1、Movement Disorders 運(yùn)動(dòng)障礙Introduction to movement disorders 運(yùn)動(dòng)障礙簡介“movement disorders ” is often used with “extrapyramidal 錐體束外 or basal ganglia 基底神經(jīng)節(jié)(BG)” diseaseLesions 損傷 of basal ganglia or pyramidal system 錐體系統(tǒng) are related to some, but not all, of the movement disordersPathways of extrapyramidal

2、system 錐體外系系統(tǒng)通路1. Cortex 皮質(zhì)-cortex2. Substatia nigra 黑質(zhì)-striatum 紋狀體3. Striatum 紋狀體-globus pallidus 蒼白球Major neurotransmitters 主要神經(jīng)遞質(zhì)Dopamine 多巴胺Acetylcholine 乙酰膽堿GABA -氨基丁酸Glutamate 谷氨酸鹽some neuropeptides 神經(jīng)肽 such as ENK 腦啡肽 and Substance P P物質(zhì)They work synchronously 同步地 to maintain normal excitati

3、on and inhibitions. Normal function of extrapyramidal system 錐體外系系統(tǒng)的主要功能Regulates muscle tone 調(diào)節(jié)肌張力Maintains posture 維持姿態(tài)Co-ordinates voluntary movement 協(xié)調(diào)隨意運(yùn)動(dòng)Basal Ganglia 基底神經(jīng)節(jié)Damage to the basal ganglia:Produces either too much activation (hyperkinetic 運(yùn)動(dòng)機(jī)能亢進(jìn)) responses= twitches 抽搐, movements bu

4、rsts 運(yùn)動(dòng)爆發(fā), jarring 不協(xié)調(diào), etc.ORProduces too little force (hypokinetic 運(yùn)動(dòng)不足)=rigidity 僵硬Parkinsons diseasePink=inhibitionBlue=excitationCommon symptoms of movement disorders 運(yùn)動(dòng)障礙的常見癥狀A(yù)kinesia 運(yùn)動(dòng)不能-rigid 僵硬Parkinsonism-brdykinesia 運(yùn)動(dòng)徐緩Dyskinesia 運(yùn)動(dòng)障礙Chorea 舞蹈病Dystonia 肌張力障礙Tremor 震顫Tics 抽搐Chorea 舞蹈病 Ch

5、orea is a rapid 快速, purposeless 無目的, irregular 不規(guī)則, jerky 急動(dòng)movement that seems to flow randomly from one part of the body to another.Dystonia 肌張力障礙 and Athetosis 手足徐動(dòng)癥Dystonia is a syndrome of sustained muscle contractions 持續(xù)的肌肉收縮 causing abnormal postures 不正常姿勢 or twisting 扭轉(zhuǎn) and repetitive moveme

6、nts 重復(fù)動(dòng)作.Athetotic movements are complex, wormlike 蟲樣, irregular, non propositional 建議（？） and predominate 支配 over postural anomalies 姿勢異常 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 再現(xiàn) voluntarily 隨意志Patient has partial c

7、ontrol 部分控制Do not interfere 妨礙 with voluntary activity 隨意活動(dòng)May persist 存留 in sleepCommon forms of movement disorders 運(yùn)動(dòng)障礙的常見形式Parkinsons DiseaseWilsons Disease (Hepatolenticular degeneration 肝豆?fàn)詈俗冃?Essential tremor 特發(fā)性震顫Sydenhams Chorea 西登哈姆氏舞蹈病(Rheumatic chorea 風(fēng)濕性舞蹈病)Tourettes Syndrome 妥瑞癥Parkinso

8、ns Disease 帕金森氏?。≒D）Is also called paralysis agitans 震顫性麻痹Is characterized by a neuronal accumulation 神經(jīng)元累積 of -synuclein 突觸核蛋白 and neuronal loss in SN 黑質(zhì)Presents with bradykinesia 運(yùn)動(dòng)徐緩, tremor 震顫, rigidity 僵硬, shuffling gait 曳行步態(tài), and flexed posture 彎曲姿勢History of PDFirst described in 1817 by an En

