Background: The mechanisms underlying the severity and wide heterogeneity of multiple sclerosis (MS) remain poorly understood. A persistent challenge has been determining whether genetic variation influences these traits. Methods: In 12,584 people with MS (pwMS), we estimated the proportion of age-related MS severity score variance attributable to additive genetic variation (SNP-heritability). Then, we interrogated for enrichment in hundreds of tissues and cell types using gene expression annotations. We performed a genome-wide association study (GWAS) using 7.8 million variants and attempted replication in an independent cohort of 9,805 pwMS. A subset of 8,325 pwMS was examined longitudinally over 54,113 visits. Results: We observed a 10% SNP-heritability for MS severity. In contrast to MS susceptibility, robust tissue-level enrichment was apparent in the brain and cervical spinal cord, but not in immune cells. We identified a novel MS severity locus (p<5×10−8) and confirmed this in the replicate population. The lead variant was associated with higher hazards of 6-month confirmed disability worsening (p=0.008) and faster EDSS worsening (p=0.002). Time to walking aid (EDSS 6.0) was 3.2 years earlier in homozygous risk carriers. Conclusions: This study identifies the first genetic modifier of MS progression, establishes the genetic contributions to its heterogeneity and describes a distinct genetic architecture from susceptibility.

Background: Only one disease modifying therapy (DMT), ocrelizumab, was found to slow disability progression in primary progressive multiple sclerosis (PPMS). Modeling the conditional average treatment effect (CATE) using deep learning could identify individuals more responsive to DMTs, allowing for predictive enrichment to increase the power of future clinical trials. Methods: Baseline clinical and MRI data were acquired as part of three placebo-controlled randomized clinical trials: ORATORIO (ocrelizumab), OLYMPUS (rituximab) and ARPEGGIO (laquinimod). Data from ORATORIO and OLYMPUS was separated into a training (70%) and testing (30%) set, while ARPEGGIO served as additional validation. An ensemble of multitask multilayer perceptrons was trained to predict the rate of disability progression on both treatment and placebo to estimate CATE. Results: The model could separate individuals based on their predicted treatment effect. The top 25% of individuals predicted to respond most have a larger effect size (HR 0.442, p=0.0497) than the entire group (HR 0.787, p=0.292). The model could also identify responders to laquinimod. A simulated study where the 50% most responsive individuals are randomized would require 6-times less participants to detect a significant effect. Conclusions: Individuals with PPMS who respond favourably to DMTs can be identified using deep learning based on their baseline clinical and imaging characteristics.

Background: Neuromuscular junction transmission impairment has been described in amyotrophic lateral sclerosis (ALS). The degree of repetitive nerve stimulation (RNS) decrement may correlate with disease activity if measurement is repeatable. We determined test-retest correlation of decremental response in patients with ALS. Methods: RNS (3 Hz) was assessed by blinded technician and clinician on median - abductor pollicis brevis (median-APB), ulnar - adductor digiti minimi (ulnar-ADM), and/or accessory - trapezius (accessory-TRAP) nerve-muscle pairs during two evaluations. Repeatability was assessed by measuring the strength of test-retest correlation using the Pearson correlation coefficient (r). Results: 24 patients were included. Decrement was measured for 16 patients on median-APB, 22 on ulnar-ADM, and 24 on accessory-TRAP. Repeated measures of decrement demonstrated strong test-retest correlation for median-APB (r = 0.82, p < 0.001) and accessory-TRAP (r = 0.87, p < 0.001). Correlation was poor in ulnar-ADM (r = −0.01, p = 0.949). Correlation was superior in median-APB muscles with higher Medical Research Council (MRC) grade strength (MRC ≥ 4, r = 0.89, p = 0.001 vs MRC < 4, r = 0.73, p = 0.062). Conclusions: Decremental response in patients with ALS has strong test-retest correlation in median-APB and accessory-TRAP, but not in ulnar-ADM.

