxiety, depression, withdrawal, and somatic problems. We then examined associations between these dimensions and three aspects of executive function at age 10 measured by the NIH Toolbox: inhibition, shifting and working memory. Worse shifting and inhibition at age 10 was associated with elevated symptoms of anxiety and withdrawal cross-sectionally, while poor inhibition was also uniquely associated with symptoms of depression. Longitudinal associations were more limited: Worse inhibition at age 10 predicted greater symptoms of withdrawal at age 12, while worse shifting predicted fewer symptoms of anxiety 2 years later. These findings suggest that poor executive function in early adolescence is associated with greater internalizing difficulties and poor inhibition may contribute to later social withdrawal.

Background: This analysis reports the impact of eptinezumab on work productivity and daily activities in patients with migraine and prior preventive treatment failures. Methods: The DELIVER study (NCT04418765) randomized adults with migraine and documented evidence of 2-4 prior preventive treatment failures to receive eptinezumab 100mg, 300mg, or placebo (IV every 12 weeks). At baseline and every 4 weeks, patients completed the migraine-specific 6-question Work Productivity Activity Impairment (WPAI:M) questionnaire (7-day recall). Changes from baseline in WPAI subscores were predefined secondary endpoints and analyzed without control for multiplicity. Results: The full analysis set included 890 patients (100mg, n=299; 300mg, n=293; placebo, n=298). Mean baseline WPAI subscores indicated a negative impact of migraine on work productivity and normal daily activities. Beginning at first post-baseline assessment at Week 4 and through Week 24, eptinezumab demonstrated larger reductions than placebo in absenteeism (P<0.05), presenteeism (P<0.001), work productivity loss (P<0.001), and activity impairment (P<0.001) subscores. Conclusions: In adults with migraine and prior preventive treatment failures, eptinezumab treatment robustly improved migraine-related absenteeism, presenteeism, work productivity loss, and activity impairment as early as Week 4 and throughout the study.

Historians have shown that philosophical discussions about the implications of relativity significantly shaped the development of European philosophy of science in the 1920s. Yet little is known about American debates from this period. This article maps the first responses to Einstein’s theory in three U.S. philosophy journals and situates these papers within the local intellectual landscape. I argue that these discussions (1) stimulated the development of a distinctly American branch of philosophy of science and (2) paved the way for the logical empiricists who emigrated to the United States in the years before World War II.

Background: Tuberculosis is an airborne disease caused by Mycobacterium Tuberculosis. Intracranial tuberculoma is a rare complication of extrapulmonary tuberculosis due to hematogenous spread to subpial and subependymal regions. Intracranial tuberculoma can occur with or without meningitis. Methods: A 3-year-old male who recently emigrated from Sudan presented to the emergency department with right-sided seizures lasting 30 minutes which were aborted with levetiracetam and midazolam. CT head revealed a multilobulated left supratentorial mass, with solid and cystic components measuring 8.0 x 4.8 x 6.5 cm. The patient had successful surgical resection of the mass which was positive for Mycobacterium Tuberculosis. He was started on rifampin, isoniazid, pyrazinamide, ethambutol, and fluoroquinolone and discharged home in stable condition. Results: Literature review on pediatric intracranial tuberculoma was performed which included 48 studies (n=49). The mean age was 8.8 ± 5.4 years with slight female predilection (59%). Predominant solitary tuberculomas (63%) were preferentially managed with both surgical resection and antitubercular therapy (ATT) compared to multifocal tuberculomas that were preferentially managed with ATT. Conclusions: Intracranial tuberculoma is a rare but treatable cause of space-occupying lesions in children. Clinicians should maintain high-level of suspicion in patients from endemic regions and involve infectious disease service early in patient’s care.

Background: Around 10% of ischemic stroke patients have pre-existing dementia and are excluded from stroke trials and routine care. Little is known about physician practices in the stroke care of people living with dementia (PLWD) leading to limited understanding of their experiences, priorities, and outcomes. This study aims to better understand PLWD through in-depth interviews. Methods: This study employs a qualitative descriptive methodology with two sets of 20 semi-structured interviews with PLWD and their primary caregivers (dyads), and with stroke physicians. Interviews with dyads investigate their experiences, priorities, and attitudes towards stroke care. Participants will be recruited through snowball sampling and interviews will be analyzed through qualitative data analysis software. Results: Initial analyses of the PLWD-caregiver dyad interviews have been completed, revealing themes of independence, uncertainty about the future, and fears of another stroke. Conclusions: As the population ages, stroke teams will likely encounter more PLWD. Engaging PLWD and their caregivers is crucial to better understand their experiences and priorities, which will inform future studies and improve their care. The findings from the dyad and physician interviews will be relevant to a broad audience, including patients, caregivers, physicians, researchers, and policymakers.

