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

摘要 癫痫猝死（SUDEP）发生在高达50%的难治性癫痫患者中， 是这个群体的主要死因因为负责SUDEP的机制尚未被 虽然定义明确，但没有具体的治疗方法来预防它。 研究表明，呼吸暂停引起的呼吸骤停通常先于心搏停止， 癫痫发作后会出现不同程度的呼吸抑制。有一个根本的差距， 了解癫痫发作如何抑制呼吸，以及为什么有些患者会出现严重的发作后呼吸道疾病， 抑郁症和其他人没有。低中枢CO2化学敏感性可导致呼吸抑制， 这可能是SUDEP的易感因素，但尚未在该人群中进行研究。长期目标是 开发新的治疗方法，以防止SUDEP通过阐明机制， 呼吸抑制，并通过识别生物标志物来识别风险最高的患者。我们的目标是 通过测量来表征CO2化学敏感性和发作后呼吸抑制之间的关系 癫痫患者在发作间期和发作后10分钟内高碳酸血症缓解反应（HCVR）的斜率 发作后状态中心假设是发作后低通气患者会更严重， 发作间期或发作后CO2化学敏感性。这一假设是根据人类和动物的 从申请人自己的实验室获得的数据，也表明血清素（5-HT）缺陷的数据， 为SUDEP做出贡献。因为已知5-HT神经元对于正常的CO2化学敏感性是重要的， 刺激呼吸和皮层唤醒，拟议研究的基本原理是，有缺陷的化疗， 敏感性可能有助于SUDEP的病理生理学。中心假设将通过以下方式进行检验： 3具体目标(1)确定基线（发作间期）中枢CO2化学敏感性与 发作后呼吸抑制(2)确定癫痫发作如何影响中枢CO2化学敏感性。(3)确定 癫痫患者HCVR随时间的稳定性，以及HCVR与癫痫的关系 控制在目标1和2中，癫痫监测单元收治的患者将在治疗期间接受HCVR测试。 发作间期和发作后期。基线HCVR的斜率将与CO2的发作变化相关 水平和其他心肺变量（目的1），以及不同癫痫发作对HCVR斜率的影响将被 目标2（Aim 2）HCVR的个体内变异性及其与癫痫控制相关的稳定性（目的 3)将通过在2年内测量4次HCVR来确定。这种方法是创新的，因为它是 第一个直接检查发作后通气和中枢CO2化学敏感性之间的关系， 发作和发作后状态。这项研究的意义在于， 参与发作后呼吸抑制可能导致识别SUDEP的新生物标志物（HCVR） 风险和开发旨在保护发作后通气的新治疗方法。

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.