Although genetic mutations are usually responsible for the initial tumor formation and progression, changes in the microenvironment also have a critical role in facilitating this process. Many ''untransformed'' cells infiltrate the tumors, and recent evidence suggests cancer cells can ‘reprogram’ normal cells by miRNAs, which are small, non-coding RNA molecules that regulate several protein targets. One prominent feature of glioma pathology is massive gliosis, an inflammatory response consisting of reactive astrocytes, in and around the tumor. We show that expression of Cx43, a major gap junction protein in astrocytes, is significantly enhanced in astrocytes at the tumor border. Using a mouse model consisting of syngeneic intracranial implantation of GL261 glioma cells into Nestin-Cre:Cx43fl/fl mice in which Cx43 is selectively eliminated in astrocytes, we demonstrate that reduction of astrocytic Cx43 decreases the dissemination of glioma cells from the tumor core. Similarly, knocking down Cx43 in astrocytes also reduces glioma invasion in a co-culture of glioma cells and astrocytes. By comparing the microRNA profiles of the astrocytes before and after co-culture with human glioma cells, we have identified a miR-5096 that appears to reprogram astrocytes to enhance the invasiveness of glioma cells. We are now examining whether we can prevent glioma cells from invading the brain and establishing recurrent secondary tumors by stopping the exchange of materials between glioma cells and astrocytes through eliminating Cx43 channel activity.

Background: Gamma Knife (GK) radiosurgery for pediatric arteriovenous malformations (AVM) of the brain presents a non-invasive treatment option. We report our institutional experience with GK for pediatric AVMs. Methods: We performed a retrospective review of all pediatric patients treated with GK for cerebral AVMs at our institution from November 2003 up to and including September 2014. Patient demographics, AVM characteristics, treatment parameters and AVM responses were recorded.Results: Nineteen patients were treated, with 4 lost to follow-up. The mean age was 14.2 years (range. 7-18 years), with 10 being males (52.6%). The mean AVM diameter and volume were 2.68 cm and 3.10 cm3 respectively. The mean Spetzler-Martin (SM) and Pollock grades of the treated AVMs were 2.4 and 0.99 respectively. The mean follow-up was 62 months. All AVMs treated demonstrated a response on follow-up imaging. Nine of 15 (60.0%) patients displayed obliteration of their AVMs. Nine of 11 patients with a minimum of 3 years follow-up (81.8%) displayed obliteration, with SM and Pollock grades correlating to the chance of obliteration in this group. Two patients developed post-GK edema requiring short course dexamethasone therapy. No other major complications occurred. No permanent complications occurred.Conclusions: GK radiosurgery for pediatric AVMs offers a safe and effective treatment option, with low permanent complication rates during early follow-up.

Objective: To assess the prevalence of pain in adults with spasticity and to assess the association between the subjective experience of pain and spasticity. Design: Cross-sectional study. Setting: outpatient spasticity management clinic of a rehabilitation centre. Patients: Patients with upper motor neuron lesions and spasticity (n=131) were recruited. Methods: We assessed pain intensity and location, relationship between spasticity and pain perception, and perception of pain relief from botulinum toxin type-A (BoNTA) injections. Main outcome measures: Pain perception rated on a 10-point numerical rating scale and pain quality. Results: 65% of the patients with spasticity reported presence of pain and 60% described it as an aching pain. More patients reported pain with movement (34%) compared to rest (21%). There was a statistically poor correlation between the severity of pain and spasticity (r=0.16; p>0.05). Most patients (80%) believed that their pain was related to spasticity and 62% reported that BoNTA injections decreased their pain. Conclusions: The high incidence of pain noted within our sample suggests that physicians may have to consider pain management as part of spasticity treatment. Participants reported that their pain was related to their spasticity, and that it decreased after BoNTA treatment. Further study is needed to explore the relationships between objective measures of spasticity and pain.

Background: In British Columbia, neuromuscular disease accounts for 31% of IVIg use, at a cost of $10.1 M. In addition to the new screening pathway, the BC Neuromuscular IVIg Program developed the Chronic High User Project to identify areas for improvement in utilization. Methods: Utilizing CTR data, all patients on IVIg maintenance therapy for approved neuromuscular conditions between April 1, 2013 and March 31, 2014 were identified. Patients receiving higher than usual IVIG treatments (CIDP and MG >1110 grams/year, MMNCB > 1400 grams/year) were evaluated. Following panel review, utilization data was compared with a second cohort (2014 to 2015) to determine impact. Following review, appropriateness of treatment was determined by consensus from a 3-member panel, and recommendations were made. Results: Of 377 patients, 38 “High Users” were identified. 29 cases were determined to be appropriate; 9 were not. There was a reduction in mean grams/episode in CIDP (1135g to 990g) and MG (1099 g to 1022g) between cohorts. The mean grams/episode for MMNCB did not change. Conclusions: In specific cases, the IVIg High User Program identified patients in whom the treatment could be optimized. However, the vast majority of use of IVIg for Neuromuscular Disease in BC is appropriate, including in patients requiring higher that “usual” doses.

