The Epilepsy Surgery Experience in Children With Infantile Epileptic Spasms Syndrome at a Tertiary Care Center in Canada.

Background: Infantile epileptic spasms syndrome is an epileptic encephalopathy, characterized by spasms, hypsarrhythmia, and developmental regression. Appropriately selected patients with infantile epileptic spasms syndrome may be candidates for epilepsy surgery. Methods: This is a single-center retrospective case series of children 0-18 years with a current or previous diagnosis of infantile epileptic spasms syndrome with a lesion on magnetic resonance imaging (MRI) and/or positron emission tomography scan who underwent epilepsy surgery at The Hospital for Sick Children (HSC) in Toronto, Canada. The records of 223 patients seen in the infantile epileptic spasms syndrome clinic were reviewed. Results: Nineteen patients met inclusion criteria. The etiology of infantile epileptic spasms syndrome was encephalomalacia in 6 patients (32%), malformations of cortical development in 12 patients (63%), and atypical hypoglycemic injury in 1 patient (5%). Nine patients (47%) underwent hemispherectomy, and 10 patients (53%) underwent lobectomy/lesionectomy. Three patients (16%) underwent a second epilepsy surgery. Fifteen patients (79%) were considered ILAE seizure outcome class 1 (completely seizure free; no auras) at their most recent follow-up visit. The percentage of patients who were ILAE class 1 at most recent follow-up decreased with increasing duration of epilepsy prior to surgery. Developmental outcome after surgery was improved in 14 of 19 (74%) and stable in 5 of 19 (26%) patients. Conclusions: Our study found excellent seizure freedom rates and improved developmental outcomes following epilepsy surgery in patients with a history of infantile epileptic spasms syndrome with a structural lesion detected on MRI brain. Patients who undergo surgery earlier have improved seizure freedom rates and improved developmental outcomes.

The Phenotypic Spectrum of Tuberous Sclerosis Complex: A Canadian Cohort.

OBJECTIVE: We aimed to further elucidate the phenotypic spectrum of Tuberous Sclerosis Complex (TSC) depending on genotype. METHODS: A retrospective review of patients seen in the TSC clinic at the Hospital for Sick Children was conducted and the frequency of TSC manifestations was compared based on genotype. RESULTS: Nineteen-patients had TSC1 mutations, 36 had TSC2 mutations and 11 had no mutation identified (NMI). Patients with TSC2 mutations had a higher frequency of early-onset epilepsy and more frequent systemic manifestations. The NMI group had milder neurologic and systemic manifestations. Our data did not demonstrate that intellectual disability and infantile spasms were more common in TSC2 mutations. CONCLUSIONS: This is the first Canadian pediatric cohort exploring the genotype-phenotype relationship in TSC. We report that some manifestations are more frequent and severe in TSC2 mutations and that NMI may have a milder phenotype. Disease surveillance and counseling should continue regardless of genotype until this is better elucidated.

Barriers in accessing medical cannabis for children with drug-resistant epilepsy in Canada: A qualitative study.

INTRODUCTION: The use of medical cannabis to treat drug-resistant epilepsy in children is increasing; however, there has been limited study of the experiences of parents with the current system of accessing medical cannabis for their children. METHODS: In this qualitative study, we used a patient-centered access to care framework to explore the barriers faced by parents of children with drug-resistant epilepsy when trying to access medical cannabis in Canada. We conducted semistructured interviews with 19 parents to elicit their experiences with medical cannabis. We analyzed the data according to five dimensions of access, namely approachability, acceptability, availability, affordability, and appropriateness. RESULTS: Parents sought medical cannabis as a treatment because of a perceived unmet need stemming from the failure of antiepileptic drugs to control their children's seizures. Medical cannabis was viewed as an acceptable treatment, especially compared with adding additional antiepileptic drugs. After learning about medical cannabis from the media, friends and family, or other parents, participants sought authorization for medical use. However, most encountered resistance from their child's neurologist to discuss and/or authorize medical cannabis, and many parents experienced difficulty in obtaining authorization from a member of the child's existing care team, leading them to seek authorization from a cannabis clinic. Participants described spending up to $2000 per month on medical cannabis, and most were frustrated that it was not eligible for reimbursement through public or private insurance programs. CONCLUSIONS: Parents pursue medical cannabis as a treatment for their children's drug-resistant epilepsy because of a perceived unmet need. However, parents encounter barriers in accessing medical cannabis in Canada, and strategies are needed to ensure that children using medical cannabis receive proper care from healthcare professionals with training in epilepsy care, antiepileptic drugs, and medical cannabis.

