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1、Parkinsons Disease,Hannah H Florida,MD,Parkinsons Disease,Originally described by James Parkinson in 1817 and characterized as Shaking Palsy.Chronic slowly prog,neurodegenerative disease of the Basal Ganglia(BG).Basic path-lack of dopamine-producing cells in the BG.,Background,MC movement disorder 1
2、-2%65 y/o15%between ages of 65 and 74Cardinal signs/Classic Triad:tremor,bradykinesia,and rigidity.Dx:2/3Onset:insidious,unilateral progressing to B/L,Tremor,RestingMC presenting symptomDxtic but not requiredPill-rolling motion of hand at 3-5 HzSuppressed by activity,sleep,concentrationIntensified b
3、y stress,fatigueMost begin unilaterally,Bradykinesia,Required for dxMost disabling SxSlowness/paucity of movement/motionAffects facial muscle masked faceInability to change direction while walking/dif walking around obstacleCauses gait/postural abnormalityClumsy or weak limb maybe early sign,Rigidit
4、y,refers to an increase in resistance to passive movement about a joint;either osclillating(cogwheel)or smooth(lead pipe).Rigidity usually is tested by flexing and extending the patients relaxed wrist.CogwheelingRacheting through the ROM due to subtle tremor superimposed on the rigidityLead pipeSmoo
5、th resistance to passive movement that is independent of velocity(in contradistinction to spasticity,which is velocity dependent)Lead pipe tone can be made more obvious with voluntary movement or mental task in the c/l limb.,Postural Instability,4th cardinal sign,but it emerges late in the disease,u
6、sually after 8 years or moreImbalance and loss of righting reflexes.Its emergence is an important milestone,because it is poorly amenable to treatment and a common source of disability in late disease.Assumption by patient of a stooped-forward posture Presence,usually,of a festinating gait pattern(s
7、tumbling forward);however,retropulsion also can occur Decreased arm swing during ambulatory activity,History,Stiffness and slowed movements Tremor or shaking at rest Difficulty getting out of a chair or rolling over in bed Frequent falls or tripping Difficulty walking Memory loss Shifting forward of
8、 posture into a stoop Speech changes(eg,whispering,rapid speech)Smaller handwriting Slowness in performing activities of daily living(ADL)Sialorrhea Decreased sense of smell,Clinical Manifestation,Physical Exam,Painful dystonia,usually occurring in the early morning Rapid,monotonous,low-volume speec
9、h Hypokinetic dysarthriaDysphagia Masklike faciesDepression Can affect up to 50%of patients Suicide riskAkathisia(inability to sit still)Seborrheic dermatitis,usually of the face and scalp Olfactory dysfunction(hyposmia),whichmay be present prior to motor symptoms and often is not recognized by the
10、patient,Physical Exam,Autonomic Dysfunction Slowed enteric motility and constipation Urinary retention and incontinence Orthostatic hypotensionPatients may experience freezing when starting to walk(start-hesitation),during turning,or while crossing a threshold,such as going through a doorway,Physica
11、l Exam,Dementia generally occurs late in PD and affects 15-30%of patients.Short-term memory and visuospatial function may be impaired,but aphasia is not present.Cognitive dysfunction within a year of onset of motor features suggests a diagnosis of Lewy body disease,a disease closely related to PD an
12、d marked by the presence of significant cortical Lewy bodies.,Classification of Parkinsons Syndrome(PS)/Parkisonism,Idiopathic PD 85%of all PS casesDrug induced Parkinsonism 7-9%Parkinson-Plus SyndromeMSA(SDS,SND,OPCD)2.5%PSP 1.5%Vascular Parkinson syndrome-3%Toxin-induced rareRecurrent Head trauma-