To investigate patterns of survival and estimate conditional survival rates among brain cancer patients in Canada. METHODS: Canadian Cancer Registry data were obtained for all patients with primary brain cancer diagnosed between 1992 and 2008 (n=38,095). Follow-up ended with patient death or December 31, 2008, whichever occurred first. Crude Kaplan-Meier estimates were calculated at one, two, and five years post-diagnosis and also used to estimate conditional survival (restricted to 2000-2008). Age group, sex, residence and microscopic confirmation were considered in estimating rates for major histology types using multivariate models. RESULTS: The overall five-year survival rate was 27%. Oligodendrogliomas had the highest 5-year survival rate (65%, 95% CI: 62.5-67.4%) and glioblastomas the lowest (4.0%, 95% CI: 3.7-4.3%). Compared to Ontario, the age- and sex-adjusted 5-year glioblastoma survival estimates were lower in British Columbia, Alberta and Manitoba-Saskatchewan, lower in all other regions for diffuse astrocytoma, and lower in Manitoba-Saskatchewan for anaplastic astrocytomas. Estimates were significantly higher for oligodendrogliomas in Alberta, and for anaplastic oligodendrogliomas in Alberta and Quebec (P<0.05). Longer term conditional survival rates (surviving an additional 2 years 1-4 years after diagnosis) varied by histologic group. CONCLUSION: There is a need to further explore the underlying reasons for the observed variation in survival rates by region in an effort to improve the prognosis of brain cancer in the Canadian patient population. Conditional survival information has value for clinicians as they plan the course of treatment and follow-up for individual patients.

Background: An increased incidence of hospital admissions coded as acute disseminated encephalomyelitis (ADEM) was noted in Winnipeg, Manitoba, Canada, during the second wave of the influenza pandemic from October 2009 to March 2010. However, it was not clear whether this was due to heightened awareness of potential neurological complications of influenza or influenza vaccination or an actual increase in the number of cases. Methods: We extracted data from the charts of 139 patients hospitalized with an International Classification of Diseases-10 discharge code indicating ADEM (G04.0) or unspecified noninfectious encephalitis or myelitis (G04.8, G04.9) between January 2006 and December 2012. Clinical and laboratory data were reviewed by a neurologist, and diagnoses were determined using the Brighton criteria. Results: Over the entire study period, there were 22 cases of ADEM. During the peak pandemic period (April-December 2009), seven patients were hospitalized with ADEM, corresponding to a rate of 7.8/million/year; 4.7 (95% confidence interval: 1.9-11.4) times higher than the rate before or after the pandemic period. Only one patient with ADEM had received the monovalent A(H1N1)pdm09 vaccine within 12 weeks of hospitalization. Conclusions: We have found an increased incidence of ADEM during the pandemic period that may be related, at least in part, to the increased incidence of influenza during that period. However, there was no temporal relationship with the administration of A(H1N1)pdm09 or seasonal influenza vaccines. Our study provides reassurance that use of these vaccines was not associated with increased risk of ADEM.

Background: Parkinson’s disease (PD) and other parkinsonian syndromes are chronic, progressive neurodegenerative diseases. With advancing disease, both motor and non-motor symptoms represent a considerable burden and symptom relief and quality of life improvement become the main goal of treatment. Botulinum toxins (BTX) are an effective treatment modality for many neurological conditions. Methods: To understand the potential usefulness of BTX in this population, we performed a retrospective chart review of all patients with a clinical diagnosis of idiopathic PD and atypical parkinsonism who received treatment with BTX injections in our center from 1995 to 2014 for a variety of symptoms. Response to BTX was assessed using a subjective Clinical Global Impression. Results: Records of 160 patients were reviewed. Probable idiopathic PD was the diagnosis in 117 patients (73.1%). The main indication for BTX treatment was pain (50.6% of cases). Other indications were the treatment of functional impairment resulting from dystonia (26.25%), sialorrhea (18.75%), freezing of gait, and camptocormia. Considering pain as indication, 81% of all patients with PD reported benefits after the first BTX injections. This benefit was maintained after the last recorded visit without significant difference in outcome compared with the first injection (p=0.067). Similar results were observed in patients with atypical parkinsonism. Conclusions: Our results confirm the safety and efficacy of different uses of BTX in the symptomatic treatment of patients with parkinsonism even in advanced stages of the disease, and suggest BTX treatment could have a safe and useful role in the treatment of pain in this population.