Background: Infantile spasms (IS) is an epileptic encephalopathy, characterized by spasms, hypsarrhythmia, and developmental regression. This is a retrospective case series of children with IS who underwent epilepsy surgery at The Hospital for Sick Children (HSC) in Toronto, Canada. Methods: The records of 223 patients seen in the IS clinic were reviewed. Results: Nineteen patients met inclusion criteria. The etiology of IS was encephalomalacia in six patients (32%), malformations of cortical development in 11 patients (58%), atypical hypoglycaemic injury in one patient (5%), and partial hemimegalencephaly in one patient (5%). Nine patients (47%) underwent hemispherectomy and 10 patients (53%) underwent lobectomy/lesionectomy. Three patients (16%) underwent a second epilepsy surgery. Fifteen patients (79%) were considered ILAE Seizure Outcome Class 1 (completely seizure free; no auras). The percentage of patients who were ILAE Class 1 at most recent follow-up decreased with increasing duration of epilepsy prior to surgery. Developmental outcome was improved in 14/19 (74%) and stable in 5/19 (26%) patients. Conclusions: Our study found excellent seizure freedom rates and improved developmental outcomes following epilepsy surgery in patients with a history of IS with a structural lesion detected on MRI brain.

Background: Chordomas are rare malignant skull-base/spine cancers with devastating neurological morbidities and mortality. Unfortunately, no reliable prognostic factors exist to guide treatment decisions. This work identifies DNA methylation-based prognostic chordoma subtypes that are detectable non-invasively in plasma. Methods: Sixty-eight tissue samples underwent DNA methylation profiling and plasma methylomes were obtained for available paired samples. Immunohistochemical staining and publicly available methylation and gene expression data were utilized for validation. Results: Unsupervised clustering identified two prognostic tissue clusters (log-rank p=0.0062) predicting disease-specific survival independent of clinical factors (Multivariable Cox: HR=16.5, 95%CI: 2.8-96, p=0.0018). The poorer-performing cluster showed immune-related pathway promoter hypermethylation and higher immune cell abundance within tumours, which was validated with external RNA-seq data and immunohistochemical staining. The better-performing cluster showed higher tumour cellularity. Similar clusters were seen in external DNA methylation data. Plasma methylome-based models distinguished chordomas from differential diagnoses in independent testing sets (AUROC=0.84, 95%CI: 0.52-1.00). Plasma methylomes were highly correlated with tissue-based signals for both clusters (r=0.69 & 0.67) and leave-one-out models identified the correct cluster in all plasma cases. Conclusions: Prognostic molecular chordoma subgroups are for the first time identified, characterized, and validated. Plasma methylomes can detect and subtype chordomas which may transform chordoma treatment with personalized approaches tailored to prognosis.

Background: In 2016, the WHO Classification of Brain Tumors included brain invasion as a standalone diagnostic criterion for grade 2 meningioma diagnosis. In this study we explored the impact of this change on the incidence and distribution of meningioma grades. Methods: All cases of meningiomas diagnosed from 2007-2020 at a tertiary care hospital were identified. The distribution of meningioma grades before (WHO 2007) and after (WHO 2016) the introduction of the 2016 WHO criteria were compared. Each case in the 2007 cohort was re-graded according to the 2016 criteria to determine the intra-class correlation (ICC) between grading criteria. Results: Of 814 cases, 532 (65.4%) were in the 2007 WHO cohort and 282 (34.6%) were in the 2016 WHO cohort. There were no differences in the distribution of meningioma grades between cohorts (p=0.11). Upon re-grading, 21 cases (3.9%) were changed. ICC between original and revised grade was 0.92 (95% CIs: 0.91-0.93). Amongst Grade 2 meningiomas with brain invasion, 75.8% had three or more atypical histologic features or an elevated mitotic index. Conclusions: Brain invasion alone has minimal impact on the incidence or distribution of specific meningioma grade tumors, likely due to cosegregation of grade elevating features.