Neurologists' perspectives on medical cannabis for pediatric drug-resistant epilepsy in Canada: A qualitative interview study.

PURPOSE: To understand the experiences with and perspectives of neurologists about the use of medical cannabis in the treatment of pediatric drug-resistant epilepsy. METHODS: In this qualitative study, we interviewed neurologists who provide care to children with drug-resistant epilepsy in Canada. Through semi-structured telephone interviews, we sought participants' views about and experiences with medical cannabis for the treatment of drug-resistant epilepsy in children. Here we present a thematic summary of the interviews. RESULTS: The 12 interviewed neurologists generally perceived medical cannabis as a viable treatment option for children with drug-resistant epilepsy; however, participants identified important gaps in the evidence and implications for their practices. Six themes were generated from the content of the interviews: learning about medical cannabis; perceptions about medical cannabis; discussing medical cannabis with parents; experiences with medical cannabis authorization; barriers to authorizing medical cannabis; and the impact of medical cannabis on clinical care. Of note, while some neurologists took on all aspects of the children's care, including medical cannabis, others referred interested families to non-neurology health care professionals. CONCLUSION: Our findings highlight the diverse opinions and experiences of neurologists in Canada with medical cannabis for the treatment of drug-resistant epilepsy in children, including with the authorization process and caring for children using medical cannabis. Additional education about medical cannabis may be warranted, in order to better prepare neurologists to have informed and open conversations with parents about this treatment option and to provide care for children using medical cannabis.

Economic Evaluation of Cannabinoid Oil for Dravet Syndrome: A Cost-Utility Analysis.

INTRODUCTION: Cannabinoid oils are being increasingly used to treat Dravet syndrome, yet the long-term costs and outcomes of this approach are unknown. Thus, we examined the cost effectiveness of cannabinoid oil as an adjunctive treatment (added to clobazam and valproate), compared with adjunctive stiripentol or with clobazam and valproate alone, for the treatment of Dravet syndrome in children. METHODS: We performed a probabilistic cost-utility analysis from the perspective of the Canadian public health care system, comparing cannabinoid oil and stiripentol (both on a background of clobazam and valproate) with clobazam and valproate alone. Costs and quality-adjusted life-years (QALYs) were estimated using a Markov model that followed a cohort of children aged from 5 to 18 years through model states related to seizure frequency. Model inputs were obtained from the literature. The cost effectiveness of adjunctive cannabinoid oil, adjunctive stiripentol, and clobazam/valproate alone was assessed through sequential analysis. The influence of perspective and other assumptions were explored in scenario analyses. All costs are expressed in 2019 Canadian dollars, and costs and QALYs were discounted at a rate of 1.5% per year. RESULTS: The incremental cost per QALY gained with the use of adjunctive cannabinoid oil, from the health care system perspective, was $32,399 compared with clobazam and valproate. Stiripentol was dominated by cannabinoid oil, producing fewer QALYs at higher costs. At a willingness-to-pay threshold of $50,000, cannabinoid oil was the optimal treatment in 76% of replications. From a societal perspective, cannabinoid oil dominated stiripentol and clobazam/valproate. The interpretation of the results was insensitive to model and input assumptions. CONCLUSION: Compared with clobazam/valproate, adjunctive cannabinoid oil may be a cost-effective treatment for Dravet syndrome, if a decision maker is willing to pay at least $32,399 for each QALY gained. The opportunity costs of continuing to fund stiripentol, but not cannabinoid oil, should be considered.

The effect of mTOR inhibition on obstructive hydrocephalus in patients with tuberous sclerosis complex (TSC) related subependymal giant cell astrocytoma (SEGA).

