Introduction: Our goal was to perform a systematic review of the literature on the use of intravenous lidocaine in pediatrics for status epilepticus (SE) and refractory status epilepticus (RSE) to determine 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 November 2014), and gray literature were searched. The strength of evidence was adjudicated using both the Oxford and GRADE methodology by two independent reviewers. Results: Overall, 20 original studies were identified, with 19 manuscripts and 1 meeting abstracts. Two hundred and thirty-five pediatric patients were treated for 252 episodes of SE/RSE. Patients had varying numbers of anti-epileptic drugs (AEDs), 2 to 8, on board prior to lidocaine therapy. During 20 of the 252 (7.9%) episodes of SE/RSE, phenytoin was on board. The dose regimen of lidocaine varied, with some utilizing bolus dosing alone; others utilizing a combination of bolus and infusion therapy. Overall, 60.0% of seizures responded to lidocaine, with complete cessation and greater than 50% reduction seen in 57.6% and 12.3% respectively. Patient outcomes were sparingly reported. Conclusions: There currently exists level 2b, GRADE C evidence to support the consideration of lidocaine for SE and RSE in the pediatric population.

Background: Debate persists in Canada about the cost and benefit of vagal nerve stimulation in patients with refractory epilepsy. The aim of our study was to evaluate the impact of a vagal nerve stimulator on the seizure frequency and the admission rate of children with refractory epilepsies over five years of follow-up. Methods: 52 patients were implanted between 2000-2013. Of these, 37 were followed at CHU Sainte-Justine and 21 kept seizure diaries. Seizure frequency was compared to the baseline at 6 months, 12 months, 24 months and 60 months of follow up using a multivariate ANOVA analysis. The hospitalization rate was calculated as the mean difference between the number of hospitalizations prior to and after the implantation. Results: Seizure frequency decreased by 58% at 6 months, by 61% at 12 months, by 53% at 24 months and by 63% at 60 months of follow up respectively compared to the baseline (p<0.001). The hospitalization rate decreased by 50.87% after surgery (p<0.001). Conclusion: In our population, vagal nerve stimulation has a sustained impact on seizure frequency and hospitalization rates. This supports previous data from our group and others on cost-effectiveness of the technique in children with refractory epilepsy.

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: 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: 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.

Background: KCNQ2 abnormalities were described in infants with benign familial neonatal seizures (BFNS) and epileptic encephalopathy (EE). Associated features possibly include abnormal neuroimaging findings such as hypomyelination and/or T2 high signal of basal ganglia. Methods: This report describes 4 infants carrying different heterozygous KCNQ2 variants and 2 infants with 20q13.33 deletions encompassing KCNQ2 gene. Results: The different KCNQ2 mutations led to EE in 3 patients and included a novel de novo missense variant, p.Arg201Cys/c.601C>T, in an infant with severe EE and global developmental delay, hyperkinetic movement disorder, autonomic dysfunction with chronic hypoventilation, apnea, low GABA levels in CSF, and hypomyelination. She died at age 3 years of respiratory failure. One patient with BFNS and normal MRI has a previously reported c.508delG frame shift mutation in KCNQ2. Of the two de novo 22q13.33 deletions (1.2Mb versus 254.1 Kb) the larger caused a more severe phenotype, including focal epilepsy from infancy until 4 years, moderate developmental delay and diffuse brain volume loss. Conclusions: Along with varied epilepsy phenotypes and neuroimaging findings KCNQ abnormalities were associated with severe autonomic dysfunction and reduced CSF GABA levels. This might have further treatment implications, besides that the altered potassium channel function itself presents a therapeutic target.

