Background: Randomized-controlled trials of thrombolysis in ischemic stroke have poorly represented patients with pre-stroke disability and the benefit of thrombolysis in this population remains uncertain. We performed a systematic review and meta-analysis to examine the outcomes of thrombolysis in patients with pre-morbid disability. Methods: In accordance with MOOSE guidelines, we retrieved studies reporting intravenous thrombolysis (IVT) in patients with pre-stroke disability (mRS=3-5) with ischemic stroke, either compared to untreated patients or to treated patients without pre-morbid disability. Primary outcome was the return to pre-morbid disability at 90-days. Results: 8 articles were included involving 103,988 patients. Patients with disability treated with IVT had better odds of returning to baseline function compared to those who did not receive IVT (OR=7.26, 95%CI=2.51-21.02). Mortality and sICH were not significantly different between patients with disability receiving IVT or not. Favourable outcomes (mRS=0-2 or return to pre-morbid mRS) and sICH were not significantly different between patients with and without disability. Mortality was three times higher in those with pre-morbid disability treated with IVT (38.2% versus 12.6%). Conclusions: Thrombolysis in patients with disability was associated with better outcomes compared to patients not receiving IVT. High-quality data comparing treated versus untreated patients with pre-morbid disability is needed to clarify this issue.

Background: Ischemic stroke (IS) may be the first sign of an occult cancer, due to an underlying paraneoplastic prothrombotic state. Predictors of occult cancer in acute IS, however, remain unclear. We performed a single-center study to identify clinical features that may distinguish cancer-associated IS from IS without recent cancer. Methods: We reviewed consecutive admissions for acute IS at our institution between January and December 2020. Recent cancer was defined as any new diagnosis of cancer up to five years prior to IS. We compared clinical features with Fisher and chi-squared tests for categorical data, as well as t-tests and Mann-Whitney U tests for continuous data. Results: We included 169 patients in the non-cancer group and 19 in the recent cancer group (median time for cancer diagnosis: 10.5 months). The most frequent primary site was the digestive system (n=5; 33.3%). Patients with recent cancer had a significantly lower mean BMI (19.3 vs 26.4 kg/m2; p=0.013), lower mean hemoglobin (123 vs 134 g/L; p=0.015), and more frequent prior venous thrombosis (15.8% vs 1.2%; p=0.008) than cancer-free patients. Conclusions: Clinical features such as lower BMI, lower hemoglobin and prior venous thrombosis may help identify cancer-associated mechanisms, as well as guide cancer screening, in IS.

Background: Face, Arm, Speech, Time (FAST) campaigns improve stroke recognition in the general population. We assessed the effect of five consecutive FAST campaigns on emergency medical services (EMS) calls for suspected strokes in Quebec, Canada. Methods: We compared with t-tests the daily EMS call volume changes in the greater Montreal area before and after five FAST campaigns held between 2015 and 2019. We used interrupted time-series to measure changes in EMS daily call volume for suspected strokes following each FAST campaign (all calls, calls <5 hours from symptom onset, calls rated 3/3 on the Cincinnati Prehospital Stroke Scale [CPSS]) and used calls for acute headaches as a comparator. Results: After five FAST campaigns, mean daily calls increased by 28% (p<0.001) for suspected strokes, compared to 10% for acute headaches (p=0.012). Significant increases in daily stroke calls were only observed after three campaigns (highest OR=1.26, 95% CI: 1.11, 1.43; p<0.001). There were no significant changes in calls after individual campaigns for strokes <5 hours from symptom onset and 3/3 CPSS strokes. Conclusions: The individual effect of FAST campaigns on daily stroke calls to EMS was inconsistent. Further refinement of FAST campaigns may help improve prompt EMS activation.

