One-third of all primary central nervous system tumors in adults are meningiomas, which arise from the meninges. Although the majority of meningioma cases are not associated with an environmental risk factor, it is well established that individuals receiving radiation treatment to the CNS are susceptible to radiation-induced meningiomas (RIMs). The genomic integrity of spontaneous meningiomas has been extensively profiled by whole genome sequencing and exome sequencing, providing a well-developed catalogue of meningioma associated mutations. In contrast, a comprehensive understanding of the molecular changes associated with RIMs is not available. Comparative genomic hybridization (CGH) has previously revealed that >90% of RIMs possess multiple regions of DNA copy number alterations, with the most common chromosomal loss being chromosome 1p and 22q. These CGH based studies of gross chromosomal alterations suggest that radiation induced meningiomas show no significant differences to spontaneous meningiomas. We have extensively characterized RIMs through the profiling of their global CpG methylation, gene expression and mutation signatures. The integration of these three platforms at base-pair resolution methylation has facilitated the identification of molecular changes that contribute to RIM. This is the largest cohort of profiled meningiomas to date, providing a robust characterization of unique RIM features that can be exploited for future therapies.

Background: The effect of the single seizure clinic (SSC) model on patient diagnosis, work-up, wait-times, and clinical care is poorly characterized. This study assesses patient characteristics and evaluates the impact of a SSC model on wait-times and access to care. Methods: A prospective study of all patients (n=200) referred to our SSC for first-seizure evaluation. Demographic, clinical, and paraclinicial variables were analyzed against a historical cohort. Binary logistic regression analysis was performed to predict impact of dichotomized variables on diagnosis of epilepsy. Diagnostic concordance between SSC nurses and epileptologists was also assessed. Results: Predominant referral sources were emergency department physicians and general practitioners. Mean wait-time for first assessment was significantly reduced by 70.5% employing the SSC model versus historical usual care. A diagnosis was established at first-contact in 80.5% of cases while 16.0% of patients required a second visit. Eighty-two patients (41.0%) were diagnosed with epilepsy. The most common non-seizure diagnosis was syncope (24.0%). An abnormal EEG was found in 93.9% of patients diagnosed with epilepsy. Sixty-three patients were started on anti-epileptic drugs. In 18% of cases driving restrictions were initiated by the SSC. There was moderate correlation between SSC nurses and physicians (kappa=0.54; p<0.001) diagnoses. Conclusions: The SSC model reduces wait-times, streamlines assessments, and impacts clinical care decisions.

Background: Rural living has been demonstrated to have an effect on a person’s overall health status, and rural residing individuals often have decreased access to health and specialized rehabilitation services. Aim: The aim of this study was to determine if there are differences in recovery from stroke between urban and rural-dwelling stroke survivors accessing an in-home, community-based, interdisciplinary, stroke rehabilitation program. Methods: Data from a cohort of 1222 stroke survivors receiving care from the Community Stroke Rehabilitation Teams between January 2009 and June 2013 was analyzed. This program delivers stroke rehabilitation care directly in a person’s home and community. Functional and psychosocial outcomes were evaluated at baseline, discharge, and six -month follow-up. A series of multiple linear regression analyses was performed to determine if rural versus urban status was a significant predictor of discharge and 6-month health outcomes. Results: The mean age of the rural cohort was 68.8 (±13.1) years (53.6% male), and the urban cohort was 68.4 (±13.0) years (44.8% male). A total of 278 (35.4%) individuals were classified as living in a rural area using the Rurality Index for Ontario. In multivariate linear regression analysis, no significant differences on the Functional Independence Measure, the Stroke Impact Scale, the Hospital Anxiety and Depression Scale, or the Reintegration to Normal Living Index were found between urban and rural cohorts. Conclusions: When provided with access to a home-based, specialized stroke rehabilitation program, rural dwelling stroke survivors make and maintain functional gains comparable to their urban-living counterparts.

Background: Pediatric neurology trainee numbers have grown considerably in Canada; recent research, however, has shown that the number of pediatric neurology graduates is outpacing the need for future pediatric neurologists. The purpose of this study was to seek the opinion of pediatric neurology program directors and trainees regarding possible solutions for this issue. Methods: Two focus groups were convened during the Canadian Neurological Sciences Federation annual congress in June 2012; one consisted of current and former program directors, and the other of current pediatric neurology trainees. Groups were asked for their perceptions regarding child neurology manpower issues in Canada as well as possible solutions. Focus groups were audio-recorded and transcribed for analysis. Theme-based qualitative analysis was used to analyze the transcripts. Results: Major themes emerging from both focus groups included the emphasis on community pediatric neurology as a viable option for trainees, including the need for community mentors; recognizing the needs of underserviced areas; and establishing academic positions for community preceptors. The need for career mentoring and support structures during residency training was another major theme which arose. Program directors and trainees also gave examples of ways to reduce the current oversupply of trainees in Canada, including limiting the number of trainees entering programs, as well as creating a long-term vision of child neurology in Canada. Conclusions: A nationwide dialogue to discuss the supply and demand of manpower in academic and community pediatric neurology is essential. Career guidance options for pediatric neurology trainees across the country merit further strengthening.

