Sodium Channel Blockers in Dravet Syndrome

Dravet syndrome is a rare and severe form of epilepsy caused by genetic mutations.

Anticonvulsants are typically used to control seizures in Dravet syndrome, and sodium channel blockers belong to a group of anticonvulsants known as ion channel modulators.

But sodium channel blockers, while commonly used to treat other forms of epilepsy, are usually avoided in people with Dravet syndrome because they are known to worsen seizures in these patients. Most Dravet syndrome patients who used or are using  sodium channel blockers started on this treatment before their condition was diagnosed.

How sodium channel blockers work

Brain cells communicate with each other via electric signals. These activate sodium channels, allowing sodium to enter nerve cells — an influx that is needed to further transmit electric signals along brain cells.

Sodium channel blockers prolong the inactive state of the channel after its activation by an electric signal. Different types of neurons can send signals that either activate or inhibit other neurons. The beneficial effect of sodium channel blockers in the treatment of seizures is thought to arise from acting on the activating neurons.

Sodium channel blockers and Dravet syndrome

Sodium channel blockers are known to aggravate seizures and status epilepticus in Dravet syndrome patients. Status epilepticus is when a seizure lasts longer than five minutes, or when several seizures occur close together without the patient have a chance to recover between seizures.

Around 70 to 85 percent of Dravet syndrome patients are known to have a mutation in the SCN1A gene. This gene provides instructions to make the NaV1.1 subunit of sodium channels.

It is not fully understood how mutations in the SCN1A gene cause seizures in Dravet syndrome, but they are thought to mainly affect sodium channels in inhibitory neurons, called GABAergic neurons, resulting in aberrant neuronal firing and seizures. Most SCN1A mutations are loss-of-function mutations, which may explain why further blocking the sodium channels aggravates seizures in Dravet patients.

Sodium channel blockers to be avoided

Sodium channel blockers include Dilantin (phenytoin), Tegretol (carbamazepine), Banzel (rufinamide), Lamictal (lamotrigine), Cerebyx (fosphenytoin), and Trileptal (oxcarbazepine). These are generally avoided in Dravet syndrome patients.

There is, however, a case report involving three male Dravet syndrome patients — ages 14, 27, and 33 and all carrying a mutation in the SCN1A gene — who were stable using lamotrigine and a combination of other antiepileptic medication for several years (6 to 15 years). Because of studies reporting lamotrigine’s risks in Dravet syndrome, the patients were weaned off this medication. All three experienced seizure exacerbation following withdrawal; their seizures became more frequent and longer in duration. Upon restarting lamotrigine, their seizure frequency again decreased.

This case study, published in 2015, suggests that lamotrigine might be beneficial for some Dravet syndrome patients. Lamotrigine not only works as a sodium channel blocker, it also blocks N-type Ca2+ channels. N-Type Ca2+ channels control the release of neurotransmitters, signaling molecules in the brain. It is not known if the treatment benefits seen in this case study were due to lamotrigine’s sodium channel blocking or Ca2+ channel blocking activity.

More than 1,250 different mutations in the SCN1A gene have been reported, and it is currently not possible to predict which patients might benefit from sodium channel blockers. Because a worsening of seizure activity occurs in most patients, however, sodium channel blockers are generally not recommended to treat Dravet syndrome.


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