神经病学课件：Movement Disorders 运动障碍

1、Movement Disorders 运动障碍Introduction to movement disorders 运动障碍简介“movement disorders ” is often used with “extrapyramidal 锥体束外 or basal ganglia 基底神经节(BG)” diseaseLesions 损伤 of basal ganglia or pyramidal system 锥体系统 are related to some, but not all, of the movement disordersPathways of extrapyramidal

2、system 锥体外系系统通路1. Cortex 皮质-cortex2. Substatia nigra 黑质-striatum 纹状体3. Striatum 纹状体-globus pallidus 苍白球Major neurotransmitters 主要神经递质Dopamine 多巴胺Acetylcholine 乙酰胆碱GABA -氨基丁酸Glutamate 谷氨酸盐some neuropeptides 神经肽 such as ENK 脑啡肽 and Substance P P物质They work synchronously 同步地 to maintain normal excitati

3、on and inhibitions. Normal function of extrapyramidal system 锥体外系系统的主要功能Regulates muscle tone 调节肌张力Maintains posture 维持姿态Co-ordinates voluntary movement 协调随意运动Basal Ganglia 基底神经节Damage to the basal ganglia:Produces either too much activation (hyperkinetic 运动机能亢进) responses= twitches 抽搐, movements bu

4、rsts 运动爆发, jarring 不协调, etc.ORProduces too little force (hypokinetic 运动不足)=rigidity 僵硬Parkinsons diseasePink=inhibitionBlue=excitationCommon symptoms of movement disorders 运动障碍的常见症状Akinesia 运动不能-rigid 僵硬Parkinsonism-brdykinesia 运动徐缓Dyskinesia 运动障碍Chorea 舞蹈病Dystonia 肌张力障碍Tremor 震颤Tics 抽搐Chorea 舞蹈病 Ch

5、orea is a rapid 快速, purposeless 无目的, irregular 不规则, jerky 急动movement that seems to flow randomly from one part of the body to another.Dystonia 肌张力障碍 and Athetosis 手足徐动症Dystonia is a syndrome of sustained muscle contractions 持续的肌肉收缩 causing abnormal postures 不正常姿势 or twisting 扭转 and repetitive moveme

6、nts 重复动作.Athetotic movements are complex, wormlike 虫样, irregular, non propositional 建议（？） and predominate 支配 over postural anomalies 姿势异常 and on the distal 末梢的 parts of limbs 四肢 and face.Tics 抽搐Twitches 抽搐 of the face, limbs or the whole body.Can be reproduced 再现 voluntarily 随意志Patient has partial c

7、ontrol 部分控制Do not interfere 妨碍 with voluntary activity 随意活动May persist 存留 in sleepCommon forms of movement disorders 运动障碍的常见形式Parkinsons DiseaseWilsons Disease (Hepatolenticular degeneration 肝豆状核变性)Essential tremor 特发性震颤Sydenhams Chorea 西登哈姆氏舞蹈病(Rheumatic chorea 风湿性舞蹈病)Tourettes Syndrome 妥瑞症Parkinso

8、ns Disease 帕金森氏病（PD）Is also called paralysis agitans 震颤性麻痹Is characterized by a neuronal accumulation 神经元累积 of -synuclein 突触核蛋白 and neuronal loss in SN 黑质Presents with bradykinesia 运动徐缓, tremor 震颤, rigidity 僵硬, shuffling gait 曳行步态, and flexed posture 弯曲姿势History of PDFirst described in 1817 by an En

9、glish physician, James Parkinson, in “An Essay on the Shaking Palsy 震颤麻痹.”The famous French neurologist, Charcot, further described the syndrome in the late 1800s.Epidemiology of PD1% of those 55 yearsRisk factors: ageing, positive family history, male gender 男性, head injury, exposure to pesticides

10、农药, consumption of well water 井水, and rural 农村 living. Factors linked to reduced incidence: coffee drinking, smoking, nonsteroidal anti-inflammatory drugs 非甾体类抗炎药, and estrogen 雌激素.Dopamine pathways 多巴胺通路 in human brainDopamine synthesis 多巴胺合成DA metabolism 多巴胺代谢DA degradation 多巴胺降解Lewy bodies 路易小体Et

