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.

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.

Objective: To evaluate epidemiological patterns and lifetime costs of traumatic brain injury (TBI) identified in the emergency department (ED) within a publicly insured population in Ontario, Canada, in 2009. Methods: A nationally representative, population-based database was used to identify TBI cases presenting to Ontario EDs between April 2009 and March 2010. We calculated unit costs for medical treatment and productivity loss, and multiplied these by corresponding incidence estimates to determine the lifetime costs of identified TBI cases across age group, sex, and mechanism of injury. Results: In 2009, there were more than 133,000 ED visits for TBI in Ontario, resulting in a conservative estimate of $945 million in lifetime costs. Lifetime cost estimates ranged from $279 million to $1.22 billion depending on the diagnostic criteria used to define TBI. Peak rates of TBI occurred among young children (ages 0-4 year) and the elderly (ages 85+ years). Males experienced a 53% greater rate of TBI and incurred two-fold higher costs compared with females. Falls, sports/bicyclist-related injuries, and motor vehicle crashes represented 47%, 12%, and 10% of TBI presenting to ED, respectively, and accounted for a significant proportion of costs. Conclusions: This study revealed an enormous health and economic burden associated with TBI identified in the ED setting. Our findings underscore the importance of ongoing surveillance and prevention efforts targeted to vulnerable populations. More research is needed to fully appreciate the burden of TBI across a variety of health care settings.

Background: Perinatal regionalization is linked to improved neonatal outcomes; however, the effects on long-term outcomes in cerebral palsy (CP) are not known. We estimate the effect of highest levels of neonatal care available at delivery on the risk of developing a nonambulatory CP status. Methods: Children with CP born in Quebec from the Canadian CP Registry excluding postneonatal causes were included (N=360). We estimate the effect of level of care available at delivery on risk of nonambulatory status among children with CP using propensity score matching and instrumental variables methods to adjust for differences in case mix among the three groups of hospitals. The outcome variable is an indicator for CP nonambulation assigned according to Gross Motor Function Classification System (levels IV and V). This study used data that predated therapeutic hypothermia in Quebec. Results: Propensity score estimates of change in the adjusted risk of having a nonambulatory CP status because of birth at level II versus level I is −0.081, 95% confidence interval (CI; −0.2182 to 0.0562); level III versus level I is −0.072 95% CI (−0.225 to 0.08), and level III versus level II is 0.157 95% CI (0.027 to 0.286). Conclusions: Differences in levels of neonatal care available at hospital where the delivery was carried out are not associated with the risk of a nonambulatory CP phenotype. This suggests that level of care and associated medical technology within the Quebec regionalized neonatal-perinatal system is used efficiently because it does not offer any further marginal benefit in the reduction of severe CP outcomes. The system works well as it is, which is supportive of the perinatal regionalization. The success of the neonatal resuscitation program and referral of high-risk births to regional hospitals with sufficient obstetric and perinatal competence and resources may contribute to this lack of variability.

Background: The StatNet electrode set is a system that can be applied by a non-electroencephalogram (EEG) technologist after minimal training. The primary objectives of this study are to assess the quality and reliability of the StatNet recordings in comparison to the conventional EEG. Methods: Over 10 months, 19 patients with suspected nonconvulsive status epilepticus were included from university hospital emergency settings. Each patient received a StatNet EEG by a trained epilepsy fellow and a conventional EEG by registered technologists. We compared the studies in a blinded fashion, for the timeframe from EEG order to the setup time, start of acquisition, amount of artifact, and detection of abnormalities. The nonparametric Mann-Whitney two-sample t test was used for comparisons. The kappa score was used to assess reliability. Results: Mean age of patients was 61±16.3 (25-93) years. The inter-observer agreement for detection of abnormal findings was 0.83 for StatNet and 0.75 for conventional EEG. Nonconvulsive status epilepticus was detected in 10% (2/19) in both studies. The delay from the time of EEG requisition to acquisition was shorter in the StatNet (22.4±2.5 minutes) than the conventional EEG (217.7±44.6 minutes; p<0.0001). The setup time was also shorter in the StatNet (9.9±0.8 minutes) compared with the conventional EEG (17.8±0.8 minutes; p<0.0001). There was no difference in the percentage of artifact duration between the two studies (p=0.89). Conclusion: This study demonstrates that StatNet EEG is a practical and reliable tool in the emergency setting, which reduces the delay of testing compared with conventional EEG, without significant compromise of study quality.