PURPOSE: Mammalian target of rapamycin inhibitors (mTORi) are known to effectively reduce the size of subependymal giant cell astrocytomas (SEGAs), which are benign brain lesions associated with Tuberous Sclerosis Complex (TSC) that commonly cause obstructive hydrocephalus (OH). This retrospective case series reviews an institutional experience of the effect of mTORi on OH in patients with TSC-related SEGA. METHODS: Thirteen of 16 identified patients with TSC-related SEGA treated with mTORi from October 2007 to December 2018 were included. Serial magnetic resonance imaging (MRI) and clinical charts were reviewed to correlate symptoms and signs of increased intracranial pressure (iICP) with ventriculomegaly on MRI. A proposed ventriculomegaly scale was used: none (< 7 mm), mild (7-10 mm), moderate (11-30 mm), and severe (> 30 mm). OH was defined as moderate or severe ventriculomegaly, based on the largest measurement. RESULTS: Patients' median age at start of mTORi was 13 (6-17) years and five (38%) patients were female. Eight patients had OH at the time of mTORi initiation, five of whom were asymptomatic. Six patients had improvement of hydrocephalus on serial MRI imaging with mTORi therapy, while seven patients had no change based on the ventriculomegaly scale used. All three patients who presented with symptoms of iICP and had OH also had papilledema. None had worsening of hydrocephalus or required shunt placement. Out of five patients with symptoms of iICP, four avoided surgery. CONCLUSION: Most patients had asymptomatic OH at the time of diagnosis, and ventricular enlargement was not correlated with iICP symptoms. mTORi was successful for treatment of OH from TSC-related SEGA, even in the setting of acute symptoms of iICP.

A Review of Investigations for Patients With Tuberous Sclerosis Complex Who Were Referred to the Tuberous Sclerosis Clinic at The Hospital for Sick Children: Identifying Gaps in Surveillance.

OBJECTIVE: As a newly established tuberous sclerosis clinic (TSC) clinic at The Hospital for Sick Children, we reviewed our referrals to determine if children with TSC received appropriate surveillance as advised by the 2012 International Tuberous Sclerosis Complex Consensus Recommendations. METHODS: We completed a retrospective review of all patients seen in the TSC clinic from January 2016 to December 2017 to determine if children referred to the clinic had appropriate surveillance as suggested by the Tuberous Sclerosis Complex Consensus Recommendations. RESULTS: Ninety patients were seen in the TSC clinic. The median age at first visit was 9.9 years, and 47 were males. Seventy-six percent had undergone genetic testing before the initial clinic visit; however, genetic counseling was completed in only 66%. Brain magnetic resonance imaging was completed in 94%, abdominal imaging was completed in 91%, and an echocardiography and electrocardiography in 88% and 83%, respectively. In addition, dermatology and ophthalmology evaluations were completed in 78% and 91%, respectively. Assessment of TSC-associated neuropsychiatric disorders (TAND) was only completed in 4% of the patients. CONCLUSIONS: Systems surveillance was completed in the majority before the first TSC clinic visit. However, TSC-associated neuropsychiatric disorder screening was completed in few cases. This suggests that referring physicians may not be familiar with the neuropsychiatric manifestations of TSC and that there may be underdiagnosed or undertreated illness. Future emphasis should be placed on educating all practitioners to assess and treat tuberous sclerosis complex-associated neuropsychiatric disorder in tuberous sclerosis complex.

Cannabis-based products for pediatric epilepsy: An updated systematic review.

PURPOSE: To provide an up-to-date summary of the benefits and harms of cannabis-based products for epilepsy in children. METHODS: We updated our earlier systematic review, by searching for studies published up to May 2019. We included randomized controlled trials (RCTs) and non-randomized studies (NRS) involving cannabis-based products administered to children with epilepsy. Outcomes were seizure freedom, seizure frequency, quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and emergency room visits. RESULTS: Thirty-five studies, including four RCTs, have assessed the benefits and harms of cannabis-based products in pediatric epilepsy (12 since April 2018). All involved cannabis-based products as adjunctive treatment, and most involved cannabidiol. In the RCTs, there was no statistically significant difference between cannabidiol and placebo for seizure freedom (relative risk 6.77, 95 % confidence interval [CI] 0.36-128.38), quality of life (mean difference [MD] 0.6, 95 %CI -2.6 to 3.9), or sleep disruption (MD -0.3, 95 %CI -0.8 to 0.2). Data from both RCTs and NRS suggest that cannabidiol reduces seizure frequency and increases treatment response; however, there is an increased risk of gastrointestinal adverse events. CONCLUSION: Newly available evidence supports earlier findings that cannabidiol probably reduces the frequency of seizures among children with drug-resistant epilepsy. PROSPERO: CRD42018084755.