Background: Pandemics may promote hospital avoidance among patients with emergencies, and added precautions may exacerbate treatment delays. Methods: We used linked administrative data and data from the Quality Improvement and Clinical Research Alberta Stroke Program – a registry capturing stroke-related data on the entire Albertan population (4.3 million) – to identify all patients hospitalized with stroke in the pre-pandemic (01/01/2016-27/02/2020) and COVID-19 pandemic (28/02/2020-30/08/2020) periods. We examined changes in stroke presentation rates and use of thrombolysis and endovascular therapy (EVT), adjusted for age, sex, comorbidities, and pre-admission care needs; and in workflow, stroke severity (National Institutes of Health Stroke Scale/NIHSS), and in-hospital outcomes. Results: We analyzed 19,531 patients with ischemic stroke pre-pandemic versus 2,255 during the pandemic. Hospitalizations/presentations dropped (weekly adjusted-incidence-rate-ratio[aIRR]:0.48,95%CI:0.46-0.50), as did population-level incidence of thrombolysis (aIRR:0.49,0.44-0.56) or EVT (aIRR:0.59,0.49-0.69). However, proportions of presenting patients receiving thrombolysis/EVT did not decline (thrombolysis:11.7% pre-pandemic vs 13.1% during-pandemic, aOR:1.02,0.75-1.38). For out-of-hospital strokes, onset-to-door times were prolonged(adjusted-coefficient:37.0-minutes, 95%CI:16.5-57.5), and EVT recipients experienced greater door-to-reperfusion delays (adjusted-coefficient:18.7-minutes,1.45-36.0). NIHSS scores and in-hospital mortality did not differ. Conclusions: The first COVID-19 wave was associated with a halving of presentations and acute therapy utilization for ischemic stroke at a population level, and greater pre-/in-hospital treatment delays. Our data can inform public health messaging and stroke care in future pandemic waves.

Background: Erenumab is an antibody anti-calcitonin gene related peptide (CGRP) receptor approved for the treatment of episodic (EM) and chronic migraine (CM). In this study, we aimed to identify the predictors of response to the treatment. Methods: This is an ongoing retrospective cohort study of 120 patients (49 with cervicalgia) with EM or CM treated with Erenumab. The first endpoint was to identify the success rate of this treatment (at least 50% reduction in monthly migraine days during the third month of the treatment). The second endpoint was to identify the predictors of response to Erenumab treatment. Results: Seventy one percent of patients achieved a favorable response (P-value<0.001) to Erenumab. Patients with cervicalgia showed a lower treatment success rate (21.1% with vs 40.8% without cervicalgia) while patients without cervicalgia showed a higher treatment success rate (78. 9% without vs 59.2% with cervicalgia) with a P-value of 0.025 and an odd ratio of 0.388 (95% CI 0.174-0.869, P-value=0.021). A similar trend was observed in patients with occipital neuralgia and obesity (P-value<0.08). Conclusions: The preliminary analysis of this study demonstrates that cervicalgia (and to a lesser extend occipital neuralgia and obesity) is a negative predictor of response to Erenumab in patients with migraine.

Background: Mutations in the slow skeletal muscle troponin T (TNNT1) gene cause a congenital nemaline myopathy resulting in death from respiratory insufficiency in early infancy. We report on four French Canadians with a novel congenital TNNT1 myopathy. Methods: Patients underwent lower extremity and paraspinal MRI, quadriceps biopsy and genetic testing. TNNT1 expression in muscle was assessed by quantitative PCR and immunoblotting. Wild type or mutated TNNT1 mRNAs were co-injected with morpholinos in a zebrafish knockdown model to assess for rescue of the morphant phenotype. Results: Four patients shared a novel missense homozygous mutation in TNNT1. They developed from childhood slowly progressive limb-girdle weakness with spinal rigidity and contractures. They suffered from restrictive lung disease and recurrent episodes of rhabdomyolysis. Older patients remained ambulatory into their sixties. Lower extremity MRI showed symmetrical myopathic changes. Paraspinal MRI showed diffuse fibro-fatty involution. Biopsies showed multi-minicores. Nemaline rods were seen in half the patients. TNNT1 mRNA expression was similar in controls and patients, while levels of TNNT1 protein were reduced in patients. Wild type TNNT1 mRNA rescued the zebrafish morphants but mutant transcripts failed to do so. Conclusions: This study expands the spectrum of TNNT1-related myopathy to include a milder clinical phenotype caused by a functionally-confirmed novel mutation.

