Research in human subjects is at the core of achieving improvements in health outcomes. For clinical trials, in addition to the peer review of the results before publication, it is equally important to consider whether the trial will be conducted in a manner that generates data of the highest quality and provides a measure of safety for the participating subjects. In Canada, there is no definitive legislation that governs the conduct of research involving human subjects, but a network of regulations at different levels does provide a framework for both principal investigators and sponsors. In this paper, we provide an overview of the federal, provincial and institutional legislation, guidelines and policies that will inform readers about the requirements for clinical trial research. This includes a review of the role of the Food and Drug Regulations under the Food and Drugs Act and the Tri-Council Policy Statement (TCPS2), an overview of provincial legislation across the country, and a focus on selected policies from institutional research ethics boards and public health agencies. Many researchers may find navigation through regulations frustrating, and there is a paucity of information that explains the interrelationship between the different regulatory agencies in Canada. Better understanding the process, we feel, will facilitate investigators interested in clinical trials and also enhance the long-term health of Canadians.

Background: Hyperacute stroke is a time-sensitive emergency for which outcomes improve with faster treatment. When stroke systems are accessed via emergency medical services (EMS), patients are routed to hyperacute stroke centres and are treated faster. But over a third of patients with strokes do not come to the hospital by EMS, and may inadvertently arrive at centres that do not provide acute stroke services. We developed and studied the impact of protocols to quickly identify and move “walk-in” patients from non-hyperacute hospitals to regional stroke centres (RSCs). Methods and Results: Protocols were developed by a multi-disciplinary and multi-institutional working group and implemented across 14 acute hospital sites within the Greater Toronto Area in December of 2012. Key metrics were recorded 18 months pre- and post-implementation. The teams regularly reviewed incident reports of protocol non-adherence and patient flow data. Transports increased by 80% from 103 to 185. The number of patients receiving tissue plasminogen activator (tPA) increased by 68% from 34 to 57. Total EMS transport time decreased 17 minutes (mean time of 54.46 to 37.86 minutes, p<0.0001). Calls responded to within 9 minutes increased from 34 to 59%. Conclusions: A systems-based approach that included a multi-organizational collaboration and consensus-based protocols to move patients from non-hyperacute hospitals to RSCs resulted in more patients receiving hyperacute stroke interventions and improvements in EMS response and transport times. As hyperacute stroke care becomes more centralized and endovascular therapy becomes more broadly implemented, the protocols developed here can be employed by other regions organizing patient flow across systems of stroke care.

Background: In this case series, functional magnetic resonance imaging was used to examine brain networks that mediate different aspects of language function in 4 young adults (17-22 years) with a history of left middle cerebral artery (MCA) stroke in childhood (<7 years of age but after the neonatal period), and five older individuals (42-57 years) with left MCA stroke as adults (>40 years of age). Although it is widely believed that altered lateralization patterns are more likely to occur following early brain injuries compared with later brain injuries, the presumed plasticity of the young brain has been challenged in recent years, particularly in the domain of language. Methods: We explored this issue by contrasting the brain activation patterns of individuals with childhood left MCA stroke and adult left MCA stroke while performing two language tasks: verb generation and picture-word matching. Importantly, both groups showed significant recovery of language function, based on standard clinical indicators. Results: Controls showed left lateralized activation for both tasks, although much more pronounced for verb generation. Adult stroke patients also showed left lateralization for both tasks, though somewhat weaker than controls. Childhood stroke patients exhibited significantly weaker lateralization than the adult group for verb generation, but there was no significant group difference for picture-word matching. Conclusions: These preliminary findings suggest that successful reorganization of language function is more likely to involve bilateral recruitment following left MCA stroke in childhood than in adulthood. Of importance, although childhood stroke patients had primarily subcortical lesions, there were substantial alterations in cortical activation patterns.