Retinal defect in children with infantile spasms of varying etiologies: An observational study.

OBJECTIVE: To determine the prevalence of retinal defect in children with infantile spasms (IS) unrelated to treatment with vigabatrin and clarify if specific primary etiologies for IS are associated with retinal defect more than others. METHODS: This was an observational cohort study including 312 patients (176 male, 136 female) with IS who were vigabatrin-naive. Participants ranged from 1.7 to 34.7 months of age (mean 8.8 months). Electroretinograms (ERGs) were performed according to the International Society for Clinical Electrophysiology of Vision. Retinal defect was identified as abnormal if the 30-Hz flicker ERG amplitude was lower than the age-corrected normal 95% prediction interval. The primary etiology for IS, as determined by the treating pediatric neurologist(s), was obtained from patient health records and classified into 1 of 9 etiologic subgroups: (1) genetic disorders alone, (2) genetic-structural disorders, (3) structural-congenital, (4) structural-acquired (perinatal), (5) structural-acquired (postnatal), (6) metabolic disorders, (7) immunologic disorders, (8) infectious, and (9) unknown causes. RESULTS: Fifty-nine of the 312 vigabatrin-naive children (18.9%) showed retinal defect and the prevalence of retinal defect was highest (24.4%) in the structural-acquired (perinatal) subgroup, which included hypoxic-ischemic defect. Retinal function compared across subgroups showed no significant difference. CONCLUSIONS: Care is required in diagnosing retinal toxicity, which would be enhanced by baseline flicker ERG in children with IS prior to starting vigabatrin.

Position Statement on the Use of Medical Cannabis for the Treatment of Epilepsy in Canada.

In Canada, recreational use of cannabis was legalized in October 2018. This policy change along with recent publications evaluating the efficacy of cannabis for the medical treatment of epilepsy and media awareness about its use have increased the public interest about this agent. The Canadian League Against Epilepsy Medical Therapeutics Committee, along with a multidisciplinary group of experts and Canadian Epilepsy Alliance representatives, has developed a position statement about the use of medical cannabis for epilepsy. This article addresses the current Canadian legal framework, recent publications about its efficacy and safety profile, and our understanding of the clinical issues that should be considered when contemplating cannabis use for medical purposes.

Énoncé de position quant à l'utilisation du cannabis médical dans le traitement de l'épilepsie. L'utilisation du cannabis à des fins récréatives a été légalisée au Canada en octobre 2018. Parallèlement à ce changement de politique, de récentes publication visant à évaluer l'efficacité du cannabis dans le traitement de l'épilepsie, de même qu'une sensibilisation médiatique accrue en ce qui concerne son utilisation, ont eu pour effet d'augmenter l'intérêt du grand public à son égard. Le Comité médical thérapeutique de la Ligue canadienne contre l'épilepsie (LCCE), de concert avec un groupe multidisciplinaire d'experts et des représentants de l'Alliance canadienne de l'épilepsie, a ainsi élaboré un énoncé de position en ce qui regarde l'utilisation du cannabis médical dans le traitement de l'épilepsie. Cet article entend donc aborder le cadre légal qui prévaut actuellement au Canada et examiner de récentes publications s'étant penchées sur le profil sécuritaire et sur l'efficacité du cannabis. De plus, nous voulons apporter un éclairage au sujet des aspects cliniques dont il faudrait tenir compte au moment d'envisager l'utilisation du cannabis à des fins médicales.

