Review articleCannabis for refractory epilepsy in children: A review focusing on CDKL5 Deficiency Disorder
Section snippets
Background
Epilepsy is the most frequent chronic neurological condition in childhood, with approximately 1 in 150 children being diagnosed with a form of epilepsy during the first 10 years of life (Aaberg et al., 2017). The quality of life for many of these patients is becoming increasingly favourable with around 4 in 5 reaching a state of remission at 5 years (Berg and Rychlik, 2015). However, the remaining 1 in 5 may experience repeated cycles of relapse and remission, or otherwise be affected by
The burden of refractory epilepsy in CDKL5 Deficiency Disorder
As defined by the International League Against Epilepsy (ILAE), epileptic encephalopathies are conditions where “the epileptic activity itself may contribute to severe cognitive and behavioral impairments above and beyond what might be expected from the underlying pathology alone, and that these can worsen over time” (Berg et al., 2010). The key concept in this definition is that a genetic mutation may be the underlying cause of the epilepsy, however, the excessive seizure activity may worsen
The history of cannabis in epilepsy
Cannabis is thought to be one of the oldest plants cultivated for human use, with uses in the manufacturing of fibre, rope and textiles dating back as early as 12,000 BCE (Friedman and Sirven, 2017). Since then, cannabis has been used for a variety of industrial applications as well as for both recreational and medical use, as illustrated in Fig. 1 (Zuardi, 2006).
The first historical mention of cannabis for medical use arises from Chinese literature around 2900 BCE, when Chinese Emperor Fu Hsi
Chemistry and mechanism of action of cannabis
Cannabis encompasses a genus of flowering plants, comprising mainly of two species: Cannabis sativa and Cannabis indica (McPartland and Guy, 2017). These complex plants contain over 100 biologically active cannabinoids, with the 2 major compounds best characterised being tetrahydrocannabinol (THC) and cannabidiol (CBD). In the plant, the cannabinoids are synthesised and collected as cannabinoid acids, but when the leaves, stems and flower pods are heated and dried to form ‘marijuana’, the acids
Preclinical evidence for cannabinoid products in epilepsy
There is growing preclinical evidence that supports the involvement of endocannabinoid signalling in early brain development, as well as the role of this system in paediatric epilepsy. Studies have described the anticonvulsant effects of cannabinoids including CBD and cannabidivarin in a variety of preclinical animal models (Hill et al., 2012, Jones et al., 2016). In addition to CBD, the anticonvulsant effects of THC have also been demonstrated in mice (Wallace et al., 2001). This protective
Clinical evidence for cannabinoid products in paediatric epilepsy
In recent years there have been a number of studies investigating the clinical utility of cannabis-derived products in paediatric epilepsy. One open-label prospective cohort study in 2016 of CBD in paediatric drug-resistant epilepsy found a median reduction of monthly motor seizures of 36.5% over 3 months, from a baseline median of 30 seizures to 16 seizures per month (Devinsky et al., 2016). In May 2017, this was expanded with a randomised double-blind placebo-controlled trial investigating
Clinical evidence for cannabis in CDKL5 Deficiency Disorder
There is growing evidence to suggest that cannabis-derived products including CBD likely reduce seizures among populations of children with mixed aetiologies of drug-resistant epilepsy (Elliott et al., 2018, Perucca, 2017). However, it is unclear how applicable this is to aetiologies of refractory epilepsy such as CDD. To date, most of the evidence for medicinal cannabis in CDD is derived from research in similar early-onset epileptic encephalopathies including Dravet syndrome and
Safety of medicinal cannabis products
The acute adverse effects of cannabinoids in patients with treatment-resistant epilepsy are well-documented in randomised controlled and open-label trials and most commonly include somnolence, sedation, diarrhoea, nausea, vomiting and appetite changes (Chen et al., 2018b, Devinsky et al., 2016). Additionally, due to their actions on inflammatory signalling, cannabinoids have been shown to induce apoptosis of certain immune cell populations in vitro, and thus constitute a theoretical risk of
Conclusion and future directions
Refractory epilepsy in children encompasses a vast group of conditions associated with intractable seizures. One of the most debilitating of these refractory epilepsies is CDD – a genetic epilepsy characterised by early-onset seizures activity, profound hypotonia, global developmental delay, and severely impaired gross motor skills (Mangatt et al., 2016). Due to the host of adverse effects and low efficacy of existing treatments, cannabis based interventions are being increasingly sought by
Literature search
The literature search was performed using medical databases EMBASE, the Cochrane Library and Medline. The following key terms were searched in various combinations: ‘cannabinoid’, ‘cannabidiol’, ‘marijuana’, ‘cannabis’, ‘medical marijuana’, ‘tetrahydrocannabinol’, ‘children’, ‘paediatric’, ‘seizure’, ‘epilepsy’, ‘CDKL5’, ‘CDD’. The reference lists of relevant results were manually assessed for potential inclusions. Articles included for review of clinical evidence primarily examined the use of
Funding
Associate Professor Helen Leonard is supported by a NHMRC Senior Research Fellowship [#1117105].
Statement of compliance
We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Declarations of interest
None.
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Cited by (18)
Cannabis use in youth: Consumption and health consequences
2023, Encyclopedia of Child and Adolescent Health, First EditionThe perceived effects of cannabis products in the management of seizures in CDKL5 Deficiency Disorder
2021, Epilepsy and BehaviorCitation Excerpt :While in part, this mismatch between caregiver perception and objective evidence of seizure control may be due to the underpowered nature of this observational study, it raises the possibility of a placebo effect associated with cannabis-based products. In the years leading up to this study, cannabis-based products attracted significant community attention, primarily driven by anecdotes of miraculous cures and a movement of public preference toward 'natural' therapies [9]. The most notable case was that of a 5-year-old girl with Dravet syndrome who went from up to 50 seizures per day, to near seizure freedom after commencing a high concentration CBD:THC product, now known as Charlotte's Web [29].
Exploring quality of life in individuals with a severe developmental and epileptic encephalopathy, CDKL5 Deficiency Disorder
2021, Epilepsy ResearchCitation Excerpt :Similarly, only a quarter of females are able to use any spoken language, signs, or abstract symbols. Lack of response to anti-epileptic medication (Fehr et al., 2016b) often necessitates the need for other therapeutic options such as ketogenic diet (Lim et al., 2017) or vagal nerve stimulation (Lim et al., 2018) whilst there is growing interest in a possible role for medical cannabis (Dale et al., 2019; Olson et al., 2019). Sleep disturbances which have an impact not only on the child but on the whole family can be extreme (Olson et al., 2019) affecting over 80 % of individuals at some point in their life course (Mangatt et al., 2016).
Cell type-specific expression, regulation and compensation of CDKL5 activity in mouse brain
2024, Molecular PsychiatryCannabidiol for the treatment of refractory epilepsy in children: a critical review of the literature
2023, Revista Paulista de Pediatria
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