Drug refractory is an important clinical problem in epilepsy, affecting a substantial number of patients globally. Mechanisms underlying drug refractory need to be understood to develop rational therapies. Current two prevailing theories on drug refractory epilepsy (DRE) include the target hypothesis and the transporter hypothesis. However, those hypotheses could not be adequate to explain the mechanisms of all the DRE. Thus, we propose another possible mechanism of DRE, which is neural network hypothesis. It is hypothesized that seizure-induced alterations of brain plasticity including axonal sprouting, synaptic reorganization, neurogenesis and gliosis could contribute to the formation of abnormal neural network, which has not only avoided the inhibitory effect of endogenous antiepileptic system but also prevented the traditional antiepileptic drugs from entering their targets, eventually leading to DRE. We will illustrate this hypothesis at molecular and structural level based on our recent studies and other related researches.
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