锥体外系疾病2-运动障碍性

锥体外系疾病（运动障碍性疾病）Extrapyramidal diseases ( movement disorders)神经病学教研室 Department of Neurology Zhijian Zhang,锥体外系疾病, 主要表现为随意运动调节功能障碍，肌力、Extrapyramidal diseases mainly impair the regulation of voluntary motor activity without,感觉及小脑功能不直接受影响。运动障碍疾病源于基底节功能紊乱。directly affecting strength, sensation, or cerebellar function. Movement disorders result from dysfunction of deep subcortical gray matter structures termed the basal ganglia.,解剖：Anatomy:基底节：尾状核、豆状核（壳核、苍白球）、屏状核和杏仁复合体。Basal ganglia: caudate nucleus, lentiform nucleus ( putamen, globus pallidus), claustrum and amygdaloid complex.,新纹状体：壳核、尾状核。Neostriatum: putamen, caudate.旧纹状体：苍白球Paleostiratum: globus pallidus古纹状体：杏仁复合体Archistriatum: amygdaloid complex,相关结构：红核、黑质、丘脑底核、中脑间质核、大脑皮质的4、6区。Dependency structure: red nucleus ( corpus rubrum), substantia nigra, mid brain interstitial nucleus, 4 and 6 regions of cerebral cortex,神经环路：Neuronal loops: 1.皮质-皮质环路：大脑皮质-尾状核、壳核-内侧苍白球-丘脑-大脑皮质1. Corticortical loop: cerebral cortex-caudate, putamen-the internal segment of the globus pallidus-thalamus-cerebral cortex,2 .黑质-纹状体环路：黑质与尾状核、壳核之间的往返联系纤维2. Nigrostriatal loop: connecting the substantia nigra, caudate and putamen,3. 纹状体-苍白球环路：尾状核、壳核-外侧苍白球-丘脑底核-内侧苍白球3. Striaropallidal loop: projects from the caudate and putamen to the external segment of the globus pallidus, then to the subthalamic nucleus, and finally to the internal segment of globus pallidus.,神经递质：乙酰胆碱（Ach）、多巴胺 (DA)、去甲肾上腺素 (NE)、5-羟色胺 (5-HT)、-氨基丁酸 (GABA) 、谷氨酸等。Neurotransmitter(NT): acetylcholine, dopamine, noradrenaline, 5- hydroxytryptamine(serotonin), gamma-aminobutyric acid, aminoglutaminic acid, etc.,临床分类：Clinical classification:1运动过多：震颤、肌张力障碍、舞蹈症、手足徐动症、抽搐1. hypercinesia: tremor, dysmyotonia, chorea, posthemiplegic chorea, tic2运动减少：帕金森病和帕金森综合征。2. hypokinesia: Parkinsons disease and Parkinsons syndrome,3. 其他疾病：共济失调、肝豆状核变性。3. Other diseases: ataxia, Kinnier-Wilson syndrome治疗原则：Therapeutic principle: 病因治疗、药物治疗、神经外科治疗、个体化原则。Etilogical treatment，drug treatment，neurosurgical therapy, individualized treatment,帕金森病 ( agitans paralysis; paralysis agitans; Parkinsons disease; PD),帕金森病又名震颤麻痹，是一种常见的中老人神经系统变性疾病，50岁以上Parkinsons disease, also named Paralysis agitans, is a kind of frequent nervous system,多见。发病率20/10万/年。患病率160/10万/年。70岁人群达120/10万/年。degenerative disease in middle and old age, it mostly occurs in the age of above 50. The attack rate is 20/100 thousand population per year, the morbidity rate is 160/100 thousand population per year, and is 120/100 thousand per year in the population of about 70 years old.,病因与病机：etiological factor and pathogenesis: 病因不明。发病可能与以下因素有关： etiology unknown. The factors bellow possibly relates the onset:,1. 年龄老化：主要发病为中老年人，但只是促发因素。Ageing: it mainly attacks aged people, but the ageing is only the precipitating factor.,2.环境因素：MPTP使ATP生成减少，自由基生成，氧化应激反应，导致多巴胺能神经元变性死亡。 