Cannabis for pediatric epilepsy : protocol for a living systematic review
Jesse Elliott, Deirdre DeJean, Tammy Clifford, Doug Coyle, Beth Potter, Becky Skidmore, Christine Alexander, Alexander E. Repetski, Bláthnaid McCoy and George A. Wells
Systematic Reviews, 2018, 7, 95
doi : 10.1186/s13643-018-0761-2
Abstract
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
Keywords : Pediatric epilepsy, Cannabis, Cannabinoids, Cannabidiol, Seizure, Efficacy, Safety, Living systematic review, Meta-analysis
Background
Interest in the use of cannabis for pediatric epilepsy has grown over the last decade, driven in part by media reports of children whose treatment-resistant epilepsy has responded to cannabis [1]. The well-publicized case of Charlotte Figi, whose parents started her on medical cannabis at age 5, is not unique [2], and many parents of children with treatment-resistant epilepsy have reported turning to alternative treatments [3], both with and without the aid of medical professionals. In particular, parents of children with treatment-resistant epilepsy (an inadequate response to two or more adequate trials of antiepileptic drugs [4]), which affects between 28 and 37% of people with epilepsy [5], have expressed great interest in the use of cannabis for the treatment of their children’s epilepsy [3]. Indeed, pediatric treatment-resistant epilepsy has potentially catastrophic consequences, including cognitive delay, behavioral problems, autism, poor quality of life, and early death [6–9].
Despite the recorded medicinal use of cannabis dating back to the second century BCE [10], there has been relatively little research into its effectiveness or safety, likely owing to its illegal status in many jurisdictions. In adults, cannabis has been reported to be effective in the treatment of nausea and vomiting due to chemotherapy, chronic pain, spasticity associated with multiple sclerosis, sleep disorders, and Tourette syndrome, with inconclusive evidence for its use in appetite stimulation in patients with HIV/AIDS, anxiety disorders, and glaucoma [11]. There is relatively little clinical evidence to support the use of cannabis in the treatment of pediatric epilepsy, and there are large discrepancies between the beliefs of health care professionals and the general public with respect to its effectiveness and safety [12]. A 2014 Cochrane review of the use of cannabinoids for the treatment of epilepsy
included four small low-quality randomized controlled trials (RCTs), none of which involved children [13]. At the time of this review, the authors concluded that there was insufficient evidence to make reliable conclusions about the efficacy or long-term safety of cannabinoids for the treatment of epilepsy [13]. However, the evidence base in this area is changing rapidly, and recently published studies have suggested a beneficial effect of cannabis in this population [14, 15], although the mechanisms underlying this response are not clear [16].
The use of cannabis in the treatment of pediatric epilepsy is an ideal topic for a living systematic review because it is a priority for decision-making, there is little certainty in the existing evidence base, and there is rapidly accumulating evidence [17]. Living systematic reviews are a relatively new approach to continually updating systematic reviews, with new evidence being incorporated as it becomes available
[17]. Unlike traditional systematic review updates, which may be undertaken infrequently, living systematic reviewers search for new studies at a priori-defined intervals and follow a set protocol for determining whether updated analysis and publication are warranted. At present, 37 studies involving the use of various forms of cannabis for the treatment of pediatric epilepsy are registered in ClinicalTrials.gov, suggesting that there will be an abundance of new data in the coming years.
In this living systematic review, we will comprehensively search the published and gray literature for studies that have evaluated the benefits and harms of cannabis for pediatric epilepsy. The results of our review will be of use to parents, clinicians, and policy makers in making treatment decisions for children with epilepsy.
Methods/design
This systematic review protocol has been submitted to PROSPERO (CRD42018084755) and follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement (Additional file 1) [18].
Patient involvement
Two family members of children with epilepsy were involved in selecting the outcome measures for inclusion in this systematic review and are co-authors of this protocol (CA, AR).
Search strategy
A search of the published and gray literature will be performed by an experienced medical information specialist to identify studies involving the use of cannabis for the treatment of pediatric epilepsy. The search strategy was developed in consultation with an experienced medical information specialist and the research team (Additional file 2). The search will be peer-reviewed by another librarian by use of the Peer Review of Electronic Search Strategies (PRESS) checklist [19]. Using the OVID platform, we will search Ovid MEDLINE®, including Epub Ahead of Print and In-Process & Other Non-Indexed Citations, Embase Classic + Embase, and PsycINFO. We will also search the Cochrane Library on Wiley. The search strategies will use a combination of controlled vocabulary (e.g., “Epilepsy”, “Cannabinoids”, “Medical Marijuana”) and keywords (e.g., “seizure”, “cannabis”, “THC”). Vocabulary and syntax will be adjusted across databases. No date or language restrictions will be imposed. Gray literature will be searched by use of CADTH’s Gray Matters Light [20], Google Scholar, the clinical trials registries ClinicalTrials.gov, and the ICTRP Search Portal of the World Health Organization.
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