The current concept in the cell cycle stipulates that constant synthesis without coupled ubiquitin- mediated proteolysis maintains the levels of cyclin-dependent kinase proteins through the cell cycle. CDK proteins are elevated in glioblastoma, which has long been thought due to gene amplifications, although the amplifications occur only in a small set of the tumors according to the genome.

In this study, we show that the G1 phase CDK6 is a substrate of both ubiquitin and small ubiquitin-like modifier-1 (SUMO1), and that CDK6 is sumoylated due to the elevated activity of SUMO1 conjugation in glioblastoma. CDK6 sumoylation at Lys 216 structurally blocks the access of ubiquitination molecules to the Lys 147 ubiquitination site; thus, CDK6 sumoylation stabilize the protein, maintains the kinase activity and drives the cell cycle through G1/S transition. Inhibition of SUMO1 conjugation causes G1 arrest and abolishes the self-renewal and tumorigenic property of glioblastoma initiating or stem cells. In conclusion, SUMO1-CDK6 conjugation constitutes a new mechanism of cell cycle control and selective inhibition of SUMO1 conjugation may provide a novel strategy for the development of the cancer stem cells-targeted treatment.

Aim: To examine cortical activation during a memory task in children with and without post-concussion symptoms (PCS) following concussion. Methods: A case-controlled study within the PlayGame Trial (www.playgametrial.ca). Children (aged 8-18 years) with PCS at 1-month post-injury were eligible. The fMRI task was a working memory task. Pre-processing and single-subject analysis were performed in FSL. Group activation and inter-group difference maps were extracted. Results: 11 symptomatic, 12 asymptomatic, and 11 controls without concussion participated. Groups were similar in age (14.9, 14.0, and 13.8yrs; p=0.46), sex (p=0.984) and time post-injury (symptomatic: 37d; asymptomatic 35d; p=0.573). Compared with controls, symptomatic children demonstrated greater activation especially in the bilateral orbito-frontal cortex and cerebellum. A similar, less pronounced pattern was observed in asymptomatic subjects. Conclusions: Similar to adult studies, increased network activation may represent decreased “efficiency” and explain the cognitive fatigue in PCS. Further, children who are “asymptomatic” may not yet be fully recovered.

Background: Our goal was to perform a systematic review of the literature on the use of therapeutic hypothermia for refractory status epilepticus (RSE) and its impact on seizure control. Methods: All articles from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to May 2014), reference lists of relevant articles, and gray literature were searched. The strength of evidence was adjudicated by two independent reviewers, using both the Oxford and GRADE methodology. Results: Overall, 13 studies were identified, with 10 manuscripts and 3 meeting abstracts. A total of 40 patients were treated. The common target temperature was 33 degrees Celsius, sustained for a median 48 hours. Patients displayed a 62.5%, 15% and 22.5% rate of seizure cessation, seizure reduction, and failure of treatment respectively. External cooling was utilized in the majority of cases. Deep venous thrombosis, coagulopathy and infections were the commonly reported complications. Two ongoing clinical trials were identified. Conclusions: Oxford level 4, GRADE D evidence exists to support the use of therapeutic hypothermia to control seizures in RSE. Further prospective study is warranted.

Objectives: Patients undergoing awake craniotomy may experience high levels of stress. Minimizing anxiety benefits patients and surgeons. Music has many therapeutic effects in altering human mood and emotion. Tonality of music as conveyed by composition in major or minor keys can have an impact on patients’ emotions and thoughts. Assessing the effects of listening to major and minor key musical pieces on patients undergoing awake craniotiomy could help in the design of interventions to alleviate anxiety, stress and tension. Methods: Twenty-nine patients who were undergoing awake craniotomy were recruited and randomly assigned into two groups: Group 1 subjects listened to major key music and Group 2 listened to minor key compositions. Subjects completed a demographics questionnaire, a pre- and post-operative Beck Anxiety Inventory (BAI) and a semi-structured open-ended interview. Results were analyzed using modified thematic analysis through open and axial coding. Results: Overall, patients enjoyed the music regardless of the key distinctions and stated they benefitted from listening to the music. No adverse reactions to the music were found. Subjects remarked that the music made them feel more at ease and less anxious before, during and after their procedure. Patients preferred either major key or minor key music but not a combination of both. Those who preferred major key pieces said it was on the basis of tonality while the individuals who selected minor key pieces stated that tempo of the music was the primary factor. Conclusion: Overall, listening to music selections was beneficial for the patients. Future work should further investigate the effects of audio interventions in awake surgery through narrative means.

