Diaphragm pacing and rehabilitation in Pompe disease

摘要 庞贝氏症是一种遗传性神经肌肉疾病，由于缺乏酶酸性α- 葡萄糖苷酶，其导致进行性膈神经病理学。由于可用的酶替代物 治疗不能治疗这种神经病理学，隔膜/膈神经肌肉功能障碍最终导致 呼吸功能不全和呼吸机依赖。因此，呼吸系统并发症是主要的 庞贝氏症的死亡原因。膈肌起搏是治疗重症肌无力的替代方法， 功能不全，通过肌内电极激活膈神经轴突。来自患者的令人兴奋的初步数据 患有庞贝氏症的患者进行了隔膜起搏，这表明它可能不仅仅是取代需要， 进行机械通气它可能对膈肌/膈神经活动有康复作用， 独立于任何类型的通气支持。虽然这些初步的发现是令人鼓舞的， 神经肌肉的可塑性几乎没有研究。 指导这一建议的基本假设是，膈肌起搏是一种新的康复方法， 增加横膈膜/膈神经活动的工具，从而提高独立潮汐的能力 卷生成。以这种方式，隔膜起搏可以促进庞贝氏症患者的呼吸机脱机。我们将 招募已接受肌内起搏器植入术的庞贝氏症患者， 慢性机械通气，然后评估起搏12周以上的康复效果， 膈肌/膈神经肌肉活动和独立呼吸能力的恢复。自发性期间 呼吸和最大自主努力，我们将研究起搏对呼吸功能的影响。此外，本发明还提供了一种方法， 直接记录人类膈肌肌电活动使用的创新应用的隔膜 肌内电极将能够纵向评估隔膜/膈活动。为了测试我们的中央 假设，我们提出了两个具体的目标：1）测试假设，一个单一的回合隔膜起搏 对横膈膜/膈神经激活和通气具有持久影响，以及2）检验以下假设： 这些效应在12周的重复的每日隔膜起搏过程中累积。这种高 风险/高影响提案将评估隔膜起搏作为一种康复工具，以增加隔膜/膈神经 提高自主呼吸能力。这项工作将提供第一个受控的经验证据， 关于隔膜起搏在庞贝氏症中恢复膈神经肌肉功能的能力， 并且可能对在其它临床病症中使用横膈膜刺激具有深远的意义， 危及呼吸。我们希望这项研究中产生的数据将成为未来机制的基础。 膈肌起搏促进神经肌肉疾病患者撤机的研究

ABSTRACT Pompe disease is an inherited neuromuscular disorder caused by a deficiency of the enzyme acid α- glucosidase, which results in progressive phrenic neuropathology. Since available enzyme replacement therapy does not treat this neuropathology, diaphragm/phrenic neuromuscular dysfunction ultimately leads to ventilatory insufficiency and ventilator dependence. Consequently, respiratory complications are the leading cause of mortality in Pompe disease. Diaphragm pacing is an alternative approach to treat critical ventilatory insufficiency, activating phrenic axons through intramuscular electrodes. Exciting preliminary data from patients with Pompe disease who have undergone diaphragm pacing suggests it may do more than replace the need for mechanical ventilation. It may have a rehabilitative effect on diaphragm/phrenic activity, restoring some independence from ventilatory support of any kind. While these initial findings are encouraging, pacing-induced neuromuscular plasticity has scarcely been studied. The fundamental hypothesis guiding this proposal is that diaphragm pacing is a novel rehabilitative tool to increase diaphragm/phrenic activity, thereby improving the capacity for independent tidal volume generation. In this way, diaphragm pacing may promote ventilator weaning in Pompe disease. We will recruit patients with Pompe disease who have undergone intramuscular pacemaker implantation to replace chronic mechanical ventilation, and then evaluate the rehabilitative effects of pacing over 12 weeks on diaphragm/phrenic neuromuscular activity and recovery of independent breathing ability. During spontaneous breathing and maximal voluntary efforts, we will investigate pacing effects on breathing function. In addition, direct recordings of human diaphragm EMG activity using an innovative application of the diaphragm intramuscular electrodes will enable longitudinal evaluations of diaphragm/phrenic activity. To test our central hypothesis, we propose two specific aims: 1) test the hypothesis that a single bout of diaphragm pacing has lasting effects on diaphragm/phrenic activation and ventilation, and 2) test the hypothesis that these effects accumulate over 12 weeks of repeated, daily diaphragm pacing sessions. This high risk/high impact proposal will evaluate diaphragm pacing as a rehabilitative tool to increase diaphragm/phrenic activity and improve independent breathing ability. This work will provide the first controlled, empirical evidence concerning the ability of diaphragm pacing to rehabilitate phrenic neuromuscular function in Pompe disease, and may have profound implications for the use of diaphragm stimulation in other clinical disorders that compromise breathing. Our hope is that data generated in this study will form the basis for a future mechanistic study of diaphragm pacing to promote ventilator weaning in neuromuscular disease.