SCN1A Patients Advised to Avoid Sodium Channel Blockers

Why Should Patients with SCN1A mutations AVOID sodium channel blockers such as Lamictal?

Sodium channel blockers are anti-epileptic drugs that work in the sodium channel to preferentially affect the sodium channel at a specific stage of its cycle of rest, activation and inactivation, often by delaying the recovery from the inactivated state, thereby producing a cumulative reduction of Na+.  Non-epileptic brains have a natural balance of excitation (that can evoke seizures) and inhibition (that can reduce seizures).   In epilepsies that are caused by a too much excitatory neurotransmission (many of the epilepsies EXCEPT SCN1A mutation related epilepsies), sodium channel blockers are beneficial because they reduce the neurotransmitters that cause too much excitation.

Based on the mechanism in which sodium channel blockers work to prevent seizure activity, one would think that a mutation in the SCN1A gene that causes the sodium channel to be ineffective (in essence, blocked)  should prevent seizures and make a person less prone to epilepsy.  However, based on the works of Bill Catterall, PhD, et al and Andrew Escayg,PhD, most SCN1A gene mutations cause a loss of function of the sodium channel that  leads to increased seizure activity because the result of this mutation leads to a decreased the amount of inhibitory neurotransmitter that normally exists in the correct amount in the brain to balance excitatory neurotransmitters that make seizure more likely to occur.  In this situation, the problem with the balance of excitation and inhibition in the brain is not too much excitation, it is too little inhibition.

Most SCN1A mutations cause a loss of function of the sodium channel, thereby making sodium channel blocking anti-epileptics a poor choice for treatment.  Giving sodium channel blocking drugs to patients with a loss of function mutation will further decrease the amount of inhibitory neurotransmitters in the brain, making the balance scale tip more toward seizure activity.

See also  Stiripentol and Anesthesia

ALL truncating mutations (frameshift or nonsense) cause a LOSS of function – these mutations comprise about 50% Dravet syndrome. Missense mutations comprise the other 50%, and it is impossible to know if a missense mutation produces a GAIN of function or a LOSS of function, as the SCN1A missense mutation type or location has not been successfully correlated to whether the mutation causes a loss or gain of function.  It is thought that most patients who have Dravet syndrome caused by a missense mutation, whether inherited or de novo, have a LOSS of function, therefore sodium channel blocking drugs should be AVOIDED.

By definition, all patients with GEFS+ have  a missense mutation because GEFS+ is an inherited condition of an SCN1A missense mutation.  Still, it is impossible to determine if the missense mutation causes a gain or loss of function, so sodium channel blockers should be used with caution.  The only way to determine if a sodium channel blocker will produce more seizures or be a therapeutic option is through a trial of the drug.  Consideration of the probability of increased seizure activity, current seizure frequency and length, and an aggressive emergency seizure plan should be exercised if an attempt to use this class of drugs is made.

In summary, most (>95%) Dravet patients produce a loss of function mutation regardless of mutation type.  A small percentage of patients with GEFS+ or Dravet  may not experience more seizures with  sodium channel blockers because they have a missense mutation that results in a gain of function in the sodium channel. Parents of children with missense mutations may choose to roll the dice and try these drugs when all else fails, but a small percentage will have a positive effect so do so with caution.

See also  Nootropic Drugs

Sodium channel blocking anti-epileptic drug includephenytoin (Dilantin)*, fosphenytoin (Cerebyx)*, carbamazepine (Tegretol), oxcarbazapine (Trileptal), lamotrigine (Lamictal), lacosamide (Vimpat), and rufinamide (Banzel)

*Phenytoin and fosphenytoin are often used in the emergency room setting intravenously to stop status epilepticus.  These medications should not be used as part of a status epilepticus protocol in patients with SCN1A mutations unless a trial with a sodium channel blocking agent has shown no increased seizure activity.