结核性脑膜炎早期诊断的相关性研究

发布时间：2018-05-08 08:24

本文选题：结核性脑膜炎 + 脑脊液　；参考：《河北医科大学》2015年博士论文

【摘要】：背景:结核性脑膜炎(Tuberculous meningitis,TBM,简称结脑)是由结核分枝杆菌(Mycobacterium tuberculosis,MTB)感染引起的中枢神经系统感染性疾病,约占结核病的10%左右。该病以脑实质和脑膜受累最常见,并可波及至脊膜、脊髓的非化脓性炎症性疾病。常继发于粟粒性肺结核或体内其它部位结核病,易感染儿童及合并人类免疫缺陷病毒感染的患者。在我国,结核病曾被称为“白色瘟疫”、“十痨九死”的疾病,50年代以前,是危害人类健康的主要杀手,80年代被认为已经被基本征服,但疾病“死亡地图”研究显示,90年代结核病又卷土重来,易感人群的数量不断增加,因此,结核病又给全人类带来了新的挑战,遏制结核病的发展已经刻不容缓。结脑是肺外结核病中最严重的表现形式,由于其最初症状不典型,常常出现误诊或漏诊而延误了诊断及治疗,加上目前耐药结核病的大量出现,致使很多结脑患者遗留了严重的后遗症甚至是很高的死亡率,给整个家庭乃至国家都带来巨大的负担。多年来,国内外学者一直致力于结脑诊断方面的研究,虽然大量的研究结果使我们对结脑有了更深的了解,但仍然有很多尚未解决的问题,因此,寻找早期、敏感、快速的诊断方法仍然是目前亟待解决的问题,同时也是防治结核病的迫切需要和降低结脑死亡率和致残率的关键所在。2009年5月,国际结核病研究小组在南非确定了临床诊断结脑的专家共识,为临床早期诊断制定了简单、容易操作的评价标准。专家共识中提到了脑脊液镜检查到抗酸杆菌、分离培养到结核分枝杆菌或者利用商业用自动PCR仪器检测到结核分枝杆菌均可作为临床确诊结脑的“金标准”,为今后临床诊断结脑提供了依据。第一部分最新临床评分标准在结核性脑膜炎诊断中的应用目的:本研究的目的是评价最新临床评分标准在结脑诊断中的应用,为临床提供简单、可行的方法。方法:选取河北医科大学第二医院神经内科2012年1月-2013年10月门诊及住院病人,剔除临床资料不全者,共175例。其中临床诊断结脑患者137例,对患者病历资料进行回顾性分析并根据最新结脑临床诊断标准进行评分,结脑组分为“确诊组”、“很可能组”及“可能组”,共117例,每组均与改良抗酸染色结果进行对比后评价最新诊断标准的临床应用价值。将确诊组与对照组患者(病毒性脑炎38例)应用病例对照研究的方法,分析临床表现、脑脊液检查、影像学检查及其他结核证据中各项指标与结脑确诊的关系,并通过Logistic回归分析对评分系统的各项指标进行多元分析,寻找影响结脑诊断的独立影响因素。结果(1)结脑组分组情况结脑组共117例患者,其中确诊组29例,很可能组28例,可能组60例。(2)各组间抗酸杆菌检出率的比较确诊组29例改良抗酸染色均为阳性,很可能组22例阳性,可能组56例阳性。结脑组抗酸杆菌总检出率为91.5%。三组间抗酸杆菌检出率比较差异有统计学意义(P0.05)。(3)单因素分析评分系统中影响结脑确诊各因素的分析显示,症状持续≥5天、颅神经麻痹、脑脊液细胞数10-500个/ul、淋巴细胞50%、蛋白1g/L、糖2.2mmol/L或低于血糖的50%、存在结核瘤、脑梗死及CT/MRI/超声提示存在颅外结核等在病例组与对照组间有统计学意义(P0.05),其他变量差异均无统计学意义(P0.05)。(4)多因素分析将可能影响结脑确诊的9项因素作为自变量引入非条件逐步Logistic回归模型进行多因素分析后,最终进入回归方程具有统计学意义的自变量有症状持续≥5天、脑脊液细胞数10-500个/ul、蛋白1g/L及糖2.2mmol/L或低于血糖的50%。建立线性模型为:Y=-42.166+39.768(细胞数10-500个/ul)+20.251(蛋白1g/L)+19.858(糖2.2mmol/L或低于血糖的50%)+4.007(症状持续≥5天)。用回归方程预测病例组的正确率为96.6%,对照组的正确率为97.4%,总正确率为97%。结论:最新临床评分标准对结脑早期诊断有很好的预测性,脑脊液检查对诊断有很大帮助,利用该评分系统可为早期诊断结脑提供可靠依据。第二部分脑脊液参数对结核性脑膜炎早期诊断的预测意义目的:脑脊液参数可为结脑的诊断提供重要信息,本研究旨在对脑脊液常规、生化、细胞学等指标进行评估,分析这些指标对结脑早期诊断的预测价值。方法:对收集的100例患者的脑脊液资料进行回顾性分析,将脑脊液蛋白含量(1 g/l)、氯化物含量(120 mmol/l)、葡萄糖含量(2.2 mmol/l)、细胞数(10-500 cells/μl)、淋巴细胞增多(50%)及嗜中性粒细胞增多(50%)等数据进行分类整理后评价其对结脑诊断的应用价值。结果:脑脊液检查各参数在结脑组与对照组差异均有统计学意义,脑脊液蛋白含量(1 g/l)、葡萄糖含量(2.2 mmol/l)、细胞数(10-500 cells/μl)及嗜中性粒细胞增多(50%)是影响结脑确诊的独立危险因素,对于预测结脑的敏感性分别为:66%、58%、86%、54%,特异性分别为:84%、98%、32%、98%。其中嗜中性粒细胞大于50%对于结脑的诊断具有很好的预测意义,结脑组中有84%的患者至少有2项阳性的脑脊液参数,而对照组仅10%有2项及以上阳性的脑脊液参数。结论:脑脊液参数变化可为临床早期诊断提供可靠依据。第三部分Ziehl-Neelsen染色荧光显微镜观察在结核性脑膜炎诊断的应用目的:本研究的目的是提高传统Ziehl-Neelsen抗酸染色的检出率,探讨一种早期确诊结核性脑膜炎的有效、便捷方法。方法:所有病例组均来自河北医科大学第二医院神经内科2012年1月-2014年1月临床诊断为结核性脑膜炎的住院及门诊患者,采用专家共识的结脑临床诊断标准对所有结脑患者进行评分。对照组为非结脑患者,对所有患者的脑脊液均行改良抗酸染色光镜及荧光显微镜观察并对结果进行分析。结果(1)一般情况病例组共99例(219份脑脊液),其中确诊组27例(104份脑脊液),很可能组22例(39份脑脊液),可能组50例(76份脑脊液)。病例组中早期(1个月)患者共68例,中期(≥1个月)患者共31例。对照组患者共56例(56份脑脊液)(2)抗酸杆菌形态光镜观察蓝色背景下抗酸杆菌被品红染成红色,有的细长略带弯曲,第二部分脑脊液参数对结核性脑膜炎早期诊断的预测意义有的呈短杆状,有的呈分叉状或球状,且能发现淋巴细胞、单核细胞及嗜中性粒细胞内的抗酸杆菌;荧光显微镜下观察黑色背景下所有细胞均不着色,仅仅抗酸杆菌被品红着色后发出红色荧光,形态与光镜下基本一致,但较光镜稍粗。(3)改良抗酸染色光镜及荧光观察的比较在52份经证实含结核分枝杆菌的脑脊液中有44份在光镜下发现抗酸杆菌,50份脑脊液在荧光显微镜下发现抗酸杆菌。改良抗酸染色荧光显微镜观察的敏感性为96.2%,阳性预测值为89.3%。光镜观察的敏感性为84.6%,两者比较差异有统计学意义(P0.05)。对照组共56份脑脊液,6份抗酸染色阳性,因此改良抗酸染色荧光显微镜观察的特异性为89.3%,阴性预测值为96.2%。如果以所有样本为研究对象,病例组光镜检出率为67.6%,荧光镜检的检出率为78.5%,两者比较差异有统计学意义(P0.05)。