Background: Human induced pluripotent stem cell-derived neural stem cells (hiPS-NSCs) represent an exciting therapeutic approach for traumatically spinal cord injury (SCI). Unfortunately, most patients are the in chronic injury phase where a dense perilesional chondroitin sulfate proteoglycan (CSPG) scar significantly hinders regeneration. CSPG-degrading enzymes can enhance NSC-mediated recovery, however, nonspecific intrathecal administration causes off-target effects. We aimed to genetically engineer hiPS-NSCs to express a scar-degrading ENZYME into their local environment to enhance functional recovery. Methods: A bicistronic scar-degrading ENZYME and RFP reporter vector was non-virally integrated into hiPS-NSCs and monoclonalized. ENZYME activity was assessed by WST-1 and DMMB biochemical assays and an in vitro CSPG spot assay with hiPS-NSC-derived neurons. To assess in vivo efficacy, T-cell deficient rats (N=60) with chronic (8wk) C6-7 SCIs were randomized to receive (1)SMaRT cells, (2)hiPS-NSCs, (3)vehicle, or (4)sham surgery. Results: SMaRT cells retained key hiPS-NSC characteristics while stably expressing ENZYME. The expressed ENZYME could appropriately degrade in vitro and ex vivo CSPGs. While blinded neurobehavioural and immunohistochemical assessments are ongoing at 40wks post-injury, an interim analysis demonstrated human cells extending remarkably long (≥20,000µm) axons along host white matter tracts. Conclusions: This work provides exciting proof-of-concept data that genetically-engineered SMaRT cells can degrade CSPGs and human NSCs can extend long-distance processes in chronic SCI.

Background The long-term cognitive and quality-of-life (QoL) outcomes after treatment of ruptured anterior communicating artery (ACoA) aneurysms are unknown. Methods Potential participants were all consecutive patients with ruptured ACoA aneurysms who were treated at one institution from July 1992 to December 2008. All potential participants were asked to complete the Cognitive Failures Questionnaire (CFQ), Center for Epidemiology Studies-Depression (CES-D) questionnaire, Short Form 36 (SF-36) questionnaire, and Telephone Interview for Cognitive Status-Modified (TICS-M). Patient charts were retrospectively reviewed for baseline demographics and clinical status, intra-operative details, and post-operative course. Reporting of cognitive and QoL assessment results was stratified by treatment method (endovascular coil embolization and surgical clipping by pterional craniotomy or orbitocranial craniotomy). Results In total, 82 patients (18 treated with coiling, 27 by orbitocranial craniotomy, and 37 by pterional craniotomy) were included in this study. In total, 32 patients (9 treated by coiling, 11 by orbitocranial craniotomy, and 16 by pterional craniotomy) completed follow-up cognitive and QoL questionnaires. The mean follow-up for patients who completed the questionnaires was 8.64±3.81 years. The three groups did not differ in questionnaires assessing cognitive status (TICS-M p=0.114, CFQ p=0.111). Moreover, there were no observed differences in QoL or depression scores between the three groups. Conclusions At long-term follow-up, QoL, cognitive, and depression test scores of patients with ruptured ACoA aneurysms are similar across open surgery and coiling modalities. Our results emphasize the importance of considering long-term outcomes with validated daily measures of functioning when reporting on outcomes after treatment for ruptured intracranial aneurysms. Larger prospective studies are required to further explore the results.

