多系统萎缩非运动症状量表研制及其证候规律和温肾健脑方疗效观察

发布时间：2018-06-26 01:29

本文选题：多系统萎缩 + 非运动症状　；参考：《北京中医药大学》2017年博士论文

【摘要】：研究背景:多系统萎缩(Multiple System Atrophy,MSA)是累及多个系统的复杂神经系统变性疾病,其广泛存在的以自主神经功能障碍为主的非运动症状(non-motor symptoms,NMS)是疾病的重要组成部分,严重影响着病情和患者生存质量。但是现有量表多为评价MSA神经功能缺损和肢体残障,不能针对其包含的复杂非运动症状进行测量,因而多系统萎缩非运动症状量表(Multiple System Atrophy Non-motor Symptoms Scale,MSA-NMSS)亟待研制,并可应用于中医药治疗MSA疗效评价方面。MSA在世界范围内目前尚缺乏有效的治疗方法,西药干预多采用对症治疗,远期疗效不明确,中药治疗MSA具有治病求本、靶点多的特点,但现有中医药治疗MSA文献缺乏是否能够延缓疾病进展的相关论证及客观指标评价;而中医药治疗的核心是病因病机分析,分析MSA证候规律和演变可以指导中医药诊治和明确预后,因此开展大样本量中药治疗MSA疗效观察及证候分析研究。研究方法:研究共分为三个部分:第一部分是MSA-NMSS的研制,参考国际患者报告结局量表研制方法,主要分为条目池构成、预调查量表形成、临床调查、条目筛选、性能考核五个步骤。①首先构建量表概念框架,MSA-NMSS是用于测量MSA非运动症状严重程度,并以患者生存质量为最后测量目的。并根据文献MSA非运动症状初步构想量表结构13个方面。条目由以下三个方面获取:理论模型即文献;参考统一多系统萎缩评估量表(UMSARS)和帕金森非运动症状量表(NMSS)等量表;应用头脑风暴法以病人为中心提出条目,并统计既往收集MSA患者70例进行整理分析。②以德尔菲专家咨询法筛选条目池,即背对背分别发往全国多临床中心MSA权威专家做出重要性评分、熟悉程度评分。进行小范围测试即语言调试和条目再改造,整理制成预调查量表。③临床调查样本量以最少条目数的5倍约200例MSA患者,同时发放UMSARS问卷;并收集年龄、文化程度与MSA患者具有可比性的健康正常人;中药治疗后3个月对MSA患者进行二次复测。④对预调查结果分别以离散趋势法、逐步回归分析进行条目筛选,用探索性因子分析求出实际维度数目并命名,再综合专家协商意见进行条目筛选,最后以Pearson相关系数和克朗巴赫系数法(Cronbach's Alpha)再次筛选条目。⑤量表考核主要分为信度、效度和反应度,信度检测用Cronbach' s Alpha法,效度考核分为效标效度即前述Pearson相关系数法,和区分效度即比较MSA和健康正常受试两类人群得分的差别。反应度用秩和分析方法判断中药治疗前后MSA患者的得分。第二部分是观察温肾健脑经验方加减治疗MSA前后的疗效。收集MSA患者中药治疗前①UMSARS评分、UMSARS第四项整体失能等级、进展程度(=评分/病程);②非运动症状尿失禁评分、夜尿次数、导尿次数,直立性血压数值。中药治疗后①半个月,1个月,3个月,6个月,12个月每一个时点UMSARS评分,UMSARS第四项整体失能等级,进展程度(=此时点评分/此时点每人病程年数);②非运动症状包括治疗后3个月、6个月、12个月尿失禁评分、夜尿次数、导尿次数,直立性血压数值;③患者主诉改善症状,改善人次,及改善率。随访记录中药治疗后24个月,36个月,48个月UMSARS评分,UMSARS第四项整体失能等级,进展程度。第三部分是对MSA进行证候特征分析。采用横断面分析方法,采集所有符合入组标准的MSA患者一般情况及证候分析所用的四诊信息,提取证候要素,统计证候要素频次,百分比,归纳证候要素组成分布;以类型或平均值为界进行证素的分组进行比较,探讨证候要素与病程、疾病严重程度、疾病分型的相关性,总结证候规律。研究结果:第一部分条目池形成共63个条目,13个维度,经德尔菲专家咨询法筛选条目池形成53个条目初稿,进行小范围测试和条目再改造,整理制成共37个条目的预调查量表。临床调查收集入组MSA患者202例,男118例,女84例,平均年龄58.97±7.94岁,平均病程5.17±2.13年。其中C型96例,P型61例;C+P型和P+C型(无法确定优势分型,根据起病症状先后)45例。健康正常人202例,男82例,女120例,平均年龄61.96±7.86岁。调查后经离散趋势、逐步回归分析、因子分析、专家协商意见进行条目筛选形成了 12个维度、35个条目的量表。以Pearson相关系数、克朗巴赫系数法为主评价量表性能,结果显示:①信度考核:量表的总alpha值=0.854,是可以接受的范围。检验每个条目对整体量表一致性的贡献程度,心慌心悸条目得分低且临床发生率低故予以删除。②效度考核:MSA患者与健康正常人的量表总分秩均值差异大,且p=0.0000.05,两组有显著性差异,说明量表总体区分效度良好。然而维度12消化功能方面,MSA患者与健康正常人差别不显著(p=0.927)。③反应度:量表总分二者差别p=0.6190.05,整体失能等级二者差别p=0.0050.01,说明治疗后3个月整体病情严重程度较治疗前显著加重,但非运动症状没有显著差异,具体表现在维度1全身症状、2认知功能、12消化功能方面,治疗后3个月明显比治疗前加重(p分别为0.044、0.000、0.001);在维度4睡眠症状、9排便功能方面,治疗后3个月明显比治疗前减轻(p分别为0.000和0.000)。目前没有相对应MSA-NMSS的统一评价指标可以用来判断治疗前后非运动症状是否真实发生了变化以验证反应度,但文献显示中药治疗主要改善血压、二便、头晕症状,临床研究前期基础显示失眠、便秘、RBD改善明显,基本与MSA-NMSS改善睡眠症状、排便功能吻合,说明MSA-NMSS具备较好的反应度。第二部分收集入组MSA患者225例,平均病程5.20±2.15年,最长者12年。C型99例,P型72例;C+P型和P+C型54例。坚持服中药MSA患者共130例。服药时间最短半个月,最长45个月。其中男性75例,女性55例,平均年龄59.10±8.08岁,平均病程4.61±2.18年,最短1年,最长11年;C型58例,P型39例,C+P或P+C型混合型33例;很可能的MSA 112例,可能的MSA 18例。UMSARS评分最高者100分。130例坚持服中药MSA患者中,因从C型转化为P型致病情恶化者14例;因骨折致病情恶化者1例;因停服中药病情恶化者13例,最短1周,最长1年,停服中药病情恶化再服中药病情好转者3例。主要分为疾病进展程度、患者主诉改善症状、非运动症状三个部分(由于数据缺失各部分病例数不同)。①病情进展程度累计396人次(不同时点人次),在中药治疗半个月时,平均病情进展程度及平均整体失能等级进展都达到顶峰,之后便开始下降,在治疗1个月时,病情平均进展程度略低于治疗前水平。在中药治疗12个月时,平均进展程度约为治疗前的4/5,平均整体失能等级进展约为治疗前的9/10,病程约是治疗前平均病程(4.4年)的5/4。在中药治疗24个月、36个月及45个月时平均进展程度和平均整体失能等级进展仍呈现下降的趋势,分别约为治疗前的4/5,3/5,2/5;以及9/10,7/10,2/5。考虑95例缺失数据因素,中药至少可以延缓57.8%(130/225)的MSA患者疾病进展。②患者主诉改善症状结果显示,MSA患者主诉改善症状前10位依次为直立性低血压或晕厥、RBD、尿失禁、拍便困难、夜尿、尿不尽、精神状态、乏力、失眠、言语含糊。其中直立性低血压或晕厥的改善率44.6%,其次为二便症状,总计改善率约56.9%,另外由于精神体力睡眠改善共计18.7%,因语声低微、双腿乏力造成的言语及行走障碍也可以得到一定缓解。