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Pathophysiology of Dravet syndrome
Cannabis sativa is considered a valuable product in the world of traditional medicine. With the advent of cannabis legalization around the world, pharmaceutical companies now fund research studies investigating the potential benefits of plant-derived cannabinoids in humans. By modulating the cannabinoid receptors’ biochemical activities, orphan receptors, serotonin receptors, and components of the endocannabinoid system, cannabis has shown promising results in the treatment of neurodegenerative diseases, mood disorders, chronic pain, and substance use addiction.
Currently, medical cannabis is only licensed for the management of rare diseases. In regions where medical cannabis is legal, the indication for use in registered patients is for orphan diseases and rare pathological conditions requiring alternative therapy. Dravet syndrome (DS), also known as severe myoclonic epilepsy in infancy (SMEI), qualifies as a rare disease with no definite treatment module. According to publications credited to the National Organization for Rare Disorders, this disease affects an estimated 1 in 15,700 individuals in the United States. DS is a severe form of epileptic encephalopathy triggered by ataxia, hypotonia, hyperthermia, developmental delay, sleep disturbances, and speech impairment.
The pathophysiology of Dravet syndrome is multifactorial and, in most diagnosed cases, associated with a loss-of-function mutation in the SCN1A gene. About 90% of mutation cases are not inherited from the parent and are new to the child; however, the risk of occurrence in families with gene mutations is significant. Epidemiological studies revealed that about 20% of diagnosed cases lack a mutation of the SCN1A gene, suggesting other causes for the rare disease.
There is a history of epilepsy or febrile seizure in approximately 25% of all diagnosed cases. Clinical presentation varies with age. In adults and older children, DS manifests as motor and cognitive dysfunction, persistent seizures, visual-motor integration, speech impairments. In childhood, the clinical presentation includes exertion, heightened sensitivity to warm baths, fever, and seizures of generalized tonic-clonic or hemiclonic variation.
CBD in the management of Dravet syndrome
As in other diseases of rare occurrence, there is no definitive cure for Dravet syndrome. However, standard therapies currently recommended aim to reduce the frequency of seizures and improve presenting symptoms. Cannabidiol has long been investigated for promising results in the treatment of seizures. By acting on the components of the endocannabinoid signaling system, CBD can influence the excitability of neurons in the central nervous system. As an inverse agonist at the cannabinoid receptor points, CBD can increase the excitability of inhibitory neurons and subsequently reduce the frequency of generation and transmission of neuronal signals. This is the logical basis for CBD’s use in the management of seizures associated with DS.
In June 2018, the U.S. Food and Drug Administration (FDA) approved Epidiolex, a purified form of CBD for the treatment of seizures associated with Dravet syndrome and Lennox-Gastaut syndrome, for use in patients two years of age and above. Since the approval of Epidiolex, different clinical studies have been conducted by independent researchers to evaluate the efficacy of the CBD-derived medication for its intended indication.
Symptoms impacted by CBD use for Dravet syndrome
- CBD reduces seizure frequency
Primarily, DS presents with severe forms of drug-resistant epilepsy, usually within the first year of life in children. In this population the seizure duration may range between 5 and 30 minutes (status epilepticus) and require immediate medical intervention. There are studies suggesting that seizure frequency improves with advancing age; however, this observation is not uniform in all diagnosed cases. Using primary cortical neurons from embryos and induced pluripotent stem cells, researchers have suggested that clinical doses of CBD, there is a significant reduction in the excitability of inhibitory neurons.
A paper presented at the 2019 American Academy of Neurology Annual Meeting detailed the result of a randomized study investigating CBD’s anti-seizure activities in about 200 children with DS. Preliminary results showed there is a 56% reduction from baseline seizures in children treated with CBD at a dose of 10 mg/kg/day. In children with a dose of 20 mg/kg/day, they reduced baseline seizures by 47%. This study supports the results of previous research, suggesting that total seizure frequency is significantly reduced in patients treated with CBD.
- CBD improves psychotic state
The psychotic symptoms observed in patients with Dravet syndrome include aggressiveness, agitation, obsessiveness, preservation, and hoarding behavior. The benefits of cannabidiol in the management of psychotic disorders have been documented by different epidemiological studies. In 2011, Schizophrenia Research published a web-based, cross-sectional study investigating the link between cannabis use and subclinical psychiatric experience. An inverse relationship between cannabidiol content in cannabis and the incidence of self-reported positive psychotic symptoms.
This study, and other similar research, have prompted clinicians to experiment with CBD as an adjunctive treatment for the psychotic symptoms associated with Dravet syndrome. Although only a few medical reviews support this approach, there are research reports suggesting that CBD reduces anxiety-like and depressive-like behaviors in animal models of DS.
- CBD improves prognosis of Dravet syndrome
Compared with epilepsy cases diagnosed in the general population, the mortality of Dravet syndrome is higher. Clinical studies suggest that sudden unexpected death in epilepsy, especially during sleep, is the most common cause of death in patients with DS. Status epilepticus also contributes significantly to the mortality rate. The estimated mortality rate by adulthood ranges between 15% and 20%. Recently, the British Journal of Pharmacology published a study conducted to determine the effects of sub-chronic CBD administration in mouse models of Dravet syndrome. By using a hybrid, heterozygous SCN1A mice, the results confirmed that CBD reduces premature mortality,and noticeably improves social behavior in test subjects.
Generally, studies on rare diseases are almost neglected in the medical community, with little research focus on developing a novel interventional approach for their management. Just as in other diseases associated with a gene abnormality, Dravet syndrome is incurable and, as such, requires alternative therapy for symptomatic management. Cannabidiol, no doubt, presents promising benefits for those symptomatic in DS as well as for other rare diseases.