Epidiolex reduces seizures in rare Dravet syndrome cases: Study
Case series details five patients with microdeletions of key chromosome
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Epidiolex (cannabidiol) reduced seizure frequency in five children with Dravet syndrome caused by 2q24.3 microdeletions, according to a case series.
Dravet syndrome is a severe form of epilepsy that begins in early infancy. A 2q24.3 microdeletion involves the loss of a segment of chromosome 2 that includes the SCN1A gene, mutations in which are a known cause of Dravet syndrome, as well as several nearby genes that have similar functions.
Some of these children also responded to Onfi (clobazam) or Depacon (sodium valproate), while others showed improvement with Fintepla (fenfluramine) or the ketogenic diet as add-on treatments.
“Our patient data suggest that [Epidiolex], [Onfi], and [Depacon] warrant earlier consideration for epilepsy management in 2q24.3-deletion patients,” researchers wrote.
Case series details were described in the study, “Efficacy of Dravet Syndrome Treatments in a Subset of Individuals with 2q24.3 Deletion: A-5 Patient Case Series,” published in the Journal of Child Neurology.
Most Dravet cases caused by SCN1A gene mutations
Most cases of Dravet syndrome are caused by mutations in the SCN1A gene, which disrupts the function of NaV1.1, a voltage-gated sodium channel (VGSC) protein found on the surface of nerve cells. These channels regulate the flow of sodium ions into nerve cells, a process that triggers the transmission of electrical impulses to other nerve cells.
Although the exact mechanism is not fully understood, it’s thought that dysfunctional NaV1.1 may compromise inhibitory neurons, or nerve cells that help suppress excessive brain activity. Without sufficient NaV1.1 function, inhibitory signals are reduced, leading to overactivation of the nervous system and seizures.
Most Dravet-causing SCN1A mutations are single changes in the genetic code, while in rare cases, patients carry 2q24.3 microdeletions. That is, they are missing a specific region on the long arm of chromosome 2 (2q), called 24.3, which encompasses SCN1A, as well as four other VGSC genes: SCN2A, SCN3A, SCN7A, and SCN9A.
Case reports suggest that patients with 2q24.3 microdeletions involving regions beyond SCN1A, particularly SCN2A and SCN3A, experienced more severe epilepsy starting in infancy, which is often resistant to anti-seizure medications.
However, “recommendations for epilepsy therapies do not exist for [Dravet] patients with 2q24.3 deletion involving other VGSC genes,” wrote a team led by researchers at the Ann & Robert H. Lurie Children’s Hospital of Chicago, who reviewed the treatment response of five Dravet patients, ages 3-15, with microdeletions.
3 0f 5 patients lacked all 5 VGSC genes
Genetic testing showed that the size of the missing region on chromosome 2 varied between patients. One child lacked SCN1A and SCN2A; another lacked SCN1A, SCN7A, and SCN9A; and three were missing all five VGSC genes.
All of them showed global developmental delay, meaning delays in two or more developmental domains (cognitive, motor, speech/language, or social/emotional).
In four out of five children, seizures began early, between three and four months of age. One child, who was missing SCN1A, SCN7A, and SCN9A, developed seizures at seven months and was the only one whose deletion did not include the SCN2A gene.
Researchers noted that all of the children experienced several different types of seizures: generalized tonic, generalized tonic-clonic, myoclonic, focal impaired consciousness, absence, focal motor, focal non-specified seizures, and spasms.
Another child who lacked the five VGSC genes exhibited choreoathetosis, a movement disorder characterized by involuntary, jerky movements (chorea) and slow, twisting motions (athetosis) of the limbs, face, or trunk.
Epidiolex was sole treatment to demonstrate efficacy in all 5 patients
All five children were treated with medications commonly used for Dravet patients: Onfi, Epidiolex, and Keppra (levetiracetam). Four also received Depacon or phenobarbital, three received Topamax (topiramate), and two received Fintepla. In addition, two underwent vagus nerve stimulation, while one was put on the ketogenic diet.
Data showed that Epidiolex was the sole treatment to demonstrate efficacy in all five patients. It reduced seizure frequency, including tonic and generalized tonic-clonic seizures, and improved seizure control and alertness, with no signs of adverse side effects.
One of the Onfi-treated patients experienced fewer generalized tonic-clonic seizures, while two, one of whom was also on the ketogenic diet, had markedly fewer myoclonic seizures. Two of the four patients who received Depacon experienced fewer seizures, including myoclonic seizures, but its efficacy either waned over time or showed adverse effects.
Vagus nerve stimulation helped stop seizures in one child (missing SCN1A and SCN2A), who also experienced fewer myoclonic seizures with Topamax, but with adverse effects. While Fintepla didn’t reduce seizure frequency, it led to better recovery after seizures.
Fintepla showed the best seizure control in one child with all five VGSC genes missing, who also responded to Onfi, in combination with the ketogenic diet, and Epidiolex. Here, Topamax was effective for generalized tonic-clonic seizures, but not myoclonic seizures, and had side effects.
None of the five patients responded to Keppra, nor did the four given phenobarbital.
“Deletions in 2q24.3 may result in a [hard-to-treat] epilepsy secondary to deletions in VGSC genes,” the researchers wrote. “Such patients may derive benefit from [Epidiolex], [Onfi], and [Depacon]. [Fintepla] and the ketogenic diet may be promising, but additional studies are necessary to assess their efficacy in this patient population,” the team added.
