复发缓解型多发性硬化分期辨治方案与疗效评价方法的探讨
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摘要
背景：
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,遗传易感个体与环境因素共同作用发生的自身免疫病。尽管MS治疗方法不断进步,治疗的有效率不断提升,MS仍然是一种无法治愈的慢性致残性疾病,且MS治疗药物的临床使用均有一定的不良反应,且药物费用昂贵,需长期使用。目前,西医的治疗方法尚未彻底解决MS的致残及复发等问题。现有的临床、基础研究表明中药治疗MS存在一定的优势,能缩短MS急性期病程,减少神经功能缺损,减少激素副作用及顺利递减激素或免疫抑制剂等,但以往中药治疗MS的研究大部分未进行明确的分型和分期,同时,由于缺乏科学的疗效评价体系,直接影响了临床疗效的衡量、确定和成果推广。因此,针对MS的不同分型和分期,及显示中药治疗MS在不同环节上的疗效,急需建立相应的治疗方案,以及与之相匹配的一套符合中医自身规律的疗效评价方法。此外,MS发病率低、个体差异大,通过随机对照临床试验建立本病中医临床疗效评价方法难度较大。
目的：
本研究以MS中最常见的临床分型——复发缓解型MS (relapsing-remitting MS, RRMS)为切入点,探索RRMS急性期和缓解期中医证候分布特点,初步建立RRMS分期辨治方案及中药治疗RRMS急性期和缓解期的疗效评价方法。
方法：
1、根据文献研究结果,充分复习国内外MS临床疗效评价的方法；系统评价中药治疗多发性硬化随机对照试验,总体评价中药治疗MS的疗效和安全性及既往研究中的不足,并总结文献中的治疗方案及疗效评价方法。
2、编制多发性硬化中医症状学调查条目池,形成多发性硬化中医四诊信息病例调查表,采用前瞻性结合横断面调查的方式,分别对RRMS急性期和缓解期患者进行中医四诊信息的采集,采集时点：RRMS急性期：复发3天以内,从入组当天、入组一周、入组二周、入组四周各时点调查1次；RRMS缓解期：入组当天、入组3月、入组6月、入组9月各时点调查1次,部分为只调查入组当天,探讨RRMS急性期和缓解期中医证候分布特点。
3、根据高颖教授多年治疗MS的经验,实验研究成果和上述的研究结果,制定RRMS分期辨治方案。采用单组设计,RRMS急性期纳入的患者在激素冲击治疗的基础上给予汤药加中药注射液的中医综合治疗,于入组当天、入组一周、入组二周、入组四各时点进行MS相关量表测评,于入组当天、入组二周行血清采集,进行细胞因子检测(INF-γ、IL-10、IL-17)。RRMS缓解期纳入的患者给予汤药治疗,于入组当天、入组3月、入组6月、入组9月各时点进行MS相关量表测评,并电话随访至入组12月,于入组期间行血清采集一次,进行细胞因子检测(INF-γ、IL-10. IL-17)。观察RRMS分期辨治方案的效果及依从性。
对本研究中所记录的各种评价量表的数据进行统计分析,通过开展多维度、多时点疗效评价,采用反应度法,初步形成中医药治疗MS多维疗效评价指标体系。
结果：
1、共计纳入16项随机对照试验,涉及913例MS患者。所纳入的研究质量普遍较差。所纳入的研究中有13项研究报道了神经功能缺损,通过Kurtzke扩展残疾状态量表(Kurtzke extended disability status scale, EDSS)评分进行测评,其中2项研究显示中药组的EDSS评分低于对照组,MD及95%CI为-0.88[-1.26,-0.50],另外8项研究进行了描述性分析,显示治疗组EDSS评分低于对照组；5项研究报道了中药治疗MS的复发率,2项研究显示,治疗组的复发率低于对照组,MD及95%CI为-0.34[-0.52,-0.16],另外3项研究进行了描述性分析,显示治疗组复发率低于对照组。次要指标如无效率、临床症状评分、神经功能评分和免疫指标的改善均优于对照组。纳入的2项研究报道了MRI病灶数目或范围,治疗组与对照组比较有改善的趋势,但无显著性差异。中药组的药物使用不良反应低于对照组,且能减轻激素使用的不良反应,仅1例出现上腹部闷痛。
2、通过频数及主成分分析方法,得到RRMS急性期湿热明显,随着急性期时间的推移,湿热之象减轻；RRMS缓解期主要证候有“气虚血瘀”、“脾肾阳虚”、“湿热互结”、“气虚血瘀,肝肾阴虚”、“肾阳亏虚,瘀血阻滞”和“瘀血阻滞”,易见肾虚证候,其中肾阳虚的患者例次多于肾阴虚。
3、RRMS分期辨治方案主要是在急性期口服以四妙丸或三仁汤为主进行加减的中药,配合静点清开灵注射液；在恢复期口服以益肾达络为主加减的中药。
Barthel指数在急性期和缓解期各时点的总体反应度均较差。在RRMS急性期研究中,EDSS评分、HAMD评分在治疗2周至4周的总体反应度较好；PDQ评分在第4周的总体反应度较差；MSQOL-54的体质、心理健康综合评分在第4周的总体反应度较好。在RRMS缓解期研究中,EDSS评分、HAMD评分及PDQ评分在各时点的总体反应度都较差；MSQOL-54的体质健康综合评分在治疗3月的总体反应度较好,心理健康综合评分在治疗6月的总体反应度较好。
结论：
1、RRMS急性期易见湿热,缓解期易见肾虚,应抓住“急性期不离湿热,缓解期莫失肾本”的病机,治以“急性期重在祛邪清湿热,缓解期重在补肾调阴阳”。
2、初步建立的RRMS分期辨治方案,在单样本研究中未发现明显的副作用,具有较好的依从性,同时具有改善其神经功能缺损,降低其复发率及无效率,改善临床症状、神经功能体征及免疫指标的趋势。
3、初步构建出以复发率作为结局指标；EDSS作为神经功能缺损的评价指标；PDQ、HAMD作为神经心理功能的评价指标；MSQOL-54作为生活质量的评价指标；相关血清学检测作为病情监测指标的疗效评价方法。
Background:
Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease which is caused by genetic and environmental factors. With the constant progress the treatment of MS and efficiency of different theraputic methods, MS is still an incurable, chronic and disabling disease. At the same time, the conventional treatments have some clinical adverse reactions and the cost is expensive. At present, the Western medicine treatment is not completely solve the problem of MS disability and relapse. Existing clinical and basic studies have shown that Chinese herbal medicine (CHM) used in the treatment for MS, achieves a certain clinical efficacy, like shorting the course of MS acute phase, reducing the neurological deficit, reducing side effects by the hormonal and smoothly decreasing hormones or immunosuppressive agents. However, there is no scientific efficacy estimation indices and specific classification and staging. Due to the lack of scientific evaluation system, it directly affects the clinical outcome measure, determine and achievement promotion. Therefore, according to the different MS typing and staging, and displaying the efficacy of traditional Chinese medicine in the treatment of MS in different aspects, to establish the corresponding treatments immediately, and a matched set its own rules in line with the traditional Chinese medicine curative effect evaluation method.In addition, because of the low incidence of MS and large individual differences, to establish the evaluation methods of TCM clinical efficacy is difficult via randomized controlled clinical trials.
Objective:
With the relapsing-remitting MS (RRMS) which is the most common clinical type in the MS as the starting point, to explore the RRMS TCM distribution characteristics in the acute stage and the remission stage, and to initially establish the scheme in syndrome differentiation and treatment by stages and the method of evaluation in the relapsing and remitting stages of RRMS.
Method:
1. According to the research results, to review clinical curative effect evaluation method by domestic and foreign MS researches. To systematically review randomized controlled trials by CHM in the treatment of MS, and to evaluate the efficacy and safety by CHM in the treatment of MS. Simultaneously, to summarize the treatment protocols and the evaluation methods.
2. To establish item pool of TCM symptoms in MS in order to form the MS clinical information of case scale. This research combined prospective study and cross-sectional survey, using the MS clinical information of case scale to collect TCM four diagnostic information of RRMS in the relapsing and remitting stages. To collect information on the first day, the day after 1 week, the day after 2 weeks and the day after 4 weeks in the relapsing stage of MS. And to collect information on the first day, the day after 3 months, the day after 6 months and the day after 9 months. So we can explore the distribution characteristics of TCM syndromes in the relapsing and remitting stages of RRMS.
