By contrast to infantile spinal muscular atrophy, which usually links to deletions in the SMN genes, fetal onset motor neuron disease is poorly reported. We collected a series of twelve cases of fetal arthrogryposis (16-31 weeks gestational age) with fetal motor neuron disease and excluded infectious diseases, lysosomal storage disease and neuroaxonal dystrophy. Of these twelve, 3 were thought to be ischemic in nature with microvascular alterations and systemic or central nervous system ischemic injury. The remaining 9 all displayed marked reduction in anterior horn motor neurons. Of these 9, four demonstrated mineralised neurons, four demonstrated either neuronal loss or cavitation in the globus pallidus, and in two, degenerating neurons were detectable in the brainstem or globus pallidus. Specific sequencing of SMN1 was performed in 6 of 9 and was reported as normal. Whole exome sequencing was performed in 4 without definitive diagnosis. We conclude that fetal motor neuron disease can be distinguished from ischemic injury, is morphologically heterogeneous, may affect the globus pallidus and is rarely linked to SMN1 mutations.

Glioblastoma is considered among the most aggressive cancers, dismal prognosis and overall survival is only 14 months, 80% of primary low grade gliomas and seccondary GBMs that progress from low grade to grade II or III WHO classification have isocitrate dehydrogenase, (IDH1) or IDH2, mutations [1]. IDH1 mutant glioma is characterized by impaired glycolysis activity resulting in an abnormal production of 2-hydroxyglutarate (2-HG) [2] resulting in an undifferentiated phenotype with permanent hyper-methylation status and enhanced proliferation and invasion[3]. Interestingly, the IDH1 mutant phenotype of U87MG glioma cells shows resistance to autophagy induced cell death even in starving and low oxygen conditions [4]. Recent evidence has demonstrated increased autophagy activity on IDH1 mt cytotoxic activity when cells are exposed to autophagy inhibitors such as chloroquine [5]. To this date it remains elusive whether increased autophagy phenotype is the result of IDH1 mutation or if it either represents a secondary co-existing condition in the setting of the IDH1 mutation. Autophagy is also a mechanism of detoxification induced by chronic heavy metal exposure in both normal and cancer cells. Thus, we hypothesized that autophagy activity in IDH1 mt glioma is partially induced by chronic heavy metal exposure, leading to increased cell survival and abnormal DNA repair. Our approach included characterization and quantification of metal content on IDH1 mt glioma cell lines and tissues, in addition to correlation analyses of the celullar metallome with autophagy markers, ROS and DNA repair of IDH1 mt glioma cells allowed us to explore targets responsible for cell survival and DNA repair response. Furthermore, we evaluated the potential therapeutic value of Chloroquine (CQ) and bafylomicin for IDH1 mutant gliomas targeting autophagy pathway in combination with TMZ and radiation. We demonstrated that 2-HG induces autophagy activity via LC3B activation, and autophagy inhibiton by beclin gene silencing results in a reduction of 2-HG leading to cell starvation and apoptosis. Remarkably, we observed a positive correlation on at least six different metals with autophagy induced LC3B and beclin1 expression that significantly differed between the mutant and the wt genotype in glioma cell lines. ROS and DNA repair were also positively associated with at least 6 different metals and only seen in the IDH1 mt cell lines, then suggesting a possible explanation for the increase on autophagy, analysis of both LC3B and beclin 1 expression demonstrated a positive correlation with Mo98, Fe54, and Zn 66 on IDH1 mt cell lines and a positively correlation with Mo98 and V concentrations in relation to H2AX expression. Co, SeO Mo, V and Mg were positively correlated to ROS expression. TMZ and CQ induced autophagy pathway activation as measured by LC3B, Beclin, Atg expression. Silencing beclin in IDH1 mutant glioma cell lines induced apoptosis and reduction on 2-HG production after treatment with TMZ and radiation. Overall the results contained in this study 1) identify cellular metal content in relationship to mechanisms leading to increased autophagy on IDH1 mt glioma cells. 2) evaluate the combination of CQ and TMZ to potentially target and inhibit autophagy as a mechanism downstream the 2-HG production in IDH1 mt glioma cells.

