Research Published December 2015 and January 2016

Clinical Research:

Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.

(Lancet Neurology, Dec. 2015) (

Data from the first large safety and tolerability study on GW Pharmaceuticals’ Epidiolex, a highly purified extraction of plant-based cannabidiol (CBD), was published. The study, led by Dr. Orrin Devinsky and clinicians across the US, included 214 patients, 33 of which had Dravet syndrome and 31 of which had Lennox-Gastaut syndrome. The median reduction in monthly motor seizures (convulsive seizures) was 36.5%, with a good tolerability profile. Side effects reported in more than 10% of the group included somnolence, decreased appetite, diarrhea, fatigue, and convulsions. The authors note that Epidiolex may indeed be a safe and effective treatment, but because this was an open label study (meaning everyone knew what they were taking), randomized controlled studies (RCTs) are necessary to determine the true safety and efficacy profile. Those studies are underway and data is expected within the year.

  • Want to learn more about the different types of clinical trials? Click here: (
  • Want to learn more about the placebo effect, its alarming 30% response rate, and how it factors into trials for epilepsy drugs? Click here: (

Mosaic mutations in early-onset genetic diseases.

(Genetics in Medicine, Dec. 2015) (

This study focused on two groups: families who had lost a child to SUDC (Sudden Unexpected Death in Children), and families with severe epilepsies. They developed and performed an in-depth method for testing for mosaicism in the patient and their parents (called “trios”) and found 6 cadses of mosaicism out of 347 trios tested that were previously deemed “de novo” because the parents originally tested negative for any mutations. More information on mosaicism can be found here: (

There was one particularly alarming case where a child was lost to SUDC at age 20 months after suffering 7 febrile seizures in her otherwise normal medical history. She has two surviving siblings: one healthy sister, and one brother with Dravet syndrome. In-depth testing showed she shared a mutation with her affected brother and their father. The father, who was previously deemed negative for any mutations and had no history of seizures, actually had a 25% mosaic load of the affected children’s mutation. The authors concluded her death was likely related to a seizure and question whether it was a case of SUDEP rather than SUDC. Over the entire group, mosaicism was detected in approximately 2% of the trios tested. While a small number, this is significant and concerning to any parent whose child is thought to have a de novo mutation.

Disorders of early language development in Dravet syndrome.

(Epilepsy and Behavior, Jan. 2016)

This was a small study of young children with Dravet, but we include it because it affirms what many parents and clinicians have observed. The authors found cognitive decline and speech impairment, characterized by relatively preserved receptive language and strong impairment of productive skills.

Basic Science and Pre-clinical Research:

Scn1a dysfunction alters behavior but not the effect of stress on seizure response.

(Genes, Brain, and Behavior, Dec. 2015) (

This study on mice with an SCN1A mutation confirmed what parents observe: In the absence of medication, the mutation itself causes deficits in social behavior, spatial memory, cued fear conditioning, prepulse inhibition, and risk assessment. Interestingly, though, mutant mice and healthy mice (“wild types”) responded similarly to stressors.

CRISPR/Cas9 facilitates investigation of neural circuit disease using human iPSCs: mechanism of epilepsy caused by an SCN1A loss-of-function mutation.

(Translational Psychiatry, Jan. 2016)

The authors of this study used fluorescent dye on induced Pluripotent Stem Cells (iPSC’s) to specifically study the effects of SCN1A mutations on inhibitory (GABAergic) neurons. iPSC’s are actual living cells that have been treated environmentally and chemically to grow into the desired cell type, in this case specific neurons. By carefully selecting and then nurturing the cells, scientists are able to study how the cells react and behave in neuronal networks without the need for harvesting brain tissue from patients. The SCN1A mutations in this set of iPSC’s lowered sodium ion current, as expected, but also lowered the activation of the inhibitory cells. This two-fold hit against the principle inhibitory neurons may shift the balance between excitation and inhibition toward an excited state.

Characterization of maturation of neuronal voltage-gated sodium channels SCN1A and SCN8A in rat myocardium.

(Molecular and Cellular Pediatrics, December 2016) (

This study on rat myocardium (heart tissue) showed that various sodium ion channels and their subunits are expressed in different proportions throughout development. SCN1A is expressed to the highest degree between Day 1 and Day 7 post birth, as seen from RNA levels, indicating its importance in maintaining a regular heart rate during this early phase of life. Interestingly, the protein level decreased after birth compared to RNA expression. Developmentally, this correlates well to the first year of life in humans, when seizures typically appear in Dravet syndrome. (

Hlf is a genetic modifier of epilepsy caused by voltage-gated sodium channel mutations.

(Epilepsy Research, Jan. 2016) (

SCN1A and SCN2A can produce different clinical pictures (phenotype) from identical mutations (genotype). The prevailing theory is that there are other modifying genes that regulate SCN1A or affect the clinical outcome somehow. The search is ongoing, and several candidates have been identified. This recent study suggested hlf (hepatic leukemia factor) modifies the effects of SCN2A by affecting the pyroxidine pathway. Pyroxidine is a common form of vitamin B6. To confirm, mice were maintained on a pyroxidine deficient diet. Seizure frequency increased and survival rate decreased. This diet was then applied to mice with SCN1A mutations, and decreased survival was noted.

The possible use of the L-type calcium channel antagonist verapamil in drug-resistant epilepsy.

(Expert Review of Neurotherapeutics, Dec. 2015) (

While not directly related to Dravet syndrome, this article on multidrug transporters (MDTs) and their role in drug resistant epilepsies caught my eye. A MDT, or p-glycoprotein, is a protein embedded in the cell membrane that exports foreign biologics from the cell. It is part of the defense line of the cells that make up the blood-brain barrier, designed to keep harmful substances out of the brain. (Learn more about the blood-brain barrier here: The article suggested that MDTs may play a role in drug resistant epilepsies by transporting anti-epileptic drugs (AEDs) out of the cells at the blood brain barrier. Verapamil, which inhibits the production of p-glycoprotein, has been used with some success in some patients with Dravet syndrome in the past.

Unaltered Network Activity and Interneuronal Firing During Spontaneous Cortical Dynamics In Vivo in a Mouse Model of Severe Myoclonic Epilepsy of Infancy.

(Cerebral Cortex, Jan. 2016)

Loss of function of inhibitory interneurons is often blamed for symptoms of Dravet and SCN1A- related epilepsies. This study showed that brain slices taken from SCN1A-mutated mice during the pre-epileptic period (before seizures developed) showed low excitability for certain inhibitory neurons, and epileptiform activity propagated more easily than in wild-type (healthy) mice. However, when optogenetic manipulation was used to reduce the activity of those types of cells in healthy mice, these results were not observed, suggesting other factors must be at play. (Optogenetics is a relatively novel approach in which light is used to stimulate certain genes to create various conditions for testing live cells.)

Serotonergic Modulation as Effective Treatment for Dravet syndrome in a Zebrafish Mutant Model.

(ACS Chemical Neuroscience, Jan. 2016)

Fenfluramine has been in the news recently regarding Dravet syndrome, since a Belgium study was published showing a reduction of seizures in 70% of patients. Fenfluramine is a 5-hydroxytryptamine (5-HT) releaser that activates multiple 5-HT receptor subtypes. This study confirmed the antiepileptic properties of fenfluramine on zebrafish with SCN1A mutations, and studied several types of receptor agonists, many of which also showed antiepileptic effects. Decreased levels of serotonin were found in the mutated zebrafish compared to their healthy counterparts.

By |2016-10-21T17:14:08+00:00February 10th, 2016|Categories: DSF Research Review|