Background: Epileptic encephalopathy (EE) is a severe condition in which epileptic activity itself may contribute to severe cognitive and behavioural impairments above and beyond what might be expected from the underlying pathology alone. Next generation sequencing technologies such as whole exome sequencing (WES) can detect underlying genetic causes of in EE. Methods: This report describes genotype-phenotype correlation of 29 subjects with unexplained epileptic encephalopathy, in whom WES, targeting a list of 557 epilepsy-associated genes was performed. Epilepsy phenotyping was done according to current ILAE recommendations. Results: Median age at seizure onset was 14 months (range 1-48). Electroclinical syndromes were applicable for 16/29, 8/16 had a definite/likely diagnosis. 6/8 subjects with West syndrome had variants in ALG13, STXBP1, PAFAH1B1, SLC35A2, CDKL5 and ADSL. 2 patients with Dravet syndrome had variants in SCN1A and PCDH19 respectively. 4/29 had unspecified EE and definite/likely diagnosis due to STXBP1, POLG, and KCNQ2 (2) variants. 4/29 had a possible diagnosis involving GABRB3, ARHGEF9, PCDH19 and SCN3A variants. Conclusions: The high diagnostic yield (definite/likely diagnosis in 11/29 = 38%), involving a broad variety of epilepsy-associated genes in different electroclinical syndromes justifies the diagnostic approach of early onset EE by next generation sequencing.

Abnormal fetal corticogenesis results in malformations of cortical development (MCD). Abnormal cell proliferation leads to microcephaly or megalencephaly, incomplete neuronal migration results in heterotopia and lissencephaly, neuronal overmigration manifests as cobblestone malformations, and anomalous postmigrational cortical organization is responsible for polymicrogyria and focal cortical dysplasias. MCD comprises various congenital brain disorders, caused by different genetic, infectious, or vascular etiologies and is associated with significant neurological morbidity. Although MCD are rarely diagnosed prenatally, both dedicated multiplanar neurosonography and magnetic resonance imaging enable good demonstration of fetal cortical development. The imaging signs of fetal MCD are: delayed or absent cerebral sulcation; premature abnormal sulci; thin and irregular hemispheric parenchyma; wide abnormal overdeveloped gyri; wide opening of isolated sulci; nodular bulging into the lateral ventricles; cortical clefts; intraparenchymal echogenic nodules; and cortical thickening. The postnatal and prenatal imaging features of four main malformations of cortical development—lissencephaly, cobblestone malformations, periventricular nodular heterotopia, and polymicrogyria—are described.

This review aimed to summarize data from peer-reviewed studies of team-coordinated and delivered early supported discharge (ESD) for postacute, poststroke rehabilitation. A systematic review was performed in Medline, Embase, and CINAHL for appropriate studies. Information on program details and patient cohorts was synthesized. All programs sought patients with mild-to-moderate functional impairment and minimal cognitive impairment (often based on Barthel Index and Mini-Mental State Examination scores, respectively). All also included at least one subjective admission criterion related to rehabilitation suitability or the suitability of the home environment. Based on the identified studies, ESD programs can assume that 15% of patients screened for ESD will be eligible and care should be provided for 4 to 5 weeks postdischarge. Although the benefits of team-coordinated and delivered ESD poststroke have been well-documented, this review may be helpful for clinicians, administrators, and policy makers looking to establish or refine an ESD program for stroke.

Despite aggressive multimodal therapy, human glioblastoma (hGBM), a highly malignant grade IV astrocytic tumour, remains incurable and inevitably relapses. Recent data has implicated intratumoral heterogeneity as the driver of therapy resistance and tumour relapse in hGBM. Thus models that capture the evolving hGBM biology in response to chemoradiotherapy will allow for the identification of cellular pathways that govern GBM therapy failure. In this study, we have developed a novel model to profile the clonal evolution of treatment naïve brain tumour initiating cell (BTIC) enriched hGBMs through chemoradiotherapy using: stem cell assays, BTIC marker expression and transcriptome analysis, immunohistochemistry, and cellular DNA barcoding technology. We report that treatment of hGBM BTICs leads to increased self-renewal capacity and higher transcript expression of stem cell genes Bmi1 and Sox2. Based on global transcriptome analysis of the in vitro treated hGBM, we also identify a hyper-aggressive form of glioma. Using our therapy-adapted hGBM-mouse xenograft model, we discover that despite tumour regression and increased mouse survival post-therapy, tumour relapse remains inevitable. The treatment-refractory cells again have increased self-renewal capacity and higher expression of Bmi1 and Sox2. Furthermore, by combining cellular DNA barcoding technology, which barcodes hGBM at single cell resolution, with our novel in vitro and in vivo therapy models, we are able to determine whether a pre-existing or a therapy driven subpopulation(s) seeds hGBM tumour relapse. Profiling the dynamic nature of heterogeneous hGBM subpopulations through disease progression and treatment may lead to the identification of novel therapeutic targets for the treatment of recurrent hGBM.