Alemtuzumab, an anti-CD52 monoclonal antibody, was recently approved for treatment of MS in Canada, having shown to significantly reduce relapses and disability in patients, particularly those who relapsed despite first line treatment. Offsetting its benefit however, is the development of novel secondary autoimmune disease, particularly affecting the thyroid gland in up to 36% of patients. The incidence of Alemtuzumab induced thyroid dysfunction (AITD) will likely rise as alemtuzumab becomes more widely used for treating MS. We review the clinical and investigational cues that help delineate the aetiology and management of thyrotoxicosis and hypothyroidism in ATID. AITD can be easily managed and we present a simple approach for its evaluation and management by neurologists that should be implemented prior to considering a referral to an internist or endocrinologist for further opinion or treatment.

We review the Saskatchewan Movement Disorders Program, which started in 1968 and has had the dual goals of patient care and research. The clinics are structured to collect research-worthy data including videos, longitudinal follow-up, and autopsy studies of patients seen in the clinics. At every clinic visit, the patient is evaluated by one or both authors. A total of 25% to 30% of the deceased come to autopsy. Frozen half-brain and formalin-fixed remnants from autopsy are preserved in our laboratories. Patients not seen in our clinic are not included in research, which makes it different from brain banks. So far, 515 cases have come to autopsy. So far, there have been 17 collaborating scientific teams from Canada, the United States, Europe, and Japan. The collaborators are not charged for access to our resources. This program offers a unique opportunity to study multiple aspects of movement disorder patients seen in clinical practice.

Background: Residents must develop a diverse range of skills in order to practice neurosurgery safely and effectively. The purpose of this study was to identify the foundational skills required for neurosurgical trainees as they transition from medical school to residency. Methods: Based on the CanMEDS competency framework, a web-based survey was distributed to all Canadian academic neurosurgical centers, targeting incoming and current PGY-1 neurosurgical residents as well as program directors. Using Likert scale and free-text responses, respondents rated the importance of various cognitive (e.g. management of raised intracranial pressure), technical (e.g. performing a lumbar puncture) and behavioral skills (e.g. obtaining informed consent) required for a PGY-1 neurosurgical resident. Results: Of 52 individuals contacted, 38 responses were received. Of these, 10 were from program directors (71%), 11 from current PGY-1 residents (58%) and 17 from incoming PGY-1 residents (89%). Respondents emphasized operative skills such as proper sterile technique and patient positioning; clinical skills such as lesion localization and interpreting neuro-imaging; management skills for common scenarios such as raised intracranial pressure and status epilepticus; and technical skills such as lumbar puncture and external ventricular drain placement. Free text answers were concordant with the Likert scale results. Discussion: We surveyed Canadian neurosurgical program directors and PGY-1 residents to identify areas perceived as foundational to neurosurgical residency education and training. This information is valuable for evaluating the appropriateness of a training program’s goals and objectives, as well as for generating a national educational curriculum for incoming PGY-1 residents.

Latino Americans are a rapidly growing ethnic group in the United States. The characteristics of glioblastoma in this population is poorly studied. We have evaluated the data of 47,540 glioblastoma patients from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. This SEER data from 1973-2000 includes up to 13 cancer registries. For 2001 to 2011, the data has improved geographic coverage with 18 registries encompassing 28% of the U.S. population.

Latinos have a lower incidence of GBM than non-Latino Whites. Gender distribution is similar. The total SEER data show that Latinos present slightly younger and have a higher incidence of giant cell glioblastoma and gliosarcoma than non-Latino Whites. Despite higher rates of radiation therapy, the one year survival rate (34.7%) for non-Latino White populations is less than for Latinos (39.0%, p <0.001). Subset analyses (2001-2011) of all the above parameters show similar results except for gliosarcoma incidence. A literature search does not identify MGMT or IDH1 data regarding Latino Americans.

We have assessed 2 prognostic markers in 30 Latino glioblastoma patients. MGMT methylation is present in 24% and IDH1 mutation is found in 12.5%. Our preliminary data suggests that Latinos may have a greater incidence of MGMT unmethylated tumors. Younger age may possibly contribute to improved survival in Latinos but the underlying molecular basis is unresolved.

