Background: We determined the association between head circumference (HC) at birth and through neonatal intensive care with neurodevelopmental outcome in preterm neonates, accounting for brain injury on MRI. Methods: 169 neonates born 24-32 weeks gestation were studied prospectively with serial MRI. HC was measured at birth and discharge from neonatal intensive care. Outcome was assessed at 18 months corrected age using Bayley Scales of Infant & Toddler Development III motor and cognitive scores. Using multivariate linear regressions we evaluated the association between HC and outcomes, accounting for severity of brain injury and postnatal infection. Results: 46 neonates had HC <10th percentile at birth (SHC) which predicted poorer motor (~4 points; p=0.001) and cognitive (~4 points; p=0.005) outcomes, relative to those with normal HC at birth. In 9 of these neonates, SHC persisted to discharge; they had dramatically lower motor scores (15 points; p=0.004) and cognitive scores (12 points; p<0.001), even after adjusting for known risk factors Those born with SHC whose HC normalized by discharge did not show significantly poorer outcomes than those born with normal HC. Conclusions: The relationship between small HC at birth and adverse neurodevelopmental outcomes can be attenuated with normalization of head growth through the period of neonatal intensive care.

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.

The Milwaukee protocol has been attributed to survival in rabies encephalitis despite a lack of scientific evidence supporting its therapeutic measures. We have reviewed the literature with reference to specific treatment recommendations made within the protocol. Current literature fails to support an important role for excitotoxicity and cerebral vasospasm in rabies encephalitis. Therapies suggested in the Milwaukee protocol include therapeutic coma, ketamine infusion, amantadine, and the screening/prophylaxis/management of cerebral vasospasm. None of these therapies can be substantiated in rabies or other forms of acute viral encephalitis. Serious concerns over the current protocol recommendations are warranted. The recommendations made by the Milwaukee protocol warrant serious reconsideration before any future use of this failed protocol.

Background: The diagnosis of a sports-related concussion is often dependent on the athlete self-reporting their symptoms. It has been suggested that improving youth athlete knowledge and attitudes toward concussion may increase self-reporting behaviour. The objective of this study was to determine if a novel Concussion-U educational program improves knowledge of and attitudes about concussion among a cohort of elite male Bantam and Midget AAA hockey players. Methods: Fifty-seven male Bantam and Midget AAA-level hockey players (mean age=14.52±1.13 years) were recruited from the local community. Each participant completed a modified version of the Rosenbaum Concussion Knowledge and Attitudes Survey–Student Version immediately before and after a Concussion-U educational presentation. Follow-up sessions were arranged 4 to 6 months after the presentation, and assessed retention of knowledge and attitude changes. Results: Forty-three players completed all three surveys. Concussion knowledge and attitude scores significantly (p<0.01) increased from pre- to post-presentation by 12.79 and 8.41%, respectively. At long-term follow-up, knowledge levels remained significantly (p<0.01) higher than baseline by 8.49%. Mean attitude scores were also increased at follow-up; however, this increase was not statistically significant. Conclusions: A Concussion-U educational program led to an immediate improvement in concussion knowledge and attitudes among elite male Bantam and Midget AAA hockey players. Increased knowledge was maintained at long-term follow-up, but improved attitude was not. Future studies should investigate whether similar educational programs influence symptom reporting and concussion incidence. In addition, they should focus on how to maintain improved concussion attitudes.

Positron emission tomography (PET) imaging of brain amyloid beta is now clinically available in several countries including the United States and the United Kingdom, but not Canada. It has become an established technique in the field of neuroimaging of aging and dementia, with data incorporated in the new consensus guidelines for the diagnosis of Alzheimer disease and predementia Alzheimer’s disease–related conditions. At this point, there are three US Food and Drug Administration– and European Union–approved tracers. Guided by appropriate use criteria developed in 2013 by the Alzheimer’s Association and the Society of Nuclear Medicine and Molecular Imaging, the utility of amyloid imaging in medical practice is now supported by a growing body of research. In this paper, we aimed to provide an update on the 2012 Canadian consensus guidelines to dementia care practitioners on proper use of amyloid imaging. We also wished to generate momentum for the industry to submit a new drug proposal to Health Canada. A group of local, national, and international dementia experts and imaging specialists met to discuss scenarios in which amyloid PET could be used appropriately. Peer-reviewed and published literature between January 2004 and May 2015 was searched. Technical and regulatory considerations pertaining to Canada were considered. The results of a survey of current practices in Canadian dementia centers were considered. A set of specific clinical and research guidelines was agreed on that defines the types of patients and clinical circumstances in which amyloid PET could be used in Canada. Future research directions were also outlined, notably the importance of studies that would assess the pharmaco-economics of amyloid imaging.