③非运动症状由于缺失数据,4个时点数据完整者38人次,不完整者111人次。38人次统计结果显示,温肾健脑经验方加减治疗后3个月较治疗前的平均尿失禁评分、平均夜尿次数有所减少(减幅分别为2%和6%),平均导尿次数(包括压腹导尿)有所增加(增幅6%)。中药治疗6个月、12个月后三者均较治疗前有所增加,12个月时增幅分别为42%、8%、59%。111人次统计结果增减趋势与38人次基本相同。直立性血压数值38人次结果显示,治疗前平均卧立位收缩压差26.32mmHg,平均卧立位舒张压差14.47 mmHg;整体治疗后平均卧立位收缩压差23.25mmHg,平均卧立位舒张压差11.84mmHg。其中,经正态分布检验治疗前与治疗后6个月平均卧立位血压差均呈正态分布,配对样本t检验显示两组收缩压有较显著差异(收缩压差*P=0.0360.05)。111人次结果示12个月时数据有所反复,但趋势大致相同。第三部分收集MSA患者共194例,其中114例男性,80例女性,平均年龄59.03±9.13岁;160例很可能的MSA,34例可能的MSA;C型93例,P型59例,C+P或P+C混合型42例;平均病程4.38±2.09年,平均UMSARS评分42.64±16.11分。主要分为证素频次分析,证素与疾病分型病程、疾病严重程度相关性,以及中药治疗前后证候变化三个部分。①证素频次显示共29种证候要素,从高到低前10位分别是血瘀、痰湿、肾(气)虚、肾阳虚、肾阴虚、痰热、血虚、脾虚、内热、阴虚。虚证中以肾虚,包括肾阳虚、肾阴虚为主,其次为血虚、脾虚、阴虚等,以肝病为主要病机的肝阴虚、肝血虚及肝风内动所占比例不高。虚证所占比例高,前5位证素三虚两实。②疾病分型辨证结果显示,MSA总体病机虚多实少,寒多热少;虚证以肾虚为主,气虚其次;实证乃痰、湿多见。P型多见热证、血虚,痰湿,和肝、心病;C型多见脾虚;C+P型多见寒证、气虚,痰湿、血瘀,及肾虚、胃病,而气陷只见于C+P型。病程分组辨证结果显示,病程延长,虚证比例增加,实证有所减少但比率不高。随病程延长而热证减少,气虚证增多,甚至出现气陷,寒证无显著变化,与前述疾病分型辨证P型热证多见,而C+P型多在疾病后期出现可多见寒证结果吻合。随病程延长,肾病、肝病、脾虚及肺虚证增加,心病及胃病减少。疾病严重程度分类辨证结果显示,疾病严重程度增加,虚证、实证都有所增加,具体表现在气虚、血虚、气陷增加,所有邪实之痰湿、血瘀、毒浊亦增加;疾病严重程度增加,热证、寒证都增多,肾、肝、心、肺之病增加,脾病不变,胃病减少。③95例MSA患者(数据缺失)温肾健脑经验方加减治疗3个月后证素频次排序前5位依次为血瘀、肾阳虚、肾虚、肾阴虚、痰湿,与前述证素频次一致,较治疗前相比痰湿减少,血瘀及肾虚无明显变化。因血瘀、痰湿都是阳气虚无力推动脉道、津液所致,可以推出MSA核心病机为肾阳虚。温肾健脑经验方加减治疗后3个月与治疗前相对比,主要证素类型无明显变化,提示MSA短期证候类型变化不大,中医治疗原则在于谨守基本病机,即温肾助阳,辨病论治为主,辨证其次。结论:MSA非运动症状量表具有良好的内部信度、区分效度,和较好的反应度,是临床上可以应用于MSA非运动症状评价的量表。温肾健脑方加减能够延缓至少58%MSA患者疾病进展,主要体现在非运动症状上,其中直立位低血压疗效突出,因此可进一步应用MSA-NMSS进行以后的中医药疗效评价;而MSA总体虚多实少,寒多热少,核心病机为肾阳虚,治法温肾助阳,与温肾健脑方的治疗原则吻合。
[Abstract]:Background: Multiple System Atrophy (MSA) is a complex neurodegenerative disease involving multiple systems, and its widespread non motor symptoms (non-motor symptoms, NMS), which are mainly independent of autonomic dysfunction (NMS), are important parts of the disease, which seriously affect the condition and the quality of life of the patients. But the existing scale In order to evaluate MSA neural function defect and limb disability, it can not be used to measure the complex non motor symptoms it contains, so the Multiple System Atrophy Non-motor Symptoms Scale (MSA-NMSS) is urgent to be developed, and it can be used in the evaluation of the curative effect of traditional Chinese medicine in the field of MSA,.MSA in the world. There is still a lack of effective treatment methods. Western medicine intervention is mostly treated with symptomatic treatment, and the long-term effect is not clear. The traditional Chinese medicine treatment of MSA has the characteristics of treatment and target, but the existing traditional Chinese medicine MSA literature is short of whether it can delay the related argument and objective evaluation of the disease progress; and the core of the Chinese medicine treatment is the etiology and pathogenesis analysis, The analysis of the regularity and evolution of MSA syndrome can guide the diagnosis and treatment of traditional Chinese medicine and clear the prognosis. Therefore, the study of the curative effect and syndrome analysis of MSA with large sample volume of Chinese medicine is carried out. The research method is divided into three parts: the first part is the development of MSA-NMSS, referring to the development method of the international patient report knot local scale, which is mainly divided into the composition of