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School of Epidemiology and Public Health, University of Ottawa, 600 Peter Morand Crescent, Ottawa, Ontario, CanadaCardiovascular Research Methods Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada
Department of Paediatrics, University of Toronto, Toronto, Ontario, CanadaDivision of Neurology, the Hospital for Sick Children Toronto, Toronto, Ontario, Canada
School of Epidemiology and Public Health, University of Ottawa, 600 Peter Morand Crescent, Ottawa, Ontario, CanadaCardiovascular Research Methods Centre, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada
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.
] and the number of studies assessing its benefits and harms has grown in parallel. In 2018, we initiated a living systematic review (LSR) of cannabis-based products for pediatric epilepsy [
]. LSRs search for newly available studies at a priori-defined intervals, allowing evidence to be incorporated into the review shortly after it becomes available. [
], we identified 23 studies, the findings of which supported a beneficial role for cannabis-based products, particularly cannabidiol (CBD), in reducing seizures among children with drug-resistant epilepsy. At that time, we also identified 33 ongoing studies, signalling that the evidence base would continue to evolve.
In this updated review, we incorporated studies published in the year following the baseline review, thus providing an up-to-date overview of the evidence base.
]. The baseline review encompassed studies published up to April 2018; the present update is current to May 9, 2019. Briefly, we searched Ovid MEDLINE, Embase, PsycINFO, and the Cochrane Library (Appendix 1), as well as ClinicalTrials.gov and ICTRP Search Portal. Two independent reviewers (J.E., D.D.) selected randomized controlled trials (RCTs) and non-randomized studies (NRS) involving children with epilepsy who were administered a cannabis-based product, compared to pharmacologic treatment (i.e., antiepileptic drugs), non-pharmacologic treatment (e.g., diet therapy, vagus nerve stimulation), placebo, usual care, or no treatment. The primary outcome was seizure freedom; secondary outcomes were seizure frequency (total, tonic-clonic, ≥50 % reduction from baseline), quality of life (QoL), sleep, status epilepticus, death, gastrointestinal adverse events (vomiting, diarrhea), and emergency room (ER) visits. Risk of bias (RoB) and certainty of the evidence was assessed (GRADE criteria) [
] Data from RCTs were pooled by random-effects meta-analyses and are reported as relative risk (RR), risk difference (RD), mean difference (MDs), or median difference with 95 % confidence intervals (CIs). Data from NRS are reported as the percentage of participants who experienced an outcome. Data were not pooled if there was substantial clinical or statistical heterogeneity (i.e., I2 >75 %). Data from the longest duration of follow-up were analyzed.
3. Results
Thirty-five studies have assessed the benefits and harms of cannabis-based treatments in children with epilepsy (4 RCTs [
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
Long-term safety and efficacy of cannabidiol in children and adults with treatmentresistant Lennox-Gastaut syndrome or Dravet syndrome: expanded access program results.
Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.
], home-made extracts,46] or “artisanal” products.20] All studies involved cannabis added to an established regimen of antiepileptic therapies; no studies involved first-line treatment. Treatment duration ranged from 10 days to 146 weeks (RCTs up to 14 wk). All RCTs involved children with Dravet or Lennox-Gastaut syndrome (LGS), while NRS enrolled a wider range of drug-resistant epilepsy syndromes and participant characteristics (Appendix 4). All RCTs were considered low RoB; NRS were at high RoB, owing primarily to lack of a control group and unblinded outcome assessment (Appendix 6). In the following sections, data are summarized for all participants; data pertaining specifically to Dravet and LGS are presented in Appendix 7.
Fig. 1PRISMA flow diagram showing selection of studies. *Includes 35 unique studies (4 randomized controlled trials, 31 non-randomized studies) available as published studies or as clinical trial records with available data.
Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.
],) have reported seizure freedom with cannabis treatment; an additional 3 studies reported that no children became seizure free (Table 1, Appendix 8). Among children with Dravet syndrome (61) who received CBD in one 14-wk RCT, [
] 5 % became seizure free, compared with none in the placebo group (n = 59; RD 5 %, 95 %CI –1 % to 11 %; low certainty). Among NRS, 8 % (95 %CI 5%–10%) became seizure free with cannabis treatment (duration: 14 d to 53 mo; very low certainty).
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
]) assessed seizure frequency (Appendix 9). Total monthly seizures were reduced by CBD compared to placebo in the RCTs (median reduction 19.8 %, 95 %CI 27.0%–12.6 %; duration: 14 wk; moderate certainty), as well as by cannabis-based products in the NRS (30%–90%; duration: 11 d to 96 wk duration; very low certainty). Data from NRS suggest that the effects are maintained through at least 48 weeks of treatment in some children [
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
]) assessed the impact of cannabis-based products on childhood QoL (Appendix 10); no studies have assessed the effect on caregivers. Evidence from three 14-wk RCTs involving children with Dravet and LGS [
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
], there was no statistically significant difference in sleep between CBD and placebo (MD –0.3, 95 %CI –0.8 to 0.2; moderate certainty). Improved sleep was reported in six NRS [
Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.
