Background: The interaction between mutations in two or more genes is increasingly recognised as an important contributor to the phenotypic variability in genetic disorders. Co-occurrence of variants in SQSTM1 and TIA1 is reported as a cause of myopathy in 3 prior cases, but limited clinical data were presented. We present detailed clinical features of a family with two siblings having a distal myopathy with rimmed vacuoles (DMRV), and genetic variants in SQSTM1 and TIA1. Methods: Clinicopathologic study of a family with DMRV to describe clinical features, laboratory and neurophysiology studies, neuroimaging, and genetic sequencing. Results: Two siblings with variants in SQSTM1 and TIA1 developed myopathy in their early 60’s, with early involvement of ankle dorsiflexors and finger extensors. A decade after onset, patients remain ambulatory and have not developed cardiac or respiratory complications. MRI of the legs showed selective involvement of adductor magnus, vastus lateralis, and in lower legs the anterior compartment and medial gastrocnemius. Muscle pathology demonstrated rimmed vacuoles, disrupted myofibrillar architecture, and mislocalised TDP43. Two unaffected family members had one genetic variant but not both. Conclusions: We describe a fourth family with co-occurrence of TIA1 and SQSTM1 genetic variants and describe their detailed phenotype. Future study should address the mechanism of the interaction between these two variants.

Background: The association of myasthenia gravis (MG) and inflammatory myositis (IM) is rare and often only one of the diseases is diagnosed. Methods: In this study, we reviewed medical records of patients seen at NMDU from 2004 to 2017 who had diagnosis of concurrent MG and IM. The data is presented descriptively. -Results: We identified 7 patients with MG-IM overlap. Clinical features, laboratory and pathology data of the patients are summarized in Table 1. Conclusions: This is one of the largest case series with MG-IM overlap. It is very important to recognize such association and the different pattern of muscle involvement because therapies may be adjusted to treat both conditions. In patients with thymic pathology, conventional disease modifying agents, IVIG and glucocorticoid in addition to thymoma resection appear to be effective. In patients with refractory MG and myositis who were AChR negative, rituximab may be effective.

Background: Duchenne muscular dystrophy (DMD) is an X-linked disorder affecting 1:3500-5000 live male births, causing a life-limiting form of muscular dystrophy. Whole exon deletions disrupting the reading frame result in near-absence of sarcolemmal dystrophin, essential for muscle function. Eteplirsen is a phosphorodiamidate morpholino oligomer (PMO) designed to induce production of internally-truncated dystrophin in certain patients. Methods: As of June 2016, 150 patients (4-19 years of age) with DMD received eteplirsen in 7 clinical trials. 143 patients received ≥1 intravenous infusion of eteplirsen (range: 0.5 - 50 mg/kg). 81 (54%) received treatment for ≥1 year (Range: 1-4+ years). Results: Common (>15%) adverse events (AEs) were cough, headache, vomiting, back pain, extremity pain, contusion, nasopharyngitis, upper respiratory tract infection, nasal congestion, arthralgia and rash. Non-serious facial flushing, erythema and mild transient temperature elevation occurred with eteplirsen. 10 (6.7%) patients experienced severe AEs; 12 (8%) patients experienced serious AEs. All serious and all but 1 severe AEs were considered unrelated to eteplirsen by the treating physicians. Serial echocardiograms in 12 treated patients demonstrated no functional decline over 4+ years. Conclusions: Eteplirsen’s tolerability will continue to be assessed in ongoing clinical trials.

An updated data summary will be presented.

Background: Congenital Myasthenic Syndromes (CMS) are heterogeneous disorders caused by genetically determined structural or functional differences in proteins involved with the neuromuscular junctions. Clinical and molecular genetics studies of CMS patients have revealed significant locus heterogeneity; there are 21 known genes related to CMS, but other genes may mimic the phenotype, justifying the use of a multi-gene panel for genetic testing Methods: Our group developed custom sequence capture probes designed to flank 27 different genes associated with CMS, including enrichment for all coding exons as well the flanking intronic regions. We enrolled 20 patients from the paediatric and adult neuromuscular clinic with a clinical phenotype of CMS. Using custom analytical, we -assessed the sequence variants and exon-level CNVs for each patient. Results: Thirteen male and seven female patients with median age of 12.25 years (range 1.5-39y) were assessed. We identified missense and CNVs in 17 patients, including established pathogenic mutations confirming the diagnosis in 5 patients Conclusions: The use of Next Generation Sequence with CNV for CMS can help determine the underlying causes of most CMS disorders and allow appropriate medical treatment, refined genetic counseling, and improved understanding of prognosis, justifying the implementation in the standard clinical screening of CMS.

