二黄方减少多发性硬化轴索损伤和复发的临床研究
|
摘要
多发性硬化(multiple sclerosis, MS)是以中枢神经系统白质脱髓鞘病变为特点的自身免疫性疾病,可能是遗传易感个体与环境因素作用而发生的自身免疫过程。MS发病率随所处的纬度而增加,专家倾向MS在我国并非少见,但属于低发病区。由于其发病率较高、呈慢性病程和倾向于年轻人罹患,而成为最重要的神经系统疾病之一。MS脱髓鞘病变可累及大脑半球、视神经、脊髓、脑干和小脑,以白质受累为主,病灶位于脑室周围是MS特征性病理表现。MS在空间上的多发性(即散在分布于中枢神经系统的多发病灶)和时间上的多发性(即病程中的缓解复发),构成了MS临床经过及其症状和体征的主要特点。每次复发残留部分症状和体征,逐渐累积而使病情加重。疾病后期疾病呈缓慢阶梯式进展,无明显缓解而逐渐加重。越来越多的研究认为临床上出现进行性不可逆的神经功能障碍可能与轴索损伤有关,而轴索损伤可能在疾病早期就已出现,因此如何在疾病早期减少轴索损伤是MS治疗的核心。磁共振波谱分析(magnetic resonance spectroscopy, MRS)是近年来用于研究脑内物质代谢的新技术,由于物质代谢异常通常早于结构的变化,所以MRS可以检测到磁共振成像(magnetic resonance image, MRI)不能显示的异常。由于MRS可以定量检测脑内N-乙酰门冬氨酸水平(轴索和神经元标志物),所以MRS是临床研究MS的重要手段之一。
1研究目的
在磁共振波谱分析定量评价多发性硬化轴索损伤的基础上,探讨轴索损伤与疾病复发、进展的关系及长期服用二黄方(1年及以上)对降低年复发率、减轻神经功能障碍、延缓疾病进展的作用；探讨减轻轴索损伤可能是二黄方发挥治疗作用的机理之一
2研究方法
67例患者均为2006年1月-2010年12月首都医科大学附属北京天坛医院神经内科和中医科住院及门诊确诊为多发性硬化的病人,中医辨证符合肝肾阴虚证型。将入组患者随机分为对照组(24例)和二黄方组(43例)。对照组在急性复发期及缓解期均行西医治疗,二黄方组在急性复发期及缓解期在西医治疗基础上,同时服用二黄方,门诊随访2年。二黄方组患者在入组时和服二黄方满1年时分别行磁共振波谱分析,检测颅内病灶侧及病灶对侧NAA、CHO、CR水平。随访满2年时比较两组及治疗前后复发次数、年复发率、EDSS评分、NAA/CR、CHO/CR水平,以评价二黄方的治疗作用。
3研究结果
3.1一般临床资料：女性患者47例,男性患者20例,女性／男性比为2.4：1。发病年龄最小15岁,最大60岁,平均32.85±10.76岁,以20-50岁(79.1%)为发病高峰期。复发次数最少1次,最多6次,平均2.21±1.37次。病程最短1年,最长7年,平均2.77±1.90年；
3.2首次发病神经系统症状：视力障碍占26.0%,感觉障碍占31.7%,运动障碍占23.1%,其他症状占19.2%；
3.3主要神经系统症状：视力障碍占22.0%,感觉障碍占29.6%,运动障碍占25.2%,其他症状占23.2%；
3.4对照组治疗后复发次数和年复发率(1.42±0.97和0.75±0.55)与治疗前(2.04±0.96和0.91±0.46)比较,差异无统计学意义,P>0.05；
3.5二黄方组治疗后复发次数和年复发率(0.63±0.58和0.31±0.29)与治疗前(2.30±1.55和1.01±0.52)比较明显下降,差异有显著统计学意义,P=0.000；与对照组比较亦明显下降,差异有显著统计学意义,P=0.006；
3.6二黄方组与对照组治疗前后EDSS无明显变化,差异无统计学意义,P>0.05；
3.7MRI病灶部位：大脑病灶占36.4%,脑干病灶占38.6%,小脑病灶占5.0%,脊髓病灶占20.0%；
3.8二黄方组治疗前病灶侧NAA/CR和CHO/CR水平(1.81±0.68和1.20±0.69)和病灶对侧(1.96±0.53和0.94±0.24)相比,差异无统计学意义,P>0.05；
3.9二黄方组治疗后病灶侧NAA/CR和CHO/CR水平(1.77±0.47和1.05±0.21)、病灶对侧NAA/CR和CHO/CR水平(1.88±0.50和1.00±0.27),与治疗前相比,差异无统计学意义,P>0.05；
3.10NAA/CR水平与发病年龄、EDSS、复发次数、年复发率无关,与病程显著相关,相关系数为0.429,P=0.006。
4结论
多发性硬化病程越长,轴索损伤越严重,长期服用二黄方(1年及以上)能有效减少复发,延缓疾病进展。减少轴索损伤可能是二黄方发挥治疗作用的机理之一
Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system, may be a process that individual genetic susceptibility and environmental factors interact. The incidence of MS increases with latitude, experts tend to MS is not uncommon in China, but a low incidence area. Because of higher incidence, chronic process and tendency to the young patients, MS is one of the most important neurological diseases. MS demyelinating lesions involve the cerebral hemispheres, optic nerve, spinal cord, brainstem and cerebellum, mainly invove white matter, pathological performance is featured by lesions located in the periventricular. Multiple space(multiple lesions in the central nervous system) and time (remission and recurrence of duration)constitute the main features of MS clinical course and its signs and symptoms. Some residual symptoms and signs are produced after each recurrence, the gradual accumulation lead to disease more serious. MS is slow stepwise progress at late phase, not s ignif icant rel ief but gradual ly increased. A growing number of studies suggest that the clinical emergence of progressive irreversible neurological dysfunction may be associated with axonal injury, axonal injury may already appeared early in the disease, how to reduce axonal injury early in the disease is the core of MS treatment. Magnetic resonance spectroscopy (MRS) is a new technology for the study of brain metabol ism in recent years, due to the abnormal metabolism usually appear earlier than changes in the structure, so MRS can detect the abnormality that magnetic resonance imaging (MRI)can not display. Brain N-acetyl aspartate level (markers of axons and neurons) can be quantitatively detected by MRS, so MRS is an important means of clinical research on MS.
