Background: Carotid atherosclerosis is a significant risk factor for stroke and has been associated with cognitive decline and dementia. Methods: We assessed 554 community-dwelling subjects from the Lothian Birth Cohort of 1936 (LBC1936) who underwent brain MRI and carotid Doppler ultrasound studies at age 73 years. The relationship between carotid stenosis and cerebral cortical thickness was examined cross-sectionally, controlling for gender, extensive vascular risk factors (VRFs), and IQ at age 11 (IQ-11). The association between carotid stenosis and a composite measure of fluid intelligence was also investigated. Results: A widespread negative association was identified between carotid stenosis and cerebral cortical thickness at age 73 years, independent of the side of carotid stenosis, other carotid measures, VRFs, or IQ-11. This association increased in an almost dose-response relationship from mild to severe degrees of carotid stenosis. A negative association was also noted between carotid stenosis and fluid intelligence, which appeared partly mediated by carotid stenosis-related thinning of the cerebral cortex. Conclusions: Carotid stenosis is associated with thinner cerebral cortex and lower fluid cognitive abilities at age 73. The findings suggest that carotid stenosis represents a marker of vascular processes that accelerate cortical aging with a negative impact on cognition, independent of measurable VRFs.

Background: NEDA is a composite measure that may ultimately influence clinical decisions concerning switches of disease modifying therapy (DMT) for relapsing remitting multiple sclerosis (RRMS) patients. Cohort studies from MS clinics suggest NEDA is not sustained over time in most patients despite DMT but may be limited by referral bias. We investigated NEDA in a population-based RRMS cohort. Methods: We identified all incident cases of RRMS in Olmsted County from 01/01/2000-12/31/2011. Retrospective chart review was conducted to determine persistence of NEDA -following RRMS diagnosis. NEDA failure was defined as new MRI activity, relapse, or expanded disability status scale (EDSS) -worsening. Results: There were 93 incident cases of RRMS with 82 individuals having sufficient follow-up to determine persistence of NEDA. Prior to NEDA failure 44 were not on DMT, 37 were on first-tier, injectable DMT, and 1 received mitoxantrone. NEDA was maintained by 63% at 1 year, 38% at 2 years, 19% at 5 years, and 12% at 10 years. Disability measured by EDSS was no different at 10 years in patients maintaining NEDA versus those that failed NEDA at one year (p=0.3). Conclusions: Maintenance of NEDA beyond 2 years is infrequent among a population-based cohort of newly diagnosed RRMS patients and similar to prior clinic-based cohorts.

Background: Limbic encephalitis (LE) is a rare autoimmune syndrome affecting limbic system structures and causing variety of manifestations including memory changes, temporal epilepsies, and psychiatric symptoms. It is a rare disease in children but with a well-recognizable combination of clinical, neuroimaging and/or histological signature. Beyond the association with anti-neuronal auto-antibodies, no clear immune system phenotype has been associated with limbic encephalitis. Our aim is to characterize the clinical and paraclinical features of non-paraneoplasic limbic encephalitis and to correlate them with potential underlying immune deficiencies. Methods: Retrospective case series of seven patients with limbic encephalitis recruited at the Montreal Children’s Hospital (MCH) with a focus on the immune- and neuro-phenotypes, including anti-neuronal antibodies, lymphocyte sub-typing, key markers of immunoglobulin and complement systems. Literature review showed 77 cases of non-paraneoplastic non-NMDA limbic encephalitis. Results: Symptoms included temporal epilepsy (n=5), psychiatric symptoms such as ADHD or autistic symptoms (n=2), and memory changes (n=3). One patient was positive for both voltage gated potassium channel antibodies (VGKC) and anti-thyroid peroxidase antibodies (TPO) and two were positive only for anti TPO antibodies. One patient showed low CD19, and immunoglobulins. Three patients showed chronic low CD56 cell count. Conclusions: The study is still ongoing, but at least 3 patients already display some traits of immune dysregulation.

