Background: Sedation in PICU masks physical exam findings, leading to diagnostic challenges. In adult models, electroencephalography can evaluate the brain’s response to sedation using feedforward connectivity and anteriorization of alpha hubs, proving useful for prognostication. Feasibility of model translation into pediatric population was assessed, with the hypothesis that the same markers of adaptive reconfiguration would correlate with a higher potential for recovering consciousness. Methods: Electroencephalograms from children undergoing sedation were analyzed for strength and direction of functional connectivity using the weighted and directed phase lag index. Target population was refined with an iterative inclusion criteria. We examined relationships between hub location reconfiguration, directed phase lag index, baseline Glasgow Coma Scale, and 3-month post-treatment Glasgow Outcome Scale-Extended. Results: Evaluation of 14 subjects showed promise in children aged 5-18 undergoing sedation with midazolam, dexmedetomidine, and propofol. Further analysis of five subjects revealed a correlation between adaptive reconfiguration during anesthesia and both higher baseline Glasgow Coma Scale and Glasgow Outcome Scale-Extended scores post-treatment. Conclusions: The findings indicate that the functional brain network connectivity model may have diagnostic and prognostic potential regarding children’s consciousness levels. While the initial data is promising, further analysis of six additional cases is pending and deemed essential to thoroughly evaluate the model’s efficacy.

Background: Medically refractory pediatric epilepsy is a disorder that can cause significant financial and physical burden. Although multiple treatments exist, cost-effectiveness remains unclear. We conducted a systematic review to assess cost-effectiveness of treatments for medically refractory pediatric epilepsy and to summarize key issues and areas for further inquiry. Methods: We searched MEDLINE and 6 other databases up to July 2022. We included partial and full economic evaluations (EEs) on treatments for medically refractory pediatric epilepsy. Pairs of reviewers independently screened the literature, extracted data, and assessed quality using the 24-item Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. We extracted data on study characteristics, health outcomes, model design, costs, and treatment characteristics. Results: We identified 37 eligible studies for analysis, 19 of which were partial EEs and 18 were full EEs. Study quality, outcomes reported, treatment comparators, and factors included in cost calculations were common influential factors in study results. Vagus nerve stimulation and cannabinoid oil were the most consistently cost-effective, in 6 of 7 and 1 of 2 studies, respectively. Other treatments were inconsistently cost-effective. Conclusions: The cost-effectiveness of treatments for medically refractory pediatric epilepsy was not definitive. Consistency in study design and inputs is necessary for future comparison of epilepsy treatment.

Background: People with epilepsy experience higher rates of cardiac arrhythmia and sudden death than the general population, with the highest risk in genetic epilepsies. Despite growing evidence of a possible cardiac contribution, routine cardiac screening for epilepsy patients is rarely performed. Methods: We performed a single center, retrospective review of patients with developmental epileptic encephalopathies caused by genetic variants expressed in the heart and brain. Clinical history, medications, age, and cardiac evaluation data were extracted. Results: Among 67 patients (56% female), 54 (81%) had at least one ECG. Twenty (37%) had an abnormal ECG. Forty-one had a repeat ECG: 8 showed persistent abnormalities, 7 resolution of abnormalities, and 7 a new abnormality. Five patients with an abnormality did not receive a follow up ECG. Two patients each had histories of cardiac arrest, syncope, and sudden death in a family member. Cardiac phenotypes differed in patients who experienced generalized tonic-clonic seizures and patients with epilepsy for 3+ years. Conclusions: Almost 1/3 of our high-risk epilepsy cohort had history of cardiac events or abnormalities on cardiac testing. Seizure type and epilepsy duration were associated with altered cardiac phenotypes. Since some findings were potentially clinically significant, routine cardiac screening of high-risk epilepsy patients may be warranted.