9、glish physician, James Parkinson, in “An Essay on the Shaking Palsy 震顫麻痹.”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、農(nóng)藥, consumption of well water 井水, and rural 農(nóng)村 living. Factors linked to reduced incidence: coffee drinking, smoking, nonsteroidal anti-inflammatory drugs 非甾體類抗炎藥, and estrogen 雌激素.Dopamine pathways 多巴胺通路 in human brainDopamine synthesis 多巴胺合成DA metabolism 多巴胺代謝DA degradation 多巴胺降解Lewy bodies 路易小體Et

11、iopathogenic mechanisms 發(fā)病機(jī)理Mechanisms-summary 機(jī)制小結(jié) Cell death may be caused by -synuclein aggregation 聚集proteosomal 蛋白酶體 and lysosomal 溶酶體 system dysfunction,reduced mitochondrial 線粒體 activity. Excitotoxicity 興奮性中毒 and inflammation are likely to play a relevant 相關(guān)的 role in progressive neuronal dege

12、neration 進(jìn)展性神經(jīng)變性.Clinical features 臨床表現(xiàn)Motor features 運(yùn)動(dòng)性特征Bradykinesia, tremor, rigidity, shuffling gait, and flexed posture 運(yùn)動(dòng)徐緩、震顫、僵硬、曳行步態(tài)和彎曲姿勢Non-motor featuresDepression and anxiety, cognition, sleep disturbances, sensory, and autonomic dysfunctions 抑郁及焦慮，認(rèn)知、睡眠障礙，感覺和自主神經(jīng)障礙Parkinsons Disease 帕金森

13、氏病（PD）Motor features 運(yùn)動(dòng)性特點(diǎn)Bradykinesia 運(yùn)動(dòng)徐緩. Slow in movement.Micrographia 寫字過小 (hypophonia 發(fā)音過弱)-soft speech“Masked face 面具面容”Tremor 震顫 at rest. 4-6Hz. “pill rolling 搓丸樣”. The lips 唇, tongue 舌, and jaw 頜 may be involved but spares 備件（？） the head.Rigidity 僵硬 .“cogwheeling 齒輪 ” or “l(fā)ead-pipe 鉛管”.Gait

14、 disturbance 步態(tài)障礙: shuffling 曳步的 short steps. Festinating (hurried) gait 慌張步態(tài).At later stage, freezing of gait 步態(tài)凍結(jié) (start hesitation).Non-motor features 非運(yùn)動(dòng)特點(diǎn)Depression and anxiety 抑郁和焦慮affects 50% of patients, intrinsic 固有的（？）cognitive impairment 認(rèn)知障礙sleep disturbances 睡眠障礙sensory abnormalities 感覺

15、異常 and pain, loss of smell (anosmia 嗅覺缺失)disturbances of autonomic function 自主神經(jīng)功能失調(diào)Diagnosis 診斷5055 years, develops slowlyAt least two of the following: tremor at rest, rigidity, bradykinesia or gait disturbance.Is responsible to dopamineExclude other parkinsonismssecondary parkinsonisms 繼發(fā)性帕金森癥Par

16、kinson-plus syndromes 帕金森疊加綜合癥Differential diagnosis 鑒別診斷Secondary Parkinsonism 繼發(fā)性帕金森癥Parkinsons-plus syndromes 帕金森疊加綜合癥Parkinsonism with abnormal metabolisms 代謝 of TAU (Tauopathies TAU蛋白病) and -synuclein 突觸核蛋白(-synucleinopathies 突觸核蛋白病)Wilsons Disease (Hepatolenticular degeneration 肝豆?fàn)詈俗冃?Essentia

17、l tremor 特發(fā)性震顫(ET)Secondary Parkinsonism 繼發(fā)性帕金森癥Vascular parkinsonism 血管性帕金森綜合征Seen in lacunar infarction 腔隙性腦梗死Poor response to L-dopaDrug-induced parkinsonism 藥源性帕金森綜合征(DIP).Drug-induced parkinsonism 藥源性帕金森綜合征(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 藥源性帕金森綜合征(DIP)可由神經(jīng)松弛劑、一些非典型抗精神病藥物、碳酸鋰, or 止吐劑(特別是甲氧氯普胺)引起。 少見：丙戊酸, 氟西汀 (抗抑郁藥)。降壓藥如利血平和-甲基多巴。暴露于毒物如CO、二硫化物、氰化物和甲醇也能導(dǎo)致帕金森癥。DIP 可能適用抗膽堿能藥物、金剛烷胺和左旋多巴治療。Differential diagnosis 鑒別診斷Secondary Parkinsonism 繼發(fā)性帕金森癥Parkinsons-plus syndromes 帕金森疊加綜合癥Parkinsonism wit

