重症肌无力临床严重程度与神经电生理特点之间的关系及雷帕霉素治疗实验性自身免疫性重症肌无力的研究

发布时间：2019-07-09 21:14

【摘要】：第一部分：重症肌无力临床严重程度与神经电生理特点之间的关系 目的 获得性重症肌无力（acquired myasthenia gravis, MG）是一种典型的由抗体介导的自身免疫性疾病，病变主要累及神经肌肉接头。电生理检查是诊断MG的重要技术方法，其中最常用的是重复神经刺激（repetitive nerve stimulation, RNS）。多数研究仅将RNS作为一种诊断方法，而较少关注复合肌肉动作电位（compoundmuscle action potential, CMAP）波幅降低程度的意义。对MG患者行针电极肌电图（needle electrode electromyography, NEMG）检查有助于明确诊断，部分MG患者可出现肌源性受损表现，但少有研究分析解释这一现象的临床意义。本研究详细分析低频RNS检查CMAP波幅降低程度和NEMG肌源性受损与临床严重程度之间的关系，以进一步探求电生理检查结果对于MG的临床意义。 材料与方法 选取2012年1月至2013年5月期间在解放军总医院神经内科住院治疗的77例MG患者为研究对象。详细记录患者基本信息。根据患者病情采用美国重症肌无力协会（myasthenia gravis foundation of America, MGFA）临床分型。对入组患者进行规范的量化MG评分（quantified myasthenia gravis scoring system, QMG）和MG日常活动评分（MG activities of daily living, MG-ADL），用上述指标反映临床严重程度。在我院肌电图室对入组患者进行面神经、副神经、腋神经和尺神经的低频RNS检查，并对所有患者进行常规NEMG检查。统计分析RNS检查CMAP波幅降低程度与临床严重程度之间的关系。分析NEMG正常组与肌源性受损组之间临床特点之间的差异。 结果 入组77例均为明确诊断的MG患者，入组患者进行低频RNS检查CMAP波幅降低程度均达诊断标准，RNS检查结果皆为阳性。CMAP波幅降低程度与QMG和MG-ADL评分之间均有良好的相关性。刺激面神经在眼轮匝肌记录时CMAP波幅降低程度与QMG评分相关性分析结果r=0.506, P 0.001，MG-ADL相关性分析结果r=0.445, P 0.001；刺激副神经在斜方肌记录时CMAP波幅降低程度与QMG评分相关性分析结果r=0.426, P=0.019，MG-ADL相关性分析结果r=0.399,P=0.029；刺激腋神经在三角肌记录时CMAP波幅降低程度与QMG评分相关性分析结果r=0.507, P 0.001，MG-ADL相关性分析结果r=0.371, P=0.008；刺激尺神经在小指展肌记录时CMAP波幅降低程度与QMG评分相关性分析结果r=0.340, P=0.018，MG-ADL相关性分析结果r=0.364, P=0.011。结果提示这种相关性在近端肌肉记录较远端肌肉记录明显。22例（28.6%）NEMG出现运动单位电位时限缩短、波幅降低，但均无异常自发电位及异常募集相，NEMG结果提示肌源性受损。肌源性受损组QMG（P0.01）和MG-ADL（P0.01）评分均显著高于正常NEMG组。肌源性受损组MGFA分型以Ⅲ型和Ⅳ型为主，正常NEMG组以I型和II型为主，两组间MGFA分型差异有统计学意义（P0.01）。而两组在性别、发病年龄、病程、起病部位及胸腺类型之间的差异均无统计学意义（P0.05）。 结论 MG患者低频RNS检查CMAP波幅降低程度与MG患者的临床严重程度有一定的相关性，这种相关性在近端肌肉记录时更明显。CMAP波幅降低程度在一定程度上可反映MG临床严重性。部分MG患者NEMG检查可出现肌源性受损表现。出现肌源性受损的患者病情较正常NEMG者更重。NEMG结果与年龄、性别、病程、起病部位、胸腺类型无关。神经电生理检查不仅仅是诊断MG的重要技术，，其在一定程度上可提示病情的严重程度。 第二部分：雷帕霉素治疗实验性自身免疫性重症肌无力的研究 目的 雷帕霉素（rapamycin, RAPA）是一种新型大环内酯类免疫抑制剂，其通过与雷帕霉素靶蛋白结合发挥生物学效应。MG是一种自身免疫性疾病，免疫抑制剂已被广泛应用于该病的治疗。目前尚无使用RAPA治疗MG的系统性研究。在本研究中我们首次尝试使用RAPA对实验性自身免疫性重症肌无力（experimentalautoimmune myasthenia gravis, EAMG）动物模型进行治疗，并初步探索RAPA对MG治疗的可能机制。 材料与方法 使用鼠源性乙酰胆碱受体（acetylcholine receptor,AChR）α亚单位97-116肽段免疫接种Lewis大鼠诱导建立EAMG动物模型，评估动物模型临床症状，对其进行抗体检测及电生理检查，以确定动物模型的成功构建。分别使用RAPA和环磷酰胺（cyclophosphamide, CTX）干预成功建立的EAMG动物模型，并观察治疗效果。使用流式细胞技术检测大鼠外周血Treg细胞和Th17细胞的数量，比较各组间两类细胞的变化情况。 结果 使用R97-116肽段免疫接种Lewis大鼠后渐出现体重下降及无力表现，抗AChR抗体阳性，低频RNS检查结果阳性，提示EAMG动物模型建立成功，造模成功率为74.28%。药物干预后大鼠局部炎症及无力症状均有好转，RAPA组死亡率低于CTX组，体重较CTX组增加。与病例对照组相比RAPA组Treg细胞比例升高、Th17细胞比例减少；CTX组Treg细胞和Th17细胞比例均降低。两组之间Treg细胞数量差异有统计学意义（P0.01）。与空白对照组相比RAPA组CD4+T细胞数量无明显减少，而CTX组则明显减少，差异有显著统计学意义（P0.01）。结论 RAPA可有效治疗R97-116肽段免疫接种Lewis大鼠诱导的抗AChR抗体阳性EAMG动物模型。与CTX相比，RAPA干预组病死率低，体重增加，提示RAPA效果优于CTX。此外与CTX相比RAPA并未明显抑制外周CD4+T细胞增殖。与病例对照组相比，RAPA干预后Treg细胞比例升高，Th17细胞比例降低。改变Treg/Th17细胞失衡状态可能是RAPA有效治疗EAMG的机制。
文内图片：
图片说明：正常大鼠与EAMG大鼠形态对比
