神經(jīng)病學課件：Movement Disorders

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. Subs

2、tatia nigra-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 postur

3、eCo-ordinates 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 movemen

4、t disordersAkinesia-rigidParkinsonism-brdykinesiaDyskinesiaChoreaDystoniaTremorticsChorea Chorea is a rapid, purposeless, irregular, jerky movement that seems to flow randomly from one part of the body to another.Dystonia and AthetosisDystonia is a syndrome of sustained muscle contractions causing a

5、bnormal postures or twisting and repetitive movements.Athetotic movements are complex, wormlike, irregular, non propositional and predominate over postural anomalies and on the distal parts of limbs and face.ticsTwitches of the face, limbs or the whole body.Can be reproduced voluntarilyPatient has p

6、artial controlDo not interfere with voluntary activityMay persist in sleepCommon forms of movement disordersParkinsons DiseaseWilsons Disease (Hepatolenticular degeneration)Essential tremorSydenhams Chorea (Rheumatic chorea)Tourettes SyndromeParkinsons Disease（PD）Is also called paralysis agitansIs c

7、haracterized by a neuronal accumulation of -synuclein and neuronal loss in SNPresents with bradykinesia, tremor, rigidity, shuffling gait, and flexed postureHistory of PDFirst described in 1817 by an English physician, James Parkinson, in “An Essay on the Shaking Palsy.”The famous French neurologist

8、, Charcot, further described the syndrome in the late 1800s.Epidemiology of PD1% of those 55 yearsRisk factors: ageing, positive family history, male gender, head injury, exposure to pesticides, consumption of well water, and rural living. Factors linked to reduced incidence: coffee drinking, smokin

9、g, nonsteroidal anti-inflammatory drugs, and estrogen.Dopamine pathways in human brainDopamine synthesisDA metabolismDA degradationLewy bodiesEtiopathogenic mechanismsMechanisms-summary Cell death may be caused by -synuclein aggregationproteosomal and lysosomal system dysfunction,reduced mitochondri

10、al activity. Excitotoxicity and inflammation are likely to play a relevant role in progressive neuronal degeneration.Clinical featuresMotor features Bradykinesia, tremor, rigidity, shuffling gait, and flexed postureNon-motor featuresDepression and anxiety, cognition, sleep disturbances, sensory, and

11、 autonomic dysfunctionsParkinsons Disease（PD）Motor features Bradykinesia. Slow in movement.micrographia (hypophonia)-soft speech“Masked face”Tremor at rest. 4-6Hz. “pill rolling”. The lips, tongue, and jaw may be involved but spares the head.Rigidity .“cogwheeling ” or “l(fā)ead-pipe”.Gait disturbance:

12、shuffling short steps. Festinating (hurried) gait.At later stage, freezing of gait (start hesitation).Non-motor featuresDepression and anxietyaffects 50% of patients, intrinsiccognitive impairment sleep disturbances sensory abnormalities and pain, loss of smell (anosmia)disturbances of autonomic fun

13、ctionDiagnosis5055 years, develops slowlyAt least two of the following: tremor at rest, rigidity, bradykinesia or gait disturbance.Is responsible to dopamineExclude other parkinsonisms secondary parkinsonisms Parkinson-plus syndromesDifferential diagnosisSecondary ParkinsonismParkinsons-plus syndrom

14、esParkinsonism with abnormal metabolisms of TAU (Taupathies) and -synuclein (-synucleinopathies)Wilsons Disease (Hepatolenticular degeneration)Essential tremor (ET)Secondary ParkinsonismVascular parkinsonismSeen in lacunar infarctionPoor response to L-dopaDrug-induced parkinsonism (DIP).Drug-induced

15、 parkinsonism (DIP)Is due to neuroleptics, some atypical antipsychosis, lithium carbonate, or antiemetic agents (especially metochlopromide). Less common: valproic acid, fluoxetine (antidepressant). Antihypertensive agents such as reserpine and alpha-methyldopa. Exposure to toxins such as CO, disulf

16、ide, 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 metabolisms of TAU (Taupathies) and -synuclein (-synucleinopathies)Wilsons Diseas

17、e (Hepatolenticular degeneration)Essential tremor (ET)Parkinsons-plus syndromesParkinsonism with abnormal metabolisms of TAU (Taupathies) Lewy body disease (dementia with Lewy bodies, DLB)Progressive supranuclear palsy (PSP)Corticobasal degeneration (CBD)Parkinsonism with abnormal metabolisms of -sy