13、rare,Idiopathic PD,D/O of the Basal Ganglia(BG)loss of dopamine producing cells in the substantia nigra(SN)and locus ceruleus(LC)Degeneration of nigrostriatal pathway(SN to corpus striatum)Sx manifest if+decreased dopamine content by 50%)Loss of inhibitory input to the cholinergic system excess exci
14、tatory outputImbalance of cholinergic input in the striatum,Basal Ganglia,The basal ganglia are a group of nuclei in the brain associated with motor functions.Nuclei:caudate,putamen substantia nigra,subthalamic,globus pallidum,Basal Ganglia,motor circuit modulates cortical output Signals from the ce
15、rebral cortex are processed through the basal ganglia-thalamocortical motor circuit and return to the same area via a feedback pathway.Output from the motor circuit is directed through the internal globus pallidus(GPi)and the substantia nigra pars reticulata(SNr).inhibitory output is directed to the
16、 thalamocortical pathway and suppresses movement.,Pathophysiology,Loss of pigmented dopaminergic neurons in the substantia nigraApproximately 60-80%of dopaminergic neurons are lost before the motor signs of PD emerge.The presence of Lewy bodies.,Lewy Bodies,Lewy bodies are concentric,eosinophilic,cy
17、toplasmic inclusions with peripheral halos and dense cores.Present within pigmented neurons of substantia nigra.Characteristic of PD but not pathognomonic,Epidemiology/M&M,Male to female ratio=3:2Prevalence=160/100,000Incidence=20/100,000 per year/general populationMorbidity=progressivemore rapid in
18、 MSA and PSPMortality=mean survival after onset 15 yrsPD survival MSA,PSPMC cause of death:pulmonary infection/aspiration,UTI,PE,Cx of falls/fractures,Etiology,UnknownTheoriesAccelerated agingGenetic susceptibilityEnvironmental FactorsOxidative stress,Accelerated Aging,Normal aging is associated wit
19、h clinical features that may resemble PD.Aging is associated with a decline of pigmented neurons in the substantia nigra and with decreased levels of striatal dopamine and dopa decarboxylase.Some authorities believe that PD may result from the effects of aging superimposed on an insult to the nigros
20、triatal system earlier in life.,Etiology Unclear,Genetic susceptibility-Twin studies inconclusiveGenetic factors play a greater role with early onset PDIncreased incidence of a family history PD observed(16%vs 4%of control)Accounts to 5%of PD cases.,Environmental factorsuse of pesticides,living in a
21、 rural environment consumption of well water exposure to herbicides proximity to industrial plants or quarries,Oxidative Stress,Free radical damage,resulting from dopamines oxidative metabolism,plays a role in the development or progression of PD.Dopamine oxidation via MAO result in formation of hyd
22、rogen peroxide.Hydrogen peroxide normally cleared by glutathione,Hydrogen peroxide reactions with ferrous ions,resulting in formation of hydroxyl radical.-hydroxyl radicals can cause damage to lipids,DNA,amino acidsPD associated with:increased dopamine turnover,decreased protective mechanisms(glutat
23、hione),increased iron(a pro-oxidation molecule),evidence of increased lipid peroxidation.,Etiology Unclear,Head Traumathe risk of developing Parkinsonism increases eightfold for patients who have had head trauma requiring hospitalization.11-fold for patients who have experienced severe head injury.D
24、ementia Pugilistica,Clues Suggesting Atypical Parkinsonism,Early onset of,or rapidly progressing dementiaRapidly progressive courseSupranuclear gaze palsyUMN signsCerebellar signs-dysmetria,ataxiaEarly urinary incontinenceEarly symptomatic postural hypotension,Parkinsons Syndrome,Parkinsons DiseaseS
25、urvival approximates US population when treatedSlow progressive onset of asymmetric bradykinesiaExcellent sustained Levodopa responseOnset with either classic pill-rolling tremor or rigidity,Parkinson-Plus syndromesShorter survival,more frequent complicationsEarly instabilityRapid disease progressio