Background: Perinatal stroke causes hemiparetic cerebral palsy. Constraint therapy (CIMT) improves function in congenital hemiparesis and adult stroke. Repetitive transcranial magnetic stimulation (rTMS) may improve function in adult stroke. The two have not been tested in perinatal stroke. Methods: PLASTIC CHAMPS (www.clinicaltrials.gov/NCT01189058) was a controlled factorial trial of rTMS and CIMT in perinatal-stroke hemiparesis. Children 6-18 years participated in a 2 week peer-supported motor learning camp, randomized to daily inhibitory rTMS (1200 stimulations, contralesional M1), CIMT, both or neither. Primary outcomes were Assisting Hand Assessment (AHA) and Canadian Occupational Performance Measure (COPM) at 1, 8, and 24 weeks. Quality-of-life, safety and tolerability were evaluated. Change was assessed across treatment groups over time (linear mixed effects model). Results: All forty-five subjects completed the trial (median 11.4yrs). COPM scores increased >100% with maximal gains at 6 months (p<0.002). Addition of rTMS and/or CIMT doubled the chances of clinically significant gains. Combined rTMS+CIMT resulted in larger AHA gains at all time points (6 months p=0.006). CIMT or rTMS alone had more modest effects. Neither treatment decreased function in either hand. Procedures were well tolerated. Conclusions: Children with hemiparesis participating in intensive, psychosocial rehabilitation programs perceive marked increases in function. Non-invasive brain stimulation may enhance motor learning therapy in perinatal stroke hemiparesis.

Background: This study examines whether age is a key determinant for inflammatory response, oligodendroglial apoptosis and axonal survival after traumatic spinal cord injury (SCI). Methods: This study includes post-mortem spinal cord tissue from 64 cases of SCI (at cervical or high-thoracic level) and 38 controls cases. Each group was subdivided into younger and elderly individuals (≥65 years). Alternating sections from 2 to 3 segments caudal to SCI and age/sex/level-matched segments from controls were stained for: (i) neuroinflammation (neutrophils, macrophages, lymphocytes); (ii) apoptotic oligodendrocytes; (iii) axons; (iv) extent of degeneration. The number of cells or axons was counted in the motor and sensory areas within the spinal cord using unbiased stereological techniques. Results: Younger and elderly individuals had statistically similar number of inflammatory cells in most of the stages post-SCI. Younger and elderly individuals had similar number of oligodendrocytes in apoptosis in all stages following SCI. The number of preserved axons did not significantly differ between younger and elderly individuals with SCI and without prior CNS injury. Extend of degeneration within the spinal cord white matter did not significantly differ between the two groups. Conclusions: Our results indicate that age at the time of injury does not adversely affect the cellular inflammatory response, oligodendroglial apoptosis and axonal survival after traumatic SCI.

Background: This study examines whether abnormal blood hemoglobin concentration (bHB) is associated with worse clinical outcomes and poorer prognosis after acute ischemic stroke. Methods: We included data from the Registry of the Canadian Stroke Network on consecutive patients with ischemic stroke who were admitted between July/2003 and March/2008. Patients were divided into groups as follows: low bHB, normal bHB, and high bHB. Primary outcome measures were the frequency of moderate/severe strokes on admission (Canadian Neurological Scale: <8), greater degree of disability at discharge (modified Rankin score: 3-6), and 30-day and 90-day mortality. Results: Higher bHB than the superior normal limit is associated with greater degree of impairment (OR=1.45, 95%CI: 1.06-1.95, p=0.0195) and disability (OR=1.49, 95%CI: 1.03-2.15, p=0.0331), and higher 30-day mortality (HR=1.98, 95%CI: 1.44-2.74, p<0.0001) after adjustment for major potential confounders. The Kaplan-Meier curves indicate that abnormal bHB is associated with higher mortality after acute ischemic stroke (p<0.0001). Lower bHB than the inferior normal limit is associated with longer stay in the acute stroke care center (OR=1.11, 95%CI: 1.02-1.22, p=0.017). Conclusions: Polycythemia on the initial admission is associated with poorer prognosis regarding the degree of impairment and disability, and 30-day mortality after an acute ischemic stroke. Anemia on admission is associated with longer stay in the acute stroke center.

Background: Dimethyl fumerate (DF) is a first line therapy for relapsing remitting multiple sclerosis (RRMS). This retrospective cohort study aims to determine adverse events (AEs) after initiation of DF in a real world clinical setting. Methods: Data from patients at the Calgary MS Clinic with RRMS who initiated DF between July 1, 2013 and December 31, 2014 were analyzed. Demographic, clinical and lab information were collected from patient electronic medical records and the clinic database. Results: This analysis included 170 patients. At treatment initiation mean age was 42.1 years, 75% were women, mean disease duration was 12.5 years, median EDSS was 2.0, and 24% were treatment naïve. Median follow-up was 6.4 months (range: 1.5-17.7). AEs occurred in 101 (59%); the most common were flushing (31%), gastrointestinal (GI) side effects (24%), and elevated liver enzymes (18%). Other less frequent AEs included lymphopenia (lymphocyte count < 0.5) (4%) and proteinuria (4%). DF was discontinued by 17 (10%); median time to discontinuation was 3.1 months. Fifteen (9%) discontinued due to AE. Conclusions: AE associated with DF in a real world clinical setting is comparable to the Canadian monograph for flushing, GI side effects, and lymphopenia but lower for elevated liver enzymes and proteinuria.