20、h abnormal metabolisms 代謝 of TAU (Tauopathies TAU蛋白病) and -synuclein 突觸核蛋白(-synucleinopathies 突觸核蛋白病)Wilsons Disease (Hepatolenticular degeneration 肝豆?fàn)詈俗冃?Essential tremor 特發(fā)性震顫(ET)Parkinsons-plus syndromes 帕金森疊加綜合癥Parkinsonism with abnormal metabolisms of TAU (Taupathies) Lewy body 路易小體 disease (de

21、mentia 癡呆 with Lewy bodies, DLB)Progressive supranuclear palsy 進(jìn)行性核上性麻痹(PSP)Corticobasal degeneration 皮質(zhì)基底節(jié)變性(CBD)Parkinsonism with abnormal metabolisms of -synuclein (-synucleinopathies)Multiple system atrophy 多系統(tǒng)萎縮(MSA)Parkinsonism with abnormal metabolisms of TAU (Taupathies) Lewy body disease (d

22、ementia with Lewy bodies, DLB), Dementia with visual hallucinations 視幻覺extremely sensitive to L-dopaProgressive supranuclear palsy (PSP)Early falls 早發(fā), supranuclear palsy 核上性麻痹(both eyes, reflexic movement is intact 反射運(yùn)動(dòng)完整)Corticobasal degeneration (CBD)alien limb 異手癥, apraxia 失用癥Parkinsonism with a

23、bnormal metabolisms of -synuclein (-synucleinopathies)Multiple system atrophy 多系統(tǒng)萎縮 (MSA)parkinsonism with signs ofCerebellar 小腦Pyramidal tract 錐體束Autonomic dysfunction 自主神經(jīng)功能障礙Parkinson-plus syndromessummaryShare parkinsonian features 共有帕金森病特征Lack of response to L-dopaSuggestive signs 提示跡象Cortical

24、dysfunctions 大腦皮層功能紊亂: dementia 癡呆, hallucination 幻覺, apraxia 失用癥, alien limb 異手癥 Ocular signs 眼部癥狀Early autonomic dysfunction 自主神經(jīng)功能障礙 and pyramidal tract signs 錐體束跡象Differential diagnosis 鑒別診斷Secondary Parkinsonism 繼發(fā)性帕金森癥Parkinsons-plus syndromes 帕金森疊加綜合癥Parkinsonism with abnormal metabolisms 代謝

25、of TAU (Tauopathies TAU蛋白病) and -synuclein 突觸核蛋白(-synucleinopathies 突觸核蛋白病)Wilsons Disease (Hepatolenticular degeneration 肝豆?fàn)詈俗冃?Essential tremor 特發(fā)性震顫(ET)Wilsons Disease (Hepatolenticular Degeneration 肝豆?fàn)詈俗冃?Defect in the metabolism of copper 銅(ceruloplasmin 血漿銅藍(lán)蛋白) affecting the liver (cirrhosis 硬

26、化), the lentiform nuclei 豆?fàn)詈薋eatures tremor, rigidity and choreiform 舞蹈病樣 movements. Corneal 角膜 Kayser-Fleischer (K-F) ring. Low serum 血清 ceruloplasmin, elevated urinary excretion of copper 高尿銅排泄.Treatment: Copper-chelating agent 銅離子螯合劑 D-penicillamin 青霉胺Corneal Kayser-Fleischer (K-F) ringEssential

27、tremor 特發(fā)性震顫(ET)a 6- to 12 Hz postural 體位性 and kinetic 行動(dòng)性tremor, bilateral 雙邊Diagnosis can be made when the course 過程 is more than 3 years. Treatment 治療Propranolol 普萘洛爾 (40 to 320mg/d) Primidone 普里米酮 (50 to 750 mg/d). Others: Benzodiazepines 苯二氮卓類, gabapentin 加巴噴丁, topiramate 托吡酯History and examina

