【作者】 尤昱中；

【导师】 樊永平；

【作者基本信息】 北京中医药大学 ， 中医内科学， 2014， 博士

【摘要】 目的通过检测复发缓解型多发性硬化(Relapsing-Remitting Multiple Sclerosis, RRMS)患者的质子共振波谱分析与弥散张量成像指标,研究并探讨中医补肾法对多发性硬化的髓鞘再生与轴索修复的作用,及其与西药治疗的差异,为中医辨证论治提供临床科学证据。材料与方法1.病例来源及分组入组患者均为2012年9月至2014年1月的就诊于首都医科大学附属北京天坛医院中医科门诊及神经内科门诊病人,并设立健康对照组。临床确诊RRMS患者56例,其中中医科门诊患者40例为中医治疗组,神经内科门诊病例16例为西药治疗组,健康人11例为健康对照组。参照中医辨证分类标准,中医治疗组分为肾虚型和其他证型,其中肾虚型患者29例,为补肾治疗组,其他证型11例,为其他证型治疗组。西药治疗组均为肾虚型。2.治疗方法与观察指标(1)治疗方法补肾治疗组肝肾阴虚型予二黄方治疗,脾肾阳虚型与二黄方加附子等治疗；其他证型治疗组主要分为气虚痰瘀型及痰热瘀阻型,依据不同证型给予相应辨证治疗：气虚痰瘀型予黄芪桂枝五物汤,痰热瘀阻型予黄连温胆汤合桃红四物汤治疗；西药治疗组予西医常规治疗。(2)观察指标及随访周期入组时详细记录各组患者一般资料,包括发病年龄、病程长短、复发次数、中医临床症状分布、神经系统症状分布,进行扩展伤残等级评分(Expended Disability Score Standard, EDSS)及中医症状评分。同时各组患者及健康对照组行头颅核磁检查,记录各组患者及健康对照组核磁质子共振波谱分析(MR Spectroscopy, MRS)及弥散张量成像(Diffusion Tensor Imaging, DTI)。MRS主要检测指标包括：N-乙酰天门冬氨酸(N-acetylaspartate,Naa1、胆碱(Choline,Cho)、总肌酸(Creatine,Cr),藉由病灶侧及正常侧Naa/Cr、Cho/Cr作为评价标准。DTI主要检测指标包括：表观弥散系数(Apparent Diffusion Coefficient, ADC)及各向异性(Fractional Anisotropy, FA)。随访周期为9个月,随访结束时三组RRMS患者再次记录中医及神经症状分布,进行扩展伤残等级评分(Expended Disability Score Standard, EDSS).中医症状评分,及头颅核磁检查,指标同前。第一部分：观察治疗前补肾治疗组、西药治疗组中医临床症状分布、神经系统症状分布、EDSS评分、中医症状评分的差异,及两组MRS、DTI指标与健康对照组差异,并比较治疗前后补肾治疗组、西药治疗组EDSS评分、中医症状评分、MRS、DTI指标变化。第二部分：观察治疗前补肾治疗组、其他证型治疗组中医临床症状分布、神经系统症状分布、EDSS评分、中医症状评分的差异,及两组MRS、DTI指标与健康对照组差异,并比较治疗前后补肾治疗组、其他证型治疗组EDSS评分、中医症状评分、MRS、 DTI指标变化。结果第一部分FMRI评价补肾为主及西药治疗促进MS神经损伤修复作用的差异1.中医临床症状分布治疗前：补肾治疗组与西药治疗组患者在中医临床症状分布无显著差异,P>0.05。治疗后：补肾治疗组在身痛、肢体无力、跟跖疼痛、四肢发麻、头晕、头痛、视力模糊、不寐、多梦、小便频急、健忘、急躁易怒及潮热盗汗等例数显著低于西药治疗组,P<0.05,提示补肾治疗组中医临床症状显著缓解。2.神经系统症状分布治疗前：补肾治疗组与西药治疗组患者在神经系统症状分布无显著差异,P>0.05。治疗后：补肾治疗组在肢体无力、感觉障碍、视力障碍、小便功能障碍、共济失调、大脑皮层功能减退及发作性症状等例数显著低于西药治疗组,P<0.05,提示补肾治疗组神经系统症状显著缓解。3.EDSS评分及中医症状评分治疗前：补肾治疗组与西药治疗组患者EDSS评分、中医症状评分均无显著差异,P>0.05。治疗后：补肾治疗组EDSS评分、中医症状评分显著低于西药治疗组,P<0.05。两组患者治疗后的EDSS评分及中医症状评分较治疗前均有所下降,而补肾治疗组下降程度更加显著,P<0.05,提示补肾治疗组神经系统功能修复较好。4.质子共振波谱分析(MRS)治疗前：补肾治疗组及西药治疗组NAA/CR比值均显著低于健康对照组,而CHO/CR比值均显著高于健康对照组,P<0.05,提示两组的髓鞘脱失及轴索损伤显著。两组间无显著差异,P>0.05。治疗后：西药治疗组NAA/CR比值显著低于健康对照组,而CHO/CR比值显著高于健康对照组,P<0.05；补肾治疗组NAA/CR比值及CHO/CR比值均和健康对照组无差异,P>0.05；而其NAA/CR比值显著高于西药治疗组,CHO/CR比值显著低于西药治疗组,P<0.05。补肾治疗组NAA/CR比值上升及CHO/CR比值下降幅度均较西药治疗组显著,P<0.05。上述结果提示补肾治疗组髓鞘修复及轴索再生显著优于西药治疗组。5.弥散张量成像分析(DTI)治疗前：补肾治疗组及西药治疗组ADC比值均显著高于健康对照组,而FA比值均显著低于健康对照组P<0.05,提示两组神经纤维束损伤显著。两组间无显著差异,P>0.05。治疗后：西药治疗组ADC比值显著高于健康对照组,而FA比值显著低于健康对照组,P<0.05；补肾治疗组ADC比值及FA比值均和健康对照组无差异,P>0.05；而其FA比值显著高于西药治疗组,ADC比值显著低于西药治疗组,P<0.05。补肾治疗组FA比值上升及ADC比值下降幅度均较西药治疗组显著,P<0.05。上述结果提示补肾治疗组神经纤维束修复显著优于西药治疗组。第二部分FMRI评价中医辨证治疗促进不同证型MS神经损伤修复作用的差异1.中医临床症状分布治疗前：补肾治疗组与其他证型治疗组患者在中医临床症状分布无显著差异,P>0.05。治疗后：补肾治疗组在筋脉拘挛、头晕、头痛及口干等例数显著低于其他证型治疗组,P<0.05,提示补肾治疗组中医临床症状缓解较佳。2.神经系统症状分布治疗前：补肾治疗组与其他证型治疗组患者在神经系统症状分布无显著差异,P>0.05。治疗后：补肾治疗组在共济失调例数显著低于其他证型治疗组,P<0.05,提示补肾治疗组神经系统症状缓解较佳。3EDSS评分及中医症状评分治疗前：补肾治疗组与其他证型治疗组患者EDSS评分、中医症状评分均无显著差异,P>0.05。治疗后：补肾治疗组EDSS及中医症状评分低于其他证型治疗组,但P>0.05,差异无统计学意义,提示补肾治疗组神经系统功能修复趋向较好。4.质子共振波谱分析(MRS)治疗前：补肾治疗组及其他证型治疗组NAA/CR比值均显著低于健康对照组,而CHO/CR比值均显著高于健康对照组P<0.05,两治疗组间无显著差异,P>0.05。治疗后：其他证型治疗组NAA/CR比值略低于健康对照组,而CHO/CR比值略高于健康对照组,P>0.05；补肾治疗组NAA/CR比值及CHO/CR比值均和健康对照组无差异,P>0.05；而其NAA/CR比值高于其他证型治疗组,CHO/CR比值低于其他证型治疗组,但差异无统计学意义,P>0.05。上述结果提示补肾治疗组髓鞘修复及轴索再生趋向优于其他证型治疗组。5.弥散张量成像分析(DTI)治疗前：补肾治疗组及其他证型治疗组ADC比值均显著高于健康对照组,而FA比值均显著低于健康对照组,P<0.05,两组间无显著差异,P>0.05。治疗后：其他证型治疗组ADC比值显著高于健康对照组,而FA比值显著低于健康对照组,P<0.05；补肾治疗组ADC比值及FA比值均和健康对照组无差异,P>0.05；而其ADC比值显著低于其他证型治疗组,FA比值显著高于其他证型治疗组,P<0.05。补肾治疗组ADC比值下降及FA比值上升幅度均较其他证型治疗组显著,P<0.05。上述结果提示补肾治疗组神经纤维束修复显著优于其他证型治疗组。结论1通过治疗前后比较,补肾治疗组中医临床症状及神经系统症状较西药治疗组及其他证型治疗组显著减少,提示补肾为主治疗MS能有效缓解临床症状。2通过治疗前后比较,补肾治疗组EDSS及中医症状评分较西药治疗组显著下降,提示补肾为主治疗MS能有效修复神经系统功能。3通过MRS检测治疗前后数据比较,补肾治疗组Naa/Cr比值较西药治疗组显著上升、Cho/Cr比值较西药治疗组显著下降,提示补肾治疗MS能有效促进髓鞘修复及轴索再生。4通过DTI检测治疗前后数据比较,补肾治疗组ADC比值均较西药治疗组及其他证型治疗组显著下降、FA比值均较西药治疗组及其他证型治疗组显著上升,提示补肾治疗MS能有效促进神经纤维束修复。更多还原