如果以病人为研究对象,病例组光镜的检出率为82.8%,荧光镜检的检出率为90.9%,两者比较差异有统计学意义(P0.05)。(4)改良抗酸染色荧光显微镜观察检出率与送检时间的关系早期(即患者出现症状到就诊时间1个月)光镜镜检的检出率为86.8%,荧光镜检的检出率为95.6%,两者比较差异有统计学意义(P0.05)。中期(即患者出现症状到就诊时间≥1个月)光镜镜检的检出率为77.4%,荧光镜检的检出率也是77.4%,两者比较差异并没有统计学意义。早期和中期改良抗酸染色荧光镜检的检出率差异有统计学意义(P0.05)。结论:改良抗酸染色荧光显微镜观察可作为早期诊断结脑的简便、快速的检测手段,临床医生应早期、多次送检以提高检出率。第四部分Gene Xpert MTB/RIF对结核性脑膜炎诊断的应用价值目的:本研究的目的是探讨Xpert MTB/RIF检测系统对结脑诊断的应用价值方法:所有病例组均来自河北医科大学第二医院神经内科2012年1月-2014年1月临床诊断为结核性脑膜炎的住院及门诊患者,共92例,对照组30例,对所有患者的脑脊液进行Xpert MTB/RIF检测并记录结果,将Xpert MTB/RIF结果分别与临床诊断、传统PCR检测及改良抗酸染色进行比较,综合评价其在结脑诊断中的应用价值。结果(1)传统PCR、改良抗酸染色及Gene Xpert MTB/RIF检测结果病例组92例患者中有82例抗酸染色阳性,11例Xpert MTB/RIF检测结果为阳性,57例经传统PCR检测后18例结果阳性,对照组30例Xpert MTB/RIF检测均为阴性结果。(2)以临床诊断作为结脑诊断的金标准,比较Gene Xpert MTB/RIF对结脑的诊断价值92例患者中11例阳性,阳性率为12.0%。其中确诊组7例阳性,很可能组4例阳性,可能组均为阴性。确诊组检出率最高,其次为很可能组,本组资料中可能组无一例检出。(3)以改良抗酸染色作为结脑诊断的金标准,比较Gene Xpert MTB/RIF对结脑的诊断价值。82例抗酸染色阳性的患者中有11例Gene Xpert MTB/RIF检测阳性,阳性率为13.4%。(4)以传统DNA检测作为结脑诊断的金标准,比较Gene Xpert MTB/RIF对结脑的诊断价值18例DNA检测阳性的患者中11例Gene Xpert MTB/RIF检测阳性,阳性率为61.1%。(5)改良抗酸染色、传统PCR检测与Gene Xpert MTB/RIF检测的比较92例患者均进行了改良抗酸染色与Gene Xpert MTB/RIF检测,经统计学比较提示两种方法差异无统计学意义(P0.05);而同时经传统PCR检测与Gene Xpert MTB/RIF检测的患者共57例,比较后发现差异有统计学意义(P0.05),传统PCR检测阳性率较高。结论:Xpert MTB/RIF检测系统可作为诊断结核性脑膜炎的金标准,但其阳性检出率较低,应对脑脊液的处理过程进一步优化,以提高其在结核性脑膜炎早期诊断中的应用价值。
[Abstract]:Background: Tuberculous meningitis (TBM) is an infectious disease of the central nervous system caused by Mycobacterium tuberculosis (MTB) infection, accounting for about 10% of tuberculosis. The disease is most common in the brain parenchyma and meninges, and can spread to the meninges and the non suppurative inflammatory diseases of the spinal cord. Disease. Often secondary to miliary tuberculosis or other parts of the body, it is easy to infect children and patients with human immunodeficiency virus infection. In our country, tuberculosis was once known as "white plague", "ten tuberculosis nine deaths", before 50s, is the main killer of human health, in 80s it was considered to have been basically conquered, But the disease "death map" research shows that in 90s, tuberculosis is coming back again and the number of susceptible people is increasing. Therefore, tuberculosis has brought new challenges to all human beings, and it is urgent to stop the development of tuberculosis. The misdiagnosis or missed diagnosis has delayed the diagnosis and treatment, as well as the large number of drug-resistant tuberculosis, resulting in serious sequelae and even high mortality in many patients. For years, scholars at home and abroad have been devoted to the research of brain diagnosis, although a large amount of research has been made. We have a deeper understanding of the brain, but there are still a lot of unsolved problems. Therefore, the search for early, sensitive and rapid diagnostic methods remains an urgent problem at the moment, and is also the key to the urgent need to prevent tuberculosis and to reduce the rate of death and disability of the brain in May, international tuberculosis (.2009). The disease research team