1Purpose
On the basis of quantitative evaluation of axonal injury in MS in the use of imaging techniques (magnetic resonance spectroscopy), to investigate the relationship between the axonal injury and progress, recurrence of the disease and explore that mitigating axonal injury may be one of the mechanisms of Erhuangfang.
2Methods
From January2006to December2010,67inpatients and outpatients were diagnosed as multiple sclerosis in department of Neurology and Traditional Chinese Medicine of Beijing Tiantan Hospital affiliated to Capital Medical University, whose syndrome types comply with Yin-deficiency of liver and kidney. Enrolled patients were randomly divided into control group (n=24) and Erhuangfang group (n=43). The control group underwent western medicine treatment in acute relapse and remission, while Erhuangfang group took Erhuangfang on the basis of western medicine treatment, they were all followed up for2years. Erhuangfang group patients underwent magnetic resonance spectroscopy to detect the level of NAA, CHO, CR of ipsilateral and contralateral lesion before they were treated and treated for1year. Followed up for at least two years, relapse frequency, annual relapse rate, EDSS, NAA/CR, CHO/CR level were compared between the two groups before and after treatment, to evaluate the therapeutic effect of Erhuangfang.
3Results
3.1General cl inical data:female47cases, male20cases, female/male rat io of2.4:1. Minimum age of onset is15-year-old, maximum age is60-year-old, average32.85±10.76-year-old,20to50-year-old (79.1%) is the peak incidence of period. The least recurrence is1time, the most is6times, an average of2.21±1.37times. The course of the disease is from1year to7years, average2.77±1.90years;
3.2The first onset nervous system symptoms:visual impairment,26.0%, sensory impairments31.7%, movement disorders (23.1%), other symptoms (19.2%);
3.3Main neurological symptoms:visual disturbances (22.0%), sensory disturbances (29.6%), movement disorders (25.2%), other symptoms (23.2%);
3.4In control group, referring to relapse frequency and annual relapse rate, the difference between posttreatment (1.42±0.97and0.75±0.55) and pretreatment (2.04±0.96and0.91±0.46) was not statistically significant (P>0.05);
3.5In Erhuangfang group, posttreatment relapse frequency and annual relapse rate (0.63±0.58and0.31±0.29) were evidently decreased than pretreatment (2.30±1.55and1.01±0.52), the difference was statistically significant (P=0.000); compared with the control group, the difference was also statistically significant (P=0.006);
3.6Between the control group and Erhuangfang group, the EDSS had no significant change before and after treatment, the difference was not statistically significant (P>0.05);
3.7The MRI lesion sites:brain lesions (36.4%), brainstem lesions (38.6%), cerebellar lesions (5.0%), spinal cord lesions (20.0%);
3.8In Erhuangfang group, touched on pretreatment level of NAA/CR and CHO/CR, the difference between ipsilateral lesion (1.81±0.68and1.20±0.69) and contralateral lesion(1.96±0.53and0.94±0.24) was not statistically significant (P>0.05);
3.9In Erhuangfang group, related to the level of NAA/CR and CHO/CR, both ipsilateral lesion and contralateral lesion, the difference between posttreatment (1.77±0.47and1.05±0.21) and pretreatment (1.88±0.50and1.00±0.27) was not statistically significant (P>0.05);
3.10NAA/CR level was not related to age of onset, EDSS, relapse frequency, annual recurrence rate, and was significantly associated with the duration, correlation coefficient was0.429, P=0.006.