Background: Patients diagnosed with Parkinson’s disease (PD) on clinics who subsequently turn out to have normal dopamine transporter images have been referred to as scans without evidence of dopaminergic deficits (SWEDDs) patients. Cardiovascular autonomic dysfunction has frequently been reported in PD. In this study, we determined the similarities and differences in cardiac autonomic dysfunction between SWEDDs and PD patients. This study investigated whether 24-hour ambulatory blood pressure monitoring (24-hour ABPM) can help identify possible cases with SWEDDs. Methods: We enrolled 28 SWEDDs patients, 46 patients with PD, and 30 healthy controls. To evaluate cardiac autonomic function, 24-hour ABPM was performed on all subjects. Cardiac metaiodobenzylguanidine (MIBG) scintigraphy was performed on the SWEDDs and PD subjects. Results: The percentage nocturnal decline in blood pressure differed significantly among SWEDDs patients, PD patients, and controls (p<0.05). In addition to the abnormal nocturnal BP, regulation (nondipping and reverse dipping) was significantly higher in SWEDDs and PD subjects than in the control subjects (p<0.05). There was no significant correlation between the % nocturnal blood pressure reduction and parameters of cardiac MIBG uptake ratio. However, orthostatic hypotension was significant correlated with the nocturnal blood pressure dip (%), nocturnal blood pressure patterns, and the cardiac MIBG uptake ratio (early and late) in combined SWEDDs and PD subjects. Conclusions: Pathologic nocturnal blood pressure regulation and nocturnal hypertension, known characteristics of PD, are also present in SWEDDs. Moreover, cardiac sympathetic denervation should not be attributed to cardiac autonomic dysfunction in SWEDDs patients. As with PD patients, the SWEDDs patients studied here tended to have cardiac autonomic dysfunction.

Medulloblastoma and neuroblastoma are aggressive solid pediatric tumors, with 5 year survival rates lower than 50-60%. In addition, more than 80% of the survivors develop permanent neurological impairments. Hence, there is a dire need to identify and validate novel, more effective and less toxic therapeutic approaches. Tumors are continually exposed to acute changes in the micro-environment, including nutrient availability. We previously showed that eukaryotic Elongation Factor-2 Kinase (eEF2K) is a critical regulator of cellular adaptation to acute metabolic stress. Based on those findings, we hypothesize that eEF2K is a marker of outcome and mediates medulloblastoma and neuroblastoma adaptation to acute stress. METHODS – Proprietary gene expression datasets (for medulloblastoma) and the R2 genomic analysis platform (for neuroblastoma) were analyzed for links between eEF2K expression and outcome. Effects of eEF2K knockdown on cell survival were evaluated in BE(2)C neuroblastoma cells. Immunoblotting and immunohistochemistry were performed on neuroblastoma cell lines and tissue microarrays (TMAs) for key molecules in the pathway. Similar studies are underway in medulloblastoma cell lines and TMAs. RESULTS - Low eEF2K mRNA expression is predictive of improved survival in medulloblastoma and neuroblastoma. Low p-eEF2 protein expression, indicative of low eEF2K activity, improves survival in human neuroblastoma. Neuroblastoma cell lines with eEF2K knockdown are more sensitive than controls to nutrient deprivation. CONCLUSIONS - eEF2K may represent a critical mechanism for adaptation to acute metabolic stress in neuroblastoma and medulloblastoma, and is therefore a promising therapeutic target. We are currently exploring the pharmacological inhibition of eEF2K in xenograft tumor models.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal degenerative neurological disease with significant effects on quality of life. International studies continue to provide consistent incidence values, though complete case ascertainment remains a challenge. The Canadian population has been understudied, and there are currently no quantitative data on the incidence of ALS in British Columbia (BC). The objectives of this study were to determine the five-year incidence rates of ALS in BC and to characterize the demographic patterns of the disease. Methods: The capture–recapture method was employed to estimate ALS incidence over a five-year period (2010-2015). Two sources were used to identify ALS cases: one database from an ALS medical centre and another from a not-for-profit ALS organization. Results: During this time period, there were 690 incident cases within the two sources. The capture–recapture method estimated 57 unobserved cases, corresponding to a crude five-year incidence rate of 3.29 cases per 100,000 (CI95%=3.05-3.53). The mean age of diagnosis was 64.6 (CI95%=59.7-69.4), with 63.5 (CI95%=56.9-70.1) for men and 65.7 (CI95%=58.6-72.7) for women. There was a slight male preponderance in incidence, with a 1.05:1 ratio to females. Peak numbers in incidence occurred between the ages of 70 and 79. Conclusions: The incidence of ALS in BC was found to be consistent with international findings though nominally higher than that in other Canadian provinces to date.