established an expert consensus on the clinical diagnosis of brain nodules in South Africa to establish simple, easy to operate evaluation criteria for early clinical diagnosis. The expert consensus referred to cerebrospinal fluid endoscopy for acid resistant bacilli, isolation and culture to Mycobacterium tuberculosis, or detection of Mycobacterium tuberculosis by commercial auto PCR instruments. The "gold standard" for clinical diagnosis of the brain provides a basis for the future clinical diagnosis of the brain. The purpose of the first part of the latest clinical scoring standard in the diagnosis of tuberculous meningitis: the purpose of this study is to evaluate the application of the latest clinical scoring standard in the diagnosis of the brain, and to provide a simple and feasible method for the treatment of the bed. Method: select Hebei The neurology department of the second hospital of Medical University in January 2012 -2013 October outpatient and hospitalized patients, excluding patients with incomplete clinical data, 175 cases, of which 137 cases of clinical diagnosis of brain patients, a retrospective analysis of the patient's medical records and according to the latest clinical diagnostic criteria, the brain group is divided into "confirmed group", "very likely group" "And" possible group ", a total of 117 cases, each group was compared with the improved acid staining results to evaluate the clinical value of the latest diagnostic criteria. The diagnosis group and the control group (38 cases of viral encephalitis) were used in a case-control study to analyze the clinical manifestations, cerebrospinal fluid examination, imaging examination and other tuberculosis evidence. The relationship between the standard and the diagnosis of the nodal brain, and the multiple analysis of the indexes of the scoring system by Logistic regression analysis to find the independent factors affecting the diagnosis of the nodal brain. Results (1) there were 117 patients in the group of brain groups, including 29 cases, 28 cases and 60 cases. (2) the detection rate of acid bacilli in each group. The improved anti acid staining was positive in 29 cases, 22 cases were positive and 56 cases were positive. The total detection rate of acid bacilli in the group of 91.5%. three groups was statistically significant (P0.05). (3) the analysis of various factors in the single factor analysis scoring system showed that the symptoms continued to be more than 5. Days, cranial nerve paralysis, the number of cerebrospinal fluid cells in 10-500 /ul, lymphocyte 50%, protein 1g/L, sugar 2.2mmol/L or lower than 50% of blood sugar, there were tuberculoma, cerebral infarction and CT/MRI/ ultrasound showed that there was statistical significance between the case group and the control group (P0.05), and the difference of other variables was not statistically significant (4) multivariate analysis. The 9 factors that may affect the diagnosis of the brain as independent variables are introduced into the non conditional stepwise Logistic regression