Removing barriers to accessing medical cannabis for paediatric patients.

Medical cannabis (MC) may offer therapeutic benefits for children with complex neurological conditions and chronic diseases. In Canada, parents, and caregivers frequently report encountering barriers when accessing MC for their children. These include negative preconceived notions about risks and benefits, challenges connecting with a knowledgeable healthcare provider (HCP), the high cost of MC products, and navigating MC product shortages. In this manuscript, we explore several of these barriers and provide recommendations to decision-makers to enable a family-centered and evidence-based approach to MC medicine and research for children.

Medical cannabis in schools: The experiences of caregivers.

Objectives: Implementing medical cannabis (MC) into a child's daily routine can be challenging and there is a lack of guidance for its therapeutic use in schools in Canada. Our objective was to learn about the experiences of caregivers of school-aged children who require MC. Methods: Qualitative description was used and caregivers were interviewed about MC in schools and in general. The transcripts were entered into Dedoose software for qualitative analysis and content analysis was performed. Sentences and statements were ascribed line by line into meaning units and labelled with codes, and organized according to categories and subcategories. Results: Twelve caregivers of school-aged children who take MC participated. The most common reasons for treatment were drug-resistant epilepsy (DRE), autism, or other developmental disorders. Approximately half of the participants' children (n = 6) took MC during the school day and most (5/6) perceived their experiences to be positive or neutral but reported a lack of knowledge about MC. While data saturation was not reached regarding MC in schools, rich dialogues were garnered about MC in general and three categories were identified: challenges (subcategories stigma, finding an authorizer, cost, dosing, and supply); parents as advocates (subcategories required knowledge, attitudes, skills, and sources of information); and caregiver relief for positive outcomes. Conclusions: Caregivers demonstrate remarkable tenacity despite the many challenges associated with MC use. Education and practice change are needed to ensure that children using MC can benefit from or continue to experience its positive outcomes within the school environment and beyond.

The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study.

BACKGROUND: Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctance to recommend Cannabis extracts given the lack of high quality safety data especially regarding the potential for harm caused by other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC). The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life. METHODS: Twenty-eight children with treatment resistant epileptic encephalopathy ranging in age from 1 to 10 years will be recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal extract on the frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between dose escalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state trough levels of bioactive cannabinoids. (iv) To determine the relation between dose escalation and incidence of adverse effects. DISCUSSION: This paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids. TRIAL REGISTRATION: http://clinicaltrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited 2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827.

Cannabinoids Used for Medical Purposes in Children and Adolescents: A Systematic Review and Meta-Analysis.

Importance: Cannabinoids are increasingly used for medical purposes in children. Evidence of the safety of cannabinoids in this context is sparse, creating a need for reliable information to close this knowledge gap. Objective: To study the adverse event profile of cannabinoids used for medical purposes in children and adolescents. Data Sources: For this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO, and the Cochrane Library were searched for randomized clinical trials published from database inception to March 1, 2024, for subject terms and keywords focused on cannabis and children and adolescents. Search results were restricted to human studies in French or English. Study Selection: Two reviewers independently performed the title, abstract, and full-text review, data extraction, and quality assessment. Included studies enrolled at least 1 individual 18 years or younger, had a natural or pharmaceutical cannabinoid used as an intervention to manage any medical condition, and had an active comparator or placebo. Data Extraction and Synthesis: Two reviewers performed data extraction and quality assessment independently. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and PRISMA-S guideline were used. Data were pooled using a random-effects model. Main Outcomes and Measures: The primary outcome was the incidence of withdrawals, withdrawals due to adverse events, overall adverse events, and serious adverse events in the cannabinoid and control arms. Secondary outcomes were the incidence of specific serious adverse events and adverse events based on organ system involvement. Results: Of 39 175 citations, 23 RCTs with 3612 participants were included (635 [17.6%] female and 2071 [57.3%] male; data not available from 2 trials); 11 trials (47.8%) included children and adolescents only, and the other 12 trials (52.2%) included children, adolescents, and adults. Interventions included purified cannabidiol (11 [47.8%]), nabilone (4 [17.4%]), tetrahydrocannabinol (3 [13.0%]), cannabis herbal extract (3 [13.0%]), and dexanabinol (2 [8.7%]). The most common indications were epilepsy (9 [39.1%]) and chemotherapy-induced nausea and vomiting (7 [30.4%]). Compared with the control, cannabinoids were associated with an overall increased risk of adverse events (risk ratio [RR], 1.09; 95% CI, 1.02-1.16; I2 = 54%; 12 trials), withdrawals due to adverse events (RR, 3.07; 95% CI, 1.73-5.43; I2 = 0%; 14 trials), and serious adverse events (RR, 1.81; 95% CI, 1.21-2.71; I2 = 59%; 11 trials). Cannabinoid-associated adverse events with higher RRs were diarrhea (RR, 1.82; 95% CI, 1.30-2.54; I2 = 35%; 10 trials), increased serum levels of aspartate aminotransferase (RR, 5.69; 95% CI, 1.74-18.64; I2 = 0%; 5 trials) and alanine aminotransferase (RR, 5.67; 95% CI, 2.23-14.39; I2 = 0%; 6 trials), and somnolence (RR, 2.28; 95% CI, 1.83-2.85; I2 = 8%; 14 trials). Conclusions and Relevance: In this systematic review and meta-analysis, cannabinoids used for medical purposes in children and adolescents in RCTs were associated with an increased risk of adverse events. The findings suggest that long-term safety studies, including those exploring cannabinoid-related drug interactions and tools that improve adverse event reporting, are needed.

