1、EFNS guidelines on the Clinical Management of AmyotrophicLateral Sclerosis(MALS)revised report of an EFNS task forceEuropean Journal of Neurology 2012,19:360375 2012中国肌萎缩侧索硬化诊断和治疗指南中国肌萎缩侧索硬化诊断和治疗指南中华神经科杂志中华神经科杂志2012年年7月第月第45卷第卷第7期期背景介绍背景介绍n肌萎缩侧索硬化（肌萎缩侧索硬化（ALSALS）是主要累及上下运动神经元的神）是主要累及上下运动神经元的神经系统变性疾病。
2、主要表现为进行性延髓，四肢以及胸腰经系统变性疾病。主要表现为进行性延髓，四肢以及胸腰部肌肉的萎缩；眼球和括约肌功能相对保留。部肌肉的萎缩；眼球和括约肌功能相对保留。2050%2050%病人出现认知障碍，病人出现认知障碍，515%515%发展为痴呆，通常为额颞叶发展为痴呆，通常为额颞叶痴呆。起病后平均痴呆。起病后平均2-42-4年因呼吸衰竭死亡。家族性年因呼吸衰竭死亡。家族性ALSALS的平的平均起病年龄为均起病年龄为43-5243-52岁，而散发病例的为岁，而散发病例的为58-6358-63岁。岁。nALSALS的早期临床表现多样，因此详细的病史，细致的体检和规范的神的早期临床表现多样，因此详
3、细的病史，细致的体检和规范的神经电生理检查对于早期诊断具有关键性作用，影像学等其他辅助检查经电生理检查对于早期诊断具有关键性作用，影像学等其他辅助检查在鉴别诊断中具有一定价值。在鉴别诊断中具有一定价值。临床检查临床检查n1.1.病史：病史：是证实疾病进行性发展的主要依据。是证实疾病进行性发展的主要依据。n2.2.体格检查体格检查：在同一区域，同时存在上、下运动神经元受累的体在同一区域，同时存在上、下运动神经元受累的体征，是诊断征，是诊断ALSALS的要点。的要点。(1)(1)下运动神经元受累体征主要包括肌肉无力、下运动神经元受累体征主要包括肌肉无力、萎缩和肌束颤动。萎缩和肌束颤动。(2)(2)
4、上运动神经元受累体征主要包括肌张力增高、上运动神经元受累体征主要包括肌张力增高、腱反射亢进、阵挛、病理征阳性等。腱反射亢进、阵挛、病理征阳性等。(3)(3)临床体检是发现上运动神经临床体检是发现上运动神经元受累的主要方法。元受累的主要方法。(4)(4)对患者进行随诊，动态观察体征的变化，也对患者进行随诊，动态观察体征的变化，也可以反映出疾病的进行性发展过程。可以反映出疾病的进行性发展过程。n3.3.当病史、体检中发现某些不能用当病史、体检中发现某些不能用ALSALS解释的表现时，如解释的表现时，如病程中出现稳定或好转、有肢体麻木疼痛等，诊断病程中出现稳定或好转、有肢体麻木疼痛等，诊断ALSAL
5、S需需慎重，并注意是否合并有其他疾病。慎重，并注意是否合并有其他疾病。神经电生理检查神经电生理检查n1.1.神经传导测定神经传导测定:主要用来诊断或排除周围神经疾病，至主要用来诊断或排除周围神经疾病，至少包括上、下肢各少包括上、下肢各2 2条神经。条神经。n(1)(1)运动神经传导测定运动神经传导测定:远端运动潜伏期和神经传导速度通常正常。随远端运动潜伏期和神经传导速度通常正常。随病情发展，复合肌肉动作电位波幅可以明显降低，传导速度也可以有病情发展，复合肌肉动作电位波幅可以明显降低，传导速度也可以有轻度减慢。轻度减慢。n(2)(2)感觉神经传导测定感觉神经传导测定:一般正常。一般正常。n n(
6、3)F(3)F波测定波测定:通常正常。当肌肉明显萎缩时，相应神经可见通常正常。当肌肉明显萎缩时，相应神经可见F F波出现率波出现率下降，而传导速度相对正常。下降，而传导速度相对正常。神经电生理检查神经电生理检查n2.2.同芯针肌电图检查同芯针肌电图检查:下运动神经元病变的判断，当肌电下运动神经元病变的判断，当肌电图显示某一区域存在下运动神经元受累时，其诊断价值与图显示某一区域存在下运动神经元受累时，其诊断价值与临床发现肌肉无力、萎缩的价值相同。临床发现肌肉无力、萎缩的价值相同。n(1)(1)进行性失神经表现进行性失神经表现:主要包括纤颤电位、正锐波。主要包括纤颤电位、正锐波。n(2)(2)慢性
7、失神经的表现慢性失神经的表现:大部分大部分ALSALS可见发放不稳定、波形复杂的运动可见发放不稳定、波形复杂的运动单位电位。单位电位。n(3)(3)同一肌肉肌电图检查表现为进行性失神经和慢性失神经共存时，同一肌肉肌电图检查表现为进行性失神经和慢性失神经共存时，对于诊断对于诊断ALSALS有更强的支持价值。有更强的支持价值。n(4)(4)检测范围检测范围:脑干，颈段，胸段和腰骶段脑干，颈段，胸段和腰骶段4 4个区域。个区域。n(5)(5)在在ALSALS病程早期，肌电图检查时可仅出现病程早期，肌电图检查时可仅出现1 1个或个或2 2个区域的下运动神个区域的下运动神经元损害，此时对临床怀疑经元损害
8、，此时对临床怀疑ALSALS的患者，需要间隔的患者，需要间隔3 3个月进行随访调查。个月进行随访调查。n(6)(6)肌电图出现肌电图出现3 3个或以上区域的下运动神经元损害时，并非都是个或以上区域的下运动神经元损害时，并非都是ALSALS。神经影像学检查神经影像学检查n1.1.有助于有助于ALSALS与其它疾病的鉴别，排除结构性损害。与其它疾病的鉴别，排除结构性损害。n2.2.可发现锥体束走行部位的异常信号。可发现锥体束走行部位的异常信号。n3.3.某些常见疾病，如颈椎病，腰椎病等可与某些常见疾病，如颈椎病，腰椎病等可与ALSALS合并存在，合并存在，需要注意鉴别。需要注意鉴别。ALS的诊断标