3. According to the experience in the treatment of MS by Professor Gao Ying for many years, her experimental research results and the above research results, we establish the scheme in syndrome differentiation and treatment by stages. Using Single-group design, patients in the relapsing stage of RRMS received routine hormonotherapy combined with CHM and Qingkailing injection. To evaluate scales on the first day, the day after 1 week, the day after 2 weeks and the day after 4 weeks. At the same time, we collected blood samples on the first day and the day after 2 weeks in order to detect cytokines, containing INF-γ, IL-10 and IL-17. Patients in the remitting stage of RRMS received CHM. with Bushen Huoxue Tongluo Method. To evaluate scales in the first day, the day after 3 months, the day after 6 months and the day after 9 months. Simultaneously, we collected blood samples in the remitting stage in order to detect cytokines, containing INF-γ, IL-10 and IL-17.
To analyze the data of record various scales and evaluate the efficacy by multiple dimensions and many time points, we establish the method of evaluation in the relapsing and remitting stages of RRMS.
Results:
1. After merger of the include trials, sixteen eligible RCTs with 913 cases were included. Thirteen studies adopted EDSS (Kurtzke extended disability status scale) and 2 of them showed that EDSS in the treatment group was lower than that in the control group, and the MD and 95%CI were-0.88 [-1.26,-0.50]. We performed descriptive analysis on other 8 studies which showed EDSS in the treatment group was lower than that in the control group. Five studies adopted recurrent frequency and 2 of them showed that recurrent frequency in the treatment group was lower than that in the control group, and the MD and 95%CI were-0.34 [-0.52,-0.16]. We performed descriptive analysis on the other 3 studies which showed EDSS in the treatment group was lower than that in the control group. Analyses of secondary outcomes such as clinical symptom score, neurological signs score and immune indices showed that integrated TCM and WM therapy was more effective than WM treatment alone. The studies displayed that the number or range of MRI lesion in the treatment group was lower than that in the control, but there was no statistical significance. The reported adverse effects of CHM was less than control group, and reduced the side effect of hormone.
2. By frequency analysis and principal component analytical method, damp-heat syndrome obviously intensified in the relapsing stage, and gradually decreased with the passage of time. In the remitting stage, there were qi deficiency and blood stasis syndrome, yang deficiency of spleen and kidney syndrome, damp-heat syndrome, qi deficiency and blood stasis and liver-kidney yin deficiency syndrome, kidney-Yang deficiency and accumulation of blood stasis and accumulation of blood stasis, kidney deficiency syndrome was the most frequent diagnoses in the remitting stage, and the kidney yang deficiency syndrome was more than the kidney yin deficiency syndrome.
3. The scheme in syndrome differentiation and treatment by stages contains oral Simiao Wan or Decoction of three kinds of kernels and intravenous Qingkailing in the relapsing stage and treated with modified Yinshendaluo in the remitting stage.
In the neurological deficit, the EDSS scores the day after 4 weeks was significantly lower than the first day. In the Neuropsychology, Except the day after 1 week, the HAMD scores in the other time points were significantly lower than the first day. In the cognitive function, There was no statistical difference in PDQ scores. In the quality of life, MSQOL-54 physical health composite score and mental health composite score in the day after 4 weeks were significantly more than the first day. In the neurological deficit, the EDSS scores the day after 9 months was significantly lower than the first day. In the Neuropsychology, the HAMD scores in the day after 9 months were significantly lower than the first day. In the cognitive function, the PDQ scores in the day after 9 months showed significant improvement. In the quality of life, MSQOL-54 physical health composite score in the day after 3 months were significantly increased. MSQOL-54 mental health composite score in the day after 6 months were significantly more than the first day.
Conclusion:
1. To treat RRMS through TCM differential diagnosis by stages, focus on the damp-heat syndrome in the relapsing stage and focus on the kidney deficiency syndrome in the remitting stage.
2. To initially establish the scheme in syndrome differentiation and treatment by stages. CHM treated RRMS with the tendency of improving the neurological deficit, the Neuropsychology, the cognitive function, the quality of life and the immune status and had no side effect.
3. To initially establish the method of evaluation in the relapsing and remitting stages of RRMS containing recurrence rate, EDSS, PDQ, HAMD, MSQOL-54 and serological detection index.