11、iopathogenic mechanisms 发病机理Mechanisms-summary 机制小结 Cell death may be caused by -synuclein aggregation 聚集proteosomal 蛋白酶体 and lysosomal 溶酶体 system dysfunction,reduced mitochondrial 线粒体 activity. Excitotoxicity 兴奋性中毒 and inflammation are likely to play a relevant 相关的 role in progressive neuronal dege

12、neration 进展性神经变性.Clinical features 临床表现Motor features 运动性特征Bradykinesia, tremor, rigidity, shuffling gait, and flexed posture 运动徐缓、震颤、僵硬、曳行步态和弯曲姿势Non-motor featuresDepression and anxiety, cognition, sleep disturbances, sensory, and autonomic dysfunctions 抑郁及焦虑，认知、睡眠障碍，感觉和自主神经障碍Parkinsons Disease 帕金森

13、氏病（PD）Motor features 运动性特点Bradykinesia 运动徐缓. Slow in movement.Micrographia 写字过小 (hypophonia 发音过弱)-soft speech“Masked face 面具面容”Tremor 震颤 at rest. 4-6Hz. “pill rolling 搓丸样”. The lips 唇, tongue 舌, and jaw 颌 may be involved but spares 备件（？） the head.Rigidity 僵硬 .“cogwheeling 齿轮 ” or “lead-pipe 铅管”.Gait

14、 disturbance 步态障碍: shuffling 曳步的 short steps. Festinating (hurried) gait 慌张步态.At later stage, freezing of gait 步态冻结 (start hesitation).Non-motor features 非运动特点Depression and anxiety 抑郁和焦虑affects 50% of patients, intrinsic 固有的（？）cognitive impairment 认知障碍sleep disturbances 睡眠障碍sensory abnormalities 感觉

15、异常 and pain, loss of smell (anosmia 嗅觉缺失)disturbances of autonomic function 自主神经功能失调Diagnosis 诊断5055 years, develops slowlyAt least two of the following: tremor at rest, rigidity, bradykinesia or gait disturbance.Is responsible to dopamineExclude other parkinsonismssecondary parkinsonisms 继发性帕金森症Par

16、kinson-plus syndromes 帕金森叠加综合症Differential diagnosis 鉴别诊断Secondary Parkinsonism 继发性帕金森症Parkinsons-plus syndromes 帕金森叠加综合症Parkinsonism with abnormal metabolisms 代谢 of TAU (Tauopathies TAU蛋白病) and -synuclein 突触核蛋白(-synucleinopathies 突触核蛋白病)Wilsons Disease (Hepatolenticular degeneration 肝豆状核变性)Essentia

17、l tremor 特发性震颤(ET)Secondary Parkinsonism 继发性帕金森症Vascular parkinsonism 血管性帕金森综合征Seen in lacunar infarction 腔隙性脑梗死Poor response to L-dopaDrug-induced parkinsonism 药源性帕金森综合征(DIP).Drug-induced parkinsonism 药源性帕金森综合征(DIP)Is due to neuroleptics, some atypical antipsychosis, lithium carbonate, or antiemeti

18、c agents (especially metoclopramide). Less common: valproic acid, fluoxetine (antidepressant). Antihypertensive agents such as reserpine and alpha-methyldopa. Exposure to toxins such as CO, disulfide, cyanide and methanol can also lead to parkinsonism. DIP may respond to anticholinergic agents, aman

19、tadine, and L-dopa.Drug-induced parkinsonism 药源性帕金森综合征(DIP)可由神经松弛剂、一些非典型抗精神病药物、碳酸锂, or 止吐剂(特别是甲氧氯普胺)引起。 少见：丙戊酸, 氟西汀 (抗抑郁药)。降压药如利血平和-甲基多巴。暴露于毒物如CO、二硫化物、氰化物和甲醇也能导致帕金森症。DIP 可能适用抗胆碱能药物、金刚烷胺和左旋多巴治疗。Differential diagnosis 鉴别诊断Secondary Parkinsonism 继发性帕金森症Parkinsons-plus syndromes 帕金森叠加综合症Parkinsonism wit

20、h abnormal metabolisms 代谢 of TAU (Tauopathies TAU蛋白病) and -synuclein 突触核蛋白(-synucleinopathies 突触核蛋白病)Wilsons Disease (Hepatolenticular degeneration 肝豆状核变性)Essential tremor 特发性震颤(ET)Parkinsons-plus syndromes 帕金森叠加综合症Parkinsonism with abnormal metabolisms of TAU (Taupathies) Lewy body 路易小体 disease (de