Background: In vitro models have suggested that stents affect atherosclerotic plaques symmetrically because of their outward radial forces. We evaluated the effects of stents on carotid plaque and the arterial wall using carotid ultrasound in carotid stenting patients to see whether these effects were borne out in vivo. Methods: From a carotid stent database, 30 consecutive patients were selected. All had carotid Doppler ultrasound performed pre- and poststenting. The diameters of the lumen at the level of stenotic plaque pre- and poststenting, the dorsal and ventral plaque thickness, and of the outer arterial wall diameter were measured. Plaque thickness was measured at the level of maximal stenosis. Nonparametric tests were used to determine whether the stent effect and luminal enlargement were based on wall remodeling or on total arterial expansion. Results: The patients were followed for an average of 22 months. Eighteen patients were male, with an average age of 70 years. A total of 87% of patients were symptomatic ipsilateral to the side of stenosis. Nine patients had angioplasty intraprocedurally. The luminal diameter increased poststenting in the region of severe stenosis. Plaque thickness, both ventrally and dorsally, decreased poststenting, with no significant difference between the ventral and dorsal plaque effects. The outer arterial wall diameters did not change. The measured lumen in the stent increased over time poststenting. Conclusions: Self-expanding nitinol stents alter the baseline ventral and dorsal plaque to a significant degree and do not significantly affect the native arterial wall and the overall arterial diameter.

Purpose: We measured anterior cerebral artery (ACA)-middle cerebral artery (MCA) and posterior cerebral artery (PCA)-MCA pial filling on single-phase computed tomography angiograms (sCTAs) in acute ischemic stroke and correlate with the CTA-based Massachusetts General Hospital (MGH) and digital subtraction angiography (DSA)-based American Society of Interventional and Therapeutic Neuroradiology (ASITN) score. Methods: Patients with acute stroke and M1 MCA±intracranial internal carotid artery occlusion on baseline CTA were included. Baseline sCTA was assessed for phase of image acquisition. An evaluator assessed collaterals using the Calgary Collateral (CC) Score (measures pial arterial filling in ACA-MCA and PCA-MCA regions separately), the CTA-based MGH score, and on DSA using the ASITN score. Infarct volumes were measured on 24- to 48-hour magnetic resonance imaging/ computed tomography. Results: Of 106 patients, baseline sCTA was acquired in early arterial phase in 9.9%, peak arterial in 50.7%, equilibrium in 32.4%, early venous in 5.6%, and late venous in 1.4%. Variance in ACA-MCA collaterals explained only 32% of variance in PCA-MCA collaterals on the CC score (Spearman’s correlation coefficient rho [rho]=0.56). Correlation between ACA-MCA collaterals and the MGH score was strong (rho=0.8); correlation between PCA-MCA collaterals and this score was modest (rho=0.54). Correlation between ACA-MCA collaterals and the ASITN score was modest (n=53, rho=0.43); and correlation between PCA-MCA collaterals and ASITN score was poor (rho=0.33). Of the CTA-based scores, the CC Score (Akaike [AIC] 1022) was better at predicting follow-up infarct volumes than was the MGH score (AIC 1029). Conclusion: Collateral assessments in acute ischemic stroke are best done using CTA with temporal resolution and by assessing regional variability. ACA-MCA and MCA-PCA collaterals should be evaluated separately.