Background: Human induced pluripotent stem cell-derived neural stem cells (hiPS-NSCs) represent an exciting therapeutic approach for traumatically spinal cord injury (SCI). Unfortunately, most patients are the in chronic injury phase where a dense perilesional chondroitin sulfate proteoglycan (CSPG) scar significantly hinders regeneration. CSPG-degrading enzymes can enhance NSC-mediated recovery, however, nonspecific intrathecal administration causes off-target effects. We aimed to genetically engineer hiPS-NSCs to express a scar-degrading ENZYME into their local environment to enhance functional recovery. Methods: A bicistronic scar-degrading ENZYME and RFP reporter vector was non-virally integrated into hiPS-NSCs and monoclonalized. ENZYME activity was assessed by WST-1 and DMMB biochemical assays and an in vitro CSPG spot assay with hiPS-NSC-derived neurons. To assess in vivo efficacy, T-cell deficient rats (N=60) with chronic (8wk) C6-7 SCIs were randomized to receive (1)SMaRT cells, (2)hiPS-NSCs, (3)vehicle, or (4)sham surgery. Results: SMaRT cells retained key hiPS-NSC characteristics while stably expressing ENZYME. The expressed ENZYME could appropriately degrade in vitro and ex vivo CSPGs. While blinded neurobehavioural and immunohistochemical assessments are ongoing at 40wks post-injury, an interim analysis demonstrated human cells extending remarkably long (≥20,000µm) axons along host white matter tracts. Conclusions: This work provides exciting proof-of-concept data that genetically-engineered SMaRT cells can degrade CSPGs and human NSCs can extend long-distance processes in chronic SCI.

Background: A major concern of patients undergoing Gamma Knife radiosurgery (GKS) for benign tumors and other conditions is the risk of a separate secondary malignancy or malignant -transformation. The incidence of radiosurgery-associated malignancy based on long-term follow-up remains unknown. Methods: We conducted a population-based cohort study to estimate the incidence rate of both malignant transformation and a separate radiation-associated malignancy in patients undergoing GKS from 1987 to 2016 at 5 centers. Results: 11 527 patients underwent radiosurgery for meningioma (n=3261), arteriovenous malformation (n=2868), trigeminal neuralgia (n=1982), vestibular schwannoma (n=1957), pituitary adenoma (n=1193), other (n=266). The follow-up time ranged from 0.3 to 23.8 years. Four cases of malignant transformation and 3 new malignant brain tumors were reported, two of which were not within the irradiated field. The incidence of malignant transformation was 6.6 per 100 000 patient-years and of new malignancy, either locally or distant, was 5 in 100 000 patient-years. These risks are not higher than the Central Brain Tumor Registry of the United States derived annual incidence rate of all primary malignant CNS tumors of 7.15 per 100 000. Conclusions: Physicians can safely counsel patients that the risk of malignancy after stereotactic radiosurgery remains extremely low, even at long-term follow-up of greater than 10 years.

Background: Studies of autopsy-confirmed cases suggest that Parkinson’s disease (PD) prognosis can be predicted using motor symptom severity at first visit. We evaluated the association between motor symptom subtype at first visit and severity at eight years disease duration among clinically-diagnosed cases at the Saskatchewan Movement Disorder Program. Methods: Retrospective data review identified 374 patients with first visit within three years of symptom onset, a clinical diagnosis of idiopathic PD, and a follow-up visit eight years after symptom onset. Subtypes were grouped as tremor-dominant (TD) if tremor was greater than rigidity and bradykinesia, akinetic-rigid (AR) if rigidity or bradykinesia was greater than tremor, and mixed (MX) if patient was neither TD nor AR based on assessment of all four limbs. Primary outcome was disease severity as measured by Hoehn & Yahr score at eight years after symptom onset. Results: The most common subtype was AR (n=164) followed by MX (n=156). TD was least common (n=54). There was no significant difference between subtypes in H&Y scores at eight years disease duration. Conclusions: These findings suggest that early PD prognosis cannot be predicted based on motor symptoms in all four limbs at first visit. Earlier studies had longer follow-up and future studies will examine progression at longer periods of disease duration.

Background: Central neuropathic pain syndromes are a result of central nervous system injury, most commonly related to stroke, spinal cord injury, or multiple sclerosis. These syndromes are much less common than peripheral etiologies, with less known regarding optimal treatment. The objective of this study was to determine the long-term clinical effectiveness of the management of central relative to peripheral neuropathic pain at tertiary pain centers. Methods: Patients diagnosed with central (n=79) and peripheral (n=710) neuropathic pain were identified from a prospective observational cohort from seven Canadian tertiary centers. Data regarding patient -characteristics, analgesic use, and patient-reported outcomes were collected at baseline and 12-month follow-up. The primary outcome was the composite of reduced average pain intensity and pain interference. Secondary outcomes included assessments of function, mood, and quality-of-life. Results: At 12-month follow-up, 13.5% (95%CI,5.6-25.8) of patients achieved ≥30% reduction in pain, whereas 38.5% (95%CI,25.3-53.0) achieved a ≥1 point reduction in pain interference; 9.6% (95%CI,3.2-21.0) of patients achieving both these measures. Patients with peripheral neuropathic pain were more likely to achieve this primary outcome at 12-months (25.3% of patients; 95%CI,21.4-29.5) (p=.012). Conclusions: Patients with central neuropathic pain were less likely to achieve a meaningful improvement in pain and function compared to patients with peripheral neuropathic pain at 12-month follow-up.