Background: We have previously shown that low-intensity ultrasound (LIUS), a noninvasive mechanical stimulus, inhibits brain edema formation induced by oxygen and glucose deprivation (OGD) or treatment with glutamate, a mediator of OGD-induced edema, in acute rat hippocampal slice model in vitro. Methods: In this study, we treated the rat hippocampal slices with N-methyl-d-aspartic acid (NMDA) or (S)-3,5-dihydroxyphenylglycine (DHPG) to determine whether these different glutamate receptor agonists induce edema. The hippocampal slices were then either sonicated with LIUS or treated with N-methyl-d-aspartic acid receptor (NMDAR) antagonists, namely, MK-801 and ketamine, and observed their effects on edema formation. Results: We observed that treatment with NMDA, an agonist of ionotropic glutamate receptors, induced brain edema at similar degrees compared with that induced by OGD. However, treatment with DHPG, an agonist of metabotropic glutamate receptors, did not significantly induce brain edema. Treatment with the NMDAR antagonists MK-801 or ketamine efficiently prevented brain edema formation by both OGD and NMDA in a concentration-dependent manner. N-Methyl-d-aspartic acid-induced brain edema was alleviated by LIUS in an intensity-dependent manner when ultrasound was administered at 30, 50, or 100 mW/cm2 for 20 minutes before the induction of the edema. Furthermore, LIUS reduced OGD- and NMDA-induced phosphorylation of NMDARs at Y1325. Conclusion: These results suggest that LIUS can inhibit OGD- or NMDA-induced NMDAR activation by preventing NMDAR phosphorylation, thereby reducing a subsequent brain edema formation. The mechanisms by which LIUS inhibits NMDAR phosphorylation need further investigation.

Background: This study is part of the Innovations in Data, Evidence and Applications for Persons with Neurological Conditions project to understand the strengths, preferences, and needs of persons with neurological conditions living in Canada. Objective: To estimate the prevalence and describe the sociodemographic and clinical characteristics of persons with multiple sclerosis in Canadian home care, nursing home, Complex Continuing Care hospitals, and inpatient mental health care settings. Methods: Cross-sectional study of adults aged 18 years and older with multiple sclerosis (MS; n=11,250) across Canada from 1996 through 2011 using interRAI Resident Assessment Instrument (RAI) comprehensive health assessments (RAI Minimum Data Set 2.0, RAI-Home Care, RAI-Mental Health). Comparisons were made to adults with Alzheimer’s disease and related dementias (n=260,910), other neurological conditions (n=163,578) and non-neurological conditions (n=571,567). Results: The prevalence of MS was highest in Complex Continuing Care hospitals (4125 cases per 100,000 patients), followed by home care (2020 cases per 100,000 patients), nursing homes (1424 cases per 100,000 patients), and mental health settings (138 cases per 100,000 patients). Persons with MS experienced greater impairment in the completion of activities of daily living, pain, pressure ulcers, swallowing difficulty, depression, and anxiety compared with peers within care settings. There were also significant differences between settings, particularly the degree of physical and cognitive impairment experienced by persons with MS. Conclusions: Except for mental health care settings, the prevalence of MS in community, institutional and hospital-based care settings exceeded that of the general population. These data describing the sociodemographic and clinical characteristics of persons with MS may be used to inform clinical practice and policy decisions for persons with MS across the continuum of care.