the entry pool. Pre survey scale formation, clinical investigation, entry screening, performance assessment five steps. First, a scale concept framework was first constructed. MSA-NMSS was used to measure the severity of MSA non motor symptoms, and the final measurement of the patient's quality of life. And according to the document MSA non motion symptom initial conception scale structure 13 aspects. The entries were from the following three Aspect acquisition: the theoretical model is the literature; refer to the unified multi system atrophy assessment scale (UMSARS) and the Parkinson non motion symptom scale (NMSS) scale; use the brainstorming method to take the patient as the center, and collect 70 cases of the previous MSA patients to carry out the analysis. Second, the Delphy expert consultation method is used to screen the entry pool, that is the back to back score. Do not send to the national multi clinical center MSA authoritative expert to make the importance score, the familiarity degree score. Carry on the small range test namely the language debugging and the item reengineering, collate into the pre survey scale. (3) the clinical survey sample volume is about 200 cases of the 5 times of the minimum number of eyes and the UMSARS questionnaire, and collect the age, the education level and the MSA The patients with comparable health were healthy and normal people; 3 months after the treatment of Chinese medicine, the MSA patients were retested two times. (4) the results were selected by the discrete trend method, stepwise regression analysis, the number and name of the actual dimension were calculated with exploratory factor analysis, and then the expert consultation was used to select the items. Finally, the Pearson correlation was related. The coefficient and the Krone Bach coefficient method (Cronbach's Alpha) were used to screen the items again. The assessment of the scale was divided into reliability, validity and responsiveness. The reliability test was based on the Cronbach's Alpha method. The validity assessment was divided into the standard validity, namely the former Pearson correlation coefficient method, and the difference between the two groups of people who were compared to MSA and healthy subjects. The score of MSA patients before and after treatment of traditional Chinese medicine was judged by rank and analysis. The second part was to observe the curative effect of warm kidney and brain experience before and after MSA treatment. To collect the UMSARS scores before the treatment of the Chinese medicine of MSA, the level of the total UMSARS loss, the degree of progression (= score / disease course), the score of incontinence and the number of nocturia, The number of urinary catheterization, erect blood pressure value. After the treatment of Chinese medicine, one half month, 1 months, 3 months, 6 months, 12 months, each time point UMSARS score, UMSARS fourth overall disability grade, progress degree (= at this point score / time point per person course year); and non motor symptoms including 3 months after treatment, 6 months, 12 months incontinence score, nocturia Number, number of urinary catheterization, erect blood pressure value; (3) patients' complaint to improve symptoms, improve person times, and improve the