Objective: Our knowledge of disease mechanisms in epilepsy is biased by findings originating from cross-sectional studies and advanced stages of epilepsy. We provide a new perspective by collecting systematically longitudinal data from patients who present in early stages (ES). Methods: The Halifax First Seizure Clinic, founded in 2008, uses a comprehensive multimodal data basis addressing clinical presentation, neuroimaging, EEG findings, genetics, cognition, comorbidities, social parameters, and life style. Follow-up visits are 6, 12 and 24 months. Results: Out of 575 patients we identified 3 subgroups 1) Strictly first seizure, n=187, 2) New-onset epilepsy (> 1 seizure < 12 months), n=149, and 3) Newly-diagnosed epilepsy (seizures > > 12 months), n=50. 189 patients were excluded (not proven seizure or other conditions e.g syncope etc.). Our interim analyses suggest: A) pharmacoresistance presents in highly diverse patterns and is rarer than expected in ES, B) Congenital malformations seem to have an excellent treatment prognosis in ES, C) Marijuana consumption is significantly more prevalent at initial assessment (comparison general population), D) Preceding psychiatric comorbidities associated with reduced amygdalar volume may be a predictor for seizure recurrence. Conclusions: The preliminary and illustrative findings of our pilot study challenge current concepts of disease evolution in epilepsy.

Background: Appropriate use criteria (AUC; Johnson et al, 2013) provide guidelines for selecting patients for whom amyloid PET could be useful. This study evaluated the impact of amyloid PET on diagnosis/management in patients likely to meet AUC. Methods: We examined 229 cases from a completed study of florbetapir amyloid PET (FBP-PET) in patients with a cognitive decline evaluation in whom Alzheimer’s Disease (AD) was suspected, but with <85% confidence in the diagnosis. All cases received a provisional diagnosis and management prior to FBP-PET. Information for 172 cases after 3-months’ follow-up was also available on actual diagnosis/management post-FBP-PET. Cases were classified as likely meeting AUC (AUC-like) or not. Results: 125/229(55%) subjects were AUC-like. NonAUC cases included typical AD, Mild Cognitive Impairment (MCI) due to AD, Cognitive Decline without objective evidence of impairment (CD) and dementia or cognitive impairment with specific nonAD diagnosis. 59/125(47%) AUC-like cases were amyloid positive (Aβ+). Among nonAUC cases, 29% (CD), 49%(MCI due to AD), 53%(non-AD) and 73%(typical AD) were Aβ+. Of 172 cases with follow-up information, diagnosis/management changed after FBP-PET in 58%/88% and 45%/77% of AUC-like and nonAUC, respectively. Conclusions: FBP-PET altered diagnosis/management in patients selected according to AUC. Additionally, AUC generally excluded patients with a relatively high (typical AD) or low (CD) probability of Aβ+ scan.

Background: Painful diabetic neuropathy (PDN) is a frequent complication of diabetes mellitus. Current treatment recommendations are based on short-term trials, generally of duration ≤3 months. Limited data are available on the long-term outcomes of this chronic disease. This study aims to determine the long-term clinical effectiveness of the management of chronic PDN at tertiary pain centres. Methods: From a prospective observational cohort study of patients with chronic neuropathic non-cancer pain recruited from seven Canadian tertiary pain centres, 43 patients diagnosed with PDN were identified for analysis. Data were collected according to Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) guidelines including Brief Pain Inventory (BPI). Results: At 12-month follow-up, 37.2% of 43 patients achieved pain reduction of ≥30%, 51.2% achieved functional improvement with a reduction of ≥1 on the Pain Interference Scale (0-10, BPI), and 30.2% (95% CI: 17.2% to 46.1%) had achieved both these measures. Symptom management included at least 2 medication classes in 55.3%, and 3 medications classes (opioids, antidepressants, anticonvulsants) in 25.5%. Conclusions: A sizable minority of patients being managed for PDN in a tertiary care setting achieve meaningful improvement. Polypharmacy, including analgesic antidepressants, anticonvulsants and opioids, is often necessary to attain symptom management.