Background: There is strong evidence that clinical outcomes are improved for stroke patients admitted to specialized Stroke Units. The Toronto Western Hospital (TWH) created a Neurovascular Unit (NVU) using resources from General Internal Medicine, Neurology, and Neurosurgery for patients with stroke and acute neurovascular conditions. Under resource-constrained conditions, the operational and economic impacts of the Neurovascular Unit were unknown. Methods: Retrospective patient-level data was studied from two years prior and one year post NVU implementation. Descriptive statistical analysis and non-parametric testing were conducted on the acute length of stay (LOS), alternate level of care LOS, total cost per bed-day and per visit, and patient flow within each medical service and hospital wide. Results: The median acute LOS per hospitalization for NVU-eligible patients decreased significantly (p=0.001). For Neurology patients, mean acute LOS decreased from 9.1 days pre-Neurovascular Unit to 7.6 days post and median acute LOS decreased from 6 to 5 days (p=0.002); however, mean alternate level of care LOS per visit more than doubled (from 1.6 to 4.1 days, p=0.001). For the Neurology service, the mean cost per visit decreased by $945, representing a 5% reduction (p=0.042) and the mean cost per bed-day decreased by $233, or 12.5% (p=0.026). Hospital wide, a saving of over C$450 000 was achieved. Conclusions: During the first year of operation, the NVU at TWH achieved decreased acute LOS per visit and lowered the total hospitalization cost per year for NVU-eligible patients. Addressing the issue of increased alternate level of care LOS could result in additional efficiencies.

Background: Stroke is a leading cause of perinatal brain injury and cerebral palsy. Term neonatal hemorrhagic stroke (NHS) is a common syndrome with poorly defined epidemiology. We aimed to determine incidence and mechanisms within a large population-based NHS sample. Methods: The Alberta Perinatal Stroke Project (APSP), a provincial registry ascertained NHS cases using exhaustive ICD-9/10 code searching (1992-2012, >2400 chart reviews). Prospective cases were captured through the Calgary Pediatric Stroke Program from 2007-2014 (n=387). All NHS cases underwent structured chart review using a data capture form and blinded review of neuroimaging. Provincial live births were obtained from statistics Canada. Outcomes were extrapolated to the Pediatric Stroke Outcome Measure (PSOM). Results: We identified 74 cases: 49 NHS (26 retrospective, 27 prospective), 4 presumed perinatal HS (PPHS), and 21 hemorrhagic transformation (HT) of ischemic injury. Incidence of NHS was 1:8800 live births (1:5820 for all forms). HT was common (28.4%) including global, arterial venous ischemic lesions. Presumed perinatal hemorrhagic stroke presented with epilepsy. No risk factor was identified in 68% of cases. Outcomes were abnormal (PSOM 1 or more) in 30% and better in the HT group. Conclusion: NHS occurs in 1:8800 live births. Imaging classification is essential to define mechanisms.

Background: The effectiveness of current self-reporting driving laws for medically-unfit potential seizure patients is unknown in Canada. We designed a prospective cohort study of patients’ self-reporting practices to the local Transportation Registry (TR) and their driving behaviors following detailed counselling at a seizure clinic in a discretionary physician-reporting jurisdiction. Methods: Medically unfit drivers, referred to our seizure clinic, who had a valid driver’s permit at the time of their episode of impaired consciousness were included. Patients’ self-reporting and driving behaviours were assessed using a standardized interview prior to a neurologist’s counseling and later at a follow-up visit. Results: Sixty three patients were included; 77% were diagnosed as having had a seizure at the time of their referral. Prior to their seizure clinic visit, 3/63 (5%) had been counseled to self-report to the TR by a non-neurologist physician, and none had done so. Following a neurologist’s documented counseling 34/63 (54%) had self-reported themselves at the follow-up seizure clinic visit, and 53/63 (84%) were not driving. Conclusion: This prospective study design is the first in North America to examine self-reporting rates for unfit drivers with a seizure disorder. Our findings suggest that self-reporting laws do not ensure high rates of self-reporting behaviors even when patients seen at a seizure clinic are appropriately counseled of their legal obligations. The rate of driving cessation appears greater than the rate of self-reporting to the TR among counseled patients.

