1、Movement DisordersIntroduction to movement disorders“movement disorders”is often used with“extrapyramidal or basal ganglia(BG)”diseaseLesions of basal ganglia or pyramidal system are related to some,but not all,of the movement disordersPathways of extrapyramidal system1.Cortex-cortex2.Substatia nigr
2、a-striatum3.Striatum-globus pallidusMajor neurotransmitters Dopamine,acetylcholineGABAglutamatesome neuropeptides such as ENK and Substance PThey work synchronously to maintain normal excitation and inhibitions.Normal function of extrapyramidal systemRegulates muscle toneMaintains postureCo-ordinate
3、s voluntary movementBasal GangliaDamage to the basal ganglia:Produces either too much activation(hyperkinetic)responses=twitches,movements bursts,jarring,etc.ORProduces too little force(hypokinetic)=rigidityParkinsons diseasePink=inhibitionBlue=excitationCommon symptoms of movement disordersAkinesia
4、-rigidParkinsonism-brdykinesiaDyskinesiaChoreaDystoniaTremorticsChorea is a rapid,purposeless,irregular,jerky movement that seems to flow randomly from one part of the body to another.Dystonia is a syndrome of sustained muscle contractions causing abnormal postures or twisting and repetitive movemen
5、ts.Athetotic movements are complex,wormlike,irregular,non propositional and predominate over postural anomalies and on the distal parts of limbs and face.Common forms of movement disordersParkinsons DiseaseWilsons Disease(Hepatolenticular degeneration)Essential tremorSydenhams Chorea(Rheumatic chore
6、a)Tourettes SyndromeParkinsons Disease（PD）Is also called paralysis agitansIs characterized by a neuronal accumulation of-synuclein and neuronal loss in SNPresents with bradykinesia,tremor,rigidity,shuffling gait,and flexed postureEpidemiology of PD1%of those 55 yearsRisk factors:ageing,positive fami
7、ly history,male gender,head injury,exposure to pesticides,consumption of well water,and rural living.Factors linked to reduced incidence:coffee drinking,smoking,nonsteroidal anti-inflammatory drugs,and estrogen.Dopamine pathways in human brainDA metabolismDA degradationLewy bodiesEtiopathogenic mech
8、anismsMechanisms-summary Cell death may be caused by-synuclein aggregationproteosomal and lysosomal system dysfunction,reduced mitochondrial activity.Excitotoxicity and inflammation are likely to play a relevant role in progressive neuronal degeneration.Clinical featuresMotor features Bradykinesia,t
9、remor,rigidity,shuffling gait,and flexed postureNon-motor featuresDepression and anxiety,cognition,sleep disturbances,sensory,and autonomic dysfunctionsParkinsons Disease（PD）Motor features Bradykinesia.Slow in movement.micrographia(hypophonia)-soft speech“Masked face”Tremor at rest.4-6Hz.“pill rolli
10、ng”.The lips,tongue,and jaw may be involved but spares the head.Rigidity.“cogwheeling”or“lead-pipe”.Gait disturbance:shuffling short steps.Festinating(hurried)gait.At later stage,freezing of gait(start hesitation).Non-motor featuresDepression and anxietyaffects 50%of patients,intrinsiccognitive impa
11、irment sleep disturbances sensory abnormalities and pain,loss of smell(anosmia)disturbances of autonomic functionDiagnosis5055 years,develops slowlyAt least two of the following:tremor at rest,rigidity,bradykinesia or gait disturbance.Is responsible to dopamineExclude other parkinsonisms secondary p
12、arkinsonisms Parkinson-plus syndromesDifferential diagnosisSecondary ParkinsonismParkinsons-plus syndromesParkinsonism with abnormal metabolisms of TAU(Taupathies)and-synuclein(-synucleinopathies)Wilsons Disease(Hepatolenticular degeneration)Essential tremor(ET)Secondary ParkinsonismVascular parkins
13、onismSeen in lacunar infarctionPoor response to L-dopaDrug-induced parkinsonism(DIP).Drug-induced parkinsonism(DIP)Is due to neuroleptics,some atypical antipsychosis,lithium carbonate,or antiemetic agents(especially metochlopromide).Less common:valproic acid,fluoxetine(antidepressant).Antihypertensi
14、ve 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,amantadine,and L-dopa.Differential diagnosisSecondary ParkinsonismParkinsons-plus syndromesParkinsonism with abnormal