Objectives: To compare growth patterns of nonfunctioning and prolactin-producing pituitary macroadenomas, and to find whether their specific growth patterns are associated with clinically significant effects on vision. Materials and Methods: From our comprehensive provincial neuropituitary registry, we retrospectively identified 35 randomly selected patients each with nonfunctioning adenomas and prolactinomas >10 mm in any dimension. MRI scans were analyzed to determine the superior and inferior growth, volume, and maximum craniocaudal height of the adenomas. Patients underwent visual field testing at diagnosis. Continuous variables were compared using Student’s t test, the Mann–Whitney U test, and ANOVA. Categorical variables were compared using the chi-square test. Results: The mean height of prolactinomas (23.2±11.3 mm) was similar to nonfunctioning adenomas (22.3±9.3 mm, p=0.8), and so were mean tumor volumes (prolactinoma=5.9±8 ml vs. nonfunctioning adenoma=4.8±5 ml, p=0.47). However, the mean suprasellar growth for prolactinomas was 2.9±5.3 mm and 7.3±4.7 mm for nonfunctioning adenomas (p<0.001), and the mean infrasellar growth was 10.2±8.0 and 5.0±6.6 mm, respectively (p=0.04). The inferior growth pattern of prolactinomas was associated with a significantly lower likelihood of having visual field abnormalities (11.4 vs. 57.1%, p<0.001). Conclusions: Prolactinomas have predominantly inferior growth compared to nonfunctioning adenomas and are less likely to cause vision changes.

Objectives: Intrathecal morphine (ITM) is an efficacious method of providing postoperative analgesia and reducing pain associated complications. Despite adoption in many surgical fields, ITM has yet to become a standard of care in lumbar spine surgery. Spine surgeons’ reticence to make use of the technique may in part be attributed to concerns of precipitating a cerebrospinal fluid (CSF) leak. Methods: Herein we describe a method for oblique intrathecal injection during lumbar spine surgery to minimize risk of CSF leak. The dural sac is penetrated obliquely at a 30° angle to offset dural and arachnoid puncture sites. Oblique injection in instances of limited dural exposure is made possible by introducing a 60° bend to a standard 30-gauge needle. Results: The technique was applied for injection of ITM or placebo in 104 cases of lumbar surgery in the setting of a randomized controlled trial. Injection was not performed in two cases (2/104, 1.9%) following preinjection dural tear. In the remaining 102 cases no instances of postoperative CSF leakage attributable to oblique intrathecal injection occurred. Three cases (3/102, 2.9%) of transient CSF leakage were observed immediately following intrathecal injection with no associated sequelae or requirement for postsurgical intervention. In two cases, the observed leak was repaired by sealing with fibrin glue, whereas in a single case the leak was self-limited requiring no intervention. Conclusions: Oblique dural puncture was not associated with increased incidence of postoperative CSF leakage. This safe and reliable method of delivery of ITM should therefore be routinely considered in lumbar spine surgery.

Objectives: Work-related traumatic brain injuries (TBIs) are not well documented in the literature. Published studies mostly rely on worker databases that fail to provide clinically relevant information. Our objective is to describe the characteristics of hospitalized patients and their work-related TBI. Methods: We used the Québec provincial trauma and TBI program databases to identify all patients with a diagnosis of work-related TBI admitted to the Montreal General Hospital, a level 1 trauma center, between 2000 and 2014. Data from their medical records were extracted using a predetermined information sheet. Simple descriptive statistics (means and percentages) were used to summarize the data. Results: A total of 285 cases were analyzed. Workplace TBI patients were middle-aged (mean, 43.62 years), overwhelmingly male (male:female 18:1), mostly healthy, and had completed a high school level education. Most workers were from the construction industry; falling was the most common mechanism of injury. The majority of patients (76.8%) presented with a mild TBI; only a minority (14%) required neurosurgery. The most common finding on computed tomography was skull fracture. The median length of hospitalization was 7 days, after which most patients were discharged directly home. A total of 8.1% died of their injuries. Conclusions: Our study found that most hospitalized victims of work-related TBI had mild injury; however, some required neurosurgical intervention and a non-negligible proportion died of their injury. Improving fall prevention, accurately document helmet use and increasing the safety practice in the construction industry may help decrease work-related TBI burden.