Background: In RRMS patients with inadequate response to prior therapy, 2 alemtuzumab courses (12 mg/day; baseline: 5 days; 12 months later: 3 days) significantly improved outcomes over 2 years (y) versus SC IFNB-1a (CARE-MS II [NCT00548405]), with durable efficacy over a 4-y extension (NCT00930553). We present 6-y efficacy (2-y core study plus 4-y extension) in patients with relapse (relapsers) between Courses (C) 1 and 2. Methods: Annualized relapse rate (ARR); 6-month confirmed disability worsening (CDW); MRI disease activity (Gd-enhancing lesions; new/enlarging T2 hyperintense lesions); brain volume loss (BVL; derived by relative change in brain parenchymal fraction). Results: 105/435 (24%) patients relapsed between C1 and C2; 33% (relapsers) versus 55% without relapse (non-relapsers) received neither alemtuzumab retreatment nor another disease-modifying therapy through Y6. ARR (Y1: 1.2) declined post-C2 (0.5), remaining low through Y6 (0.2 [0.1, non-relapsers]; 10/105 [10%] relapsed). Through Y6, patients remained CDW-free (60% [relapsers]; 75% [non-relapsers]), Gd-enhancing lesion-free (94% [relapsers]; 90% [non-relapsers]), new/enlarging T2 hyperintense lesion-free (68% [relapsers]; 69% [non-relapsers]), and MRI disease activity-free (68% [relapsers]; 69% [non-relapsers]). Alemtuzumab slowed median percent yearly BVL (Y6: -0.13% [relapsers]; -0.10% [non-relapsers]). Conclusions: Patients relapsing between C1 and C2 improved post-C2 through Y6. These findings support administering 2 alemtuzumab courses to achieve optimal and durable benefit.

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: 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.

Background: Atrial fibrillation (AF) is associated with increased risk of ischemic stroke. In Canada, the contemporary burden of AF-related stroke is incompletely characterized. Our objective was to determine temporal trends in hospital admissions and in-hospital mortality for AF-related stroke in Canada from 2007 to 2015. Methods: We conducted a retrospective cohort study using Canadian national administrative data to identify admissions to hospital for stroke with comorbid AF between 2007 and 2015. We analyzed temporal trends in age- and sex-standardized proportion of admissions with comorbid AF and associated in-hospital mortality. Results: There were 222,100 admissions to hospital for ischemic (182,990) or hemorrhagic (39,110) stroke. The age-sex adjusted proportion of ischemic stroke admissions with comorbid AF increased from 16.2% to 20.5% (p for trend = 0.02) between 2007 and 2015, and was stable among hemorrhagic stroke. In-hospital mortality for ischemic stroke with comorbid AF decreased from 21.6% to 15.0% (p for trend = 0.001). Conclusions: Rates of hospital admission for ischemic stroke with comorbid AF have increased, while associated in-hospital mortality has decreased. These results identify AF as an important continued focus for stroke prevention. Our findings provide insight into current trends and highlight the need for continued focus on AF-related stroke.

Background: There is no available estimate of the incidence and mortality of epilepsy in all age groups in the Canadian population. This study aimed to measure the incidence, prevalence, mortality and the secular trends for epilepsy in Saskatchewan between 2005 and 2010. Methods: A population-based cohort study was established from Saskatchewan’s provincial health administrative data. The population was followed until termination of coverage, death, or 31 December 2010. Individuals with epilepsy were identified based on ICD codes algorithms from 2005 to 2010. Results: The age-standardized incidence of epilepsy was 62 per 100,000 person-year. The age-standardized incidence rate of epilepsy in self-declared Registered Indians was 122 per 100,000 person-year. There was a significant decrease in the incidence of epilepsy for all groups over the study period. The age-standardized prevalence of epilepsy was 9 per 1,000 people. There was a significant increase in the prevalence of epilepsy over this time period. The adjusted mortality rate was 0.023 per 1000 person-year, and the all-cause Standardized Mortality Ration for epilepsy was 2.45. The SMR remained constant over the six-year period of the study. Conclusions: This study is the first in Canada to measure the incidence and all-cause mortality of epilepsy in all age groups.