This review centers on the discoveries made during more than six decades of neuroscience research on the role of gamma-amino-butyric acid (GABA) as neurotransmitter. In doing so, special emphasis is directed to the significant involvement of Canadian scientists in these advances. Starting with the early studies that established GABA as an inhibitory neurotransmitter at central synapses, we summarize the results pointing at the GABA receptor as a drug target as well as more recent evidence showing that GABAA receptor signaling plays a surprisingly active role in neuronal network synchronization, both during development and in the adult brain. Finally, we briefly address the involvement of GABA in neurological conditions that encompass epileptic disorders and mental retardation.

RESUMÉ: Le chemin long et sinueux pour que le GABA soit reconnu comme un neurotransmetteur. Cette revue est axée sur les découvertes réalisées durant plus de six décennies de recherche en neurosciences sur l’acide gamma-aminobutyrique (GABA) comme neurotransmetteur. À cet effet, nous mettons une emphase particulière sur le rôle significatif de chercheurs canadiens dans ce domaine de recherche. En prenant comme point de départ les premières études qui ont établi que le GABA était un neurotransmetteur au niveau de synapses centrales, nous faisons le sommaire des résultats identifiant le récepteur GABA comme étant une cible thérapeutique ainsi que des données plus récentes montrant que la signalisation du récepteur GABAA joue, de façon surprenante, un rôle actif dans la synchronisation du réseau neuronal, tant au cours du développement que dans le cerveau adulte. Finalement, nous traitons brièvement du rôle de GABA dans les maladies neurologiques incluant les troubles épileptiques et l’arriération mentale.

Dravet syndrome is not one of the most frequent severe epilepsies affecting infants during the first year of life. In the most recent epidemiological study, in Sweden, its estimated incidence was 1 in 33,000 live births. On December 31, 2011, its prevalence was 1 in 45,700 children aged less than 18 years. Nonetheless, it is now well known by many child neurologists for several reasons. First, its genetic aetiology was demonstrated almost 15 years ago, and an animal model was created shortly thereafter, allowing experimental work focused on the underlying mechanisms of the disease. Second, the clinical characteristics of the typical form of Dravet syndrome are well defined, enough to allow early diagnosis. Third, although the epileptic seizures are highly pharmacoresistant, we now have at our disposal a specific therapeutic strategy that allows one to avoid the most severe seizures in a number of patients due to the new drug stiripentol, used in different associations. Nevertheless, this therapeutic strategy should not be limited to seizure control and needs to take into account all other aspects of the disease. The aim of this symposium is to present a synthesis of the diagnosis and treatment of Dravet syndrome with a focus on family needs.

Although intravenous thrombolysis increases the probability of a good functional outcome in carefully selected patients with acute ischemic stroke, a substantial proportion of patients who receive thrombolysis do not have a good outcome. Several recent trials of mechanical thrombectomy appear to indicate that this treatment may be superior to thrombolysis. We therefore conducted a systematic review and meta-analysis to evaluate the clinical effectiveness and safety of new-generation mechanical thrombectomy devices with intravenous thrombolysis (if eligible) compared with intravenous thrombolysis (if eligible) in patients with acute ischemic stroke caused by a proximal intracranial occlusion. We systematically searched seven databases for randomized controlled trials published between January 2005 and March 2015 comparing stent retrievers or thromboaspiration devices with best medical therapy (with or without intravenous thrombolysis) in adults with acute ischemic stroke. We assessed risk of bias and overall quality of the included trials. We combined the data using a fixed or random effects meta-analysis, where appropriate. We identified 1579 studies; of these, we evaluated 122 full-text papers and included five randomized control trials (n=1287). Compared with patients treated medically, patients who received mechanical thrombectomy were more likely to be functionally independent as measured by a modified Rankin score of 0-2 (odds ratio, 2.39; 95% confidence interval, 1.88-3.04; I2=0%). This finding was robust to subgroup analysis. Mortality and symptomatic intracerebral hemorrhage were not significantly different between the two groups. Mechanical thrombectomy significantly improves functional independence in appropriately selected patients with acute ischemic stroke.

