儿童脑性瘫痪的中医康复评定及相关证候的分子生物学机制研究
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摘要
脑性瘫痪指的是从出生前到出生后1个月以内因各种原因所致的非进行性脑损伤,主要表现为中枢性运动障碍及姿势异常,同时经常伴有其他如智力低下等并发障碍。目前在现代康复医学中,对脑瘫的康复评定已经有一整套相对成熟的标准,可以较好地指导物理治疗、作业治疗及语言训练等。中医治疗在脑瘫患儿的功能康复方面以其独特的疗效一直被社会广泛关注。但是,从文献分析来看,目前针对脑瘫的中医康复治疗多以针灸和按摩为主,中药治疗较少;众医家多针对功能障碍的肌肉关节部位进行局部治疗,整体辨证论治者少,且对本病未形成统一的辨证标准。辨证论治是中医基础理论体系的基本特点和主要内容,是指导中医康复治疗的基础。因此,进行脑瘫的证候学研究对于指导中医康复治疗有重要的意义。本课题从理论研究入手,结合临床和实验研究,对脑性瘫痪的中医证候学特点及相关分子生物学机制进行研究,为更好地发挥中医治病特点、辨证施治奠定基础。
1理论研究
中医古代医籍中无与“脑性瘫痪”直接对应的病名,其相关记载多见于儿科论著中涉及“五硬”、“五软”、“五迟”、“抽搐”、“惊风”的篇章。本研究对中医散在文献进行整理,从脑瘫的病因病机、发病过程、脏腑间关系及功能障碍特点等几方面进行探讨,归纳出“肝风内动”证与脑瘫运动功能障碍之间的关系。结果显示,脑瘫运动功能下降,其病标为肝风内动,而病本在于脾肾两虚。现代医学研究认为,谷氨酸的兴奋毒性是急慢性脑损伤和脑瘫发生后导致神经发育异常的重要机制之一。Glu是中枢神经系统中重要的兴奋性氨基酸神经递质而GABA是中枢重要的抑制性氨基酸神经递质。Glu与GABA两种物质在体内维持动态平衡,共同调节神经系统正常功能。但当其二者的拮抗水平不相平衡时,则可出现中枢神经调控功能的紊乱,并可影响不成熟脑的正常发育。在外周肢体即表现为痉挛、不自主运动等运动功能障碍。将中枢神经Glu/GABA系统的平衡失调与外周肢体的肝风内动证相联系,通过“滋水涵木”与“扶土抑木”来平熄肝风,肝的正常功能得以恢复的同时,中枢的兴奋/抑制递质系统也将趋于平衡。在此理论研究的基础上,我们开展了其后的实验研究,以验证补肾滋阴类中药及健脾补气类中药通过改善Glu/GABA系统的平衡来改善脑瘫患儿运动功能的效果。
2临床研究
脑瘫患儿的运动功能障碍为其标识性特点,同时可伴有其他多重障碍。本研究对脑瘫儿童的粗大运动功能、步态特征及智商作出了评定,对患儿的中医证候作出了调查,同时研究比较了中医证候与现代康复学评定结果的相关性。本研究旨在为制订中医康复评定标准及在辨证指导下的中医康复治疗提供一定依据。
2.1脑性瘫痪患儿中医症状证候分布特征的研究
本研究以确诊为脑性瘫痪的4～12岁儿童90例为研究对象,通过对症状证候的整体判别我们可以看出,儿童脑性瘫痪证候表现为虚实夹杂。虚证的分布由多至少分别为肾精不足、脾气虚、肾阴虚、肺气虚、肝阴虚;实证的分布由多至少分别为瘀阻脑络、胃热、胃肠气滞、痰蒙心神。总体趋势是虚证的出现率偏高,并多伴随痰、瘀、湿、热、气滞等实邪。
2.2脑性瘫痪儿童粗大运动功能评定及与中医证候的相关性研究
本研究以确诊为脑性瘫痪的4～12岁儿童90例为研究对象,通过对粗大运动功能评价的对比研究可以发现痉挛型与手足徐动型患儿的粗大运动功能总评分与分级分布无明显差异,两型患者均存在着粗大运动功能障碍。但是观察量表不同的功能区发现手足徐动型患儿下肢功能优于痉挛型患儿;痉挛型患儿下肢功能优于手足徐动型患儿,因此康复评定和治疗时不可一概而论。通过对中医证候与粗大运动功能的相关性研究可以看出中医证候的分布与粗大运动功能评分呈负相关,随着前十位中医证候出现频率的上升粗大运动功能评分有下降的趋势。其中出现率在50%以上肾精不足证、脾气虚证、肝风内动证和肾阴虚证与运动功能障碍关系密切。
2.3痉挛型脑性瘫痪患儿足底压力步态特征分析
痉挛型脑瘫占全体脑瘫患者的70%以上,由于小腿三头肌、跖屈肌痉挛而使踝关节跖屈挛缩所以步行功能往往受到影响。本研究选取痉挛型脑瘫患儿和正常儿童各40例,采用Footscan足底压力测试系统进行步态分析。本次研究中痉挛型脑瘫患儿与正常儿童对照组相比,存在病理性的足内翻和足外翻,本次调查中以足前部过度外翻的情况多见;足前部,足中部触地时间占站立相的比例较对照组高。因此,足前部的过度翻转对整个踝足稳定性的影响更加有意义。
2.4脑瘫患儿步态特征分析及其中医机理探讨
本研究选取脑瘫患儿50例和正常儿童40例,采用Footscan足底压力测试系统进行步态分析并对脑瘫患儿进行中医证候学调查,对中医各单证候积分与步态基础参数值进行了直线相关研究。本调查显示,与同龄正常儿童相比,脑瘫患儿步长缩短,步频与步速降低,脑瘫患儿组的足轴与前进方向夹角明显大于正常儿童组,脑瘫组儿童步态的足底压力曲线合力中心偏移率明显高于正常组儿童,双侧足底压力曲线不对称,同侧不同的步态周期足底压力曲线也形态各异,反映了脑瘫儿童的姿势控制、平衡协调能力极差,从而影响了步态的稳定性。通过对步态参数与中医证候作相关性研究,发现肝风内动、肾精不足、肾阴虚、脾气虚及瘀阻脑络、痰蒙心神证的出现在一定程度上导致了步态平衡能力的下降。通过其机理分析,认为对于脑瘫患儿,脾肾两脏的亏虚是导致肝风内动的基本因素,其三脏功能失调导致瘀血痰湿的生成,在这些因素共同作用下,躯体平衡能力下降,出现步态异常。
2.5脑性瘫痪患儿智力评价与粗大运动功能及中医证候的相关性研究
智力损伤是脑性瘫痪的主要并发症之一。本研究以确诊为脑性瘫痪的4～12岁儿童90例为研究对象,对其进行韦氏智力量表测试。结果显示70%的患儿存在智力缺损,其中痉挛型患儿的平均智商水平低于手足徐动型患儿。痉挛型患儿的智商水平与粗大运动功能分级相关,而对于手足徐动型患儿其两者无明显相关,这可能与两型脑性瘫痪患儿的神经系统受损部位不同有关。通过对中医证候的调查我们发现,瘀阻脑络及痰蒙心神证患儿出现中重度智力缺损频率增高。在使用中医治疗对脑瘫患儿进行智力康复时,应结合全身辨证,标本兼治。祛瘀化痰勿忘补肾健脾。
3实验研究
宫内感染是出生前阶段中最常见的高危因素,造成胎儿宫内窘迫,导致缺氧缺血性脑损伤,而脑瘫则是胎儿宫内窘迫和产程中缺氧在出生后的表现和继续。本课题通过建立运宫内感染导致脑瘫新生大鼠模型,从行为学角度评价模型动物运动功能的变化;采用免疫组化,荧光定时定量PCR等实验技术方法,系统地观察模型大鼠额叶皮质区Glu、GABA受体亚单位及其mRNA表达的变化。并应用“大定风珠”与“补中益气汤”对模型动物进行干预,通过以方测证的中医证候学研究方法,分析脑瘫运动功能障碍的机理和中医证候学特点,为更好地在辨证指导下进行中医康复治疗奠定基础。
3.1脑性瘫痪大鼠动物模型的建立
本实验采用为孕鼠腹腔注射LPS造成新生大鼠脑性瘫痪的动物模型。对腹腔注射LPS的孕鼠娩出的新生大鼠进行神经行为学检测,检测涵盖随意运动、肌张力、肌力、姿势、不自主运动等多个项目,以此为依据筛选出脑瘫大鼠。本实验以此作为脑瘫动物模型的筛选标准。结果显示筛选出的脑瘫大鼠表现为反应迟钝、自主活动减少、运动速度缓慢、运动活动性降低、出现不同程度的肌张力增强、肌力下降、姿势异常和运动稳定性降低。部分出现震颤与抽搐。该表现符合脑瘫脑损伤的神经行为学特点。对筛选出的脑瘫大鼠的脑组织切片进行HE染色。镜下观察筛选出的脑瘫大鼠脑组织损害符合脑瘫病理学改变,脑瘫模型成立。
