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  3. 3. IDIOPATHICPARKINSON’S DISEASERisk factorsa. Ageb. Sex (M > F)c. Family historyd. History of exposure to toxins: higher risk with exposureto pesticides, herbicides, welding (manganese poisoning),or for agricultural workerse. History of head trauma2. Inherited parkinsonism
  4. 4. The onset is usually asymmetric, and tremor isthe most common presenting signa. Tremor1) Characterized as rest tremor2) May also be a postural or kinetic tremor (rest tremortypically dampens with posture or action)3) Usually unilateral onset in an extremity4) Tremor may spread to involve contiguous extremitiesb. Rigidity1) Not velocity-dependent or direction-dependent2) “Cogwheeling”: usually indicative of superimposedtremor
  5. 5. c. Bradykinesia1) Reduced arm swing2) Generalized slowness in movements3) Slowness and difficulty with manual dexterity4) Micrographia5) Masked facies (hypomimia)6) Sialorrhea because of bulbar bradykinesiad. Postural instability1) Loss of postural reflexes2) Retropulsion as may be found on the “pull test”
  6. 6. e. Gait disturbance1) Stooped posture: characteristic “shuffling” festinating gait withshort stride, with tendency to lean forward2) Propulsion: involuntary and unwanted forward accelerationwhen patient wants to stop3) Difficulty initiating gait and gait “freezing” after gait alreadyinitiated (sudden inability to take another step)4) Difficulty with turns
  7. 7. f. Associated features1) Hypokinetic speech: characterized by reduced amplitude and sometimes acceleration of rate2) Autonomic featuresa) Most commonly, orthostatism, usually not a presenting featureb) Other less common features: urinary symptoms (hesitancy, nocturia,incontinence), sexual dysfunction, intermittent increased sweating3) Behavioral and cognitive featuresa) Bradyphrenia (mental slowing), with difficulty with attention, and poorinitiation and working memoryb) Depression in up to 2/3 of patients and anxiety (especially associated withakinetic “off” state)c) Dementia may develop after many yearsi) Difficulty with frontal lobe executive and visuospatial functions, with somelanguage deficitsii) Difficulty with attentional tasks and those involving timed responses
  8. 8. 4. Sleep disorders. REM behavior may precede onset ofparkinsonism by several years in IPD or DLB. Restless legssyndrome (RLS) and/or periodic limb movements during sleepmay be associated with IPD. Discomfort due to rigidity andinability to turn in bed can cause sleep fragmentation
  9. 9. Neuroimaginga. Magnetic resonance imaging (MRI): generally not helpfulb. Fluorodopa positron emission tomography (PET): reduceduptake in dopaminergic striatal and nigrostriatal pathways,proportional to severity of disease and pathology
  10. 10. HISTOPATHOLOGYa. Macroscopic pigmentary loss and microscopic neuronalloss of substantia nigra pars compacta, with microglialactivation and cytoplasmic pigmentation of macrophagesb. Locus ceruleus, intermediolateral cell column, and dorsalmotor nucleus of the vagus nerve may be affectedc. Lewy bodies in surviving neurons in areas affected(sparing neocortex): cytoplasmic inclusions with denseeosinophilic core containing hyperphosphorylatedneurofilament proteins, lipids, iron, ubiquitin, and α-synuclein
  12. 12. A. LEVODOPAShould be taken on empty stomach because it competes with aminoacids in crossing the blood-brain barrier by a transporter.Formulations:Immediate release (IR) carbidopa-levodopa& Controlled-release (CR)carbidopa-levodopaIncrements in dose should be made weekly because a week isrequired to determine cumulative effect of drug.Simpler to use and initiate than the agonists. Most efficacious andpotent medical treatment. Greater incidence of motor fluctuations anddyskinesias than with dopamine agonistsResponse to medications. Absence of benefit from adequate dosagesof dopaminergic drugs, especially levodopa, casts doubt on thediagnosis of IPD and suggests a diagnosis of secondary causes ofparkinsonism or one of the Parkinson-plus syndromes