Background: Parkinson disease (PD) presents with motor and non-motor symptoms (NMS). The NMS often precede the onset of motor symptoms, but may progress throughout the disease course. Tremor dominant, postural instability gait difficulty (PIGD), and indeterminate phenotypes can be distinguished using Unified PD Rating scales (UPDRS-III). We hypothesized that the PIGD phenotype would be more likely to develop NMS, and that the non-dopamine–responsive axial signs would correlate with NMS severity. Methods: We conducted a retrospective cross-sectional chart review to assess the relationship between NMS and PD motor phenotypes. PD patients were administered the NMS Questionnaire, the UPDRS-III, and the Mini-Mental State Examination score. The relationship between NMS burden and PD subtypes was examined using linear regression models. The prevalence of each NMS among difference PD motor subtypes was analyzed using chi-square test. Results: PD patients with more advanced disease based on their UPDRS-III had higher NMS Questionnaire scores. The axial component of UPDRS-III correlated with higher NMS. There was no correlation between NMS and tremor scores. There was a significant correlation between PIGD score and higher NMS burden. PIGD group had higher prevalence in most NMS domains when compared with tremor dominant and indeterminate groups independent of disease duration and severity. Conclusions: NMS profile and severity vary according to motor phenotype. We conclude that in the PD population, patients with a PIGD phenotype who have more axial involvement, associated with advanced disease and poor motor response, have a higher risk for a higher NMS burden.

Background: Psychogenic movement disorders (PMD) is a group of disorders that cannot be attributed to any structural or biochemical abnormality, but has an underlying psychiatric illness. The profile of PMD varies according to country and socioeconomic factors. Methods: The present study reports the clinical profile of patients with PMD from India. Seventy-three patients with documented or clinically established PMD were seen over a period of 14 years with detailed neurological and psychiatric examinations. Results: The mean age at presentation was 29.1±15.1 years (women, 51%). Approximately 30% were ≤18 years of age (boys, 63.6%). The onset of symptoms was abrupt in 61.6% and the initial body part most often affected was right upper limb (adults, 29.4%; children, 31.8%). Tremor was observed in 31.4% of adults and 9% of children, whereas myoclonus was more common in children (36.4%). Tremors were more often seen in women (42.3%) than in men (20%), whereas myoclonus was almost equally prevalent in girls (37.5%) and boys (35.7%). Depression was the most common psychiatric comorbidity (men, 16%; women, 15.4%). About 42.5% required hospital admission and 57.5% had significant reduction or complete cessation of PMD after counseling, antidepressants, and/ or placebo. Conclusions: PMD was equally prevalent among women and men. Tremor was most often observed in adults, whereas myoclonus was most often observed in children. Electrophysiology and placebo were useful supplementary tools for diagnosing PMD.

Background: The Canadian GILENYA® Go ProgramTM provides education and support to people with relapsing-remitting multiple sclerosis during fingolimod treatment. Methods: Data were collected and analyzed from the time of the first individual enrolled in March 2011 to March 31, 2014. Individuals were excluded if they withdrew from the program prior to receiving the first dose, or had not completed the first dose observation (FDO) at the time of data cut-off. Reports of adverse effects were validated with a database of adverse events reported to Novartis Pharmaceuticals Canada Inc. Results: A total of 2,399 individuals had completed FDO at the end of the three-year observation period. Mean age was 41.2 years; 75.2% were female. The most recent prior therapies reported were interferon-β agents (50.2%), glatiramer acetate (31.1%), natalizumab (14.2%), no prior therapy (3.3%), and other agent (1.1%). Reasons for switching to fingolimod were lack of efficacy (34.9%), side effects (34.6%), and dissatisfaction with injections/infusion (30.4%). Continuation rates with fingolimod at 12, 24 and 30 months were 80.7%, 76.6% and 76.0%, respectively. The discontinuation rate due to reported lack of efficacy during the three-year period was 1.3%. There was 94.4% adherence to the scheduled ophthalmic examination. Conclusions: The GILENYA® Go ProgramTM captures data for virtually all fingolimod-treated patients in Canada, enabling the evaluation of fingolimod use in routine practice. Ongoing patient support and reminders to take the medication, in conjunction with physicians’ and/or patients’ perception of the efficacy and tolerability of fingolimod, resulted in a high rate of continuation during longer-term therapy.

Background: Current opinions regarding the use of dexamethasone in the treatment of chronic subdural hematomas (CSDH) are only based on observational studies. Moreover, the use of corticosteroids in asymptomatic or minimally symptomatic patient with this condition remains controversial. Here, we present data from a prospective randomized pilot study of CSDH patients treated with dexamethasone or placebo. Methods: Twenty patients with imaging-confirmed CSDH were recruited from a single center and randomized to receive dexamethasone (12 mg/day for 3 weeks followed by tapering) or placebo as a conservative treatment. Patients were followed for 6 months and the rate of success of conservative treatment with dexamethasone versus placebo was measured. Parameters such as hematoma thickness and clinical changes were also compared before and after treatment with chi-square tests. Adverse events and complications were documented. Results: During the 6-month follow-up, one of ten patients treated with corticosteroids had to undergo surgical drainage and three of ten patients were treated surgically after placebo treatment. At the end of the study, all remaining patients had complete radiological resolution. No significant differences were observed in terms of hematoma thickness profile and impression of change; however, patients experienced more severe side effects when treated with steroids as compared with placebo. Dexamethasone contributed to many serious adverse events. Conclusions: Given the small sample size, these preliminary results have not shown a clear beneficial effect of dexamethasone against placebo in our patients. However, the number of secondary effects reported was much greater for corticosteroids, and dexamethasone treatment was responsible for significant complications.