3.2中药对脑性瘫痪大鼠动物模型行为学影响研究
本实验通过神经行为学检测方法,包括体现随意运动的斜坡实验,体现肌力的悬吊实验及体现姿势Tarlov分级评定和体现肌张力的Ashworth评分等,从行为学层面观察脑瘫大鼠的运动功能改变,以及中药“大定风珠”与“补中益气汤”对运动的调节作用。结果显示补中益气汤组随意运动、姿势评分增加,肌力明显提高,肌张力下降,仍存在有不自主运动的情况;大定风珠组随意运动、姿势评分增加,肌力提高,肌张力下降,未出现不自主运动。通过扶土抑木法与滋水涵木法治疗均可以改善姿势与随意运动。扶土抑木法可以提高主动肌肌力以对抗拮抗肌的张力,滋水涵木法可以用过缓解肌肉痉挛状态及不自主的运动来改善运动功能。
3.3脑性瘫痪大鼠Glu、GABA受体含量及mRNA的变化
Glu/GABA的平衡在神经兴奋性毒性导致的脑损害程度上起着重要的作用。本实验选取Glu受体NMDAR1、NMDAR2B及GABA受体GABABR1作为主要的研究指标,采用免疫组织化学与RT-PCR方法,对各指标在皮质区中的表达变化进行观察,分析脑瘫新生大鼠上述指标的变化及中药方的影响作用。结果显示脑瘫模型组与正常对照组比较NR1、NR2B受体含量呈升高趋势,GABABR1受体含量呈下降趋势,脑瘫模型组与正常对照组比较NR1mRNA、NR2BmRNA与GABABR1mRNA含量均呈升高趋势。补中益气汤与大定风珠都能从蛋白和基因水平下调脑瘫大鼠中枢兴奋性NMDA受体NR1、NR2B的表达。大定风珠可以从蛋白和基因水平上调脑瘫大鼠中枢抑制性受体GABABR1的表达,但是补中益气汤的上调程度不明显。
4小结
儿童脑性瘫痪证候表现为虚实夹杂,在肾精不足、脾气虚、肾阴虚等虚证基础上伴随有血瘀、痰湿、动风等实证的出现。脑瘫的主要功能障碍为运动功能障碍,其与智力障碍等互相影响,互为因果。脑瘫的运动功能障碍包括其自主活动受限,步态异常与不自主动作、病理反射增多可以辨为中医的肝风内动证。结合其全身辨证,其内风的出现与先天肾精不足、后天脾气亏虚共同导致精血阴液不足,引发阴虚风动有关。故本病应以“滋水涵木”及“扶土抑木”之法以平熄肝风。实验研究显示扶土抑木法中药可以降低中枢皮质的兴奋性递质受体表达;滋水涵木法中药既可以降低中枢皮质的兴奋性递质受体表达又可以促进抑制性递质受体的表达。推测此两种治法可能在调节中枢兴奋性/抑制性受体作用平衡的机制上改善了脑瘫的运动功能。
Cerebral palsy(CP) is most commonly seen inborn brain disorder syndrome of childen or happened in children's perinatal period.The main symptom of the CP is centrocinesia disorder and abnormal gesture.It is often accompanied by mental retardation and vision disorder,acoustic disorder,speech disorder and epilepsy. The distinctive curative effect of TCM therapy is always be interested by the researchers.It is the most important point of the TCM theory system that determination of treatment based on differentiation of symptoms and signs. Therefore,we start from the theoretical research,and through clinical and experimental studies on the characteristics of Chinese syndromes and the mechanisms of molecular biology research about the motor dysfunction caused by CP,in order to give better play to the Chinese medicine treatment,and lay the foundation for Differential Treatment of the motor dysfunction of CP.
1.Theoretical Study
We study the motor dysfunction caused by CP based on the theory of endogenous liver wind of TCM.The abnormal gesture and muscular tension and involuntary movement are expressions of the liver wind,which is caused by asthenia of both the spleen and kidney.Modern medicine discovers,the exitotoxicity by the Glu is one of the important neurological mechanism of the CP. The dynamic balance of these two transmitters relates to the normal function of the NS,which is concerned with the function of liver of TCM.We can treat the motor dysfunction of CP from invigorate the kidney and the spleen.Through the therapy of "nourishing the kidney is adopted to treat yin deficiency in the liver and kidney" and "reinforcing the spleen to restrain the abnormal function of the liver", we can extinguish the liver wind and elevate the motor function of the CP.
2 Clinical Studies