Environmental factor: The MPTP reduces the generation of ATP, preciptitates the generation of free radical and increases the oxidative stress, which results in the degeneration and death of dopamine neurons.,3.遗传因素：10%-15%病人有家族史，多呈常染色体显性遗传。Hereditary factor: 10-15 percent patients have the family history, and most of them belong to autosomal dominant inheritance.,4. 其他：氧自由基、羟自由基、兴奋性氨基酸。目前认为是多因素作用的结果。Other factors: free radical, hydroxy radical, excitatory amino acids.Recently the occurence of this disease is considered as the effective result of multiple factors,病理与生化病理：Pathology and biochemical pathology:1. 病理： 含色素的神经元变性、缺失，尤以黑质致密部DA能神经元为著。出现路易小体,苍白小体。 1. pathology: The loss and degeneration of pigmentosus neurons, especial the dopamine neurons in the substantia nigra. The lewy bodies and pale bodies can be seen also.,该二小体尚可在老年痴呆、共济失调、毛细血管扩张症和哈-斯二氏病见到。 These two bodies also can be seen in senile dementia, ataxia, telangiectasia and Hallervoeden-spatz disease.,2.生化病理： PD 患者黑质-纹状体通路变性，纹状体DA含量显著降低（减少80%以上）， 2. biochemical pathology: Because the degeneration of substantia nigra- striatum pathway, the content of DA in striatum remarkably decrease (over 80 percent),造成Ach系统功能相对亢进，导致基底节输出过多，丘脑-皮质反馈活动受到过度抑制， the acetylcholine system exerts a excitatory effect, which results in the over output of basal ganglia, the inhibition of the feed backing activity of thalamus opticus-cortex,其对皮质的易化作用受到削弱，因此产生肌张力增高、动作减少等运动症状。 and the impairment of facilitation effect to cortex, so the movement disorder symptoms appear, such as hypermyotonia, and reduction of movement,临床表现：Clinical manifestation:1.大部分60岁以后发病。1. symptoms occur mostly in the age of 60, or older.2.起病隐袭，缓慢发展，逐渐加剧。2. insidious onset, slow development, gradual aggravation,3.主要症状为静止性震颤、肌张力增高、运动迟缓等。首发症状：60-70%震颤，12%步行障碍，10%肌强直，10%运动迟缓。 3. present symptoms are static tremor, hypermyotonia, bradykinesia. First symptoms: tremor 60-70%, walking disorder 12%, myotonia 10%, bradykinesia10%.,65-70%从一侧上肢开始，渐波及同侧下肢，对侧上肢与下肢。 25-30%从一侧下肢开始。震颤: 静止性，紧张加剧，搓丸样动作These symptoms 65-70% start from one side upper extremity, gradually to same side lower extremity, then the opposite side extremities. Tremor: static, it increases with emotional stress, the fingers appear the pill-rolling- like action.,肌强直: 铅管样，齿轮样强直。路标现象。Rigidity: lead pipe-like, cogwheel rigidity. A road sign phenomenon. 运动障碍: 随意动作减少，面具脸，写字过小征。 motor disorder: voluntary action decreases, mask-like face, gradual smaller lettering,姿势步态异常： 慌张步态等。 Posture and gait irregularity: such as the festinating gait. 其他：Myerson征，流口水，多汗，脂颜，便秘，认知功能减退，抑郁，失眠， Others: Myerson syndrome, dribbling, colliquative sweating, lipoids face, constipation, hypofunction of cognition, depression and insomnia,静坐不能，疼痛，麻木，下肢浮肿，尿频，视幻觉等。