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Background: Variants in CLCN4 are implicated in neurodevelopmental disorder, X-linked intellectual disability, and epileptic encephalopathy. CLCN4 encodes ClC-4, which is hypothesized to play a role in ion homeostasis and intracellular trafficking. ClC-4 relies on its formation of heterodimers with ClC-3, which possesses signals for target organelles. Methods: Case-Series. Then, we performed heterologous expression, patch-clamp electrophysiology, confocal microscopy, and protein biochemistry experiments to characterize our patients’ ClC-4 variants. Results: All three male patients had developmental and epileptic encephalopathy. Patients #1 and #2 had normal-appearing brains on MRI and no dysmorphic features. Patient #3 had: microcephaly, microsomia, complete agenesis of the corpus-callosum; and, cerebellar and brainstem hypoplasia. Patient #1 had recurrent status epilepticus separated by months of seizure freedom, while Patient #2 and #3 had brief, daily seizures. The p.Gly342Arg variant impaired the heterodimerization capability of ClC-4. The p.Ile549Leu and p.Asp89Asn variants exhibited early transport-activation, with p.Asp89Asn favouring higher transport-activity of ClC-4. Conclusions: We extend the phenotypic spectrum of CLCN4 variants and demonstrate the pathological functional-consequences of three previously unclassified variants. The p.Gly342Arg variant lead to a loss-of-function phenotype; however, the p.Ile549Leu and p.Asp89Asn variants likely caused gain-of-function phenotypes. Targeted animal or induced pluripotent stem-cell models are needed to further understand epileptogenic mechanisms of CLCN4 variants.
Background: The late-onset cerebellar ataxias (LOCAs) have until recently resisted molecular diagnosis. Contributing to this diagnostic gap is that non-coding structural variations, such as repeat expansions, are not fully accessible to standard short-read sequencing analysis. Methods: We combined bioinformatics analysis of whole-genome sequencing and long-read sequencing to search for repeat expansions in patients with LOCA. We enrolled 66 French-Canadian, 228 German, 20 Australian and 31 Indian patients. Pathogenic mechanisms were studied in post-mortem cerebellum and induced pluripotent stem cell (iPSC)-derived motor neurons from 2 patients. Results: We identified 128 patients who carried an autosomal dominant GAA repeat expansion in the first intron of the FGF14 gene. The expansion was present in 61%, 18%, 15% and 10% of patients in the French-Canadian, German, Australian and Indian cohorts, respectively. The pathogenic threshold was determined to be (GAA)≥250, although incomplete penetrance was observed in the (GAA)250-300 range. Patients developed a slowly progressive cerebellar syndrome at an average age of 59 years. Patient-derived post-mortem cerebellum and induced motor neurons both showed reduction in FGF14 RNA and protein expression compared to controls. Conclusions: This intronic, dominantly inherited GAA repeat expansion in FGF14 represents one of the most common genetic causes of LOCA uncovered to date.
Background: Lower socioeconomic status is associated with worse outcomes after stroke. We evaluated the differences in acute revascularization treatments in patients with acute ischemic stroke (AIS) who were materially deprived compared to those who were not. Methods: In a population-based cohort study, we used linked administrative data to identify community-dwelling adults hospitalized for AIS between 2017-2022 in Ontario, Canada. The main exposure was neighborhood-level material deprivation quintiles. Multivariable logistic regression was used to obtain the adjusted odds ratio (aOR) of receiving revascularization treatments (thrombolysis or thrombectomy) for patients in each deprivation quintile compared to the least deprived quintile. Results: We identified 57,709 patients (median age 74 years; 45.9% female). Compared to patients in the least deprived quintile, those with higher deprivation were younger and more likely to have hypertension and diabetes, but less likely to have atrial fibrillation. Compared to patients in the least deprived quintile, fewer patients in the very deprived quintile (17.9% vs 19.6%, aOR 0.88, 95%CI [0.82,0.95]) and in the most deprived quintile (16.6% vs 19.6%, 0.77 [0.71,0.83]) received revascularization treatments. Conclusions: Our results suggest disparities in the use of acute ischemic stroke revascularization treatments by socioeconomic status despite access to universal health care.