The main symptom of the CP is centrocinesia disorder and abnormal gesture. It is often accompanied by mental retardation and vision disorder,acoustic disorder,speech disorder and epilepsy.In this part we observed the Chinese Syndromes of CP,combining with the evaluation of the gross motor function,the intelligence quotient,and the gait analysis,and conducted a relevance study between the Chinese syndromes and these evaluations.The key elements are as follows:
2.1 The study on the characteristics of Chinese Syndromes of the children of CP
We selected 90 children of CP,whose age were from 4 to 12 years old.We found that deficiency syndrome accompanied with excess syndrome were always appeared in the children of CP.we concluded the ten of the most Chinese Syndromes appeared.The deficient syndromes were deficiency of kidney-essence, deficiency of spleen-Qi,deficiency of kidney-yin,deficiency of lung-QI,and deficiency of liver-Yin,the sthenia syndromes were blood stasis,gastric heat, stagnation of qi of the stomach intestine and mental confusion due to phlegm.The tendency is the frequency of the deficiency syndromes was higher,and accompanied with the sthenia syndromes,such as phlegm,blood stasis,moist,heat, stagnation of the qi,and so on.
2.2 Related research on gross motor function evaluation and Chinese syndromes of CP
We selected 90 children of CP,whose age were from 4 to 12 years old and evaluated them with the GMFM scale and GMFCS scale.The result showed there is no obvious difference between the children of the spastic cerebral palsy and athetosis cerebral palsy in GMFM score and GMFCS score.But through the deeper research,we found the motor function of lower limb of athetosis CP is better than spastic CP,and the motor function of upper limb of spastic CP is better than athetosis CP.There is negative correlation between the gross motor function and the Chinese syndrome,the syndrome of deficiency of kidney-essence, deficiency of spleen-Qi,endogenous liver wind and deficiency of kidney-yin were intimate with the gross motor functional disturbance of CP.
2.3 A study of the gait character of spastic cerebral palsy
Forty children with spastic cerebral palsy and forty healthy children with normal walking ability were involved in this research.Footscan 7 gait analysis system was used to measure foot initial touchdown part,the ratio of different part touchdown phase to single supporting phase,the degree of strephenopodia and strephexopodia in different part.Two groups' characteristic parameters were analyzed by statistics method.Differences were found in foot first touchdown part between two groups.The phenomenon that toes or metatarsus or whole foot first touch the earth was found in children with spastic cerebral palsy.The ratio of anterior foot and middle foot touchdown phase to single supporting phase were higher than normal children.In spastic cerebral palsy group the phenomenon of strephexopodia was more serious than strephenopodia during anterior foot touchdown phase.Conclusion:Lots of children with spastic cerebral palsy were suffering longtime compression pain and strephexopodia with anterior foot,active rectification must be perform during rehabilitation care.