Introduction: Impaired collateral circulation can lead to stroke during carotid endarterectomy. Carotid stump pressure (CSP) is used as a surrogate measure of collateral flow. The objective was to determine whether anatomical features obtained from digital subtraction angiography correlate with CSP during temporary internal carotid artery occlusion. The second objective was to use these features in combination to predict CSP. Methods: Digital subtraction angiographies from 102 patients obtained before endarterectomy were reviewed for anatomical variables including: degree of ipsilateral and contralateral carotid artery stenosis; patency of the anterior communicating artery; presence of cross-flow into ipsilateral middle cerebral artery branches; and size (< or ≥1 mm calibre) of the ipsilateral proximal anterior cerebral (A1), the contralateral A1, and the ipsilateral posterior communicating arteries. At surgery, systemic mean arterial pressure (MAP) and CSP were recorded. Multiple regression analysis was used to assess for anatomical features significantly associated with CSP. A “predicted CSP” equation was applied to 54 subsequent patients and correlated with measured CSP. Results: Variables correlating with CSP included MAP (p=0.001); the presence of severe contralateral carotid stenosis (p=0.002); patency of the anterior communicating artery (p=0.013); and the size of the contralateral A1 segment (p=0.029). Angiographic cross-flow, ipsilateral A1 size, and ipsilateral posterior communicating artery size were not significant. Predicted CSP correlated significantly with measured CSP (p<0.0001; R2=0.34). Conclusions: Anatomical features and systemic MAP are associated with carotid stump pressure during internal carotid artery occlusion and account for a significant amount of its variation.

Background: In 1999, the Institute of Medicine reported that, in the United States, 44,000 to 98,000 people die annually as a result of avoidable medical errors. Among the many initiatives undertaken to stem avoidable surgical errors, the World Health Organization (WHO) Surgical Safety Checklist has certainly been one of the most successful. Many surgical units have implemented adapted versions of the WHO Surgical Safety Checklist, audited their performance and discussed issues relating to the implementation process. However, such literature is still lacking in neurosurgery. Methods: A prospective observational study of 171 neurosurgical cases was conducted over an 8-week period. An independent observer assessed compliance with and completeness of the three steps in the perioperative checklist: Sign-in, Time-out and Sign-out. Factors that may reduce compliance were also analyzed. Results: Compliance with the Sign-in, Time-out and Sign-out steps was 82%, 99% and 93% respectively. On average, 92% of the Time-out elements were verified. The emergent nature of a surgery was the only factor that caused a statistically significant reduction in compliance with the checklist. Overall compliance diminished during the observation period. Conclusion: In this internal audit study, compliance with the preoperative checklist reached a satisfactory level. Further work is still needed, however, on some aspects of our surgical strategy, namely, a relatively low compliance rate with the Sign-in process was recorded and emergent cases were associated with decreased performance.

Background:DEPDC5 gene, mapped to 22q12.2-q12.3, has been associated with a variety of familial epilepsies, including FFEVF, autosomal dominant nocturnal frontal lobe epilepsy, and familial TLE. Notably, DEPDC5 has never been linked to increased risk of sudden unexpected death in epilepsy (SUDEP). Methods: Cases review. Results: We studied a three-generation, non-consanguineous, French-Canadian family with nine clinically affected individuals. The index case is a 39-year-old man who started having seizures (as 2rily GTCS) at the age of 13 years. EEGs showed interictal discharges over the right anterior-temporal region. Brain MRI was unremarkable. Two individuals in this family suffered definite autopsy-confirmed SUDEP, at the ages of 58 and 50 years, respectively. Overall, seizure-history in this family can be summarized by an onset before reaching adulthood followed by subsequent progressive decrease in seizure frequency. Seizures were predominantly nocturnal 2rily GTC. Genetic analysis revealed a pathogenic heterozygous variant in the DEDPC5 gene (p.Gln216, c.646C>T), which results in a premature stop codon, in all affected family members plus on heatlhy relative. Importantly, all the subjects were cognitively intact, and there was no history of cardiac symptomatology/cardiovascular risk factor. Conclusions: The finding in this family suggests that DEPDC5 mutations may be a risk factor for SUDEP.