Background: Low-intensity transcranial ultrasound (TUS) is a non-invasive neuromodulation technique, which in theta burst mode (tbTUS) can increase cortical excitability. Parkinson’s disease (PD) has altered cortical excitability of motor cortex (M1). We evaluated the neurophysiological and clinical effects of M1 tbTUS in PD patients. Methods: Sixteen PD patients (4F, 59.5±9.7 years) in ON and OFF dopaminergic medication states, and 15 controls (5F, 61.9±8.7 years) were evaluated. tbTUS was applied for 80 seconds at M1 with 20W/cm2. Motor evoked potential (MEP) was recorded at baseline, at 5-minutes (T5), T30, and T60 after tbTUS. Motor (m)UPDRS was evaluated in PD at baseline and T60. Results: A linear mixed model on MEP amplitudes comparing PD-ON, PD-OFF and controls showed significant effect of time (F=4.83, p=0.003). Post-hoc analysis showed significant difference between baseline and T30 timepoints (p=0.0003). The MEP increase at T30 was higher in controls (66%), followed by PD-ON (41%) and PD-OFF (21%). PD-ON showed reduced mUPDRS at T60 when compared to PD-OFF, with significant effect of time (F=6.14, p=0.017) and group (F=5.39, p=0.025). Conclusions: tbTUS induced motor cortical plasticity is reduced in PD-OFF, that is partially restored by dopaminergic medications.Repeated sessions of tbTUS can be further investigated as a novel non-invasive treatment for PD.
Background: Orbital infarction syndrome (OIS) is a rare entity defined as acute ischemia of intraorbital structures. Three case reports of OIS post-endovascular thrombectomy (EVT) have recently been published, two demonstrating absent choroid blush (CB) on digital subtraction angiogram (DSA). Our goals are to determine the true incidence of OIS post-EVT and to identify imaging findings (e.g. CB) that may alert neurologists to potential cases. Methods: A retrospective cohort study including all EVT patients from Health Sciences Center (HSC), Winnipeg in 2019-20 was performed. Patient charts were reviewed to determine the incidence of OIS. Pre- and post-EVT DSA images were reviewed, and the sensitivity and specificity of absent CB for OIS was calculated. Results: Out of 248 patients, 13 were excluded for incomplete charts, and 4 cases (1.7%) of OIS were discovered. During sensitivity/specificity analysis of absent CB for OIS, 51 patients were excluded for inadequate imaging. There were 4 true positives, 0 false-negatives, 113 true-negatives, and 67 false-positives; resulting in a sensitivity of 100% and worst-case scenario specificity of 63% (assuming all 51 indeterminate cases were false positives). Conclusions: OIS is rare post-EVT with an incidence of 1.7%. Absent CB is very sensitive for diagnosing OIS with lower specificity.
Background: The adult spinal cord contains a population of ependymal-derived neural stem/progenitor cells (epNSPCs) with the potential to enhance endogenous regeneration. However, little is known about the mechanisms that regulate the activation of these cells after injury. Recently, we discovered that glutamate excitotoxicity, a hallmark in the pathophysiology of acute SCI, promotes epNSPC proliferation/survival. Here, we characterize the downstream signaling pathways involved in this response and target this mechanism in vivo to enhance the endogenous regenerative capacity of these cells. Methods: epNSPCs were isolated from the central canal region of the adult spinal cord. In vitro pathway analysis was conducted using immunohistochemistry, RNAseq and Western Blot. In vivo, rats underwent SCI and at 1-week post-injury were randomized to receive CX546 (positive AMPAR modulator), or vehicle-control. Animals underwent behavioural testing and spinal cords were extracted for analysis. Results: Glutamate excitotoxicity leads to calcium influx in epNSPCs via AMPARs and together with Notch signaling drives proliferation and astrocytic differentiation. Positive modulation of AMPARs subacutely after SCI enhances epNSPC proliferation, astrogliogenesis, neurotrophin production, neuronal survival and functional recovery. Conclusions: We uncover an important mechanism by which AMPARs regulate the growth/phenotype of epNSPCs which can be targeted therapeutically to harness the regenerative potential of the injured spinal cord.
Background: We aimed to develop an efficient and reliable artificial intelligence solution to automate prediction of neurosurgical intervention using acute traumatic brain injury computed tomography (CT) scans. Methods: TBI patients were identified from 2005 - 2022 at a Level 1 Canadian trauma center. Model training, validation, and testing was performed using head CT scans with patient-level labels corresponding to whether the patient received neurosurgical intervention. The finalized model was then deployed in a simulated prospective fashion on all TBI patients presenting to our center over an 18-month epoch. Results: 2,806 TBI scans were utilized for development of the Automated Surgical Intervention Support Tool (ASIST-TBI). 612 additional consecutive scans were used for simulated prospective model deployment. Prediction of neurosurgical intervention exhibited an area under receiver operating curve (AUC) of 0.92, accuracy of 0.87, sensitivity of 0.87, and specificity of 0.88 on the test dataset. On simulated prospective data, the results were: AUC 0.89, sensitivity 0.85, specificity 0.84 and accuracy of 0.84. Conclusions: We demonstrate the development and validation of ASIST-TBI, a machine learning model that accurately predicts whether TBI patients will need neurosurgical intervention. This model has potential application to optimize decision support and province-wide efficiency of inter-facility TBI triage to tertiary care centers.
