Treatment of status epilepticus: a translational proposal.

描述(由申请人提供)： 本项目旨在研究亚低温治疗难治性癫痫持续状态(RSE)。在退伍军人重症监护室，RSE是一个越来越常见的问题。这可能是由于生命支持系统和ICU技术的改进，由于EEG记录的可用性增加，以及对“微妙”癫痫状态(SE)和其他因素的认识增加。RSE的治疗效果很差，死亡率和发病率都很高。需要新的治疗方法。深低温(200摄氏度)在心脏手术和神经外科手术中临床使用。中低温(32-330℃)是新生儿缺氧缺血性脑病、心脏骤停后脑病和创伤性脑损伤的常规治疗方法。事实证明，在这些条件下，低温治疗是安全有效的。它还被证明可以抑制癫痫发作的活性。然而，它很少用于治疗RSE，我们对它的适应症和有效性缺乏基本的了解。我们将在两种实验性癫痫持续状态模型中测试深低温降低癫痫发作活性的假设，该模型分别由化学物质(锂和匹罗卡品)或电刺激(穿透通路)诱导。 大脑。我们将比较深低温和亚低温，并测试不同的亚低温持续时间，以了解较长时间的亚低温在终止RSE方面是否与短时间的深低温一样有效。我们将比较两种提供低温的方法：全身降温和头部降温(“凉帽”)。对于相同水平的顶叶皮质降温，我们预计全身降温在终止SE方面比“凉帽”法更有效。最后，我们将研究低温治疗对RSE的长期后果的影响：神经元损伤、血脑屏障破坏、细胞介导性炎症、癫痫发生和行为障碍。我们希望低温治疗能减少所有这些并发症。在这项研究结束时，我们希望能够确定在实验性癫痫持续状态治疗中最有效的低温深度、持续时间和方法。

DESCRIPTION (provided by applicant): PROJECT SUMMARY This project proposes to study hypothermia as a treatment of refractory status epilepticus (RSE). RSE is an increasingly common problem in VA Intensive Care Units. This may be due to improvement in life support systems and ICU technology, to increased availability of EEG recordings and increased recognition of "subtle" status epilepticus (SE) and other factors. The results of treatment of RSE are very poor, with high mortality and morbidity. New treatments are needed. Deep hypothermia (200 C) is used clinically during cardiac surgery and neurosurgery. Moderate hypothermia (32-330 C) is used routinely in the treatment of neonatal hypoxic- ischemic encephalopathy, of post-cardiac arrest encephalopathy and of traumatic brain injury. Hypothermia has proved safe and effective in those conditions. It has also been shown to inhibit seizure activity. Yet, it is rarely used to treat RSE, and we lack a basic understanding of its indications and effectiveness in RSE. We will test the hypothesis that deep hypothermia reduces seizure activity in two models of experimental status epilepticus induced respectively by chemical (lithium and pilocarpine) or by electrical (perforant path) stimulation of the brain. We will compare deep and mild hypothermia, and will test different durations of mild hypothermia, to find out whether longer durations of mild hypothermia can be as effective in terminating RSE as short durations of deep hypothermia. We will compare two methods for delivering hypothermia: whole body cooling and head cooling ("cool cap"). For the same level of cooling of parietal cortex, we expect whole body cooling is more effective than the "cool cap" method in terminating SE. Finally, we will study the effect of hypothermia treatment on the long-term consequences of RSE: neuronal injury, blood-brain barrier breakdown, cell-mediated inflammation, epileptogenesis and behavioral deficits. We expect hypothermia treatment to reduce all of these complications. At the end of this study, we expect to be able to define the depth, duration and method of hypothermia that is most effective in the treatment of experimental status epilepticus.