Background: Central neuropathic pain syndromes are a result of central nervous system injury, most commonly related to stroke, traumatic spinal cord injury, or multiple sclerosis. These syndromes are distinctly less common than peripheral neuropathic pain, and less is known regarding the underlying pathophysiology, appropriate pharmacotherapy, and long-term outcomes. The objective of this study was to determine the long-term clinical effectiveness of the management of central neuropathic pain relative to peripheral neuropathic pain at tertiary pain centers. Methods: Patients diagnosed with central (n=79) and peripheral (n=710) neuropathic pain were identified for analysis from a prospective observational cohort study of patients with chronic neuropathic pain recruited from seven Canadian tertiary pain centers. Data regarding patient characteristics, analgesic use, and patient-reported outcomes were collected at baseline and 12-month follow-up. The primary outcome measure was the composite of a reduction in average pain intensity and pain interference. Secondary outcome measures included assessments of function, mood, quality of life, catastrophizing, and patient satisfaction. Results: At 12-month follow-up, 13.5% (95% confidence interval [CI], 5.6-25.8) of patients with central neuropathic pain and complete data sets (n=52) achieved a ≥30% reduction in pain, whereas 38.5% (95% CI, 25.3-53.0) achieved a reduction of at least 1 point on the Pain Interference Scale. The proportion of patients with central neuropathic pain achieving both these measures, and thus the primary outcome, was 9.6% (95% CI, 3.2-21.0). Patients with peripheral neuropathic pain and complete data sets (n=463) were more likely to achieve this primary outcome at 12 months (25.3% of patients; 95% CI, 21.4-29.5) (p=0.012). Conclusion: Patients with central neuropathic pain syndromes managed in tertiary care centers were less likely to achieve a meaningful improvement in pain and function compared with patients with peripheral neuropathic pain at 12-month follow-up.

We review the central nervous system anatomy in nine cases of amniotic rupture sequence, all of which had neuropathological examinations. Of these, four had normal brains, and in none of these was the cranial vault involved, and one had cleft lip and palate. Of the remaining five, all had portions of the scalp, calvarium and dura replaced by amnionic membrane directly overlying arachnoid. In one, the membrane covered a narrow necked large encephalocele, and the contained brain demonstrated extensive disruption and degeneration. In the remaining four, one demonstrated cranioplacental adhesion, and in three there was a broad based encephalocele covered in large part by amnion. Two of these four cases demonstrated holoprosencephaly. One case with holoprosencephaly and one without demonstrated marked aqueductal stenosis, and two of the four demonstrated aqueductal occlusion or near occlusion by neuroglial excrescences. None demonstrated ventriculomegaly. Three of these four cases demonstrate varying degrees of mechanical distortion and secondary pathology. We conclude that brains with amnionic rupture sequence demonstrate both malformation and deformation, which likely points to the embryonic stage origin of the lesion.

Background: Increased cerebral perfusion pressure (CPP)>70 mmHg has been associated with acute respiratory distress syndrome (ARDS) after traumatic brain injury (TBI). Since this reported association, significant changes in ventilation strategies and fluid management have been accepted as routine critical care. Recently, individualized perfusion targets using autoregulation monitoring suggest CPP titration>70 mmHg. Given these clinical advances, the association between ARDS and increased CPP requires further delineation. Objective: To determine the association between ARDS and increased CPP after TBI. Methods: We conducted a single-center historical cohort study investigating the association of increased CPP and ARDS after TBI. We collected demographic data and physiologic data for CPP, intracranial pressure, mechanical ventilation, cumulative fluid balance and delta/driving pressure (ΔP). We collected outcomes measures pertaining to duration of ventilation, intensive care unit admission length, hospitalization length and 6-month neurological outcome. Results: In total, 113 patients with severe TBI and multimodal neuromonitoring were included. In total, 16 patients (14%) developed ARDS according to the Berlin definition. There was no difference in the mean CPP during the first 7 days of admission between patients who developed ARDS (74 mmHg SD 18 vs. 73 mmHg SD 18, p=0.86) versus those who did not. Patients who developed ARDS had a higher ΔP (15 mmHg [5] vs. 12 mmHg [4], p=0.016) and lower lung compliance (35 ml/cmH2O [10] vs. 49 ml/cmH2O [18], p=0.024) versus those who did not. Conclusion: We did not observe an association between increased CPP and ARDS. Patients with ARDS had higher ΔP and lower lung compliance.