Background: Obstructive sleep apnea (OSA) may be associated with sleep difficulties and decreased rapid eye movement (REM) sleep. Lemborexant (LEM), a dual-orexin-receptor-antagonist approved to treat adults with insomnia, increases total sleep time (TST) and REM sleep, and demonstrated respiratory safety in subjects with mild through severe OSA. Sleep architecture was thus analyzed after LEM treatment in those subjects. Methods: Studies E2006-A001-102 and E2006-A001-113 enrolled adults with mild (apnea-hypopnea index [AHI] ≥5 – <15) or moderate (AHI ≥15 – <30)/severe (AHI ≥30) OSA without insomnia. Subjects received LEM 10mg (LEM10) or placebo (PBO) in 2 treatment periods, Days 1 (D1) and 8 (D8), separated by ≥14 days. Least-squares-mean (minutes) for each sleep stage was compared. Treatment-emergent adverse events (TEAEs) were recorded. Results: Thirty-nine subjects with mild and 33 with moderate/severe OSA were randomized. On both days, TST was significantly higher in the LEM period for these subjects. Total non-REM on D1 in subjects with mild OSA and on both days in subjects with moderate/severe OSA were higher with LEM than PBO; REM also significantly increased in subjects with mild and moderate/severe OSA. Most TEAEs were mild. Conclusions: In OSA subjects without insomnia, LEM was associated with higher TST, non-REM, and REM versus PBO.

Background: 5-Aminolevulinic acid (5-ALA) is a prodrug used to selectively illuminate high-grade glioma (HGG) tissue intra-operatively, shown to nearly double complete resection rates in a 2006 multicentre, phase III clinical trial. Here, we review the history of the 2020 approval of 5-ALA in Canada and present some of the first preliminary results on resection rates, survival analysis, and adverse effects from a single Canadian center. Methods: We enrolled 76 patients (median age 61 years, 42 male) with suspected HGG amenable to surgical resection between June 2020 and January 2023. Gross total resection was defined by the absence of enhancing lesions on postoperative MRI. We compared the survival distributions of confirmed HGG cases with complete vs. incomplete resection using a log-rank test and Kaplan-Meier statistic. Results: 52 patients were confirmed as having a HGG based on a pathological diagnosis. In 32 of these patients (60.3%) a gross total resection was achieved. 82.76% were still alive at 180 and 270 days, and 72.73% at 360 days. 47.8% had a survival of 600 or more days. Conclusions: 5-ALA fluorescence-guided surgery resulted in high complete resection rates, and improved overall survival comparable to the literature with no notable adverse side effects.

Background: Inadequate pain control after spine surgery is common, but its impact on long-term surgical outcomes has not been studied. Accordingly, this study aimed to investigate the relationship between poor postoperative pain control and surgical outcomes. Methods: Consecutive adult patients undergoing elective spine surgery were enrolled. Poor surgical outcome was defined as failure to achieve a minimal clinically important difference (MCID) of 30% improvement on the Oswestry Disability Index or Neck Disability Index at follow-up (3-months, 1-year, 2-years). Poor pain control was defined as a mean numeric rating scale score of >4 within 24-hours postoperatively. Univariable analyses followed by multivariable random-effects models were used, after adjusting for known risk factors that impact surgical outcomes. Results: 42.8% of 1305 patients failed to achieve MCID at follow-up. 56.9% had poor postoperative pain control. Poor pain control was independently associated with failure to achieve MCID (OR 2.15 [95%CI=1.42-3.25], p<0.001), after adjusting for age (p=0.15), sex (p=0.59), PHQ-9 score (p=0.030), ASA physical status >2 (p<0.001), ≥3 motion segment surgery (p=0.003), revision surgery (p=0.032), and follow-up time (p<0.001). Conclusions: Poor pain control 24-hours after elective spine surgery was an independent risk factor for poor surgical outcome. Perioperative strategies to improve pain control may lead to improved outcomes.

Background: Saccade and pupil responses are potential neurodegenerative disease biomarkers due to overlap between oculomotor circuitry and disease-affected areas. Instruction-based tasks have previously been examined as biomarker sources, but are arduous for patients with limited cognitive abilities; additionally, few studies have evaluated multiple neurodegenerative pathologies concurrently. Methods: The Ontario Neurodegenerative Disease Research Initiative recruited individuals with Alzheimer’s disease (AD), mild cognitive impairment (MCI), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, progressive supranuclear palsy, or Parkinson’s disease (PD). Patients (n=274, age 40-86) and healthy controls (n=101, age 55-86) viewed 10 minutes of frequently changing video clips without instruction while their eyes were tracked. We evaluated differences in saccade and pupil parameters (e.g. saccade frequency and amplitude, pupil size, responses to clip changes) between groups. Results: Preliminary data indicates low-level behavioural alterations in multiple disease cohorts: increased centre bias, lower overall saccade rate and reduced saccade amplitude. After clip changes, patient groups generally demonstrated lower saccade rate but higher microsaccade rate following clip change to varying degrees. Additionally, pupil responses were blunted (AD, MCI, ALS) or exaggerated (PD). Conclusions: This task may generate behavioural biomarkers even in cognitively impaired populations. Future work should explore the possible effects of factors such as medication and disease stage.