Acathisia, pain, numbness, edema of lower limbs, frequent micturition, optical illusion.,研究进展 近来的进展认为帕金森病实质上是涉及全脑的渐进变性疾患，首先出现的是嗅觉的减退，在黑质的变性超过一定程度时出现帕金森症状，晚期出现抑郁、精神异常及痴呆等全脑功能的衰退。,辅助检查：Auxiliary examination1.生化检测：高效液相色谱示脑脊液与尿液中高香草酸、5-羟吲哚乙酸降低。1. biochemical detection: high performance liquid chromatogram shows increased homovanillic acid (HVA) and decreased 5-hydroxyindole acetic acid in cerebral spinal fluid and urine.,2.基因检测：少数家族性患者有基因突变。2. genic detection: gene mutations were found in a few familial patients.,3.功能显象：PET 与SPECT可发现患者脑内 DAT功能显著降低，且可早期发现， D2型DA 受体活性 3. Functional image: with PET and SPECT method, the DAT function in brain was detected to be significantly decreased in patients in early stage, the activity of D2 type receptor was,在疾病早期超敏，后期降低，以及DA递质合成减少。对PD的诊断与监测均有价值。 supersensitive in early stage, then decreased with the decreased synthesis of DA transmitter. This phenomenon is valuable for the diagnosis and monitoring of PD.,诊断：Diagnosis根据年龄、临床表现、病程发展。According to age, clinical manifestation, course of disease.,鉴别诊断： Differential diagnosis1.继发性PD：均有明显的病因可寻。1. Secondary PD: usually there are evident etiological factors（1）脑炎后帕金森综合征：甲型脑炎后，罕见。乙型脑炎、爱滋病。 (1) Postencephalitic parkinsonism: post- encephalitis A, hardly seen. encephalitis B, AIDS.,（2） 药物或中毒性帕金森综合征：神经安定剂（酚噻嗪类，丁酰苯类）、利血平、灭吐灵、甲基多巴、锂、氟桂嗪、 (2) medical or toxical parkinsonism: neuroleptic (phenothiazines, butyrophenones ), reserpine, paspertin, methyldopa, lithium (Li), flunarizine,脑益嗪。MPTP、锰、二硫化碳，一氧化碳中毒后遗症等。 cinnarizine. The sequela of MPTP, manganese( Mn), carbon bisulfide, carbon monoxide poisoning.,（3） 动脉硬化性帕金森综合征：病史、锥体束征、高血压等可资鉴别。(3) arteriosclerosis parkinsonism: the differentiation depends on the medical record, pyramid sign, and hypertension.（4） 外伤性：病史可鉴。(4) Traumatic parkinsonism: according to the medical history.,2.伴发帕金森表现的其他神经变性疾病（帕金森迭加综合征）：The other neurodegenerative diseases accompanying parkinsonism (parkinsonism plus )（1）进行性核上性麻痹：垂直凝视不能，假性球麻痹，锥体束征，震颤不明显，对多巴反应差。 (1)Progressive supranuclear palsy: unable vertical steady fixation, supranuclear paralysis, pyramid sign, mild tremor, poor dopa reaction.,（2）多系统萎缩：(2) multiple system atrophy (MSA)*纹状体黑质变性：病理征、晕厥。striatonigral degeneration: pathological sign, faint*Shy-Drager综合征：直立性低血压（差距40以上），性功能障碍，晕厥为主。Shy-Drager symptom： postural hypotension（difference over 40 mmHg ）, sexual disturbance, faint.,*橄榄脑桥小脑萎缩：小脑症状、锥体束征、脊髓症状。影象学可提供证据。Olive pons cerebellar atrophy: cerebellar symptom, pyramid sign, cord symptom.Evidences can be found with imageology(3) 帕金森综合征-痴呆-ALS复合体：Parkinsons syndrome-dementia-ALS(amyotrophic lateralizing sclerosis) complex,(4) 皮质基底节变性：额顶叶限局性萎缩、气球样皮质细胞肥大、黑质色素脱失和 corticobasal degeneration（CBD）：fronto-parietal lobes focal atrophy; balloon-like cortic cells hypertrophy, pigment loss in substantia nigra and,广泛的神经元丧失。可有肢体失用症，多巴类药及其激动剂有效。 General loss of neurons. There may be limbs parectropia. Medication such as dopa alike and dopa- excitomotor will be effective,（5）偏侧萎缩/偏侧帕金森综合征：病侧出现症状，同侧常有轻度萎缩。