Decision Models for Assessing the Cost Effectiveness of Treatments for Pediatric Drug-Resistant Epilepsy: A Systematic Review of Economic Evaluations.

BACKGROUND: Drug-resistant epilepsy affects about one-third of children with epilepsy and is associated with high costs to the healthcare system, yet the cost effectiveness of most treatments is unclear. Use of cannabis-based products for epilepsy is increasing, and the cost effectiveness of such strategies relative to conventional pharmacologic treatments must be considered. OBJECTIVE: The objective of this systematic review was to identify economic evaluations of cannabis-based treatments for pediatric drug-resistant epilepsy. We also sought to identify and appraise decision models that have been used in economic evaluations of pharmacologic treatments (i.e., antiepileptic drugs) in this population. METHODS: Electronic searches of MEDLINE, EMBASE, and the Cochrane library, as well as a targeted grey literature search, were undertaken (11 June 2018). Model-based full economic evaluations involving cannabis-based treatments or pharmacologic treatments for drug-resistant epilepsy in children were eligible for inclusion. Two independent reviewers selected studies for inclusion, and study quality was assessed by use of the Drummond and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklists. Study findings, as well as model characteristics, are narratively summarized. RESULTS: Nine economic evaluations involving children with drug-resistant epilepsy were identified; however, none involved cannabis-based treatments. All studies involved pharmacologic treatments compared with other pharmacologic treatments or non-pharmacologic treatments (i.e., ketogenic diet, epilepsy surgery, vagus nerve stimulation). Few studies have assessed the cost effectiveness of pharmacologic treatments in specific drug-resistant epilepsy syndromes, including Dravet and Lennox-Gastaut syndromes. Five included studies involved use of Markov models with a similar structure (i.e., health states based on seizure frequency relative to baseline). There was a wide range of methodological quality, and few studies fully addressed context-specific issues such as weight gain and treatment switching. CONCLUSION: Whether cannabis-based treatments for pediatric drug-resistant epilepsy represent good value for money has yet to be investigated. Economic evaluations of such treatments are needed and should address issues of particular importance in pediatric epilepsy, including weight gain over time, switching or discontinuation of treatments, effectiveness of interventions and comparators, and long-term effectiveness beyond the duration of available clinical studies. PROSPERO REGISTRATION: CRD42018099591.

Cost-effectiveness of cannabinoids for pediatric drug-resistant epilepsy: protocol for a systematic review of economic evaluations.

BACKGROUND: Drug-resistant epilepsy negatively impacts the quality of life and is associated with increased morbidity and mortality and high costs to the healthcare system. Cannabis-based treatments may be effective in reducing seizures in this population, but whether they are cost-effective is unclear. In this systematic review, we will search for cost-effectiveness analyses involving the treatment of pediatric drug-resistant epilepsy with cannabis-based products to inform decision-making by public healthcare payers about reimbursement of such products. We will also search for cost-effectiveness analyses of other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as estimates of healthcare resource use, costs, and utilities, for use in a subsequent cost-utility analysis to address this decision problem. METHODS: We will search the published and gray literature for economic evaluations of cannabis-based products and other pharmacologic treatments for pediatric drug-resistant epilepsy, as well as resource utilization and utility studies. Two independent reviewers will screen the title and abstract of each identified record and the full-text version of any study deemed potentially relevant. Study and population characteristics, the incremental cost-effectiveness ratio (ICER), as well as total costs and benefits, will be extracted, and quality will be assessed by use of the Drummond and CHEERS checklists; context-specific issues will also be considered. From model-based cost-utility and cost-effectiveness analyses, we will extract and summarize the model structure, including health states, time horizon, and cycle length. From resource utilization studies, we will extract data about the frequency of resource use (e.g., neurology visits, emergency department visits, admissions to hospital). From utility studies, we will extract the utility for each health state, the source of the preferences (e.g., child, parent, patient, general public), and the method of elicitation. DISCUSSION: Drug-resistant epilepsy in children is associated with important costs to the healthcare system, and decision-makers require high-quality evidence on which to base reimbursement decisions. The results of this review will be useful to both decision-makers considering the decision problem of whether to reimburse cannabis-based products through public formularies and to analysts conducting studies in this area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO no.: CRD42018099591 .