model for multiple factors analysis. After the regression equation has statistical significance, the symptom continues to be more than 5 days, the number of cerebrospinal fluid cells is 10-500 /ul, the protein 1g/L and sugar 2.2mmol/L or lower blood glucose 50%. establish a linear model. Y=-42.166+39.768 (cell number 10-500 /ul) +20.251 (protein 1g/L) +19.858 (sugar 2.2mmol/L or lower than 50% of blood sugar) +4.007 (symptoms lasting more than 5 days). The correct rate of the case group was predicted by the regression equation 96.6%, the correct rate in the control group was 97.4%, the total correct rate was 97%. conclusion: the latest clinical scoring standard has a good preview of the early diagnosis of the brain. The evaluation of cerebrospinal fluid (CSF) has great help for diagnosis. Using this scoring system can provide a reliable basis for early diagnosis of the brain. Second the predictive significance of the parameters of cerebrospinal fluid to the early diagnosis of tuberculous meningitis: the parameters of cerebrospinal fluid can provide important information for the diagnosis of the brain, and this study aims at the routine, biochemical and cytological study of cerebrospinal fluid. Evaluation and analysis of these indexes to predict the early diagnosis of the brain. Methods: the cerebrospinal fluid data of 100 patients collected were analyzed retrospectively, the content of cerebrospinal fluid protein (1 g/l), chloride content (120 mmol/l), glucose content (2.2 mmol/l), cell number (10-500 cells/ Mu L), lymphocyte increase (50%) and neutrophils The application value of granulocytosis (50%) and other data was evaluated. Results: the differences in the cerebrospinal fluid examination parameters in the brain group and the control group were statistically significant, the content of cerebrospinal fluid protein (1 g/l), glucose content (2.2 mmol/l), the number of fine cell (10-500 cells/ Mu L) and neutrophils (50%) were affected. The independent risk factors for brain diagnosis were 66%, 58%, 86%, 54%, respectively: 84%, 98%, 32%. 98%. neutrophils greater than 50% had a good predictive value for the diagnosis of the brain, 84% of the patients in the brain group had at least 2 positive cerebrospinal parameters, while only 10% in the control group were 2. Conclusions: the changes in cerebrospinal fluid parameters can provide a reliable basis for early clinical diagnosis. Third Ziehl-Neelsen staining fluorescence microscopy is used to observe the application of the diagnosis of tuberculous meningitis. The purpose of this study is to improve the detection rate of traditional Ziehl-Neelsen anti acid staining and to explore an early diagnosis. Effective and convenient methods of nuclear meningitis. Methods: all cases were from the neurology department of the second hospital of Hebei Medical University in January -2014 January 2012, which were clinically diagnosed as tuberculosis meningitis inpatients and outpatients. All the patients were scored by the expert consensus nodal clinical diagnostic