Cannabis for refractory epilepsy in children : a review focusing on CDKL5 Deficiency Disorder
Tristan Dale, Jenny Downs, Heather Olson, Ann Marie Bergin, Stephanie Smith and Helen Leonard
Epilepsy Research, 2019
Severe paediatric epilepsies such as CDKL5 Deficiency Disorder (CDD) are extremely debilitating, largely due to the early-onset and refractory nature of the seizures. Existing treatment options are often ineffective and associated with a host of adverse effects, causing those that are affected to seek alternative treatments. Cannabis based products have attracted significant attention over recent years, primarily driven by reports of miraculous cures and a renewed public preference for ‘natural’ therapies, thus placing intense pressure on health professionals and the government for regulatory change. This study provides a comprehensive overview of the potential role for cannabis in the treatment of CDD. Key areas discussed include the history, mechanism of action, efficacy and safety of cannabis based preparations as well as the burden related to CDD. The evidence supports the use of cannabinoids, especially cannabidiol, in similar forms of refractory epilepsy including Dravet and Lennox-Gastaut syndromes. Evidence for cannabinoids specifically in CDD is limited but growing, with multiple anecdotal reports and an open-label trial showing cannabidiol to be associated with a significant reduction in seizure activity. This review provides the first comprehensive overview of the potential role for cannabis based preparations in the treatment of CDD and provides justification for further clinical and observational research.
Key Words : CDKL5 Deficiency Disorder; cannabis; cannabidiol; paediatric; epilepsy; encephalopathy
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 non-remitting, refractory epilepsy. These nonremitting forms are typically characterised by seizures that are poorly responsive to available treatment options including antiepileptic drugs, the ketogenic diet, high doses of steroids, and neurostimulation therapies (Granata et al., 2009). Patients with these forms of severe, refractory epilepsy are at increased risk of mortality due to accidents, sudden unexpected death in epilepsy as well as respiratory infections (French, 2007; Laxer et al., 2014). These seizure related accidents occur at high frequency, particularly in those who are mobile, and include lacerations, head injury, burns and dental injuries (Wirrell, 2006). Adding to this burden is the extensive impairment of neurodevelopment caused by the underlying epileptogenic processes, which appears to be independent of the seizures themselves (Laxer et al., 2014). One of the most debilitating forms of treatment-resistant epilepsy is CDKL5 Deficiency Disorder (CDD) – a genetic epilepsy characterised by early-onset intractable seizures, global developmental delay, profound hypotonia and severe impairment in gross motor skills (Mangatt et al., 2016). This early onset encephalopathy is also associated with poorer child health including sleep disturbances, respiratory and gastrointestinal issues, which in turn contribute to the severe impact of this disorder that extends beyond individuals affected, causing reduced parental wellbeing and poorer quality of life for affected families (Fehr et al., 2013; Mori et al., 2017). Since seizures in CDD are often resistant to available medication, dietary, and neurostimulation therapies in isolation, a combination of treatments is regularly trialled, often with little effect. Indeed, the polytherapy of these treatments may even exacerbate the cognitive, psychiatric, and motor deficiencies that are associated with the underlying condition (Cramer et al., 2010; Perucca and Gilliam, 2012). Additionally, they may introduce a host of adverse systemic effects including sedation, somnolence, distractibility, hyperactivity, insomnia, and dizziness (Aldenkamp et al., 2016; Perucca and Gilliam, 2012). Even in the absence of adverse effects on neurological examination, the use of multiple treatment options may cause a worsening of perceived quality of life, cognitive deficits and behavioural problems (Lagae, 2006). Therefore, there is urgent need for safer and more effective antiseizure therapies for CDD and other refractory epilepsies in children. In recent years, this has led patients and families to seek alternatives for seizure control, such as medicinal cannabis. Cannabis treatments for epilepsy have been the subject of prominent attention in the community, primarily driven by the appeal of a ‘natural’ product and anecdotal reports of miracle cures (Maa and Figi, 2014; McLaren et al., 2008). This public pressure has encouraged rapid legislative and regulatory changes. However, scientific evidence on the safety and efficacy of cannabinoids in refractory epilepsy is essential before this can be considered a potential mainstream treatment. Despite the growing interest in cannabis for the treatment of refractory epilepsy, there has been no comprehensive review of the evidence for cannabis based preparations in the treatment of CDD. Therefore, this article aims to provide a thorough narrative review of the history, mechanism of action, efficacy and safety of medicinal cannabis preparations for childhood onset refractory epilepsy, with a focus on CDD.