Factors which might influence outcome in patients with meningioma are not well-understood. Previous studies have examined associations of laboratory blood values including hemoglobin levels with patient outcomes in cancer. We hypothesized those changes in CBC before tumor resection can be used as one of the prognostic factors for tumor recurrence/progression in meningioma. To address this, we gathered the clinical and pre-operative CBC results for final analysis from 226 patients (64 males and 162 females) who underwent craniotomy for primary meningioma (grades: 157 WHO GI, 59 GII, 10 GIII) at our institution between 2001 and 2015.Individual parameters were analyzed for correlation with progression-free survival. The median recurrence free survival (RFS) was not reached and follow-up ranged 0.3-14 years. Fifty-six patients (25%) had anemia and 30% of the patients showed leukocytosis using standard cut-offs. On univariate analyses, low hemoglobin (Hb) level, as well as high leukocytes (Lkc), neutrophil (Neutro) and monocyte counts correlated with worse RFS. As expected, tumor grade was correlated with RFS. Low Hb level, high Lkc and Neutro counts were all significantly associated with RFS after adjusting for grade. Strikingly, 32% of patients with pre-operative anemia experienced a recurrence at 5 years, compared with only 11% of non-anemic patients. Conclusion: In this exploratory study, we find that pre-operative CBC data, which is readily available, may contain prognostic information relevant to subsequent risk of recurrence or progression in meningioma. While the biological mechanism for these associations is not clear, they represent hypotheses for further investigation.

Background: Despite the ease of intraoperative injection, intrathecal morphine (ITM) is rarely provided in lumbar spine surgery. We therefore sought to demonstrate the safety and efficacy of ITM following lumbar fusion. Methods: In this double-blind trial, 150 patients undergoing elective instrumented lumbar fusion were randomly assigned to receive a single injection of ITM (0.2 mg) or placebo (saline) prior to wound closure. Primary outcomes were postoperative pain on the visual-analog scale during the inital 24 hours after surgery and respiratory depression. Secondary outcomes included related adverse events, opioid requirements, and length of stay. Outcome curves were estimated in an intention-to-treat, repeated-measures analysis. Results: Age, disability, operative times, and pre-operative pain were similar in both groups. ITM was associated with less pain both at rest (p<0.002) and with movement (p<0.02) during the initial 24 hours following surgery. ITM did not increase the cumulative incidence of respiratory depression (hazard ratio 0.86, p=0.66). While ITM reduced postoperative opioid requirements (p<0.03), there was no significant difference in length of stay (p=0.67). Adverse events did not significantly differ between groups. The early benefits of ITM on postoperative pain were no longer apparent after 48 hours. Conclusions: A single ITM injection safety reduces postoperative pain following lumbar fusion. (ClinicalTrials.gov NCT01053039)

Background: In response to the rising incidence of concussions among children and adolescents, the province of Ontario recently introduced the Ontario Policy/Program Memorandum on Concussions (PPM No. 158) requiring school boards to develop a concussion protocol. As this is the first policy of its kind in Canada, the impact of the PPM is not yet known. Methods: An electronic survey was sent to all high school principals in the Toronto District School Board 1 year after announcement of the PPM. Questions covered extent of student, parent, and staff concussion education along with concussion management protocols. Results: Of 109 high school principals contacted, 39 responded (36%). Almost all schools provided concussion education to students (92%), with most education delivered through physical education classes. Nearly all schools had return to play (92%) and return to learn (77%) protocols. Although 85% of schools educated staff on concussions, training was aimed at individuals involved in sports/physical education. Only 43.6% of schools delivered concussion education to parents, and many principals requested additional resources in this area. Conclusions: One year after announcement of the PPM, high schools in the Toronto District School Board implemented significant student concussion education programs and management protocols. Staff training and parent education required further development. A series of recommendations are provided to aid in future concussion policy development.

