The role of central CO2 chemosensitivity in postictal respiratory depression and SUDEP

摘要 高达50%的难治性癫痫患者会发生癫痫猝死(SUDEP)， 是这群人的主要死因。因为负责SUDEP的机制还没有 明确定义，没有特定的治疗方法来预防它。来自人类和动物的最新观察 研究表明，癫痫引起的呼吸骤停通常先于心搏停止，而且许多患者 癫痫发作后出现不同程度的呼吸抑制。有一个根本性的差距， 了解癫痫发作如何抑制呼吸，以及为什么一些患者会出现严重的后遗症呼吸 抑郁症和其他人则不是。低中枢二氧化碳化学敏感性可导致呼吸抑制，以及 这可能是SUDEP的先天诱因，但尚未在该人群中进行研究。长期目标是 通过阐明癫痫诱发的机制来开发新的治疗方法来预防SUDEP 通过识别生物标记物来识别风险最高的患者。这里的目标是 通过测量来表征二氧化碳化疗敏感性与后遗症呼吸抑制的关系 癫痫患者发作间期和发作期高碳酸血症呼吸反应的斜率 后遗症。中心假说是低血压病患者术后低通气量更严重。 发作间期或发作后对二氧化碳的化疗敏感性。这一假说是基于人和动物提出的。 从申请人自己的实验室获得的数据，也表明5-羟色胺(5-羟色胺)缺陷的数据可能 为SUDEP做出贡献。因为已知5-羟色胺神经元对正常的二氧化碳化学敏感性很重要， 刺激呼吸和大脑皮层觉醒，这项拟议研究的理由是，有缺陷的化学物质- 敏感性可能与SUDEP的病理生理机制有关。核心假说将通过追查来检验 3具体目标。(1)确定基线(发作间期)中枢二氧化碳敏感性与 后遗症呼吸抑制。(2)确定癫痫发作对中枢二氧化碳化学敏感性的影响。(三)确定 癫痫患者HCVR随时间变化的稳定性及其与癫痫的关系 控制力。在AIMS 1和2中，癫痫监测股入院的患者将在 发作间期和发作后。基线hcvr的斜率将与二氧化碳的发作变化相关联。 水平和其他心肺变量(目标1)，不同癫痫发作对HCVR斜率的影响将为 已测量(目标2)。HCVR的个体内变异性及其稳定性与癫痫控制(AIM)的关系 3)将通过在两年内测量4次HCVR来确定。这种方法是创新的，因为它 首次直接检测脑脊液后通气量与中枢二氧化碳化疗敏感性的关系 发作期和发作后状态。这项拟议的研究具有重要意义，因为确定了 参与后遗症呼吸抑制可能导致SUDEP一个新的生物标志物(HCVR)的识别 风险和开发新的治疗方法，以保护死后的通风。

Abstract Sudden Unexpected Death in Epilepsy (SUDEP) occurs in up to 50% of patients with refractory epilepsy and is the leading cause of death in this population. Because the mechanisms responsible for SUDEP have not been clearly defined, there are no specific treatments to prevent it. Recent observations from human and animal studies indicate that seizure-induced respiratory arrest typically precedes asystole, and that many patients experience varying degrees of respiratory depression following seizures. There is a fundamental gap in understanding how seizures depress respiration, and why some patients develop severe postictal respiratory depression and others do not. Low central CO2 chemosensitivity can contribute to respiratory depression, and it is possible that this predisposes to SUDEP, but has not been studied in this population. The long-term goal is to develop new treatments to prevent SUDEP by elucidating the mechanisms responsible for seizure-induced respiratory depression and by identifying biomarkers to identify patients at highest risk. The objective here is to characterize the relationship between CO2 chemosensitivity and postictal respiratory depression by measuring the slope of the hypercapnic ventilatory response (HCVR) in patients with epilepsy during the interictal and postictal states. The central hypothesis is that postictal hypoventilation will be more severe in patients with low interictal or postictal CO2 chemosensitivity. This hypothesis has been formulated based on human and animal data obtained from the applicants’ own laboratories, data that also suggest serotonin (5-HT) defects may contribute to SUDEP. Because 5-HT neurons are known to be important for normal CO2 chemosensitivity that stimulates breathing and cortical arousal, the rationale for the proposed research is that defective chemo- sensitivity might contribute to the pathophysiology of SUDEP. The central hypothesis will be tested by pursuing 3 specific aims. (1) Determine the relationship between baseline (interictal) central CO2 chemosensitivity and postictal respiratory depression. (2) Determine how seizures affect central CO2 chemosensitivity. (3) Determine the stability of the HCVR over time in patients with epilepsy, and the relationship of the HCVR to epilepsy control. In Aims 1 and 2 patients admitted to the Epilepsy Monitoring Unit will undergo HCVR testing during the interictal and postictal periods. The slope of the baseline HCVR will be correlated with ictal changes in CO2 levels and other cardiorespiratory variables (Aim 1), and the effect of different seizures on HCVR slope will be measured (Aim 2). The intraindividual variability of the HCVR and its stability in relation to epilepsy control (Aim 3) will be determined by measuring the HCVR 4 times over 2 years. This approach is innovative because it is the first to directly examine the relationship between postictal ventilation and central CO2 chemosensitivity in the ictal and postictal states. The proposed research is significant because identifying the mechanisms involved in postictal respiratory depression may lead to identification of a novel biomarker (HCVR) for SUDEP risk and to development of new treatments designed to defend ventilation in the postictal period.