28、tion features that would question 懷疑 the diagnosis of idiopathic 特發(fā)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 懷疑 the diagnosis of idiopathic 特發(fā)性 Parkinsons Disease癥狀/體征考慮選擇的診斷病史首發(fā)癥狀進(jìn)行性核上性麻痹（PSP）神經(jīng)松弛劑運(yùn)用藥源性帕金森癥40歲前發(fā)生如果為帕金森癥，考慮遺傳因素與不明原因的肝臟疾病相關(guān)聯(lián)威爾遜氏病突然發(fā)病血管性帕金森癥體格檢查首發(fā)癡呆癥狀路易體癡呆直立位顯著多系統(tǒng)萎縮（MSA）早期構(gòu)音障礙多系統(tǒng)萎縮（MSA）缺乏震顫各種帕金森疊加綜合癥高頻率(8-10Hz) 對稱性震顫特發(fā)性震顫Treatment of PDGeneral considerations 概論Sympt

31、om responsiveness 癥狀反應(yīng)Bradykinesia, rigidity, and abnormal posture respond well early in the course of illness. In contrast 與此相反, cognitive 認(rèn)知 symptoms, and autonomic dysfunction 自主神經(jīng)功能障礙 respond poorly.Regular activity 常規(guī)活動(dòng)Physical and mental activities.Slow increment of dose 緩慢增加劑量low initiation 開

32、始 and a slow increment of drug doseAge difference 年齡差異older patients (70 years) :dopamine replacement 多巴胺替代younger patients: dopamine receptor agonists.Treatment of PDAnticholinergic agents 抗膽堿能藥Antiglutamatergic agents 抗谷氨酸藥Dopaminergic agents 多巴胺能藥: most effectiveNeuroprotective therapy 神經(jīng)保護(hù)治療Surg

33、ical treatment and deep brain stimulation 腦深層刺激(DBS)Treatment of PDDrug choicesAnticholinergic 抗膽堿能藥: Trihexyphenidyl(苯海索，安坦) 1-2 mg, tid; Procyclidine（開馬君，環(huán)丙啶）2.5mg tid gradually increased to 2030mg/d. Side effects include blurring 視物模糊, retention 尿儲(chǔ)留, constipation 便秘. Avoid use in older patients a

34、s initiation therapy 起始治療Antiglutamatergic 抗谷氨酸藥: Amantadine(金剛烷胺) 0.1g tidL-dopaLD doseEquivalency, mgAvailable strength, mgInitial doseOther considerationsMadopa（美多巴） (Ldopa/benserazide芐絲肼)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、尼麥)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 分劈藥片

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 同時(shí) with MAOI Dopamine agonistsAvailable strength, mgInitial dosemgTarget doseAs monotherapy mg/dTarget doseAs adjunct to LD mg/dOther considerations 注意事項(xiàng)Non-ergot alkoloidsRopinirole(d2

37、+d3)羅匹尼羅0.25,0.5, 1,2,3,4,50.25 tid12-246-16Hepatic metabolism 肝臟代謝Pramipexole(d3)普拉克索0.125,0.25,1,1.50.125, tid1.5-4.50.375-3Renal metabolism 腎臟代謝Piribedil(d2+d3)吡貝地爾5050, qd150-250Ergot alkaloids 麥角堿Pergolide 倍高利特0.05,0.25,1.00.05 tid0.5-60.3-3Valvular heart disease 心瓣膜病bromocriptine溴隱亭2.5,5.01.25

38、Bid to tid7.5-153.75-7.5Pulmonary 肺 and retroperitoneal fibrosis 腹膜后纖維化Levodopa 左旋多巴 induced motor complications 運(yùn)動(dòng)并發(fā)癥In 90% of patients with PD received L-dopa 5 to 10 years.Two forms: Motor fluctuation 運(yùn)動(dòng)波動(dòng)Dyskinesia 運(yùn)動(dòng)障礙: (coreiform（？）, athetotic 手足徐動(dòng)癥)Treatment: Chronic release formulation 緩釋配方(

