Abstracts

Rationale: NaV1.1 sodium channel mutations are a well-known cause of epilepsy, with nonsense mutations often leading to a Dravet Syndrome phenotype. The conventional wisdom is that the many anticonvulsant medications that act on sodium channels should be avoided, although this is only supported by anecdotal evidence, a few case reports and retrospective reviews. In this study we use two computational thalamocortical models to predict the effects of carbamazepine in patients Dravet syndrome secondary to truncation mutations. Methods: A thalamocortical model described by Destexhe (400 neurons with 2 cortical and 2 thalamic neuron populations) was modified to incorporate sodium channels with slow and fast inactivation. Truncation mutation was then simulated by reducing interneuron sodium channel conductance by 50%. Effects of carbamazepine and oxcarbazepine were then simulated by increasing the fast inactivation time of sodium channels in cortical neurons, while effects of eslicarbazepine and lamotrigine were simulated by increasing slow inactivation time. Standard Hodgkin Huxley type sodium channels were then substituted into a more complex thalamocortical model described by Hill and Tonini (over 50,000 neurons with twelve cortical populations representing two distinct cortical areas and six thalamic populations representing two distinct areas), and truncation mutations and the effects of carbamazepine were again simulated. Results: Introduction of truncation mutation into the Destexhe model reduced the amplitude of sodium currents from interneurons, decreasing the number of action potentials from this population of neurons and leading to periods of prolonged bursting from pyramidal neurons akin to tonic seizures.  Similar effects were seen in the complex model.  In the Destexhe model, simulation of carbamazepine and oxcarbazepine reduced spiking rates in both populations, decreasing incidence of seizures.  Simulation of eslicarbazepine and lamotrigine also decreased action potentials in both populations but did not prevent seizures.  In the Hill model, the truncation mutation led to less pronounced but clearly present increased focal bursting corresponding to epileptiform activity.  Simulation of carbamazepine led to varied effects depending on background activity of the network; in some cases focal epileptiform activity was decreased, while in other cases more diffuse epileptiform activity emerged. Conclusions: This study provides mechanistic evidence that sodium channel anticonvulsants can be beneficial in Dravet syndrome, although effects may be variable and difficult to predict.  Dravet syndrome is characterized by both focal and generalized seizures; the Hill model suggests that sodium channel anticonvulsants may improve focal but worsen generalized seizure types.  The discordance between the results of the two models may be secondary to the different scales of the two models, or more likely may be due to differing implementations of sodium channels.  In the future, model results could be clinically validated with patients who have known sodium channel electrophysiology and clinical data documenting efficacy of sodium channel drugs.  If validated, the model then could be used to predict the potential benefit of sodium channel anticonvulsants in a given patient with a known sodium channel mutation.  This represents a prime application for computer modeling in personalized medicine for patients with epilepsy. Funding: No funding was received in support of this abstract.