Background: Longitudinal data on health-related quality of life (HRQOL) and fatigue in paediatric Duchenne muscular dystrophy (DMD) are limited. Recently, fatigue was reported to be the greatest predictor of poor HRQOL in paediatric DMD. Understanding the trajectory of HRQOL and its relationship with fatigue may facilitate the development of improved therapeutic strategies. Our objective was to describe three-year changes in HRQOL and fatigue in children with DMD. Methods: Patients identified via the Canadian Neuromuscular Disease Registry received mailed questionnaires (2013–2016). HRQOL was assessed using the PedsQLTM GCS and NMM domains, and fatigue was assessed using the MFS domain (patient- and parent-report). Mean three-year change in scores were computed. Pearson correlations were computed between three-year change in HRQOL and fatigue. Results: Mean decline in MFS scores for patient- and parent-reports were 1.03 and 1.19, respectively. Mean decline in GCS scores for patient- and parent-report were 1.75 and 4.13, respectively. Mean change in NMM scores for patient- and parent-report were 0.72 and -8.36, respectively. Change in MFS score was associated with changes in GCS (r=0.72, p<0.001) and NMM scores (r=0.84, p<0.001) by patient-report. Conclusions: Children with DMD experience worse fatigue and HRQOL over time. Parents perceive a greater decline in HRQOL over time compared to patients.

Background: This work proposes a hypothetical model that integrates human factors (e.g. inherent ability and acquired expertise) and task factors (e.g. pre-procedural data, visual and haptic information) to better understand the hand ergonomics adaptation needed for optimal safety and efficiency during simulated brain tumor resections. Methods: Hand ergonomics of neurosurgeons, residents and medical students were assessed during simulated brain tumors resection on the NeuroVR virtual reality neurosurgical simulation platform. Spatial distribution of time expended, force applied, and tumor volume removed, and other metrics were analyzed in each tumor quadrant (Q1 to Q4). Results: Significant differences were observed between the most favorable hand ergonomics condition (Q2) and the unfavorable hand ergonomics condition (Q4). Neurosurgeons applied more total force, more mean force, and removed less tumor per unit of force applied in Q4. However, total volume removed was not significant between the two quadrants indicating hand ergonomics adaptation in order to maximize tumor removal. In comparison, hand ergonomics of medical students remained unchanged in all quadrants, indicating a learning phenomenon. Conclusions: Neurosurgeons are more capable of adapting their hand ergonomics during simulated brain tumor resections. Our proposed hypothetical model integrates our findings with the literature and highlights the importance of experience in the acquisition of adaptive hand ergonomics.

Background: Indonesia is a vast archipelago country with over 17,000 islands. Many of the islands are in underdeveloped provinces with no neurosurgeon. Neurosurgery is often considered an expensive and sophisticated field to fund. Our neurosurgery department used the vision and mission of the medical faculty, which is “globally respected and locally rooted” to make a difference in many of the islands. Methods: Careful selection of provinces and candidates that involve local governments and hospitals within the province. This includes resident recruitment, planning and developing neurosurgical infrastructure in the province. Our program uses innovative neurosurgical techniques that are standardized to be applicable in underdeveloped areas. The residents are exposed to their province and hospital during the training. We optimize IT interaction, including teleconference, videoconference and telemedicine Results: At the fifth year of our program, we have sixteen residents from 8 underdeveloped provinces and have established MoU with 4 local hospitals around Indonesia. We have also sent residents to rural areas. We routinely participate in international teleconferences and videoconferences, including those with the Saskatchewan team. Conclusions: A well planned and structured neurosurgical program, with standardized processes and involvement of local officials, combined with extensive use of IT, is effective in preparing neurosurgeons who can provide quality care in underdeveloped regions.

