Background: The coronavirus disease 2019 (COVID-19) pandemic has led an implementation of institutional infection control protocols. This study will determine the effects of these protocols on outcomes of acute ischemic stroke (AIS) patients treated with endovascular therapy (EVT). Methods: Uninterrupted time series analysis of the impact of COVID-19 safety protocols on AIS patients undergoing EVT. We analyze data from prospectively collected quality improvement databases at 9 centers from March 11, 2019 to March 10, 2021. The primary outcome is 90-day modified Rankin Score (mRS). The secondary outcomes are angiographic time metrics. Results: Preliminary analysis of one stroke center included 214 EVT patients (n=144 pre-pandemic). Baseline characteristics were comparable between the two periods. Time metrics “last seen normal to puncture” (305.7 vs 407.2 min; p=0.05) and “hospital arrival to puncture” (80.4 vs 121.2 min; p=0.04) were significantly longer during pandemic compared to pre-pandemic. We found no significant difference in 90-day mRS (2.0 vs 2.2; p=0.506) or successful EVT rate (89.6% vs 90%; p=0.93). Conclusions: Our results indicate an increase in key time metrics of EVT in AIS during the pandemic, likely related to infection control measures. Despite the delays, we found no difference in clinical outcomes between the two periods.

Background: Obsessive compulsive disorder (OCD) and major depressive disorder (MDD) are common, often refractory, neuropsychiatric conditions for which new treatment approaches are urgently needed. Magnetic resonance guided focused ultrasound (MRgFUS) is a novel surgical technique permitting incisionless ablative neurosurgery. Methods: We examined the safety profile, clinical response, and imaging correlates of MRgFUS anterior capsulotomy (MRgFUS-AC) in patients with refractory OCD (n=7) and MDD (n = 10). Results: There were no serious adverse clinical or radiographic events. 5/7 OCD patients and 3/10 MDD patients met pre-established clinical response criteria. Neurocognitive performance improved on several measures of executive function (p<0.05). By 6 months, there were significant reductions in cerebral glucose metabolism, and reductions in the bilateral tracts connecting the thalamus with the orbitofrontal cortices, anterior cingulate cortex (p<0.05). Preoperative functional connectivity between the right ventral striatum and hippocampus was predictive of eventual clinical response (p-FDR<0.05). Conclusions: MRgFUS-AC is safe and demonstrates important evidence of efficacy in treatment resistant psychiatric disease, particularly OCD. The procedure was associated with structural and metabolic changes in brain networks implicated in affective regulation, Resting-state fMRI offers the ability to predict response, and potentially select patients most likely to improve.

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: Despite treatment, gliomas often exhibit disease progression, leading to recurrent glioblastoma (GBM) or malignant transformation of low-grade gliomas (LGG) associated with treatment resistance and poor prognosis. To date, the molecular factors driving glioma recurrence are poorly understood. Methods: We analyzed a cohort of 324 glioma samples from our institution including a unique cohort of 81 patients with matched primary and recurrent tumour pairs. We performed a paired, integrated multi-platform analysis consisting of DNA methylation profiling on all 324 samples, gene expression on 87 samples, and matched plasma cell-free DNA methylome analysis on 82 samples. Results: LGG that undergo malignant transformation are associated with DNA hypomethylation at recurrence, including decreased tumour purity and increased copy number variation. Integrated pathway analyses identified IL-6, associated with multiple pro-oncogenic pathways, and CCR2, associated with the recruitment of tumour-associated macrophages, as top genes involved in malignant transformation. Matched plasma methylation demonstrated a shift in the methylation signature at recurrence that can prove valuable as a non-invasive biomarker for early detection of malignant progression. Conclusions: We provide the first detailed description of the epigenetic evolution of gliomas and identify epigenetic drivers of malignant transformation including non-invasive biomarkers for early detection of malignant progression.