Cannabis-based products for pediatric epilepsy: A systematic review.

OBJECTIVE: To assess the benefits and harms of cannabis-based products for pediatric epilepsy. METHODS: We identified in this living systematic review randomized controlled trials (RCTs) and nonrandomized studies (NRSs) involving children with epilepsy treated with cannabis-based products. We searched MEDLINE, Embase, PsycINFO, Cochrane Library, and gray literature (April 25, 2018). The primary outcome was seizure freedom; secondary outcomes were seizure frequency (total, ≥50% reduction), quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and visits to the emergency room. Data were pooled by random-effects meta-analysis. Risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome. RESULTS: Four RCTs and 19 NRSs were included, primarily involving cannabidiol. All RCTs were at low risk of bias, whereas all NRSs were at high risk. Among RCTs, there was no statistically significant difference between cannabidiol and placebo in seizure freedom (relative risk [RR] = 6.77, 95% confidence interval [CI] = 0.36-128.38; 1 RCT), quality of life (mean difference = 0.6, 95% CI = -2.6 to 3.9; 3 RCTs), sleep disruption (mean difference = -0.3, 95% CI = -0.8 to 0.2; 3 RCTs), or vomiting (RR = 1.00, 95% CI = 0.51-1.96; 4 RCTs). There was a statistically significant reduction in the median frequency of monthly seizures with cannabidiol compared with placebo (-19.8%, 95% CI = -27.0% to -12.6%; 3 RCTs) and an increase in the number of participants with at least a 50% reduction in seizures (RR = 1.76, 95% CI = 1.07-2.88; 1 RCT) and diarrhea (RR = 2.25, 95% CI = 1.38-3.68; 3 RCTs). Death and status epilepticus were infrequently reported. SIGNIFICANCE: Evidence from high-quality RCTs suggests that cannabidiol probably reduces seizures among children with drug-resistant epilepsy (moderate certainty). At this time, the evidence base is primarily limited to cannabidiol, and these findings should not be extended to all cannabis-based products.

The role of surgery in refractory epilepsy secondary to polymicrogyria in the pediatric population.

OBJECTIVE: Polymicrogyria (PMG) is a common malformation of cortical development. Many patients with PMG will have medically refractory epilepsy but the role of epilepsy surgery is unclear. The objective of this study was to assess the efficacy of surgical resection/disconnection in achieving seizure control in pediatric patients with PMG. METHODS: A retrospective review of children undergoing epilepsy surgery for PMG between 2002 and 2017 at The Hospital for Sick Children in Toronto, Canada, was performed. RESULTS: A total of 12 children aged 6 months to 17.8 years (median 8.8 years) underwent resective surgery (7 children) or functional hemispherectomy (5 children). Gross total resection or complete disconnection of PMG was carried out in 7 of 12 children. Follow-up duration was between 1 and 9 years (median 2.1 years). Nine children remained seizure-free at last follow-up. Complete resection or disconnection of PMG led to seizure freedom in 6 of 7 patients (86%), whereas subtotal resection produced seizure freedom in 3 of 5 patients (60%). SIGNIFICANCE: We present one of the largest surgical series of pediatric PMG patients. Seizure outcomes were best with complete resection/disconnection of PMG. However, tailored resections based on electroclinical and neuroradiologic data can produce good outcomes and remain an appropriate strategy for patients with extensive PMG.

A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome.

INTRODUCTION: Both Δ9 Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects. Cannabis oils are used to treat seizures in drug-resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy. Primary objective was to establish dosing and tolerability of TIL-TC150 - a cannabis plant extract produced by Tilray®, containing 100 mg/mL CBD and 2 mg/mL THC- in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life. METHODS: Twenty children received add-on therapy with TIL-TC150. The dose ranged from 2 to 16 mg/kg/day of CBD and 0.04 to 0.32 mg/kg/day of THC. Patients were monitored for tolerability and adverse events, and secondary objectives. RESULTS: Nineteen participants completed the 20-week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14-0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%. CONCLUSIONS: TIL-TC150 was safe and well tolerated in our subjects. TIL-TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC-containing cannabinoid preparations.