Background: Our aim was to develop a National Quality Indicators Set for the Care of Adults Hospitalized for Neurological Problems, to serve as a foundation to build regional or national quality initiatives in Canadian neurology centres. Methods: We used a national eDelphi process to develop a suite of quality indicators and a parallel process of surveys and patient focus groups to identify patient priorities. Canadian content and methodology experts were invited to participate. To be included, >70% of participants had to rate items as critical and <15% had to rate it as not important. Two rounds of surveys and consensus meetings were used identify and rank indicators, followed by national consultation with members of the Canadian Neurological Society. Results: 38 neurologists and methodologists and 56 patients/caregivers participated in this project. An initial list of 91 possible quality indicators was narrowed to 40 indicators across multiple categories of neurological conditions. 21 patient priorities were identified. Conclusions: This quality indicators suite can be used regionally or nationally to drive improvement initiatives for inpatient neurology care. In addition, we identified multiple opportunities for further research where evidence was lacking or patient and provider priorities did not align.
Background: Systemic corticosteroids (CS) are first-line therapy for many neuromuscular diseases. Although long-term use is associated with many adverse effects, guidelines regarding prevention and management of CS-induced (CSI) complications in neurology are lacking, introducing potential practice variation. We aimed to evaluate Canadian neuromuscular neurologist practices for screening and management of CSI complications. Methods: A web-based anonymous questionnaire was disseminated to 99 Canadian neuromuscular neurologists addressing the screening, prevention, monitoring and treatment of CSI adverse effects, such as infection and osteoporosis. Results: 71% completed the survey. Of those, 52% perform screening blood work prior to initiating CS, 56.3% screen for infections, and 18.3% for osteoporosis. The majority monitor glycemic control and blood pressure. 28.6% never use pneumocystis jiroveci pneumonia prophylaxis, and 28.6% routinely recommend vaccinations prior to CS initiation (most commonly influenza and pneumococcal). 80.0% recommended calcium supplementation to prevent osteoporosis. 36% were unaware of any existing guidelines for preventing CSI complications, and 91% endorsed a need for neurology-specific guidelines. Additional data and details of responses will be presented. Conclusions: There is substantial variability in the management of CSI adverse effects among neuromuscular neurologists. This suggests a need for neurology-specific guidelines to help standardize practice.
Background: The Canadian Registry for Amyloidosis Research (CRAR) is a nationwide disease registry of transthyretin (ATTR) and light-chain (AL) amyloidosis. Recent advances in disease-modifying therapy have improved prognosis, however there is a critical need for real-world evidence to address knowledge gaps, particularly longer-term therapeutic outcomes and surveillance strategies. Methods: A multi-stakeholder process was undertaken to develop a consensus dataset for ATTR- and AL-amyloidosis. This process included surveys to rank the importance of potential data items, and a consensus meeting of the CRAR steering committee, (comprised of multidisciplinary clinical experts, and patient organization representatives). Patients and patient organizations supported the development and implementation of a patient-reported dataset. Results: Consensus data items include disease onset, progression, severity, treatments, and outcomes, as well as patient-reported outcomes. Both prospective and retrospective (including deceased) patient cohorts are included. Further baseline data will be presented on an initial cohort of patients. Conclusions: CRAR has been established to collect a longitudinal, multidisciplinary dataset that will evaluate amyloidosis care and outcomes. CRAR has launched at multiple specialty amyloidosis centers nationally and is continually expanding. The growth of this program will promote opportunities to assess real-world safety and efficacy and inform the cost-effectiveness of therapies while supporting patient recruitment for research.
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.