4Conclusion
The duration of multiple sclerosis is more longer, axonal injury is more serious, long-term use (>1years) of Erhuangfang can effectively reduce relapse and slow disease progression. Reducing axonal injury may be one of the mechanisms that play a therapeutic role.
1研究目的
在磁共振波谱分析定量评价多发性硬化轴索损伤的基础上,探讨轴索损伤与疾病复发、进展的关系及长期服用二黄方(1年及以上)对降低年复发率、减轻神经功能障碍、延缓疾病进展的作用；探讨减轻轴索损伤可能是二黄方发挥治疗作用的机理之一
2研究方法
67例患者均为2006年1月-2010年12月首都医科大学附属北京天坛医院神经内科和中医科住院及门诊确诊为多发性硬化的病人,中医辨证符合肝肾阴虚证型。将入组患者随机分为对照组(24例)和二黄方组(43例)。对照组在急性复发期及缓解期均行西医治疗,二黄方组在急性复发期及缓解期在西医治疗基础上,同时服用二黄方,门诊随访2年。二黄方组患者在入组时和服二黄方满1年时分别行磁共振波谱分析,检测颅内病灶侧及病灶对侧NAA、CHO、CR水平。随访满2年时比较两组及治疗前后复发次数、年复发率、EDSS评分、NAA/CR、CHO/CR水平,以评价二黄方的治疗作用。
3研究结果
3.1一般临床资料：女性患者47例,男性患者20例,女性／男性比为2.4：1。发病年龄最小15岁,最大60岁,平均32.85±10.76岁,以20-50岁(79.1%)为发病高峰期。复发次数最少1次,最多6次,平均2.21±1.37次。病程最短1年,最长7年,平均2.77±1.90年；
3.2首次发病神经系统症状：视力障碍占26.0%,感觉障碍占31.7%,运动障碍占23.1%,其他症状占19.2%；
3.3主要神经系统症状：视力障碍占22.0%,感觉障碍占29.6%,运动障碍占25.2%,其他症状占23.2%；
3.4对照组治疗后复发次数和年复发率(1.42±0.97和0.75±0.55)与治疗前(2.04±0.96和0.91±0.46)比较,差异无统计学意义,P>0.05；
3.5二黄方组治疗后复发次数和年复发率(0.63±0.58和0.31±0.29)与治疗前(2.30±1.55和1.01±0.52)比较明显下降,差异有显著统计学意义,P=0.000；与对照组比较亦明显下降,差异有显著统计学意义,P=0.006；
3.6二黄方组与对照组治疗前后EDSS无明显变化,差异无统计学意义,P>0.05；
3.7MRI病灶部位：大脑病灶占36.4%,脑干病灶占38.6%,小脑病灶占5.0%,脊髓病灶占20.0%；
3.8二黄方组治疗前病灶侧NAA/CR和CHO/CR水平(1.81±0.68和1.20±0.69)和病灶对侧(1.96±0.53和0.94±0.24)相比,差异无统计学意义,P>0.05；
3.9二黄方组治疗后病灶侧NAA/CR和CHO/CR水平(1.77±0.47和1.05±0.21)、病灶对侧NAA/CR和CHO/CR水平(1.88±0.50和1.00±0.27),与治疗前相比,差异无统计学意义,P>0.05；
3.10NAA/CR水平与发病年龄、EDSS、复发次数、年复发率无关,与病程显著相关,相关系数为0.429,P=0.006。
4结论
多发性硬化病程越长,轴索损伤越严重,长期服用二黄方(1年及以上)能有效减少复发,延缓疾病进展。减少轴索损伤可能是二黄方发挥治疗作用的机理之一
Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system, may be a process that individual genetic susceptibility and environmental factors interact. The incidence of MS increases with latitude, experts tend to MS is not uncommon in China, but a low incidence area. Because of higher incidence, chronic process and tendency to the young patients, MS is one of the most important neurological diseases. MS demyelinating lesions involve the cerebral hemispheres, optic nerve, spinal cord, brainstem and cerebellum, mainly invove white matter, pathological performance is featured by lesions located in the periventricular. Multiple space(multiple lesions in the central nervous system) and time (remission and recurrence of duration)constitute the main features of MS clinical course and its signs and symptoms. Some residual symptoms and signs are produced after each recurrence, the gradual accumulation lead to disease more serious. MS is slow stepwise progress at late phase, not s ignif icant rel ief but gradual ly increased. A growing number of studies suggest that the clinical emergence of progressive irreversible neurological dysfunction may be associated with axonal injury, axonal injury may already appeared early in the disease, how to reduce axonal injury early in the disease is the core of MS treatment. Magnetic resonance spectroscopy (MRS) is a new technology for the study of brain metabol ism in recent years, due to the abnormal metabolism usually appear earlier than changes in the structure, so MRS can detect the abnormality that magnetic resonance imaging (MRI)can not display. Brain N-acetyl aspartate level (markers of axons and neurons) can be quantitatively detected by MRS, so MRS is an important means of clinical research on MS.
