The model for treating epilepsy continues to reduce the effectiveness of available therapies in status epilepticus, according to a study that will be presented on Dec. 4 at the 2017 American Epilepsy Society (AES) annual meeting in Washington, DC (abstract 3.259).

Epilepsy. (Source: Flickr)

Clinicians and professional societies generally favor use of monotherapy in both chronic epilepsy and status epilepticus (SE). While recent research has demonstrated that multiple neurotransmitter pathways play important roles in SE, AES guidelines advise clinicians to target only GABAergic networks initially.

The study presenters state that “during SE, trafficking of synaptic GABAA and glutamate receptors causes both a failure of GABAergic inhibition and an increase in glutamatergic excitation. This suggests that therapy targeting both inhibitory and excitatory networks may be more effective than monotherapy.”

The researchers tested this theory by comparing treatment of severe SE in a rat model with monotherapy with a variety of antiepileptic drugs to treatment with a combination of midazolam, ketamine and valproate. They found that benzodiazepine monotherapy reduced SE-related mortality, but did not stop SE itself. Used as single agents, midazolam, ketamine, valproate and other antiepileptic drugs did not stop SE.

A combination of low-dose midazolam with ketamine and valproate, however, did stop SE and reduce the number of post-treatment seizures. The researchers also found that two-drug combinations also worked better than monotherapy, as long as one of the drugs was an NMDA antagonist.

Isobolograms demonstrated that the drugs had therapeutic synergy but did not increase each other’s toxicity. Rats treated with ketamine did not have the widespread neuronal injury seen in those who received sham treatment or midazolam.

The researchers concluded that adding an NMDA antagonist to SE treatment “had major benefits for both SE termination and neuropathological consequences” and that combination s of GABAA agonist, NMDA antagonist and another antiepileptic drug are much more effective and less toxic than monotherapy.