A multi-centre, tolerability study of a cannabidiol-enriched Cannabis Herbal Extract for chronic headaches in adolescents: The CAN-CHA protocol.

INTRODUCTION: Cannabis products have been used in the management of headaches in adults and may play a role in pediatric chronic pain. Canadian pediatricians report increasing use of cannabis for the management of chronic headaches, despite no well-controlled studies to inform its dosing, safety, and effectiveness. The aim of our clinical trial is to determine the dosing and safety of a Cannabidiol (CBD)-enriched Cannabis Herbal Extract (CHE) for the treatment of chronic headaches in adolescents. METHODS AND ANALYSIS: Youth, parents, and an expert steering committee co-designed this tolerability study. Twenty adolescents (aged 14 to 17 years), with a chronic migraine diagnosis for more than 6 months that has not responded to other therapies will be enrolled into an open label, dose escalation study across three Canadian sites. Study participants will receive escalating doses of a CBD-enriched CHE (MPL-001 with a THC:CBD of 1:25), starting at 0.2-0.4 mg/kg of CBD per day and escalating monthly up to 0.8-1.0 mg/kg of CBD per day. The primary objective of this study is to determine the safety and tolerability of CBD-enriched CHE in adolescents with chronic migraine. Secondary objectives of this study will inform the development of subsequent randomized controlled trials and include investigating the relationship between the dose escalation and change in the frequency of headache, impact and intensity of pain, changes in sleep, mood, function, and quality of life. Exploratory outcomes include investigating steady-state trough plasma levels of bioactive cannabinoids and investigating how pharmacogenetic profiles affect cannabinoid metabolism among adolescents receiving CBD-enriched CHE. DISCUSSION: This protocol was co-designed with youth and describes a tolerability clinical trial of CBD-enriched CHE in adolescents with chronic headaches that have not responded to conventional therapies. This study is the first clinical trial on cannabis products in adolescents with chronic headaches and will inform the development of future comparative effectiveness clinical trials. TRIAL REGISTRATION: CAN-CHA trial is registered with ClinicalTrials.gov with a number of register NCT05337033.

New presentation of CLIFAHDD syndrome with a novel variant in NALCN gene: A report of a rare case.

Key Clinical Message: Congenital Contractures of Limbs and Face, Hypotonia, and Developmental Delay (CLIFAHDD) syndrome is a recently described type of distal arthrogryposis which unlike other subtypes is associated with developmental delay and various neurologic presentation. Epilepsy and ataxia have been reported. We add paroxysmal dyskinesia to the clinical spectrum. Understanding the molecular mechanism can help developing targeted therapy in future. Abstract: This study resulted in identification of a novel variant in NALCN gene leading to autosomal dominant CLIFAHDD syndrome. Our patient presented with a form of nonepileptic paroxysmal dyskinesia. This is a new phenotype that has not been described previously.

Are Ketamine Infusions a Viable Therapeutic Option for Refractory Neonatal Seizures?

Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist that works by binding to the phencyclidine-binding site, thereby blocking influx of cations through the NMDA receptor channel. The use of ketamine to treat refractory status epilepticus in adults and older children is well documented. Maturational changes in neonatal NMDA and γ-aminobutyric acid receptor expression and function make NMDA receptor antagonists, like ketamine, attractive potential therapeutic agents for treatment of refractory seizures in the newborn. However, descriptions of its use in this age group are limited to two case reports. Concerns regarding potential ketamine-mediated neurotoxicity in the immature brain require further investigation.

Cannabis for Pediatric Epilepsy.