2.4 The study of the gait character and the TCM mechanism of which in the children of CP
We selected 50 children of CP and 40 normal children.The gait analysis was carried out and the research of the linear correlation between the gait underlying parameters and The Chinese syndrome was progressed.We found that,in the children of CP,the step length is shorter,step frequency and gait speed is lower than the normal children.The excursion frequency of the resultant centre from planta pressure curve is higher,the included angle between the foot axis and the proceed direction is bigger than the normal children.These were caused by the abnormal gesture and disability of the balance in children of CP.We also found that the Chinese syndromes of deficiency of kidney-essence,deficiency of kidney-yin,deficiency of spleen-qi,mental confusion due to phlegm,blood stasis can cause the balance founction of the gait descend.Through the analysis of the mechanism,we believe asthenia of both the spleen and kidney is the basic reason which caused endogenous liver wind,and the dysfunction of these three organs can caused the blood stasis and phlegmatic hygrosis.Under the effect of all these Chinese syndrome,the balance of the body was broken-down,and abnormal gaits were appeared.
2.5 Related research on intellectual evaluation,gross motor function evaluation and Chinese syndromes of CP
We selected 90 children of CP,whose age were from 4 to 12 years old,and evaluated their intelligence by WIPSI.The result showed that the IQ of the athetosis CP is better than the spastic CP.There is positive correlation between the IQ and the GMFCS score of the the spastic CP,and no correlation of the athetosis CP.We also found that the children who have the syndromes of blood stasis, phlegmatic hygrosis and mental confusion due to phlegm always displaied as midrange or serious dysgnosia.
3.Experimental Studies
Intrauterine infection is one of the most important high risk factor causing CP, which can make fetal distress in uterus and lead to HIE,and CP is the appearance and continuator following fetal distress in uterus and HIE.In this part,We evaluated the neuroethology changes through establishing animal models of CP. We use immunohistochemistry and fluorescence quantitative PCR methods to observe the changes of rats Glu/GABA receptors and mRNA in Cortex of frontal lobe,and use different Chinese herbs to intervene for animal models in order to investigate their roles in medicine mechanisms.Main content and the results are as follows:
3.1 Establishing rat model of sports fatigue
In this study,we established CP animal model by LPS peritoneal injection leading to intrauterine infection.The neuroethology evaluations were proceeded on the neonate rat.The evaluation included voluntary movement evaluation, muscular tension evaluation,muscle power evaluation,gesture evaluation and involuntary movement evaluation,these were looked on as the sieve standard of the CP animal model.The result showed,the sieved CP rats were appeared as reaction clumsy,voluntary movement decreasing,abnormal gesture and motor stability decreasing,and some of the CP rats occurred thrill and hyperspasmia. These appearances were consistent with the neuroethological characters of CP.We proceeded HE drum dyeing on the brain section of the CP rats,the result showed that the brain damage were consistent with the pathological changes of CP.
3.2 Assessing the ethology changes of the CP rats under the effect of the Chinese herb medicines intervening on.
In this part we use neuroethological examination,which included slopes reflect experiment,suspension experiment,Tarlov score,Ashworth score,to observe the changes of the motor function of the CP rats and the effect of the Chinese herb medicines "Large Wind-Expelling Decoction" and "Bu Zhong Yi Qi soup".The result showed that as the rats of "Bu Zhong Yi Qi soup" group,whose voluntary movement score and gesture score and animal force increasing, muscular tension descending,and still had involuntary movements.As the rats of "Large Wind-Expelling Decoction" group,whose voluntary movement score and gesture score and animal force increasing,muscular tension descending,and had no involuntary movements.We can make the conclusion through the therapy of "reinforce the spleen to restrain the abnormal function of the liver",the agonist muscle force can be elevated,and oppose the antagonistic muscle,and improve the gesture or voluntary movement.Through the therapy of "nourishing the kidney is adopted to treat yin deficiency in the liver and kidney",the abnormal state of muscle spasm and involuntary movement can be improved.
3.3 changes of expression of Glu/GABA receptors and the mRNA in the Cortex of frontal Iobe of the CP rats
The imbalance of the transmitters Glu/GABA was one of the important factor which lead to exitotoxicity in CNS.In this part,we selected Glu receptor NMDAR1、NMDAR2B and GABA receptor GABABR1 as the target,through immunohistochemistry and fluorescence quantitative PCR methods,we observed the changes of rats GLU/GABA receptors and mRNA in Cortex of frontal lobe, and analysised the effect of Chinese herb medicines.The result showed,compared with normal control group,the CP model group's NR1、NR2B receptors upgraded and GABABR1 receptor descended and the mRNA of NR1、NR2B、GABABR1 receptors were all up-regulation.Both"Large Wind-Expelling Decoction" and "Bu Zhong Yi Qi soup" could down regulate expression of the NMDA receptors from the level of proteinum and gene."Large Wind-Expelling Decoction" could up-regulate expression of the GABA receptors from proteinum level and gene level.