18、nuclein (-synucleinopathies)Multiple system atrophy (MSA)Parkinsonism with abnormal metabolisms of TAU (Taupathies) Lewy body disease (dementia with Lewy bodies, DLB), Dementia with visual hallucinationsextremely sensitive to L-dopaProgressive supranuclear palsy (PSP)Early falls, supranuclear palsy

19、(both eyes, reflexic movement is intact)Corticobasal degeneration (CBD)alien limb, apraxiaParkinsonism with abnormal metabolisms of -synuclein (-synucleinopathies)Multiple system atrophy (MSA)parkinsonism with signs ofcerebellar, pyramidal tract autonomic dysfunction. Parkinson-plus syndromessummary

20、Share parkinsonian featuresLack of response to L-dopaSuggestive signsCortical dysfunctions : demetia, hallusination, apraxia, alien limbOcular signsEarly autonomic dysfunction and pyramidal tract signsDifferential diagnosisSecondary ParkinsonismParkinsons-plus syndromesParkinsonism with abnormal met

21、abolisms 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), the lentiform nucleiFeatures tremor,

22、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 tremor, bilateral Diagnosis

23、 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/signsAlternative diagnosis to

24、 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 symptomLewy body demen

25、tiaProminent 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 illness. In c

26、ontrast, 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.Treatme

27、nt 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（開馬君，環(huán)丙啶）2.5mg tid gradually increased to 20

28、30mg/d. Side effects include blurring, retention, constipation. Avoid use in older patients as initiation therapyAntiglutamatergic: Amantadine(金剛烷胺) 0.1g tidL-dopaLD doseEquivalency, mgAvailable strength, mgInitial doseOther considerationsMadopa（美多巴） (Ldopa/benserazide)100100/25200/50200/500.5 tab t

29、idTarget dose=3-6 100/25 tabs/dCarbidopa/ levodopa IR25/100(Sinemet,信尼麥)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 with foodCarbidopa/ levodopa/entacopone25/100/20012012.5/50/20025/100/20037.

30、5/150/20025/100/2001 tab bid to tidDo not split tabletCarbidopa/levodopa/phenylalanine10010/100/3.425/100/3.425/250/825/100/3.40.5 tab tidDo not take concomitantly with MAOI Dopamine agonistsAvailable strength, mgInitial dosemgTarget doseAs monotherapy mg/dTarget doseAs adjunct to LD mg/dOther consi

31、derationsNon-ergot alkoloidsRopinirole(d2+d3)羅匹尼羅0.25,0.5, 1,2,3,4,50.25 tid12-246-16Hepatic metabolismPramipexole(d3)普拉克索0.125,0.25,1,1.50.125, tid1.5-4.50.375-3Renal metabolismPiribedil(d2+d3)吡貝地爾5050, qd150-250Ergot alkoloidsPergolide0.05,0.25,1.00.05 tid0.5-60.3-3Valvular heart diseasebromocript

32、ine2.5,5.01.25Bid 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 formulation(CR), DA receptor agonistLevodo

33、pa 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 (cramp in the leg)Levodopa comp

34、lications-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 failures and “delayed-o

35、n”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 formulationNeuroprot

36、ective therapyNonsteroidal anti-inflammatory agents or estrogen. Selegiline (MAOI, 2.55mg, qd to bid). Large dose of CoQ10 (1200mg/d). Others acetyl-levo-carnitine(乙酰左旋肉堿) and creatine monohydrate (一水肌酸).Surgical treatment and deep brain stimulation (DBS)Surgical treatmentPallidotomy, thalamotomy. N

37、o 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 choicesNeurotransplantati

38、on is 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 a

39、nd Essential Tremor.Motor complications: motor fluctuation and dyskinesiaDopamine replacement therapy can alleviate syndromes but cannot cureSydenhams ChoreaMost common cause of chorea in childrenTypical age is 8-9yrs with female preponderance.4-8 weeks after GABHS pharyngitis.20 35% may have hemich

40、orea.Hypotonia, emotional lability, ADHD, tics, OCD symptoms may accompany it.60-80%pts have cardiac involvement.Sydenhams choreaSelf limited disorder with remission within 6-9 months.Recurrence is reported in 20-50% of patientsInv: ASO titres, throat culture, cardiac examination.Treatment:Penicilli

41、n 1014 days for streptococcus infection. Steroidal or non-steroidal anti-inflammation agentsSodium Valproate, Carbamazepine, Pimozide.Rheumatic fever prophylaxis.Hyperkinetic DisorderTourettes SyndromeThree stages:Only multiple tics (twitches of the face, limbs or the whole body)Inarticulate cries a

42、re added to multiple ticsEmission 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