1Purpose
On the basis of quantitative evaluation of axonal injury in MS in the use of imaging techniques (magnetic resonance spectroscopy), to investigate the relationship between the axonal injury and progress, recurrence of the disease and explore that mitigating axonal injury may be one of the mechanisms of Erhuangfang.
2Methods
From January2006to December2010,67inpatients and outpatients were diagnosed as multiple sclerosis in department of Neurology and Traditional Chinese Medicine of Beijing Tiantan Hospital affiliated to Capital Medical University, whose syndrome types comply with Yin-deficiency of liver and kidney. Enrolled patients were randomly divided into control group (n=24) and Erhuangfang group (n=43). The control group underwent western medicine treatment in acute relapse and remission, while Erhuangfang group took Erhuangfang on the basis of western medicine treatment, they were all followed up for2years. Erhuangfang group patients underwent magnetic resonance spectroscopy to detect the level of NAA, CHO, CR of ipsilateral and contralateral lesion before they were treated and treated for1year. Followed up for at least two years, relapse frequency, annual relapse rate, EDSS, NAA/CR, CHO/CR level were compared between the two groups before and after treatment, to evaluate the therapeutic effect of Erhuangfang.
3Results
3.1General cl inical data:female47cases, male20cases, female/male rat io of2.4:1. Minimum age of onset is15-year-old, maximum age is60-year-old, average32.85±10.76-year-old,20to50-year-old (79.1%) is the peak incidence of period. The least recurrence is1time, the most is6times, an average of2.21±1.37times. The course of the disease is from1year to7years, average2.77±1.90years;
3.2The first onset nervous system symptoms:visual impairment,26.0%, sensory impairments31.7%, movement disorders (23.1%), other symptoms (19.2%);
3.3Main neurological symptoms:visual disturbances (22.0%), sensory disturbances (29.6%), movement disorders (25.2%), other symptoms (23.2%);
3.4In control group, referring to relapse frequency and annual relapse rate, the difference between posttreatment (1.42±0.97and0.75±0.55) and pretreatment (2.04±0.96and0.91±0.46) was not statistically significant (P>0.05);
3.5In Erhuangfang group, posttreatment relapse frequency and annual relapse rate (0.63±0.58and0.31±0.29) were evidently decreased than pretreatment (2.30±1.55and1.01±0.52), the difference was statistically significant (P=0.000); compared with the control group, the difference was also statistically significant (P=0.006);
3.6Between the control group and Erhuangfang group, the EDSS had no significant change before and after treatment, the difference was not statistically significant (P>0.05);
3.7The MRI lesion sites:brain lesions (36.4%), brainstem lesions (38.6%), cerebellar lesions (5.0%), spinal cord lesions (20.0%);
3.8In Erhuangfang group, touched on pretreatment level of NAA/CR and CHO/CR, the difference between ipsilateral lesion (1.81±0.68and1.20±0.69) and contralateral lesion(1.96±0.53and0.94±0.24) was not statistically significant (P>0.05);
3.9In Erhuangfang group, related to the level of NAA/CR and CHO/CR, both ipsilateral lesion and contralateral lesion, the difference between posttreatment (1.77±0.47and1.05±0.21) and pretreatment (1.88±0.50and1.00±0.27) was not statistically significant (P>0.05);
3.10NAA/CR level was not related to age of onset, EDSS, relapse frequency, annual recurrence rate, and was significantly associated with the duration, correlation coefficient was0.429, P=0.006.
4Conclusion
The duration of multiple sclerosis is more longer, axonal injury is more serious, long-term use (>1years) of Erhuangfang can effectively reduce relapse and slow disease progression. Reducing axonal injury may be one of the mechanisms that play a therapeutic role.
引文
1. Yulin G, Robert I, Gross man. Magnetization transfer histogram analysis of gray matter in relapsing remitting multiple sclerosis. AJNR,2001; 22(3):470.
2. Trapp BD, Ransohoff RM, Fisher E, et al. Axonal transaction in the lesions of multiple sclerosis. N Eng J Med,1998; 338:278-285.
3. Trapp BD, Ransohoff RM, Fisher E, et al. Neurodegeneration in Multiple Sclerosis:relations to nerological disability. Neuroscientist,1999; 5: 48-57.
4. Bjartmar C, Kidd C, Ransohoff RM, et al. A real-time insight into disease progression and the role of axonal injury in multiple sclerosis. Arch Neurol, 2001; 58:65-70.
5.De Stefano N, Narayanan S, Francis GS, et al. Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol,2001; 58:65-70.