9、准的诊断标准nThe diagnosis of ALS requires the presence of:(positive criteria)n下运动神经元损害表现，包括临床表现上未累及的肌肉出现特异的肌电图表现n上运动神经元损害表现n症状和体征的进展性表现nThe diagnosis of ALS requires the absence of(diagnosis by exclusion):n感觉障碍的表现n括约肌障碍 n视觉障碍n自主神经功能障碍n基底神经节功能障碍n阿尔茨海默病样痴呆nALS”类似”综合症nThe diagnosis of ALS is supported by:n束
10、颤出现在一个或多个区域n肌电图提示神经源性损害n正常的运动和感觉神经传导n无传导阻滞ALS的诊断标准的诊断标准nThe Revised El Escorial research diagnostic criteria for ALS with the Awaji electrodiagnostic algorithm included n临床确诊临床确诊ALSALSn临床神经电生理检查证实至少有三个区域存在上下运动神经元同时受累的证据n临床确诊临床确诊ALS-ALS-实验室检查支持实验室检查支持n临床神经电生理检查证实有一个区域存在上或/和下运动神经元受累的证据n携带病理性SOD1-基因突变n
11、临床拟诊临床拟诊ALSALSn临床神经电生理检查证实至少有两个区域存在上下运动神经元同时受累的证据n临床可能临床可能ALSALSn临床神经电生理检查证实有一个区域存在上或/和下运动神经元受累的证据n或至少两个区域仅有上运动神经元受累证据n神经影像学和实验室检查排除了其他疾病ALS的诊断标准的诊断标准当所测定肌肉同时存在慢性失神经的表现时，束颤电位与纤颤电位、正锐波具有同等临床意义。The Awaji criteria have a significant clinicalimpact allowing earlier diagnosis and clinical trial entry in
12、ALS.Arch Neurol.2012;69(11):1410-1416Awaji ALS criteria increase the diagnostic sensitivity in patients with bulbar onset.clin Neurophysiol(2011)。ALS的治疗的治疗1.1.神经保护神经保护/延缓病情发展的药物延缓病情发展的药物n1.Patients with ALS should be offered treatment with riluzole 50 mg twice daily(level A).n2.Treatment should be i
13、nitiated as early as possible after diagnosis(GCPP).n3.Patients with progressive muscular atrophy,primary lateral sclerosis or hereditary spastic paraplegia should as a rule not be treated with riluzole(GCPP).n4.Currently,there is insufficient evidence to recommend treatment with vitamins,testostero
14、ne,antioxidants such as co-enzyme Q-10 and gingko biloba,intravenous immunoglobulin therapy,cyclosporin,interferons,Copaxone,KDI tripeptide,neurotrophic factors(including BDNF,IGF-1 and mecasermin rinfabate),ceftriaxone,creatine,gabapentin,minocycline,stem cells or lithium(GCPP).（GCPP：Good Clinical
15、Practice Point）ALS的治疗的治疗2.2.对症治疗（流涎）对症治疗（流涎）nTreat sialorrhoea in ALS with amitriptyline,oral or transdermal hyoscine,or sublingual atropine drops(GCPP).n1.In patients with refractory sialorrhoea,botulinum toxin injections into the parotid and/or submandibular gland are effective and generally well
16、tolerated(level B for botulinum toxin type B,level C for type A toxin).n2.Irradiation of the salivary glands may be tried when pharmacological treatment fails(GCPP).n3.Surgical interventions are not recommended(GCPP).ALS的治疗的治疗n2.2.对症治疗（支气管分泌物）对症治疗（支气管分泌物）n1.A mucolytic including N-acetylcysteine,200