rate. Follow up records of Chinese medicine 24 months, 36 months, 48 months UMSARS score, UMSARS fourth overall disability grade, progress degree. The third part is the analysis of the syndrome characteristics of MSA. Cross sectional analysis method, collect all conforms The general situation of the standard MSA patients and the four diagnosis information used in the syndrome analysis, the factor of syndrome, the frequency, the percentage, the distribution of the components of the syndromes, and the comparison between the groups of the syndromes with the type or the average value, and the correlation between the syndrome factors and the disease course, the severity of the disease, the classification of the disease, and the summary of the correlation between the syndrome factors and the classification of the disease. The first part of the entry pool formed a total of 63 items, 13 dimensions, the Delphy expert consultation method selected the entry pool to form the first draft of 53 entries, and carried out a small range test and remolding, and made up a total of 37 items of pre survey. 202 cases of MSA patients, 118 men and 84 women were collected in the clinical survey. Age 58.97 + 7.94 years, the average course of disease was 5.17 + 2.13 years, of which type C 96 cases, P type 61 cases, C+P type and P+C type (unable to determine the dominant classification, according to the onset of symptoms successively) 45 cases, healthy and normal people 202 cases, male 82 cases, 120 cases, average age 61.96 + 7.86 years. After the investigation, the discrete trend, stepwise regression analysis, factor analysis, expert consultation carry on entry 12 dimensions and 35 objective scales were formed. The performance of the scale was evaluated by the Pearson correlation coefficient and the Krone Bach coefficient method. The results showed that: (1) the reliability assessment: the total alpha value =0.854 of the scale was acceptable. The degree of contribution of each item to the overall scale of the scale was tested. The scores of palpitation and palpitation were low and clinical. There was a significant difference in the total score of the total score of MSA patients and healthy people, and p=0.0000.05, and the two groups had significant differences, which showed that the scale of the scale was good. However, there was no significant difference between the MSA patients and the healthy people (p=0.927) in the dimension of the digestive function (p=0.927). (3) the degree of reactivity: the difference of the total score of the scale of two was p =0.6190.05, the difference of overall disability grade two was p=0.0050.01, indicating that the overall severity of the disease was significantly worse 3 months after treatment, but there was no significant difference in non motor symptoms, specifically in dimension 1, 2 cognitive function and 12 digestive function, 3 months after treatment was significantly higher than that before treatment (P was 0.044,0.000,0.001, respectively. In dimension 4 sleep symptoms and 9 defecation, 3 months after treatment was significantly less than before treatment (P 0 and 0 respectively). There is no unified assessment of MSA-NMSS at present to determine whether non motor symptoms are true before and after treatment to verify the