Intra-operative cortical motor mapping using subdural grid electrodes in children undergoing epilepsy surgery evaluation and comparison with the conventional extra-operative motor mapping.

OBJECTIVES: The objective of this study was to review our experience with intra-operative "train of five" stimulation using subdural grid for motor mapping in children undergoing epilepsy surgery evaluation. METHODS: Twenty consecutive children below 18-years of age with drug-refractory epilepsy who underwent invasive-EEG monitoring using subdural-grid placement and intra-operative motor mapping using direct cortical stimulation by sub-dural grid electrodes (IODCS-SDG) at our institution between January-2016 and June-2017 were reviewed. Stimulation was delivered through the subdural-grid electrodes using a train-of-five pulses and muscle responses were recorded by motor-evoked-potentials (MEPs). Intra-operative direct cortical stimulation delivered through a ball-tipped probe (IODCS-probe) and extra-operative motor-mapping (EODCS-SDG) were also performed. RESULTS: IODCS-SDG was completed in 20 patients and subsequent EODCS-SDG was done in 17/20 patients. MEP responses were more commonly obtained in the deltoid (19/20), extensor-digitorum-communis (20/20) and first-dorsal-interosseus (19/20). The median thresholds varied between 40 V and 60 V for the six muscle groups. The respective IODCS-probe thresholds tended to be similar. No stimulation-provoked seizures or anaesthesia-related complications were noted during IODCS-SDG. EODCS-SDG could not be completed in 4/17 children and mapping data obtained was frequently inadequate. Nine patients demonstrated 100% concordance between IODCS-SDG and EODCS-SDG for the common mapped body regions. Stimulation-provoked seizures during EODCS-SDG were seen in 6/17 (35.3%) and after-discharges in 7/17 (41.2%) children. CONCLUSIONS: IODCS-SDG could be performed safely in children with drug refractory epilepsy undergoing invasive EEG monitoring. SIGNIFICANCE: IODCS-SDG may be a useful adjunct to EODCS-SDG in motor mapping for children.

Cannabis for pediatric epilepsy: protocol for a living systematic review.

BACKGROUND: Pediatric epilepsy, including treatment-resistant forms, has a major effect on the quality of life, morbidity, and mortality of affected children. Interest has been growing in the use of medical cannabis as a treatment for pediatric epilepsy, yet there has been no comprehensive review of the benefits and harms of cannabis use in this population. In this systematic review, we will search for, synthesize, and assess the published and gray literature in order to provide usable and relevant information to parents, clinicians, and policy makers. METHODS: We will perform a living systematic review of studies involving the use of cannabis to treat pediatric epilepsy. We will search the published and gray literature for studies involving children with any type of epilepsy taking any form of cannabis. Studies will be selected for inclusion by two independent reviewers. The primary outcome is seizure freedom. Secondary outcomes are seizure frequency, quality of life (child, caregiver), quality and quantity of sleep, status epilepticus, tonic-clonic seizures, death (all-cause, sudden unexpected death in epilepsy), gastrointestinal adverse events (diarrhea, vomiting), and visits to the emergency room. The quality of each included study will be assessed. If data are sufficient in quantity and sufficiently similar, we will conduct pairwise random-effects meta-analysis. We will repeat the literature search every 6 months to identify studies published after the previous search date. Sequential meta-analysis will be performed as necessary to update the review findings. DISCUSSION: Our review aims to provide a comprehensive and up-to-date summary of the available evidence to inform decisions about the use of cannabis in children with treatment-resistant epilepsy. The results of this review will be of use to parents, clinicians, and policy makers as they navigate this rapidly evolving area. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018084755.

Economic Evaluation of Stiripentol for Dravet Syndrome: A Cost-Utility Analysis.