Background: Respiratory infection can be an immediate precursor to stroke and myocardial infarction (MI). Influenza vaccination is associated with reduced risk of MI. This relationship has also been suggested for stroke although it is unclear if the effect is consistent across age and risk groups. Methods: Using administrative data in Alberta from September 2009 – December 2018 we modelled the hazard of any stroke for individuals recently exposed (< 182 days) to the influenza vaccine compared to those without recent exposure adjusted for age, sex, anticoagulant use, atrial fibrillation, COPD, diabetes, hypertension, income quintile, and rural/urban home location. Results: 4,141,209 adults (29,687,899 person-years) were included; 1,769,565 (43%) received at least one vaccination in the 10-year time span. 38,126 stroke events were recorded. Adjusted for demographics and comorbidities, recent influenza vaccination significantly reduced the hazard of stroke (HR: 0.77; 95% CI: 0.76 – 0.79). This effect persisted across all stroke subtypes and across all ages and risk profiles. Conclusions: There is a 23% reduction in hazard of stroke among those recently vaccinated against influenza compared to those who were not. Protection extended to the entire adult population and was not limited to high-risk groups only.

Background: Canadian Stroke Best Practice Recommendations recommend both cardiac monitoring and transthoracic echocardiography (TTE) to assess for cardioembolic sources of stroke. TTE has a diagnostic yield, which is historically low at 5-10%. The goal of this project was to evaluate the practicality of a bedside, focused approach to TTE in ischemic stroke. Methods: A cross-sectional study evaluating patients undergoing echocardiography for evidence of possible cardioembolic stroke was developed. It compared the standard and focused TTE imaging approaches. Of the 61 patients reported, data is currently available for 15 participants. Independent samples t-test were performed to compare measurements. Results: Mean time to finish image acquisition for the focused, bedside TTE was significantly shorter than the complete TTE (12 min or less vs 30 min or more) (p<0.0001). No cardiac sources of stroke were found by either mechanism in this cohort, representing 100% agreement between the two modalities. Conclusions: Focused, bedside echocardiography studies are quicker to execute and employ more affordable, portable, digital TTE devices. The test is done at bedside, reducing the need for patient transport. Image acquisition takes approximately half the time to obtain, potentially allowing for more rapid clinical decision making and facilitation of discharge from hospital.

Background: Visual impairment can impact 70% of individuals who have experienced a stroke. Identification and remediation of visual impairments can improve overall function and perceived quality of life. Our project aimed to improve visual assessment and timely intervention for patients with post-stroke visual impairment (PSVI). Methods: We conducted a quality improvement initiative to create a standardized screening and referral process for patients with PSVI to access an orthoptist. Post-stroke visual impairment was identified using the Visual Screen Assessment (VISA) tool. Patients filled out a VFQ-25 questionnaire before and after orthoptic assessment, and differences between scores were evaluated. Results: Eighteen patients completed the VFQ-25 both before and after orthoptic assessment. Of the vision related constructs, there was a significant improvement in reported outcomes for general vision (M=56.9, SD=30.7; M=48.6, SD=16.0), p=0.002, peripheral vision (M=88.3, SD=16; M=75, SD=23.1), p= 0.027, ocular pain (M=97.2, SD=6.9; M=87.5, SD=21.4), p=0.022, near activities (M=82.4, SD=24.1; M=67.8, SD=25.6), p<0.001, social functioning (M=90.2, SD=19; M=78.5, SD=29.3), p=0.019, mental health (M=84.0, SD=25.9; M=70.5, SD=31.2), p=0.017, and role difficulties (M=84.7, SD=26.3; M=67.4, SD=37.9), p=0.005. Conclusions: Orthoptic assessments for those with PSVI significantly improved perceived quality of life in a numerous vision related constructs, suggesting it is a valuable part of a patient’s post-stroke recovery.

Background: Patient with small thalamic infarct may present with a variety of subtle and seemingly disconnected sensory deficits which can be easily missed. Methods: Here we report a case of an 80 years ‘old Chinese female presenting sudden onset persistent sensory symptoms over perioral area and right hand. The patient underwent further investigation with Brain MRI. The patient underwent further investigation with Brain MRI. A literature review was conducted and the patient’s clinical finding was compared with the literature. Results: The patient’s presentation was consistent with clinical manifestation of type 1 Cheiro-Oral syndrome. Brain MRI performed the day after admission revealed small non-hemorrhagic infarction involving the left thalamus. The diagnosis was type 1 cheiro-oral syndrome secondary to left thalamic ischemic stroke. Conclusions: This report highlights both clinical presentations of cheiro-oral syndrome and correlating clinical symptomatology with anatomic localization. It is important for physicians to recognize this rare condition with subtle presentations for complete work-up and definitive treatment.