Background: Sample entropy (SampEn) can quantify the unpredictability of a physiological signal. We sought to assess if SampEn on EEG could reflect recent seizure activity. Methods: Charts of all patients undergoing an outpatient EEG between January and March 2018 were reviewed to assess seizure occurrences in the follow-up period between the two clinical visits surrounding the EEG. 9s-EEG segments were extracted at pre-specified time points. SampEn was calculated for all segments and values aggregated at the 25thpercentile. We performed a multivariate zero-inflated analysis to test the association between SampEn and seizure rate around the EEG, after controlling for age, presence of IED, presence of abnormal slowing, and presence of a focal brain lesion. Results: 269 EEGs were screened and 133 met inclusion criteria (112 patients). 80 EEGs (60%) were from patients with epilepsy, of which 47 had at least one seizure within the year preceding the EEG. Remaining EEGs were from patients who were deemed not to have epilepsy at last follow-up. Each 1SD decrease in SampEn was associated with a 3.93-fold increase in the rate of daily seizures (95% CI: 1.19–12.99, p = 0.02). Conclusions: Sample entropy of EEG is a potential objective method to assess contemporary seizure occurrence.

Background: In March 2021, at a press conference, the presence of a cluster of patients, claimed to have a novel neurological syndrome, was announced in New Brunswick. These patients were suggested to have symptoms reminiscent of CJD. The onset of disease was between 2015 and 2021. The size of this cluster has been reported as approximately 50 cases. Further news publications have suggested that various environmental factors were causing this disease. Methods: Between 2019 and 2021 eight patients have died in this cluster. Their neuropathological findings are reported here. Results: There was one case of metastatic carcinoma, one case of FTLD-TDP43, one case of neocortical Lewy body pathology, one case of neocortical Lewy body pathology and AD, 2 cases of AD with vascular pathology, one case of mainly vascular pathology, and one case without significant pathology (consistent with patient’s history). In all these patients no evidence for a prion disease was found, nor novel pathology. Conclusions: We suggest that these 8 patients represent a group of misclassified clinical diagnoses. Classical probability theorem based statistical evaluation shows that this group of deceased patients is representative for the entire cluster at a p=0.0001 level, which would suggest that the entire cluster is based on misdiagnoses.

Background: Quantitative susceptibility mapping (QSM) is an MR sequence that has potential as a biomarker in concussion. We compared QSM in pediatric concussion patients versus a comparison group of children with orthopedic injuries (OI) and assessed QSM’s performance relative to the current clinical benchmark (5P risk score) for predicting persistent postconcussion symptoms (PPCS). Methods: Children (N=967) aged 8-16.99 years with either concussion or OI were prospectively recruited from 5 Canadian centers. Participants completed QSM at a post-acute assessment 2-33 days post-injury. QSM z-score metrics for 9 regions of interest (ROI) were derived from 371 children (concussion=255, OI=116). PPCS at 1-month post-injury was defined using reliable change methods. Results: The concussion and OI groups did not differ significantly in QSM across ROI. Increased frontal white matter (WM) susceptibility predicted reliable increases in parent-rated cognitive symptoms (p=0.001). Together, frontal WM susceptibility and the 5P risk score were better at predicting persistent cognitive symptoms than the 5P risk score alone (p=0.0021). AUC were 0.71 (95%CI: 0.62-0.80) for frontal WM susceptibility, 0.67 (95%CI: 0.56-0.78) for the 5P risk score, and 0.73 (95%CI: 0.64-0.82) for both. Conclusions: This is the first study to demonstrate a potential imaging biomarker that predicts persistent symptoms in children with concussion compared to the current clinical benchmark.

Background: Despite efforts toward gender equality in clinical trial enrollment, females are frequently underrepresented and gender-specific data analysis is often unavailable. The purpose of this study was to determine if gender equality exists in the management of degenerative lumbar disease. Methods: Part 1: A systematic scoping review was conducted according to PRISMA guidelines, in order to synthesize the adult surgical literature regarding gender differences in pre- and post-operative clinical assessment scores for patients diagnosed with degenerative lumbar disease.

Part 2: An ambispective cohort analysis (multi-variate logistic regression) of the Canadian Spine Outcomes Research Network registry was performed to address knowledge gaps identified in “Part 1”. Results: Part 1: Thirty articles were identified, accounting for 32,951 patients. Female patients have worse absolute pre-operative pain, disability and health-related quality-of-life (HRQoL). Following surgery, females have worse absolute pain, disability, and HRQoL, but demonstrate an equal or greater interval change compared to males.