Objective: Given the difficult to navigate literature on social determinants in Indigenous traumatic brain injury (TBI) we wished to identify all available literature on the social determinants of health linked to TBI in the North American Indigenous populations. Methods: We performed a systematically conducted review. We searched MEDLINE, BIOSIS, EMBASE, Global Health, SCOPUS, and Cochrane Library from inception to January 2016. A two-step review process of the search results was performed, applying defined inclusion/exclusion criteria. The final group of articles had the data extracted and summarized. Results: Ten manuscripts were identified to discuss some social determinant linked to TBI in the North American Indigenous populations. Two studies were focused on Canadian populations, with the remaining 8 studies focused on populations within the United States. Six social health determinants were identified within the studies, including: Rural location (Physical Environment) in seven studies, Male gender in five studies and Female gender in one study (in the setting of interpersonal violence) (Gender), Substance use in four studies and failure to utilize personal protective equipment in one study (Personal Health Practices and Coping Skills), Interpersonal Violence in one study (Social Environment), availability of rehabilitation services in one study (Health Services), and lack of family and friend presence during meetings with healthcare professionals in one study (Social Support Network). Conclusions: To date, little literature is available on the social determinants that impact TBI in the North American Indigenous population. Further research is warranted to better determine the incidence and social determinants associated.

Background: Vagus nerve stimulation (VNS) therapy has been widely recognized as an alternative for the treatment of drug-resistant epilepsy, although modification of antiepileptic drugs (AEDs) during VNS treatment could explain the improvement in patients. Methods: We retrospectively assessed the efficacy of VNS in 30 adult patients with epilepsy treated with >6 months of follow-up. The criteria for implantation were the following: (1) not a candidate for resective epilepsy surgery, (2) drug-resistant epilepsy, (3) impairment of quality of life, (4) no other option of treatment, and (5) patients with idiopathic generalized epilepsy who fail to be controlled with appropriate AEDs. We assessed sociodemographics, seizure etiology, seizure classification, and AEDs used during treatment with VNS. We assessed adverse effects and efficacy. Responder rate was defined as >50% seizure improvement from baseline. Results: Thirty patients (females, 18; males, 12; age, 35.1±13.3 years) were included. After 6, 12, 24, and 36 months of follow-up, the response rates were: 13/30 (43%), 13/27 (48%), 9/22 (41%), and 8/16 (50%), respectively; none was seizure free. Fifty-seven percent, 33%, 59%, and 81% of patients had changes of medication type or dose at 6, 12, 24, and 36 months respectively. In the majority of patients, the change of medication consisted of an increase in the dose of AEDs. Conclusions: Our study shows that VNS is an effective therapy, although significant changes in medications were done along with the therapy; therefore, the real effect of VNS could be controversial.

Objective: Refractory status epilepticus (RSE) can influence the outcome of status epilepticus (SE). In the present study, we report the aetiology and predictors of outcomes of RSE in a developing country. Methods: This is a prospective hospital-based study of SE patients (continuous seizures for five minutes or more). Those who had SE persisting after two antiepileptic drugs were defined as having RSE. We present the demographic information, duration, and type of SE, and we note its severity using the status epilepticus severity score (STESS), its aetiology, comorbidities and imaging findings. The outcome of RSE was defined as cessation of seizures and the condition upon discharge, as assessed by the modified Rankin Scale. Results: A total of 35 (42.5%) of our 81 patients had RSE. The median duration of SE before starting treatment was 2 hours (range=0.008-160 h). The most common causes of RSE were stroke in 5 (14.3%), central nervous system (CNS) infections in 12 (34.3%) and metabolic encephalopathies in 13 (37.1%) patients. Some 21 (60%) patients had comorbidities, and the STESS was favourable in 7 (20%) patients. A total of 14 (20%) patients died, but death was directly related to SE in only one of these. Some 10 patients had super-refractory status epilepticus, which was due to CNS infection in 5 (50%) and metabolic encephalopathy in 3 (30%). On multivariate analysis, an unfavourable STESS (p=0.05) and duration of SE before treatment (p=0.01) predicted RSE. Metabolic aetiology (p=0.05), mechanical ventilation (p<0.001) and age >60 years (p=0.003) were predictors of poor outcomes. Conclusions: RSE was common (42.5%) among patients with SE in a tertiary care center in India. It was associated with high mortality and poor outcomes. Age above 60 years and metabolic aetiology were found to be predictors of poor outcomes.