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: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing degenerative motor neuron disease that results in significant muscle weakness. Defects in energy metabolism and difficulties in swallowing eventually lead to a reduction in body mass. Weight loss exacerbates symptoms and serves as an independent negative prognostic factor. Percutaneous endoscopic gastrostomy (PEG) is often inserted in patients with ALS to either supplement or replace oral feeding. However, the criteria for PEG placement and timing of insertion are important clinical decisions that have not been fully studied. Given the absence of guiding evidence, the aim of this project was to better understand how Canadian ALS clinics make decisions regarding gastrostomy feeding. Methods: ALS clinical directors across Canada were asked if they had written guidelines for timing of PEG insertion and if not, what criteria they use to make this decision. Responses from 10 of 17 centres contacted were received. Results: The approach to supplemental nutrition management in Canadian clinics varies in the absence of formal guidelines. Only one centre has a written set of centre-specific protocols in place. Most clinics considered some combination of respiratory decline, weight loss, dysphagia and/or patient readiness when reaching a decision. However, the absolute threshold and mechanism of measuring the individual criteria differed between clinics. Conclusions: Practices generally reflect international published recommendations but vary on the emphasis of specific criteria. Further research is required to determine the optimal timing and criteria to place gastrostomy feeding tubes in the ALS population.

Background: The head impulse test (HIT) is an evidenced based clinical tool to differentiate between peripheral and central causes of vertigo. Our objective was to determine the rate of utilization of the HIT in the emergency room (ER). Methods: A retrospective chart review of patients presenting to the ER over one year who received a final diagnosis of dizziness or vertigo. Details of clinical examinations, investigations, and diagnosis were recorded. Patients were grouped into episodic, acute constant, and chronic vertigo groups. Results: HIT was performed in only 31 of 642 (5%) patients with vertigo. In the acute constant group it was negative in 6 of 6 patients ultimately diagnosed with stroke and positive in 6 of 13 cases of peripheral vertigo.Discussion: Despite good published evidence regarding its use the HIT is under-utilized in the ER. Physicians need to be aware of the HIT and newer video HITs and make use of them in practice.

Objective background: The Montreal Cognitive Assessment (MoCA) is a questionnaire that has been developed to help physicians around the world diagnose a patient’s cognitive ability. Available in multiple languages and for use in multiple countries worldwide, the goal of this study was to validate the alternate versions 2 and 3 of the French MoCA test to assist physicians in the detection of mild cognitive impairment (MCI), while decreasing the learning effect upon frequent testing. Methods: A validation study was conducted at the MoCA Clinic and Institute in Québec, Canada. The subject population consisted of 25 patients diagnosed with MCI meeting Petersen criteria and 25 healthy subjects serving as the normal control (NC) group. Three MoCA test versions were administered in the French language in random order within one session. Scores obtained in all three versions in MCI and NC groups were assessed for reliability and consistency from one version to the next. Results: On average, scores obtained in each subject group (MCI and NC) fell within their corresponding diagnostic ranges (score above 26 points for NC patients versus scores below 26 points for MCI patients). Difference in scores observed between the original French MoCA version and the two alternate versions in each subject cohort were minimal and not considered clinically significant. Conclusions: All three test versions of the French MoCA are considered equivalent in diagnostic reliability and consistency and contribute to decreasing the potential learning effect when patients are required to repeat the test frequently.