Part 2: Data was analyzed for 5,039 patients. Significant gender differences in pre-operative utilization of healthcare resources (medication use, diagnostic testing, medical and allied healthcare professional visits) were identified. Conclusions: Significant gender disparities in clinical assessment scores and the pre-operative utilization of healthcare resources were identified for patients undergoing surgery for degenerative lumbar disease.

Background: Proteogenomics, the integration of proteomics and RNASeq expands the discovery landscape for candidate expressed gene networks to obtain novel insights into host response in post-infectious hydrocephalus (PIH). We examined the cerebrospinal fluid (CSF) of infants with PIH, and case controlled against age-matched infants with non-postinfectious hydrocephalus (NPIH) to probe the molecular mechanisms of PIH, leveraging molecular identification of bacterial and viral pathogens. Methods: Ventricular CSF samples of 100 infants ≤ 3 months of age with PIH (n=64) and NPIH (n=36) were analyzed with proteomics and RNASeq. 16S rRNA/DNA sequencing and virome capture identified Paenibacillus spp. and cytomegalovirus as dominant pathogenetic bacteria implicated in our PIH cohort. Proteogenomics assessed differential expression, gene set enrichment and activated gene pathways. Results: Of 616 proteins and 11,114 genes, there was enrichment for the immune system, cell-cell junction signaling and response to oxidative stress. Proteogenomics yielded 33 functionally and genetically associated gene sets related to neutrophil activation, platelet activation, and cytokines (interleukins and interferon) signaling. Conclusions: We identified PIH patients with severe disease at time of hydrocephalus surgery, to have differential expression of proteins/genes involved in neuroinflammation, ependymal barrier integrity and reaction to oxidative stress. Further studies are needed to examine those proteins/genes as biomarkers for PIH.

Background: The frontal eye fields (FEFs) are linked to oculomotor control and hypothesized to reside in the prefrontal cortex, where electrical stimulation reportedly evokes contraversive eye movements. The exact location and function of the FEFs in humans is controversial. Stereo-electroencephalography (SEEG) is a minimally invasive technique used to guide epilepsy surgery. It provides a unique opportunity to collect human neurophysiological data outside of the operating room and has been used by other groups to advance our understanding of specific brain functions. Methods: Two pediatric subjects undergoing non-lesional epilepsy workup were enrolled into this prospective, IRB-approved study, and received brain MRI prior to SEEG implantation. SEEG recordings were collected with video of the subjects’ eyes while performing gaze-related tasks. Results: Stimulation testing elicited contraversive head turning with or without eye deviation, and hemifacial spasm, depending on the site of stimulation. Low-threshold sites eliciting these stereotyped movements were located just deep to the inferior precentral gyrus. Stimulation of sites in the posterior middle frontal gyrus did not elicit eye movements. Conclusions: Our findings suggest that the FEFs are located more posteriorly than widely held, involving the motor cortex. Further testing in pediatric and adult subjects is warranted to confirm this hypothesis.

Background: All guidelines for DBS in Parkinson’s disease (PD) include a contraindication for ‘dementia’. It is unclear where this cut-off should occur and if patients with mild cognitive impairment (MCI) do not do as well. This prospective cohort analysis assessed if pre-operative cognition affected post-operative quality of life. Methods: PD patients receiving bilateral STN-DBS (n=100) were prospectively studied using STROBE guidelines. All had Montreal Cognitive Assessment (MoCA), motor (UPDRS), mood (BDI-II), and quality of life (Parkinson Disease Questionnaire summary index, PDQ-39-SI). Two cohorts, pre-operative MCI (MoCA:18-25) and normal cognition (MoCA:26-30), had post-operative PDQ-39-SI at 1-year. The primary outcome was the proportion of patients with an improved PDQ-39-SI at 1-year. Results: Cohorts were not significantly different in age, severity of illness, response to dopamine, or mood. MCI was present in 27/100. Improved quality of life at 1-year occurred in 75% with normal cognition and 70% with MCI (p=0.54) with RR=1.1 (95% CI, 0.8-1.5). Linear regression analysis showed no correlation between pre-operative cognition and post-operative outcome (R2=0.02). Conclusions: Parkinson’s patients with MCI should be offered DBS if their motor symptoms require surgery. Guidelines for DBS surgery in PD should change from “dementia is contraindicated” to “patients require adequate cognitive functioning, MoCA greater than equal to 18.”