criteria. The control group was a non nodule patient, All patients' cerebrospinal fluid was observed with modified acid staining light microscopy and fluorescence microscopy. Results (1) the general case group was 99 cases (219 cerebrospinal fluid), of which 27 cases (104 cerebrospinal fluid), 22 cases (39 cerebrospinal fluid) and 50 cases (76 cerebrospinal fluid), and the early (1 months) patients in the case group. A total of 68 cases, intermediate (> 1 months) patients with 31 cases, 56 cases (56 cerebrospinal fluid) (56 cerebrospinal fluid) (2) acid bacilli (2) observed the acid bacilli morphological light microscope, the acid bacillus was dyed red under the blue background, some elongated and slightly curved, and the second part of the cerebrospinal fluid parameters had a short pole shape in the prediction of the early diagnosis of tuberculous meningitis, and some were bifurcated. All cells in the black background were not coloured under fluorescent microscope. Only acid resistant bacilli were stained with red color after coloring of fuchsin. The morphology was basically consistent with light microscope, but slightly thicker than light microscope. (3) improved acid staining light microscopy and fluorescence view. 44 of the 52 confirmed cerebrospinal fluid containing Mycobacterium tuberculosis found anti acid bacilli under light microscope, 50 cerebrospinal fluid found acid bacillus under fluorescence microscope. The sensitivity of improved anti acid staining fluorescence microscopy was 96.2%, and the sensitivity of positive predictive value of 89.3%. optical microscopy was 84.6%. Study significance (P0.05). The control group had 56 cerebrospinal fluid and 6 acid positive staining. Therefore, the specificity of the improved acid staining fluorescence microscope was 89.3%, and the negative predictive value was 96.2%. if all the samples were studied, the detection rate of light microscopy in the case group was 67.6% and the fluoroscopy detection rate was 78.5%, and the difference was statistically significant. (P0.05) if the patient was taken as the study object, the detection rate of light microscopy in the case group was 82.8% and the detection rate of fluoroscopy was 90.9%, and the difference was statistically significant (P0.05). (4) the detection of the relationship between the detection rate of the improved acid staining fluorescence microscope and the time of delivery (that is, the symptoms to the time of treatment for 1 months) was detected by light microscopy. The rate of detection was 86.8%, the detection rate of fluoroscopy was 95.6%, and the difference was statistically significant (P0.05). The detection rate of light microscopy was 77.4% in the middle period (that is, the symptoms of patients were more than 1 months), and the detection rate of fluoroscopy was 77.4%. There was no statistical difference between the two. The difference in detection rate was statistically significant (P0.05). Conclusion: modified acid staining fluorescence microscopy can be used as a simple and rapid detection method