BACKGROUND: Dravet syndrome is a catastrophic form of pediatric treatment-resistant epilepsy with few effective treatment options. Stiripentol is approved for use in Canada for treatment of Dravet syndrome, but the associated long-term costs and benefits have not been well-studied and its cost effectiveness is unclear. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of stiripentol as an adjunctive treatment to clobazam and valproate for treatment of Dravet syndrome from the perspective of the Canadian public healthcare payer. METHODS: A cost-utility analysis was performed to estimate the costs and quality-adjusted life-years (QALYs) associated with adjunctive stiripentol treatment compared with clobazam and valproate alone in children with Dravet syndrome. Transition probabilities, drug efficacy, utility weights, and costs were obtained from a review of the literature. Probabilistic analyses were conducted using a Markov model with health states related to seizure frequency. A 10-year horizon was used. The incremental cost per QALY gained (incremental cost-effectiveness ratio [ICER]) for adjunctive use of stiripentol was calculated, and assumptions were explored in scenario analyses. All costs are expressed in 2017 Canadian dollars ($Can). RESULTS: Compared with clobazam and valproate alone, the adjunctive use of stiripentol is associated with an ICER of $Can151,310. At a willingness-to-pay threshold of $Can50,000, the probability that stiripentol was the optimal treatment was 5.2%. The cost of stiripentol would need to be reduced by 61.4% for stiripentol to be cost effective. CONCLUSION: From the perspective of the Canadian public healthcare payer, stiripentol is not cost effective at its current price at a willingness-to-pay threshold of $Can50,000. Funding stiripentol will be associated with important opportunity costs that bear consideration.

Risk factors for surgical site infection after intracranial electroencephalography monitoring for epilepsy in the pediatric population.

OBJECTIVE Intracranial electroencephalography (iEEG) monitoring is an important method of identifying the seizure focus in patients with medically refractory epilepsy. While previous studies have demonstrated low rates of surgical complications, reported rates of surgical site infection (SSI) are highly variable. To date, no studies have specifically evaluated the patient or operative risk factors contributing to SSI. The goals of this study were to examine the rate of SSI after iEEG monitoring for epilepsy workup in pediatric patients and to determine the variables that might contribute to the development of SSI. METHODS A retrospective analysis of hospital charts at the Hospital for Sick Children was performed for all patients who had undergone iEEG monitoring between 2000 and 2016. Univariate and multivariate analyses were performed to look for statistically significant variables in relation to SSI. RESULTS Among 199 patients eligible for analysis, 8 (4.0%) developed SSIs within a period ranging from 21 to 51 days postoperatively. Univariate analysis yielded 4 factors related to SSI: number of people present in the operating room on electrode insertion (p = 0.02), length of insertion surgery (p = 0.04), previous operation at the same surgical site (p = 0.04), and number of depth electrodes inserted (p = 0.01). Multivariate analysis revealed that both the number of people present during the implant operation (OR 0.08, 95% CI 0.01-0.70) and the number of depth electrodes inserted (OR 3.52, 95% CI 1.44-8.59) independently contributed to SSI. CONCLUSIONS This is the largest case series and the first comprehensive review of both patient and operative risk factors in the development of SSI from iEEG monitoring in a pediatric population. The authors' institution had a lower rate of infection than those in most other studies, which could be explained by their protocol of administering intravenous antibiotics perioperatively and post-implant removal antibiotics for 14 days. The authors found a correlation between SSI and the number of people present during the implant operation, as well as the number of depth electrodes; both may contribute to breaks in sterility.

"Saved by the Bell": Near SUDEP during intracranial EEG monitoring.

SUDEP is the sudden unexpected death of a person with epilepsy, when no structural or toxicological cause of death can be found. The majority of witnessed cases are reported to be preceded by a convulsive seizure and postictal hypoventilation. Here, we report an 8-year-old girl with drug-resistant focal seizures secondary to a focal cortical dysplasia type IIb. While undergoing invasive intracranial monitoring with subdural and depth electrodes, she had a clinical apnea event recorded on video, followed by bradycardia, which required resuscitation. Her intracranial electroencephalogram (EEG) during the event showed diffuse slowing and attenuation of cortical activity, with bradycardia that responded to positive pressure ventilation with oxygen. This near SUDEP event was not preceded by either an electroclinical or electrographic seizure. This is the first report of a witnessed, near-SUDEP event during intracranial monitoring. It emphasizes the fact that near-SUDEP can occur without a preceding seizure.