Background: Continuous spike and waves during slow-wave sleep (CSWS) is a childhood-onset epileptic encephalopathy that is characterized by clinical seizures, electrical status epilepticus during sleep (ESES), and neurocognitive regression. Early intervention can preserve neurocognitive development, and vagus nerve stimulator (VNS) therapy had positive outcomes in the few previously reported case reports. We present three patients with intractable CSWS unresponsive to medications, who had a positive response to VNS therapy. Methods: Review of clinical records of three pediatric patients diagnosed with CSWS were compared for selected clinical outcomes and electrographic data both prior to and in the years following the initiation of VNS therapy. Results: Three patients now aged 13, 16 and 20 years, were treated with VNS following intolerance and a lack of response to multiple medications (5-9) for CSWS. The ketogenic diet was not an option. The CSWS resolved in all three patients, resulting in improved cognitive function. Patient 3 had resurgence of CSWS on EEG when the VNS settings inadvertently reset to the factory settings and improved with adjustment in the cycling. Conclusions: In patients who are unresponsive to medication, VNS provides an alternative option for resolving CSWS to preserve and, in some cases, potentially restore neurocognitive function.

Background: Aromatic l-amino acid decarboxylase (AADC) deficiency is a metabolic disorder that causes deficient serotonin, dopamine, and catecholamine synthesis. How children respond to neurological insult post intracranial gene therapy remains underreported. We present a 10 year old girl with profound neurological injury after a brief in-hospital cardiac arrest, secondary to viral infection-induced respiratory failure, 4 years after gene therapy. Methods: Patient’s chart review included brain imaging, clinical notes, laboratory results, and treatment. Results: MRI showed symmetric abnormalities in the basal ganglia, thalami, cortex, and cerebellar hemispheres. CSF analysis showed homovanillic acid 27 nmol/L (reference range 167-563) and 5-hydroxyindoleacetic acid 7 nmol/L (reference range 67-189). She developed generalized dystonia and oculogyric crises which were not seen since before gene therapy. There was poor catecholamine production causing refractory hypotension. She required a one-month stay in ICU for hypotension and status dystonicus. Dystonia was controlled with high doses of 6 agents. Conclusions: We describe a patient with AADC deficiency post gene therapy who experienced disproportionately severe neurological injury and decreased AADC activity after hypoxic neurological insult. There may be unique considerations of dopaminergic neuron integrity, AADC gene promoter sensitivity, and cerebrovascular autoregulation in children with AADC deficiency post gene therapy.

Background: Deep Brain Stimulation (DBS) has become increasingly prevalent in the management of paediatric movement disorders, with the globus pallidus interna (GPi) serving as the most utilized target. However, limitations exist, including variable responses in genetic versus acquired forms of movement disorder and structural damage in the GPi would preclude its use as a target. Given these limitations, there is a pressing need to explore alternative targets. We investigated the application of non-GPi targets in paediatrics through a systematic review. Methods: Individual data points were gathered from references identified through a systematic electronic search and analysed descriptively. We included paediatric patients (0-18 years) with movement disorders who underwent non-GPi-DBS. We excluded adults and other indications. Results: Preliminarily, 64 patients were identified from 40 references. Dystonia was the most common movement disorder type, followed by tremor and chorea. The subthalamic nucleus was the frequent DBS target for dystonia, yielding promising outcomes of improvement as measured on the Burke-Fahn-Marsden movement scale ranging from 43% to 95%. The ventral intermediate nucleus was the second most employed target, demonstrating favourable results. Conclusions: Non-pallidal DBS targets hold promise as potentially efficient and safe. However, to further validate their effectiveness and safety, larger multi-centre randomized studies are required.

Background: Children with neurological injuries/insults carry the highest risk of death and disability in Pediatric and Neonatal ICUs. These patients comprise 25-30% of admissions and have a myriad of diagnoses. Longitudinal outcome data is required to inform treatment effects and innovation strategies. NCC at the Alberta Children’s Hospital (ACH) participates in acute, subacute, and long-term/outpatient management with an aim to use comprehensive clinical data to improve outcomes. Methods: A prospective, longitudinal, population-based observational cohort study of NCC patients from local NICUs, PICU, and a NCC follow-up program, with comprehensive data from clinical records, development scores and QoL assessments. Results: Since 2019, 929 patients have been enrolled including: 407 neonates, 167 infants, 106 preschool-age and 100 school-age children, and 152 adolescents. The most common reasons for NCC consult were paroxysmal events (36%), encephalopathy (27%) and neonatal HIE (20%). Conclusions: Our database encapsulates the diverse nature of NCC patients and has enabled cohort-specific studies (e.g., neonatal HIE and ECLS outcomes). Program evolution will further facilitate higher powered research studies through large enrollment, comprehensive data capture (with a provincial EHR), and longitudinal outcomes. Engagement with staff and families will also inform treatment and afford evidence-based counseling to families.

