Treatment of Status Epilepticus: A Translational Proposal

描述(由申请人提供)： 癫痫持续状态的治疗：翻译建议癫痫是退伍军人管理局门诊最常见的诊断，OEF/OIF的大量创伤性脑损伤预计将导致退伍军人中癫痫的发生率显著增加。这项研究利用美国药典中提供的药物，将我们对受体贩运在实验性SE中的作用的调查转化为治疗原则。癫痫持续状态(SE)的治疗仍然无效，在最近基于人群的研究中，死亡率为27%。一旦癫痫发作开始，它们就会自我维持，独立于最初的触发因素，并产生时间依赖性的药物耐药性。我们的工作(Naylo Et Al J Neurosci 2005)表明，反复癫痫发作导致突触GABAA受体内化(和暂时失活)和突触NMDA受体增加，这两者都是癫痫诱导的适应不良受体运输的结果。这些变化提示了自持性癫痫(突触中较少的GABAA受体和更多的NMDA受体)和药物耐药(GABA能药物的突触靶点较少)的发生机制。他们还提出，在SE中，综合疗法比单一疗法(目前的黄金标准)更有可能成功，因为治疗应该至少有两个靶点：GABAA受体(或者阻止它们的内化和/或最大限度地刺激那些留在突触中的受体)和NMDA受体(防止它们移动到突触，或者降低它们的活性)。同时针对GABAA和NMDA系统的联合治疗尚未得到广泛测试。我们的初步研究探索了这种组合的使用，使用目前批准的或接近批准的药物，并能够用低剂量的亚麻醉剂抗惊厥药物来阻止严重的实验性SE。这种以受体为基础的药物选择方法的治疗成功将证实受体转运在SE病理生理学中的重要性，并可极大地提高SE的治疗效果。我们将使用锂和匹罗卡品化学诱导SE，或通过刺激穿孔通路电诱导SE，并在3个时间点进行治疗：第二次强烈发作后，发作开始后30分钟，或发作开始后2小时。脑电和行为将被记录24小时，并用适当的软件进行分析。急性组织学结果将在72小时后评估，慢性癫痫的发生、行为和组织学将在SE后3个月进行研究。将研究治疗时机的重要性。我们的初步结果表明，在阻止严重的实验性癫痫发作方面，小剂量抗惊厥药物(包括GABAA激动剂和NMDA阻滞剂)的联合治疗远比相同药物的单一治疗有效，我们希望本研究建立的治疗原则将导致临床治疗癫痫持续状态的方法有所改善。 公共卫生相关性： 在美国，癫痫持续状态每年影响12.6万至19.5万例患者，估计每年有2.2万至4.2万名患者死亡。这是VH.A.急诊室中最常见的神经急救之一，事实上，有史以来对癫痫持续状态进行的最大规模的研究是VA合作研究。癫痫持续状态也是创伤性脑损伤(TBI)的常见后果，TBI是OEF/OIF退伍军人中最常见的身体损伤。

DESCRIPTION (provided by applicant): Treatment Of Status Epilepticus: A Translational Proposal Epilepsy is the most common diagnosis in VA outpatient clinics, and the large number of traumatic brain injuries in OEF/OIF is expected to result in a significant increase in its frequency among veterans. This study translates our investigations of the role of receptor trafficking in experimental SE into principles of treatment, using drugs available in the US pharmacopeia. Treatment of status epilepticus (SE) remains ineffective, with a mortality of 27% in recent population-based studies. Once seizures have started, they become self-sustaining, independent of their original trigger, and develop time-dependent pharmacoresistance. Our work (Naylor et al J Neurosci 2005) has shown that repeated seizures cause an internalization (and temporary inactivation) of synaptic GABAA receptors and an increase in synaptic NMDA receptors, which both result from seizure-induced, maladaptive receptor trafficking. These changes suggest a mechanism for the development of self-sustaining seizures (fewer GABAA receptors and more NMDA receptors in synapses) and for pharmacoresistance (fewer synaptic targets for GABAergic drugs). They also suggest that, in SE, polytherapy is more likely to be successful than monotherapy (the current gold standard), since treatment should have at least 2 targets: GABAA receptors (either preventing their internalization and/or maximally stimulating those that are left in the synapse), and NMDA receptors (preventing their movement to the synapse, or reducing their activity). Combination treatments aimed at the GABAA and NMDA systems simultaneously have not been tested extensively. Our preliminary studies explored the use of such combinations, using drugs which are currently approved for human use or are close to approval, and were able to stop severe experimental SE with low subanesthetic doses of anticonvulsants. Therapeutic success with this receptor-based approach to drug selection would confirm the importance of receptor trafficking in the pathophysiologiy of SE, and could greatly improve the effectiveness of treatment of SE. We will induce SE chemically with lithium and pilocarpine, or electrically by stimulating the perforant path, and will treat at 3 time points: after the second intense seizure, 30minutes after seizure onset, or 2 hours after seizure onset. Electroencephalogram and behavior will be recorded for 24 hours and analyzed with appropriate software. Acute histological outcome will be assessed at 72 hours, chronic epileptogenesis, behavior and histology will be studied > 3 months after SE. The importance of timing of treatment will be studied. Our preliminary results suggest that combinations of low doses of anticonvulsants which include GABAA agonists and NMDA blockers are far more effective than monotherapy with the same agents in stopping severe experimental SE, and we hope that the principles of treatment established in this study will lead to improvements in the way we treat status epilepticus clinically. PUBLIC HEALTH RELEVANCE: NARRATIVE Status epilepticus affects 126,000 to 195,000 cases a year in the USA, with an estimated mortality of 22- 42,000 patients yearly. It is one of the most common neurological emergencies in V.H.A. Emergency Rooms, and indeed the largest study of status epilepticus ever carried out was a VA Cooperative study. Status epilepticus is also a frequent consequence of traumatic brain injury (TBI), the most frequent physical injury in OEF/OIF veterans.