目前全球癫痫患病人口已经超过6500万，其中30%-40%为药物难治性癫痫。药物难治性癫痫患者常伴有不同程度的心脏自主神经功能损伤，但既往相关研究的结论不相一致、甚至相互矛盾。而迷走神经刺激作为治疗药物难治性癫痫的辅助技术，虽然在临床上取得了广泛的应用，但迷走神经刺激的急性、长期心脏自主神经功能效应仍不清楚。此外，迷走神经刺激治疗癫痫的疗效存在极大的个体差异，很大程度上阻碍了迷走神经刺激疗法的临床推广。本文主要基于心电信号评估药物难治性癫痫患者的心脏自主神经功能及其急性、长期迷走神经刺激效应，在此基础上探索个体化刺激参数设计方法和迷走神经刺激治疗癫痫的疗效预测因子。首先，在传统心率变异性分析方法的基础上，结合相位整序信号平均、多尺度熵方法，分析了70例药物难治性癫痫患者和50例健康对照的24小时动态心电信号，结果表明药物难治性癫痫患者的心脏自主神经功能受损，主要表现为交感神经和迷走神经张力的减弱和心率复杂度的降低。此外，药物难治性癫痫患者的心率变异性昼夜节律被整体抑制，这种心脏自主神经功能失调的情况在夜间表现的尤为突出，可能与夜间癫痫猝死的高发生率有关。其次，基于32例接受迷走神经刺激手术的药物难治性癫痫患者术前基线和术后12个月以及32例健康对照的24小时动态心电信号，研究了长期迷走神经刺激的心脏自主神经功能效应，揭示了迷走神经刺激在治疗癫痫的同时，一定程度上逆转了药物难治性癫痫患者原本损伤的心率复杂度，改善了心脏自主神经功能。而不同参数迷走神经刺激的急性心脏自主神经功能效应研究结果表明，电流幅度与迷走神经刺激引起的心率变异性参数的变化量呈显著正相关。最后，基于32例药物难治性癫痫患者急性、长期迷走神经刺激的心脏自主神经功能效应，发现了迷走神经刺激疗效与心率复杂度改善及心率变异性指标变化量的关系，为迷走神经刺激治疗癫痫的机制提供了新的线索，也为个体化刺激参数选择提供了客观依据。此外，本文首次提出了基于术前心电信号的迷走神经刺激疗效预测因子，并验证了其可行性，为临床迷走神经刺激手术适应证患者的筛选提供了客观的依据，有利于提高其整体临床疗效。
More than 65 million people worldwide have epilepsy, with 30%-40% of these patients being refractory to medical treatment and are considered as drug-resistant epilepsy. Drug-resistant epilepsy is related to the dysfunction of the autonomic nervous system. Previous studies have investigated the effects of epilepsy on the cardiac autonomic control, with findings being mixed or even contradictory. Despite the growing application of vagus nerve stimulation (VNS) as an adjunctive therapy for drug-resistant epilepsy in the clinic, the acute and long-term effects of VNS on cardiac autonomic regulation in patients with drug-resistant epilepsy remains poorly understood and needs further research. There are large individual differences in the efficacy of VNS for treatment of drug-resistant epilepsy, which limits the use of VNS in patients with epilepsy and hinders clinical application. The present studies were designed to evaluate the cardiac autonomic function and to elucidate possible acute and long-term effects of VNS on heart rate variability (HRV) in patients with drug-resistant epilepsy. This was conducted by using long-term and short-term ambulatory electrocardiogram (ECG) recordings. Furthermore, the aim of our studies were to explore the programming method of patient-specific stimulation parameters and to identify predictive factors for seizure reduction after VNS treatment.Firstly, traditional HRV analysis as well as phase rectified signal averaging (PRSA) and multiscale entropy methods were used to analyze 24-hour ambulatory ECG recordings of 70 patients with drug-resistant epilepsy and 50 healthy controls. The results showed that the cardiac autonomic control of heart rate is impaired in drug-resistant epilepsy, with worse heart rhythm complexity and combined inhibition of sympathetic and vagal tone. In addition, the cardiac autonomic dysregulation of patients with drug-resistant epilepsy was also reflected by alterations in circadian rhythm of HRV, with more obvious suppression observed during the night time. This suggested that nocturnal inhibition of HRV may contribute to the high risk of sudden unexpected death in epilepsy (SUDEP) during the night.Secondly, 24-hour ECG signals were recorded at the baseline and after 12 months of VNS treatment in 32 patients with drug-resistant epilepsy, which were compared to 32 healthy control subjects. HRV indices were analyzed to elucidate the possible long-term effects of VNS on cardiac autonomic regulation. The results indicated that long-term VNS provides palliation of seizure reduction for patients with drug-resistant epilepsy and, at least, partially reversing the heart rhythm complexity. Therefore, VNS can improve cardiac autonomic function, which is impaired due to epilepsy. Moreover, the acute effects of different stimulation parameters of VNS on cardiac autonomic function showed that there is a significant positive correlation between the amplitude of the output current and changes in HRV parameters.Finally, our study demonstrated that the efficacy of VNS is associated with improvement of heart rhythm complexity and changes in HRV indices, based on the analysis of acute and long-term effects of VNS on cardiac autonomic function for 32 patients with drug-resistant epilepsy. The result provides a new clue on the mechanism of VNS treatment in epilepsy and also gives an objective basis for the selection of individual stimulus parameters of VNS. To the best of our knowledge, this is the first study that has focused on predicting VNS outcome with preoperative HRV measurements in patients with drug-resistant epilepsy. This knowledge on HRV as predictors of VNS responsiveness is important for objectively optimizing patient selection and is conductive to improving the overall clinical efficacy of VNS treatments.