The current literature on the role of brain microbleeds (MB) on the neuropsychological outcomes of Alzheimer’s disease (AD) is heterogeneous. We therefore meta-analytically examined the neuropsychological literature pertaining to MBs in AD. Using a priori selected criteria, studies with cross-sectional neuropsychological assessment on MBs and AD were reviewed. Six of 122 studies met selection criteria and provided neuropsychological data on either AD with MB and without MB, or in contrast to healthy controls. The global neuropsychological difference between AD with MB and AD without MB based on random effect model was nonsignificant, heterogeneous, and small (Effect Size =−0.155; 95% confidence interval =−0.465 to 0.155; p value =0.326; Heterogenity: Q-value =12.744; degrees of freedom =5; p =0.026; I2 =61%). The contribution of MBs to cognitive deficits in AD remains unclear. Future studies of MB in AD should strive to use standardized neuroimaging techniques with high sensitivity for MB, a common standard for MB definition, and neuropsychological tests sensitive for detecting subtle cognitive impairment.

Glioblastoma Multiforme is the most common malignant primary brain tumor, having a mean overall survival <2 years. The lack of an efficient immune response against the tumor have been attributed to its immunosuppressive capabilities and an immunosuppressing local environment. Aim: We set out to design a chimeric molecule that recognizes and binds tissue inducible metalloproteinase known to be induced in GBM cells (MMP-2) on one end. Its other end, the effector domain, mobilizes and recruits cytotoxic T-cells to mount an effective anti-tumor reaction. Methods: The targeting moiety is the small 36-amino acids Chlorotoxin, derived from the venom of the Israeli Yellow scorpion. The effector end is a single chain HLA-A2 (Human leukocyte antigen subtype A2) covalently bound to phosphoprotein-65 derived from the cytomegalovirus, to which most of the human population has developed a specific immune response. Results: The molecular construct was cloned and expressed in E.coli. The protein product was isolated, purified, and then folded in vitro. Various activity assays employed demonstrated retained activity of each domain, including flow-cytometry, intracellular staining, fluorescence immunohistochemistry, radiolabeled toxicity assays etc. Initial in-vivo studies show great promise. Conclusions: We present a proof of concept study for a new immunotherapy approach to battle GBM. A molecular construct which contains a non-antibody compact and highly specific targeting domain, combined with the ability to recruit anti-CMV T-cell lymphocyte population. The recruitment of potent memory CTL’s to the tumor’s milieu may prove resistant to the previously described local immunosuppressive environment brought about by the tumor.

Background: Many Canadians with multiple sclerosis (MS) have recently travelled internationally to have procedures for a putative condition called chronic cerebrospinal venous insufficiency (CCSVI). Here, we describe where and when they went and describe the baseline characteristics of persons with MS who participated in this non–evidence-based medical tourism for CCSVI procedures. Methods: We conducted a longitudinal observational study that used online questionnaires to collect patient-reported information about the safety, experiences, and outcomes following procedures for CCSVI. A convenience sample of all Albertans with MS was recruited between July 2011 and March 2013. Results: In total, 868 individuals enrolled; 704 were included in this cross-sectional, baseline analysis. Of these, 128 (18.2%) participants retrospectively reported having procedures for CCSVI between April 2010 and September 2012. The proportion of participants reporting CCSVI procedures declined from 80 (62.5%) in 2010, to 40 (31.1%) in 2011, and 8 (6.3%) in 2012. In multivariable logistic regression analysis, CCSVI procedures were independently associated with longer disease duration, secondary progressive clinical course, and greater disability status. Conclusions: Although all types of people with MS pursued procedures for CCSVI, a major driver of participation was greater disability. This highlights that those with the greatest disability are the most vulnerable to unproven experimental procedures. Participation in CCSVI procedures waned over time possibly reflecting unmet expectations of treated patients, decreased media attention, or that individuals who wanted procedures had them soon after the CCSVI hypothesis was widely publicized.