Background: Infections are hypothesized to trigger certain autoimmune diseases; however, data surrounding incidence trends of pediatric neuro-autoimmune disorders during the COVID-19 pandemic are lacking. Our retrospective study thus assessed the incidence of pre-defined autoimmune disorders diagnosed at the Children’s Hospital of Eastern Ontario in Ottawa, Canada between October 2017 and June 2023. Methods: Inpatient and outpatient charts were queried to identify subjects with neuro-autoimmune disorders or type 1 diabetes (T1D) as a non-neurological autoimmune comparison group. Monthly incidences were calculated and grouped based on three COVID-19 pandemic restriction periods: the pre-restrictions period (October 2017-March 2020), intra-restrictions period (April 2020-June 2022), and post-restrictions period (July 2022-June 2023). Poisson regression models were fit to the incidence data. Results: New diagnoses of neuro-autoimmune disorders and T1D were identified in 86 and 591 subjects, respectively. Incidence of neuro-autoimmune disorders decreased significantly during the intra-pandemic restrictions period when compared to the pre-pandemic period (IRR=0.56, 95% CI: 0.32-0.93, P<0.05). Albeit not statistically significant, the incidence then increased to higher than pre-pandemic levels during the post-restrictions period. T1D showed no significant changes in incidence. Conclusions: Incidence of neuro-autoimmune disorders, but not T1D, decreased during COVID-19 pandemic restrictions, which may be due to reduced transmission of key infectious triggers.

Background: Spinal Muscular Atrophy (SMA) is a rare, genetic disorder marked by motor neuron degeneration, causing progressive muscle weakness. SMA significantly impacts patients and their families. This study investigates HRQOL in a longitudinal SMA cohort. Methods: The study used the Canadian Neuromuscular Disease Registry to examine HRQOL in children aged 6-10 years with genetically confirmed SMA. HRQOL was evaluated using the PedsQL™ Measurement Model. This tool is validated in children and adolescents with various health conditions. The PedsQL Neuromuscular Module which has been validated in SMA was also used. Results: Eight participants completed the PedsQL generic and Neuromuscular Module at timepoint 1 (TP1) and 2 (TP2). The mean scores at TP1 were 49.66 (SD=5.05) for the generic PedsQL and 61.06 (SD=18.37) for the Neuromuscular Module. At TP2, mean scores increased to 59.32 (SD=13.08) and 74.86 (SD=9.88), respectively. The overall mean change over the two timepoints was +9.66 (SD=15.16) for the Generic PedQL and +13.80 (SD=23.03) for the Neuromuscular Module. Six participants were on disease modifying treatment. Conclusions: HRQOL scores in SMA patients improved over the study period. The enhancement in HRQOL may indicate the positive impact of diseases modifying treatments of SMA that became available during that time.

Background: Necrotizing anti-HMGCR myopathy is rare in children. Pediatric cases are not typically associated with statin use or malignancy. Methods: Retrospective chart review (January 2009 to December 2023) identified cases of anti-HMGCR myopathy at our hospital. Results: Two patients were identified. Patient A, presented at 8 yo with a 2 year history of proximal muscle weakness. His CK was 4,840 U/L (normal <205 U/L) with a high anti-HMGCR antibody titre. His Childhood Myositis Assessment Scale (CMAS) score was 33/52. Monthly IVIG was started and his muscle strength and CK improved. Two years later, weekly methotrexate was started for persistent mild CK elevation (602 to 869 U/L). At 11 years old, 3 years after diagnosis, his CMAS score was 47 and he could participate in soccer with mild fatigue. Patient B, presented at 8 yo with acute proximal weakness, rash and CMAS 13/52. His CK was 20,185 U/L with elevated anti-HMGCR antibody titre. He received oral corticosteroids, weekly methotrexate and monthly IVIG. At 10 yo, 2 years after diagnosis, he is asymptomatic with CMAS 51. He is maintained on methotrexate monotherapy. Conclusions: Anti-HMGCR antibody myopathy requires prompt diagnosis to obviate muscle necrosis and long-term complications. Our patients showed clinical and CMAS improvement with treatment.

