Sodium Channel Blocker Phenytoin Eases Seizures in 4 Dravet Patients

Findings counter recommendation that patients avoid sodium channel blockers

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Long-term use of the sodium channel blocker phenytoin led to reductions in seizure frequency for four male patients with Dravet syndrome, according to a study in Australia.

Weaning off the medication caused seizures to worsen, and re-starting it lowered seizure frequency and improved alertness.

The findings are in contrast to the longstanding recommendation that Dravet syndrome patients should avoid sodium channel blockers due to their potential for seizure exacerbation.

“Clinical trials exploring the use of phenytoin in Dravet syndrome are required to establish whether phenytoin has a place in the treatment of this disease, both acutely and over the long-term,” researchers wrote.

The study, “Does long-term phenytoin have a place in Dravet syndrome?,” was published as a brief communication in the Annals of Clinical and Translational Neurology.

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Anti-seizure sodium channel blockers are often used for other types of epilepsy

Up to 90% of Dravet syndrome cases are caused by mutations in the SCN1A gene, which provides instruction to build a protein called NaV 1.1 that forms part of a sodium channel. These channels work to help nerve cells fire electrical impulses.

Each mutation can affect the function of these sodium channels in different ways, but most SCN1A mutations in Dravet are thought to lead to a loss of NaV 1.1 function. This may impair the activity of inhibitory nerve cells that are needed to suppress the excessive firing of signals that causes seizures.

Anti-seizure medications that work by blocking sodium channels are often used to treat other types of epilepsy, as well as status epilepticus, which are life-threatening seizure episodes lasting at least five minutes that are also common in Dravet.

However, it’s long been thought that because sodium channels are likely suppressed in Dravet, such treatments might actually make seizures worse in this type of epilepsy.

Although contraindicated for Dravet, there is limited clinical data to describe the effects of specific sodium channel blockers, such as phenytoin (sold as Dilantin, with generic versions available), in this patient population. As such, these medications might still be effective for some Dravet patients.

Now, a research team in Australia has studied the long-term effects of phenytoin treatment in four Dravet male patients with SCN1A mutations.

Introducing phenytoin did not exacerbate seizures in any patient, nor did it trigger onset of new seizure types.

Phenytoin led to reduction in seizures in all 4 patients

Three of patients were 17–18 years old, and one was 28. All carried different SCN1A mutations.

They began treatment with phenytoin in addition to two other anti-seizure medications at an age between 2 and 8 years. All four had previously tried four to seven other anti-seizure treatments, but continued to experience seizures and/or status epilepticus.

Shortly after starting phenytoin, all four patients saw a reduction in seizure frequency.

Notably, one patient had no seizures at all for four weeks after starting phenytoin, compared with two to three weekly seizures in the two years prior.

For another patient, starting phenytoin resulted in four years without any status epilepticus. That patient had previously experienced three hospital admissions per month for such life-threatening episodes.

“Introducing phenytoin did not exacerbate seizures in any patient, nor did it trigger onset of new seizure types,” the researchers wrote.

Two patients were on phenytoin for one year, one for five years, and another (the older patient) for 20 years, before weaning off treatment. Treatment reduction led to a two- to four-fold increase in seizure frequency and length, “which required the phenytoin dose to be increased,” the team wrote.

One patient was able to be completely weaned off the medication on the first attempt, but still, his seizures increased.

“With the re-introduction of phenytoin, there was sustained improvement in seizure frequency and duration in all four patients with a median follow-up period of 4 years,” the researchers wrote.

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‘Limited evidence’ to support avoiding phenytoin treatment for Dravet

Recommencing phenytoin treatment also improved alertness in all patients. However, it had no effect on cognitive function, with the degree of intellectual disability remaining stable, but moderate to severe.

“On dissecting the literature, there is limited evidence to support the avoidance of phenytoin in Dravet syndrome,” the researchers wrote, noting that other types of sodium channel blockers, such as carbamazepine (sold as Tegretol and others) and oxcarbazepine (sold as Trileptal and others) could have different effects in Dravet.

“Variable efficacy within [sodium channel blockers] in Dravet syndrome emphasizes that we cannot adopt a whole-of-class approach to prescribing these drugs,” they added.

Still, it isn’t clear why phenytoin was so effective in these four patients.

“A complex interplay between the SCN1A [mutation], [anti-seizure medications] and their metabolism, and the patient’s genetic background, contribute to the variable efficacy of phenytoin in patients with Dravet syndrome,” the team concluded.