左旋多巴有效。 Hemiatrophy/hemiparkinsonism: hemilatera symptom and mild atrophy. Levodopa is effective.,3.遗传性帕金森综合征3. Heritage parkinsonism（1）常染色体显性路易体病：早期的痴呆、幻觉、肌阵挛、步态障碍，对左旋多巴反应差。 (1) Autosomal dominant lewy body disease: early dementia, illusion, myoclonus, gait disorder, poor reaction to levodopa.,（2） 肝豆状核变性：年龄小、肝损、角膜K-F环，血清铜、铜蓝蛋白、铜氧化酶活性降低，尿铜增加。 (2) Kinnier-Wilson syndrome: young, liver injured, cornea K-F sign. serum copper and copper-protein are decreased, and the activity of copper oxidase is decreased also. Urine copper is increased.,（3)亨廷顿舞蹈病：家族史、痴呆、遗传学检查 (3) Humtingtons chorea: family history, dementia, test of genetics4. 抑郁症：不具有肌强直与运动迟缓，抗抑郁制剂有效。4. Depressive disorder: without myotonia and bradykinesia, anti-depressive medication is effective,5特发性震颤：震颤以姿势性与运动性，年龄早，饮酒或用心得安可缓解。无肌强直与运动迟缓。1/3有家族史。5. Essential tremor: posture and motility tremor, young, relieving after drink or administrating propranolol, without myotonia and bradykinesia. 1/3 have family history.,治疗：treatment:目标：减轻症状、延缓进程、提高生存质 量。Goal: relieving symptom, postponing process, enhancing living quality方法：依个体情况选择治疗（年龄、病情、药物反应等）Approach: The choice of therapies depends on the individual condition( age, state of illness, and the reaction to medication),1 神经保护治疗1. neuro-protection treatment （1） 单胺氧化酶抑制剂：B型单胺氧化酶抑制剂应用较广。常用丙炔苯丙胺（司来吉兰），每次5毫克，1-2次/天，晨服。不良反应：兴奋、失眠、幻觉、妄想和胃肠不适。 Monoamine oxidase inhibitor( MAOI): MAO-B is generally used. Selegiline frequently used, 5mg, 1-2 time per day morning. adverse effect:Exciting, insomnia, illusion, delusion and upset gastro-intestinal,（2） 其他：抗组胺药、神经营养因子、免疫调节剂、抗氧化剂、自由基清除剂等。 Others: antihistamine drug, neurotrophic factor, immunomodulator, antioxidant, free radical scavenger,2 非多巴胺能药物2. Non-dopaminergic drugs （1） 抗胆碱能药物：安坦：1-2毫克，每日3次。有胆碱能副作用，青光眼与前列腺肥大禁用。 Anticholinergic agents: antan, 1-2mg, Tid. Side effect: cholinergic effect, the uses in glaucoma and prostatic hypertrophy are forbidden,（2） 金刚烷胺：促进DA合成与释放，减少DA再吸收，早期患者可与安坦合用或单用。副作用：浮肿、不宁。肾功能不全、癫痫、溃疡、肝病慎用。哺乳期妇女禁用。0.1 2次/天Amantadine: facilitating the synthesis and releasing of DA, reducing the resorption of DA, it can be used in the early stage of disease combined antan or not. Side effect: swollen, restless. Cautious in renal inadequacy, epilepsy, ulcer and liver disease. Women in lactation are forbidden.,（3）其他：抗抑郁药治疗抑郁症，-受体阻滞剂治疗姿势性震颤，氯硝基安定治疗痛性强直和构音困难，氯氮平治疗幻觉等精神症状。 Others: antidepressant for depression, - acceptor blocker for postural tremor, clonazepam for painful stiffness and dyslalia, clozapine for psychiatric symptom, such as illusion,3 多巴胺能药物3. Dopaminergic drugs1）左旋多巴及复方左旋多巴：美多巴（加 卞丝肼，4：1），心宁美（信尼麦，加甲基多巴）。levodopa and benserazide : madopar (plus benserazide), sinemet(plus methyldopa)用药时机：年老患者可早期选用。