The knowledge to action (KTA) process proposed by Graham et al (2006) is a framework to facilitate the development and application of research evidence into clinical practice. The KTA process consists of the knowledge creation cycle and the action cycle. The Evidence Based Review of Stroke Rehabilitation is a foundational part of the knowledge creation cycle and has helped guide the development of best practice recommendations in stroke. The Rehabilitation Knowledge to Action Project is an audit-feedback process for the clinical implementation of best practice guidelines, which follows the action cycle. The objective of this review was to: (1) contextualize the Evidence Based Review of Stroke Rehabilitation and Rehabilitation Knowledge to Action Project within the KTA model and (2) show how this process led to improved evidence-based practice in stroke rehabilitation. Through this process, a single centre was able to change clinical practice and promote a culture that supports the use of evidence-based practices in stroke rehabilitation.

Background: Autistic regression (AR) accounts for 20-40% of patients with Autism Spectrum Disorder (ASD) .1 Literature demonstrates specific immune changes in AR patients,2 as well as association between AR and autoimmune thyroiditis.3 Our study explores the clinical association between AR and autoimmunity, focusing on possible precipitants and familial autoimmunity, in comparison with patients with infantile autism (IA). Methods: charts of children diagnosed with ASD in 2014 were reviewed, and patients were classified as either AR or IA based on Autism Diagnostic Interview (ADI-R) criteria.4 Information regarding pregnancy, perinatal complications, febrile illness preceding the diagnosis, and family history of autoimmune conditions was collected. Results: 206 children had IA and 33 had AR. No difference was found in prevalence of pregnancy or perinatal complications. The incidence of febrile illness in the 6 months prior to diagnosis and the prevalence of familial autoimmunity, were significantly higher in the AR group (p<0.001). Diabetes type I, celiac disease, autoimmune thyroiditis, and inflammatory bowel disease were more common in families of AR patients (p<0.05). Conclusions: the association between AR and preceding febrile illness, as well as familial autoimmunity, supports the notion of AR as a separate entity within ASD, possibly mediated by autoimmune changes.

Background: The Canadian Neurological Society commissioned a manpower survey in 2012 to assess Canadian neurological manpower and resources.Methods: Surveys were sent electronically to all Canadian neurologists with available email addresses. Responses were analysed for effects of physician gender, age, geographic location (eastern or western Canada) or type of practice (academic, community). Questions focused on work patterns, neurologic conditions treated, access to or performance of procedures, and service and manpower issues.Results: A total of 694 of 854 neurologists in Canada were surveyed and 219 (32%) responded. Respondents were 70% male with mean age of 50 years. Neurologists worked an average of 57 hours/week and saw a mean of 40 patients per week. There were significant differences in number of patients seen, types of practice, and areas of neurological specialization between community and academic neurologists. Fifty percent of neurologists report shortages of neurologists in their community, particularly of general adult neurologists. Wait times for neurological services exceeded international standards for consultations and also were longer than Canadian averages for other specialists. More community (18%) than academic (5%) neurologists planned to retire within the next 5 years.Conclusions: The demand for neurological services continues to outstrip resources despite the increased number of neurologists. Impending retirement of community neurologists will exacerbate manpower issues unless adequate numbers of trainees choose general neurologic practice in the community as a career.

Dravet syndrome is one of the most severe epilepsy syndromes of early childhood, and it comes with very high morbidity and mortality. The typical presentation is characterized by hemiclonic or generalized clonic seizures triggered by fever during the first year of life, followed by myoclonic, absence, focal and generalized tonic-clonic seizures. Non-convulsive status epilepticus and epileptic encephalopathy are common. Development is normal in the first year of life, but most individuals eventually suffer from intellectual impairment. Dravet syndrome is associated with mutations in the sodium channel alpha1 subunit gene (SCN1A) in 70-80% of individuals. SCN1A mutation results in inhibition of the GABAergic inhibitory interneurons, leading to excessive neuronal excitation. The “interneuron hypothesis” is the current most accepted pathophysiological mechanism of Dravet syndrome. The mortality rate is increased significantly in Dravet syndrome. Ataxia, a characteristic crouched gait and Parkinson’s symptoms may develop in some individuals. It is likely that Dravet syndrome is underdiagnosed in adults with treatment-resistant epilepsy. Early diagnosis is important to avoid anti-seizure medications that exacerbate seizures.