Objective: The Montreal Cognitive Assessment (MoCA) is a general cognitive screening tool that has shown sensitivity in detecting mild levels of cognitive impairment in various clinical populations. Although mood dysfunction is common in referrals to memory clinics, the influence of mood on the MoCA has to date been largely unexplored. Method: In this study, we examined the impact of mood dysfunction on the MoCA using a memory clinic sample of individuals with depressive symptoms who did not meet criteria for a neurodegenerative disease. Results: Half of the group with depressive symptoms scored below the MoCA-suggested cutoff for cognitive impairment. As a group, they scored below healthy controls, but above individuals with Alzheimer’s disease and frontotemporal dementia. A MoCA subtask analysis revealed a pattern of executive/attentional dysfunction in those with depressive symptoms. Conclusions: This observed negative impact of depressive symptomatology on the MoCA has interpretative implications for its utility as a cognitive screening tool in a memory clinic setting.

A point mutation resulting in a specific amino acid change(K27M) in either one of the genes encoding histone H3, H3F3A (H3.3) or HIST1H3B/C/I (H3.1)is present in most pediatric intrinsic pontine gliomas, and has been described in other midline locations. The objective of the present study was to determine the frequency and location of this mutation in diffuse infiltrating gliomas in young adults. The study group consisted of 22 consecutive diffuse gliomas in patients under the age of 40 treated at St. Michael’s Hospital, an adult hospital in the University of Toronto system. Ultra-sensitive digital droplet PCR, a method capable of highly sensitive and specific mutation detection affecting either H3.3 or H3.1, was performed on sample DNA to determine H3K27M status. The H3K27M mutation was detected in the gliomas of five patients, aged 17 to 34 years. The male: female ratio was 3:2. The allele frequency ranged from 26% to 44%, reflecting the infiltrating character of the tumors. Three of the tumors where located in the thalamus, one in the medulla, and one was intraventricular. In terms of grading, one tumor was considered WHO grade II, two III, and two IV. In contrast, most tumors in patients with gliomas lacking the K27M mutation (17 subjects, age 19 to 39 years) were located in the lobes of the cerebral hemispheres, with the following exceptions: 1 in the thalamus, 1 in the hypothalamus, 1 in the cerebellum, and 1 periventricular. WHO grades were 1 II, 9 III, 7 IV. Correlation with patient outcome is ongoing. We conclude that the H3K27M is common in thalamic gliomas in young adult patients, and rare or absent in lobar hemispheric gliomas.

Background: Dysphagia is a devastating complication of stroke and can lead to malnutrition, immobility, aspiration pneumonia, and death. Guidelines advocate screening all patients with acute stroke for swallowing impairment. However, previous research suggests only 60% are screened, and it is unclear what factors contribute to receiving dysphagia screening. Methods: We used the Ontario Stroke Registry to identify patients who were admitted to Regional Stroke Centres from 2010-2013. We used multivariable regression to identify predictors of receiving a dysphagia screen within 72 hours. Results: Among 7172 patients with acute ischemic stroke, 1705 patients (23.8%) did not undergo screening. Factors increasing the odds of being tested were: Stroke unit admission (adjusted odds ratio aOR 6.5), presenting with speech deficits (aOR 1.9) or weakness (aOR 1.5), or receiving thrombolysis (aOR 1.9). Seizure (aOR 0.49) and mild stroke (aOR 0.59 vs moderate stroke) decreased the odds of being tested. Among those with mild strokes who received a swallowing screen, 33% failed. *All p<0.0001. Conclusions: Patients with mild stroke are at risk of not being screened for dysphagia, despite a significant fail rate among those tested. This may expose untested patients to a higher risk of complications from dysphagia, and suggests a gap in process of care that should be addressed.