Objective: Neuronal ceroid-lipofuscinoses are a heterogeneous group of inherited disorders in which abnormal lipopigments form lysosomal inclusion bodies in neurons. Kufs disease is rare, and clinical symptoms include seizures, progressive cognitive impairment, and myoclonus. Most cases of Kufs disease are autosomal recessive; however, there have been a few case reports of an autosomal dominant form linked to mutations within the DNAJC5 gene. Methods: We describe a family with Kufs disease in which the proband and three of her four children presented with cognitive impairment, seizures, and myoclonus. Results: Genetic testing of all four children was positive for a c.346_348delCTC(p.L116del) mutation in the DNAJC5 gene. The proband brain had an abundance of neuronal lipofuscin in the cerebral cortex, striatum, amygdala, hippocampus, substantia nigra, and cerebellum. There were no amyloid plaques or neurofibrillary tangles. Immunohistochemistry demonstrated that the cholinergic neurons and cholinergic projection fibers were spared, but there was a profound loss of choline acetyltransferase within the caudate, putamen, and basal forebrain. This suggests a loss of choline acetyltransferase as opposed to a loss of the neurons. Conclusions: This report describes the clinical history of autosomal dominant Kufs disease, the genetic mutation within the DNAJC5 gene, and the neuropathological findings demonstrating depletion of choline acetyltransferase in the brain.

Objective: Hockey is a popular sport played by many First Nation youth. Concussion frequently goes unrecognized and unreported in youth hockey. Unintentional injuries among Indigenous youth occur at rates three to four times the national Canadian average. The study sought to examine knowledge, attitudes and sources of concussion information among First Nations people attending a provincial hockey tournament. Methods: A cross-sectional survey was undertaken. The survey by Mzazik et al. were modified to use in this study. Participants included youth (6-18 years) hockey players (n=75), parents (n=248) and coaches (n=68). The main outcome measure was total knowledge index (TKI) which consisted of the sum of correct responses to 15 multiple choice questions. Additional data gathered included demographics, concussion history, attitudes toward concussion and sources of information. Descriptive statistics included proportion comparisons. Variables were tested using χ2 and analysis of variance. Results: Overall TKI scores (out of a total of 15) were low; players (5.9±2.8), parents (7.5±2.6) and coaches (7.9±2.6). Participants with higher knowledge scores reported more appreciation of the seriousness of concussion. Sources of information about concussion differed by study group, suggesting the need for multiple knowledge translation strategies to reach youth, parents and coaches. Conclusions: Future initiatives are urgently needed to improve education and prevention of concussion in First Nations youth hockey. Collaborating and engaging with communities can help to ensure an Indigenous lens for culturally safe interventions.

Background: Stereoelectroencephalography has been in regular use at the Montreal Neurological Institute since 1972. The technique has been in constant evolution to incorporate advances in materials, imaging, and robotics technology. MRI-compatible electrodes were introduced in 2007 and robotics in 2011. Here we report on the technique, safety, and advantages of our current method of stereoelectroencephalography implantation. Methods: We retrospectively reviewed all patients who underwent stereoelectroencephalography by the senior author. Technical, clinical, and radiological complications, and postimplantation outcomes were analyzed. Only patients implanted with MRI-compatible electrodes were included to review MRI abnormalities with electrodes in situ. Results: A total of 53 patients were implanted with 550 electrodes (average=10.4 per patient), for an average duration of 14.6 days. There was no mortality, infection, or new neurologic deficit. Two patients had a superficial screw plunge without clinical consequence. Four patients demonstrated asymptomatic MRI abnormalities (7.54% per patient, or 0.72% per electrode). MRI with electrodes in situ was used for neuronavigation in all 29 who underwent resection and yielded a histopathological diagnosis of focal cortical dysplasia in 15 MRI-negative patients. Conclusions: The technique of stereoelectroencephalography described here was associated with no clinical morbidity although not without technical complications or radiologic (MRI) abnormalities. We should therefore remain vigilant in refining the technique and minimizing the number of electrodes required to answer a well-developed hypothesis regarding the epileptogenic zone. The use of MRI-compatible electrodes allowed neuronavigation using the images with the electrodes in situ, which was useful to tailor the eventual definitive resection and in localizing MRI-negative lesions.