6. Bjartmar C, Trapp BD. Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol,2001; 14:271-278.
7. Bjartmar C, Yin X, Trapp B. Axonal pathology in myelin disorders. J Neurocytology,1999; 28:383-395.
8. Sahenk Z, Chen L, Mendell JR. Effects of PMP22 duplication and deletions on the axonal cytoskeleton. Ann Neurol,1999; 45:16-24.
9. Smith KJ, Kapoor R, Hall SM, et al. Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol,2001; 49(4):470-479.
10. De stefano N, Matthews PM, Fu L, et al. Axonal damage correlates with disability in patients with relapsing remitting mutiple sclerosis. Results of a longitudinal magentic resonance spectroscopy study[J]. Brain,1998; 121: 1469-1477.
11.Miller DH, Grossman RI, Reingold SC, McFarland HF. The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain 1998; 121:3 24.
12.杨承志,郑阿娟.磁共振波谱分析在多发性硬化研究中应用.中国医学影像学杂志,2005,13(1)：50-52.
13. Antonio Martinez-Yelamos, Albert Saiz, Jordi Bas, et al. Tau protein in cerebrospinal fluid:a possible marker of poor outcome in patients with early relapsing-remitting multiple sclerosis. Neuroscience Letters 2004; 363:14 17.
14.M Colucci, L Roccatagliata, E Capello, et al. The 14-3-3 protein in multiple sclerosis:a marker of disease severity. Mult iple Sclerosis 2004;10:477-481.
15.De stefano N, Matthews PM, Fu L, et al. Axonal damage correlates with disability in patients with relapsing remitting mutiple sclerosis. Results of a longitudinal magentic resonance spectroscopy study[J]. Brain,1998; 121:1469-1477.
16. Miller DH, Grossman RI, Reingold SC, McFarland HF. The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain 1998;121:3 24.
17.周金黄.中药免疫药理学.人民军医出版社,1994：33.
18.孙怡.中医药防治多发性硬化的研究.中医杂志,1997,38(2).
19.王平,樊永平,张星虎.多发性硬化的中西医研究进展.中国医药学报2004,19(5)：303-305.
20.杨晓晖.清开灵注射液治疗多发性硬化1例.北京中医药大学学报,1995,18(6)：35.
21.宋春杰,尹岭,朱克.清开灵有效治疗实验性自身免疫性脑脊髓炎.中国神经免疫与神经病学杂志2003,10(3)：156-158.
22.樊永平,王平,张星虎.中药治疗多发性硬化的临床疗效观察.中华医学会第八届全国神经免疫学术会议,中国西安,2004年6月,38.
23.孙怡.辩证治疗多发性硬化22例临床观察.中医杂志,1992,33(10)：31-32.
24.李青,詹青,琚坚.詹文涛教授辨证治疗多发性硬化经验.北京中医药大学学报(中医临床版)2003,10(1)：18-20.
25.邱仕君.邓铁涛教授对多发性硬化的辨治经验.新中医,2000,32(8)：9-10.
26. Marco Rovaris, Antonio Gallo, et al. Axonal Injury and Overall Tissue Loss Are Not Related in Primary Progressive Multiple Sclerosis. Arch Neurol 2005; 62:898-902.
27.E.Kapaki,G. P.Paraskevas, M. Michalooulous, K. Kilid ires, Increased cerevralspinal fluid tau protein in multiple sclerosis, Eur. neuro.43 (2000) 228-232.
28. Sat oh J, Yuki take M,et al. Detection of the 14-3-3 protein in the cerebrospinal fluid of Japanese multiple sclerosis pat ients present ing with severe myelitis. J Neurol Sci 2003; 212:11-20.
29.杨桂芬.多发性硬化的组织-病理学改变与1H-MRS表现.国外医学临床放射学分册,2004,27(6)：349-352.
30. Ricarda Diem, Muriel B Sattler, et al. Combined therapy with me3. thylprednisolone and erythropoietin in a model of multiple sclerosis. Brain 2005; 128:375-385.
31.李海峰.干扰素β治疗复发-缓解型多发性硬化.中国新药与临床杂志,2004,23(4)：250-255.
32.王蕾,赵晖,樊永平等.补肾对脑脊髓炎大鼠生长相关蛋白-43及微管相关蛋白-2的影响.首都医科大学学报,2007,28(6)：748-752.
1. Keiko Imamura. Proton MR spectroscopy of the brain with a focus on chemical issues. Magnetic Resonance in Medical Secience,2003,2:117-132.
2. Tong ZY, Toshiaki Y, Wang YJ. Proton magnetic resonance spectroscopy of normal human brain and glioma:a quantitive in vivo study. Chin Med J,2005,118(15):1251-1257.
3. Venkatesh SK,Gupta RK, Pal L, et al. Spectroscopic increase in choline signal is a nonspecific marker for differenciation of infective/inflammatory from neoplastic lesion of the brain,Magn Reson Imaging,2001,14:8-15.