Background:The Neurosurgical Atlas is a neurosurgical website with informative chapters and videos to promote excellence and safety in neurosurgical techniques. Here, we present our analysis of this website’s viewing data and describe how online neurosurgical resources are being utilized. We hope this will be a useful guide for neurosurgeons interested in online multimedia education. Methods: We analyzed Google Analytics data from The Neurosurgical Atlas between June 2016 and August 2017 which tracked user demographics, geographical location, and the videos watched. Views were also analyzed categorically by dividing videos into six neurosurgical topics and into basic and advanced levels as per their surgical complexity. Results: There were 246,259 website visits and 143,868 video plays. The most frequent age groups were 25-34 (44%) and 35-44 (24%). 71% of visitors were male. Most visitors were from the US (29.52%) and Brazil (6.43%). Website visits and video plays increased over time, with multiple peaks corresponding to promotional email updates. The six neurosurgical topics were all similarly popular. Conclusions: Our study presents the first piece of evidence demonstrating the feasibility and popularity of a free online resource in neurosurgical education. Our experience highlights the growing demand for free-access online chapters, anatomical illustrations, and operative videos.

Background: Graduating residents require general palliative care skills. In Canada, there is no standardized palliative care curriculum for specialty trained residents. The objective of this research is to develop an evidence-based palliative care curriculum designed to provide neurology residents with the general palliative care skills required for providing patient care along the continuum of life. Methods: A needs assessment was performed in Neurology at Western University using qualitative analysis techniques. Residents completed the following:. A curricular outline was developed based on the Kolb learning style inventory (LSI), a knowledge pre-test, the Palliative Medicine Comfort and Confidence Survey and a review of the literature. Two iterations of the curriculum have been developed. Results: Residents identified a need for additional training in supportive and palliative care skills. Based on the Kolb LSI, 9/16 (56.3%) of neurology residents are “accommodators”. General principles identified for inclusion included: symptom management, communication, psychosocial aspects of care, care coordination and access, and myths and pitfalls in palliative care. Conclusions: This project is designed to identify the current palliative educational needs for Neurology residents. The results suggest that specialty trained residents are receptive to embedding training in the principles of palliative care within their training programs.

Background: With advancements in technology, the use of video as a pedagogical method in medical education has gained in popularity, and may aid in teaching clinical skills. In the UBC MD program, videos have been used to assist in teaching the -neurological exam for several decades, but the currently available videos are outdated and not of contemporary quality. Methods: Drawing upon the cognitive theory of multimedia learning from Mayer and Moreno (2003) which describes methods to maximize learning by minimizing cognitive load, we developed a tool to systematically assess pedagogical videos. We inventoried twelve existing neurology videos and analyzed their use of methods such as weeding (removing extraneous information), signalling (visually highlighting important information), and chunking (grouping similar information together). Results: Generally, older videos had poor audiovisual quality that introduced extraneous load, while more current videos had higher production value, albeit inconsistent with the depth of their content. We therefore produced a new three-part neurological exam video series. We wrote storyboards, filmed with a focus on visually depicting the exam and findings, and edited to elucidate relevant physiological concepts. Conclusions: The end product has been adopted by the UBC MD program, and can be shared with other programs who may wish to adopt them.

Background: Neurosurgical education is one of the most exciting topics in contemporary neurosurgery. Passing the final boards is a real challenge. Methods: We conducted a prospective study of 48 candidates who attended the hot-seat sessions during CCN review over three years. Detailed statistical analysis was conducted. Those who attended the Hot seats (Group 1) and those who didn’t (Group 2). The neurosurgery exam simulation was conducted using both MCQ and Oral simulated exams with clinical cases led by world expert faculty in a lecture format for the MCQ and 15-minute mock oral sessions which was video-taped scoring candidates in a standardized fashion for their performance. Results: Group 1 had a better MCQ performance (83 %) compared to group 2 (61 %). Candidates were better in data gathering, differential diagnosis and management. They were worst in simulating surgical techniques and follow-up plans. Geographical characterization showed a big range of intra and inter variability in performances. Interestingly, candidates with excellent MCQ performance had moderate hot seat performance while those with moderate MCQ performance did much better during the hot seat session. Conclusions: Our preliminary results showed that simulation of board exams is a method that will help neurosurgery residents not only pass their board exams, but also achieve the best marks.