4.Summary
According to the literatures study,we research on syndrome characteristics and mechanisms of molecular biology of the motor dysfunction caused by CP.In theoretical study,we start from the etiology,pathogenesis through the in-depth excavation of the liver's function,and explain the motor dysfunction of CP from the theory of endogenous liver wind.In clinical studies,we observed Chinese syndrome of CP,combining with rehabilitation assessments,we studied the relevance of Chinese syndromes and gross motor functions,intelligence quotient, gait characters.In the experimental studies,we established rat model of CP,and assessed neuroethological ability of the animal model.Then we use immunohistochemistry and fluorescence quantitative PCR methods systematically observaed the changes of subunit receptors of Glu/GABA in the expression of mRNA and protein levels.At the same time,we use different Chinese herbs intervening animal models in order to investigate the role of drug mechanisms and the model's characteristics of Chinese Syndrome.All the studies give a good play to the characteristics of Chinese medicine treatment and lay the foundation for studying differential treatment of motor dysfunction of CP.
1理论研究
中医古代医籍中无与“脑性瘫痪”直接对应的病名,其相关记载多见于儿科论著中涉及“五硬”、“五软”、“五迟”、“抽搐”、“惊风”的篇章。本研究对中医散在文献进行整理,从脑瘫的病因病机、发病过程、脏腑间关系及功能障碍特点等几方面进行探讨,归纳出“肝风内动”证与脑瘫运动功能障碍之间的关系。结果显示,脑瘫运动功能下降,其病标为肝风内动,而病本在于脾肾两虚。现代医学研究认为,谷氨酸的兴奋毒性是急慢性脑损伤和脑瘫发生后导致神经发育异常的重要机制之一。Glu是中枢神经系统中重要的兴奋性氨基酸神经递质而GABA是中枢重要的抑制性氨基酸神经递质。Glu与GABA两种物质在体内维持动态平衡,共同调节神经系统正常功能。但当其二者的拮抗水平不相平衡时,则可出现中枢神经调控功能的紊乱,并可影响不成熟脑的正常发育。在外周肢体即表现为痉挛、不自主运动等运动功能障碍。将中枢神经Glu/GABA系统的平衡失调与外周肢体的肝风内动证相联系,通过“滋水涵木”与“扶土抑木”来平熄肝风,肝的正常功能得以恢复的同时,中枢的兴奋/抑制递质系统也将趋于平衡。在此理论研究的基础上,我们开展了其后的实验研究,以验证补肾滋阴类中药及健脾补气类中药通过改善Glu/GABA系统的平衡来改善脑瘫患儿运动功能的效果。
2临床研究
脑瘫患儿的运动功能障碍为其标识性特点,同时可伴有其他多重障碍。本研究对脑瘫儿童的粗大运动功能、步态特征及智商作出了评定,对患儿的中医证候作出了调查,同时研究比较了中医证候与现代康复学评定结果的相关性。本研究旨在为制订中医康复评定标准及在辨证指导下的中医康复治疗提供一定依据。
2.1脑性瘫痪患儿中医症状证候分布特征的研究
本研究以确诊为脑性瘫痪的4～12岁儿童90例为研究对象,通过对症状证候的整体判别我们可以看出,儿童脑性瘫痪证候表现为虚实夹杂。虚证的分布由多至少分别为肾精不足、脾气虚、肾阴虚、肺气虚、肝阴虚;实证的分布由多至少分别为瘀阻脑络、胃热、胃肠气滞、痰蒙心神。总体趋势是虚证的出现率偏高,并多伴随痰、瘀、湿、热、气滞等实邪。
2.2脑性瘫痪儿童粗大运动功能评定及与中医证候的相关性研究
本研究以确诊为脑性瘫痪的4～12岁儿童90例为研究对象,通过对粗大运动功能评价的对比研究可以发现痉挛型与手足徐动型患儿的粗大运动功能总评分与分级分布无明显差异,两型患者均存在着粗大运动功能障碍。但是观察量表不同的功能区发现手足徐动型患儿下肢功能优于痉挛型患儿;痉挛型患儿下肢功能优于手足徐动型患儿,因此康复评定和治疗时不可一概而论。通过对中医证候与粗大运动功能的相关性研究可以看出中医证候的分布与粗大运动功能评分呈负相关,随着前十位中医证候出现频率的上升粗大运动功能评分有下降的趋势。其中出现率在50%以上肾精不足证、脾气虚证、肝风内动证和肾阴虚证与运动功能障碍关系密切。
2.3痉挛型脑性瘫痪患儿足底压力步态特征分析
痉挛型脑瘫占全体脑瘫患者的70%以上,由于小腿三头肌、跖屈肌痉挛而使踝关节跖屈挛缩所以步行功能往往受到影响。本研究选取痉挛型脑瘫患儿和正常儿童各40例,采用Footscan足底压力测试系统进行步态分析。本次研究中痉挛型脑瘫患儿与正常儿童对照组相比,存在病理性的足内翻和足外翻,本次调查中以足前部过度外翻的情况多见;足前部,足中部触地时间占站立相的比例较对照组高。因此,足前部的过度翻转对整个踝足稳定性的影响更加有意义。
2.4脑瘫患儿步态特征分析及其中医机理探讨
本研究选取脑瘫患儿50例和正常儿童40例,采用Footscan足底压力测试系统进行步态分析并对脑瘫患儿进行中医证候学调查,对中医各单证候积分与步态基础参数值进行了直线相关研究。本调查显示,与同龄正常儿童相比,脑瘫患儿步长缩短,步频与步速降低,脑瘫患儿组的足轴与前进方向夹角明显大于正常儿童组,脑瘫组儿童步态的足底压力曲线合力中心偏移率明显高于正常组儿童,双侧足底压力曲线不对称,同侧不同的步态周期足底压力曲线也形态各异,反映了脑瘫儿童的姿势控制、平衡协调能力极差,从而影响了步态的稳定性。通过对步态参数与中医证候作相关性研究,发现肝风内动、肾精不足、肾阴虚、脾气虚及瘀阻脑络、痰蒙心神证的出现在一定程度上导致了步态平衡能力的下降。通过其机理分析,认为对于脑瘫患儿,脾肾两脏的亏虚是导致肝风内动的基本因素,其三脏功能失调导致瘀血痰湿的生成,在这些因素共同作用下,躯体平衡能力下降,出现步态异常。