Background: Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction in which a clinical diagnosis may be confirmed with serological testing. The most common autoantibodies used to support a diagnosis of MG are anti-acetylcholine receptor antibodies and anti-muscle-specific tyrosine kinase antibodies. In cases in which both of these autoantibodies are negative (termed double-seronegative [dSNMG]), other autoantibodies such as low-density lipoprotein receptor-related protein 4 (LRP4) may be used to aid in diagnosis. Methods: We have undertaken a systematic literature review to identify studies that have assessed the frequency of anti-LRP4 antibodies in dSNMG patients and the characteristics of anti-LRP4+ dSNMG patients (epidemiology, clinical features, electromyographic findings, or management). PubMed, EMBASE, Medline, and Scopus were searched on January 14, 2017, using the medical subject headings “myasthenia gravis” and “low-density lipoprotein receptor-related protein 4” or “LRP4.” Results: The initial search identified 367 articles. Fourteen publications met the inclusion criteria. There were ten cross-sectional research studies, three were case series, and one was a case report. The majority of studies were limited by small sample sizes of LRP4+ dSNMG. There has been a wide range of frequencies of anti-LRP4 antibodies detected in different MG patient populations, some involving different laboratory techniques. Conclusions: LRP4+ dSNMG is more likely than LRP4– dSNMG to have a younger onset of disease and occur in females. LRP4+ dSNMG most often is mild in severity and often involves isolated ocular weakness. It typically responds well to pyridostigmine or prednisone.

Background: Despite medical advances, almost a third of people with epilepsy have medically refractory epilepsy (MRE). With failure of pharmaceutical options, patients are turning to alternative treatment options. Marijuana use in epilepsy has received extensive attention. Two recent studies evaluated the opinions of marijuana use in individuals with epilepsy, but had discrepant marijuana use rates. Methods: The first 200 adult patients with a known diagnosis of epilepsy seen at Hamilton General Hospital after June 1, 2017 were invited to participate. Standardized paper questionnaires gathered information about demographics, epilepsy history, and marijuana use. Results: One hundred forty participants returned questionnaires; 29.5% were active marijuana users; 24.5% had consumed marijuana in the past. Increased seizure frequency was significantly associated with marijuana use. There was a non-significant trend towards increased marijuana use with males and MRE. Almost half the active marijuana users noted improvement in seizure frequency. No participants experienced worsening of epilepsy with marijuana use. Side effects were common (30%), most frequent being mood. Conclusions: Prevalence of marijuana use among people with epilepsy is higher in our study population compared to an Australian cohort, but similar to Canadian studies. Marijuana use was significantly associated with increased seizure frequency. The majority of patients perceived benefit with regard to seizure control.

Background: Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer in adults. Recent efforts have elucidated genetic features of tumor cells and thus enhanced our knowledge of GBM pathophysiology. The most recent clinical trials report median overall survival between 14 and 20 months. However, real-world outcomes are quite variable and there is a paucity of data within the literature. Methods: Three hundred seventy two GBM patients were diagnosed in the province of British Columbia between January 2013 and January 2015. We have performed a retrospective review on the survival outcomes of the 278 patients who underwent surgical resection as part of the initial treatment. Results: Our results indicate a median age of 61.8y at time of diagnosis with a slight preponderance of males. The median overall survival was 10 months for patients who underwent surgery. As expected, patients over the age of 65 and those with worse initial Karnofsy Performance Status (KPS) scores had a poorer prognosis. Moreover, we have found extent of resection (EOR), treatment strategies and treatment location affect overall survival. Conclusion: The present study highlights factors which affect patient survival after surgery in British Columbia. Our outcomes are slightly worse than survival reported in the US. Variability in pathologic classification and in treatment strategy likely contribute to this difference. Further efforts should ensure access to the gold-standard of care.