Background: Sellar masses (SM) are mostly benign growths of pituitary or nonpituitary origin that are increasingly encountered in clinical practice. To date, no comprehensive population-based study has reported the epidemiology of SM from North America. Aim: To determine the epidemiology of SM in the province of Nova Scotia, Canada. Methods: Data from all pituitary-related referrals within the province were prospectively collected in interlinked computerized registries starting in November 2005. We conducted a retrospective analysis on all patients with SM seen within the province between November 2005 and December 2013. Results: A total of 1107 patients were identified, of which 1005 were alive and residing within the province. The mean age at presentation was 44.6±18 years, with an overall female preponderance (62%) and a population prevalence rate of 0.1%. Of patients with SM, 837 (83%) had pituitary adenomas and 168 (17%) had nonpituitary lesions. The relative prevalence and standardized incidence ratio, respectively, of various SM were: nonfunctioning adenomas (38.4%; 2.34), prolactinomas (34.3%; 2.22), Rathke’s cyst (6.5%; 0.5), growth hormone–secreting adenomas (6.5%; 0.3), craniopharyngiomas (4.5%; 0.2), adrenocorticotropic hormone–secreting adenomas (3.8%; 0.2), meningiomas (1.9%), and others (3.9%; 0.21). At presentation, 526 (52.3%) had masses ≥1 cm, 318 (31.6%) at <1 cm, and 11 (1.1%) had functioning pituitary adenomas without discernible tumor, whereas tumor size data were unavailable in 150 (14.9%) patients. The specific pathologies and their most common presenting features were: nonfunctioning adenoma (incidental, headaches, and vision loss), prolactinomas (galactorrhea, menstrual irregularity, and headache), growth hormone–secreting adenomas (enlarging extremities and sweating), adrenocorticotropic hormone-secreting adenoma (easy bruising, muscle wasting, and weight gain) and nonpituitary lesions (incidental, headaches, and vision problems). Secondary hormonal deficiencies were common, ranging from 19.6% to 65.7%; secondary hypogonadism, hypothyroidism, and growth hormone deficiencies constituted the majority of these abnormalities. Conclusions: This is the largest North American study to date to assess the epidemiology of SM in a large stable population. Given their significant prevalence in the general population, more studies are needed to evaluate the natural history of these masses and to help allocate appropriate resources for their management.

Objective: The adverse events (AEs) with botulinum toxin type-A (BoNTA), used for indications other than spasticity, are widely reported in the literature. However, the site, dose, and frequency of injections are different for spasticity when compared to the treatment for other conditions and hence the AEs may be different as well. The objective of this study was to summarize the AEs reported in Canada and systematically review the AEs with intramuscular botulinum toxin injections to treat focal spasticity. Methods: Data were gathered from Health Canada (2009-2013) and major electronic databases. Results: In a 4 year period, 285 AEs were reported. OnabotulinumtoxinA (n=272 events): 68% females, 53% serious, 18% hospitalization, and 8% fatalities. The type of AEs reported were – muscle weakness (19%), oropharyngeal (14%), respiratory (14%), eye related (8%), bowel/bladder related (8%), and infection (5%). IncobotulinumtoxinA (n=13): 38% females, 62% serious, and 54% hospitalization. The type of AEs reported were – muscle weakness (15%), oropharyngeal (15%), respiratory (38%), eye related (23%), bowel/bladder related (15%), and infection (15%). Commonly reported AEs in the literature were muscle weakness, pain, oropharyngeal, bowel/bladder, blood circulation, neurological, gait, and respiratory problems. Conclusion: While BoNTA is useful in managing spasticity, future studies need to investigate the factors that can minimize AEs. A better understanding of the underlying mechanisms of the AEs can also improve guidelines for BoNTA administration and enhance outcomes.

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.

Russian-born, Vienna-trained neurologist and neuropathologist Ilya Mark Scheinker collaborated with Josef Gerstmann and Ernst Sträussler in 1936 to describe the familial prion disorder now known as Gerstmann-Sträussler-Scheinker disease. Because of Nazi persecution following the annexation of Austria by Nazi Germany, Scheinker fled from Vienna to Paris, then after the German invasion of France, to New York. With the help of neurologist Tracy Putnam, Scheinker ended up at the University of Cincinnati, although his position was never guaranteed. He more than doubled his prior publications in America, and authored three landmark neuropathology textbooks. Despite his publications, he was denied tenure and had difficulty professionally in the Midwest because of prejudice against his European mannerisms. He moved back to New York for personal reasons in 1952, dying prematurely just 2 years later. Scheinker was twice uprooted, but persevered and eventually found some success as a refugee.