Epilepsy is a chronic disease characterized by recurrent unprovoked seizures. Up to 30% of children with epilepsy will be refractory to standard anticonvulsant therapy, and those with epileptic encephalopathy can be particularly challenging to treat. The endocannabinoid system can modulate the physiologic processes underlying epileptogenesis. The anticonvulsant properties of several cannabinoids, namely Δ-tetrahydrocannabinol and cannabidiol (CBD), have been demonstrated in both in vitro and in vivo studies. Cannabis-based therapies have been used for millennia to treat a variety of diseases including epilepsy. Several studies have shown that CBD, both in isolation as a pharmaceutical-grade preparation or as part of a CBD-enriched cannabis herbal extract, is beneficial in decreasing seizure frequency in children with treatment-resistant epilepsy. Overall, cannabis herbal extracts appear to provide greater efficacy in decreasing seizure frequency, but the studies assessing cannabis herbal extract are either retrospective or small-scale observational studies. The two large randomized controlled studies assessing the efficacy of pharmaceutical-grade CBD in children with Dravet and Lennox-Gastaut syndromes showed similar efficacy to other anticonvulsants. Lack of data regarding appropriate dosing and pediatric pharmacokinetics continues to make authorization of cannabis-based therapies to children with treatment-resistant epilepsy challenging.

Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study.

Purpose: There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy. We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study. Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 Δ9-tetrahydrocannabinol (THC): CBD up to 10-12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (Css, Min) of selected cannabinoids were quantified. Results: All seven participants tolerated the CHE up to 10-12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. CSS, Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. CSS, Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, CSS, Min levels of THC remained lower than what would be expected to cause intoxication. Conclusion: The preliminary data suggest an initial CBD target dose of 5-6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.

Tuberous sclerosis with open lipped schizencephaly.

Tuberous sclerosis is a multisystem disorder that is transmitted in an autosomal dominant fashion. It affects approximately 1 in 10,000 live births. A growing body of evidence implicates a defect of cell maturation and migration in the pathogenesis of many of the lesions in tuberous sclerosis affecting the central nervous system. There have been numerous case reports of various abnormalities of neuronal migration associated with tuberous sclerosis. To our knowledge, there has only been one case of schizencephaly reported in a patient with tuberous sclerosis. The present report describes a male with tuberous sclerosis and an extensive open lipped schizencephalic cleft affecting his right frontoparietal lobe. This case supports the hypothesis that the cerebral lesions in tuberous sclerosis are secondary to a defect in neuronal maturation and migration.

Successful Treatment of Paroxysmal Movement Disorders of Infancy With Dimenhydrinate and Diphenhydramine.

BACKGROUND: Paroxysmal movement disorders including paroxysmal tonic upward gaze of infancy and paroxysmal dystonia of infancy are benign but uncommon movement disorders seen in young children. Although symptoms are intermittent and resolve spontaneously, they can cause discomfort and distress for the child. Current treatment options are limited to dopaminergic agents or anticonvulsants with limited efficacy. PATIENT DESCRIPTION: The authors present a child with paroxysmal tonic upward gaze of infancy and another with paroxysmal dystonia of infancy, both of whom responded successfully to treatment with low-dose dimenhydrinate or diphenhydramine, respectively. DISCUSSION: Dimenhydrinate and diphenhydramine both exert anticholinergic activity and have limited toxicity at low doses. This property makes either compound an attractive therapeutic option for paroxysmal movement disorders in infancy. These agents are generally well tolerated.

Atypical presentations of leigh syndrome: a case series and review.

Patients with Leigh syndrome classically present in early childhood with developmental regression, ataxia, and hypotonia with subsequent respiratory and brainstem dysfunction. However, the clinical presentation can be highly variable. This report presents five cases of Leigh syndrome with atypical presentations. The first patient is a 17-month-old female who presented with progressive limb weakness diagnosed as Guillain-Barre syndrome. Postmortem examination demonstrated Leigh syndrome confined to the spinal cord. The case series then describes two sisters one of whom presented at 11 years of age with central respiratory failure and encephalopathy. Her 15-year-old sister presented with a progressive diplegia. The fourth patient presented with bronchiolitis and apnea at 3 months of age due to bilateral brainstem lesions. Her second cousin presented at 6 months of age with hypotonia, blindness, and tonic seizures. All patients had laboratory and radiologic findings consistent with Leigh syndrome. Evidence of spinal cord involvement was observed on magnetic resonance imaging in four of the five patients. Leigh syndrome can involve any level of the neuroaxis, resulting in a wide variety of presentations. Many atypical variants are observed, of which clinicians should be aware. Evidence of brainstem or spinal cord involvement should also be sought in patients with Leigh syndrome.