Background: Trials of endovascular thrombectomy (EVT) for acute stroke have excluded patients with pre-morbid disability. We performed a meta-analysis to assess the effectiveness and safety of EVT in patients with pre-morbid disability. Methods: According to PRISMA guidelines, we searched for studies describing outcomes in patients with pre-morbid disability (modified Rankin Scale [mRS] 2-5), treated with EVT or medical management (MM). Random-effects meta-analysis was used to pool outcomes including return to baseline mRS at 90 days, symptomatic ICH (sICH), and 90-day mortality. Results: We analyzed 14 studies of patients with pre-morbid disability (mRS2-5: EVT=1,373, MM=253). Compared to medical therapy, EVT was associated with higher likelihood of return to baseline mRS (OR=2.37, 95%CI:1.39-4.04) and a trend towards lower mortality (OR=0.68, 95%CI:0.46-1.02), with similar odds of sICH (OR 1.01, 95%CI:0.49-2.08). In studies comparing patients with vs. without pre-morbid disability treated with EVT, similar results were found except that pre-morbid disability, when defined more strictly as mRS 3-5, was associated with mortality (OR 3.49, p<0.001). Conclusions: In patients with pre-morbid disability, EVT carries a higher chance of return to baseline mRS compared to patients treated with MM or without pre-morbid disability, although with higher mortality than patients without pre-morbid disability. These findings merit validation with randomized controlled trials.

Background: Previous studies of neonatal cerebral venous sinus thrombosis (CVST) have focused on term infants, and studies of preterm infants are lacking. In this study, we examined the clinical and radiological features, treatment and outcome of CVST in preterm infants. Methods: This was a retrospective cohort study of preterm infants (gestational age <37 weeks) with radiologically confirmed CVST. All MRI/MRV and CT/CTV scans were re-reviewed. Clinical and radiological data were analysed using descriptive statistics, ANOVA and chi-square tests. Results: A total of 26 preterm infants with CVST were included. Of these, 65% were late preterm, 27% very preterm and 8% extreme preterm. Most (73%) were symptomatic at presentation with seizures or abnormal exam. Transverse (85%) and superior sagittal (42%) sinus were common sites of thrombosis. Parenchymal brain injury was predominantly periventricular (35%) and deep white matter (31%) in location. Intraventricular hemorrhage occurred in 46%. Most infants (69%) were treated with anticoagulation. None of the treated infants had hemorrhagic complications. Outcome at follow-up ranged from no impairment (50%), mild impairment (25%) and severe impairment (25%). Conclusions: Preterm infants with CVST are often symptomatic and have white matter brain lesions. Anticoagulation treatment of preterm CVST appeared to be safe and was not associated with hemorrhagic complications.

Background: Genetic neuromuscular diseases (NMD) are a heterogeneous group of disorders comprised hundreds of genes. Despite the advanced genetic testing modalities, about 40 % of patients with NMD do not have a diagnosis. Muscle MRI has been proven as a useful tool to orientate the genetic testing by looking at the muscle involvement severity pattern. Moreover, muscle MRI patterns can be specific and informative for muscular dystrophies and yet can be characteristic and diagnostic. Methods: Systematic review was conducted to review muscle MRI patters for all Limb Girdle Muscle Dystrophies (LGMD). Then, we applied artificial intelligence (AI) on muscle MRI patterns for LGMDs and other NMDs using open database containing muscle MRIs Mercuri scores from 950 individuals. Results: AI and machine learning were applied on 10 types of NMD muscle MRI Mercuri scores that represented muscle involvement based on the degree of fatty infiltration. Different models were generated, the one with highest accuracy was used. When tested on new patients, it achieved a 90% accuracy. Subsequently, was turned into a mobile application. Conclusions: Muscle MRI is a valuable tool to help in NMD diagnosis. Specific muscle involvement pattern can be predictive. Besides, AI facilitates the interpretation and comprehension of muscle imagining in NMD.