Cannabidiol: A therapeutic option for Lennox-Gastaut syndrome?
Rajalaxmi Natarajan, PhD
Thu, 02/11/2016
What is Lennox-Gastaut syndrome?
Lennox-Gastaut syndrome (LGS) is a form of severe childhood epilepsy that firsts manifests in children between the ages of 2 to 5 years and often persists into adulthood. Children with this syndrome have life-long behavioral, psychological and cognitive problems. There is also an increased risk of death due to uncontrolled seizures and/ injuries from sudden drop attacks.
What causes Lennox-Gastaut syndrome?
There are multiple causes known for LGS. In 70-80% of the patients, LGS is secondary to another underlying pathology such as brain damage (For example: hypoxic-ischemic injury, frontal lobe damage, meningitis, encephalitis or birth defects) or developmental disorders (such as tuberous sclerosis).
Recently, advances in genome/exome sequencing have allowed researchers to identify the many spontaneously arising (de novo) genetic mutations1 responsible for LGS. Interestingly, they include a diverse group of genes encoding neurotransmitter receptors (GABRA1, GRIN1, GRIN2B), ion channels (CACNA1A), regulatory molecules (CDH2, hnRNPs), signaling molecules (mTOR kinase, Arf GEF) and others.1
Discovery of these genes now offers researchers the ability to generate cell and animal models that can be used to understand molecular mechanisms causing this syndrome as well as to develop targeted therapeutics for LGS patients carrying those particular mutations.
Why is Lennox-Gastaut syndrome difficult to treat?
This epileptic syndrome manifests as frequent seizures that are of different types (e.g.: drop attacks, tonic, tonic-clonic, myoclonic etc), which makes it among the most challenging forms of epilepsy to treat. Treating one type of seizure can exacerbate the occurrence of other type and combination therapy poses increased incidences of adverse side effects. LGS seizures are very often resistant to treatments and so far, scientific studies have not identified a single efficacious drug.
Can cannabidiol (CBD) be developed as a therapeutic for LGS patients?
Answer: Its efficacy and safety are not clear and needs to be rigorously evaluated.
In the last few years, many anecdotal cases, reported in the popular press suggest that marijuana plant extracts enriched in cannabidiol (CBD) can decrease the frequency and severity of seizures, especially among patients of another severe and intractable childhood epilepsy, Dravet syndrome. But hardly any properly conducted clinical trials exist to support this claim. The only known studies that exist are -
A brief online survey2 of parents who administered cannabidiol- extracts to treat their children’s epilepsy. This study conducted by UCLA researchers included only children with LGS or infantile spasms. (Infantile spasms is another type of severe childhood epilepsy with an earlier age of onset). 85% of the parents reported a reduction in the frequency of seizures and 14% reported complete absence of seizures after about 6 months of CBD treatment.
However, only 36% of Lennox-Gastaut patients showed reduction in motor seizures and none of the patients were free of seizures after three (3) months of treatment in an open-label multi-center clinical trial3 conducted to test if the addition of CBD to the existing anti-epileptic regimens would be safe and efficacious in children and young adults. Most patients (79%) had moderate side effects such as patients diarrhea, reduced appetite etc. and 30% of them experienced severe adverse events including death.
It is crucial to keep in mind that these studies are based on self-reporting (i.,e parents or care-givers counted the number of motor seizures daily), were not controlled (i.,e compared to an identical placebo-treated group of patients), not randomized (i.,e where patients are not randomly assigned to treatment group or placebo control group) or blinded (i.,e where patients and families are not aware of the treatment they are receiving). Hence, a valid concern among epileptologists is that personal bias and beliefs of patient’s families or care-givers could have influenced the reported outcomes and may not be a true assessment of the drug's performance.
This is especially critical for CBD trials given the intense media coverage. Some researchers have observed that placebo effect is more predominant for cannabis-derived drugs than other anti-epileptic drugs. This likely explains the dramatic difference in results between the two studies.
In conclusion, efficacy and side-effects of CBD need to be further evaluated. Rigorously controlled and randomized trial(s) are required before it can be considered as a treatment option for LGS patients.
References:
1) Epi4K Consortium and Epilepsy Phenome/Genome project. Nature 501, 217–221 (12 September 2013) doi: 10.1038/nature12439. De novo mutations in epileptic encephalopathies
2) Hussain et al., Epilepsy Behav. 2015 Jun; 47:138-41. doi: 10.1016/j.yebeh.2015.04.009. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.
3) Devinskly et al., Lancet Neurol. 2015 Dec 23. pii: S1474-4422(15)00379-8. doi: 10.1016/S1474-4422(15)00379-8. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.
Resources:
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