degree of reactivity, but the literature shows that traditional Chinese medicine treatment mainly improves blood pressure. Two stool, dizziness symptoms, early clinical research foundation showed insomnia, constipation, RBD improved obviously, basically with MSA-NMSS to improve sleep symptoms and defecation function, indicating that MSA-NMSS has a better degree of reactivity. Second part of the group of MSA patients were collected in 225 cases, the average course of disease was 5.20 + 2.15 years, the oldest was 99 cases of.C type, P type 72 cases, and C+P type and P+C type 54 cases. A total of 130 patients with Chinese traditional Chinese medicine (MSA) were taken for a shortest period of half a month and the longest period of 45 months, including 75 men and 55 women, with an average age of 59.10 + 8.08 years, with an average course of 4.61 + 2.18 years, the shortest 1 years, and the longest 11 years; C type 58, P 39, C+P or P+C mixed 33; the possible MSA 112, and possible MSA cases.UMSARS score the highest score.13 Of the 0 cases of Chinese traditional Chinese medicine MSA, 14 cases were transformed from type C to P type, 1 cases were exacerbated by fracture, 13 cases with deteriorating Chinese medicine, the shortest 1 weeks, the longest 1 years, 3 cases of Chinese traditional medicine deteriorated and then the improvement of Chinese medicine. The main complaint was to improve the symptoms and non motor symptoms three. The average progress degree and the average overall loss level of the disease were all reached the peak at the half month of Chinese medicine treatment. The average progress degree of the disease was slightly lower than that of the pre treatment water during the 1 month treatment. After 12 months of Chinese medicine treatment, the average progress was about 4/5 before treatment. The average overall loss of energy was about 9/10 before treatment. The course of the disease was about the average course of disease (4.4 years) before treatment (4.4 years) for 24 months, 36 months and 45 months. Not about 4/5,3/5,2/5 before treatment; and 9/10,7/10,2/5. considering 95 missing data factors, Chinese medicine can at least delay the disease progression of 57.8% (130/225) of MSA patients. Patients complained of improvement of the symptoms, and the first 10 patients complained of improving symptoms were orthostatic low blood pressure or syncope, RBD, urinary incontinence, bowel difficulty, nocturia, and urine. The improvement rate of erect hypotension or syncope was 44.6%, followed by two stool, the total improvement rate was about 56.9%, and the improvement of mental and physical sleep was 18.7%, and the speech and walking disorders caused by the weakness of the legs were also relieved. Missing data, 38 person times of 4 time point data and 111 person times of incomplete person, the average urine incontinence score after 3 months after treatment with warm kidney and brain experience was decreased (2% and 6% respectively), and the average number of urine conduction (including abdominal catheterization) increased (6%). Traditional Chinese Medicine (increase 6%). Traditional Chinese medicine (increase 6%). Chinese traditional medicine (6%). The average number of urinary incontinence (including abdominal catheterization) increased (6%). The