26、nPoor response to LevodopaPyramidal and cerebellar signsEarly dysarthria,dysphasia,Parkinson-Plus Syndrome,PSPSupranuclear downgaze palsy,square wave jerksUpright posture/frequent fallsPseudobulbar emotionalityFurrowed brows/stareCorticobasal degenerationcognitive impairmentUnilat,coarse tremor,limb
27、 apraxia/limb dystonia-myoclonus/alien limb,Parkinson-Plus Syndrome,MSACerebellar ataxia,pyramidal weakness,autonomic failure,nocturnal stridorShy-Drager syndromeAutonomic insufficiency-orthostasis,impotenceStriatonigral degenerationTremor less prominentOlivopontocerebellar atrophyCerebellar ataxia,
28、dysarthria,Differential Diagnosis,Diffuse Lewy body diseaseEarly onset dementiaDelusions/hallucinationsAgitationAlzheimers diseaseDementia primary clinical sxRest tremor rare,Differential Diagnosis,Hereditary disorders associated with parkinsonismWilsons diseaseHuntingtons diseaseDentatorubro-pallid
29、oluysian atrophy(DRPLA)Machado-Joseph diseaseor spinal cebellar ataxia(SCA-3),Differential Diagnosis,Secondary ParkinsonismDrug inducedToxin inducedMetabolicStructural lesions(vascular parkisonism,etc)HydrocephalusInfections,Drug-Induced Parkinsonism,Antipsychotics/neurolepticsHaldol,chlorpromazine,
30、thioridazine,resperidone,olanzapineAntiemetics-MC drugs causing PSMetoclopramide,prochlorperazineDopamine depletorsmethyldopa,reserpine containing anti-HTNCombination drugs-know components Triavil(amitriptyline+perphenazine),Metabolic/Infectious Causes,MetabolicOften reversibleHypo or hyperthyroidis
31、mHypo or hyperparathyroidismLiver failureCentral pontine myelinolysis-rapid correction of hyponatremia,InfectiousPost-encephalitisCreutzfeld-Jakob disease-Infectious masses compressing SN/BG HIV,Toxin-Induced Parkinsonism,MPTPCyanideIronManganeseCarbon disulfide/monoxidePesticides/organic solventsLe
32、admethanol,Vascular Parkinsonism,Abrupt onset,usually unilateralStep-wise or no progressionOther signs-hemiparesis,aphasia,hyperreflexiaInfarcts on neuroimaging helpful in confirming dx,Hydrocephalus induced Parkinsonism,Can be communicating or obstructiveNPH-idiopathicClinical triadParkisonism/gait
33、 disorderUrinary/fecal incontinencedementia,PD vs Essential Tremor,ET should be tremor with no other signs of parkinsonismBoth can have kinetic and rest componentCogwheel rigidity can be found in ET,Treatment Options,Preventive=no definite one availableSymtomaticPharmacologicalSurgicalNon-motor mana
34、gementRestorative-experimental onlyTransplantationNeurotrophic factorsNonpharmacologic approachesPT/OT/ST,Drug Classes in PD,Dopaminergic agentsLevodopa(LD)Dopaminergic Agonists-Bromocriptine,Ropinirole,PramipexoleCOMT inhibitorsTolcapone,EntacaponeLD+Entacapone(Stalevo)MAO-B inhibitors-Selegiline(E
35、ldepryl)AnticholinergicsTrihexyphenidyl,Benztropine Antivirals-Amantadine,Medical Management Algorithm,Surgical Management,Candidates for ablative surgery or deep brain stimuation disabling medication-resistant tremor levodopa-responsive patients with medication-resistant disabling motor fluctuation
36、s and/or levodopa-induced dyskinesia.no significant cognitive impairment,mood or behavioral disturbancesNo other factors that may increase the risk of surgery.,Surgical Management,AblativeThalamotomyRelieves tremorsPallidotomyImproves cardinal signsSubthalamotomyImproves cardinal signsMotor fluctuat
37、ions,dyskinesia,Surgical Management,Ablative complicationsSpeech impairmentsCognitive deficitsDysphasia,Surgical Management,Deep drain stimulationThalamicDec.tremor in 90%of ptNo effect on cardinal signsPallidalImproves cardinal signs,dyskinesiaSubthalamicImproves cardinal signs,dyskinesia,motor flu