[Abstract]:The first part: the relationship between the clinical severity of myasthenia gravis and the physiological characteristics of the nerve Objective Acquired myasthenia gravis (MG) is a typical autoimmune disease mediated by an antibody. The electrical physiological examination is an important technique for the diagnosis of MG, most commonly used for repetitive neural stimulation, R. NS). Most studies only use the RNS as a diagnostic method and less attention to the extent of the amplitude of the complex muscle action potential (CMAP) The results of the study on the electromyography (NEMG) of the needle electrode in MG patients can help to make a clear diagnosis, and some MG patients may have myogenic damage, but few studies have been used to explain this phenomenon. The relationship between the amplitude reduction of CMAP and the severity of NEMG myogenic damage and the severity of NEMG was analyzed in detail in this study. The meaning of the bed. Materials and Methods:77 MG patients hospitalized in the Department of Neurology of the General Hospital of the PLA from January 2012 to May 2013 The patient is the subject of the study. The basic information of the patient was recorded. According to the patient's condition, the American myasthenia gravis association (America, MG) FA) Clinical classification. The standard quantitative MG score (QMG) and MG activity of daily living (MG-ADL) of the patients in the enrolled group were measured with the above-mentioned indexes. The clinical severity was shown. The patients were enrolled in the EMG room of our hospital for low-frequency RNS examination of the facial nerve, the secondary nerve, the axillary nerve and the ulnar nerve, and all the patients were treated normally. Regulatory NEMG examination. Statistical analysis of RNS to check CMAP amplitude reduction and clinical severity To analyze the relationship between the normal group of NEMG and the group of myogenic damage. characteristic The difference between the results was that all 77 patients were MG patients with clear diagnosis, and the patients were enrolled in low-frequency RNS to check the amplitude of the CMAP wave amplitude to reach the diagnostic criteria. The results of the RNS test were positive. The amplitude of the CMAP was reduced to the QMG and MG-ADL. The results of the correlation between the amplitude of CMAP and the score of QMG were r = 0.506, P 0.001, MG-ADL, r = 0.445, P 0.001 respectively. 426, P = 0.019, MG-ADL correlation analysis result r = 0.399, P = 0.029; the degree of CMAP wave amplitude reduction and QMG score correlation analysis result r = 0.507, P 0.001, MG-ADL correlation analysis result r = 0 at the time of deltoid muscle recording. Results r = 0.340, P = 0.018, MG-ADL correlation analysis result r = 0. 364, P = 0.011. The results suggested that the correlation was significant in the proximal muscle.22 (28.6%) of the NEMG showed a short time period and a decrease in amplitude, but there was no abnormal self-interest and abnormal raised phase, and NE The results indicated that the MG-ADL (P0.01) and MG-ADL (P0.01) scores of the myogenic damaged group were all higher than those of the MG-ADL (P0.01). It was significantly higher than that of the normal NEMG group. The type of MFA in the myogenic damaged group was dominated by type 鈪

本文编号：2512456