Background: A major concern of patients undergoing Gamma Knife radiosurgery (GKS) for benign tumors and other conditions is the risk of a separate secondary malignancy or malignant -transformation. The incidence of radiosurgery-associated malignancy based on long-term follow-up remains unknown. Methods: We conducted a population-based cohort study to estimate the incidence rate of both malignant transformation and a separate radiation-associated malignancy in patients undergoing GKS from 1987 to 2016 at 5 centers. Results: 11 527 patients underwent radiosurgery for meningioma (n=3261), arteriovenous malformation (n=2868), trigeminal neuralgia (n=1982), vestibular schwannoma (n=1957), pituitary adenoma (n=1193), other (n=266). The follow-up time ranged from 0.3 to 23.8 years. Four cases of malignant transformation and 3 new malignant brain tumors were reported, two of which were not within the irradiated field. The incidence of malignant transformation was 6.6 per 100 000 patient-years and of new malignancy, either locally or distant, was 5 in 100 000 patient-years. These risks are not higher than the Central Brain Tumor Registry of the United States derived annual incidence rate of all primary malignant CNS tumors of 7.15 per 100 000. Conclusions: Physicians can safely counsel patients that the risk of malignancy after stereotactic radiosurgery remains extremely low, even at long-term follow-up of greater than 10 years.

Introduction: In an effort to better understand why cognitively normal patients were referred to a memory clinic, we sought to identify features of “worried well” patients to better identify those more likely to be cognitively normal. Methods: In total, 375 consecutive patients referred by primary care practitioners to a Rural and Remote Memory Clinic were categorized into two groups based on their neurologic diagnosis, “worried well” (cognitively normal, N=81) or “other” (patients with any neurologic diagnosis, N=294). Data collected included: age, sex, years of formal education, Mini-Mental Status Examination score from initial visit, Center for Epidemiologic Studies Depression Scale score, Self-Rating of Memory Scale, alcohol consumption, marital status, hours per week of work, past medical history, sleep concerns, and family history of memory concerns. The two groups were compared using t-tests and χ2 tests. The same comparison was done between the same set of “worried well” patients (cognitively normal, N=81) and the subgroup of patients with a diagnosis of Alzheimer’s disease (N=146) from the “other” group. Results: Significant differences included younger age, more formal education, more frequently having previous psychiatric diagnosis and more self-reported alcohol consumption in the “worried well” group. The “worried well” and “Alzheimer’s disease” comparison had the same significant differences as the “worried well” and “other” comparison. Conclusion: We observed a pattern of differences unfold between the “worried well” patients and those with cognitive disease. No one variable was pathognomonic of a “worried well” patient. However, taking all the above into account when evaluating a patient may help clinically.

The enzyme polynucleotide kinase/phosphatase (PNKP) plays a key role in DNA repair by resolving the chemistry at DNA strand breaks. Mutations in PNKP (chromosome 19q13.4) are known to cause MCSZ, a serious neurodevelopmental disorder, but to date there has been no link to cancer initiation or progression. However, a child with MCSZ recently presented at Seattle Children's Hospital with a 3-cm glioblastoma. The child was shown to have two germline mutations in PNKP. To study the effects of the PNKP mutations found in this patient, we generated mutant PNKP cDNAs carrying either the individual mutations or the double mutation using site directed mutagenesis. These cDNAs were incorporated into bacterial and mammalian expression vectors. The bacterially expressed mutant proteins as well as the wild type have been purified and are undergoing testing for PNKP DNA kinase and phosphatase activity. The PNKP cDNAs, fused to GFP, were expressed in Hela and HCT116 human cancer cell lines. High-content analysis and micro-irradiation techniques are being used to determine PNKP localization within the cells and recruitment to damaged DNA. Our preliminary results indicate that the mutations alter the ratio of nuclear to cytoplasmic PNKP compared to the wild-type protein.