38、ctuations,Future Management,Neural transplantationdopamine-producing cells,ex.fetal nigral cells.Gene therapy,Managing Early Complications:Altered Mental States,Confusion,sedation,dizziness,hallucinations,delusionsReduce/eliminate CNS-active drugs of lesser priorityAnticholinergics-SedativesAmantadi
39、ne-Muscle relaxantHypnotics-Urinary antispasmodicsReduce dosage of DA,COMT inhibitor or LD,Late Complications,Motorfluctuations,dyskinesias,dystonia,freezing,fallsBehavioral/neuropsychological Depression,sleep d/o,psychosisAutonomicOH,hyperhidrosis,constipation,impotence,urinary incontinence or rete
40、ntion,Stages in Decline of response to Levodopa(LD),I:Pt not aware of effect of individual doseII:Mid afternoon loss of benefitIII:Loss of sleep benefit;early morning akinesia,possible foot dystoniaIV:regular“wearing off”q 4 hrs at first,shortens with timeV:Frequent wearing off,abrupt on-off,unpredi
41、ctable dose response,LD Response Fluctuations,Peripheral causes:delayed gastric emptyingdietary proteinshort plasma half-lifeCentral causes:pulsating delivery to striatal receptorsimpaired storage capacityalteration of DA receptor,Off-Period Dystonia,Appears when LD dose is low esp in early AMw/or w
42、/o parkinsonismDose adjustments,add ons:More frequent LD dosing to avoid low plasma levelsAdd DA,COMT inhibitor,MAO-B inhibitor,Wearing Off,Regular and predictable decline in response 2-4 hrs after LD doseMost common motor fluctuationDose adjustment,ad-ons:Change to LD-CR,or increase LD freqReduce L
43、D,add DA or COMT inhibitor,On-off Response,Sudden and unpredictable off periods unrelated to dosing scheduleOne of the hardest features to manageDose adjustments,add-ins:Reduce LD,add DA,Freezing and Falls,Freezing motoric block;at initiation of gait,turning,narrow spacesuse auditory(marching steps
44、to the beat of a metronome),visual,proprioceptive cues(mental rehearsal and imaging)FallsPhysical therapy evaluationCane,scooter,wheelchair may be necessary,Cognitive Assessment,Memory difficulties:11-29%of PD patientsBenign forgetfulnessDeliriumAlzheimers diseaseOther dementiasEvaluationBrain imagi
45、ngLumbar punctureEEGBlood work for thyroid profile,vitamin B12,serology,chemistry panel,Psychosis,FeaturesVivid dreams/nightmares,disorientation,hallucinations,delusional thoughtSimplify medical regimenStop unnecessary non-PD medsStop:anticholinergic drugs,amantadine,selegiline,dopamine agonists,COM
46、T inhibitorsChange from CR to standard carbidopa/levodopaTry atypical antipsychotic agentsTry low-potency traditional antipsychotic agents,Depression,Reported in 30-90%of PD patientsDifficult to discern from vegetative symptomsDepression may be related to a deficit in serotonergic neurotransmission
47、or to decreased cortical levels of norepinephrine and dopamine.Usually responds quickly to medicationsSelective serotonin re-uptake inhibitorsTricyclic AntidepressantsIf ECT needed,will transiently improve PD symptoms,Anxiety/Restlessness,Primary anxiety disorder:treat with benzodiazepinesAssociated
48、 with“off-periods”or low-levopoda levels:adjust levopoda dosingRestless Leg Syndrome:benzodiazepines,narcotics,levopoda,dopamine agonists,Sleep Disorders,Insomnia careful historydifficulty with sleep initiation:tricyclic agents,benzodiazepines,diphenhydramine,chloral hydratetreat depressionREM-behav
49、ioral disorder:clonazepamExcessive daytime sleepinesscorrect poor sleep at nightdiscontinue anticholinergics,amantadinereduce dopamine agonist,levopoda dosages if possibleselegeline,caffeine,methylphenidate 5-20 mgs/d,Orthostatic Hypotension,Tilt table training for severe casesTaper anti-hypertensiv
50、e agentsTaper non-PD drugsIncrease salt intakeElevate HOB,arising slowly,isometric exercisesCompression stockings,abdl bindersFludrocortisone(0.1-0.4mg/d)Midodrine(2.5-20mg/d),Urinary Incontinence/Frequency,Rule out urinary tract infectionBladder evaluation fordetrusor hyperactivity*oxybutinin 5-30m