Background: Duchenne muscular dystrophy (DMD) causes progressive muscle wasting. The Canadian Neuromuscular Disease Registry (CNDR) previously developed a comprehensive DMD dataset in accordance with the International Classification of Functioning, Disability, and Health (ICF). Our objective was to develop a brief ICF core set that best aligns with the priorities of individuals and families affected by DMD. Methods: A literature review of best practices was prepared and reviewed by a multidisciplinary team at the CNDR. The entire process involved patient and parent input and participation and was compliant with the World Health Organization guideline to develop brief ICF core sets. Results: An eight step process was developed. In brief, these included multi-stakeholder consensus meetings, ranking surveys, mapping to international standards, further consensus meeting, evaluation of clinical feasibility in multidisciplinary clinics across Canada, an integrated literature review, and development of a finalized brief ICF core set for DMD. Conclusions: The process of identifying the priorities of those living with DMD using the brief ICF core set will support post-marketing surveillance of novel therapies. The next step in this project will be to identify the specific outcome measures that best align with the brief ICF core set for DMD, for their eventual inclusion in the CNDR registry.

Background: Climate change, and fossil fuel combustion threaten the health of children globally through direct and indirect mechanisms,1 such as the exacerbation of ambient air pollution.1,2 Increased ambient air pollutant concentrations are associated with emergency department (ED) visits for episodic and paroxysmal neurologic conditions in adults in the Toronto region of Canada.4,5 We hypothesize that, in Calgary, Alberta, increased ambient air pollutants will be positively associated with the daily burden of pediatric ED presentations for migraine and seizures, and that a greater effect size may be present due to increased regional variability in ambient PM2.5 concentrations.3,4 Methods: Emergency records from the National Ambulatory Care Reporting System, comprising 17552 primary seizure and headache cases between 0-18 years of age and presenting to Calgary-region emergency departments between January 2012-December 2021, will be included. Quasi-Poisson regression modeling incorporating ambient air pollutants, seasonality and meteorological covariates will estimate relative risk and 95% confidence intervals of ED visit counts relative to increases in air pollutants. Results: Results currently pending and will be available for presentation. Conclusions: Significant results may inform further inquiry into the impact of air pollutants on children with neurological conditions and identify potential contributions of air quality to healthcare service demand in the Calgary region.

Background: Trofinetide significantly improved core symptoms of Rett syndrome (RTT) with an acceptable safety profile in LAVENDER. Here, we report the safety and efficacy results of LILAC and LILAC-2, open-label extension studies of LAVENDER. Methods: Females with RTT, aged 5–21 years, received twice-daily, oral trofinetide in LILAC for 40 weeks. Participants who completed LAVENDER and LILAC continued trofinetide in LILAC-2, a 32-month extension study. Safety assessments included the incidence of adverse events (AEs). Efficacy endpoints included the Rett Syndrome Behaviour Questionnaire (RSBQ) and the Clinical Global Impression–Improvement (CGI-I) scale. Results: Overall, 154 patients were enrolled in LILAC. The most common AEs were diarrhea (74.7%) and vomiting (28.6%). The mean (standard error [SE]) change from the LAVENDER baseline to Week 40 in the LILAC study in RSBQ was -7.3 (1.62) and -7.0 (1.61) for participants treated with trofinetide and placebo in LAVENDER, respectively. Mean (SE) CGI-I scores compared with the LILAC baseline at Week 40 were 3.1 (0.11) and 3.2 (0.14) for patients treated with trofinetide and placebo in LAVENDER, respectively. Similar safety and efficacy trends were observed in LILAC-2. Conclusions: Trofinetide continued to improve symptoms of RTT in LILAC and LILAC-2 with a safety profile consistent with LAVENDER.

