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.

POLR3A variants with striatal involvement and extrapyramidal movement disorder.

Biallelic variants in POLR3A cause 4H leukodystrophy, characterized by hypomyelination in combination with cerebellar and pyramidal signs and variable non-neurological manifestations. Basal ganglia are spared in 4H leukodystrophy, and dystonia is not prominent. Three patients with variants in POLR3A, an atypical presentation with dystonia, and MR involvement of putamen and caudate nucleus (striatum) and red nucleus have previously been reported. Genetic, clinical findings and 18 MRI scans from nine patients with homozygous or compound heterozygous POLR3A variants and predominant striatal changes were retrospectively reviewed in order to characterize the striatal variant of POLR3A-associated disease. Prominent extrapyramidal involvement was the predominant clinical sign in all patients. The three youngest children were severely affected with muscle hypotonia, impaired head control, and choreic movements. Presentation of the six older patients was milder. Two brothers diagnosed with juvenile parkinsonism were homozygous for the c.1771-6C > G variant in POLR3A; the other seven either carried c.1771-6C > G (n = 1) or c.1771-7C > G (n = 7) together with another variant (missense, synonymous, or intronic). Striatal T2-hyperintensity and atrophy together with involvement of the superior cerebellar peduncles were characteristic. Additional MRI findings were involvement of dentate nuclei, hila, or peridentate white matter (3, 6, and 4/9), inferior cerebellar peduncles (6/9), red nuclei (2/9), and abnormal myelination of pyramidal and visual tracts (6/9) but no frank hypomyelination. Clinical and MRI findings in patients with a striatal variant of POLR3A-related disease are distinct from 4H leukodystrophy and associated with one of two intronic variants, c.1771-6C > G or c.1771-7C > G, in combination with another POLR3A variant.

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.

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.

Cannabis for the treatment of paediatric epilepsy? An update for Canadian paediatricians.

The plant Cannabis sativa produces over 140 known cannabinoids. These chemicals generate considerable interest in the medical research community for their possible application to several intractable disease conditions. Recent reports have prompted parents to strongly consider Cannabis products to treat their children with drug resistant epilepsy. Physicians, though, are reluctant to prescribe Cannabis products due to confusion about their regulatory status and limited clinical data supporting their use. We provide the general paediatrician with a brief review of cannabinoid biology, the literature regarding their use in children with drug resistant epilepsy, the current Health Canada and Canadian Paediatric Society recommendations and also the regulations from the physician regulatory bodies for each province and territory. Given the complexities of conducting research on Cannabis products for children with epilepsy, we also discuss outstanding research objectives that must be addressed to support Cannabis products as an accepted treatment option for children with refractory epilepsy.

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.

Neonatal seizures: diagnosis and management.

The recognition of epileptic seizures in newborns is challenging as neonates exhibit a variety of paroxysmal motor phenomena, some epileptic but others not. The distinction, frequently requiring video-EEG monitoring, is crucial for management. Causes are often multi-factorial, specific to country/region, and change over time. Hypoxia-ischemia and infection are still common in both developed and developing countries. Venous and arterial strokes are being increasingly recognized. Treatable conditions, including inborn errors of metabolism, must be anticipated and considered early in the course. Etiology is the principal determinant of outcome. Management is based on uncontrolled studies and expert opinions. Information on neonatal seizures is reviewed, and suggestions for management provided. Phenobarbital remains the first anti-epileptic drug of choice, worldwide. Pharmacogenetic information and hepatic or renal dysfunction will influence doses of all drugs. The toxicity of excipients present in intravenous medicines should be kept in mind, especially when infusions are given to critically ill neonates. Therapeutic trials with pyridoxine or ideally pyridoxal phosphate, folinic acid and biotin should be considered early, if seizures are intractable. The management of electrographic seizures without clinical seizures needs critical study. When anti-epileptic drug treatment is required, maintenance should be for a short duration if seizures are of an acute symptomatic nature.

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.

The Concept of an Epilepsy Brain Bank.

Epilepsy comprises more than 40 clinical syndromes affecting millions of patients and families worldwide. To decode the molecular and pathological framework of epilepsy researchers, need reliable human epilepsy and control brain samples. Brain bank organizations collecting and supplying well-documented clinically and pathophysiologically tissue specimens are important for high-quality neurophysiology and neuropharmacology studies for epilepsy and other neurological diseases. New development in molecular mechanism and new treatment methods for neurological disorders have evoked increased demands for human brain tissue. An epilepsy brain bank is a storage source for both the frozen samples as well as the formaldehyde fixed paraffin embedded (FFPE) tissue from epilepsy surgery resections. In 2014, the University of Saskatchewan have started collecting human epilepsy brain tissues for the first time in Canada. This review highlights the necessity and importance of Epilepsy Brain bank that provides unique access for research to valuable source of brain tissue and blood samples from epilepsy patients.