Background: Despite advances in neonatal care, neonates with moderate to severe HIE are at high risk of mortality and morbidity. we report the impact of a dedicated NNCC team on short term mortality and morbidities. Methods: A retrospective cohort study on neonates with moderate to serve HIE between July 1st 2008 and December 31st 2017. primary outcome : a composite of death and/or brain injury on MRI. Secondary outcomes: rate of cooling, length of hospital stay, anti-seizure medication burden, and use of inotropes. A regression analysis was done adjusting for gestational age, birth weight, gender, out-born status, Apgar score at 10 minutes, cord blood pH, and HIE clinical staging Results: 216 neonates were included, 109 before NNCC implementation, and 107 thereafter. NNCC program resulted in reduction in the primary outcome (AOR: 0.28, CI: 0.14-0.54, p<0.001) and brain injury (AOR: 0.28, CI: 0.14-0.55, p<0.001). It decreased average length of stay/infants by 5 days (p=0.03), improved cooling rate (73% compared to 93% , p <0.001), reduced: seizure misdiagnosis (71% compared to 23%, P <0.001), anti-seizure medication burden (P = 0.001), and inotrope use (34% compared to 53%, p=0.004) Conclusions: NNCC program decreased mortality and brain injury , shortened the length of hospital stay and improved care of neonates with significant HIE.

Background:ATP8A2 mutations have only recently been associated with human disease. We present the clinical features from the largest cohort of patients with this disorder reported to date. Methods: An observational study of 9 unreported and 2 previously reported patients with biallelic ATP8A2 mutations was carried out at multiple centres. Results: The mean age of the cohort was 9.4 years old (range: 2.5-28 yrs). All patients demonstrated developmental delay, severe hypotonia and movement disorders: chorea/choreoathetosis (100%), dystonia (27%) or facial dyskinesia (18%). Hypotonia was apparent at birth (70%) or before 6 months old (100%). Optic atrophy was observed in 75% of patients who had a funduscopic examination. MRI of the brain was normal for most patients with a small proportion showing mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Epilepsy was seen in two older patients. Conclusions:ATP8A2 gene mutations have emerged as a cause of a novel phenotype characterized by developmental delay, severe hypotonia and hyperkinetic movement disorders. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation. Early recognition of the cardinal features of this condition will facilitate diagnosis of this disorder.

Background: Registered EEG technologists (RETs) are trained in both the technical aspects of EEG and in preliminary EEG interpretation. However, there is little research evaluating the accuracy of EEG interpretation by RETs. Methods: Retrospective study of consecutive routine EEG recordings performed at SickKids Hospital. Preliminary reports by RETs and final reports by neurophysiologists were compared in 5 domains: background activity, focal abnormalities, ictal and inter-ictal epileptiform discharges and summary. Results: 500 EEG recordings were analyzed. Sensitivity and specificity of RET reports was high for the assessment of background (85%, 93%), focal slowing (84%, 93%) and inter-ictal epileptiform discharges (92%, 90%). RET reports identified ictal EEG patterns in 32 cases vs. 29 cases identified by neurophysiologists. RET reports were 100% accurate for noting no EEG change for all of 11 cases with non-epileptic events. Conclusions: Preliminary EEG reports by RETs were sensitive and specific for all EEG domains analyzed. In the majority of cases, the preliminary interpretation made by the RET was concordant with the final report of the neurophysiologist. Given these findings, RETs may be able to participate in the screening of routine EEG recordings in order to enhance the productivity of busy EEG laboratories.

Background: Currently, there is limited insight in to the function of the mesial frontal negative motor area (NMA) and the anatomic structures implicated in its function. Methods: We present a patient with a Rett-like phenotype, refractory frontal lobe epilepsy, and reflexogenic seizures in which backpatting induced atonic seizures with a semiology resembling the patient falling asleep. The patient underwent video EEG monitoring and ictal/interictal SPECT imaging capturing the reflexogenic seizures. Iterative reconstruction was performed, with images co-registered to previously acquired MRI with subtraction Ictal-Interictal imaging co-registered to MRI. Results: Interictally, the patient’s EEG showed a slow background and right frontal spikes. Ictally, the patient had numerous subclinical frontal seizures. The reflexogenic seizures had an ictal pattern at the vertex (Cz) with the ictal SPECT imaging, showing hyperperfusion in the right mesial frontal region, both paramedian precentral and postcentral gyri, and right basal ganglia. Conclusions: Our findings support the hypothesis that the negative motor area may be activated by the primary sensory cortex; moreover, the ictal SPECT now suggests involvement of the basal ganglia in the NMA’s function.