Administration opportunity: aged patients may be used in early stage of disease,用药方法：由小到大Administration method: the dosage increases gradually副作用：周围性为恶心、低血压，心律失常。中枢性为症状波动、运动障碍、精神症状等。 Side effect: peripheral side effects: nausea, hypotension, arrhythmia. Central side effect: fluctuated symptom, motor disorder, psychiatric symptom, etc.,禁用：前列腺肥大、窄角型青光眼、严重肝肾功能不全。Forbidden: prostatic hypertrophy, narrow angle glaucoma, severe liver and renalInadequacy.长期及大剂量使用可出现：long-term and large dosage will cause:,*症状波动：因药物作用时间缩短和血药浓度不稳定，出现剂末运动不能和双向运动障碍。 fluctuated symptom: because of the reduction of drug reaction time, and the astable drug concentration in blood, the end of dose akinesis and bidirection motor disorder appear.,开-关（on-off）现象。低张力冻结现象与药物慢性中毒和病情加重有关，改变用药途径、方法、剂型及阿扑吗啡有时可缓解症状。 on-off phenomenon. low tension freezing phenomenon is related to chronic intoxication and the aggravated disease. Change in the way of administration, dose, dosage form and giving apomorphine some times will relieve these symptoms.,*异动症：舞蹈样，手足徐动样或肌阵挛性运动异常，可波及局部或全身。与纹状体受体的超敏感有关，减药或给泰必利有效。 Abnormal involuntary movement: dancing-like, athetosis-like, or myoclonic abnormal movement involve local or all over the body. This phenomenon is related to the supersensitivity of receptor in striatum, reducing dose or giving tiapride will be effective.,2） DA受体激动剂：溴隐亭、培高利特（协良行,因为其有引起心脏瓣膜与肺纤维化的副作用，2008年我国停用，替代药品为森福罗，是新一代非麦角类多巴胺受体激动剂，化学名为普拉克索。 为非麦角碱类D2和D3受体激动剂 ）。DA receptor agonist: Bromocriptine, pergolide3）儿茶酚-氧位-甲基转移酶抑制剂：托卡朋等。Catechol-o- methyltransferases: Tolcapone, etc.,4 外科治疗：4. Surgical therapy:1）重建性手术：体内移植多巴胺能神经元。正在研究之中。 Reconstructive procedure: dopaminergic neuron transplantation in vivo.2）破坏性手术：苍白球毁损术、丘脑毁损术、深部脑刺激Destructive procedure: globus pallidus lesion, thalamus lesion, deep brain stimulation,预后：prognosis:慢性发展（也有快发展的），无根治方法，多死于并发症（肺炎、骨折）。Usually this disease aggravates slowly( but there are fast develop case), can not be cured completely, most die of complication(pneumonia, bone fracture),小舞蹈病 chorea minor,小舞蹈病又称风湿性舞蹈病，Sydenham舞蹈病, 是风湿热在神经系统的表现。Chorea minor also named rheumatic chorea, sydenham chorea, it is the manifestation of rheumatic fever in nervous system.,病因及病机Etiological factor and pathogenesis与A族溶血性链球菌感染有关。患者血清中可查到抗神经元抗体。Onset is related to the A group hemolytic streptococcal infection, the anti-neuron antibody can be found in the patients serum.,病理pathology黑质、纹状体、丘脑底部、小脑齿状核、大脑皮质可逆性炎症性改变。90%尸解可发现有风湿性心脏病的证据。Reversible inflammatory changes appear in substantia nigra, striatum,subthalamus, dentate body of cerebellum, cortex. 90% necroscopy can find evidences for rheumatic heart disease.,临床表现Clinical manifestationa) 约80%患者为5-15岁，女多于男，约1.5：1到3.2：1。About 80% patients are around the age of 5-15 years, female more than male, about 1.5: 1 to 3.2: 1.,b)多为亚急性或隐袭发病。1/3病例出现舞蹈症状前2-6个月或更长时间内有溶血性链球菌感染史。 most are subacute or smoldering onset. 