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神 经 病 学 研 究 所读 书 报 告 会,Treatment of progressive multiple sclerosis: what works, what does not, and what is needed进展型多发性硬化十大常见症状的治疗策略Lancet Neurol 2015; 14: 194207报告人：项尚 导师： 胡纪源,多发性硬化的定义,多发性硬化（multiple sclerosis,MS）是世界性分布的中枢神经系统（CNS）白质脱髓鞘疾病，是遗传易感个体与环境因素共同作用导致的自身免疫病。主要临床特征：1.症状和体征的空间多发性2.病程的时间多发性。,多发性硬化的病因及发病机制,多发性硬化的病因及发病机制迄今不明，目前普遍认为，MS是在复杂的遗传易感性背景下，由于环境因素如地域、气候及感染等的参与，引发的免疫系统的异常，导致中枢神经系统炎性脱髓鞘性病变。,多发性硬化的临床分型,1.复发缓解型MS(RRMS):是临床最常见的类型，多在20至40岁发病，急性或亚急性起病，神经系统症状一般持续24小时以上，在其后数日内症状部分或完全缓解。2.原发进展型MS(PPMS):约占10%，起病年龄多在40岁后，隐袭或慢性起病，起病后轻截瘫或轻偏瘫在数周至数月至数年缓慢进展，病变主要累及脊髓，常见肢体无力，下肢麻木，以及共济失调，呈渐进性恶化病程，预后不良。3.继发进展型MS(SPMS):大多数RRMS患者经一段时间可转变为此型，病情逐渐进展而无明显缓解。4.进展复发型MS(PRMS)：临床少见，病情呈逐渐进展，随后又有加重或复发。,目录,Introduction,Symptoms,Treatment,Conclusions,Introduction,Disease-modifying drugs have mostly failed as treatments for progressive multiple sclerosis. Management of the disease therefore solely aims to minimise symptoms and, if possible, improve function.,应用的疾病修饰治疗：一线 干扰素- 醋酸格拉默二线 环磷酰胺 米托蒽醌 芬戈莫德 那他珠单抗 达利珠单抗 利妥昔单抗,Symptoms,疲倦,膀胱功能障碍,肌痉挛,假性延髓情绪,共济失调,认知功能障,疼痛,肢体无力,抑郁,平衡与运动功能障碍,十大常见症状,Treatment,1.Balance and mobility impairment (平衡与运动功能障碍)Multiple sclerosis causes a wide range of neurological deficits, which often interact to cause mobility difficulties. Within 1015 years of disease onset, 80% of patients have walking difficulties, which is of major concern to people with the disorder who report mobility as their most valued bodily function, with more impairment in people with progressive forms of multiple sclerosis than in those with RRMS.,1.1 the cause of impaired balance and mobility is probably multifactorial and hypotheses about the key mechanisms vary. impaired central integration of visua,vestibular, and somatosensory input is key, the cerebellum could be the main contributor.,Treatment,1.2 A range of interventions aimed at enhancing balance in standing and walking are used in clinical practice, the most common of which is physiotherapy. specific balance exercises, neuromuscular facilitation resistance training, aerobic training, but their relative effectiveness is not known either for those with RRMS or progressive disease.,Treatment,神经肌肉促进技（神经生理疗法)： 将神经生理学和神经发育学的基本知识运用运动疗法的基本操作中以治疗神经、肌肉，特别是中枢神经系统损伤引起的运动功能障碍的一类治疗方法,所谓促进技术就是利用各种方法刺激运动通路上的各级运动神经元，调节他们的兴奋性，以获得正确的运动输出的方法。,1.3 Neural plasticity is enhanced following task-specific rehabilitation特定任务的康复训练). Therefore, balance and mobility interventions are thought to provide the appropriate task-specific stimuli to help neural re-organisation of central sensory integration, thereby leading to improved stability.,Treatment,In summary insufficient evidence exists to support balance or mobility retraining as effective interventions for people with progressive disease, although data from mixed patient samples are promising.,Treatment,Treatment,2.Weakness (肢体无力)Weakness is present in up to 70% of people with multiple sclerosis. the lower limbs（the most ） although weakness in the upper limbs, trunk, respiratory muscles is also problematic.,Treatment,2.1 systematic review and meta-analysis provides strong evidence in support of the use of resistance training to improve lower limb strengthweight machines, free weights, and resistance bandsalthough Other forms of strength training (eg, locomotor training, cycling, and aquatics) can also enhance lower limb strength.2.2 Preliminary research suggests that exercise might delay disease progression by reducing inflammation （减轻炎症）and encouraging neuronal repair.,Treatment,2.3 Weakness in multiple sclerosis was, until fairly recently, not thought to be amenable to drug treatment. a recent Cochrane review of 4-aminopyridine shows that, in a subset of patients, this well tolerated drug improved walking speed and muscle strength of the lower extremities. Therefore, at present, no recommendations can be made for those with progressive disease in relation to the effect of 4-aminopyridine on weakness or mobility.,4- 氨基吡啶：可通过延长神经动作电位持续时间、增强动作电流来恢复阻滞的脱髓鞘神经的传导,从而改善多发性硬化(MS)的临床征象。,Treatment,3.Ataxia (共济失调)3.1 An estimated 80% of patients with multiple sclerosis experience ataxia at some point in their disease course. A range of treatments are availablepharmacotherapy（药物治疗） (eg, isoniazid（异烟肼）, pyridoxine（维生素B6）, and cannabis(大麻), stereotactic neurosurgery（立体定向神经外科治疗 ）(thalamotomy or deep-brain stimulation), and neurorehabilitation（神经康复）.,Treatment,3.2 The only Cochrane review that has focused specifically on ataxia in multiple sclerosis concluded that insufficient evidence exists for the efficacy and tolerability of pharmacotherapies to treat this aspect of the disease. This is also the case for neurosurgery and neurorehabilitation,Treatment,4.Fatigue (疲倦)4.1 Fatigue occurs in up to 80% of patients with multiple sclerosis and is reported more frequently in progressive than in relapsing-remitting disease. It is an important determinant of quality of life, with two-thirds of patients reporting fatigue as one of their most troubling symptoms. Effective treatment remains