【Abstract】 ObjectiveCompared with the western medicine treatment effects, we research and confer repair and regeneration of myelin sheath, axon and nerve fiber of TCM tonifying the kidney treating the relapsing-remitting multiple sclerosis patients by detecting MR Spectroscopy and Diffusion Tensor Image to provide the TCM diagnosis theory scientific evidence.Materials and Methods1. Patient source and divisionThe experiment patients come from Sep.2012to Jan.2014Beijing Tiantan Hospital TCM and neurology department out-hospital patients. We establish the health control group. There are56diagnosed relapsing remitting multiple sclerosis(RRMS) patients, including40ones from TCM and16ones from the neurology departments. The health control group includes11healthy persons. According to the TCM diagnosis criteria, the TCM patients are divided into the kidney deficiency type and the other TCM types. The tonifying the kidney group includes29kidney deficiency type patients. The other TCM type treatment group includes11the other TCM type patients. The western medicine treatment group includes16kidney deficiency type patients.2. Treatment and observed indexes(1) Treatment The tonifying the kidney group patients are given Erhuang formula for Gan Shen yin deficiency ones and Erhuang formula adding Fuzi for Pi Shen yang deficiency ones. The other TCM type treatment group patients are divided into Qi deficiency phlegm stasis type and phlegm heat stasis type. The Qi deficiency phlegm stasis type patients are given Huangqi guizhi wu wu formula and the phlegm heat stasis type ones are given Huanglian wendan formula and Taohong siwu formula. The western medicine treatment patients are given the normal western medicine.(2) Observed indexes and periods The patients are recorded the general data, including the age of first attack, disease duration, relapsing times, TCM clinic syndromes distribution, neurologic systematic syndromes distribution, Expended Disability Score Standard(EDSS) and TCM syndromes scores. The patients and health control group persons receive MRI detection and are recorded the lesion and normal sides data of MR Spectroscopy(MRS) and Diffusion Tensor Imaging(DTI) data. MRS data include N-acetylaspartate(Naa), Choline(Cho) and Creatine(Cr). The MRS observed indexes include Naa/Cr and Cho/Cr ratios of lesion and normal sides. The DTI observed indexes include Apparent Diffusion Coefficient(ADC) and Fractional Anisotropy(FA) of lesion and normal sides. The observing period is9months. After the continuous9months treatment, the three RRMS patients are recorded TCM and neurologic syndromes distribution. They are evaluated EDSS and TCM syndromes scores. They also receive MRI detection and the observed indexes are mentioned on the above.Section1:Before treatment, the TCM clinic syndromes distribution, neurologic systematic syndromes distribution, EDSS and TCM syndromes scores difference is observed between the tonifying the kidney and western medicine treatment groups. The MRS and DTI observed indexes difference is compared among the two groups and the health control group. Before and after treatment, the tonifying the kidney and western medicine treatment