Background: High volumes, ill patients, and steep learning curves can make neurosurgical rotations challenging for medical students. Furthermore, existing rotations often lack neurosurgery-specific orientation materials and level-appropriate pre-reading resources reducing the educational yield of short rotations. This is compounded by the lack of mandatory neurosurgical rotations across medical schools. We hypothesized that a “Neurosurgery Clerkship Manual” covering key orientation, knowledge, and practical topics would enhance educational experiences and generate sustained knowledge retention. Methods: Students rotating through neurosurgery at three hospitals were randomized to receive(intervention) or not receive(control) free access to the manual before their rotation. Participants completed surveys before, immediately after, and 4-weeks after the rotation assessing expectations, experiences, and clinically-relevant knowledge. Results: 61 participants were randomized between 2014 and 2017 with 43(70.5%) completing all three questionnaires. Baseline demographics, characteristics, and experiences were not significantly different. Those receiving the manual reported increased rotation enjoyment(p=0.02), decreased stress levels (p=0.05), and a greater feeling of being “part of the team”(p=0.01). There were also reductions in feeling like they were “not learning” (p=0.01). Finally, those receiving the manual demonstrated significantly better knowledge after the rotation (91.6%vs80.9%;p=0.04) which was sustained at 4-weeks post-rotation (89.2%vs79.0%;p=0.05). Conclusions: A simple and inexpensive clerkship manual can improve the neurosurgery rotation experience and knowledge retention for medical students.

Background: An “epidemic” of concussions has been widely reported. We explored the annual incidence of reported concussion or other brain injury, over 20 years within Canada in order to explore the magnitude of this reported epidemic. Methods: Two Canadian nationally representative health surveys have serially collected injury data associated with disability. The National Population Health Survey (NPHS) (1994-9) collected data on “concussion”, and the Canadian Community Health Survey (CCHS) (2000-current) has collected data on “concussion or other brain injury”. Data on respondents 12 years and older reporting concussion with or without other brain injury within the past year were examined in order to produce serial incidence data. Results: Nationally representative data were available biennially from 1994/95 through 2013/14 with the exception of 2007/08 and 2011/12. The incidence of reported concussions, or concussions and other brain injury has been stable until 2005/06 when the reported annual incidence started an upward slope to levels 250% higher (p<0.001) without any apparent stabilization by 2013/14, when approximately 1 in 200 Canadians 12 years and older report concussion or other brain injury as their most significant injury associated with disability in the previous 12 months. Conclusions: There is currently a pandemic of reported brain injury in Canada.

Background: In the elderly population, use of antithrombotic therapy (AT), antiplatelets (AP – aspirin, clopidogrel) and/or anticoagulants (AC – warfarin, DoAC – Dabigatran, Rivaroxaban, Apixaban), to prevent thrombo-embolic events must be carefully weighed against the risk of intracranial hemorrhage (ICH) with trauma. We hypothesize that for all patients 65yro+ with head trauma, those on AT will be more likely to sustain a traumatic brain injury, ICH, and poorer outcomes. Methods: Data was collected from all head trauma patients 65yo+ presenting to our tertiary trauma center (level 1) over a 24-month period; age, gender, injury mechanism, medications, International Normalized Ratio, reversal therapy, Glasgow Coma Scale (GCS), ICH, surgery, Extended Glasgow Outcome Scale score (GOSE) and mortality. Results: 1365 patients were identified; 724 on AT (413 AP, 151 AC, 59 DoAC, 48 2AP, 38 AP+AC, 15 AP+DoAC) and 474 not (non-AT). When adjusted for covariates, AT patients were more likely to have ICH (p=0.0004), more invasive surgical interventions (p=0.0188), functional dependency (GOSE≤4; p<0.0001) and mortality (p<0.0001). Risk of mortality is notably high with 2AP (OR 5.74; p=0.0003) and AC+AP (OR 4.12; p=0.0118). Conclusions: Elderly trauma patients on AT, especially combination therapy, have higher risks of ICH and poorer outcomes compared to those who are not.

