芬戈莫德治疗多发性硬化的中枢神经系统作用机制研究进展

多发性硬化(MS)是一种中枢神经系统广泛脱髓鞘性自身免疫性疾病,至今无特效治疗方法。芬戈莫德(FTY720)是近年研发的一种能有效治疗复发缓解型MS的新型药物。早前认为抑制淋巴细胞迁移可能是其主要作用机制,新近发现芬戈莫德能直接作用于中枢神经系统,并可能是其治疗MS更为重要的机制。文中就芬戈莫德直接作用于中枢神经系统及其相关机制研究进展作一综述。     

鞘氨醇-1-磷酸受体调节疗法在多发性硬化治疗中的研究进展

多发性硬化是一种以中枢神经系统慢性炎症、脱髓鞘和轴突损伤为主要特征的自身免疫性疾病,发病机制至今仍未阐明。近10年来口服免疫调节治疗正在兴起,其中鞘氨醇-1-磷酸受体调节剂在多发性硬化的治疗中取得了令人瞩目的疗效。文中主要关注S1P/S1PR信号通路在治疗多发性硬化中的作用、机制和临床应用现状以及展望。     

中枢神经系统脱髓鞘病变与复发-缓解型多发性硬化

参照Poser诊断标准．对1999年1月～2004年1月问经临床、头部和脊髓MRI、脑脊液IgG合成率和VEP检查后，诊断为中枢神经系统脱髓鞘病的53例患者．经5年临床和MRI随访．有36例符合缓解-复发型多发性硬化(MS)的临床确诊和实验室支持诊断标准，现将病情演变及诊断经过进行分析．以探讨复发-缓解型MS的早期诊断，为预防复发、控制病情进展提供治疗方面依据。     

复发缓解型多发性硬化47例短期预后

复发缓解型是多发性硬化 (ＭＳ)最常见的临床类型 ,反复发作和疾病进展最终导致神经功能的不可逆损伤 ,我们观察ＭＳ发病 5年的情况。资料和方法 :1 988～ 1 997年首次发病 ,在我科就诊的ＭＳ患者 47例 ,其中男 1 9例 ,女 2 8例 ,均符合Ｐｏｓｅｒ等提出的复发缓解型ＭＳ诊断标准。除外标准为 :(1 )诊断为ＭＳ临床可能或可疑者 ,(2 )距首次发病时间不足 5年者 ,(3)发病 5年后失随访者。根据病历资料和问卷调查结果进行回顾性分析。残疾的标准 :排除任何与复发有关的神经功能缺损后 ,患者日常生活活动受损不可逆持续至少 3个月 ,用Ｂａｒｔｈ…     