Molecular studies suggest that anaplastic oligodendrogliomas (OIII) can be subdivided into clinically relevant subgroups. We analyzed a retrospective series of 40 consecutive OIII operated at our institution and compared them to 10 grade II oligodendrogliomas (OII). Chromosome 9p status was compared to Bcl1, Myc and p16 expression by immunohistochemistry, clinical and histological data, and to event free survival (EFS) and overall survival (OS).

Chromosome 9p deletion was observed in 55 % of OIII (22/40) but not in OII, and correlated with both OS and EFS. Bcl1 expression was significantly higher in OIII (45 % versus 14% for OII) and correlated with MIB-1 expression, vascular proliferation, tumour necrosis and a shorter EFS. Myc expression was correlated with histologic grade (27% in OII, 35% in OIII) and to a shorter EFS in chromosome 9p non-deleted OIII. p16 expression was not correlated with grade but revealed two distinct expression profiles according to chromosome 9p status. In 9p non-deleted oligodendrogliomas, p16 hyperexpression was correlated with shorter OS in both OII and OIII whereas absence of p16 expression was correlated with shorter OS and EFS in 9p deleted OIII.

Objectives: The objective of this study was to evaluate the feasibility and implementation of a standardized medically supervised concussion protocol established between a city-wide AAA hockey league and a multi-disciplinary concussion program. Methods: We conducted a retrospective review of injury surveillance, clinical and healthcare utilization data from all athletes evaluated and managed through the Winnipeg AAA Hockey concussion protocol during the 2016-2017 season. We also conducted post-season email surveys of head coaches and parents responsible for athletes who competed in the same season. Results: During the 2016-2017 season, 28 athletes were evaluated through the medically supervised concussion protocol, with two athletes undergoing evaluation for repeat injuries (a total of 30 suspected injuries and consultations). In all, 96.7% of the athletes managed through the concussion protocol were captured by the league-designated Concussion Protocol Coordinator and 100% of eligible athletes underwent complete medical follow-up and clearance to return to full hockey activities. Although 90% of responding head coaches and 91% of parents were aware of the concussion protocol, survey results suggest that some athletes who sustained suspected concussions were not managed through the protocol. Head coaches and parents also indicated that athlete education and communication between medical and sport stakeholders were other elements of the concussion protocol that could be improved. Conclusion: Successful implementation of a medically supervised concussion protocol for youth hockey requires clear communication between sport stakeholders and timely access to multi-disciplinary experts in traumatic brain and spine injuries. Standardized concussion protocols for youth sports may benefit from periodic evaluations by sport stakeholders and incorporation of national guideline best practices and resources.

BACKGROUND: Exercise has been shown to benefit health-related fitness, psychosocial health, and disease outcomes in cancer survivors. PURPOSE: To review the evidence on exercise for individuals diagnosed with Neurological Cancer (NC); present data on NC participants in the ACE pilot and ongoing implementation study; and propose a framework to incorporate exercise into the care of NC survivors in Alberta. METHODS: The ACE program is open to survivors with any cancer diagnosis at any stage of treatment. Exercise programming consists of two training sessions per week, with the pilot and implementation studies being 8 and 12 weeks in duration respectively. Outcomes are assessed at study baseline, post-exercise intervention, and 24-week follow-up, and include recruitment and follow-up rates, health-related fitness, psychosocial outcomes, and cancer symptoms. RESULTS: NC survivors represented 7 of 80 participants in the ACE pilot; however, only 3 of the 7 (43%) completed the study. Findings suggested a need for consideration of supervised exercise for some survivors with NC. To date, 14 NC survivors have enrolled in the ACE implementation study. Participants are screened and then referred to either supervised clinic-based or community-based exercise. Seven of 9 participants have completed the ACE intervention, and 5 of 5 have completed the 24-week follow-up. NC participants improved or maintained health-related physical fitness, and reported reduced symptom burden and fatigue. CONCLUSION: Preliminary results suggest exercise training is feasible and beneficial for NC survivors. To optimize recruitment and outcomes, efforts are needed to better identify, screen, and refer survivors to appropriate exercise programming.