scarce.,Treatment,4.2 Successful treatment of fatigue with use of behavioural approaches is increasingly recognised to possibly affect the underlying biology. Therefore, future studies, in addition to focusing on progressive disease, should incorporate biomarkers to elucidate the potential mechanisms underpinning any observed behavioural changes.,Treatment,5.Bladder dysfunction(膀胱功能障碍)Most people with multiple sclerosis experience bladder problems during their lives. These difficulties correlate highly with quality of life. A reduction in the frequency of incontinence is important from a psychological and self-esteem perspective.,Treatment,5.1 In initial stages of bladder overactivity, pharmacological agents such as anticholinergics(抗胆碱能药物) (eg, oxybutynin奥西布宁) and antimuscarinic agents(抗毒蕈碱类药物 )(eg, solifenacin索菲那新) are typically used. More recently, botulinum toxin肉毒素 injections have received US Food and Drug Administration approval for the treatment of urinary incontinence resulting from detrusor逼尿肌 overactivity caused by multiple sclerosis.,Treatment,5.2 Neurogenic bladder depends on severity, rehabilitative methods such as facilitated emptying through intermittent catheterisation 间断导尿术)or external compression 外界压迫)(suprapubic bladder compression耻骨弓上膀胱压迫)are the approaches typically recommended for the management of neurogenic bladder. Assistive devices have been assessed to direct the timing of catheterisation, which is usually based on symptoms, post-void residuals, or a set schedule.,Treatment,6.Spasticity（肌痉挛）6.1 Spasticity in multiple sclerosis is a manifestation of disrupted descending motor pathways caused by axonal degeneration or demyelination. Around 6090% of people with multiple sclerosis will develop spasticity during their lifetime.,Treatment,Spasticity,localise 局部的,multifocal, or regional多部位的或区域,reducing the range of movement across joints关节活动范围减小,increasing stiffnes 活动僵硬感增加,pressure sores继发压疮,contributing to pain, contracture疼痛、 关节挛缩,Treatment,Treatment of Spasticity,pharmacological agents口服药物,rehabilitative therapies神经康复治疗,surgical procedures外科手术治疗,invasive 侵入性操作,Treatment,6.2 The existing small sample progressive MS research show that physiotherapy in addition to botulinum toxin type A injection had superior effects to botulinum toxin alone.,Treatment,7.Pain (疼痛),extremity pain (26.6%),trigeminal neuralgia (3.8%,Headache(42%）,back pain (20%),Treatment,7.1 Treatment for pain is very much pharmacologically based. Pain medications can account for nearly 30% of all drug use for all multiple sclerosis symptoms, but patient satisfaction with their pain management is generally low. Medication treatment trials in progressive multiple sclerosis are scarce, but in one study of SPMS, intrathecal baclofen and morphine were reportedly effective.,.巴氯芬鞘内注射(ITB)：是通过注射泵将小剂量巴氯芬缓慢持续注入脊髓蛛网膜下腔， 可以持久而有效地治疗严重痉挛状态。,Treatment,7.2 The research data about rehabilitative interventions for pain in progressive forms of MS are scarce. Positive findings indicate that bodyweight-supported treadmill training (体重支持行走训练)can reduce pain. In addition, transcutaneous electrical nerve stimulation(经皮神经电刺激) and exercise or massage studies (锻炼或按摩疗法)also indicate beneficial effects.,Treatment,8.Cognitive dysfunction (认知功能障碍)8.1 The prevalence of cognitive dysfunction varies from roughly 40% in RRMS to 60% in SPMS. Rates of dysfunction are higher in SPMS than in PPMS. The cognitive domains affected most frequently are those of information processing speed, memory, and executive function.,Treatment,8.2 The pharmacological treatment of cognitive dysfunction in MS has yielded mixed results. Disease-modifying therapies have proved disappointing, notwithstanding their ability to bring about improvement in brain MRI metrics.Currently has related research suggests that interferon beta-1b (干扰素-1b) can improve the cognitive power of the patients with SPMS(secondary progressive MS); also droperidol methylphenidate(哌醋甲酯), modafinil(莫达非尼) and l-amphetamine( L- 苯丙胺 )seems to have certain curative effect.,Treatment,8.3 In summary, insfficient evidence currently exists to support medication or cognitive retraining as effective treatments for cognitive impairment in progressive multiple sclerosis ,although promising data for cognitive retraining (认知功能再训练)in mixed samples of patients with MS are duly noted. Exercise seems to benefit cognition, but replication studies are needed and the best type of exercise needs to be clarified.,Treatment,9.Depression (抑郁状态)9.1 Between a third and half of all patients with multiple sclerosis will develop major depression during the course of their lives. it is also a major determinant of quality of life. Therefore, the fact that depression is often overlooked in neurological clinics and, even when detected, inadequately treated.,Treatment,9.2 A Cochrane review of antidepressant medication for multiple sclerosis-related depression noted modest benefits and prominent side-effects, focused on various forms of psychotherapy for patients with multiple sclerosis was more enthusiastic about cogniti