干扰素-β治疗复发-缓解型多发性硬化系统评价

目的评价干扰素-β(IFN-β)治疗复发-缓解型多发性硬化的有效性和安全性。方法检索Cochrane临床对照试验中心注册库、美国国立医学图书馆、荷兰医学文摘、CINAHL、LILACS、PEDRO、中国生物医学文献数据库、临床试验注册中心和世界卫生组织国际临床试验注册平台(检索截止时间:2014年6月);并通过阅读相关论文参考文献,联系参与IFN-β治疗多发性硬化临床试验的研究者和企业,进一步获取研究信息或未发表的数据。由两名评价人员独立筛选研究、提取研究信息和数据、评价偏倚风险。应用Review Manager软件(Version 5.3.3)进行Meta分析,GRADEpro软件评价研究设计和实施过程中的局限性(偏倚风险)、结果的不一致性和不精确性、证据的间接性和发表偏倚对主体证据质量的影响。结果共检索相关文献576篇,阅读标题和摘要后初步筛选出26项研究;进一步阅读全文后纳入5项研究(共2129例复发-缓解型多发性硬化患者:高剂量IFN-β组1076例、安慰剂组1053例)。所有纳入的研究均为IFN-β单药治疗且随访时间≥1年的随机双盲安慰剂对照平行临床试验。大多数研究存在方法学局限性,主要缺陷为随访偏倚风险较高,且数据分析未使用意向治疗原则,仅919例受试者(43.17%)的数据可用于分析随访2年时的主要结局。Meta分析显示,IFN-β可轻微减少随访2年时复发病例数(RR=0.810,95%CI:0.740~0.890;P=0.000)和残疾进展病例数(RR=0.700,95%CI:0.550~0.880;P=0.002);敏感性分析(最差情况的演示分析)显示,IFN-β治疗无效(RR=1.110,95%CI:0.730~1.680,P=0.620;RR=1.310,95%CI:0.600~2.890,P=0.500)。共1581例患者(74.26%)的数据可用于分析随访1年时至少复发1次的病例数(RR=0.740,95%CI:0.590~0.930;P=0.010),绝对危险降低率为13.24%,需治疗的病例数为8例,表明需要治疗8例患者才可防止1例在第1年内复发。但在年复发率方面,IFN-β治疗无效。IFN-β常导致注射部位局部反应、寒颤、发热、肌肉疼痛、流感样症状、头痛、血清丙氨酸转氨酶和天冬氨酸转氨酶水平升高等不良事件,但并不增加外周血淋巴细胞和中性粒细胞减少、抑郁、自杀行为或自杀观念的发生。结论高质量证据显示,IFN-β治疗复发-缓解型多发性硬化可轻微降低第1年内的复发病例数,但超过1年的疗效尚不能确定。目前尚无足够证据证明IFN-β在减少残疾进展病例数方面的疗效,尚待高质量的随机对照临床试验评价其长期有效性。     

复发缓解型多发性硬化患者疲劳的发生率及相关因素

目的 探讨复发-缓解型多发性硬化(relapsing remitting multiple sclerosis, RRMS)患者疲劳症状的发生率及相关危险因素。方法 收集2018年8月至2021年7月南京梅山医院神经内科收治的RRMS患者共80例,平均年龄(42.5±8.9)岁,其中男性38例,女性42例。根据患者是否发生疲劳将患者分为疲劳组(n=39)和非疲劳组(n=41)。采用自编问卷收集患者人口学资料与临床特征资料;采用疲劳影响量表修订版(MFIS)评估患者的疲劳症状,以MFIS分≥38定义为疲劳;采用贝克抑郁量表第2版中文版评估抑郁症状;采用临床扩展致残量表(EDSS)评估神经系统损伤程度;采用健康状况调查问卷(SF-36)评估健康状况。比较疲劳组和非疲劳组间临床资料的差异,并采用二元多因素Logistics回归分析RRMS患者疲劳的相关危险因素。结果 RRMS患者疲劳的发生率为48.8%(39/80),二元多因素Logistic回归分析显示,年龄(OR=0.91,95%CI:0.84～0.99)、躯体健康总评分(OR=0.99,95%CI:0.97～1.00)和精神健康总评分...     

复发缓解型多发性硬化患者脑灰质弥散张量成像研究

目的利用弥散张量成像(DTI)直方图分析,明确复发缓解型多发性硬化(RRMS)患者表现正常脑灰质(NAGM)是否存在隐匿性损伤,并研究脑灰质DTI直方图指标与扩展残疾功能状态量表(EDSS)评分的相关性。方法对24例RRMS患者和24名性别及年龄匹配的健康志愿者行常规磁共振成像(MRI)和DTI检查,分割提取NAGM后,绘制出NAGM的平均弥散率直方图并对其进行分析。结果RRMS患者NAGM的平均弥散率[(1·134±0·086)×10-3mm2/s]明显高于健康志愿者[(0·993±0·042)×10-3mm2/s,t=7·198,P<0·01],平均弥散率直方图峰位置[(0·880±0·089)×10-3mm2/s]也明显高于健康志愿者[(0·812±0·017)×10-3mm2/s,t=3·685,P=0·001],而平均弥散率直方图峰高(6·138‰±1·371‰)明显低于健康志愿者(8·889‰±1·339‰,t=7·032,P<0·01)。RRMS患者NAGM的平均弥散率直方图各指标间的相关性明显高于健康志愿者。在RRMS患者,所有NAGM的平均弥散率直方图指标与EDSS评分均无相关性。结论RRMS患者的NAGM内存在隐匿性损伤。     