Background: CTS and PPR are common EEG findings that are classically associated with CECTS and GGE respectively. PPD and sleep spindles are physiologic phenomenon that occur in respond to intermittent photic stimulation and sleep respectively. Methods: We reviewed EEG studies with CTS, PPR, asymmetric PPD, or asymmetric sleep spindles. For CTS, we determined sensitivity, specificity, PPV and NPV for a diagnosis of CECTS. For PPR, we determined the same diagnostic outcome measures for a diagnosis of GGE or JME. For each of asymmetric PPD and asymmetric sleep spindles, we determined the same diagnostic outcome measures for the presence of a structural abnormality on brain MRI. Results: CTS had 83% specificity and 75% PPV in children with normal neurological examination. PPR had high specificity of 92% and NPV 92% for GGE; for JME, PPR also had high sensitivity (92%). Asymmetric PPD had low sensitivity for structural brain abnormalities (17%), with specificity 80%. In contrast, asymmetric sleep spindles had higher sensitivity and specificity, 44% and 97%, respectively. Conclusions: CTS are seen with CECTS and other conditions. PPR is highly indicative of a GGE, though may be seen other conditions. Relative attenuation of sleep spindles is a more reliable indicator of structural brain malformation than asymmetric PPD.

Background: With the now routine use of next-generation sequencing it is important to know the baseline outcomes as they relate to clinical care for pediatric epilepsy in Ontario. We sought to assess the diagnostic yield of genetic epilepsy panel testing and characterize the impact on patient care. Methods: We conducted a retrospective chart review of patients with epilepsy seen at CHEO between 2012-2020 with genetic testing. 227 patients met our inclusion criteria. Patient charts were reviewed for clinical details, co-morbidities, genetic testing results, and changes to management. Results: Diagnostic yield was 19% for multi-gene epilepsy panel testing. A further 10% received a diagnosis from additional genetic testing. The diagnostic yield was significantly higher in patients with a younger age of onset of seizures. A direct change in clinical management as a result of the molecular diagnosis was evident for 9% of patients; however, all diagnoses impacted prognosis and family counselling. Conclusions: The diagnostic yield of genetic epilepsy panel testing conducted at CHEO is comparable to other reported rates. Genetic testing resulted in clinical benefits of recurrence risk counselling, prognostic information and though a direct change in management was advised in a minority of individuals, targeted treatment recommendations will continue to increase with ongoing testing.

Background: In Canada, 7% of children are born preterm between 29 and 36 weeks gestational age (GA). Electroencephalography (EEG) provides a bedside evaluation of brain activity, yet the clinical significance of several EEG patterns requires further study. The goal of this study is to determine the EEG features at term equivalent age (TEA) that correlate with neurodevelopmental evaluation at TEA in infants born between 29-36 weeks GA. Methods: Prospective cohort study of preterm infants born 29-36 weeks GA with 1 hour EEG recording at TEA. EEG discontinuity index (proportion <25mcV amplitude) and spectral power densities were calculated as well as the mean and maximum values of interburst intervals. At TEA, neurodevelopment was evaluated using the General Movement Optimality Score (GMOS). Linear regression analyses were used to evaluate the association between EEG features and neurodevelopmental assessment. Results: Eighty-two children (median GA 33.6 weeks) were included (47 males). Median GMOS was 29.0 (IQR 24.3-35.0). A greater EEG discontinuity index was associated with reduced GMOS (B -6.85; 95% CI -12.13,-1.57; p=0.012). Conclusions: At TEA, a greater EEG discontinuity index was associated with a more abnormal neurodevelopmental assessment. Ongoing longitudinal neurodevelopmental assessments are needed to better evaluate the prognostic potential of TEA EEG.