4.孙家瑜,肖家和,周翔平等.多发性硬化的MRS表现特征评价.华西医学,2007,22(1)：51-53.
5. Vermathen P, Capizzano AA, Maudsley AA. Administration and 1H MRS detection of histidine in human brain:application to in vivo pH measurement[J]. Magn Reson Med,2000,43(5):665-675.
6. Opstad KS, Provencher SW,Bell BA,et al. Detection of elevated glutathione in meningiomas by quantitative in vivo 1H MRS. Magn Reson Med,2003,49:632-637.
7. Krouwer HGJ, Kim TA, Rand SC, et al. Single voxel proton MRS of non neoplastic brain lesion suggestive of a neoplasm. AJNR,1998,19::95-103.
8. Gajewicz W, Papierz W, Szymczak W, et al. The use of proton MRS in the differential diagnosis of brain tumors and tumor-like processes. Med Sci Monit,2003,9:97-105.
9. Degaonkar MN, Khubchandhani M,Dhawan JK, et al. Sequential proton MRS study of brain metabolite changes monitored during a complete pathological cycle of demyelination and remyelination in a lysophosphatidyl choline(Lpe)-induced experimental demyelinating lesion model. NMR Biomed,2002,15(4):293.
10. Kapeller P,Brex PA,Chard D, et al.Quantitative 1H-MRS imaging 14 years after presenting with a clinically isolated syndrome suggestive of multiple sclerosis.Mult Scler,2002,8(3):207.
11. Gonen 0, Catalaa I, Babb JS,et al. Total brain N-acetylaspartate:A new measure of disease load in MS. Neurology,2000,54 (1):15.
12. Mario Quarantelli, Andrea Ciarmiello, Vincenzo Brescia Morra,el al. Brain tissue volume changes in relapsing remitting multiple sclerosis:correlation with lesion load. Neuro Image,2003,18:360.
13. Matilde Inglese, Yulin Ge, Massimo Filippi,et al. Indirect evidence for early widespread gray matter involvement in relapsing remitting multiple sclerosis. Neuro Image,2004,21:1825.
1 Polman C H,Reingold S C, Edan G, et al. Diagnostic criteria for multiple sclerosis:2005 revisions to the "McDonald Criteria" [J].Ann Neurol,2005,58 (6):840-846.
2周莉樊永平叶明.59例多发性硬化患者不同中医证型的免疫学研究.中国中西医结合杂志,2007,27(7)：599-601.
3陈克龙,樊永平.多发性硬化中医证型分类的文献分析.辽宁中医杂志,2011,38(1)：85-87.
4樊永平,尤昱中,陈克龙,等.261例多发性硬化患者临床特点和中医证候分布.首都医科大学学报,2012,33(3)：301-306.
5胡学强,麦卫华,王敦敬.多发性硬化413例患者的临床表现特点.中华神经科杂志,2004,37(1)：7-10.
6王蕾,樊永平,刘秀贞,等.二黄方防治实验性变态反应性脑脊髓炎的实验研究.2005,20(8)：475-477.
7樊永平,刘秀贞,王蕾,等.二黄方对EAE大鼠外周血NK细胞和细胞因子的影响.北京中医药大学学报,2007,30(3)：165-168.
8周莉,樊永平,王蕾,等.二黄方对EAE大鼠细胞因子及Th1/Th2平衡的影响.首都医科大学学报,2009,30(1)：20-23.
9樊永平,周莉,王蕾,等.二黄方对EAE大鼠急性期血浆MCP-1、TNF-α水平的影响.北京中医药,2009,28(3)：225-227.
10樊永平,宋丽君,叶明,等.二黄胶囊对实验性自身免疫性脑脊髓炎大鼠中枢神经系统细胞因子和淋巴细胞亚群免疫组化表达的影响.中国实验方剂学杂志,2010,16(5)：142-146.
11李康宁,樊永平,陈克龙,等.二黄胶囊对实验性变态反应性脑脊髓炎模型大鼠急性期炎性反应和髓鞘修复的影响.首都医科大学学报,2011,32(1)：110-115.
12樊永平,王平,张星虎,等.二黄方治疗多发性硬化急性发作的机制研究.中华中医药杂志,2007,22(1)：25-29.
13周莉,樊永平.二黄方减少多发性硬化轴索损伤和复发临床研究.中国中医药信息杂志,2012,19(8)：14-15.
2. Trapp BD, Ransohoff RM, Fisher E, et al. Axonal transaction in the lesions of multiple sclerosis. N Eng J Med,1998; 338:278-285.
3. Trapp BD, Ransohoff RM, Fisher E, et al. Neurodegeneration in Multiple Sclerosis:relations to nerological disability. Neuroscientist,1999; 5: 48-57.