Background: Medulloblastoma (MB) is the most common solid malignant pediatric brain neoplasm. Group 3 (G3) MB, particularly MYC amplified G3 MB, is the most aggressive subgroup with the highest frequency of children presenting with metastatic disease, and is associated with a poor prognosis. To further our understanding of the role of MSI1 in MYC amplified G3 MB, we performed an unbiased integrative analysis of eCLIP binding sites, with changes observed at the transcriptome, the translatome, and the proteome after shMSI1 inhibition. Methods: Primary human pediatric MBs, SU_MB002 and HD-MB03 were kind gifts from Dr. Yoon-Jae Cho (Harvard, MS) and Dr. Till Milde (Heidelberg) and cultured for in vitro and in vivo experiments. eCLIP, RNA-seq, Polysome-seq, and TMT-MS were completed as previously described. Results:MSI1 is overexpressed in G3 MB. shRNA Msi1 interference resulted in a reduction in tumour burden conferring a survival advantage to mice injected with shMSI1 G3MB cells. Robust ranked multiomic analysis (RRA) identified an unconventional gene set directly perturbed by MSI1 in G3 MB. Conclusions: Our robust unbiased integrative analysis revealed a distinct role for MSI1 in the maintenance of the stem cell state in G3 MB through post-transcriptional modification of multiple pathways including identification of unconventional targets such as HIPK1.

Background: Gaze behavior differences between expert and novice surgeons have been established in previous studies mainly from the general surgery field.Limited information is available about surgeon’s visual attention during microsurgery procedures where surgical microscope is used. Methods: 4 experts and 3 novices performed 37 independent sutures under the surgical microscope.Eye movements of surgeons and scene video of the surgical performance were recorded.Total suturing time and subtask times were compared between level of expertise.We defined three discrete surgical actions and examined eye gaze (fixation) directly related to each of these actions.Fixation duration (measured by total,pre-action,and post-action duration) were compared between expert and novice, over 3 subtasks (piercing, exiting and cutting) and between pre- and post-action phases. Results: Expert surgeons completed the suture with shorter total time than novices.On average,expert displayed longer fixation time than novice.Experts also maintained their visual engagement constantly over the 3 level of subtask in comparison to novices who required a longer fixation time for the challenging subtask (piercing).Experts use longer pre- than post-action fixation, and this pattern is distributed over all three subtasks.This gaze engagement strategy was not shown in novices. Conclusions: The action-related fixation can be used to evaluate microsurgeons’ level of expertise and in surgical education for gaze training.

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: Anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis is an autoimmune disease associated with antibodies against heteromers NR1 and NR2 subunits of the cell surface of the NMDA receptors, causing many psychiatric and neurological symptoms. This includes new-onset refractory status epilepticus. Methods: A 33-year-old previously healthy female developed new-onset refractory status epilepticus caused by anti- NMDA receptor encephalitis without the presence of tumours. Results: The clinical course was complicated by prolonged status epilepticus, which was refractory to many antiepileptic drugs (levetiracetam, phenytoin, carbamazepine, topiramate, lacosamide, valproic acid), ketamine, propofol, midazolam, including inhalation agents (isoflurane). Also, she received first (intravenous immunoglobulin, intravenous methylprednisolone, and plasmapheresis), second-line immunotherapy (rituximab) and prophylaxis bilateral oophorectomy without clinical or electrographic improvement. However, the patient drug-resistant status epilepticus markedly improved both clinically and electrographically following seven sessions of electroconvulsive therapy. Conclusions: Electroconvulsive therapy should be considered as adjuvant therapy for the treatment of immunotherapy resistant encephalitis.

Background: Autoimmune encephalitis (AE) is a recently described entity that presents with seizures, neuropsychiatric manifestations, and movement disorders. This observational chart review of AE aims to assess the burden of AE and related disorders at two Vancouver academic medical centers. Methods: All patients with Mitogen Laboratory AE antibody testing in 2018 were identified. Electronic hospital records were used to determine patient characteristics. Results: 1266 unique tests were ordered on 315 inpatients and outpatients. Of 37/315 (11.7%) seropositive patients, 26/37 (70.2%) patients had clinical data. Seropositive results included autoantibodies to NMDA (n=3), LG1 (n=2), CASPR2 (n=1) and paraneoplastic autoantibodies included GAD65 (n=2), PNMA2 (n=5), recoverin (n=3). There were four AE cases in 14 seronegative patients based on discharge diagnosis. 15/30 of patients had seizures and three developed status epilepticus. 15 had neuropsychiatric manifestations. 14 had a movement disorder. For inpatients, average length of stay was 24.3 days and there were 5 intensive care unit (ICU) admissions. Immunotherapies used included corticosteroids, PLEX, rituximab, IVIg, and cyclophosphamide. Conclusions: In two hospitals serving approximately two million people in 2018, there were 30 cases of AE in 2018. AE presents with a broad range of neurologic symptoms and seronegative testing does not preclude AE.