Background: Medical school and residency training in ophthalmoscopic evaluation is limited, reducing diagnostic accuracy. We sought to evaluate the efficacy of self-study using an ophthalmoscopy simulator to improve the technical motor skills involved in direct funduscopy in postgraduate pediatric residents. Methods: In this randomized-controlled study, 17 pediatric residents (postgraduate years 1-3) were randomized to control (n=8) or intervention (n=9) groups. Participants were asked to correctly identify the funduscopic findings presented to them on an ophthalmoscopy simulator after being trained on its use. Each participant was asked to review 20 images of the fundus, and then record their multiple-choice response on a scantron sheet listing all possible funduscopic pathologies. Pre- and post-intervention testing was performed. Survey data assessing exposure to funduscopy skills during undergraduate and postgraduate training and overall experience with the simulator were collected. Results: Most (65% [11/17]) participants reported minimal or no formal teaching in ophthalmology during their undergraduate medical studies. Average pre-intervention score (of 20) was 10.24±1.75 (51%) for the entire group, with no statistically significant difference between average pre-score in the control (10.63±1.77) versus intervention (9.89±1.76, p=0.405) groups. Intervention subjects experienced a statistically significant improvement in scores (9.89±1.76 vs. 12.78±2.05, p=0.006 [95% confidence interval 4.80-0.98]), but control subjects did not. Conclusions: A single session with an ophthalmoscopy simulator can improve diagnostic accuracy in postgraduate pediatric trainees. Use of ophthalmoscopy simulation represents a novel addition to traditional learning methods for postgraduate pediatric residents that can help trainees to improve their confidence and accuracy in performing this challenging examination.

The case of James Cagney adds interesting details to the history of concussion. It is underappreciated that a movie-star of Cagney’s stature incurred multiple concussions over many years. Moreover, the fact that he sustained one of these concussions in Canada while filming Captains of the Clouds, a major Hollywood film, is essentially unknown, and was seldom discussed by Cagney despite his willingness to discuss his many other concussions. The scene showing this concussion was left in the final released version of the movie, making it one of the earliest filmed concussions and the first concussion ever filmed in Technicolor.

Chronic traumatic encephalopathy (CTE) is suggested to be a progressive neurodegenerative disease, characterized by tau deposits in the depth of cortical sulci in neurons and in glioneuronal complexes around blood vessels. Few studies have suggested that it is caused by multiple concussions or subconcussive brain injuries. A recent publication showed that most American football players whose brain were donated to the Boston University concussion center had CTE (Mez et al. 2017). Over the last 6 years, with the help of neuropathologist colleagues across Canada, we have collected the brains of 33 high level professional and amateur athletes. These include 5 National hockey league (NHL) players, 15 Canadian football league (CFL) players, 3 College football players, 3 College hockey players, 2 professional boxers, 1 professional bull rider, 1 BMX champion, 1 rugby player and 2 skiers. All were male and the ages ranging from 15 to 87 years. Our results indicate that only a small portion of cases have CTE. Moreover, most cases are low stage (stage 1 or 2) and this pathology is mainly seen in some of the younger players. Older players either have no pathological findings or have other neurodegenerative diseases such as Alzheimer’s disease. The disparity of results between the 2 groups will be discussed.