for early diagnosis of brain. The clinical value of fourth parts of Gene Xpert MTB/RIF for the diagnosis of nuclear meningitis is to be used by clinicians to improve the detection rate. To explore the application value of Xpert MTB/RIF detection system to brain diagnosis: all case groups were from the neurology department of the second hospital of Hebei Medical University in January January 2012 -2014 in the clinical diagnosis of tuberculosis meningitis inpatients and outpatients, a total of 92 cases, 30 cases of the control group, Xpert MTB/RIF detection of all the patients' cerebrospinal fluid. The results were recorded, and Xpert MTB/RIF results were compared with clinical diagnosis, traditional PCR detection and modified acid staining, and their application value in brain diagnosis was evaluated synthetically. Results (1) there were 82 cases of acid staining positive in 92 patients with traditional PCR, improved acid staining and Gene Xpert MTB/RIF detection results, and 11 cases of Xpert MTB/RIF test. The test results were positive in 57 cases, 18 cases were positive after the traditional PCR test, and 30 cases of Xpert MTB/RIF in the control group were negative results. (2) the clinical diagnosis was used as the gold standard for the diagnosis of the brain, and the diagnostic value of Gene Xpert MTB/RIF on the nodal brain was positive in 92 cases, and the positive rate of the positive rate was 12.0%. in 7 cases, and the possibility group was 4 cases. The positive rate of the group was negative. The positive rate of the confirmed group was the highest, the next was the possible group, and there was no case in the group. (3) to improve the anti acid staining as the gold standard for the diagnosis of the brain, compare the diagnostic value of Gene Xpert MTB/RIF to the nodal brain, and 11 cases of Gene Xpert MTB/RIF detection positive in the patients with positive acid staining with acid staining. The sex rate was 13.4%. (4) with the traditional DNA detection as the gold standard for the diagnosis of the brain, and compared the diagnostic value of Gene Xpert MTB/RIF to the nodal brain. 11 cases of Gene Xpert MTB/RIF detection in 18 cases of DNA positive were positive, the positive rate was 61.1%. (5) modified acid staining, and the comparison between the traditional PCR and Gene 92 cases was carried out. The improved acid staining and Gene Xpert MTB/RIF detection showed that there was no statistical difference between the two methods (P0.05), while 57 cases were detected by traditional PCR and Gene Xpert MTB/RIF, and the difference was statistically significant (P0.05) and the positive rate of traditional PCR was higher. Conclusion: Xpert MTB/RIF detection system can be found. As a gold standard for the diagnosis of tuberculous meningitis, its positive detection rate is relatively low, and the treatment process of cerebrospinal fluid should be further optimized to improve it.

【学位授予单位】：河北医科大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R529.3

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