Background: There is not enough evidence to prove either invasive Wada or non-invasive fMRI test predicts postoperative memory changes more accurately in patients with refractory temporal lobe epilepsy (TLE). In this study, concordance between fMRI and Wada test for postoperative assessment of visual memory is investigated. Methods: fMRI test with a novel scene-encoding task were conducted on our cohort of patients. fMRI laterality indices (LI) were then defined as a ratio (L-R)/(L+R) between the number of activated voxels in the left and right of two regions: hippocampus+parahippocampus (Region A) and temporal lobe - (hippocampus+parahippocampus) (Region B). fMRI results were divided into the right (LI < -0.2), left (LI > 0.2) or bilateral (-0.2 < LI <0.2) hemispheric memory dominance and compared to the results of the Wada test. Results: 19 patients were studied (14 left TLE, 3 right TLE and 2 bilateral TLE). The concordance rate between Wada and fMRI tests was 36.8% and 42.1% for regions A and B. Conclusions: Based on the results, the concordance rate between the Wada test and the fMRI test is not high. As a future work, we will investigate the correlation of each test to postoperative memory outcome.

Background: The hedgehog pathway (Hh) is an important developmental signaling pathway that is commonly dysregulated in brain tumors, most notably in medulloblastomas. To identify novel therapeutic targets within the Hh pathway, we performed the first quantitative proteome-wide evaluation of phosphorylation events resulting from in vitro SHH administration and occurring throughout Hh-driven cerebellar development in vivo. Methods: Multiplexed quantitative mass spectrometry was done using Tandem Mass Tags 10-plex reagents, TiO2 phosphopeptide enrichment and HPLC-MS/MS/MS. Results: Motif analysis of 2-fold changing phosphorylation events suggested casein kinase 2 (CK2) was responsible for mediating 45% of all changes in phosphorylation. Epistasis studies revealed that CK2 activity is necessary for hedgehog signaling and affects terminal signaling components, thereby circumventing challenges of emergence of resistance and a priori resistance that are commonly encountered with existing small molecule inhibitors in medulloblastoma. In vivo, mice harboring MB allografts resistant to current therapies showed near-complete cessation of tumor growth in response to a CK2 inhibitor. Conclusion: Our use of developmental phosphoproteomics revealed casein kinase 2 as a key regulator of hedgehog signaling and therapeutic target in medulloblastoma. Our success establishes a foundation for us, and others, to apply a similar approach in different tumor initiating pathways.

Background: Malignant brain tumors have a dismal prognosis, with residual after surgery necessitating adjuvant chemoradiotherapy. We previously demonstrated that targeted Natural Killer (NK-92) cells could be delivered to the brain using a combination of MRI-guided focused ultrasound and Definity microbubbles. Once in the CNS, they can track to malignant tissues without inflicting collateral damage. The HER2 receptor is expressed by epithelial tumours including both breast and glioblastoma; breast tumors with HER2-amplification have a higher risk of CNS metastasis, and poorer prognosis. Methods: We investigated whether multiple combined treatments of targeted NK-92 cells and focused ultrasound with microbubbles could slow tumour growth and improve survival in an orthotopic HER2-amplified rodent brain tumour model using a human breast cancer line as a prototype. Results: Early daily treatments with targeted NK-92 cells and ultrasound improved survival and decreased tumour volumes compared with bi-weekly treatments, or either treatment alone. The intensive treatment paradigm resulted in cure in 50% of subjects. Conclusions: Many tumour proteins could be exploited for targeted therapy with the NK-92 cell line, and combined with the mounting safety evidence for transcranial ultrasound, this may soon provide a non-invasive and highly targeted treatment option for patients with brain tumours.