15、metabolisms of-synuclein(-synucleinopathies)and TAU(Taupathies)Wilsons Disease(Hepatolenticular degeneration)Essential tremor(ET)Parkinsons-plus syndromesParkinsonism with abnormal metabolisms of-synuclein(-synucleinopathies)Multiple system atrophy(MSA)Lewy body disease(dementia with Lewy bodies,DLB
16、)Parkinsonism with abnormal metabolisms of TAU(Taupathies)Progressive supranuclear palsy(PSP)Corticobasal degeneration(CBD)Parkinsonism with abnormal metabolisms of-synuclein(-synucleinopathies)Multiple system atrophy(MSA)parkinsonism with signs ofCerebellar,pyramidal tract and autonomic dysfunction
17、.Lewy body disease(dementia with Lewy bodies,DLB),Dementia with visual hallucinationsextremely sensitive to L-dopaParkinsonism with abnormal metabolisms of TAU(Taupathies)Progressive supranuclear palsy(PSP)Early falls,supranuclear palsy(both eyes,reflexic movement is intact)Corticobasal degeneration
18、(CBD)alien limb,apraxiaParkinson-plus syndromessummaryShare parkinsonian featuresLack of response to L-dopaSuggestive signsCortical dysfunctions:demetia,hallusination,apraxia,alien limbOcular signsEarly autonomic dysfunction and pyramidal tract signsDifferential diagnosisSecondary ParkinsonismParkin
19、sons-plus syndromesParkinsonism with abnormal metabolisms of TAU(Taupathies)and-synuclein(-synucleinopathies)Wilsons Disease(Hepatolenticular degeneration)Essential tremor(ET)Wilsons Disease(Hepatolenticular Degeneration)Defect in the metabolism of copper(ceruloplasmin)affecting the liver(cirrhosis)
20、,the lentiform nucleiFeatures tremor,rigidity and choreiform movements.Corneal Kayser-Fleischer(K-F)ring.Low serum ceruloplasmin,elevated urinary excretion of copper.Treatment:Copper-chelating agent D-penicillaminCorneal Kayser-Fleischer(K-F)ringEssential tremor(ET)a 6-to 12 Hz postural and kinetic
21、tremor,bilateral Diagnosis can be made when the course is more than3 years.Treatment Propranolol(40 to 320mg/d)primidone(50 to 750 mg/d).Others:Benzodiazepines,gabapentin,topiramateHistory and examination features that would question the diagnosis of idiopathic Parkinsons DiseaseSymptoms/signsAltern
22、ative diagnosis to considerHistoryFalls as the first symptomPSPExposure to neurolepticsDrug-induced ParkinsonismOnset prior to age 40If PD,think genetic causesAssociated with unexplained liver diseaseWilsons DiseaseSudden onset of parkinsonismVascular ParkinsonismPhysical examDementia as first sympt
23、omLewy body dementiaProminent orthostasisMSAEarly dysarthriaMSALack of tremorVarious Parkinsons-plus syndromesHigh frequency(8-10Hz)symmetric tremorEssential tremorTreatment of PDGeneral considerationsSymptom responsivenessBrdykinesia,rigidity,and abnormal posture respond well early in the course of
24、 illness.In contrast,cognitive symptoms,and autonomic dysfunction respond poorly.Regular activityPhysical and mental activities.Slow increment of doselow initiation and a slow increment of drug doseAge differenceolder patients(70 years):dopamine replacementyounger patients:dopamine receptor agonists
25、.Treatment of PDAnticholinergic agentsAntiglutamatergic agentsDopaminergic agents:most effectiveNeuroprotective therapySurgical treatment and deep brain stimulation(DBS)Treatment of PDDrug choicesAnticholinergic:Trihexyphenidyl(苯海索，安坦)1-2 mg,tid;Procyclidine（开马君，环丙啶）2.5mg tid gradually increased to
26、2030mg/d.Side effects include blurring,retention,constipation.Avoid use in older patients as initiation therapyAntiglutamatergic:Amantadine(金刚烷胺)0.1g tidL-dopaLD doseEquivalency,mgA v a i l a b l e strength,mgInitial doseOther considerationsMadopa（美多巴）(Ldopa/benserazide)100100/25200/50200/500.5 tab
27、tidTarget dose=3-6 100/25 tabs/dCarbidopa/levodopa IR25/100(Sinemet,信尼麦)10010/10025/10025/1000.5 tab tidTarget dose=3-6 25/100 tabs/dCarbidopa/levodopa CR50/20015025/10050/20050/2001 tab bid to tidI n c r e a s e d bioavailability with foodC a r b i d o p a/levodopa/entacopone25/100/20012012.5/50/20
28、025/100/20037.5/150/20025/100/2001 tab bid to tidD o n o t s p l i t tabletCarbidopa/levodopa/phenylalanine10010/100/3.425/100/3.425/250/825/100/3.40.5 tab tidD o n o t t a k e concomitantly with MAOI Dopamine agonistsA v a i l a b l e strength,mgInitial dosemgTarget doseAs monotherapy mg/dTarget do