Objective: The Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) is a consensus-based collection of neuropsychological tests that evaluate cognitive functioning in individuals with multiple sclerosis (MS). The tests are typically scored using each respective published test manual, leaving the examiner to make interpretations from norms derived from different American populations. Given demographic differences, this may lead to misinterpretation of findings in Canadians. Our goal was to establish both discrete and regression-based normative data for the MACFIMS based on a largely co-normed Canadian population to allow for improved psychometric interpretation. Methods: MACFIMS data sets were aggregated from across three different Canadian cities (Ottawa, Toronto, and London), yielding a total of 330 healthy control participants from four different studies evaluating cognition in individuals with MS. Given the variety of contributing studies, there was variability in terms of the number of participants completing each measure. Results: Both age-based discrete normative data and demographically adjusted (sex, age, and education) regression-based formulae were established. The demographic variables varied in their contribution to each MACFIMS test in the regression models, predicting 0 to 18% of the variance. Conclusions: Provision of these regression-based formulae will allow for more accurate interpretation of Canadian-derived MACFIMS scores by allowing clinicians to correct for all relevant demographic variables simultaneously, leading to improved clinical decision making for individuals with multiple sclerosis.

Background: This study assesses the value of the video head impulse test (vHIT) for early diagnosis of vestibular neuritis (VN) among acute vertigo. Methods: Thirty-three cases of vestibular neuritis (VN), 96 patients with other acute vertigo (AV), and 50 cases of normal controls used vHIT to quantitatively test a pair of horizontal vestibulo-ocular reflection (VOR) gains, two pairs of vertical VOR gains, and the corresponding three pairs of VOR gain asymmetry. The peculiarity of VOR gains in VN and the differences between VN and other AV, normal controls by vHIT, were collected and analyzed. Results: There were statistically significant differences in the three pairs of VOR gains asymmetry between VN and other AV, and normal controls (P<0.01). The sensitivity was 87.9% and specificity was 94.3% in differentiating VN from normal and other acute vertigo by vHIT. Conclusions: This study shows vHIT has advantages in the diagnosis of VN in acute vertigo with good sensitivity and specificity and indicates a widespread clinical application.

Background: Individuals with Parkinson’s disease (PD) often present with visual symptoms (e.g., difficulty in reading, double vision) that can also be found in convergence insufficiency (CI). Our objective was to estimate the prevalence of CI-type visual symptomatology in individuals with PD, in comparison with controls. Methods: Participants ≥50 years with (n=300) and without (n=300) PD were recruited. They were administered the Convergence Insufficiency Symptom Survey (CISS–15) over the phone. A score of ≥21 on the CISS–15, considered positive for CI-type symptomatology, served as the cutoff. Data from individuals (n=87 with, n=94 without PD) who were approached but who reported having a known oculovisual condition were analysed separately. Student’s t test and chi-square at the 0.05 level were employed for statistical significance. Results: A total of 29.3% of participants with versus 7.3% without PD presented with a score of ≥21 on the CISS–15 (p=0.001). Of the participants having a known oculovisual condition, 39.1% with versus 19.1% without PD presented with a score of ≥21 on the CISS–15 (p=0.01). Conclusions: The prevalence of CI-type visual symptoms is higher in individuals with versus without PD whether or not they have a coexisting oculovisual condition. These results suggest that PD per se places individuals with the disease at greater risk of visual symptomatology. These results further underline the importance of providing regular eye exams for individuals with PD.