Background: SMA affects individuals with a broad age range and spectrum of disease severity. Risdiplam (EVRYSDI®) is a centrally and peripherally distributed, oral SMN2 pre-mRNA splicing modifier. Methods: SUNFISH is a multicenter, two-part, randomized, placebo-controlled, double-blind study in patients with Types 2/3 SMA. Part 1 assessed the safety, tolerability and pharmacokinetics/pharmacodynamics of different risdiplam dose levels in patients with Types 2/3 SMA. Part 2 assessed the efficacy and safety of the selected dose of risdiplam versus placebo in Type 2 and non-ambulant Type 3 SMA. In Part 2, participants were treated with risdiplam or placebo for 12 months, then received risdiplam in a blinded manner until month 24. At month 24, patients were offered the opportunity to enter the open-label extension phase. Results: Change from baseline in MFM32 total score (Part 2- primary endpoint) in patients treated with risdiplam versus placebo was met at month 12. These increases in motor function were sustained in the second and third year after risdiplam treatment. Here we present 4-year efficacy and safety data from SUNFISH. Conclusions: SUNFISH is ongoing and will provide further long-term efficacy and safety data of risdiplam in a broad population of individuals with SMA.

Background: Wolfram syndrome (WFS) is a genetic disorder clinically characterized by optic atrophy (OA), diabetes mellitus, sensorineural deafness, and diabetes insipidus. It is caused by mutations in WFS1 (mono- or biallelic) or CISD2 (biallelic) genes. Neuroradiological features include cerebellar and/or brainstem atrophy with visual pathway and white matter involvement. We report two subjects with WFS in which multifocal, progressive, and contrast-enhancing white matter abnormalities (WMA) led to the consideration of multiple sclerosis (MS). Methods: We retrospectively analyzed the clinical, genetic, and radiological data from two unrelated subjects with genetically confirmed WFS and multifocal WMA. Results: Subject I: a 43-year-old woman, heterozygous for a known WFS1 variant, had a history of congenital deafness and OA. The brain MRI documented progressive multifocal WMA including pericallosal lesions. Subject II: a 28-year-old woman, compound heterozygous for two WFS1 variants, was known for OA and diabetes mellitus. The brain MRI revealed multifocal periventricular, callosal, subcortical, and juxtacortical WMA, with some enhancing after gadolinium injection. Conclusions: Our report expands the WFS spectrum of white matter involvement to include progressive, seemingly inflammatory lesions. Although we cannot exclude a dual diagnosis, the roles of WFS1 and CISD2 in myelination suggest a selective white matter vulnerability in WFS.

Background: Fluctuation-related pain (worse in OFF periods) is a frequent and disabling symptom in Parkinson’s disease (PD). As evidence-based treatments to treat pain in PD are limited, exploring alternatives to treat it are imperative. Apomorphine is the only antiparkinsonian agent compatible with levodopa in improving PD motor symptoms and is usually well tolerated. We explored the effects of apomorphine in PD fluctuation-related pain. Methods: Small pilot double-blind, placebo controlled, randomized crossover study evaluating the safety and efficacy of subcutaneous apomorphine vs. placebo on fluctuation-related PD pain including participants experiencing pain during OFF periods. Primary outcomes: changes in a Visual Analogue Scale for pain and MDS-UPRDS III from baseline to 30 and 60 minutes after injections (two doses, separated by 60 min) and adverse events. Domperidone was used as premedication to avoid nausea/vomiting. Results: 16 patients were screened and 11 completed the study. All participants tolerated both treatments without significant side effects. Efficacy results remain blinded until the end of February 2023 and will be shown at the conference. Conclusions: Apomorphine, recently approved by Health Canada as an adjunctive therapy in PD patients and experiencing “off” periods, has shown to be safe when used to treat fluctuation-related PD pain. Efficacy outcomes will be soon available.

The COVID-19 pandemic has had a disproportionate effect on older adults and their family caregivers (FCGs). For FCGs, the pandemic has impacted almost every dimension of their lives and caregiving routines, from their own risk of becoming ill to their access to resources that support caregiving. The purpose of this mixed-methods study was to examine the impact of COVID-19 on FCGs’ ability to provide care for their family member with dementia. A total of 115 FCGs who identified as having their family member living with dementia residing in the community completed the survey. Ten family caregivers participated in the follow-up focus groups. Recommendations to address the needs of FCGs now and in the future include: (1) making resources for care provision consistently available and tailored, (2) providing support for navigating the health care system, and (3) supplying concise information on how to provide care during public health emergencies.