17、400 mg three times daily,may be beneficial(GCPP).n2.Beta-receptor antagonists and a nebulizer with saline and/or an anticholinergic bronchodilator and/or a mucolytic and/or furosemide may be used in combination.(GCPP).n3.The patient and carer should be taught the technique of assisting expiratory mo
18、vements using a manual-assisted cough(can also be performed by a physical therapist)(GCPP).ALS的治疗的治疗2.2.对症治疗（假性延髓麻痹性情绪障碍）对症治疗（假性延髓麻痹性情绪障碍）n1.Inform the patient and relatives that emotional lability is not a sign of an additional mood disorder but is because of the effects of ALS on the brain(GCPP).n
19、2.Troublesome emotional lability should be treated(GCPP).Antidepressants such as amitriptyline(in particular in patients with drooling),fluvoxamine and citalopram are usually sufficient(level C).n3.A combination of dextrometorphan and quinidine has been shown to be effective(level A).ALS的治疗的治疗2.2.对症
20、治疗（痛性痉挛）对症治疗（痛性痉挛）n1.Levetiracetam may be tried.If unsuccessful or side effects,quinine sulphate(200 mg twice daily)may be of benefit(GCPP).n2.Physiotherapy,physical exercise and/or hydrotherapy may be helpful(GCPP).2.2.对症治疗（痉挛状态）对症治疗（痉挛状态）n1.Regular physical therapy can help relieve significant spa
21、sticity(GCPP).n2.Antispastic drugs such as baclofen and tizanidine may be tried(GCPP).n3.If spasticity is severe despite oral medications,intrathecal baclofen may be helpful(GCPP).n4.Hydrotherapy with exercises in warm pools(3234C)and cryotherapy may be considered(GCPP).ALS的治疗的治疗2.2.对症治疗（抑郁焦虑）对症治疗（抑
22、郁焦虑）n1.Treat depression in ALS with an appropriate antidepressant,for example amitriptyline,an SSRI,or mirtazapine.SSRI may be preferably in elderly or cognitively impaired patients(GCPP).n2.Treat anxiety with bupropion or benzodiazepines such as diazepam tablets or suppositories,Temesta tablets 0.5
23、 mg two or three times daily,or sublingual lorazepam(GCPP).2.2.对症治疗（失眠疲劳）对症治疗（失眠疲劳）n1.Treat insomnia with amitriptyline,mirtazapine or appropriate hypnotics(e.g.zolpidem)(GCPP).n2.For debilitating fatigue,modafinil may be considered(level A).ALS的治疗的治疗3.3.营养管理营养管理n1.Bulbar dysfunction and nutritional
24、 status,including body weight,should be checked at each visit.(GCPP).n2.Patients should be referred to a dietitian as soon as dysphagia appears.(GCPP).n3.The timing of PEG/PRG is based on an individual approach taking into account bulbar symptoms,malnutrition(weight loss of over 10%),respiratory fun