Background: Veno-venous extracorporeal membrane oxygenation (VV-ECMO) is an invasive intervention for patients with respiratory failure associated with COVID-19. This meta-analysis aims to determine the incidence of neurovascular complications in COVID-19 patients requiring VV-ECMO. Methods: Systematic literature search of MEDLINE, Embase, PsycINFO, and Cochrane databases was performed to identify studies that reported neurovascular complications of adult COVID-19 patients on VV-ECMO for respiratory failure. Case series and reports were excluded. Studies with 95% or more of its patients on VV-ECMO were pooled for meta-analysis. Results: Eighteen studies (n=1968) were included for meta-analyses. In COVID-19 patients requiring VV-ECMO, the incidences of intracranial hemorrhage and ischemic stroke were 11% [95% CI, 8–15%] and 2% [95% CI, 1–3%], respectively. Intraparenchymal and subarachnoid hemorrhages accounted for 73% and 8% of all intracranial hemorrhages, respectively. The risk ratio of mortality in COVID-19 patients with neurovascular complications on VV-ECMO compared to patients without neurovascular complications was 2.24 [95% CI, 1.46–3.46]. Conclusions: COVID-19 patients requiring VV-ECMO have a higher incidence of intracranial hemorrhage compared to historical data in non-COVID-19 patients (11% vs. 8%), while the incidence of ischemic stroke is similar (2%) in both cohorts. COVID-19 patients with neurovascular complications on VV-ECMO are at an increased risk of death.
Background: Colony stimulating factor 1 receptor (CSF1R) mutations have various clinical, often overlapping, phenotypes. Methods: Case report and literature review. Results: We present a case of a previously independent 49-year-old woman with a 3-year history of early- and insidious-onset, rapidly progressive symptoms resembling CBS (parkinsonism, severe apraxia, global cognitive impairments, personality changes, depression, and functional decline). Brain MRI showed severe atrophy with frontoparietal predilection, asymmetric ex vacuo dilatation, atrophic corpus callosum, and patchy, asymmetric T2/FLAIR hyperintensities in the subcortical white matter. Spine MRI showed no cord signals. Brain MR spectroscopy revealed elevated choline with reduced N-acetyl-aspartate levels. The vasculitis screening, and leukodystrophy and CADASIL workups were all unremarkable. Finally, whole exome sequencing was done and a heterozygous variant of CSF1R (c.1735C>T, p.Arg579Trp) was found. Conclusions: Our patient’s novel CSF1R variant was found to be associated with ALSP. This report supports the utility of a comprehensive genetic testing in adult patients clinically presenting as CBS but with white matter abnormalities on T2-weighted MRI. Given that ALSP has several other clinical and radiologic mimickers, whole exome sequencing proves fundamental and can improve the diagnostic rates and understanding of ALSP. A well-informed diagnosis can lead to appropriate preventive genetic counseling to affected families.
Background: What matter (WM) is particularly sensitive to ischemia and WM changes are observed following onset of ischemic stroke as well as during expansion of the stroke lesion. To better correlate neurobehavioural and functional assessments in our models we have developed imaging methods to aid in the differentiation and quantification of WM injury. Methods: We employ 3 mouse models of stroke: photothrombotic, temporary middle cerebral artery occlusion, and intracerebral hemorrhage. Naïve controls and surgical shams (for each model) are also characterized. We use Fourier transform infrared (FTIR) imaging and synchrotron-based X-ray fluorescence microscopy (XFM) to visualize metabolites and elemental markers, respectively. These post-mortem imaging techniques are combined with conventional histology to confirm neuroanatomic features and cell types. Results: The metabolic profile of WM in naïve, sham, and stroke models has been characterized in C57BL/6 mice. The metabolic markers we identify are highly specific and enable the automated differentiation of WM from other tissues. Our methods have been re-tooled to identify degeneration and injury of WM regions. Conclusions: The combination of FTIR imaging and XFM afford the means to readily differentiate WM changes following stroke onset. Significant dysregulation can be observed before the core or penumbra of the stroke lesion reaches WM-containing regions.
Background: We aim to assess the effect of simultaneous acute code stroke activation(ACSA) in patients undergoing reperfusion therapies in the emergency department on home time at 90 days. Methods: We assessed ACSA over 20 months from the QuICR(Quality Improvement and Clinical Research Alberta Stroke Program) Registry. We defined Simultaneous reperfusion therapy as, ACSA within 60 min of the arrival of any patient receiving intravenous thrombolysis or ACSA within 150 min of the arrival of any patient receiving endovascular thrombectomy (based on the Canadian Triage and Acuity Scale, average localdoor-to-needle and door-to-puncture times)Results: A total of 2607 ACSA occurred at a mean±SD of 130.8±17.1 per month during the study period. 545 (20.9%) underwent acute reperfusion therapy with a mean age of 70.6±14.2 years, 45.9%(n=254) were female and a median (IQR) NIHSS of 13(8-18). Simultaneous reperfusion therapies occurred in 189(34.6%). There was no difference in the median door-to-CT time between the simultaneous (16, 11-23 min) and non-simultaneous (15, 11–21 min, p=0.3) activations. There was no difference in the median home time at 90 days between the two groups. Conclusions: Simultaneous ACSA occurs in one-third of patients receiving acute reperfusion therapies. An optimal workflow may help mitigate the clinical and system burden associated with simultaneity.