复发缓解型多发性硬化患者的抑郁症状与疲劳及生活质量的相关性

目的:探讨复发缓解型多发性硬化患者抑郁症状与疲劳及生活质量的相关性。方法:选取复发缓解型多发性硬化患者共80例,采用自编问卷收集患者人口学资料与疾病相关信息;采用贝克抑郁量表第2版中文版(BDI-Ⅱ)评估抑郁症状;采用疲劳影响量表修订版(MFIS)评估疲劳症状;采用健康状况调查问卷(SF-36)评估生活质量。结果:复发缓解型多发性硬化患者BDI-Ⅱ分为(10.43±6.74)分,其中,轻度抑郁11.3%(9/80),中度抑郁11.3%(9/80),重度抑郁1.3%(1/80)。多因素线性回归分析结果显示,BDI-Ⅱ评分与年龄(β=0.17,95%CI:0.01～0.33)和MFIS分(β=0.14,95%CI:0.06～0.22)正相关,与情感角色(β=-0.05,95%CI:-0.08～-0.01)和精神健康(β=-0.59,95%CI:-0.20～-0.04)负相关(P<0.05或P<0.01)。结论:复发缓解型多发性硬化患者抑郁症状的发生率较高,需要重点关注高龄、疲劳程度重及生活质量较差的患者。     

孤立病灶的脱髓鞘与多发性硬化

复发 缓解型多发性硬化 (relapsing remittingmultiplesclerosis,RRMS)活动期可采用激素治疗 ,缓解期和继发进展期也有干扰素 β(interferon β)、glatirame和米妥蒽醌等免疫抑制疗法 ,但尚无充足证据表明它们可以阻止疾病的进展和功能缺损的发生。当患者已经有两次临床发作符合MS诊断标准时 ,就已经存在了部分不可逆性损害。近年来研究发现 ,在第一次脱髓鞘发作时为数相当的患者就存在了MS样改变 ,且随访发现超过半数的患者将在未来 5～ 10年发展成临床确诊的MS(clinicallydefiniteMS ,CDMS)。目前将临床上只有一次发作和一个部位…     

Fingolimod for the treatment of relapsing multiple sclerosis

Fingolimod is the first oral agent approved in the USA for the treatment of relapsing forms of multiple sclerosis. Fingolimod is a sphingosine 1-phosphate receptor modulator that binds to sphingosine 1-phosphate receptors on lymphocytes, resulting in a downregulation of the receptor and a reversible sequestration of lymphocytes in lymphoid tissue. Effector memory T cells are not sequestered so that immune surveillance may be minimally affected. Two large-scale Phase III clinical trials have demonstrated the efficacy of fingolimod compared with placebo and intramuscular interferon β-1a in relapsing-remitting multiple sclerosis. Due to its mechanism of action, fingolimod administration may be associated with first-dose bradycardia and macular edema. Therefore, patients should be observed for 6 h at the time of their first dose and undergo ophthalmologic evaluation prior to treatment initiation and at 3-4 months after initiation.     