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.

Nonepileptic motor phenomena in the neonate.

The newborn infant is prone to clinical motor phenomena that are not epileptic in nature. These include tremors, jitteriness, various forms of myoclonus and brainstem release phenomena. They are frequently misdiagnosed as seizures, resulting in unnecessary investigations and treatment with anticonvulsants, which have potentially harmful side effects. Unfortunately, there is a paucity of literature about many of these phenomena in the newborn, and some of the major textbooks refer to these events as nonepileptic seizures, leading to further confusion for the practitioner. The present paper aims to review these phenomena with special emphasis on differentiating them from epileptic seizures, and offers information on treatment and prognosis wherever possible.

Efficient Hemorrhage Control Skills Training for Healthcare Employees.

BACKGROUND: Several national initiatives are aimed at training citizens to assist bleeding victims. The purpose of this study was to evaluate an effort to quickly and efficiently teach basic bleeding control techniques to a clinical and nonclinical workforce. STUDY DESIGN: The research study was conducted at 4 hospitals in a mid-sized metropolitan area. In spring 2017, the trauma department at a Level I trauma center set an ambitious goal to provide hands-on training to 1,000 employees during the course of 6 weeks. Trainings occurred in small groups and lasted approximately 6 to 10 minutes, during which time participants were taught and practiced 2 skills: packing a wound and holding direct pressure, and applying a stretch-wrap-and-tuck tourniquet. Participants completed pre- and post-surveys indicating their likelihood to use these skills. RESULTS: More than 1,000 individuals were trained, and there were survey data for 870 participants. More than 40% of participants worked in nonclinical roles and 29% had no first aid or medical training. After completing skills training, 98% of participants indicated that they would be likely to take action to assist a bleeding victim and that they could correctly apply direct pressure or a tourniquet to control severe bleeding. CONCLUSIONS: Results demonstrate that basic hemorrhage control skills can be taught to clinical and nonclinical people in brief, hands-on training. Efforts like this can be deployed across large workplace environments to prepare the maximum number of employees to take action to assist bleeding victims.

Experience of psychogenic nonepileptic seizures in the Canadian league against epilepsy: A survey describing current practices by neurologists and epileptologists.

PURPOSE: Psychogenic nonepileptic seizures (PNES) are one of the most common differential diagnoses of epilepsy. Our objective is to describe current medical care in Canada and identify patterns of practice and service gaps. METHODS: In 2015, a 36-question survey was sent via email to the 131 members of the Canadian League Against Epilepsy. The questions were designed after literature review and discussion with the ILAE PNES Task Force. Questions were separated into 5 sections: 1) the role of the respondent and their exposure to PNES, 2) diagnostic methods, 3) management of PNES, 4) etiological factors, and 5) problems accessing health care. RESULTS: Sixty-two questionnaires were analyzed (response rate: 47%). Most respondents were epileptologists (76%). The majority of respondents personally diagnosed PNES and communicated the diagnosis to the patient, but only 55% provided follow-up within their practice and only 50% recommended or arranged treatment. Many (35%) were either unfamiliar with the diagnosis of PNES or inexperienced in arranging or offering treatment. Most (79%) provided follow-up to patients with concomitant epilepsy, but when PNES was the sole diagnosis follow-up rates were low. Although 84% of respondents felt that individualized psychological therapy was the most effective treatment, 40% of patients were not referred to psychotherapy and in most cases availability such therapy was low (30-60%). CONCLUSIONS: Canadian health professionals' understanding of PNES mostly reflects current international expert opinion. Once diagnosis is made however, the majority of patients are discharged from neurological services without appropriate psychological care.

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.

Hashimoto Encephalopathy Presenting With Stroke-Like Episodes in an Adolescent Female: A Case Report and Literature Review.

BACKGROUND: Hashimoto encephalopathy is a rare form of encephalopathy thought to be of autoimmune etiology. Cognitive changes and seizures are the most commonly reported presenting manifestation. Stroke-like episodes have also been documented in these individuals. We describe a rare adolescent with Hashimoto encephalopathy who presented with stroke-like symptoms. PATIENT DESCRIPTION: A previously well 15-year-old girl experienced sudden-onset language disturbance and right hemiparesis. Her symptoms resolved, but weeks later, she began experiencing refractory seizures, episodes of status epilepticus, and cognitive decline. An extensive evaluation was unremarkable, but thyroid peroxidase antibodies were elevated, and a diagnosis of Hashimoto encephalitis was made. Steroid therapy was initiated, and her symptoms resolved with return to baseline cognitive function. CONCLUSION: Hashimoto encephalopathy is a highly treatable condition that may be considered in the differential diagnosis of children and adolescents presenting with stroke-like symptoms.