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,遗传易感个体与环境因素共同作用发生的自身免疫病。尽管MS治疗方法不断进步,治疗的有效率不断提升,MS仍然是一种无法治愈的慢性致残性疾病,且MS治疗药物的临床使用均有一定的不良反应,且药物费用昂贵,需长期使用。目前,西医的治疗方法尚未彻底解决MS的致残及复发等问题。现有的临床、基础研究表明中药治疗MS存在一定的优势,能缩短MS急性期病程,减少神经功能缺损,减少激素副作用及顺利递减激素或免疫抑制剂等,但以往中药治疗MS的研究大部分未进行明确的分型和分期,同时,由于缺乏科学的疗效评价体系,直接影响了临床疗效的衡量、确定和成果推广。因此,针对MS的不同分型和分期,及显示中药治疗MS在不同环节上的疗效,急需建立相应的治疗方案,以及与之相匹配的一套符合中医自身规律的疗效评价方法。此外,MS发病率低、个体差异大,通过随机对照临床试验建立本病中医临床疗效评价方法难度较大。
目的：
本研究以MS中最常见的临床分型——复发缓解型MS (relapsing-remitting MS, RRMS)为切入点,探索RRMS急性期和缓解期中医证候分布特点,初步建立RRMS分期辨治方案及中药治疗RRMS急性期和缓解期的疗效评价方法。
方法：
1、根据文献研究结果,充分复习国内外MS临床疗效评价的方法；系统评价中药治疗多发性硬化随机对照试验,总体评价中药治疗MS的疗效和安全性及既往研究中的不足,并总结文献中的治疗方案及疗效评价方法。
2、编制多发性硬化中医症状学调查条目池,形成多发性硬化中医四诊信息病例调查表,采用前瞻性结合横断面调查的方式,分别对RRMS急性期和缓解期患者进行中医四诊信息的采集,采集时点：RRMS急性期：复发3天以内,从入组当天、入组一周、入组二周、入组四周各时点调查1次；RRMS缓解期：入组当天、入组3月、入组6月、入组9月各时点调查1次,部分为只调查入组当天,探讨RRMS急性期和缓解期中医证候分布特点。
3、根据高颖教授多年治疗MS的经验,实验研究成果和上述的研究结果,制定RRMS分期辨治方案。采用单组设计,RRMS急性期纳入的患者在激素冲击治疗的基础上给予汤药加中药注射液的中医综合治疗,于入组当天、入组一周、入组二周、入组四各时点进行MS相关量表测评,于入组当天、入组二周行血清采集,进行细胞因子检测(INF-γ、IL-10、IL-17)。RRMS缓解期纳入的患者给予汤药治疗,于入组当天、入组3月、入组6月、入组9月各时点进行MS相关量表测评,并电话随访至入组12月,于入组期间行血清采集一次,进行细胞因子检测(INF-γ、IL-10. IL-17)。观察RRMS分期辨治方案的效果及依从性。
对本研究中所记录的各种评价量表的数据进行统计分析,通过开展多维度、多时点疗效评价,采用反应度法,初步形成中医药治疗MS多维疗效评价指标体系。
结果：
1、共计纳入16项随机对照试验,涉及913例MS患者。所纳入的研究质量普遍较差。所纳入的研究中有13项研究报道了神经功能缺损,通过Kurtzke扩展残疾状态量表(Kurtzke extended disability status scale, EDSS)评分进行测评,其中2项研究显示中药组的EDSS评分低于对照组,MD及95%CI为-0.88[-1.26,-0.50],另外8项研究进行了描述性分析,显示治疗组EDSS评分低于对照组；5项研究报道了中药治疗MS的复发率,2项研究显示,治疗组的复发率低于对照组,MD及95%CI为-0.34[-0.52,-0.16],另外3项研究进行了描述性分析,显示治疗组复发率低于对照组。次要指标如无效率、临床症状评分、神经功能评分和免疫指标的改善均优于对照组。纳入的2项研究报道了MRI病灶数目或范围,治疗组与对照组比较有改善的趋势,但无显著性差异。中药组的药物使用不良反应低于对照组,且能减轻激素使用的不良反应,仅1例出现上腹部闷痛。
2、通过频数及主成分分析方法,得到RRMS急性期湿热明显,随着急性期时间的推移,湿热之象减轻；RRMS缓解期主要证候有“气虚血瘀”、“脾肾阳虚”、“湿热互结”、“气虚血瘀,肝肾阴虚”、“肾阳亏虚,瘀血阻滞”和“瘀血阻滞”,易见肾虚证候,其中肾阳虚的患者例次多于肾阴虚。
3、RRMS分期辨治方案主要是在急性期口服以四妙丸或三仁汤为主进行加减的中药,配合静点清开灵注射液；在恢复期口服以益肾达络为主加减的中药。
Barthel指数在急性期和缓解期各时点的总体反应度均较差。在RRMS急性期研究中,EDSS评分、HAMD评分在治疗2周至4周的总体反应度较好；PDQ评分在第4周的总体反应度较差；MSQOL-54的体质、心理健康综合评分在第4周的总体反应度较好。在RRMS缓解期研究中,EDSS评分、HAMD评分及PDQ评分在各时点的总体反应度都较差；MSQOL-54的体质健康综合评分在治疗3月的总体反应度较好,心理健康综合评分在治疗6月的总体反应度较好。
结论：
1、RRMS急性期易见湿热,缓解期易见肾虚,应抓住“急性期不离湿热,缓解期莫失肾本”的病机,治以“急性期重在祛邪清湿热,缓解期重在补肾调阴阳”。
2、初步建立的RRMS分期辨治方案,在单样本研究中未发现明显的副作用,具有较好的依从性,同时具有改善其神经功能缺损,降低其复发率及无效率,改善临床症状、神经功能体征及免疫指标的趋势。
3、初步构建出以复发率作为结局指标；EDSS作为神经功能缺损的评价指标；PDQ、HAMD作为神经心理功能的评价指标；MSQOL-54作为生活质量的评价指标；相关血清学检测作为病情监测指标的疗效评价方法。
Background:
Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease which is caused by genetic and environmental factors. With the constant progress the treatment of MS and efficiency of different theraputic methods, MS is still an incurable, chronic and disabling disease. At the same time, the conventional treatments have some clinical adverse reactions and the cost is expensive. At present, the Western medicine treatment is not completely solve the problem of MS disability and relapse. Existing clinical and basic studies have shown that Chinese herbal medicine (CHM) used in the treatment for MS, achieves a certain clinical efficacy, like shorting the course of MS acute phase, reducing the neurological deficit, reducing side effects by the hormonal and smoothly decreasing hormones or immunosuppressive agents. However, there is no scientific efficacy estimation indices and specific classification and staging. Due to the lack of scientific evaluation system, it directly affects the clinical outcome measure, determine and achievement promotion. Therefore, according to the different MS typing and staging, and displaying the efficacy of traditional Chinese medicine in the treatment of MS in different aspects, to establish the corresponding treatments immediately, and a matched set its own rules in line with the traditional Chinese medicine curative effect evaluation method.In addition, because of the low incidence of MS and large individual differences, to establish the evaluation methods of TCM clinical efficacy is difficult via randomized controlled clinical trials.
Objective:
With the relapsing-remitting MS (RRMS) which is the most common clinical type in the MS as the starting point, to explore the RRMS TCM distribution characteristics in the acute stage and the remission stage, and to initially establish the scheme in syndrome differentiation and treatment by stages and the method of evaluation in the relapsing and remitting stages of RRMS.
Method:
1. According to the research results, to review clinical curative effect evaluation method by domestic and foreign MS researches. To systematically review randomized controlled trials by CHM in the treatment of MS, and to evaluate the efficacy and safety by CHM in the treatment of MS. Simultaneously, to summarize the treatment protocols and the evaluation methods.
2. To establish item pool of TCM symptoms in MS in order to form the MS clinical information of case scale. This research combined prospective study and cross-sectional survey, using the MS clinical information of case scale to collect TCM four diagnostic information of RRMS in the relapsing and remitting stages. To collect information on the first day, the day after 1 week, the day after 2 weeks and the day after 4 weeks in the relapsing stage of MS. And to collect information on the first day, the day after 3 months, the day after 6 months and the day after 9 months. So we can explore the distribution characteristics of TCM syndromes in the relapsing and remitting stages of RRMS.