25、ction and the patients general condition(GCPP).n4.When PEG is indicated,patient and carers should be informed:(i)of the benefits and risks of the procedure;(ii)that it is possible to continue to take food orally as long as it is possible;and(iii)that deferring PEG to a late disease stage may increas
26、e the risk of the procedure(GCPP).n5.PRG is a suitable alternative to PEG(GCPP).n6.Prophylactic medication with antibiotics on the day of the operation may reduce the risk of infection(GCPP).n7.NGT feeding may be used in the short-term and when PEG or PRG is not suitable(GCPP).ALS的治疗的治疗4.4.呼吸支持呼吸支持n
27、1.Symptoms or signs of respiratory insufficiency(including symptoms of nocturnal hypoventilation)should be checked at each visit(GCPP).n2.Forced vital capacity and vital capacity are the most available and practical tests for the regular monitoring of respiratory function(GCPP).n3.NIPPV should be co
28、nsidered in preference to IMV in patients with symptoms or signs of respiratory insufficiency(GCPP).n4.NIPPV can prolong survival for many months(level A)and may improve the patients quality of life(level C).n5.The medical treatment of intermittent dyspnoea should involve:a.for short dyspnoeic bouts
29、:relieve anxiety and give lorazepam 0.52.5 mg sublingually;b.for longer phases of dyspnoea(30 min):give morphine 2.5 mg orally or s.c.(GCPP)n6.For the medical treatment of chronic dyspnoea,start with morphine 2.5 mg orally four to six times daily.(GCPP).ALS的未来方向的未来方向nBeing a syndrome with low incide
30、nce and short survival,most recommendations are GCPPs based on the consensus of experts in the field of ALS.Further randomized and double-blind clinical trials are urgently needed to improve the management of ALS.nResearch recommendationsn1.Further studies of biomarkers(imaging,blood and cerebrospin
31、al fluid proteomics and metabolomics,neurophysiological markers)to aid earlier specific ALS diagnosis and to monitor possible effects in clinical trials.n2.Further studies to optimize the symptomatic treatment of muscle cramps,drooling and bronchial secretions in patients with ALS.n3.Better criteria
32、 for defining the use of PEG,PRG,NIV and IMV.n4.Further studies to evaluate the effects of PEG/PRG,cough-assisting devices and ventilation support on quality of life and survival.n5.Systematic studies to assess cognitive impairment and the frequency of frontal lobe dysfunction in ALS and to standardize clinical,neuropsychological and neuroradiological methods in this field.Future ALS diagnostic criteria should include parameters regarding cognitive dysfunction and dementia.