Background: Approximately 25% of encephalitis cases in North America are immune mediated. For most forms of autoimmune encephalitis (AIE), risk of relapse is unclear and little evidence exists to guide which patients have the highest risk and whether standard treatments reduce this risk. Our objective was to determine the factors associated with AIE relapse. Methods: We performed a chart review consisting of patients with AIE presenting to the Calgary Neuro-Immunology Clinic and Tom Baker Cancer Centre between 2015 and 2020. Predictors of relapse were determined with use of t-test. Results: Outcome data was assessable in 39/40 patients, 17/39 (44%) patients relapsed. Seropositive patients and those with abnormal CSF were more likely to relapse, although neither reached statistical significance (p=0.12, 0.059). Patients with longer duration of steroid and steroid sparing treatment prior to relapse, and those on steroids at the time of relapse, had milder relapses (p=0.024, 0.026, 0.047). There was no difference in steroid or steroid sparing treatment use at 3, 6, and 12 months between groups. Conclusions: Risk of relapse in AIE is high (44%), with most relapses occurring in the first 3 years. Continuous immunosuppression lessens the severity of relapse, although our study did not confirm it reduced the occurrence of relapse.

Background: Anti-N-methyl-D-aspartate receptor encephalitis (NMDArE) is commonly associated with ovarian teratomas, surgical resection of which can lead to significant neurologic improvement. However, the necessity of aggressive resection at the time of diagnosis is unknown; specifically, whether unilateral or bilateral oophorectomy, versus lesionectomy and partial oophorectomy (ovariotomy), is required. Methods: Eleven patients with NMDArE who underwent ovarian resection between January 1st 2012 and December 31st 2020 were retrospectively identified. Primary outcome was good one-year functional status, defined as modified Rankin Scale (mRS) score of 0-1. Results: Median age at encephalitis onset was 24 years (19–38); median delay from symptom onset to surgery was 39 days (16–129). Six patients (54.5%) had good mRS scores, unrelated to surgical resection type. Conclusions: Added clinical benefit of aggressive ovarian resection techniques at one-year follow-up was not identified in our data. Further longitudinal studies are needed to determine the indications for different surgical techniques in patients with NMDArE.

Ovarian resection approaches and associated functional outcomes in patients with NMDArE

Background: We reviewed our autoimmune encephalitis neural antibody testing using brain tissue indirect immunofluorescence (TIIF) and cell-based assays (CBAs) after one year. Methods: Samples were tested from March 2019–March 2020 by TIIF and CBA for anti-NMDAR, LGI1, CASPR2, AMPAR, GABA(B)R, DPPX, IgLON5 and GAD65. Weakly positive or positive CBA, with or without corresponding TIIF positivity, was reported positive. Clinical questionnaires were submitted for clinical-serological correlation. Patients with a compatible clinical phenotype and no more likely alternative diagnosis were classified as true-positives, while all others were flagged as possible false-positives. Results: Twenty of 373 patients (5.4%) had a positive neural antibody. All anti-LGI1 (N=4), GAD65 (N=4), and GABA(B)R (N=1) were classified as true-positives. In contrast, only 3/6 anti-CASPR2 and 3/5 anti-NMDAR were classified as true-positives. Among true-positives, 2/4 anti-LGI and 3/3 anti-CASPR2 were positive by CBA only. All possible false-positive results exhibited only weak serum staining by CBA, with negative serum TIIF and negative CSF CBA/TIIF (if available). Conclusions: Clinical sensitivity of CBA seems higher than TIIF for neural antibodies studied herein, but may come at some expense to clinical specificity. Among patients with weak serum staining by CBA, correlation with serum TIIF, CSF CBA/TIIF, and clinical presentation is recommended.

Background: Early treatment of autoimmune encephalitis (AE) can improve outcomes. Despite expert recommendation, it remains unclear if suspected AE patients consistently receive empiric treatments prior to availability of antibody results. Methods: Retrospective chart review of patients referred for AE testing in Manitoba. Primary outcomes were the proportion of patients treated empirically prior to the availability of antibody results. Incidence, clinical presentation, investigations, complications, mortality rates, and hospital course were secondary outcome measures. Results: We identified 151 patients from 2012-2018. 43 patients met inclusion criteria. The annual incidence of AE in Manitoba was 0.37/100,000. 28/43 (65%) patients were treated prior to availability of antibody results (“Early group”). 15/43 (35%) patients did not receive treatment (“Late group”). Significantly more Early group patients had repeat immunotherapy (p=0.001), abnormal MRI (p=0.027), and investigations for malignancy (p=0.015). Durations of hospital and intensive care admission, complication rates, and mortality rates were not different between the two groups. Conclusions: This is the first-ever AE incidence, timing, and management study of a comprehensive Canadian geopolitical and medical catchment area. Just over 1/3 of suspected AE over seven years were not treated prior to antibody results becoming available. Patients treated earlier did not experience greater complication rates.