Acyclovir treatment of relapsing-remitting multiple sclerosis

Acyclovir treatment was used in a randomized, double-blind, placebo-controlled clinical trial with parallel groups to test the hypothesis that herpes virus infections are involved in the pathogenesis of multiple sclerosis (MS). Sixty patients with the relapsing-remitting form of MS were randomized to either oral treatment with 800 mg acyclovir or placebo tablets three times daily for 2 years. The clinical effect was investigated by an extensive test battery consisting of neurological examinations, neuro-ophthalmological and neuropsychological tests, and evoked potentials. Results were based on intent-to-treat data and the primary outcome measure was the exacerbation rate. In the acyclovir group (n = 30), 62 exacerbations were recorded during the treatment period, yielding an annual exacerbation rate of 1.03. The placebo group (n = 30) had 94 exacerbations and an annual exacerbation rate of 1.57. Thus, 34% fewer exacerbations were encountered during acyclovir treatment. This difference in exacerbation rate between the treatment groups was not significant (P = 0.083). However, this trend to a lower disease activity in acyclovir-treated patients was supported in subsequent data analysis. If the patients were grouped according to exacerbation frequencies, i.e. into low (0–2), medium (3–5) and high (6–8) rate groups, the difference between acyclovir and placebo treatment was significant (P = 0.017). Moreover, in a subgroup of the population with a duration of the disease of at least 2 years providing an exacerbation rate base-line before entry, individual differences in exacerbation rates were compared between the 2-year pre-study period and the study period in acyclovir-treated (n = 19) and placebo (n = 20) patients and acyclovir-treated patients showed a significant reduction of exacerbations (P = 0.024). Otherwise, neurological parameters were essentially unaffected by acyclovir treatment and there were no convincing signs of reduced neurological deterioration in the acyclovir group. This study indicates that acyclovir treatment might inhibit the triggering of MS exacerbations and thus suggests that acyclovir-susceptible viruses might be involved in the pathogenesis of MS. This possibility warrants further investigation.     

Clinical and demographic predictors of long-term disability in patients with relapsing-remitting multiple sclerosis: a systematic review

OBJECTIVE: To identify clinical and demographic factors associated with long-term disability in patients with relapsing-remitting multiple sclerosis. DATA SOURCES: We searched the MEDLINE (1966-May 2005), EMBASE, CINAHL, Cochrane, and PsycINFO computerized databases, and reviewed reference lists of retrieved articles. STUDY SELECTION: We included studies that examined predictors of long-term disability in patients with relapsing-remitting multiple sclerosis. We excluded studies that did not distinguish relapsing-remitting multiple sclerosis from primary progressive multiple sclerosis, enrolled fewer than 40 subjects, observed subjects for less than 5 years, or collected follow-up information in less than 80% of the inception cohort. DATA EXTRACTION: Two reviewers assessed study quality in 4 domains: cohort assembly, definitions and assessments of prognostic factors and outcomes, and statistical methods. One reviewer extracted data on the direction, magnitude, precision, and statistical significance of the effect of each predictor on prognosis. DATA SYNTHESIS: Heterogeneity of study designs precluded us from pooling the results of 27 eligible studies. Study quality was limited by cross-sectional design, enrollment of prevalent cases from referral centers, and lack of multivariate adjustment. Sphincter symptoms at onset (hazard ratio, 1.1-3.1), incomplete recovery from the first attack (hazard ratio, 1.3-3.3), and a short interval between the first and second attack (hazard ratio, 1.6-1.9) were most strongly and consistently associated with poor prognosis. Other factors widely believed to be of prognostic importance, including sex and age at onset, demonstrated inconsistent or weak effects on prognosis. CONCLUSIONS: The most robust predictors of long-term physical disability in relapsing-remitting multiple sclerosis are sphincter symptoms at onset and early disease course outcomes. These factors can be used to guide treatment decisions for drugs with significant toxicities.     

Alemtuzumab in the treatment of relapsing-remitting multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disorder characterized by CNS inflammation, demyelination and cellular damage with atrophy. Most patients with MS initially present with a relapsing-remitting course, with periodic episodes of neurologic symptomatology that do not follow a predictable pattern. In order to maintain a stable clinical course, it is felt to be important to control the number and severity of relapses, as disability, at least in part, is a cumulative effect of damage from multiple lesions within the brain and spinal cord. Historically, MS has not been considered curable, because the immune system could not be adequately normalized over the course of a lifetime. Alemtuzumab (Campath-1H; Campath(?), Genzyme, MA, USA) has recently been investigated in a Phase II clinical trial in the treatment of relapsing-remitting MS. The results observed in the study are very encouraging and multiple insights have been made into the nature of autoimmunity in general based on the clinical response to this monoclonal antibody. Enrollment in two pivotal Phase III clinical trials of alemtuzumab in MS is now complete.