groups’ TCM and neurologic syndromes distribution, EDSS and TCM syndromes scores are compared. Besides, the two groups’MRS and DTI observed indexes changes are compared.Second2:Before treatment, we observe the TCM clinic syndromes distribution, neurologic systematic syndromes distribution, EDSS and TCM syndromes scores of the tonifying the kidney and other TCM treatment groups. We compare the MRS and DTI indexes difference among the two groups and the health control group. Before and after treatment, we also compare the TCM and neurologic syndromes distribution, EDSS and TCM syndromes scores, MRS and DTI indexes changes between the the tonifying the kidney and other TCM treatment groups.ResultsSection1:FMRI estimate the nerve damage and repair difference between the tonifying the kidngy and western medicine treating MS patients1. TCM syndromes distribution Before treatment, there is no distribution difference between the tonifying the kidney and western medicine treatment groups with P>0.05. After treatment, the tonifying the kidney group’s number of patients complaining bodily pain, impotent limbs, heels irritation, limbs numbness, giddiness, cephalalgia, blurred vision, insomnia, dreamy rest, urgent urination, obliviousness, fidget, hectic fever and night sweat is obviously lowered than the western medicine treatment group’s number with P<0.05. It shows the tonifying the kidney group’s TCM syndromes get recovery remarkably.2. Neurologic syndromes distribution Before treatment, there is no distribution difference between the tonifying the kidney and western medicine treatment groups with P>0.05. After treatment, the tonifying the kidney group’s number of patients complaining impotent limbs, sensation paralysis, blurred vision, failed urination, ataxia, decreased cerebrum cortex function and relapsing syndromes is obviously lowered than the western medicine treatment group’s number with P<0.05. It shows the tonifying the kidney group’s neurologic syndromes get recovery remarkably. 3. EDSS and TCM syndromes scores Before treatment, there is no EDSS and TCM syndromes scores difference between the tonifying the kidney and western medicine treatment groups with P>0.05. After treatment, the tonifying the kidney group’s EDSS and TCM syndromes scores are obviously lowered than those of the western medicine treatment group with P<0.05. The two groups’EDSS and TCM syndromes scores decrease after treatment. The tonifying the kidney group’s EDSS and TCM syndromes scores decrease more obviously with P<0.05. It shows the tonifying the kidney group’s neurologic function get recovery remarkably.4. MR Spectroscopy(MRS) Before treatment, the tonifying the kidney and western medicine treatment groups’NAA/CR ratios are obviously lower and CHO/CR ratios are obviously higher than the ratios of the health control group with P<0.05. It shows the two groups’demyelination and axonal damage is obvious. There is no difference between the ratios of the two groups with P>0.05. After treatment, the western medicine treatment group’s NAA/CR ratio is obviously lower than the ratio of the health control group. The western medicine treatment group’s CHO/CR ratio is obviously higher than the ratio of the health control group with P<0.05. There is no difference between the two ratios of the tonifying the kidney group and the health control group with P>0.05. The tonifying the kidney group’s NAA/CR ratio is