Background: Surgical instruments used in patients with prion disease must be decontaminated or decommissioned to prevent iatrogenic transmission. This is only done when the diagnosis of prion disease is known. To assess the potential for iatrogenic transmission, we determined the prevalence of surgeries and use of precautions in patients with prion disease at two academic medical centers. Methods: Clinical details, results of investigations, and surgical interventions (performed within one-year of symptom onset) were extracted for patients with probable/definite prion disease at Mayo Clinic (n=107; 1-2014 to 12-2020) and Washington University School of Medicine (n=14; 2-2015 to 12-2019). Results: Twenty-six patients (21.5%) underwent 32 procedures, including 2 high-risk procedures involving the brain. Most procedures (17/32, 53%) occurred in the 1-year period preceding the onset of symptoms attributed to CJD. History of arthritis (OR: 7.4, 95%CI: 1.05-51.8), lack of behavioral symptoms (OR: 3.0, 95%CI 0.97-9.1), and greater time (months) from symptom onset to first MRI (OR: 1.1, 95%CI 1.03-1.2) were independently associated with odds of undergoing an invasive procedure. Prion disease precautions were observed in one case (diagnostic brain biopsy). Conclusions: Procedures were common in patients with diagnosis of prion disease; precautions were not. Coordinated approaches to screening and reporting are needed to prevent iatrogenic transmission.

Background: Assays capable of detecting prions in CSF (e.g., RT-QuIC) have greatly improved the antemortem diagnosis of Creutzfeldt-Jakob disease (CJD) yet take time to conduct and are not widely accessible. There is a need to identify clinical features and common tests that identify mimics at presentation. Methods: Mimics were identified within longitudinal studies of rapidly progressive dementia at study sites. Mimics met clinical criteria for probable CJD but did not have CJD. Clinical features were compared between mimics and patients with CJD assessed at Mayo Clinic Enterprise (n=79) and Washington University in St. Louis (n=10; Jan-2014 to Oct-2020). Results: Mimics (10/155; 6.5%) were diagnosed with autoimmune encephalitis (n=7), neurosarcoidosis, frontotemporal lobar degeneration with motor neuron disease, and unknown dementia. Age-at-symptom onset, gender, presenting symptoms, and EEG and MRI findings were similar between mimics and CJD patients. Focal motor abnormalities (49/93, 10/10), elevations in CSF leukocytosis (4/92, 5/10) and protein (39/92, 9/10) were more common in mimics (p<0.01). Neural-specific autoantibodies associated with autoimmune encephalitis were detected within the serum (4/9) and CSF (5/10) of mimics, but not CJD cases. Conclusions: Autoimmune encephalitis, neurosarcoidosis and neurodegenerative diseases may mimic CJD at presentation and should be considered in patients with early motor dysfunction and abnormal CSF studies.

Background: Discussions around driving cessation between clinicians and dementia patients are challenging. Patients view giving up their license as losing their independence. We sought to develop a tool that enables standardized and consistent driving messaging across clinicians working in a specialist memory clinic, across the span of cognitive disorders Methods: We developed a driving recommendations generator that allows clinicians to produce information handouts personalized to individual patient capabilities and needs. Clinicians select from a list of established recommendations that were developed with neurologist and geriatrician input, and consistent with provincial requirements. Recommendations cover patients’ current driving ability, road safety examinations, alternate transportation, and license revocation. Early driving retirement is emphasized and encouraged, to proactively support patients’ choices, safety and independence. Recommendation and handouts are printed for the patients. Results: Patients reported that the recommendations were easy to read and understand, and helped them to implement physician suggestions. All surveyed clients recommended continuing to provide such recommendations to future patients and families. Clinicians agreed that the tool helped them to save time, and simplified the process of finding accurate information to provide patients. Conclusions: Clinicians have found the system timesaving and useful for simplifying the process of providing helpful, informative resources for patients.