1/3 patients had the history ofhemolytic streptococcal infection 2-6 months or longer before those chorea symptoms appear.,c)早期精神症状：激动、易激惹、注意力散漫、学业退步，行为改变。 Psychiatric symptom in early stage: agitating, irritable, difficult to focus attention, school work retrogression, behavior change,d) 早期运动症状：动作不协调、字迹歪斜、持物不稳、行走摇晃。 Motor symptoms in early stage: action out of step, askew handwriting, unsteadiness in hold, shaky walking.,a)舞蹈样动作：常双侧，约20%为偏侧或局限。面部最明显，挤眉弄眼、噘嘴、吐舌、鬼脸。 Chorea-like action: usually bilateral, about 20% are one side or focal. Most in face, tapir mouth, tongue protrusion, grimace.,肢体出现极快的、不规则的、无目的的、不自主运动，变幻莫测。 Extremities appear fast, irregular, purposeless involuntary movement in an unpredictable way.,上肢比下肢明显，情绪紧张时加重，安静减轻，睡时消失。常在2-4周内加重，3-6个月缓解。Upper limb is more obvious than lower limb, aggravation in emotional stress, relief at rest, disappearing at bedtime. Usually aggravating during 2-4 weeks, relieving after 3-6 months.,b)肌张力及肌力减退：肌张力及肌力的减退使腕、掌、指关节过伸，称舞蹈病手姿。 Muscular tension and muscle strength decrease: hyperextension appear at the joints of wrist, palm, and finger, called chorea gesture.,因手指的小幅舞动可在握手时感觉出患者的手时紧时松，称挤奶妇手法，或盈亏征。 Because the finger flexion-extension, examiner can find patients finger flexion-extension chorea resulting in the characteristic oscillating milkmaid grip, or wax-waning sign.,肌张力及肌力减退与舞蹈样动作、共济失调一起构成小舞蹈病三联征。 muscular tension and muscle strength decrease, chorea-like action, and ataxia constitute the chorea minor triad.,c)精神症状：躁动不安、精神错乱、幻觉、妄想，称躁狂性舞蹈病。Psychiatric symptom: restlessness, mental disorder, illusion, delusion, called chorea insaniens.,d)其他风湿病表现：发热、风湿性关节炎、风湿性心脏炎、皮下结节、血沉加快、抗“O”滴度增加。Othe rheumatic disorder features: fever, rheumatic arthritis, rheumatic heart disease, subcutaneous nodule, raised blood sedimentation, raised ASO titre .,辅助检查auxiliary examination1.血清学检查：白细胞增加、血沉增快、粘蛋白增多、C反应蛋白效价提高、抗“O”滴度增加。Serologic examination: raised leucocyte, raised blood sedimentation, raised mucoprotein, raised ASO titre .,2.咽拭子培养：A组溶血性链球菌。Pharynx swab culture: A group hemolytic streptococcus.3.脑电图：无特异性。轻度弥漫性慢波活动。EEG(electroencephalogram): non-specificity,4.影象学：CT可见尾状核区低密度灶及水肿，MRI可见尾状核、壳核、苍白球增大，T2高信号。PET可见纹状体呈高代谢改变，可恢复。Screenage: low density focus and edema can be seen in caudate nucleus area with CT scan, The swelling and T2 high signal can be seen in caudate, putamen, and globus pallidus with MRI. The Hypermetabolism in striatum can be seen with PET, and it is retrievable.,5.肌电图：持续大于100毫秒的电活动发放。EMG: persistent electric activity releasing over 100 milliscond,诊断及鉴别诊断Diagnosis and differential diagnosis诊断依据年龄、特征性舞蹈病三联征、风湿病的其他表现。 According to age, marked chorea triad and the other features of rheumatic disease,鉴别诊断Differential diagnosis1.习惯性痉挛：多见在儿童，特点是刻板的动作重复，常局限在同一肌肉或肌群；无肌力、肌张力及共济运动的异常。 Habit spasm: mainly in children, stereotyped repeating movement, usually is limited in same m