Background: Wernicke encephalopathy (WE) is a neurological emergency defined by acute encephalopathy, oculomotor dysfunction, and ataxia. Pediatric cases of WE are underdiagnosed despite having a similar incidence to adults. There are no available treatment guidelines for pediatric WE. Prompt treatment with thiamine can prevent devastating consequences. Methods: A rapid review of the literature of the past 20 years with selected relevant older articles was conducted for the research question “How does child and adolescent thiamine therapy management for Wernicke Encephalopathy compare to adult guidelines?” All articles reporting the investigation, management and treatment of Wernicke encephalopathy – both non alcohol related and alcohol-related pediatric cases – were included. Articles not reporting clinical outcomes were excluded. Results: Eleven case studies including one available review article, met the inclusion and exclusion criteria. An algorithm was created for the organization of published reports of the management of WE for children and adolescents. Key considerations were included for the prevention, identification, acute and ongoing management of patients with WE. Conclusions: The recognition of risk factors for thiamine deficiency and symptoms of acute WE should prompt immediate treatment with thiamine – as a routine and safe therapy in the pediatric population.

Background: Neurodegeneration with Brain Iron Accumulation (NBIA) is a heterogenous group of disorders with the common theme of iron accumulation in the basal ganglia. These disorders typically present in childhood with progressive neurodegeneration and neuropsychiatric symptoms. Caring for an individual with NBIAs is intensive, however it is unknown what factors impact caregiver well-being and quality of life. Methods: Common themes were obtained via literature review of quality of life surveys in children with neurological and chronic illnesses. Five domains were addressed: Diagnosis, Communication, Symptom Management, Clinical Experience and Resources/Support. The survey was approved by the Family Advisory Committee at the CHEO Research Institute and the CHEO REB. The survey was distributed via the Rare Connect Platform to Canadian caregivers. Results: Survey responses are being analyzed and will be presented at the CNSF. Within each domain, Likert scales will be analyzed. Domains will be ranked according to the caregiver responses. Conclusions: Results of this survey will assist in developing care management guidelines, resources for families and help with future advocacy for patients and families affected by NBIAs. The results will also help guide future NBIA Canada Family Conferences.

Background: Intracranial hemorrhage (ICH) in newborns poses a significant challenge to wellbeing and development. In preterm neonates, germinal matrix hemorrhage is most common. In term neonates, prevalence and type of ICH has not been well elucidated. This systematic review aims to assess prevalence, type, and risk factors of ICH in term neonates. Methods: A systematic review was conducted. Inclusion criteria was ICH in neonates born at 37+ weeks gestation. Exclusion criteria was one type of ICH, one risk factor, sample size <20, text not in English, full text not accessible. Eligible studies were evaluated by two authors, data was extracted and analyzed using a predesigned template and MetaXL. Results: A total of 1226 records were initially identified and 20 studies were included in the final analysis. The overall prevalence of ICH was 9.3%. This was subdivided into an asymptomatic subgroup (5.8%) and symptomatic subgroup (29.3%). Analysis showed CT detected ICH most commonly. Extra-axial hemorrhage was most commonly detected (~30%), with subdural more common than extradural hemorrhages. The odds of having an ICH was significantly higher with instrumental delivery (3.75%). Conclusions: This shows that prevalence of ICH is relatively high in symptomatic children. Measured prevalence varies according to the type of modality used for screening.

Background: Cortical myoclonus originates at cerebral cortex, predominantly occurring on voluntary movements. Few case reports described usage of Acetazolamide (ACZ) for myoclonus. Methods: Chart review of 2 patients was performed. Literature review was conducted on myoclonus and ACZ using Pubmed. Results: 22-year-old female was diagnosed with Progressive Myoclonic Epilepsy (PME) secondary to a KCNC1 mutation. Her symptoms started at 10 years old with bilateral tonic clonic seizures (BTCS), later developing progressive ataxia and myoclonus, involving face and limbs, which worsened with stimulus and menses. Medications included Perampanel, Clonazepam and Levetiracetam, however myoclonus was still limiting. At the age of 19, ACZ 250 mg BID was started for 2 weeks around her menses. Follow up revealed significant improvement of myoclonus, resulting in better ambulation, balance and speech, sustained 2.5 years after. 67-year-old male presented BTCS at the age of 53 along with cortical myoclonus, dementia and ataxia, leading to diagnosis of PME with a mutation on IRF2BPL. Improvement of myoclonus occurred with ACZ 250 mg BID biweekly, although balance and cognition still deteriorated. Conclusions: Previous literature outlines 4 cases of action myoclonus that responded to ACZ. We believe that ACZ should be considered to treat myoclonus, especially in cases with cortical involvement and hormonal fluctuations.