39、CR), DA receptor agonistLevodopa induced motor complicationsMotor fluctuation 運(yùn)動(dòng)波動(dòng)End of dose (wearing off 藥效漸消)Unpredicted motor fluctuation(“on-off ”)Dose failures 劑量時(shí)效 and “delayed-on”Dyskinesia 運(yùn)動(dòng)障礙: (coreiform, athetotic)Peak-dose dyskinesia 峰期不自主舞蹈樣運(yùn)動(dòng)di-phasic dyskinesia 雙相障礙: dyskinesia-impro

40、vement-dyskinesiaEarly AM dystonia 肌張力障礙 (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 緩釋配方, add adjunct 附加 agents (entacapone 恩他卡朋, amantadine 金剛烷胺, 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 劑量 or time, add DA agonistEarly AM dystonia (cramp in the leg)CR formulationNeuroprotective therapy 神經(jīng)保護(hù)性治療Nonsteroidal anti-inflammatory agents 非甾體類抗炎藥 or estrogen 雌激素. Selegiline 司來吉蘭(MAOI, 2.55mg, qd to bid). Large dose of CoQ10 (1200mg/d). Others acetyl-levo-carnitine(乙酰左旋肉堿) an

43、d creatine monohydrate (一水肌酸).Surgical treatment and deep brain stimulation 腦深部刺激 (DBS)Surgical treatmentPallidotomy 蒼白球毀損術(shù), thalamotomy 丘腦切開術(shù). No better than antiparkinson medication 抗帕金森藥物. Postural instability and falling 姿態(tài)不穩(wěn)或摔倒, hypophonia 發(fā)音過弱, micrographia 寫字過小, drooling 流涎, and autonomic dys

44、function 自主神經(jīng)功能障礙, are unlikely to benefit from surgery.Deep brain stimulation (DBS) offers impressive results in properly selected patients.Other treatment choicesNeurotransplantation 神經(jīng)移植 is disappointing Direct infusion 輸注 of GDNF (glial cell-derived growth factor 神經(jīng)膠質(zhì)細(xì)胞源性的神經(jīng)營養(yǎng)因子) to the putamen

45、殼核 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以運(yùn)動(dòng)徐緩、震顫、僵硬、曳行步態(tài)和彎曲姿勢為特征。 鑒別診斷：繼發(fā)性帕金森癥、帕金森疊加綜合癥、威爾遜氏病和特發(fā)性震顫運(yùn)動(dòng)并發(fā)癥：運(yùn)動(dòng)波動(dòng)和運(yùn)動(dòng)障礙多巴胺替代療法可以緩解癥狀但不能根治疾病Sydenhams Chorea 西登哈姆氏舞蹈病Most common cause of chorea in childrenTypical age is 8-9yrs with female preponderance 多數(shù).4-8 weeks after GABHS pharyn

47、gitis 溶血性鏈球菌性喉炎.20 35% may have hemichorea 偏身舞蹈病.Hypotonia 肌張力減退, emotional lability 情緒不穩(wěn), ADHD 注意力不集中, tics 抽搐, OCD 強(qiáng)迫癥 symptoms may accompany it.60-80%pts have cardiac involvement 牽連.Sydenhams chorea 西登哈姆氏舞蹈病Self limited disorder 自限性疾病 with remission 緩解 within 6-9 months.Recurrence 復(fù)發(fā) is reported

48、in 20-50% of patientsInv: ASO titres 抗鏈球菌溶血素O滴度, throat culture 咽培養(yǎng), cardiac examination 心臟檢查.Treatment:Penicillin 青霉素 1014 days for streptococcus 鏈球菌 infection.Steroidal 甾體 or non-steroidal anti-inflammation agents 非甾體類抗炎藥Sodium Valproate 丙戊酸鈉, Carbamazepine 卡馬西平, Pimozide 哌迷清.Rheumatic fever proph

49、ylaxis. 預(yù)防風(fēng)濕熱Hyperkinetic Disorder 過度活躍癥Tourettes Syndrome 抽動(dòng)穢語綜合征Three stages:Only multiple tics 多發(fā)性抽動(dòng)癥(twitches 抽搐 of the face, limbs 四肢 or the whole body)Inarticulate cries 口齒不清的呼喊（？） are added to multiple ticsEmission of articulate words 表達(dá)吐詞清晰的言語 with echolalia 模仿言語 repeating what others have said or done and coprolalia 穢語癥 uttering of obscene words 發(fā)出淫穢的詞語（罵臟話?。?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 過度活