Background: Epileptic spasms (ES) are a devastating seizure type with poor neurodevelopmental outcome; 1/3 are resistant to treatment with first line therapies. Recently attention has been drawn to the ketogenic diet (KD) as a potentially effective therapy, though data regarding optimal time of initiation, and its sustained effectiveness, are lacking. Methods: Retrospective chart review of all patients with ES treated with KD at BC Children’s Hospital between 2002 and 2020 (n=28) with comparison of spasm response based on age of initiation of KD in two groups: < 12 months (n=11) and ≥ 12 months (n=17). Results: Comparing the <12 months and ≥ 12 months groups showed: unknown etiology in 9% vs 25%; spasm freedom for 3 months on KD in 18% vs 41%; median time to spasm freedom was 2 vs 6 weeks; relapse after a period of spasm freedom occurred in 66% vs 70%. Conclusions: Although more effective in children ≥ 12 months of age in the first 3 months, spasm freedom in either group was not sustained with KD. KD is recommended as early therapy for refractory ES, but this study suggests clinicians be aware the KD has limited efficacy in long-term control of ES and must be used with other therapies.

Background: Background: Lennox-Gastaut syndrome (LGS) is a severe form of pediatric epilepsy that is classically defined by a triad of drug-resistant seizures, characteristic EEG patterns, and intellectual disability. Long-term prognosis is generally poor with progressive intellectual deterioration and persistent seizures. At present, there are few reported cases of LGS and Trisomy 21 (T21) in the literature. To further delineate the spectrum of epilepsy in T21, we reviewed children with T21 and LGS at one center over 28 years. Methods: Methods: This is a retrospective case series. At our institution, all EEG results are entered into a database, which was queried for patients with T21 from 1992-2019. Pertinent electro-clinical data was obtained from medical records. Results: Results: 63 patients with T21 and epilepsy, 6 (10%) had LGS and were included in the study. Four of the six patients were male and 5/6, had neuro-imaging, which was normal. Follow-up ranged from 3-20 years. Notably, 5/6 had predominant myoclonic seizures throughout the course of their epilepsy, associated with generalized spike-wave discharges. Conclusions: Conclusions: Myoclonic seizures appear to be a predominant seizure type in patients with T21, suggestive that T21 patients may have a unique pattern of LGS.

Background: MT-TA (OMIM 590000), one of 22 mitochondrial transfer-RNA (mt-tRNA) genes, encodes the mt-tRNA for alanine. Pathogenic variants in mt-tRNA genes affect the translation of respiratory chain complexes I, III, and IV; which leads to mitochondrial dysfunction and a clinically variable phenotype. MT-TA pathogenic variants have been described in only seven patients, all of whom had isolated myopathy Methods: Case report. Results: Our patient initially presented with drug-resistant West syndrome, later evolving towards a Lennox Gastaut phenotype. Although she had hypotonia, serum creatine kinase and electromyography were normal. Brain-MRI showed bilateral symmetric hypointense T1, hyperintense T2-fluid-attenuated-inversion-recovery and restricted-diffusion signal changes in the dentate nuclei. Mitochondrial genome testing identified a previously published pathogenic variant in MT-TA (m.5591G>A) with 14% blood heteroplasmy and 16% urine heteroplasmy. The variant was absent in serum sampled from the patient’s mother Conclusions: Our case extends the phenotypic spectrum of MT-TA variants to include developmental and epileptic encephalopathy, in the apparent absence of muscle disease. We hypothesize that our patient may have the greatest degree of heteroplasmy in brain tissue; however, animal models and induced pluripotent stem cell (iPSC) models are needed to identify the precise mechanism by which MT-TA dysfunction results in variable phenotypes with variable degrees of heteroplasmy.