21、mentia 痴呆 with Lewy bodies, DLB)Progressive supranuclear palsy 进行性核上性麻痹(PSP)Corticobasal degeneration 皮质基底节变性(CBD)Parkinsonism with abnormal metabolisms of -synuclein (-synucleinopathies)Multiple system atrophy 多系统萎缩(MSA)Parkinsonism with abnormal metabolisms of TAU (Taupathies) Lewy body disease (d

22、ementia with Lewy bodies, DLB), Dementia with visual hallucinations 视幻觉extremely sensitive to L-dopaProgressive supranuclear palsy (PSP)Early falls 早发, supranuclear palsy 核上性麻痹(both eyes, reflexic movement is intact 反射运动完整)Corticobasal degeneration (CBD)alien limb 异手症, apraxia 失用症Parkinsonism with a

23、bnormal metabolisms of -synuclein (-synucleinopathies)Multiple system atrophy 多系统萎缩 (MSA)parkinsonism with signs ofCerebellar 小脑Pyramidal tract 锥体束Autonomic dysfunction 自主神经功能障碍Parkinson-plus syndromessummaryShare parkinsonian features 共有帕金森病特征Lack of response to L-dopaSuggestive signs 提示迹象Cortical

24、dysfunctions 大脑皮层功能紊乱: dementia 痴呆, hallucination 幻觉, apraxia 失用症, alien limb 异手症 Ocular signs 眼部症状Early autonomic dysfunction 自主神经功能障碍 and pyramidal tract signs 锥体束迹象Differential diagnosis 鉴别诊断Secondary Parkinsonism 继发性帕金森症Parkinsons-plus syndromes 帕金森叠加综合症Parkinsonism with abnormal metabolisms 代谢

25、of TAU (Tauopathies TAU蛋白病) and -synuclein 突触核蛋白(-synucleinopathies 突触核蛋白病)Wilsons Disease (Hepatolenticular degeneration 肝豆状核变性)Essential tremor 特发性震颤(ET)Wilsons Disease (Hepatolenticular Degeneration 肝豆状核变性)Defect in the metabolism of copper 铜(ceruloplasmin 血浆铜蓝蛋白) affecting the liver (cirrhosis 硬

26、化), the lentiform nuclei 豆状核Features tremor, rigidity and choreiform 舞蹈病样 movements. Corneal 角膜 Kayser-Fleischer (K-F) ring. Low serum 血清 ceruloplasmin, elevated urinary excretion of copper 高尿铜排泄.Treatment: Copper-chelating agent 铜离子螯合剂 D-penicillamin 青霉胺Corneal Kayser-Fleischer (K-F) ringEssential

27、tremor 特发性震颤(ET)a 6- to 12 Hz postural 体位性 and kinetic 行动性tremor, bilateral 双边Diagnosis can be made when the course 过程 is more than 3 years. Treatment 治疗Propranolol 普萘洛尔 (40 to 320mg/d) Primidone 普里米酮 (50 to 750 mg/d). Others: Benzodiazepines 苯二氮卓类, gabapentin 加巴喷丁, topiramate 托吡酯History and examina

28、tion features that would question 怀疑 the diagnosis of idiopathic 特发性 Parkinsons DiseaseSymptoms/signsAlternative diagnosis to considerHistoryFalls as the first symptomPSPExposure to neurolepticsDrug-induced ParkinsonismOnset prior to age 40If PD, think genetic causesAssociated with unexplained liver

29、 diseaseWilsons DiseaseSudden onset of parkinsonismVascular ParkinsonismPhysical examDementia as first symptomLewy body dementiaProminent orthostasisMSAEarly dysarthriaMSALack of tremorVarious Parkinsons-plus syndromesHigh frequency(8-10Hz) symmetric tremorEssential tremorHistory and examination fea

30、tures that would question 怀疑 the diagnosis of idiopathic 特发性 Parkinsons Disease症状/体征考虑选择的诊断病史首发症状进行性核上性麻痹（PSP）神经松弛剂运用药源性帕金森症40岁前发生如果为帕金森症，考虑遗传因素与不明原因的肝脏疾病相关联威尔逊氏病突然发病血管性帕金森症体格检查首发痴呆症状路易体痴呆直立位显著多系统萎缩（MSA）早期构音障碍多系统萎缩（MSA）缺乏震颤各种帕金森叠加综合症高频率(8-10Hz) 对称性震颤特发性震颤Treatment of PDGeneral considerations 概论Sympt