Background: Transplantation of neural stem/progenitor cells (NSPCs) following spinal cord injury (SCI) is a promising strategy to enhance regeneration but is limited by poor survival of grafted cells. Recently, we demonstrated for the first time that the excitatory neurotransmitter glutamate, which is released after SCI, promotes survival/proliferation of spinal cord NSPCs via the AMPA subtype of glutamate receptors. Here, we examine the therapeutic potential of selective AMPA receptor modulation on NSPC survival using allosteric AMPA receptor modulators known as ampakines. Methods: NSPCs from the periventricular region of the adult rat spinal cord were treated with ampakines CX614 and CX546 for 72h either alone or in the presence of low-dose glutamate (50uM). Results: Treatment with CX-546 or CX-614 in the presence of glutamate led to a significant increase in live cell numbers. This was due to both a reduction in cell death and increase in cellular proliferation. Ampakine/glutamate treatment led to a significant increase in cell survival compared to controls in the setting of oxidative stress. Conclusions: We present the first examination of the effect of allosteric AMPA receptor modulators on adult spinal cord--derived NSPCs. Positive modulation of AMPA receptors may be a promising therapeutic strategy in the subacute/chronic phases after SCI to increase survival of endogenous or transplanted NSPCs.

Background: Stroke in the young is particularly tragic because of its potential for life time disability. Although a large number of studies have been published Worldwide. Very few have looked at etiologies in the youth of the Middle East,and none have focused on Oman. Methods: Retrospective,single center study,carried out at the Royal Hospital in Muscat. Chart review identifying all patients under 50 years of age admitted for acute stroke from 2009-2014. We analyzed the detailed history,examination and brain imaging (CT or MRI) for each case. We identified 588 young patients,163 of these were excluded due to other diagnosis or absence of neuroimaging (CT or MRI). Results: Out of the 425 stroke cases,67.3% were men. IS occurred in 69.6% compared to 30.4% for HS. Hypertension was the number one risk factor for both IS and HS,with a prevalence 50.7% and 60.5% respectively. DM was the second leading risk factor,with a prevalence of 32.1% in IS and 27.1% in HS. Underlying etiologies were identified in only 35.5% of cases in IS and 29.5% in HS.Cardiac etiology and vasculopathy were commonest for IS. Aneurysm was the main underlying etiology for HS. Conclusions: IS was more frequent than HS.Hypertension and DM were the leading risk factors for both stroke subtypes. Cardioembolism and vasculopathy were the main etiologies for IS.Cerebral aneurysm for HS.

Background: The natural history of small unruptured intracranial aneurysms (UIAs) <7mm is 0 to 1.3% per year. Our centre provides cerebrovascular care for the entire province allowing for long-term follow-up. We studied the safety of observation for aneurysms <7mm. Methods: We performed a retrospective chart review of patients with intracranial aneurysm referred to our centre between July 2008 and April 2015. Aneurysm characteristics and current status (followed, treated, not followed), were collected along with patient factors. Follow-up duration for each aneurysm was used to calculate total follow-up in aneurysm-years. Statistical evaluation consisted of multivariate analysis and logistic regression analysis. Results: 428 patients harbouring 497 aneurysms <7mm were identified. 67 presented with rupture. Of the remaining 430 aneurysms, there was a 9.3% treatment rate. 2 cases of rupture occurred in those patients who were followed, creating a 0.5% rupture rate. 325 aneurysms were followed for 631.3 total cumulative aneurysm-years, an average of 1.9 aneurysm-years. Smoking status and hypertension associated with presence of aneurysm (p≈0.009,0.026, respectively). Conclusions: In our selected patient group there is a low yearly rate of aneurysm rupture, and observation of aneurysms <7mm is safe. Hypertension and smoking were associated with the development of aneurysm. 9.3% of patients were treated, likely leading to a reduced natural history risk.