Background: Sleep-wake states (SWS) affect the expression of interictal epileptiform discharges (“spikes”), which affects resultant source localization calculations used in epilepsy evaluation. We hypothesize that spike localizations from non-REM sleep 1-3 are most concordant with one another. Methods: We used Standardized low-resolution brain electromagnetic tomography (sLORETA) in Curry 8 software to calculate source localization voxels of spikes in N1-3, REM, or wakefulness (W). We assessed voxel concordance between N1-N2-N3/N1-N2-W/N1-N3-W/N2-N3-W/REM-N1-N2/REM-N1-N3/REM-N2-N3/REM-N1-W/REM-N2-W/REM-N3-W. We classified concordances into those containing and not containing a SWS (e.g. N1 vs. not-N1 = N1-N2-N3/N1-N2-W/N1-N3-W/REM-N1-N2/REM-N1-N3/REM-N1-W vs. REM-N2-W/REM-N3-W/REM-N2-N3/N2-N3-W) for comparison. Results: Concordances did not differ for N1-3 or W. However, concordances with REM were lower than those without REM as a fraction of source localization space (median 32.1% vs. 56.1%, p<0.001) and cortical grey matter (median 20.4% vs. 27.3%, p=0.003). Conclusions: As expected, source localizations from spikes in N1, N2, and N3 did not significantly differ from one another because these three states are constituent members of non-REM sleep. Surprisingly, however, source localizations derived from awake spikes – not a constituent of non-REM sleep – also did not differ. In contrast, REM was most different by reproducibly exhibiting the least three-way concordance. These findings reinforce the unique localizing ability of REM sleep.

Background: Electrophysiological tests such as the tapping test are used to distinguish functional and organic tremors, in which patients with functional tremor commonly show entrainment and amplitude reduction (>50% decrease relative to baseline) of contralateral tremor during tapping. While these features are suggested to be specific to functional tremor, the tapping test in Parkinson’s disease (PD) tremor has not been tested. Methods: We evaluated 18 PD patients (2F, age 64.17±7.30 [mean±SD] years) with rest and postural tremors using surface electromyography and triaxial accelerometry. Patients were recorded while tapping at 1, 3 and 5 Hz with the contralateral arm at rest or outstretched. Tremor amplitude and frequency were calculated using power spectrum analysis from accelerometer recordings. Results: Reduction of rest tremor amplitude was observed in 3/18 patients during 1 and 3 Hz tapping. Reduction was seen in 3/16 and 1/16 patients with postural tremors at 1 and 3 Hz tapping, respectively. Frequency shifts (>1.5 Hz) were observed in 3/18 rest tremors and 6/16 postural tremors. Seven patients exhibited rest and/or postural tremor entrainment during 3 or 5 Hz tapping. Conclusions: Distractibility and entrainment can be found in PD tremor. The tapping test may not reliably distinguish between PD tremor and functional tremor.

Background: We evaluated the utility of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) in predicting risk of gastrostomy tube (G-tube) insertion in patients with ALS. Methods: We conducted a retrospective study using the Pooled Resource Open-Access ALS Clinical Trials Database. People with ALS, at least two ALSFRS scores, and baseline swallowing subscore >1 were included. G-tube outcome was defined as reaching a swallowing subscore ≤1. Predictors were ALSFRS bulbar subscores (swallowing, speech, salivation). Survival analyses estimated median time to outcome and cumulative probability of outcome within 91 days. Individuals were censored at last ALSFRS score. Results: We included 6,943 participants. Median [95% CI] time to G-tube insertion was 245 [228, 285], 562 [547, 621], and 1,268 [980, 1,926] for baseline swallowing subscores of 2, 3, and 4, respectively. Probability of G-tube insertion was associated with baseline swallowing, speech, and salivation subscores (log-rank test p < 0.0001). For patients who transitioned to a swallowing subscore of 2 or 3, 18.1% [95% CI 16.1, 20.3] and 1.9% [95% CI 1.3, 2.7] required G-tube insertion within 91 days of score transition. Conclusions: ALSFRS bulbar subscores may identify patients at risk of G-tube insertion. Probability of G-tube insertion within 91 days is low if swallowing subscore ≥3.