31、om responsiveness 症状反应Bradykinesia, rigidity, and abnormal posture respond well early in the course of illness. In contrast 与此相反, cognitive 认知 symptoms, and autonomic dysfunction 自主神经功能障碍 respond poorly.Regular activity 常规活动Physical and mental activities.Slow increment of dose 缓慢增加剂量low initiation 开

32、始 and a slow increment of drug doseAge difference 年龄差异older patients (70 years) :dopamine replacement 多巴胺替代younger patients: dopamine receptor agonists.Treatment of PDAnticholinergic agents 抗胆碱能药Antiglutamatergic agents 抗谷氨酸药Dopaminergic agents 多巴胺能药: most effectiveNeuroprotective therapy 神经保护治疗Surg

33、ical treatment and deep brain stimulation 脑深层刺激(DBS)Treatment of PDDrug choicesAnticholinergic 抗胆碱能药: Trihexyphenidyl(苯海索，安坦) 1-2 mg, tid; Procyclidine（开马君，环丙啶）2.5mg tid gradually increased to 2030mg/d. Side effects include blurring 视物模糊, retention 尿储留, constipation 便秘. Avoid use in older patients a

34、s initiation therapy 起始治疗Antiglutamatergic 抗谷氨酸药: Amantadine(金刚烷胺) 0.1g tidL-dopaLD doseEquivalency, mgAvailable strength, mgInitial doseOther considerationsMadopa（美多巴） (Ldopa/benserazide苄丝肼)100100/25200/50200/500.5 tab tidTarget dose=3-6 100/25 tabs/dCarbidopa/ levodopa 卡比多巴/左旋多巴 IR25/100(Sinemet,信

35、尼麦)10010/10025/10025/1000.5 tab tidTarget dose=3-6 25/100 tabs/dCarbidopa/ levodopa CR50/20015025/10050/20050/2001 tab bid to tidIncreased bioavailability 生物利用度with foodCarbidopa/ levodopa/entacapone 恩他卡朋25/100/20012012.5/50/20025/100/20037.5/150/20025/100/2001 tab bid to tidDo not split tablet 分劈药片

36、Carbidopa/levodopa/phenylalanine 苯丙氨酸10010/100/3.425/100/3.425/250/825/100/3.40.5 tab tidDo not take concomitantly 同时 with MAOI Dopamine agonistsAvailable strength, mgInitial dosemgTarget doseAs monotherapy mg/dTarget doseAs adjunct to LD mg/dOther considerations 注意事项Non-ergot alkoloidsRopinirole(d2

37、+d3)罗匹尼罗0.25,0.5, 1,2,3,4,50.25 tid12-246-16Hepatic metabolism 肝脏代谢Pramipexole(d3)普拉克索0.125,0.25,1,1.50.125, tid1.5-4.50.375-3Renal metabolism 肾脏代谢Piribedil(d2+d3)吡贝地尔5050, qd150-250Ergot alkaloids 麦角碱Pergolide 倍高利特0.05,0.25,1.00.05 tid0.5-60.3-3Valvular heart disease 心瓣膜病bromocriptine溴隐亭2.5,5.01.25

38、Bid to tid7.5-153.75-7.5Pulmonary 肺 and retroperitoneal fibrosis 腹膜后纤维化Levodopa 左旋多巴 induced motor complications 运动并发症In 90% of patients with PD received L-dopa 5 to 10 years.Two forms: Motor fluctuation 运动波动Dyskinesia 运动障碍: (coreiform（？）, athetotic 手足徐动症)Treatment: Chronic release formulation 缓释配方(

39、CR), DA receptor agonistLevodopa induced motor complicationsMotor fluctuation 运动波动End of dose (wearing off 药效渐消)Unpredicted motor fluctuation(“on-off ”)Dose failures 剂量时效 and “delayed-on”Dyskinesia 运动障碍: (coreiform, athetotic)Peak-dose dyskinesia 峰期不自主舞蹈样运动di-phasic dyskinesia 双相障碍: dyskinesia-impro

40、vement-dyskinesiaEarly AM dystonia 肌张力障碍 (cramp in the leg 腿部抽搐)Levodopa complications-summaryComplicationsManagement1)Motor fluctuationEnd of dose (wearing off)Increase drug taking time, shift to CR formulation 缓释配方, add adjunct 附加 agents (entacapone 恩他卡朋, amantadine 金刚烷胺, etc.)Unpredicted motor fl

41、uctuation(“on-off ”)Difficult. CR formulation, add dopamine agonistDose failures and “delayed-on”Caffeine 咖啡因 may be beneficial 2) Dyskinesia: (coreiform, athetotic)Peak-dose dyskinesiaReduce single dose, dopamine agonist at later stageDi-phasic dyskinesia:dyskinesia-improvement-dyskinesiaDifficult.