2.5脑性瘫痪患儿智力评价与粗大运动功能及中医证候的相关性研究
智力损伤是脑性瘫痪的主要并发症之一。本研究以确诊为脑性瘫痪的4～12岁儿童90例为研究对象,对其进行韦氏智力量表测试。结果显示70%的患儿存在智力缺损,其中痉挛型患儿的平均智商水平低于手足徐动型患儿。痉挛型患儿的智商水平与粗大运动功能分级相关,而对于手足徐动型患儿其两者无明显相关,这可能与两型脑性瘫痪患儿的神经系统受损部位不同有关。通过对中医证候的调查我们发现,瘀阻脑络及痰蒙心神证患儿出现中重度智力缺损频率增高。在使用中医治疗对脑瘫患儿进行智力康复时,应结合全身辨证,标本兼治。祛瘀化痰勿忘补肾健脾。
3实验研究
宫内感染是出生前阶段中最常见的高危因素,造成胎儿宫内窘迫,导致缺氧缺血性脑损伤,而脑瘫则是胎儿宫内窘迫和产程中缺氧在出生后的表现和继续。本课题通过建立运宫内感染导致脑瘫新生大鼠模型,从行为学角度评价模型动物运动功能的变化;采用免疫组化,荧光定时定量PCR等实验技术方法,系统地观察模型大鼠额叶皮质区Glu、GABA受体亚单位及其mRNA表达的变化。并应用“大定风珠”与“补中益气汤”对模型动物进行干预,通过以方测证的中医证候学研究方法,分析脑瘫运动功能障碍的机理和中医证候学特点,为更好地在辨证指导下进行中医康复治疗奠定基础。
3.1脑性瘫痪大鼠动物模型的建立
本实验采用为孕鼠腹腔注射LPS造成新生大鼠脑性瘫痪的动物模型。对腹腔注射LPS的孕鼠娩出的新生大鼠进行神经行为学检测,检测涵盖随意运动、肌张力、肌力、姿势、不自主运动等多个项目,以此为依据筛选出脑瘫大鼠。本实验以此作为脑瘫动物模型的筛选标准。结果显示筛选出的脑瘫大鼠表现为反应迟钝、自主活动减少、运动速度缓慢、运动活动性降低、出现不同程度的肌张力增强、肌力下降、姿势异常和运动稳定性降低。部分出现震颤与抽搐。该表现符合脑瘫脑损伤的神经行为学特点。对筛选出的脑瘫大鼠的脑组织切片进行HE染色。镜下观察筛选出的脑瘫大鼠脑组织损害符合脑瘫病理学改变,脑瘫模型成立。
3.2中药对脑性瘫痪大鼠动物模型行为学影响研究
本实验通过神经行为学检测方法,包括体现随意运动的斜坡实验,体现肌力的悬吊实验及体现姿势Tarlov分级评定和体现肌张力的Ashworth评分等,从行为学层面观察脑瘫大鼠的运动功能改变,以及中药“大定风珠”与“补中益气汤”对运动的调节作用。结果显示补中益气汤组随意运动、姿势评分增加,肌力明显提高,肌张力下降,仍存在有不自主运动的情况;大定风珠组随意运动、姿势评分增加,肌力提高,肌张力下降,未出现不自主运动。通过扶土抑木法与滋水涵木法治疗均可以改善姿势与随意运动。扶土抑木法可以提高主动肌肌力以对抗拮抗肌的张力,滋水涵木法可以用过缓解肌肉痉挛状态及不自主的运动来改善运动功能。
3.3脑性瘫痪大鼠Glu、GABA受体含量及mRNA的变化
Glu/GABA的平衡在神经兴奋性毒性导致的脑损害程度上起着重要的作用。本实验选取Glu受体NMDAR1、NMDAR2B及GABA受体GABABR1作为主要的研究指标,采用免疫组织化学与RT-PCR方法,对各指标在皮质区中的表达变化进行观察,分析脑瘫新生大鼠上述指标的变化及中药方的影响作用。结果显示脑瘫模型组与正常对照组比较NR1、NR2B受体含量呈升高趋势,GABABR1受体含量呈下降趋势,脑瘫模型组与正常对照组比较NR1mRNA、NR2BmRNA与GABABR1mRNA含量均呈升高趋势。补中益气汤与大定风珠都能从蛋白和基因水平下调脑瘫大鼠中枢兴奋性NMDA受体NR1、NR2B的表达。大定风珠可以从蛋白和基因水平上调脑瘫大鼠中枢抑制性受体GABABR1的表达,但是补中益气汤的上调程度不明显。
4小结
儿童脑性瘫痪证候表现为虚实夹杂,在肾精不足、脾气虚、肾阴虚等虚证基础上伴随有血瘀、痰湿、动风等实证的出现。脑瘫的主要功能障碍为运动功能障碍,其与智力障碍等互相影响,互为因果。脑瘫的运动功能障碍包括其自主活动受限,步态异常与不自主动作、病理反射增多可以辨为中医的肝风内动证。结合其全身辨证,其内风的出现与先天肾精不足、后天脾气亏虚共同导致精血阴液不足,引发阴虚风动有关。故本病应以“滋水涵木”及“扶土抑木”之法以平熄肝风。实验研究显示扶土抑木法中药可以降低中枢皮质的兴奋性递质受体表达;滋水涵木法中药既可以降低中枢皮质的兴奋性递质受体表达又可以促进抑制性递质受体的表达。推测此两种治法可能在调节中枢兴奋性/抑制性受体作用平衡的机制上改善了脑瘫的运动功能。
Cerebral palsy(CP) is most commonly seen inborn brain disorder syndrome of childen or happened in children's perinatal period.The main symptom of the CP is centrocinesia disorder and abnormal gesture.It is often accompanied by mental retardation and vision disorder,acoustic disorder,speech disorder and epilepsy. The distinctive curative effect of TCM therapy is always be interested by the researchers.It is the most important point of the TCM theory system that determination of treatment based on differentiation of symptoms and signs. Therefore,we start from the theoretical research,and through clinical and experimental studies on the characteristics of Chinese syndromes and the mechanisms of molecular biology research about the motor dysfunction caused by CP,in order to give better play to the Chinese medicine treatment,and lay the foundation for Differential Treatment of the motor dysfunction of CP.