Background: The relationship between timing of direct enteral feeding tube (DET; gastrostomy/jejunostomy) placement and outcomes after stroke is unknown. Methods: We used the Ontario Stroke Registry and linked administrative databases to identify patients with acute stroke between 2003-2013 who received DET during hospital admission. We used multiple logistic regression and Cox proportional hazard models to determine the association between time from admission to DET placement and outcomes of severe disability at discharge (modified Rankin Scale score 4-5) and 30-day mortality after DET placement, adjusting for age, sex, co-morbidities, stroke type, stroke severity, intensive care or stroke unit admission, palliation, and hospital type. Results: 1,342 patients met our inclusion criteria. There was a lower hazard of 30-day mortality for each week in delay to DET placement (adjusted HR 0.89, 95%CI 0.80 to 0.99), but higher odds of severe disability (adjusted OR 1.36, 95%CI 1.14 to 1.62). Patients with DET placement within 1 week had the highest 30-day mortality compared to subsequent weeks (adjusted HR 1.59, 95%CI 1.05 to 2.4). Conclusions: Delayed DET placement after stroke is associated with lower 30-day mortality but greater disability. Thirty-day mortality was highest in those who received DET within 1 week of admission. These associations may inform decisions regarding timing of DET placement after stroke.

Objectives: Glioblastoma is a lethal disease in the elderly population. We aimed to evaluate disease and treatment outcomes in the oldest-old patients. Methods: Patients >80 years old with histologically confirmed glioblastoma treated between 2004 and 2009 were identified. We included patients managed with best supportive care (BSC), temozolomide (TMZ) alone, radiotherapy (RT) alone, or concomitantly with TMZ (CRT). Survival outcomes were analyzed using the Kaplan–Meier method. Results: Ultimately, 48 patients were analyzed. Median age and Eastern Cooperative Oncology Group (ECOG) Performance Status were 82 years and 2, respectively. The median Age-Adjusted Charlson Index (AAC) was 6. Gross total and subtotal resections were performed in 16.7% and 18.8% of patients, respectively. Biopsy followed by RT alone was the treatment modality for 23/48 (47.9%), while 17/48 (35.4%) received surgery followed by RT alone or CRT. A total of 8 (16.7%) were managed with BSC after biopsy. Median overall survival (OS) and progression-free survival (PFS) were 4.1 (95% confidence interval [95% CI] 3.3-4.9) and 2.7 (95% CI 1.5-3.9) months, respectively. Improved median OS was observed in those treated with surgical resection followed by RT alone or CRT (7.1 months), compared to biopsy followed by RT alone (4.2 months) or BSC (2.0 months; p=0.002). Surgical resection, age≤85, and AAC<6 were associated with better OS (p=0.032, p=0.031, and p=0.02, respectively). Cause of death was neurological progression in 56% of cases. RT was well-tolerated. Conclusions: PFS and OS outcomes remain poor in the oldest-old patients (>80 years old). Younger age, lower AAC, surgical resection, and adjuvant treatment were associated with improved OS.

Objective: The concomitant presence of pituitary adenoma (PA) with Rathke’s cleft cyst (RCC) is rare, and most of the literature published is case reports. RCC’s clinicopathological features have not been well described. Methods: We retrospectively reviewed the data of 15 patients with PA associated with RCC. We also provide a systematic review of the literature. Results: The patients included males and seven females. The transsphenoidal approach was adopted for all patients except one, who underwent right frontal craniotomy. Complete resection was achieved in nine cases, with grossly complete resection in five and partial removal in one. Of the PA subtypes available, five patients had nonfunctional pituitary adenomas, three had multiple-hormone secreting PAs, three had prolactin-producing adenomas, and one had a growth hormone-secreting adenoma. All of the patients’ symptoms and abnormal endocrine test results resolved or were relieved after surgery. The mean follow-up time was 27.6±16.6 months. All of the patients recovered well and had no signs of recurrence during their follow-up, except for one patient. Conclusions: A cyst-like signal indicated on images or cystic materials encountered during operation in a patient with PA suggest the possibility of PA associated with RCC. Transsphenoidal surgery is the preferred approach and can resolve or relieve patients’ symptoms to a great extent. Histologically, nonfunctional PA and prolactinoma are the most common types of PA coexisting with RCC; the mechanisms of PA associated with RCC need to be investigated further.