4. Bjartmar C, Kidd C, Ransohoff RM, et al. A real-time insight into disease progression and the role of axonal injury in multiple sclerosis. Arch Neurol, 2001; 58:65-70.
5.De Stefano N, Narayanan S, Francis GS, et al. Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch Neurol,2001; 58:65-70.
6. Bjartmar C, Trapp BD. Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr Opin Neurol,2001; 14:271-278.
7. Bjartmar C, Yin X, Trapp B. Axonal pathology in myelin disorders. J Neurocytology,1999; 28:383-395.
8. Sahenk Z, Chen L, Mendell JR. Effects of PMP22 duplication and deletions on the axonal cytoskeleton. Ann Neurol,1999; 45:16-24.
9. Smith KJ, Kapoor R, Hall SM, et al. Electrically active axons degenerate when exposed to nitric oxide. Ann Neurol,2001; 49(4):470-479.
10. De stefano N, Matthews PM, Fu L, et al. Axonal damage correlates with disability in patients with relapsing remitting mutiple sclerosis. Results of a longitudinal magentic resonance spectroscopy study[J]. Brain,1998; 121: 1469-1477.
11.Miller DH, Grossman RI, Reingold SC, McFarland HF. The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain 1998; 121:3 24.
12.杨承志,郑阿娟.磁共振波谱分析在多发性硬化研究中应用.中国医学影像学杂志,2005,13(1)：50-52.
13. Antonio Martinez-Yelamos, Albert Saiz, Jordi Bas, et al. Tau protein in cerebrospinal fluid:a possible marker of poor outcome in patients with early relapsing-remitting multiple sclerosis. Neuroscience Letters 2004; 363:14 17.
14.M Colucci, L Roccatagliata, E Capello, et al. The 14-3-3 protein in multiple sclerosis:a marker of disease severity. Mult iple Sclerosis 2004;10:477-481.
15.De stefano N, Matthews PM, Fu L, et al. Axonal damage correlates with disability in patients with relapsing remitting mutiple sclerosis. Results of a longitudinal magentic resonance spectroscopy study[J]. Brain,1998; 121:1469-1477.
16. Miller DH, Grossman RI, Reingold SC, McFarland HF. The role of magnetic resonance techniques in understanding and managing multiple sclerosis. Brain 1998;121:3 24.
17.周金黄.中药免疫药理学.人民军医出版社,1994：33.
18.孙怡.中医药防治多发性硬化的研究.中医杂志,1997,38(2).
19.王平,樊永平,张星虎.多发性硬化的中西医研究进展.中国医药学报2004,19(5)：303-305.
20.杨晓晖.清开灵注射液治疗多发性硬化1例.北京中医药大学学报,1995,18(6)：35.
21.宋春杰,尹岭,朱克.清开灵有效治疗实验性自身免疫性脑脊髓炎.中国神经免疫与神经病学杂志2003,10(3)：156-158.
22.樊永平,王平,张星虎.中药治疗多发性硬化的临床疗效观察.中华医学会第八届全国神经免疫学术会议,中国西安,2004年6月,38.
23.孙怡.辩证治疗多发性硬化22例临床观察.中医杂志,1992,33(10)：31-32.
24.李青,詹青,琚坚.詹文涛教授辨证治疗多发性硬化经验.北京中医药大学学报(中医临床版)2003,10(1)：18-20.
25.邱仕君.邓铁涛教授对多发性硬化的辨治经验.新中医,2000,32(8)：9-10.
26. Marco Rovaris, Antonio Gallo, et al. Axonal Injury and Overall Tissue Loss Are Not Related in Primary Progressive Multiple Sclerosis. Arch Neurol 2005; 62:898-902.
27.E.Kapaki,G. P.Paraskevas, M. Michalooulous, K. Kilid ires, Increased cerevralspinal fluid tau protein in multiple sclerosis, Eur. neuro.43 (2000) 228-232.
28. Sat oh J, Yuki take M,et al. Detection of the 14-3-3 protein in the cerebrospinal fluid of Japanese multiple sclerosis pat ients present ing with severe myelitis. J Neurol Sci 2003; 212:11-20.
29.杨桂芬.多发性硬化的组织-病理学改变与1H-MRS表现.国外医学临床放射学分册,2004,27(6)：349-352.
30. Ricarda Diem, Muriel B Sattler, et al. Combined therapy with me3. thylprednisolone and erythropoietin in a model of multiple sclerosis. Brain 2005; 128:375-385.
31.李海峰.干扰素β治疗复发-缓解型多发性硬化.中国新药与临床杂志,2004,23(4)：250-255.
32.王蕾,赵晖,樊永平等.补肾对脑脊髓炎大鼠生长相关蛋白-43及微管相关蛋白-2的影响.首都医科大学学报,2007,28(6)：748-752.
1. Keiko Imamura. Proton MR spectroscopy of the brain with a focus on chemical issues. Magnetic Resonance in Medical Secience,2003,2:117-132.