3. According to the experience in the treatment of MS by Professor Gao Ying for many years, her experimental research results and the above research results, we establish the scheme in syndrome differentiation and treatment by stages. Using Single-group design, patients in the relapsing stage of RRMS received routine hormonotherapy combined with CHM and Qingkailing injection. To evaluate scales on the first day, the day after 1 week, the day after 2 weeks and the day after 4 weeks. At the same time, we collected blood samples on the first day and the day after 2 weeks in order to detect cytokines, containing INF-γ, IL-10 and IL-17. Patients in the remitting stage of RRMS received CHM. with Bushen Huoxue Tongluo Method. To evaluate scales in the first day, the day after 3 months, the day after 6 months and the day after 9 months. Simultaneously, we collected blood samples in the remitting stage in order to detect cytokines, containing INF-γ, IL-10 and IL-17.
To analyze the data of record various scales and evaluate the efficacy by multiple dimensions and many time points, we establish the method of evaluation in the relapsing and remitting stages of RRMS.
Results:
1. After merger of the include trials, sixteen eligible RCTs with 913 cases were included. Thirteen studies adopted EDSS (Kurtzke extended disability status scale) and 2 of them showed that EDSS in the treatment group was lower than that in the control group, and the MD and 95%CI were-0.88 [-1.26,-0.50]. We performed descriptive analysis on other 8 studies which showed EDSS in the treatment group was lower than that in the control group. Five studies adopted recurrent frequency and 2 of them showed that recurrent frequency in the treatment group was lower than that in the control group, and the MD and 95%CI were-0.34 [-0.52,-0.16]. We performed descriptive analysis on the other 3 studies which showed EDSS in the treatment group was lower than that in the control group. Analyses of secondary outcomes such as clinical symptom score, neurological signs score and immune indices showed that integrated TCM and WM therapy was more effective than WM treatment alone. The studies displayed that the number or range of MRI lesion in the treatment group was lower than that in the control, but there was no statistical significance. The reported adverse effects of CHM was less than control group, and reduced the side effect of hormone.
2. By frequency analysis and principal component analytical method, damp-heat syndrome obviously intensified in the relapsing stage, and gradually decreased with the passage of time. In the remitting stage, there were qi deficiency and blood stasis syndrome, yang deficiency of spleen and kidney syndrome, damp-heat syndrome, qi deficiency and blood stasis and liver-kidney yin deficiency syndrome, kidney-Yang deficiency and accumulation of blood stasis and accumulation of blood stasis, kidney deficiency syndrome was the most frequent diagnoses in the remitting stage, and the kidney yang deficiency syndrome was more than the kidney yin deficiency syndrome.
3. The scheme in syndrome differentiation and treatment by stages contains oral Simiao Wan or Decoction of three kinds of kernels and intravenous Qingkailing in the relapsing stage and treated with modified Yinshendaluo in the remitting stage.
In the neurological deficit, the EDSS scores the day after 4 weeks was significantly lower than the first day. In the Neuropsychology, Except the day after 1 week, the HAMD scores in the other time points were significantly lower than the first day. In the cognitive function, There was no statistical difference in PDQ scores. In the quality of life, MSQOL-54 physical health composite score and mental health composite score in the day after 4 weeks were significantly more than the first day. In the neurological deficit, the EDSS scores the day after 9 months was significantly lower than the first day. In the Neuropsychology, the HAMD scores in the day after 9 months were significantly lower than the first day. In the cognitive function, the PDQ scores in the day after 9 months showed significant improvement. In the quality of life, MSQOL-54 physical health composite score in the day after 3 months were significantly increased. MSQOL-54 mental health composite score in the day after 6 months were significantly more than the first day.
Conclusion:
1. To treat RRMS through TCM differential diagnosis by stages, focus on the damp-heat syndrome in the relapsing stage and focus on the kidney deficiency syndrome in the remitting stage.
2. To initially establish the scheme in syndrome differentiation and treatment by stages. CHM treated RRMS with the tendency of improving the neurological deficit, the Neuropsychology, the cognitive function, the quality of life and the immune status and had no side effect.
3. To initially establish the method of evaluation in the relapsing and remitting stages of RRMS containing recurrence rate, EDSS, PDQ, HAMD, MSQOL-54 and serological detection index.
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