], with a higher proportion reported in cross-sectional studies22,25,35,46] (74 %, 95 %CI 54%–94%) compared with retrospective cohort studies (8 %, 95 %CI 4%–11%) (duration: 2 wk to 57 mo; very low certainty). Impaired sleep was reported in six NRS,21,31,32,36,39,46] affecting 3 % (95 %CI 1%–6%) of children who received a cannabis-based product (duration: 10 d to 53 mo; very low certainty).
3.5 Status epilepticus
Status epilepticus was reported in eleven studies (three RCTs, [
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
]) among children who received a cannabis-based product (Appendix 12). In the RCTs, there was no statistically significant difference in the frequency of status epilepticus among children with Dravet or LGS who received CBD or placebo for 14 weeks [
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
] (RR 1.39, 95 %CI 0.55–3.47; low certainty). Among NRS, 7 % (95 %CI 4%–9%) of children who received a cannabis-based product experienced status epilepticus, with higher rates reported among children with Dravet [
] who received more than 20 mg/kg/d of CBD compared to 20 mg/kg/d (median duration: 263, 274 d).
3.6 Death
Twenty-six deaths, including seven owing to sudden unexpected death in epilepsy, have been reported among 1713 children who received a cannabis-based treatment (Appendix 13) in 10 studies (one RCT, [
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.
]; Appendix 14). Risk of diarrhea was higher among those who received CBD compared to placebo (RR 2.25, 95 %CI 1.38–3.68; low certainty) despite no overall significant difference in gastrointestinal adverse events. In the NRS, gastrointestinal adverse events have been reported for 2 %–60 % of participants who received a cannabis-based product (vomiting: 3 %–40 %; diarrhea: 2 %–35 %), with high heterogeneity between studies.
] reported no statistically significant difference in the monthly rate of visits per child before or during cannabis treatment (12-wk treatment). Sands and colleagues [
] reported that, of children who had an ER visit during the 6-month baseline period, all had fewer visits during the treatment period (4–53 mo).
4. Discussion
This updated review incorporating studies published up to May 2019, reflecting a 52 % increase in the evidence base in the previous year. This is an active area of research, and clinicians require up-to-date evidence summaries on which to base treatment decisions. The findings of newly available studies were consistent with earlier studies, although the certainty of evidence did not change for any outcome, and no new RCTs were published during the update period. We identified an additional 32 clinical studies that have yet to report results (Appendix 16), including six RCTs, suggesting that further evidence will be available for future updates of this LSR. Because the certainty of the evidence is currently low for most outcomes, additional evidence may change the effect estimates and give clinicians more confidence in the effects of cannabis-based treatments in this population. Importantly, ongoing studies may provide data for longer treatment durations, helping us to better understand the long-term effects of cannabis-based products.
4.1 Limitations
First, most available evidence is from NRS, all of which are at risk of important sources of bias, primarily related to study design (e.g., lack of a comparison group, unblinded outcome assessment), and the certainty of the evidence from such studies is very low. Second, most studies have involved Epidiolex (purified pharmaceutical-grade CBD), and may not be generalizable to other cannabis-based products (e.g. CBD-THC cannabis oil). Third, most studies have involved participants with Dravet or LGS, and less is known about the effects on other epilepsy syndromes. Fourth, the treatment duration of the included studies was variable, ranging from 10 days to 146 weeks, with evidence from RCTs available only up to 14 weeks of treatment. The long-term effects of these products have not been evaluated in long-term randomized studies.
4.2 Conclusion
Newly available studies support CBD as an effective treatment option for reducing the frequency of seizures among children with drug-resistant epilepsy. Products containing both CBD and THC may also be effective; however, most available evidence pertains to pharmaceutical-grade CBD alone. This is an active area of research, and future updates will include additional evidence as it becomes available.
Author’s contributions
JE, TC, DC, BP, CA, AR, BM and GW designed the study. BS developed and executed the search strategy. JE and DD selected studies for inclusion and extracted data. JE analyzed the data and wrote the first draft of the manuscript, which was critically revised for intellectual content by all authors. All authors approved the final version submitted for publication.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of Competing Interest
Bláthnaid McCoy is principal investigator in a study of cannabinoids for Dravet syndrome. Alexander Repetski is director of communications at a licensed cannabis producer. Deirdre DeJean is an employee of CADTH; this work was unrelated to her employment and was not funded by CADTH. The remaining authors have no conflicts of interest.
Appendix A. Supplementary data
The following is Supplementary data to this article:
Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
Long-term safety and efficacy of cannabidiol in children and adults with treatmentresistant Lennox-Gastaut syndrome or Dravet syndrome: expanded access program results.
Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.
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