Background: Acute Necrotizing Encephalopathy (ANEC) is a rare neuroinflammatory disorder involving the deep grey matter following viral infection and has been associated with the RANBP2 gene. We aimed to evaluate clinical and imaging features in ANEC patients. Methods: This retrospective chart review of ANEC patients (2012-2020) seen at a tertiary pediatric center included analysis of outcomes including ANE-Severity Score, Expanded Disability Status Scale (EDSS) and the modified Rankin Scale (mRS), semi-quantitative imaging scores (degree of swelling or hemorrhage rated 0 (none)-5 (severe/massive)), and dichotomous outcomes including RANBP2 gene status, influenza status. Results: 20 patients were included (Avg. age at presentation 3.5 yrs IQR=3.56., F:M 2.33:1). 3/20 experienced recurrences. All patients with recurrences were positive for RANBP2 mutations. 10/20 patients were influenza positive. 7/20 were RANBP2 mutation positive. We observed higher likelihood of hemorrhage in influenza-positive compared to negative patients (W=78, p=0.048). Kaplan-Meier survival curve analysis revealed that patients without brainstem lesions were more likely to reach minimal/no disability (EDSS<=2) than patients with brainstem lesions (p=0.035). Conclusions: Hemorrhage is more likely to be seen in children with ANEC who are positive for influenza. RANBP2 status was predictive of relapse but not predictive of overall outcome.

Background: Pediatric-onset multiple sclerosis (MS) is associated with a high rate of disease activity. However, only a single DMT – fingolimod – has been approved by Health Canada for children, in 2018. In this study, we describe trends in the treatment of pediatric-onset MS in Alberta. Methods: We performed a retrospective review of Alberta administrative health databases, identifying cases of MS under 19 years of age from January 1, 2011 - December 31, 2020. Pharmacy dispenses of MS DMTs were identified by Anatomical Therapeutic Chemical classification code and grouped as injectables (glatiramer acetate, interferon-beta) or newer agents (all others). Results: 79 incident cases of pediatric MS were identified during the study period. 47/79 (59%) had at least one DMT dispense, with the first dispense occurring a median 263 days (IQR 134.5-988) from the index date at a median age of 17.2 years (IQR 16.0-18.6). Injectables accounted for all initial DMT dispenses < 19 years of age prior to 2019, while from 2019-2020 injectables accounted for only 3/15 (20%) initial dispenses, with rituximab (5/15, 33%) being the most common initial DMT in those years. Conclusions: The treatment of children with MS in Alberta has rapidly evolved, shifting shift towards earlier treatment using newer high-efficacy agents.

Background: Severity of HIE is based on Sarnat classification; however, it is difficult to predict precise neurodevelopmental outcomes as this only provides a single snapshot in time. We aimed to use machine-based learning to better understand variables contributing towards HIE severity. Methods: Patients with HIE treated with hypothermia were studied between 2014 and 2020 at level 3 NICUs in Calgary, Alberta. Clinical information contained 23 features including specifics of clinical examination, blood work, MRI and EEG findings, and medications. Random forest models were trained to examine features most predictive of HIE severity. Results: Two hundred and six patients were eligible. By grouping patients based on the initial Sarnat score and post-cooling exam, features correctly predicted groups 43% and 73% of the time, respectively. Precision, accuracy, and recall was best for the mild group. Using MRI and day 1 seizures it was 54% and 67% predictive, respectively. Features contributing most included arterial pH, initial lactate, and overall EEG findings. There are ongoing analyses for further classification. Conclusions: Machine-based learning can improve predictive models for patient outcomes. There is benefit in using variables outside of the initial examination to improve classification. We aim to expand this model to include detailed neurodevelopmental outcomes to improve prognostication.

Background: Spinal muscular atrophy (SMA) is the leading genetic cause of infant death and the second most common autosomal recessive disorder; most cases are due to homozygous deletion of SMN1 gene. Methods: This study uses the Canadian Paediatric Surveillance Program to determine the minimum annual incidence of 5q-SMA from birth to 18 years of age in Canada. The protocol can be accessed at www.cpsp.cps.ca/surveillance. Results: Eighteen cases were reported in 2020-2021. Ten (55%) cases were reported from Ontario and the remaining cases were reported from Atlantic Canada and Western Canada. Their median age was 11 months (IQR 4–21); 61% were male. The most common presenting symptoms were hypotonia and delayed motor milestones in 12 (86%) and 10 (71%) cases respectively. On average, the diagnosis was delayed after onset of symptoms by three months for SMA Type 1, by eight months for Type 2, and by 18 months for Type 3. Twelve (86%) cases received nusinersen as their first disease-modifying treatment. Conclusions: Early recognition and newborn screening are essential to reduce diagnostic delay and enable timely treatment of SMA. Other data sources including the Canadian Neuromuscular Disease Registry and molecular genetic laboratories will be used to estimate the annual incidence of pediatric SMA in Canada.

Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that is associated with long-term reduced quality of life and impaired functioning. ADHD is commonly associated with sleep disturbances that can contribute to many difficulties in a child’s life. This study aims to elucidate this complex relationship by utilizing a subset of the Adolescent Brain Cognitive Development (ABCD) database. Methods: The population included a group of children with ADHD age 10-13 years (n=212) and a matched typically developing (TD) group (n=212). Sleep data was obtained through Fitbit actigraphy measures, and the Parent Sleep Disturbance Scale (SDS). Behavioural and emotional subscores were obtained from the Child Behaviour Checklist (CBCL). Results: There were no significant correlations between the actigraphy and SDS sleep data. SDS sleep data were significantly different between ADHD and control groups, while actigraphy data was not. Sleep latency (measured by actigraphy) and 3 out of 6 of the SDS subscores were significantly related to behavioural scores. Conclusions: The results of this study indicate that sleep may not be an important mediator of behaviour and emotional responses in children with ADHD. Future studies should explore both influences on sleep parameters as well as behaviour and other measures important to families.

Background: The aim of this study was to identify possible risk factors associated with term-born newborns with cerebral palsy and PWMI on imaging. Methods: This is a case-controlled study with cases from the Canadian Cerebral Palsy Registry and controls from Alberta Pregnancy Outcomes and Nutrition Study. PWMI was diagnosed based on MRI reports and 160 cases were compared to 1950 controls. Risk factor were selected a priori; including pregnancy complications, toxin exposure, perinatal infection, sex, small for gestational age, and perinatal adversity. Multivariate regression binomial model was used to calculate odds ratios(OR) and 95% confidence intervals(CI). Results: Multivariable analyses suggested PWMI was associated with pregnancy complications(OR=3.35; 95% CI=2.23-4.94), antenatal toxin exposure(OR=2.45; 95% CI=1.67-3.55), perinatal infection(OR=3.61; 95% CI=1.96-6.29) and perinatal adversity(OR=2.03; 95% CI=1.42-2.94). Term born males were not more likely to have PWMI compared to females(OR=1.37; 95% CI=0.98-1.93). Multiple regression analyses suggested independent associations between PWMI and pregnancy complications(OR=3.63; 95% CI 2.40-5.40), antenatal toxin exposure(OR=2.62; 95% CI 1.77-3.84), perinatal infection(OR=3.42; 95% CI 1.83-6.05) and perinatal adversity(OR=2.49; 95% CI= 1.71-3.69). Conclusions: Risk factors such as pregnancy complications, toxin exposure, perinatal infection and perinatal adversity are associated with PWMI in term-borns, suggesting a ‘two-hit’ model that could involve an interaction among both antenatal and perinatal variables.

Background: Tuberous Sclerosis Complex (TSC) is a genetic disease that affects multiple body systems with the neurological manifestations causing the greatest disease burden. The objective of this study was to understand the scope of neurological TSC care delivery across Canada. Methods: A survey was developed after literature review and discussion amongst two Paediatric Epileptologists and one Nurse Practitioner with expertise in TSC. Canadian Paediatric Neurologists participated via an anonymous web-based survey through the Canadian League Against Epilepsy (CLAE) and Canadian Neurological Sciences Federation (CNSF). Results: Fifty-eight responses were received. A dedicated TSC clinic was reported by 24% (n=14). Sixty percent (n= 35) reported preforming serial screening EEG monitoring in infants and 58% (n= 34) started prophylactic therapy when EEG abnormalities occurred. Vigabatrin was used in 37% (n=21). For management of drug-resistant epilepsy, surgery was reported as the preferred therapeutic option in 57% (n=32) of respondents. Barriers to treatment identified were a lack of multi-disciplinary care, unfamiliarity with new therapies and insufficient resources. Conclusions: Our findings demonstrate the variability in neurological care delivery of patients with TSC. With few dedicated TSC clinics, there is a need for the establishment of a national network to support clinical practice, research and education.