average number of urinary incontinence was increased (6%). The average urine incontinence score was reduced (2% and 6%). Treatment for 6 months, 12 months after the three more than before the treatment, 12 months, the increase was 42%, 8%, the 59%.111 people's statistical results were basically the same as 38 people. The average vertical blood pressure value of 38 people showed that the mean horizontal position systolic pressure difference before treatment was 26.32mmHg, the mean horizontal position diastolic pressure difference was 14.47 mmHg; the overall treatment was flat. The contractile pressure difference was 23.25mmHg, and the mean horizontal position diastolic pressure difference was 11.84mmHg.. The mean blood pressure difference between the normal distribution test and the 6 months after treatment was positive. The paired sample t test showed that there was a significant difference between the two sets of systolic pressure (systolic pressure difference *P= 0.0360.05).111 times and the data were negative for 12 months. The third part collected 194 cases of MSA patients, including 114 cases of men and 80 women, with an average age of 59.03 + 9.13 years; 160 were likely to be MSA, 34 possible MSA; C type 93, P 59, C+P or P+C mixed, average course 4.38 + 2.09 years, average UMSARS score of 42.64 + divide. There were three parts of the course of the classification of the disease, the severity of the disease, and the change of the syndromes before and after the treatment of Chinese medicine. (1) the frequency of the syndrome showed a total of 29 syndromes, and the 10 were blood stasis, phlegm dampness, kidney (QI) deficiency, kidney yang deficiency, kidney yin deficiency, phlegm fever, blood deficiency, spleen deficiency, internal heat, yin deficiency. Mainly, the second is blood deficiency, spleen deficiency, yin deficiency, liver yin deficiency, liver deficiency and liver wind internal movement, the proportion of liver blood deficiency and liver wind internal movement is not high. The proportion of deficiency syndrome is high and the first 5 syndromes three deficiency two. See type.P multi see heat syndrome, blood deficiency, phlegm dampness, liver and heart disease, C type of spleen deficiency, type C+P mostly seen in cold syndrome, Qi deficiency, phlegm dampness, blood stasis, kidney deficiency, stomach disease, and stomach disease only in C+P type. There was no significant change in the syndrome of cold and cold syndrome, and P type heat syndrome was common with the syndrome differentiation and syndrome differentiation of the preceding diseases, but the occurrence of type C+P more in the later period of the disease was consistent with the result of cold syndrome. With the extension of the disease, kidney disease, liver disease, spleen deficiency and lung deficiency syndrome increased, heart disease and stomach disease decreased. The classification of disease severity showed that the severity of disease increased, deficiency syndrome, positive evidence All of them increased, manifested in Qi deficiency, blood deficiency, and increased air flow. All phlegm dampness, blood stasis and toxic turbidity increased, and the severity of the disease increased.
【学位授予单位】：北京中医药大学
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R277.7

【参考文献】