Background: Cerebral venous thrombosis is a rare cause of stroke, with a number of well-defined risk factors. However, there exist few studies that describe trends in the prognosis of this disease over time. Methods: A retrospective study was performed on patients diagnosed with cerebral venous thrombosis at the University of Alberta Hospital during two time periods: 1988-1998 (21 patients) and 1999-2009 (40 patients). Signs and symptoms, risk factors, imaging findings, etiologies, treatment modalities, and status at discharge were examined. Results: Headache, nausea and vomiting, focal motor deficit, and seizure were the most common signs and symptoms, and active hormonal contraception was the most commonly identified risk factor between the two cohorts. Hematoma and hyperdense sinuses were the most commonly identified CT findings between groups. Thrombophilia and the use of hormonal contraception were the most frequently identified etiologies between the two cohorts. Treatment was similar, with the majority of patients in both cohorts receiving unfractionated heparin as first-line therapy. Patients in the 1999-2009 cohort were significantly less likely to have a severe deficit or be dead at discharge (odds ratio [OR]=0.178; 95% confidence interval [CI95%]=0.051, 0.625) and were more likely to have a favorable modified Rankin Scale score of 0 or 1 at discharge (OR=7.98; CI95%=1.79, 35.71). Conclusions: Our data indicate a reduction in severe residual symptoms at discharge and improved functional status at discharge for patients presenting with cerebral venous thrombosis from 1999 to 2009, as compared with 1988-1998.

Background: Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease resulting in muscle weakness, dysarthria and dysphagia, and ultimately respiratory failure leading to death. Half of the ALS patients survive less than 3 years, and 80% of the patients survive less than 5 years. Riluzole is the only approved medication in Canada with randomized controlled clinical trial evidence to slow the progression of ALS, albeit only to a modest degree. The Canadian Neuromuscular Disease Registry (CNDR) collects data on over 140 different neuromuscular diseases including ALS across ten academic institutions and 28 clinics including ten multidisciplinary ALS clinics. Methods: In this study, CNDR registry data were analyzed to examine potential differences in ALS care among provinces in time to diagnosis, riluzole and feeding tube use. Results: Significant differences were found among provinces, in time to diagnosis from symptom onset, in the use of riluzole and in feeding tube use. Conclusions: Future investigations should be undertaken to identify factors contributing to such differences, and to propose potential interventions to address the provincial differences reported.

Eosinophils may affect each stage of tumor development. The presence of eosinophils appears to correlate with longer patient survival in several non-CNS malignant tumors. Tumor-associated tissue eosinophilia (TATE) has been increasingly recognized. Two previous studies (Hayes RL, et al. 1995; 2001) revealed eosinophils in the intracavitary tissues of malignant gliomas following the infusion of IL-2 combined with activated autologous killer cells, but not in the primary operative specimens. Our recent study (Lu JQ, et al. 2014) demonstrated the infiltration of eosinophils in 19 of 44 pilocytic astrocytomas but not in 10 ependymomas. In the present study, we examined 7 cases of subependymal giant cell astrocytoma (SEGA; 4 with tuberous sclerosis; age range: 13 – 33 years; 4 males and 3 females), as SEGA is well known to contain infiltrating mast cells and lymphocytes. Five of 7 SEGA contained eosinophils that were focally scattered to rare in frequency; intratumoral and/or perivascular in location. In comparison, only one of 8 consecutive cases of glioblastoma showed infiltrating eosinophils. The incidence of TATE is significantly higher in SEGA than that in glioblastoma (71.4 % versus 12.5%; p=0.04, by Fisher’s exact test) but is not significantly different from that in pilocytic astrocytoma (71.4 % versus 43.2%, previously reported; p=0.232). Our findings support the concept that eosinophils may play a functional role in the development of astrocytic tumors, especially those with longer patient survival.