1.Theoretical Study
We study the motor dysfunction caused by CP based on the theory of endogenous liver wind of TCM.The abnormal gesture and muscular tension and involuntary movement are expressions of the liver wind,which is caused by asthenia of both the spleen and kidney.Modern medicine discovers,the exitotoxicity by the Glu is one of the important neurological mechanism of the CP. The dynamic balance of these two transmitters relates to the normal function of the NS,which is concerned with the function of liver of TCM.We can treat the motor dysfunction of CP from invigorate the kidney and the spleen.Through the therapy of "nourishing the kidney is adopted to treat yin deficiency in the liver and kidney" and "reinforcing the spleen to restrain the abnormal function of the liver", we can extinguish the liver wind and elevate the motor function of the CP.
2 Clinical Studies
The main symptom of the CP is centrocinesia disorder and abnormal gesture. It is often accompanied by mental retardation and vision disorder,acoustic disorder,speech disorder and epilepsy.In this part we observed the Chinese Syndromes of CP,combining with the evaluation of the gross motor function,the intelligence quotient,and the gait analysis,and conducted a relevance study between the Chinese syndromes and these evaluations.The key elements are as follows:
2.1 The study on the characteristics of Chinese Syndromes of the children of CP
We selected 90 children of CP,whose age were from 4 to 12 years old.We found that deficiency syndrome accompanied with excess syndrome were always appeared in the children of CP.we concluded the ten of the most Chinese Syndromes appeared.The deficient syndromes were deficiency of kidney-essence, deficiency of spleen-Qi,deficiency of kidney-yin,deficiency of lung-QI,and deficiency of liver-Yin,the sthenia syndromes were blood stasis,gastric heat, stagnation of qi of the stomach intestine and mental confusion due to phlegm.The tendency is the frequency of the deficiency syndromes was higher,and accompanied with the sthenia syndromes,such as phlegm,blood stasis,moist,heat, stagnation of the qi,and so on.
2.2 Related research on gross motor function evaluation and Chinese syndromes of CP
We selected 90 children of CP,whose age were from 4 to 12 years old and evaluated them with the GMFM scale and GMFCS scale.The result showed there is no obvious difference between the children of the spastic cerebral palsy and athetosis cerebral palsy in GMFM score and GMFCS score.But through the deeper research,we found the motor function of lower limb of athetosis CP is better than spastic CP,and the motor function of upper limb of spastic CP is better than athetosis CP.There is negative correlation between the gross motor function and the Chinese syndrome,the syndrome of deficiency of kidney-essence, deficiency of spleen-Qi,endogenous liver wind and deficiency of kidney-yin were intimate with the gross motor functional disturbance of CP.
2.3 A study of the gait character of spastic cerebral palsy
Forty children with spastic cerebral palsy and forty healthy children with normal walking ability were involved in this research.Footscan 7 gait analysis system was used to measure foot initial touchdown part,the ratio of different part touchdown phase to single supporting phase,the degree of strephenopodia and strephexopodia in different part.Two groups' characteristic parameters were analyzed by statistics method.Differences were found in foot first touchdown part between two groups.The phenomenon that toes or metatarsus or whole foot first touch the earth was found in children with spastic cerebral palsy.The ratio of anterior foot and middle foot touchdown phase to single supporting phase were higher than normal children.In spastic cerebral palsy group the phenomenon of strephexopodia was more serious than strephenopodia during anterior foot touchdown phase.Conclusion:Lots of children with spastic cerebral palsy were suffering longtime compression pain and strephexopodia with anterior foot,active rectification must be perform during rehabilitation care.