Background: NURTURE (NCT02386553) is an ongoing open-label single-arm efficacy/safety study of intrathecal nusinersen in infants who initiate treatment in a presymptomatic stage of spinal muscular atrophy (SMA). Methods: Enrolled infants were age ≤6 weeks at first dose, clinically presymptomatic, had genetically diagnosed SMA, and 2 or 3 copies of SMN2. Primary endpoint is time to death or respiratory intervention (≥6 hours/day continuously for ≥7 days or tracheostomy). Results: As of July 5, 2017, 25 infants (2 copies SMN2, n=15;3 copies, n=10) were enrolled. All infants were alive. Two infants (both with 2 copies SMN2) required respiratory intervention (but not tracheostomy or permanent ventilation) during an acute, reversible viral infection and thus met the primary -endpoint. At last visit, 22/24 (92%) infants had achieved WHO motor milestones sitting without support and 8/16 (50%;2 SMN2, n=3/11;3 SMN2, n=5/5) on study >13 months achieved walking alone. AEs were reported in 24/25 (96%) infants; most 20/25 (80%) had AEs that were mild/moderate in severity; 9 had serious AEs. Four infants had an AE possibly related to study drug, which resolved despite continued treatment. No new safety concerns were identified. Conclusions: Nusinersen continued to benefit infants who initiated treatment in a presymptomatic stage of SMA.

Study Support: Biogen

Background: EMBRACE (NCT02462759) Part 1 is a randomized, double-blind, sham-procedure controlled study assessing safety/tolerability of intrathecal nusinersen (12-mg equivalent dose) in symptomatic infants/children with SMA who were not eligible to participate in ENDEAR or CHERISH. Methods: Eligible participants had onset of SMA symptoms at ≤6 months with 3 SMN2 copies; onset at ≤6 months, age >7 months and 2 copies; or onset at >6 months, age ≤18 months, and 2/3 copies. Safety/tolerability was the primary endpoint. Exploratory endpoints included Hammersmith Infant Neurological Examination Section 2 (HINE-2) motor milestone attainment, change in ventilator use, and growth. Results: EMBRACE Part 1 was terminated early based on positive results from ENDEAR. Safety/tolerability was similar to previous trials. More nusinersen-treated (11/14;79%) vs. sham–treated individuals (2/7;29%) were HINE-2 motor milestone responders. Between Day 183 and 302, mean (SD) hours of ventilator use changed by +1.236 (3.712) hours in nusinersen-treated (n=12) and +2.123 (3.023) hours in sham–treated individuals (n=7). Similar increases in weight and body length were observed in nusinersen-treated and sham–treated individuals by Day 183. Conclusions: In EMBRACE Part 1, nusinersen demonstrated a favorable benefit-risk profile. These results add to the aggregated efficacy, safety/tolerability data of nusinersen in SMA.

Study Supported by: Ionis and Biogen

Background: Spinal Muscular Atrophy (SMA) is an autosomal recessive neurodegenerative disease. In June 2017, Health Canada approved Nusinersen, currently the only available drug for SMA. Since 2016, patients in Ontario have been treated clinically with Nusinersen through different access programs. Methods: Retrospective case series of patients with SMA treated clinically with Nusinersen in Ontario, describing clinical characteristics and logistics of intrathecal Nusinersen administration. Results: Twenty patients have been treated across four centres. To date, we have reviewed 8 cases at one centre (seven SMA Type I, one SMA Type II). Age at first dose ranged from 3-156 months and disease duration 9-166 months. Patients had received 4-7 doses at last evaluation. Three patients with scoliosis (2 with spinal rods) required fluoroscopy-guided radiologist administration, and 4 required general anesthesia. No complications/adverse events were reported. At last follow up, 5/8 families reported improved daily activities. Of 5 patients with baseline and follow up motor function testing, 3 demonstrated improved scores. One patient died due to respiratory decline at age 9 months, despite improved motor outcome scores. Conclusions: We describe the first Canadian post-marketing experience with Nusinersen. Timely dissemination of this information is needed to guide clinicians, hospital administrators, and policy-makers.