Programmed Cell Death – 1 (PD1) inhibition activates tumor-specific T-lymphocytes and is an effective clinical therapy against some cancers. Preclinical data regarding immune checkpoint inhibitors against malignant glioma is scant, and interim analyses of clinical trials suggest modest effect in patients as single agents. We examined PD-1 inhibition in murine glioblastoma models in combination with other immunomodulatory agents. Methods – Syngeneic glioma tumors (GL261 and CT2A) were implanted intracranially in C57/Bl6 mice. In separate experiments, PD-1 inhibition was combined with antibody blockade of t-cell immunoglobulin and mucin protein (TIM3), ligation of OX40 on T-lymphocytes, or vaccination with irradiated GM-CSF expressing tumor cells. Systemic antitumor immunity and tumor infiltrating lymphocytes were analyzed by ELISPOT assay and flow cytometry, respectively. Results - In both syngeneic glioma models, day 3,6, and 9 systemic delivery of a monoclonal antibody against PD-1 led to increased survival vs. controls. In animals with GL261 intracranial tumors, survival was improved by combination of PD-1 blockade with subcutaneous injection of irradiated GM-CSF expressing GL261 tumor cells, with antibody blockade of t-cell immunoglobulin and mucin protein 3 (TIM3), or binding of OX40 on T-lymphocytes by an activating antibody. In most cases, ELISPOT analyses demonstrated enhanced Th1 immunity by combination immunotherapies. Vaccination was associated with an increased intratumoral CD8+ T lymphocyte / FoxP3+ T lymphocyte ratio. Conclusion –Blockade of PD-1 on T lymphocytes in glioma-bearing mice is active. Both antitumor immunity and survival can be enhanced by combination of PD-1 inhibition with agents that activate antitumor immunity by complementary mechanisms.

Objective: To study the relationship of Nε-(carboxymethyl)-lysine level (CML) with microstructure changes of white matter (WM), and cognitive impairment in patients with type 2 diabetes mellitus (T2DM) and to discuss the potential mechanism underlying T2DM-associated cognitive impairment. Methods: The study was performed in T2DM patients (n=22) with disease course ≥5 years and age ranging from 65 to 75 years old. A control group consisted of 25 sex- and age-matched healthy volunteers. Fractional anisotropy (FA) of several WM regions was analyzed by diffusion tensor imaging scan. Plasma CML levels were measured by enzyme-linked immunosorbent assay, and cognitive function was assessed by Mini-Mental State Examination and Montreal cognitive assessment (MoCA). Results: The total Mini-Mental State Examination score in the patient group (25.72±3.13) was significantly lower than the control group (28.16±2.45) (p<0.05). In addition, the total MoCA score in the patient group (22.15±3.56) was significantly lower than the control group 25.63±4.12) (p<0.01). In the patient group, FA values were significantly decreased in the corpus callosum, cingulate fasciculus, inferior fronto-occipital fasciculus, parietal WM, hippocampus, and temporal lobes relative to corresponding regions of healthy controls (p<0.05). Plasma CML level was negatively correlated with average FA values in the global brain (r=−0.58, p<0.01) and MoCA scores (r=−0.47, p<0.05). Conclusions: In T2DM, WM microstructure changes occur in older patients, and elevations in CML may play a role in the development of cognitive impairment.

Background: Approximately 30% of patients with epilepsy have medically intractable seizures, and a proportion of them are candidates for surgical treatment. The efficacy and safety of epilepsy surgery have been supported by a large number of studies, yet only a small minority of such patients in Ontario receive surgery. Methods: Family physicians in Ontario were surveyed regarding demographics, referral practices and general knowledge about epilepsy surgery. Four hundred surveys were mailed to randomly selected family physicians using contact information from the College of Physicians and Surgeons of Ontario website. Results: The response rate was 50%. The majority of family physicians (81%) always refer patients with epilepsy, most often to neurologists. General knowledge of epilepsy was mixed, with 53.7% feeling that surgery should be considered in selected cases for the treatment of epilepsy, though 53.2% did not know what type of epilepsy could be surgically treated. Conclusions: The results suggest a relatively low level of knowledge among family physicians in terms of when surgery ought to be considered, the types of epilepsy that are amenable to surgical treatment and the risks and benefits of epilepsy surgery. A lack of knowledge in these areas may partly underlie the low referral rates of epilepsy patients, though the results show that the majority of family physicians refer their patients with epilepsy to neurologists. Other factors must be considered, such as access to neurologists, epileptologists and surgical resources. Education campaigns directed at family physicians may improve knowledge and change referral practices. Future studies need to examine these possibilities.