Cannabis for refractory epilepsy in children: A review focusing on CDKL5 Deficiency Disorder

Dale, Tristan; Downs, Jenny; Olson, Heather E.; Bergin, Ann M.; Smith, Stephanie; Leonard, Helen

doi:10.1016/j.eplepsyres.2019.02.001

Cited by 21 publications

(14 citation statements)

References 97 publications

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“…Children are most detrimentally affected by refractory epilepsy, as they are not only at increased risk of death due to seizure-related accidents and respiratory infections, but they also have impaired neurodevelopment that might be caused by underlying epileptogenic processes, independent of the seizures themselves [54]. Refractory epilepsy affects approximately 10–20% of minors with epilepsy, and it can have devastating implications for their education, cognitive function, and social activities [55]. Families of affected epileptic individuals have advocated for alternative solutions, such as the use of medical cannabis, as many cases of refractory epilepsy prove to be resistant to current treatment options [3].…”

Section: Cannabinoids Are An Emerging Treatment For Drug-resistantmentioning

confidence: 99%

The Interplay between the Endocannabinoid System, Epilepsy and Cannabinoids

Cheung

Peiris

Wallace

et al. 2019

IJMS

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Epilepsy is a neurological disorder that affects approximately 50 million people worldwide. There is currently no definitive epilepsy cure. However, in recent years, medicinal cannabis has been successfully trialed as an effective treatment for managing epileptic symptoms, but whose mechanisms of action are largely unknown. Lately, there has been a focus on neuroinflammation as an important factor in the pathology of many epileptic disorders. In this literature review, we consider the links that have been identified between epilepsy, neuroinflammation, the endocannabinoid system (ECS), and how cannabinoids may be potent alternatives to more conventional pharmacological therapies. We review the research that demonstrates how the ECS can contribute to neuroinflammation, and could therefore be modulated by cannabinoids to potentially reduce the incidence and severity of seizures. In particular, the cannabinoid cannabidiol has been reported to have anti-convulsant and anti-inflammatory properties, and it shows promise for epilepsy treatment. There are a multitude of signaling pathways that involve endocannabinoids, eicosanoids, and associated receptors by which cannabinoids could potentially exert their therapeutic effects. Further research is needed to better characterize these pathways, and consequently improve the application and regulation of medicinal cannabis.

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Section: Cannabinoids Are An Emerging Treatment For Drug-resistantmentioning

confidence: 99%

The Interplay between the Endocannabinoid System, Epilepsy and Cannabinoids

Cheung

Peiris

Wallace

et al. 2019

IJMS

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“…Our findings of epileptic discharges in Cdkl5 -/y mouse pups at P12, therefore could be temporally relevant to the time window of seizure onset in children with CDD, in terms of KCC2 expression. Given that children with CDD are often not responsive to AEDs or responding without long-term efficacy (Muller et al, 2016;Dale et al, 2019;Olson et al, 2019), the KCC2 activators could be a potential alternatives for CDD treatment based on our findings.…”

Section: Discussionmentioning

confidence: 68%

Deficiency of cyclin-dependent kinase-like 5 causes spontaneous epileptic seizures in neonatal mice

Liao

Lee

et al. 2020

Preprint

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Number of pages (37)• Number of figures (7), tables (1), multimedia (2), and 3D models (0)• Number of words for abstract (237), introduction (507), and discussion (1278) 2 Abstract Cyclin-dependent kinase-like 5 (CDKL5), an X-linked gene encoding a serine-threonine kinase, is enriched in the mammalian forebrain and critical for neuronal maturation and synaptic function. Mutations in this gene cause CDKL5 deficiency disorder (CDD) that is characterized by early-onset epileptic seizures, autistic behaviors and intellectual disability. Although numerous CDD symptoms have been recapitulated in mouse models, spontaneous seizures have not been reported in mice with CDKL5 deficiency.Here, we present the first systematic study of spontaneous seizures in a mouse model of CDD. Through wireless electroencephalographic (EEG) recording and simultaneous videotaping, we observed epileptiform discharges accompanied with ictal behaviors in pups lacking CDKL5 at a selective time window during the pre-weaning period. The seizure-like patterns of EEG showed robust increase in total number of spike events, the total number and duration of bursts in Cdkl5 null pups compared to wild-type littermate controls at the age of postnatal day 12 (P12). The mutants displayed not only jerky and spasm-like movements during the prolonged bursts of discharges at P12, but also strengthened ictal grasping in both juvenile stage and adulthood. In addition, loss of CDKL5 remarkably reduced the phosphorylation of K + /Clco-transporter 2, which may impede GABA-mediated inhibition, in the cortex of P12 mouse pups. Our study reveals previously unidentified phenotypes of early-onset seizures in CDKL5-deficient mice, highlights the translational value of mouse models of CDD and provides a potential molecular target for early diagnosis and treatment for CDD.3 Significance StatementCyclin-dependent kinase-like 5 (CDKL5) is an X-linked gene encoding a serinethreonine kinase. Mutations in this gene cause CDKL5 deficiency disorder (CDD), a rare disease characterized by developmental delays, autistic behaviors and early-onset epilepsy. Even though many symptoms of CDD patients have been phenocopied in mice, spontaneous seizures are yet to be reported in mouse models of CDD. Here, for the first time, we identified early-onset seizures and ictal behaviors in neonatal pups of CDKL5deficient mice. Loss of CDKL5 also selectively reduced protein levels of phosphorylated K+/Cl-cotransporter 2 in neonatal cortex of mice. Our study reveals an indispensible role of CDKL5 in regulating neuronal excitability in developing brains and highlights the translational significance of the CDD mouse models.6

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“…17 Epileptic encephalopathies are usually associated with DRE and seizures can be difficult to control with the available treatment options including antiepileptic drugs, KGD, and neurostimulation therapies. 18 This highlights the importance of developing novel treatment options to overcome the burden of epilepsy, and genotype-driven precision medicine brings hope. Some patients, who once thought to have untreatable diseases, are getting better care and more effective therapies.…”

Section: Discussionmentioning

confidence: 99%

GRIN2A-Related Severe Epileptic Encephalopathy Treated with Memantine: An Example of Precision Medicine

2019

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Epileptic spasm (ES) is one of the seizure types which is difficult to treat. Next-generation sequencing has facilitated rapid gene discovery that is linked to ES and GRIN2A being one of them. Genotype-driven precision medicine is on the horizon and is a targeted treatment approach toward the precise molecular cause of the disease. GRIN2A gene encodes for a subunit of N-methyl-D-aspartate (NMDA) receptor and it has been suggested from in vitro studies and few case reports that memantine, a NMDA receptor antagonist, was shown to reduce seizures in patients with GRIN2A mutations. Here, we describe a patient with a novel GRIN2A mutation and severe drug-resistant ES who became seizure free with memantine.

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Cannabis for refractory epilepsy in children: A review focusing on CDKL5 Deficiency Disorder

Cited by 21 publications

References 97 publications

The Interplay between the Endocannabinoid System, Epilepsy and Cannabinoids

The Interplay between the Endocannabinoid System, Epilepsy and Cannabinoids

Deficiency of cyclin-dependent kinase-like 5 causes spontaneous epileptic seizures in neonatal mice

GRIN2A-Related Severe Epileptic Encephalopathy Treated with Memantine: An Example of Precision Medicine

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