Background: With the advance of technology, our capacity to assess patients with dementia is also developing. It is possible to administer cognitive examinations using technology, such as the iPad-based Toronto Cognitive Assessment, but hitherto difficult to autonomously administer them. Many of the ’inputs’ from patients could be easily scored with software, but highly variable inputs such as the clock drawing are extremely difficult to score, precluding automated administration and scoring. This work focuses on the development of a neural network designed to assess cube drawings, infinity drawings, and clock drawings. Methods: 3200 drawings, evenly split between clocks, cubes and infinities were generated, with half being correct and half incorrect. A SqueezeNet was trained on 2000 images, validated on 800 drawings, and then tested on 400 drawings. Results: The SqueezeNet was able to achieve 97% accuracy on 400 images it had never seen before in categorizing images as “Cube”, “Clock”,

“Infinity”, or “Other” (incorrectly drawn). Conclusions: This neural network can successfully determine the difference between correctly and incorrectly drawn images commonly used in cognitive examinations, overcoming the final barrier to autonomously administering and scoring cognitive examinations. Next steps are to clinically validate an autonomous examination program which has been modeled after the Addenbrooke Cognitive Examination-3.

Background: Machine learning (ML) methods hold promise in allowing early detection of dementia. We performed a systematic review to assess the quality of published evidence for using ML methods applied to drawing tests of cognition, and to describe the accuracy of the methods. Methods: Embase, Medline, and Cochrane Central Library databases were searched for potential studies up to December 8, 2018 by four independent reviewers. Included articles satisfied the following criteria: 1) use of ML on 2) a drawing test in order to 3) assess cognition. The quality of evidence was then assessed using GRADE methodology. Results: The initial search yielded 4620 citations. Of these, 64 were eligible for full text review. 18 articles then met inclusion criteria. Median AUC across all models was 0.765, with certain ML algorithms performing better in terms of AUC or diagnostic accuracy. However, based on GRADE, the quality of evidence was deemed very low. Conclusions: ML has been applied by several groups to drawing tests of cognition. The quality of evidence is currently too low to make recommendations on their use. Future work must focus on improving reporting, and using standard algorithms and larger, more diverse datasets to improve comparability and generalizability.

Background: The IVS10+14 mutation in the microtubule-associated protein tau gene, MAPT, is a rare point mutation that dysregulates tau splicing resulting in pathological aggregation. This mutation has been identified in three families with severe neurodegenerative disease. We characterized the clinicopathological features of a fourth, Canadian family with the IVS10+14 MAPT mutation and compared them to previously reported families. Methods: Clinical and neuropathological records from three family members with the IVS10+14 MAPT mutation were reviewed. Neuropathological section from one available case were analyzed. Results: Considerable interfamilial phenotypic heterogeneity is reported in all cohorts that express the IVS10+14 MAPT mutation, with prominent motor, cognitive, behavioural, and respiratory symptoms. The Canadian cohort also expressed profound sensory and sleep abnormalities, not reported previously. In the two siblings with available neuropathological records, neuropathological changes ranged from mild to severe. Conclusions: All families expressing the IVS10+14 MAPT mutation display striking inter- and intrafamilial clinical and neuropathologic phenotypic variability. Our cohort adds sensory and sleep abnormalities as potential symptoms and illustrates a lack of clear clinicopathological correlates for these heterogenous symptoms.

Reference: Maxwell et al. 2021. Clinical and Neuropathological Variability in the Rare IVS10+14 Tau Mutation. Neurobiology of Aging. In Press. DOI: 10.1016/j.neurobiolaging.2021.01.004.

Background: Concern around perceived neurocognitive decline is increasing, leading to increased number of referrals and anxiety for patients. We aimed to explore the likelihood of the “worried well” experiencing neurocognitive decline. Methods: 166 “worried well” patients who attended the Rural and Remote Memory Clinic between 2004 and 2019 were included. Mini Mental Status Examination, Center for Epidemiologic Studies Depression Scale, and Functional Assessment Questionnaire scores were measured and compared at initial assessment and at 1-year follow-up. MMSE scores over time were assessed with a mean follow-up of 2.95 years (SD 2.87). Results: There was no statistically significant difference in MMSE, CESD, or FAQ scores between clinic day and one-year follow-up, and no consistent pattern of MMSE score over time. Of the 166 patients with SCI on initial assessment, nine were eventually given a neurological diagnosis. Conclusions: There is no pattern of neurologic decline observed in the “worried well”. Though the likelihood of a patient with SCI developing a neurological diagnosis is reassuringly low, (9/166), it is not irrelevant. This, along with the benefits of early diagnosis and treatment for dementia, leads us to believe that patients with SCI should still be seen in follow-up at least at the one-year mark.