Background: Myotonic dystrophy type 1 is an autosomal dominant condition affecting distal hand strength, energy, and cognition. Increasingly, patients and families are seeking information online. An online neuromuscular patient portal under development can help patients access resources and interact with each other regardless of location. It is unknown how individuals living with myotonic dystrophy interact with technology and whether barriers to access exist. We aimed to characterize technology use among participants with myotonic dystrophy and to determine whether there is interest in a patient portal. Methods: Surveys were mailed to 156 participants with myotonic dystrophy type 1 registered with the Canadian Neuromuscular Disease Registry. Results: Seventy-five participants (60% female) responded; almost half were younger than 46 years. Most (84%) used the internet; almost half of the responders (47%) used social media. The complexity and cost of technology were commonly cited reasons not to use technology. The majority of responders (76%) were interested in a myotonic dystrophy patient portal. Conclusions: Patients in a Canada-wide registry of myotonic dystrophy have access to and use technology such as computers and mobile phones. These patients expressed interest in a portal that would provide them with an opportunity to network with others with myotonic dystrophy and to access information about the disease.

Background: Preliminary studies have supported the utility of exercise as a treatment for Charcot–Marie–Tooth disease (CMT) patients. Despite being the most common inherited neuropathy, there remains a paucity of guidelines for CMT management. Methods: A retrospective chart review was performed on 297 CMT patients. Self-reported exercise and strength results from standardized dynamometer testing were obtained from adult patients’ first visits. Values were converted and analyzed based on previously reported age- and sex-matched normative values. Results: Participants with CMT2 had greater strength values than those with CMT1 in hand grip, elbow flexion, and dorsiflexion (p<0.05). Participants with CMT1 and CMT2 who exercised were statistically significantly stronger in elbow flexion and dorsiflexion than those who did not exercise. Conclusions: These preliminary results suggest that self-directed exercise is associated with greater strength in CMT patients of both CMT1 and CMT2 subtypes. Self-directed exercise may be a convenient, sustainable, and effective method of improving strength and decreasing disability in this population. Future research should explore the type of exercise prescription that best addresses the needs of the CMT population.

Background: Neurofibromatosis type 1 (NF1) is a common single-gene disorder. A multidisciplinary approach to the management of NF1 patients is necessitated by the heterogeneity of clinical manifestations. Although multidisciplinary paediatric clinics have been well established, there is a dearth of such resources for adults with NF1. Herein we report our one-year institutional experience with a multidisciplinary adult NF1 clinic. Methods: A multidisciplinary team was assembled, and an NF Patient Registry Initiative questionnaire was adapted to collect patient-reported data during clinics. Multiple databases were searched to identify publications pertaining to the experience of other multidisciplinary NF1 clinics focusing on adult patients. Data on patient epidemiology and clinical staff were compared to our data. Results: A total of 77 patients were scheduled, and 68 attended the clinic, of whom 66 completed the intake questionnaire. The demographic and clinical data from this Canadian population are mostly consistent with previous reports, with some exceptions. Clinical data related to immune system involvement such as asthma, airway/breathing-related difficulties or allergies were striking in our NF1 population. Six relevant published reports of other NF1 clinics were identified. Reports from these studies pertained to periods ranging from 10 to 38 months, and the number of adults assessed ranged from 19 to 177 patients. Conclusions: The structure of our clinic and the patient volume are comparable to those of other established centres found in the literature. Our data offer valuable cross-sectional prevalence statistics in the Canadian population. The patient-reported data concerning involvement of the immune system contribute to an emerging recognized medical concern within the NF1 population and warrant further clinical and basic investigation.

Trigeminal neuralgia (TN) associated with multiple sclerosis (MS) was first described in Lehrbuch der Nervenkrankheiten für Ärzte und Studirende in 1894 by Hermann Oppenheim, including a pathologic description of trigeminal root entry zone demyelination. Early English-language translations in 1900 and 1904 did not so explicitly state this association compared with the German editions. The 1911 English-language translation described a more direct association. Other later descriptions were clinical with few pathologic reports, often referencing Oppenheim but citing the 1905 German or 1911 English editions of Lehrbuch. This discrepancy in part may be due to the translation differences of the original text.