發(fā)布時(shí)間：2019-07-09 21:14

【摘要】：第一部分：重癥肌無(wú)力臨床嚴(yán)重程度與神經(jīng)電生理特點(diǎn)之間的關(guān)系 目的 獲得性重癥肌無(wú)力（acquired myasthenia gravis, MG）是一種典型的由抗體介導(dǎo)的自身免疫性疾病，病變主要累及神經(jīng)肌肉接頭。電生理檢查是診斷MG的重要技術(shù)方法，其中最常用的是重復(fù)神經(jīng)刺激（repetitive nerve stimulation, RNS）。多數(shù)研究?jī)H將RNS作為一種診斷方法，而較少關(guān)注復(fù)合肌肉動(dòng)作電位（compoundmuscle action potential, CMAP）波幅降低程度的意義。對(duì)MG患者行針電極肌電圖（needle electrode electromyography, NEMG）檢查有助于明確診斷，部分MG患者可出現(xiàn)肌源性受損表現(xiàn)，但少有研究分析解釋這一現(xiàn)象的臨床意義。本研究詳細(xì)分析低頻RNS檢查CMAP波幅降低程度和NEMG肌源性受損與臨床嚴(yán)重程度之間的關(guān)系，以進(jìn)一步探求電生理檢查結(jié)果對(duì)于MG的臨床意義。 材料與方法 選取2012年1月至2013年5月期間在解放軍總醫(yī)院神經(jīng)內(nèi)科住院治療的77例MG患者為研究對(duì)象。詳細(xì)記錄患者基本信息。根據(jù)患者病情采用美國(guó)重癥肌無(wú)力協(xié)會(huì)（myasthenia gravis foundation of America, MGFA）臨床分型。對(duì)入組患者進(jìn)行規(guī)范的量化MG評(píng)分（quantified myasthenia gravis scoring system, QMG）和MG日�；顒�(dòng)評(píng)分（MG activities of daily living, MG-ADL），用上述指標(biāo)反映臨床嚴(yán)重程度。在我院肌電圖室對(duì)入組患者進(jìn)行面神經(jīng)、副神經(jīng)、腋神經(jīng)和尺神經(jīng)的低頻RNS檢查，并對(duì)所有患者進(jìn)行常規(guī)NEMG檢查。統(tǒng)計(jì)分析RNS檢查CMAP波幅降低程度與臨床嚴(yán)重程度之間的關(guān)系。分析NEMG正常組與肌源性受損組之間臨床特點(diǎn)之間的差異。 結(jié)果 入組77例均為明確診斷的MG患者，入組患者進(jìn)行低頻RNS檢查CMAP波幅降低程度均達(dá)診斷標(biāo)準(zhǔn)，RNS檢查結(jié)果皆為陽(yáng)性。CMAP波幅降低程度與QMG和MG-ADL評(píng)分之間均有良好的相關(guān)性。刺激面神經(jīng)在眼輪匝肌記錄時(shí)CMAP波幅降低程度與QMG評(píng)分相關(guān)性分析結(jié)果r=0.506, P 0.001，MG-ADL相關(guān)性分析結(jié)果r=0.445, P 0.001；刺激副神經(jīng)在斜方肌記錄時(shí)CMAP波幅降低程度與QMG評(píng)分相關(guān)性分析結(jié)果r=0.426, P=0.019，MG-ADL相關(guān)性分析結(jié)果r=0.399,P=0.029；刺激腋神經(jīng)在三角肌記錄時(shí)CMAP波幅降低程度與QMG評(píng)分相關(guān)性分析結(jié)果r=0.507, P 0.001，MG-ADL相關(guān)性分析結(jié)果r=0.371, P=0.008；刺激尺神經(jīng)在小指展肌記錄時(shí)CMAP波幅降低程度與QMG評(píng)分相關(guān)性分析結(jié)果r=0.340, P=0.018，MG-ADL相關(guān)性分析結(jié)果r=0.364, P=0.011。結(jié)果提示這種相關(guān)性在近端肌肉記錄較遠(yuǎn)端肌肉記錄明顯。22例（28.6%）NEMG出現(xiàn)運(yùn)動(dòng)單位電位時(shí)限縮短、波幅降低，但均無(wú)異常自發(fā)電位及異常募集相，NEMG結(jié)果提示肌源性受損。肌源性受損組QMG（P0.01）和MG-ADL（P0.01）評(píng)分均顯著高于正常NEMG組。