Targeting pharmacoresistant epilepsy and epileptogenesis with a dual-purpose antiepileptic drug

Objective – Drugs used to treat epilepsy are known as anti-epileptic drugs (AEDs) but AEDs effectively reduce seizures in only two-thirds of patients, the remaining third not gaining sufficient relief from seizures. This is known as refractoriness and is an issue that epilepsy researchers are actively trying to solve. In acquired epilepsies, an initiating event like meningitis or stroke can eventually lead to development of spontaneous seizures (i.e. epilepsy). The process by which a normal brain transforms into one capable of generating seizures is known as ‘epileptogenesis.’ Unfortunately, at present, there are no drugs that can effectively halt this phenomenon.

One can imagine that a drug that can stop refractoriness and epileptogenesis would be important clinically. The authors of a recent study asked whether eslicarbazepine acetate (shortened to ESL) could address both these issues. Eslicarbazepine acetate is converted to eslicarbazepine in the body; and its use in Europe and the US has been approved in partial-onset epilepsy. For this study, the authors used experimental animals that had been given a convulsant to make them epileptic and resected tissue from individuals with refractory epilepsy.

Results: A number of AEDs work by blocking sodium (Na+) channels, hence suppressing neuronal activity. If AEDs cannot block Na+ channels effectively, one can see how they may not be able to block seizures either. Indeed, this has been proposed to be one of the mechanisms of refractoriness. In this study, the authors found ESL was able to block Na+ channels effectively again. Hence, one could say that ESL might effectively overcome refractoriness.

In another set of experiments, the scientists found that ESL blocked a particular type of calcium channels known as CaV3.2. These channels allow calcium to enter into neurons and are thought to contribute to epileptogenesis. ESL was shown to decrease two other proposed markers of epileptogenesis – mossy fiber sprouting and neurodegeneration. Additionally, ESL decreased the number of spontaneous seizures in animals that were given a convulsant. These results allude to the anti-epileptogenic actions of ESL.

Interpretation: The clinical implications of a drug that not only decreases refractoriness but also halts epileptogenesis are substantial. One interpretation of this study is that ESL could be used as a general anti-epileptogenic agent. At present, clinicians have no way of stopping epilepsy after a stroke or meningitis. Although more experiments need to be done, it could be that people who have had stroke or meningitis could be given ESL to stop epileptogenesis and hence, epilepsy. No such drug exists at this time.

Summary for specialists