Background: Women are reported to have worse outcomes than men following ischemic stroke despite similar treatment effects for thrombolysis and endovascular treatment. Methods: We performed a post-hoc analysis of patients with acute ischemic stroke and intracranial occlusion enrolled in INTERRSeCT, an international prospective cohort study. We compared workflow times, reperfusion therapy choices, and 90-day modified Rankin scale (mRS) scores. Results: We included 575 patients, mean age 70.2 years (SD: 13.1) and 48.5% female. There were no significant sex differences in onset-to-CT (males: 115 minutes [IQR: 72-171], females: 114 minutes [IQR: 75-196] ) or CT-to-thrombolysis time (males: 24 minutes [IQR: 17-32], females: 23 minutes [IQR: 18-36]). However, female participants had a 12-minute faster CT-to-groin-puncture time, p=0.001. Reperfusion therapies did not significantly differ by sex. Reperfusion therapies included thrombolysis alone (males: 46%, females: 49%), EVT alone (males: 34%, females: 34%), thrombolysis plus EVT (males: 8%, females 9%) and conservative management (males: 12%, females: 8%). Median 90-day mRS was 2 (IQR: 1-4) in both males and females, p=0.1. Conclusions: In the INTERRSeCT cohort, rates of reperfusion therapy, workflow times and 90-day outcomes were similar between sexes, suggesting that women are not subject to any poorer performance in key quality indicators for reperfusion treatment for acute stroke.
Background: We aim to assess the role of quantitative electroencephalography (QEEG) derived indices to predict post-stroke disability. Methods: We included observational studies (sample-size≥10) of patients with stroke who underwent EEG and a follow-up outcome assessment was available either in form of a modified Rankin scale (mRS) or National Institute of stroke scale (NIHSS) or Fugl-Meyer scale (FMA). QEEG indices analyzed were delta-alpha ratio (DAR), delta-theta-alpha-beta ratio (DTABR), brain symmetry (BSI) and pairwise derived brain symmetry (pdBSI). Results: Twelve studies (11 had only ischemic stroke, and one had both ischemic and hemorrhagic stroke), including 513 participants were included for meta-analysis. Higher DAR was associated with worse mRS (n=300, Pearson’s r 0.26, 95% CI 0.21-0.31). Higher DTABR was associated with worse mRS (n=337, r 0.32, 95% CI 0.26-0.39). Higher DAR was associated with higher NIHSS (n=161, r 0.42, 95% CI0.24-0.6). Higher DTABR was associated with higher NIHSS (n=172, r 0.49, 95% CI 0.31-0.67). pdBSI was inversely associated with FMA (n=20, r-0.50 95% CI -0.86-(-0.14)) and BSI was not associated with FMA (n=21, r -0.3 95% CI -0.81-0.22). Conclusions: QEEG-derived indices have the potential to assess post-stroke disability. Adding QEEG to the clinical and imaging biomarkers may help in better prediction of post-stroke recovery.
Background: To clarify the landscape of molecular diagnoses (MDs) in early-onset epilepsy individuals, we determined the prevalent MDs stratified by age at seizure onset (SO) and the time to MD in children with SO <36 months of life. Methods: A panel of up to 302 genes associated with epilepsy was utilized and ordering physicians provided the age of SO. Diagnostic yield analyses were performed for SO ages including <1 mo, 1-2 mo, 3-5 mo, 6-11 mo, 12-23 mo, and 24-35 mo. The time to MD (MD age - SO age) was determined for the top 10 genes in each SO category. Results: 15,074 individuals with SO <36 months of life were tested. Predominant MD findings are as follows: KCNQ2 in neonates with SO at <1mo, KCNQ2 and CDKL5 for SO between 1-2 mo, PRRT2 and SCN1A for SO between 3-11 mo, and SCN1A for SO between 12-36 months. The median time to MD varied by gene. For example, there was no delay in the median time to MD for the GLDC, KCNQ2, and SCN2A genes while the median delay for MECP2, SLC2A1, and other genes was ≥ 12 months. Conclusions: These data highlight the importance of comprehensive early testing in children with early-onset epilepsy.
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.