肌源性受損組MGFA分型以Ⅲ型和Ⅳ型為主，正常NEMG組以I型和II型為主，兩組間MGFA分型差異有統(tǒng)計(jì)學(xué)意義（P0.01）。而兩組在性別、發(fā)病年齡、病程、起病部位及胸腺類型之間的差異均無(wú)統(tǒng)計(jì)學(xué)意義（P0.05）。 結(jié)論 MG患者低頻RNS檢查CMAP波幅降低程度與MG患者的臨床嚴(yán)重程度有一定的相關(guān)性，這種相關(guān)性在近端肌肉記錄時(shí)更明顯。CMAP波幅降低程度在一定程度上可反映MG臨床嚴(yán)重性。部分MG患者NEMG檢查可出現(xiàn)肌源性受損表現(xiàn)。出現(xiàn)肌源性受損的患者病情較正常NEMG者更重。NEMG結(jié)果與年齡、性別、病程、起病部位、胸腺類型無(wú)關(guān)。神經(jīng)電生理檢查不僅僅是診斷MG的重要技術(shù)，，其在一定程度上可提示病情的嚴(yán)重程度。 第二部分：雷帕霉素治療實(shí)驗(yàn)性自身免疫性重癥肌無(wú)力的研究 目的 雷帕霉素（rapamycin, RAPA）是一種新型大環(huán)內(nèi)酯類免疫抑制劑，其通過(guò)與雷帕霉素靶蛋白結(jié)合發(fā)揮生物學(xué)效應(yīng)。MG是一種自身免疫性疾病，免疫抑制劑已被廣泛應(yīng)用于該病的治療。目前尚無(wú)使用RAPA治療MG的系統(tǒng)性研究。在本研究中我們首次嘗試使用RAPA對(duì)實(shí)驗(yàn)性自身免疫性重癥肌無(wú)力（experimentalautoimmune myasthenia gravis, EAMG）動(dòng)物模型進(jìn)行治療，并初步探索RAPA對(duì)MG治療的可能機(jī)制。 材料與方法 使用鼠源性乙酰膽堿受體（acetylcholine receptor,AChR）α亞單位97-116肽段免疫接種Lewis大鼠誘導(dǎo)建立EAMG動(dòng)物模型，評(píng)估動(dòng)物模型臨床癥狀，對(duì)其進(jìn)行抗體檢測(cè)及電生理檢查，以確定動(dòng)物模型的成功構(gòu)建。分別使用RAPA和環(huán)磷酰胺（cyclophosphamide, CTX）干預(yù)成功建立的EAMG動(dòng)物模型，并觀察治療效果。使用流式細(xì)胞技術(shù)檢測(cè)大鼠外周血Treg細(xì)胞和Th17細(xì)胞的數(shù)量，比較各組間兩類細(xì)胞的變化情況。 結(jié)果 使用R97-116肽段免疫接種Lewis大鼠后漸出現(xiàn)體重下降及無(wú)力表現(xiàn)，抗AChR抗體陽(yáng)性，低頻RNS檢查結(jié)果陽(yáng)性，提示EAMG動(dòng)物模型建立成功，造模成功率為74.28%。藥物干預(yù)后大鼠局部炎癥及無(wú)力癥狀均有好轉(zhuǎn)，RAPA組死亡率低于CTX組，體重較CTX組增加。與病例對(duì)照組相比RAPA組Treg細(xì)胞比例升高、Th17細(xì)胞比例減少；CTX組Treg細(xì)胞和Th17細(xì)胞比例均降低。兩組之間Treg細(xì)胞數(shù)量差異有統(tǒng)計(jì)學(xué)意義（P0.01）。與空白對(duì)照組相比RAPA組CD4+T細(xì)胞數(shù)量無(wú)明顯減少，而CTX組則明顯減少，差異有顯著統(tǒng)計(jì)學(xué)意義（P0.01）。結(jié)論 RAPA可有效治療R97-116肽段免疫接種Lewis大鼠誘導(dǎo)的抗AChR抗體陽(yáng)性EAMG動(dòng)物模型。與CTX相比，RAPA干預(yù)組病死率低，體重增加，提示RAPA效果優(yōu)于CTX。此外與CTX相比RAPA并未明顯抑制外周CD4+T細(xì)胞增殖。與病例對(duì)照組相比，RAPA干預(yù)后Treg細(xì)胞比例升高，Th17細(xì)胞比例降低。改變Treg/Th17細(xì)胞失衡狀態(tài)可能是RAPA有效治療EAMG的機(jī)制。
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圖片說(shuō)明：正常大鼠與EAMG大鼠形態(tài)對(duì)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

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