2. Tong ZY, Toshiaki Y, Wang YJ. Proton magnetic resonance spectroscopy of normal human brain and glioma:a quantitive in vivo study. Chin Med J,2005,118(15):1251-1257.
3. Venkatesh SK,Gupta RK, Pal L, et al. Spectroscopic increase in choline signal is a nonspecific marker for differenciation of infective/inflammatory from neoplastic lesion of the brain,Magn Reson Imaging,2001,14:8-15.
4.孙家瑜,肖家和,周翔平等.多发性硬化的MRS表现特征评价.华西医学,2007,22(1)：51-53.
5. Vermathen P, Capizzano AA, Maudsley AA. Administration and 1H MRS detection of histidine in human brain:application to in vivo pH measurement[J]. Magn Reson Med,2000,43(5):665-675.
6. Opstad KS, Provencher SW,Bell BA,et al. Detection of elevated glutathione in meningiomas by quantitative in vivo 1H MRS. Magn Reson Med,2003,49:632-637.
7. Krouwer HGJ, Kim TA, Rand SC, et al. Single voxel proton MRS of non neoplastic brain lesion suggestive of a neoplasm. AJNR,1998,19::95-103.
8. Gajewicz W, Papierz W, Szymczak W, et al. The use of proton MRS in the differential diagnosis of brain tumors and tumor-like processes. Med Sci Monit,2003,9:97-105.
9. Degaonkar MN, Khubchandhani M,Dhawan JK, et al. Sequential proton MRS study of brain metabolite changes monitored during a complete pathological cycle of demyelination and remyelination in a lysophosphatidyl choline(Lpe)-induced experimental demyelinating lesion model. NMR Biomed,2002,15(4):293.
10. Kapeller P,Brex PA,Chard D, et al.Quantitative 1H-MRS imaging 14 years after presenting with a clinically isolated syndrome suggestive of multiple sclerosis.Mult Scler,2002,8(3):207.
11. Gonen 0, Catalaa I, Babb JS,et al. Total brain N-acetylaspartate:A new measure of disease load in MS. Neurology,2000,54 (1):15.
12. Mario Quarantelli, Andrea Ciarmiello, Vincenzo Brescia Morra,el al. Brain tissue volume changes in relapsing remitting multiple sclerosis:correlation with lesion load. Neuro Image,2003,18:360.
13. Matilde Inglese, Yulin Ge, Massimo Filippi,et al. Indirect evidence for early widespread gray matter involvement in relapsing remitting multiple sclerosis. Neuro Image,2004,21:1825.
1 Polman C H,Reingold S C, Edan G, et al. Diagnostic criteria for multiple sclerosis:2005 revisions to the "McDonald Criteria" [J].Ann Neurol,2005,58 (6):840-846.
2周莉樊永平叶明.59例多发性硬化患者不同中医证型的免疫学研究.中国中西医结合杂志,2007,27(7)：599-601.
3陈克龙,樊永平.多发性硬化中医证型分类的文献分析.辽宁中医杂志,2011,38(1)：85-87.
4樊永平,尤昱中,陈克龙,等.261例多发性硬化患者临床特点和中医证候分布.首都医科大学学报,2012,33(3)：301-306.
5胡学强,麦卫华,王敦敬.多发性硬化413例患者的临床表现特点.中华神经科杂志,2004,37(1)：7-10.
6王蕾,樊永平,刘秀贞,等.二黄方防治实验性变态反应性脑脊髓炎的实验研究.2005,20(8)：475-477.
7樊永平,刘秀贞,王蕾,等.二黄方对EAE大鼠外周血NK细胞和细胞因子的影响.北京中医药大学学报,2007,30(3)：165-168.
8周莉,樊永平,王蕾,等.二黄方对EAE大鼠细胞因子及Th1/Th2平衡的影响.首都医科大学学报,2009,30(1)：20-23.
9樊永平,周莉,王蕾,等.二黄方对EAE大鼠急性期血浆MCP-1、TNF-α水平的影响.北京中医药,2009,28(3)：225-227.
10樊永平,宋丽君,叶明,等.二黄胶囊对实验性自身免疫性脑脊髓炎大鼠中枢神经系统细胞因子和淋巴细胞亚群免疫组化表达的影响.中国实验方剂学杂志,2010,16(5)：142-146.
11李康宁,樊永平,陈克龙,等.二黄胶囊对实验性变态反应性脑脊髓炎模型大鼠急性期炎性反应和髓鞘修复的影响.首都医科大学学报,2011,32(1)：110-115.
12樊永平,王平,张星虎,等.二黄方治疗多发性硬化急性发作的机制研究.中华中医药杂志,2007,22(1)：25-29.
13周莉,樊永平.二黄方减少多发性硬化轴索损伤和复发临床研究.中国中医药信息杂志,2012,19(8)：14-15.