2.4 The study of the gait character and the TCM mechanism of which in the children of CP
We selected 50 children of CP and 40 normal children.The gait analysis was carried out and the research of the linear correlation between the gait underlying parameters and The Chinese syndrome was progressed.We found that,in the children of CP,the step length is shorter,step frequency and gait speed is lower than the normal children.The excursion frequency of the resultant centre from planta pressure curve is higher,the included angle between the foot axis and the proceed direction is bigger than the normal children.These were caused by the abnormal gesture and disability of the balance in children of CP.We also found that the Chinese syndromes of deficiency of kidney-essence,deficiency of kidney-yin,deficiency of spleen-qi,mental confusion due to phlegm,blood stasis can cause the balance founction of the gait descend.Through the analysis of the mechanism,we believe asthenia of both the spleen and kidney is the basic reason which caused endogenous liver wind,and the dysfunction of these three organs can caused the blood stasis and phlegmatic hygrosis.Under the effect of all these Chinese syndrome,the balance of the body was broken-down,and abnormal gaits were appeared.
2.5 Related research on intellectual evaluation,gross motor function evaluation and Chinese syndromes of CP
We selected 90 children of CP,whose age were from 4 to 12 years old,and evaluated their intelligence by WIPSI.The result showed that the IQ of the athetosis CP is better than the spastic CP.There is positive correlation between the IQ and the GMFCS score of the the spastic CP,and no correlation of the athetosis CP.We also found that the children who have the syndromes of blood stasis, phlegmatic hygrosis and mental confusion due to phlegm always displaied as midrange or serious dysgnosia.
3.Experimental Studies
Intrauterine infection is one of the most important high risk factor causing CP, which can make fetal distress in uterus and lead to HIE,and CP is the appearance and continuator following fetal distress in uterus and HIE.In this part,We evaluated the neuroethology changes through establishing animal models of CP. We use immunohistochemistry and fluorescence quantitative PCR methods to observe the changes of rats Glu/GABA receptors and mRNA in Cortex of frontal lobe,and use different Chinese herbs to intervene for animal models in order to investigate their roles in medicine mechanisms.Main content and the results are as follows:
3.1 Establishing rat model of sports fatigue
In this study,we established CP animal model by LPS peritoneal injection leading to intrauterine infection.The neuroethology evaluations were proceeded on the neonate rat.The evaluation included voluntary movement evaluation, muscular tension evaluation,muscle power evaluation,gesture evaluation and involuntary movement evaluation,these were looked on as the sieve standard of the CP animal model.The result showed,the sieved CP rats were appeared as reaction clumsy,voluntary movement decreasing,abnormal gesture and motor stability decreasing,and some of the CP rats occurred thrill and hyperspasmia. These appearances were consistent with the neuroethological characters of CP.We proceeded HE drum dyeing on the brain section of the CP rats,the result showed that the brain damage were consistent with the pathological changes of CP.
3.2 Assessing the ethology changes of the CP rats under the effect of the Chinese herb medicines intervening on.
In this part we use neuroethological examination,which included slopes reflect experiment,suspension experiment,Tarlov score,Ashworth score,to observe the changes of the motor function of the CP rats and the effect of the Chinese herb medicines "Large Wind-Expelling Decoction" and "Bu Zhong Yi Qi soup".The result showed that as the rats of "Bu Zhong Yi Qi soup" group,whose voluntary movement score and gesture score and animal force increasing, muscular tension descending,and still had involuntary movements.As the rats of "Large Wind-Expelling Decoction" group,whose voluntary movement score and gesture score and animal force increasing,muscular tension descending,and had no involuntary movements.We can make the conclusion through the therapy of "reinforce the spleen to restrain the abnormal function of the liver",the agonist muscle force can be elevated,and oppose the antagonistic muscle,and improve the gesture or voluntary movement.Through the therapy of "nourishing the kidney is adopted to treat yin deficiency in the liver and kidney",the abnormal state of muscle spasm and involuntary movement can be improved.
3.3 changes of expression of Glu/GABA receptors and the mRNA in the Cortex of frontal Iobe of the CP rats
The imbalance of the transmitters Glu/GABA was one of the important factor which lead to exitotoxicity in CNS.In this part,we selected Glu receptor NMDAR1、NMDAR2B and GABA receptor GABABR1 as the target,through immunohistochemistry and fluorescence quantitative PCR methods,we observed the changes of rats GLU/GABA receptors and mRNA in Cortex of frontal lobe, and analysised the effect of Chinese herb medicines.The result showed,compared with normal control group,the CP model group's NR1、NR2B receptors upgraded and GABABR1 receptor descended and the mRNA of NR1、NR2B、GABABR1 receptors were all up-regulation.Both"Large Wind-Expelling Decoction" and "Bu Zhong Yi Qi soup" could down regulate expression of the NMDA receptors from the level of proteinum and gene."Large Wind-Expelling Decoction" could up-regulate expression of the GABA receptors from proteinum level and gene level.
4.Summary
According to the literatures study,we research on syndrome characteristics and mechanisms of molecular biology of the motor dysfunction caused by CP.In theoretical study,we start from the etiology,pathogenesis through the in-depth excavation of the liver's function,and explain the motor dysfunction of CP from the theory of endogenous liver wind.In clinical studies,we observed Chinese syndrome of CP,combining with rehabilitation assessments,we studied the relevance of Chinese syndromes and gross motor functions,intelligence quotient, gait characters.In the experimental studies,we established rat model of CP,and assessed neuroethological ability of the animal model.Then we use immunohistochemistry and fluorescence quantitative PCR methods systematically observaed the changes of subunit receptors of Glu/GABA in the expression of mRNA and protein levels.At the same time,we use different Chinese herbs intervening animal models in order to investigate the role of drug mechanisms and the model's characteristics of Chinese Syndrome.All the studies give a good play to the characteristics of Chinese medicine treatment and lay the foundation for studying differential treatment of motor dysfunction of CP.
引文
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