Background: The pathophysiology of subarachnoid hemorrhage (SAH) is complex and includes disruption of the blood-brain barrier (BBB). We freshly isolated BBB endothelial cells (BECs) by 2 distinct methods after experimental SAH and then interrogated their gene expression profiles with the goal of uncovering new therapeutic targets. Methods: SAH was induced using the prechiasmatic blood injection mouse model. BBB permeability studies were performed by administering intraperitoneal cadaverine dye injections at 24h and 48h. BECs were isolated either by sequential magnetic-based sorting for CD45-CD31+ cells or by fluorescence-activated cell sorting (FACS) for Tie2+Pdgfrb- cells. Total RNA was extracted and analyzed using Affymetrix Mouse Gene 2.0 ST Arrays. Results: BBB impairment occurred at 24h and resolved by 48h after SAH. Analysis of gene expression patterns in BECs at 24h reveal clustering of SAH and sham samples. We identified 707 (2.8%) significant differentially-expressed genes (403 upregulated, 304 downregulated) out of 24,865 interrogated probe sets. Many significantly upregulated genes were involved in inflammatory pathways. These microarray results were validated with real-time polymerase chain reaction (RT-PCR). Conclusions: This study is the first to investigate in an unbiased manner, whole genome expression profiling of freshly-isolated BECs in an SAH animal model, yielding targets for novel therapeutic intervention.

Background: Status epilepticus (SE) is a frequent admission diagnosis to paediatric intensive care units (PICUs) and is associated with variable outcomes. We have audited our experience of patients presenting in SE at a Canadian PICU to determine unfavorable outcome variables. Methods: Charts of patients <18 years of age presenting in SE to a tertiary care PICU over a 10-year period were audited. Data were analyzed at three care-points: transport, the emergency department (ED) and the PICU. Patient outcome before PICU discharge was categorized as “favorable” for return to pre-status functioning level or “unfavorable” for new deficit/death. Student’s t-test and the Kruskal-Wallis test were used for analysis of normal and skewed continuous variables, respectively, and either Chi-square test or Fisher’s exact test for categorical variables. Results: 189 patients (54% males) were identified with a median age of 1.9 years. Idiopathic SE had the highest incidence; infectious/vascular etiologies were associated with more unfavorable outcomes. Progression to refractory SE in the ED had a higher incidence of death (p<0.05). Patients with an unfavorable outcome had a higher incidence of apnea during transport (p=0.01), longer hospital stays (p<0.05), need for therapeutic coma (p=0.01), longer duration of therapeutic coma (p<0.05), need for mechanical ventilation (p<0.05), and recurrent or refractory seizures during inpatient stay (p<0.05). Multivariate analysis of unfavorable outcomes of patients in SE presenting to the PICU included renal failure, cerebral edema, apnea during transport, refractory seizures, and recurrent seizures. Conclusions: Refractory seizures in children presenting with SE are associated with worsened outcomes in the PICU.

We aimed to investigate the feasibility of delivering stereotactic radiosurgery (SRS) or hypofractionated stereotactic radiotherapy with the hybrid MRI-LINAC (MRL) system for patients with single brain metastases, and to characterize the dosimetric impact at tissue-air interfaces resulting from the electron return effect (ERE). Material/Methods: 24 patients treated for intact single brain metastases were selected for analysis. Three optimized radiotherapy plans with the same prescribed dose were generated for each case: 1) standard noncoplanar volumetric modulated arc therapy (VMAT), 2) coplanar step-and-shoot intensity modulated radiotherapy (IMRT) on the MRL in the absence (MRL_B=0), and 3) in the presence of the transverse magnetic field (MRL_B=1.5). The plans were evaluated using cumulative dose-volume histograms (DVHs) and by calculation of Paddick conformity index (PCI), V100%, V12Gy minus gross tumor volume (V12Gy – GTV), and V2Gy. The dosimetric impact of ERE to the skin and air cavities was quantified using a 5 mm rim of tissue around tissue-air boundaries. Results: All plans met the objectives with respective to target coverage and OAR constraints. Differences between all investigated dosimetric parameters significantly favored the VMAT plans as compared to the MRL_B=0 and MRL_B=1.5 plans, except for V2Gy. The VMAT plans showed a higher mean (±standard deviation) PCI compared to the MRL_B=0 and MRL_B=1.5 plans (0.85±0.08 vs. 0.79±0.09 vs. 0.78±0.11). In the presence of the magnetic field, ERE resulted in a statistically significant but small increase in mean dose and D2cc in the skin (0.08 Gy, p < 0.0001 and 0.66 Gy, p < 0.0001, respectively) and around air cavities (0.07 Gy, p = 0.0092 and 0.25 Gy, p = 0.0004, respectively). Conclusions: Stereotactic radiation to single brain metastases is feasible using the MRL Monaco treatment planning system; however, in its current iteration, application to small targets deserve careful consideration given the technical limitations resulting in less favorable plan quality compared to that of a noncoplanar standard VMAT technique. The dosimetric impact of ERE at tissue-air boundaries is minor and does not compromise target conformity or dose gradient.