obviously higher than the ratio of the western medicine treatment group. The tonifying the kidney group’s CHO/CR ratio is obviously lower than the ratio of the western medicine treatment group with P<0.05. The tonifying the kidney group’s NAA/CR ratio increasing and CHO/CR ratio decreasing margins are obviously wider than the margins of the western medicine treatment group with P<0.05. It shows the tonifying the kidney group’s myelin sheath repair and axon regeneration is obviously better than that of the western medicine treatment group.5. Diffusion Tensor Imaging(DTI) Before treatment, the tonifying the kidney and western medicine treatment groups’ADC ratios are obviously higher and CHO/CR ratios are obviously lower than the ratios of the health control group with P<0.05. It shows the two groups’nerve fiber damage is obvious. There is no difference between the ratios of the two groups with P>0.05. After treatment, the western medicine treatment group’s ADC ratio is obviously higher than the ratio of the health control group. The western medicine treatment group’s FA ratio is obviously lower than the ratio of the health control group with P<0.05. There is no difference between the two ratios of the tonifying the kidney group and the health control group with P>0.05. The tonifying the kidney group’s FA ratio is obviously higher than the ratio of the western medicine treatment group. The tonifying the kidney group’s ADC ratio is obviously lower than the ratio of the western medicine treatment group with P<0.05. The tonifying the kidney group’s FA ratio increasing and ADC ratio decreasing margins are obviously wider than the margins of the western medicine treatment group with P<0.05. It shows the tonifying the kidney group’s nerve fiber tract repair is obviously better than that of the western medicine treatment group.Section2:FMRI estimate the nerve damage and repair difference between the different TCM types diagnosing and treating MS patients1. TCM syndromes distribution Before treatment, there is no distribution difference between the tonifying the kidney and the other TCM treatment groups with P>0.05. After treatment, the tonifying the kidney group’s number of patients complaining spasm, giddiness, cephalalgia and thirsty is obviously lowered than the other TCM treatment group’s number with P<0.05. It shows the tonifying the kidney group’s TCM syndromes get better recovery.2. Neurologic syndromes distribution Before treatment, there is no distribution difference between the tonifying the kidney and other TCM treatment groups with P>0.05. After treatment, the tonifying the kidney group’s number of patients complaining ataxia is obviously lowered than the other TCM treatment group’s number with P<0.05. It shows the tonifying the kidney group’s neurologic syndromes get better recovery.3. EDSS and TCM syndromes scores Before treatment, there is no EDSS and TCM syndromes scores difference between the tonifying the kidney and other TCM treatment groups with P>0.05. After treatment, the tonifying the kidney group’s EDSS and TCM syndromes scores tend to be lower than those of the other TCM treatment group with P>0.05. The tonifying the kidney group’s EDSS and TCM syndromes scores decreasing margins tend to be wider than those of the other TCM treatment group. It shows the tonifying the kidney group’s neurologic function tends to get better recovery.4. MR Spectroscopy(MRS) Before