Background: Transitioning from medical school to residency is difficult and stressful, necessitating innovation in easing this transition. In response, a Canadian neurosurgical Rookie Camp was designed and implemented to foster acquisition of technical, cognitive and behavioral skills among incoming Canadian post graduate year one (PGY-1) neurosurgery residents. Methods: The inaugural Rookie Camp was held in July 2012 in Halifax. The curriculum was developed based on a national needs-assessment and consisted of a pre-course manual, 7 case-based stations, 4 procedural skills stations and 2 group discussions. The content was clinically focused, used a variety of teaching methods, and addressed multiple CanMEDS competencies. Evaluation included participant and faculty surveys and a pre-course, post-course, and 3-month retention knowledge test. Results: 17 of 23 PGY-1 Canadian neurosurgical residents participated in the Camp. All agreed the course content was relevant for PGY-1 training and the experience prepared them for residency. All participants would recommend the course to future neurosurgical residents. A statistically significant improvement was observed in knowledge related to course content (F(2,32) = 7.572, p<0.002). There were no significant differences between post-test and retention-test scores at three months. Conclusion: The inaugural Canadian Neurosurgery Rookie Camp for PGY-1 residents was successfully delivered, with engagement from participants, training programs, the Canadian Neurosurgical Society, and the Royal College. In addition to providing fundamental knowledge, which was shown to be retained, the course eased junior residents’ transition to residency by fostering camaraderie and socialization within the specialty.

Background: Global variation in the incidence of multiple sclerosis (MS) is generally ascribed to differences in genetic and environmental risk factors. Here we investigate temporal trends in the incidence of MS and related disorders in British Columbia, Canada, from 1986 to 2010, focusing particularly on the Asian ethnic subpopulation. Methods: A longitudinal database was screened to identify newly diagnosed cases of MS and related disorders, including neuromyelitis optica and clinically isolated syndromes. Age-standardized, sex-specific mean annual incidence was calculated for the Asian and non-Asian population of British Columbia for 5-year intervals from 1986 to 2010. Temporal changes and cohort differences in incidence rates and demographic characteristics were evaluated. Results: During this period, the incidence of MS and related disorders in the non-Asian population remained relatively unchanged, from 10.41 (95% confidence interval [CI]: 9.87-10.97) to 9.91 (95% CI: 9.46-10.39) per 100,000 (p=0.167). In contrast, incidence in the Asian population doubled during the same period. This increase was driven by a precipitous rise in the incidence of MS in females from 0.71 (95% CI: 0.01-1.50) to 2.08 (95% CI: 1.43-2.91) per 100,000 (p=0.004), including both Canadian-born and immigrant Asians. The incidence of neuromyelitis optica did not change significantly during this period. Conclusions: The incidence of MS may be increasing among females in the Asian ethnic population of British Columbia.

Background: Improvement of health-related quality of life (HRQOL) is a major goal in chronic disease management and HRQOL has become an important outcome in clinical trials. Longitudinal data on HRQOL are needed to elucidate change over time and to assess effectiveness of interventions; such research is lacking in the paediatric Duchenne Muscular Dystrophy (DMD) population. Methods: We followed up participants from our initial HRQOL study in 2013 a year and a half later. Multidimensional generic and disease-specific measures from the Pediatric Quality of Life Inventory were used to assess HRQOL from child and parent perspectives. Mean changes in HRQOL were calculated. Results: Data collection is ongoing and currently, data from 16 families (out of the initial 98) are available. Preliminary results indicated that by both child and parent reports, there were declines in all domains of HRQOL except for social function, in which there was a slight improvement. Mean decline in HRQOL scores ranged from 1.6 to 8.6 for child reports; and 3.3 to 7.7 for parent reports. Conclusion: HRQOL of boys with DMD deteriorates over time. Our results may be helpful in interpreting patient reported outcomes in forthcoming clinical trials and determining minimally clinically important changes in this population.

The biology of the endocannabinoid system in the brain provides a possible basis for a beneficial pharmacological effect of marijuana on seizures. However, evidence for efficacy of cannabis treatment of epilepsy is anecdotal because no acceptable randomized controlled trials have been done. Proper dosage and means of administration remain unknown. Cannabis is safer than other controlled substances, including tobacco or alcohol, and appears to be relatively safe compared with most pharmaceuticals used to treat epilepsy. This is a review of this topic from a Canadian perspective.