Department of Neurology, School of Medicine and Center for Neuroscience, University of California, Davis, Sacramento, California 95817, USA.
Epilepsia. 2013 May;54 Suppl 2:33-40. doi: 10.1111/epi.12182.
Pharmacoresistance to antiepileptic drugs (AEDs) is a barrier to seizure freedom for many persons with epilepsy. For nearly two decades, pharmacoresistance has been framed in terms of factors affecting the access of AEDs to their molecular targets in the brain or the actions of the drugs on these targets. Shortcomings in this prevailing view led to the formulation of the intrinsic severity hypothesis of pharmacoresistance to AEDs, which is based on the recognition that there are neurobiologic factors that confer phenotypic variation among individuals with etiologically similar forms of epilepsy and postulates that more severe epilepsy is more difficult to treat with AEDs. In recent years, progress has been made identifying potential genetic mechanisms of variation in epilepsy severity, including subclinical mutations in ion channels that increase or reduce epilepsy severity in mice. Efforts are underway to identify clinically important genetic modifiers. If it can be demonstrated that such severity factors play a role in pharmacoresistance, treatments could be devised to reverse severity mechanisms. By overcoming pharmacoresistance, this new approach to epilepsy therapy may allow drug refractory patients to achieve seizure freedom without side effects.
抗癫痫药物（AED）的药物抵抗是许多癫痫患者无法摆脱癫痫的障碍。近二十年来，药物抵抗一直被认为是影响 AED 进入大脑中其分子靶点或药物对这些靶点作用的因素。这种流行观点的缺陷导致了 AED 药物抵抗的固有严重程度假说的提出，该假说基于这样的认识，即存在神经生物学因素，使具有病因相似形式癫痫的个体表现出表型变异，并假设更严重的癫痫更难以用 AED 治疗。近年来，在确定癫痫严重程度变化的潜在遗传机制方面取得了进展，包括离子通道的亚临床突变，这些突变会增加或降低小鼠的癫痫严重程度。目前正在努力确定具有临床重要意义的遗传修饰因子。如果可以证明这种严重程度因素在药物抵抗中起作用，那么可以设计治疗方法来逆转严重程度机制。通过克服药物抵抗，这种新的癫痫治疗方法可能使药物难治性患者在没有副作用的情况下实现无癫痫发作。