29、seAs adjunct to LD mg/dOther considerationsN o n-e r g o t alkoloidsRopinirole(d2+d3)罗匹尼罗0.2 5,0.5,1,2,3,4,50.25 tid12-246-16H e p a t i c metabolismPramipexole(d3)普拉克索0.125,0.25,1,1.50.125,tid1.5-4.50.375-3Renal metabolismPiribedil(d2+d3)吡贝地尔5050,qd150-250Ergot alkoloidsPergolide0.05,0.25,1.00.05 t
30、id0.5-60.3-3Valvular heart diseasebromocriptine2.5,5.01.25Bid to tid7.5-153.75-7.5Pulmonary and retroperitoneal fibrosisLevodopa induced motor complicationsIn 90%of patients with PD received L-dopa 5 to 10 years.Two forms:Motor fluctuationDyskinesia:(coreiform,athetotic)Treatment:Chronic release for
31、mulation(CR),DA receptor agonistLevodopa induced motor complicationsMotor fluctuationEnd of dose(wearing off)Unpredicted motor fluctuation(“on-off”)Dose failures and“delayed-on”Dyskinesia:(coreiform,athetotic)Peak-dose dyskinesiadi-phasic dyskinesia:dyskinesia-improvement-dyskinesiaEarly AM dystonia
32、(cramp in the leg)Levodopa complications-summaryComplicationsManagement1)Motor fluctuationEnd of dose(wearing off)Increase drug taking time,shift to CR formulation,add adjunct agents(entacopone,amantadine,etc.)Unpredicted motor fluctuation(“on-off”)Difficult.CR formulation,add dopamine agonistDose f
33、ailures and“delayed-on”Caffeine may be beneficial 2)Dyskinesia:(coreiform,athetotic)Peak-dose dyskinesiaReduce single dose,dopamine agonist at later stageDi-phasic dyskinesia:dyskinesia-improvement-dyskinesiaDifficult.Increase dosage or time,add DA agonistEarly AM dystonia(cramp in the leg)CR formul
34、ationNeuroprotective therapyNonsteroidal anti-inflammatory agents or estrogen.Selegiline(MAOI,2.55mg,qd to bid).Large dose of CoQ10(1200mg/d).Others acetyl-levo-carnitine(乙酰左旋肉碱)and creatine monohydrate(一水肌酸).Surgical treatment and deep brain stimulation (DBS)Surgical treatmentPallidotomy,thalamotom
35、y.No better than antiparkinson medication.Postural instability and falling,hypophonia,micrographia,drooling,and autonomic dysfunction,are unlikely to benefit from surgery.Deep brain stimulation(DBS)offers impressive results in properly selected patients.Other treatment choicesNeurotransplantation is
36、 disappointing Direct infusion of GDNF(glial cell-derived growth factor)to the putamen 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 T
37、remor.Motor complications:motor fluctuation and dyskinesiaDopamine replacement therapy can alleviate syndromes but cannot cureHyperkinetic DisorderTourettes SyndromeThree stages:1.Only multiple tics(twitches of the face,limbs or the whole body)2.Inarticulate cries are added to multiple tics3.Emissio
38、n of articulate words with echolalia repeating what others have said or done and coprolalia uttering of obscene words are added in this stageOnset is typically 2-15 years of ageDrugs that block dopamine(e.g.,haloperidol)ameliorate the disorderHyperkinetic DisorderTardive DyskinesiaOccurs in 20-40%of
39、 individuals who are long time(at least 3 months)users of conventional antipsychoticsConventional or classic antipsychotics(e.g.,haloperidol)block dopamine receptorsSymptoms include:ChoreaTicsAkathisia compulsive,hyperactive,and fidgeting movements of the legs(静坐不能)DystoniaPossible causes are supers
40、ensitivity of dopamine neurons after prolonged suppression Atypical antipsychotics are good at suppressing psychoses and they have fewer motor side effects Clinical correlations of basal ganglia lesionsC l i n i c a l syndromesM o s t c o m m o n locationDrugs that are beneficialA k i n e s i a-rigi
41、d syndromesParkinsonismS N c (l e s s o f t e n striatum,GP)Dopamine agonist or replacementDyskinesiaChoreaStriatum,especially c a u d a t e N,l e s s common subthalamic NGABAegic(benzodiazepines),anti-dopamine(tetrabenazine,heloperidol)BallismSubthalamic N(less often striatum)anti-dopamine(tetraben
42、azine,heloperidol)GABAergic(baclofen,clonazepam)DystoniaStriatum,especially putamen(less often thalamus GP,extra-BG sites)Anticholinergic,GABA-B agonist(baclofen)TremorVa r i a b l e,o f t e n outside BGAnticholinergic(anti-adrenergic or promidone for ET)TicsUnknown(ventral striatum?)Antipsychotics(typical or atypical)Further thinkingANY QUESTIONS?Thank You