Background: Eagle syndrome (also known as stylohyoid syndrome) and fibromuscular dysplasia (FMD) are rare conditions that have both been shown to be associated with cervical artery dissections (CAD). Direct mechanical injury from a neighboring bony fragement can produce arterial dissections and is the proposed mechanism in Eagle syndrome. The etiology of FMD remains unclear, however, similar shearing stresses have been proposed. We present a case in which both of these conditions were present. Methods: Case report Results: A previously healthy 52 year old male presented with an acute left MCA syndrome with computer tomography angiography followed by convensional angiography confirming a complete occlusion of the left ICA at the carotid bifurcation with evidence of a dissection of the proximal cervical carotid artery. Luminal irregularities proximal to the dissection and also of the right ICA were in keeping with fibromuscular dysplasia. A carotid stent was placed and a thrombectomy was performed for a proximal left M2 occlusion. On further review of the CT, the patient had markedly elongated styloid processes bilaterally, meeting criteria for Eagle syndrome. Conclusions: Previous literature has not described these two conditions coexisiting. We question whether chronic mechanical stress from an elongated styloid process could lead to arteries having an irregular or beading appearance resembling fibromuscular dysplasia.

Background: Anemia following aneurysmal subarachnoid hemorrhage (aSAH) has been associated with poor outcome, but complications from transfusion have limited aggressive management of anemic patients. This study examined the relationship between hemoglobin levels, transfusion and outcome following aSAH. Methods: We performed a post-hoc analysis of the CONSCIOUS-1 trial. Poor outcome was defined as a 3-month modified Rankin Scale > 2. Minimum hemoglobin levels were evaluated as predictors of outcome using logistic regression analysis, ROC curve analysis, and LOWESS curves. Propensity score matching was used to assess the effect of transfusion on poor outcome in patients with minimum hemoglobin levels between 70-90 and 80-100 g/L. Results: Lower minimum hemoglobin levels were associated with poor outcome on both univariate (p<0.001) and multivariate (p=0.012) analysis. Area under the ROC curve for minimum hemoglobin was 0.673. Youden index analysis found a minimum hemoglobin threshold of 91.5 g/L maximally predictive for good functional outcome. Propensity score matching showed a trend towards poor outcome in transfused patients with minimum hemoglobin levels between 70-90 and 80-100 g/L (p=0.052 and 0.09). Conclusions: This work suggests that decreasing hemoglobin is an independent predictor of poor outcome following aSAH. However, there was a trend towards poor outcome in transfused patients. The optimal transfusion threshold should be evaluated by prospective trials.

Background: Strokes can cause a variety of cardiovascular complications. The underlying mechanisms are largely unknown but there is evidence that dysautonomia plays a role in stroke induced-heart injury (SIHI) and arrhythmias triggered by damage of specific brain regions involved in the autonomic regulation of cardiac functions. Understanding these mechanisms could aid in preventing these cardiovascular consequences. We hypothesize that compared to -patients with sinus rhythm (SR) or with cardiogenic atrial fibrillation known before the stroke (cKAF) or diagnosed after the stroke (cAFDAS), those with neurogenic AFDAS (nAFDAS) will show a specific pattern of autonomic functioning. Methods: We will prospectively evaluate 200 ischemic stroke patients at the London Health Sciences Center University Hospital. Participants will undergo continuous electrocardiographic monitoring during 14 days. Based on pre-specified criteria, patients with AFDAS will be classified into presumably neurogenic vs cardiogenic. We will assess autonomic function within 14 days after stroke onset by using the Autonomic Reflex Screening. We will compare markers of cardiac dysfunction with autonomic changes, as well as specific stroke topographies for SR, cKAF, cAFDAS, and nAFDAS. Results: We are currently performing an interim analysis. Conclusions: Characterizing the autonomic changes that occur after ischemic stroke and their relationship with heart injury will help to advance knowledge on the pathophysiology of SIHI.