Introduction: The Circle of Willis (CoW) is the most effective collateral circulation to the brain during internal carotid artery (ICA) occlusion. Carotid stump pressure (CSP) is an established surrogate measure of the cerebral collateral circulation. This study aims to use hemodynamic and computed tomography angiography measurements to determine the strongest influences upon the dependent variable, CSP. These findings could help clinicians noninvasively assess the adequacy of the collateral circulation and facilitate surgical risk assessment in an outpatient setting. Methods: CSP and mean arterial pressure were measured during carotid endarterectomy or during carotid balloon test occlusion in 92 patients. Intracranial arterial diameters were measured on computed tomography angiography at 16 different locations. Univariate and multivariate analyses were used to determine the key factors associated with CSP. In a subgroup of individuals (n=27) with severe (>70% North American Symptomatic Carotid Endarterectomy Trial) contralateral stenosis or occlusion, the same analysis was performed. Results: The contralateral anterior cerebral artery proximal to anterior communicating artery (A1) of the CoW had the strongest influence upon CSP, followed by the mean arterial pressure, the contralateral ICA diameter, and the anterior communicating artery diameter (R2=0.364). In the subgroup with high-grade contralateral ICA stenosis, the ipsilateral posterior communicating artery exerted the strongest influence (R2=0.620). Conclusions: During ICA occlusion, the anterior CoW dominates in preserving collateral flow, especially the contralateral A1 segment. In individuals with high-grade contralateral carotid stenosis, the posterior communicating artery calibre becomes a dominant influence. The most favourable anatomy consists of large contralateral A1 and anterior communicating arteries, and no contralateral carotid stenosis.

Meningiomas are the most common primary benign brain tumor. Radiosurgery (primary or adjuvant) allows excellent local control. The Geriatric scoring system (GSS) for pre-operative risk stratification and outcome prediction of patients with meningiomas has been previously reported. The GSS incorporates eight tumor and patient parameters on admission. A GSS score higher than 16 was previously reported to be associated with a more favorable outcome. We assessed the validity of the GSS score and its influence on outcome in patients treated with gamma-knife radiosurgery (GKRS). Methods: Patients treated with single session GKRS for WHO-1 meningioma during 1989-2013 at the University of Virginia were reviewed. A cohort of 323 patients, 50.2% (n=162) males. Median age was 56 (29-84), and median follow-up was 53.6 (6-235) months. Median tumor volume was 4.5 cm3 (0.2-23). Median margin and maximal doses were 15 Gy (8-36) and 32.3 Gy (20-65), respectively. Results: Tumor volume control was achieved in 87% (n=281), and post-GKRS clinical neurological improvement reported in 66.3% (n=214). The median change in KPS was +10 (range -30 to +40). The most common complication was intermittent headaches (34.1%, n=110) and cranial nerve deficits (14.2%, n=46). The GSS (calculated and grouped as GSS>16 and GSS<=16) was found to correlate with different Post-GKRS functional status (p<0.0001) and tumor control (p=0.028). Conclusion: The GSS, used for risk stratification and outcome prediction in patients with meningiomas seems valid for patients undergoing single session GRKS. GSS score greater than 16 is associated with a better long-term functional status and tumor control.

Background: Chronic ataxia, greater than two months in duration, is encountered relatively commonly in clinical pediatric neurology practise and presents with diagnostic challenges. It is caused by multiple and diverse disorders. Our aims were to describe the neuroimaging features and the value of repeat neuroimaging in pediatric chronic ataxia to ascertain their contribution to the diagnosis and management. Materials and Methods: A retrospective charts and neuroimaging reports review was undertaken in 177 children with chronic ataxia. Neuroimaging in 130 of 177 patients was also reviewed. Results: Nineteen patients had head computed tomography only, 103 brain magnetic resonance imaging only, and 55 had both. Abnormalities in the cerebellum or other brain regions were associated with ataxia. Neuroimaging was helpful in 73 patients with 30 disorders: It was diagnostic in 9 disorders, narrowed down the diagnostic possibilities in 14 disorders, and revealed important but non-diagnostic abnormalities, e.g. cerebellar atrophy in 7 disorders. Having a normal magnetic resonance imaging scan was mostly seen in genetic diseases or in the early course of ataxia telangiectasia. Repeat neuroimaging, performed in 108 patients, was generally helpful in monitoring disease evolution and in making a diagnosis. Neuroimaging was not directly helpful in 36 patients with 10 disorders or by definition the 55 patients with unknown disease etiology. Conclusions: Normal or abnormal neuroimaging findings and repeat neuroimaging are very valuable in the diagnosis and management of disorders associated with pediatric chronic ataxia.