42、 Increase dosage 剂量 or time, add DA agonistEarly AM dystonia (cramp in the leg)CR formulationNeuroprotective therapy 神经保护性治疗Nonsteroidal anti-inflammatory agents 非甾体类抗炎药 or estrogen 雌激素. Selegiline 司来吉兰(MAOI, 2.55mg, qd to bid). Large dose of CoQ10 (1200mg/d). Others acetyl-levo-carnitine(乙酰左旋肉碱) an

43、d creatine monohydrate (一水肌酸).Surgical treatment and deep brain stimulation 脑深部刺激 (DBS)Surgical treatmentPallidotomy 苍白球毁损术, thalamotomy 丘脑切开术. No better than antiparkinson medication 抗帕金森药物. Postural instability and falling 姿态不稳或摔倒, hypophonia 发音过弱, micrographia 写字过小, drooling 流涎, and autonomic dys

44、function 自主神经功能障碍, are unlikely to benefit from surgery.Deep brain stimulation (DBS) offers impressive results in properly selected patients.Other treatment choicesNeurotransplantation 神经移植 is disappointing Direct infusion 输注 of GDNF (glial cell-derived growth factor 神经胶质细胞源性的神经营养因子) to the putamen

45、壳核 has been encouraging.Summary of PDFeatured by bradykinesia, tremor, rigidity, shuffling gait and flexed posture. Differential diagnosis :Secondary Parkinsonisms, Parkinsons-plus syndromes, Wilsons Disease and Essential Tremor.Motor complications: motor fluctuation and dyskinesiaDopamine replaceme

46、nt therapy can alleviate syndromes but cannot cureSummary of PD以运动徐缓、震颤、僵硬、曳行步态和弯曲姿势为特征。 鉴别诊断：继发性帕金森症、帕金森叠加综合症、威尔逊氏病和特发性震颤运动并发症：运动波动和运动障碍多巴胺替代疗法可以缓解症状但不能根治疾病Sydenhams Chorea 西登哈姆氏舞蹈病Most common cause of chorea in childrenTypical age is 8-9yrs with female preponderance 多数.4-8 weeks after GABHS pharyn

47、gitis 溶血性链球菌性喉炎.20 35% may have hemichorea 偏身舞蹈病.Hypotonia 肌张力减退, emotional lability 情绪不稳, ADHD 注意力不集中, tics 抽搐, OCD 强迫症 symptoms may accompany it.60-80%pts have cardiac involvement 牵连.Sydenhams chorea 西登哈姆氏舞蹈病Self limited disorder 自限性疾病 with remission 缓解 within 6-9 months.Recurrence 复发 is reported

48、in 20-50% of patientsInv: ASO titres 抗链球菌溶血素O滴度, throat culture 咽培养, cardiac examination 心脏检查.Treatment:Penicillin 青霉素 1014 days for streptococcus 链球菌 infection.Steroidal 甾体 or non-steroidal anti-inflammation agents 非甾体类抗炎药Sodium Valproate 丙戊酸钠, Carbamazepine 卡马西平, Pimozide 哌迷清.Rheumatic fever proph

49、ylaxis. 预防风湿热Hyperkinetic Disorder 过度活跃症Tourettes Syndrome 抽动秽语综合征Three stages:Only multiple tics 多发性抽动症(twitches 抽搐 of the face, limbs 四肢 or the whole body)Inarticulate cries 口齿不清的呼喊（？） are added to multiple ticsEmission of articulate words 表达吐词清晰的言语 with echolalia 模仿言语 repeating what others have said or done and coprolalia 秽语症 uttering of obscene words 发出淫秽的词语（骂脏话！） are added in this stageOnset is typically 2-15 years of ageDrugs that block dopamine (e.g., haloperidol 氟哌啶醇) ameliorate 改善 the disorderHyperkinetic Disorder 过度活