Background: Antithrombosis (AT), with antiplatelets or anticoagulants, is a significant risk factor for the development of chronic subdural hematomas (cSDH). Resumption of AT following hematoma evacuation is variable, with scant evidence for guidance. Methods: We retrospectively analyzed 479 patients with surgically-evacuated cSDH at St. Michael’s Hospital from 2007-2012. Collected variables included type of AT, indication for AT, timing and type of postoperative complications, and restart intervals for AT agents. Postoperative complications were classified as major or minor hemorrhages, or thromboembolism. Results: Among all patients, 14.8% experienced major hemorrhage, 23.0% minor hemorrhage, and 1.67% thromboembolism. Patients on any preoperative AT were at higher risk of major hemorrhage (OR=1.93, p=0.014), experienced earlier major hemorrhage (mean 16.2 versus 26.5d, p=0.052) and earlier thromboembolism (mean 2.7 versus 51.5d, p=0.036). The type of agent did not affect complication frequency or timing. Patients restarted on any AT postoperatively were at decreased risk of major rebleed following resumption, than those not restarted (OR=0.06, p<0.01). Conclusions: Patients on preoperative AT experienced thromboembolism significantly earlier, at 3d postoperatively, with no increase in rebleed risk following AT resumption. We provide cursory evidence that resuming AT early, at 3d postoperatively, may be safe. Larger prospective studies are required for definitive recommendations.

Background: Horse riding is a hazardous activity with the potential for serious injury. Equestrian-related injuries account for a higher rate of injury per number of riding hours than motorcyclists and automobile racers. There is a lack of literature pertaining to equestrian-related brain injuries. The objectives of this study were to describe the incidence, characteristics, and mechanisms of equestrian-related brain injuries sustained amongst Canadians between 1990 and 2014. Methods: Data were obtained from the Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP) database. The study population consisted of individuals who sustained equestrian-related brain injuries between the years 1990 and 2014 and presented to one of 15 participating emergency departments. Results: Brain injuries accounted for 13.3% (N=1060) of all equestrian-related injuries. The greatest proportion of injuries occurred amongst individuals aged 15-19 years, followed by individuals aged 0-4 years. The predominant mechanism of injury was falls. 17.9% of individuals were admitted to hospital. Normalized rates of injury increased from 1990 to 2010. Conclusions: Brain injuries sustained while participating in equestrian are often of a greater severity than injuries sustained while participating in other recreational activities. A clear understanding of the epidemiology and mechanisms of equestrian-related brain injuries must be achieved in order to effectively implement prevention efforts.

Background: The purpose of this study was to develop a novel, simple and effective model of fusiform artery aneurysms in rabbits using a combination of periaortic calcium chloride (CaCl2) and elastase incubation. Methods: Fusiform aneurysms were developed in three New Zealand White rabbits by exposing a 2 cm segment of the right carotid artery to CaCl2 (0.5 mol/L) and pancreatic porcine elastase (75 U) for 20 minutes. The left carotid was used as a control. Vessel diameter was measured by serial digital subtraction angiography imaging at weeks 2, 4 and 6. Animals were sacrificed on week 6 and histopathological studies were performed. Results: All rabbits developed a fusiform aneurysm, with an average dilation ratio of 105%±10% by week 6. No mortality was reported. Histopathological studies revealed pathological features consistent with fusiform aneurysms. Conclusions: This novel rabbit model of fusiform carotid aneurysms is the first in the literature by using a combination of periaortic CaCl2 and elastase incubation. This is a simple, reliable, and effective technique and results in a potentially valuable model for the study of fusiform aneurysms and possible therapeutic interventions, such as flow diversion.

Background: Deficiencies in design and reporting of randomized controlled trials (RCTs) limit their validity. The quality of recent RCTs in neurosurgery was analyzed to assess adequacy of design and reporting. Methods: A high-yield search of the MEDLINE and EMBASE databases (2000-present) was conducted. The CONSORT and Jadad scales were used to assess the quality of design/reporting. A PRECIS-based scale was used to designate studies on the pragmatic-explanatory continuum. Spearman’s test was used to assess correlations. Regression analysis was used to assess associations. Results: Sixty-one articles were identified. Vascular was the most common sub-specialty (37%). The median CONSORT and Jadad scores were 36 (IQR 27.5-39) and 3 (IQR 2-3). Blinding, sample size calculation and allocation concealment were most deficiently reported. The quality of reporting did not correlate with the study impact. The majority of studies (83%) had pragmatic objectives; while pragmatic studies had compatible design factors, trials with explanatory objectives were less successful. Conclusions: The prevalence and quality of neurosurgical RCTs is low. Many study designs are not compatible with stated objectives. Given the role of RCTs as one of the highest levels of evidence, it is critical to improve on their methodology and reporting. Alternative methodologies merit discussion.