Objective: Oxidative stress is involved in the pathogenesis of multiple system atrophy (MSA). The aim of this study is to examine oxidant biomarkers including homocysteine (Hcys), bilirubin, uric acid, lipids, and potential environmental risk factors and to ascertain whether these data correlate with MSA in a Chinese population. Methods: In this study, serum levels of Hcys, bilirubin, uric acid, and lipids were studied in 55 MSA patients and 76 healthy controls (HCs). Education, anti-parkinsonian agent usage, smoking, drinking, farming, and living area of the subjects also were analyzed. The Unified MSA Rating Scale (UMSARS), Hoehn & Yahr stage, International Cooperative Ataxia Rating Scale, and Mini-Mental State Examination were used to assess the disease severity, the parkinsonism, ataxia, and the cognitive ability of MSA, respectively. Results: The levels of Hcys were higher (p<0.001) and those of total bilirubin (p=0.007), indirect bilirubin (p=0.011), and total cholesterol (p=0.046) were lower in MSA patients than in healthy controls, whereas uric acid levels did not differ significantly between MSA and healthy controls. Moreover, Hcys levels in MSA patients had positive correlations with illness duration (rs=0.422, p=0.001) and UMSARS-I (rs=0.555, p<0.001), respectively. High-density lipoprotein cholesterol levels were negatively correlated with UMSARS-I (rs=−0.325, p=0.015). Farming was more frequent in MSA patients (1-20 years: odds ratio, 6.36; p<0.001; >20 years: odds ratio, 10.26; p=0.001), whereas current smoking was less frequent (odds ratio, 0.13, p=0.002). Conclusions: Elevated Hcys and decreased high-density lipoprotein cholesterol may be associated with the disease severity of MSA. Environmental exposures such as farming and smoking may contribute to the occurrence but not the progression of MSA.

Background: Hereditary spastic paraplegia (HSP) is a neurodegenerative disease that is characterized by progressive weakness and spasticity of the lower extremities; HSP can present as complicated forms with additional neurological signs. More than 70 disease loci have been described with different modes of inheritance. Methods: In this study, nine subjects from a Chinese family that included two individuals affected by HSP were examined through detailed clinical evaluations, physical examinations, and genetic tests. Targeted exome capture technology was used to identify gene mutations. Results: Two novel compound heterozygous mutations in the SPG 11 gene were identified, c.4001_4002insATAAC and c.4057C>G. The c.4001_4002insATAAC mutation leads to a reading frame shift during transcription, resulting in premature termination of the protein product. The missense mutation c.4057C>G (p.H1353D) is located in a highly conserved domain and is predicted to be a damaging substitution. Conclusions: Based on the results described here, we propose that these novel compound heterozygous mutations in SPG 11 are the genetic cause of autosomal recessive HSP in this Chinese family.

Background: Computed tomography perfusion (CTP) is increasingly being used in the setting of acute ischemic stroke (AIS). The aim of the current study was to compare the prognostic utility of, and inter-observer variation between, baseline appearances on non-contrast CT (using Alberta Stroke Program Early CT score(ASPECTS)) and on CTP for predicting final infarct volume. We also assessed impact of training on interpretation of these images. Methods: Retrospectively, plain head computed tomography (CT) and CTP images at presentation and CT or diffusion imaging on follow up of patients with AIS were analyzed. The lesion volume on different CTP parameters was then correlated with the final infarct volume. This analysis was done by a Neuroradiologist, a stroke Neurologist and a medical student. Kappa statistics and Intra-class correlation coefficients were used for agreement between readers. Pearson correlation coefficients were used.Results: Thirty eight patients with AIS met all inclusion criteria. There was very good agreement among all readers for the CTP parameters. There was only fair agreement for ASPECT score. Correlation coefficient (r-square) between CTP parameters and final infarct volume showed that cerebral blood volume was the best parameter to predict the final infarct volume followed by cerebral blood flow and time to peak. The best reader to predict the final infarct volume on the initial CT perfusion study was the neuroradiologist followed by medical student and stroke neurologist. Conclusions: Cerebral blood volume defect correlated the best with the final infarct volume. There was a very good inter-observer agreement for all the CTP maps in predicting the final infarct volume despite the wide variation in the experience of the readers.

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.