treatment, the tonifying the kidney and other TCM treatment groups’NAA/CR ratios are obviously lower and CHO/CR ratios are obviously higher than the ratios of the health control group with P<0.05. It shows the two groups’ demyelination and axonal damage is obvious. There is no difference between the ratios of the two groups with P>0.05. There is no difference among the two ratios of the tonifying the kidney, TCM treatment and the health control groups after treatment with P>0.05. The tonifying the kidney group’s NAA/CR ratio tends to be higher than the ratio of the other TCM treatment groups. The tonifying the kidney group’s CHO/CR ratio tends to be lower than the ratio of the other TCM treatment group with P<0.05. The tonifying the kidney group’s NAA/CR ratio increasing and CHO/CR ratio decreasing margins tend to be wider than the margins of the other TCM treatment group with P>0.05. It shows the tonifying the kidney group’s myelin sheath repair and axon regeneration tends to be better than that of the other TCM treatment group.5. Diffusion Tensor Imaging(DTI) Before treatment, the tonifying the kidney and other TCM treatment groups’ADC ratios are obviously higher and FA ratios are obviously lower than the ratios of the health control group with P<0.05. There is no difference between the ratios of the two groups with P>0.05. After treatment, the other TCM treatment group’s ADC ratio is obviously higher than the ratio of the health control group. The other TCM treatment group’s FA ratio is obviously lower than the ratio of the health control group with P<0.05. There is no difference between the two ratios of the tonifying the kidney group and the health control group with P>0.05. The tonifying the kidney group’s ADC ratio is obviously lower than the ratio of the other TCM treatment group. The tonifying the kidney group’s FA ratio is obviously higher than the ratio of the other TCM treatment group with P<0.05. The tonifying the kidney group’s FA ratio increasing and ADC ratio decreasing margins are obviously wider than the margins of the other TCM treatment group with P<0.05. It shows the tonifying the kidney group’s nerve fiber tract repair is obviously better than that of the other TCM treatment group.Conclusion1. Compared with the western medicine treatment and other TCM treatment groups, the tonifying the kidney group’s TCM clinic and neurologic systematic syndromes decrease obviously after treatment. It shows tonifying the kidney treating MS can effectively improve the clinical syndromes.2. Compared with the western medicine treatment group, the tonifying the kidney group’s EDSS and TCM syndromes scores decrease obviously after treatment. It shows tonifying the kidney treating MS can improve neurologic function remarkably.3. Compared with the western medicine treatment group, the tonifying the kidney group’s NAA/CR ratio increase and CHO/CR ratio decrease obviously after treatment. It shows tonifying the kidney treating MS can effectively promote myelin sheath repair and axon regeneration.4. Compared with the western medicine treatment and other TCM treatment groups, the tonifying the kidney group’s ADC ratio decrease and FA ratio increase obviously after treatment. It shows tonifying the kidney treating MS can effectively promote nerve fiber tract repair.Above all, tonifying the kidney treating MS can effectively promote the damaged nerve repair and regeneration.更多还原