  13. 13. Adverse effectsa) Nauseai) Due to premature conversion of levodopa todopamine in the circulation by the peripheraldopa decarboxylase enzyme (L-aromatic aminoacid decarboxylase)May be treated with dry bread or cracker (low protein), addingcarbidopa to each dose, domperidone (Motilium)
  14. 14. b)Dyskinesiasi) Dystonia (parkinsonian)ii) Choreiform (levodopa-induced): reduce dose of levodopa forpeak-dose dyskinesiasc) Orthostatic hypotension d) Visual hallucinations and psychosise) Insomnia and vivid dreams
  15. 15. DOPAMINE AGONISTS1) Directly activate dopamine receptors2) More likely than levodopa to produce psychosis,hallucinations, and orthostatic hypotention3) Less likely than levodopa to produce dyskinesias4) Synergistic effect with concomitant use of levodopa toexacerbate dyskinesias while reducing the “off” state,necessitating a lower levodopa dose
  16. 16. Pergolide and bromocriptine:Ergot derivatives, higher chance of ergot side effects such aspotential for vasoconstriction (e.g., Reynaud’s phenomenon),erythromelalgia, fibrotic degeneration of cardiac valves,pulmonary and retroperitoneal fibrosisPramipexole and ropinirole:nonergolines, have lower rate of adverse effects than traditionaldopamine agonists above; may rarely cause sleep attacks and legedema
  17. 17. COMT INHIBITORS1) They inhibit catechol O-methyltransferase (COMT) and increase plasma level of levodopa. They act to prolong “on” time.Have predisposition to levodopa-induced dyskinesias and otheradverse effects (e.g., nausea), sometimes requiring decrease inlevodopa dose2) Formulations:a) Tolcapone (Tasmar)i) Rarely used because of reported cases of acute fulminant liverfailure, requiring frequent monitoring of liver function enzymesii) Reversible central- and peripheral-acting COMT inhibitorb) Entacapone (Comtan)i) Reversible peripheral-acting (including gastrointestinal tract,erythrocytes, and liver)ii) Shorter duration of action than tolcaponeiii) Given as 200-mg dose with each dose of levodopa
  18. 18. Other adverse effects: abdominal cramps, abdominal pain, severediarrhea (1.3% of patients) related to allergic hypersensitivity—otherwise, well tolerated
  19. 19. ANTICHOLINERGIC AGENTS1) Usually less effective than levodopa or dopamine agonists2) May be selectively more effective for tremor and dystoniapoorly responsive to levodopa or dopamine agonist when added3) Most commonly used formulations: trihexyphenidyl(Artane) and benztropine mesylate (Cogentin)4) Adverse effects: dry mouth, blurred vision, urinaryretention, forgetfulness, hallucinations, psychosis
  20. 20. ADJUNCTIVE THERAPY1) Amantadinea) Used in early stages: may delay need for levodopab) Used as adjunctive therapy: reduce the required doses ofdopaminergic treatmentc) May be effective in reducing levodopa-induced dyskinesiasd) Excreted unchanged in the urine: dose needs to be reduced inpatients with renal impairment and in elderlye) Can cause cognitive impairment
  21. 21. 2) Selegiline:a) Selectively inhibits monoamine oxidase (MAO)-B and not MAO-A atdoses below 10 mg dailyb) Daily dose above 10 mg can inhibit MAO-A and may inducehypertensive crisis with ingestion of tyramine-containing foodc) Delays the need for levodopa if started early, but no long-termbenefitd) Unclear if it has neuroprotective effecte) Metabolized to amphetamine and methamphetaminef) May have a synergistic effect with levodopa
  22. 22. GENERAL APPROACH TO INITIAL SYMPTOMATIC TREATMENTIN MILD TO MODERATE PARKINSONISM1) Consider treatment with levodopa or dopamine agonist ifsymptoms interfere with daily activity2) If minimal interference with daily activity: may start withselegiline, amantadine, or anticholinergic agent3) Onset of symptoms at young age (<40-50 years): manyprefer to start with dopamine agonist (no motor fluctuationsor dyskinesias in absence of levodopa, much less potentthan levodopa) or combination therapy (levodopa anddopamine agonist)4) Onset of symptoms at older age: start with levodopa IR25/100 3 times daily 1 hour before meals and titrate weekly orconsider an agonist; initial dose may be smaller and titrationslower if nausea or other prominent adverse effects
  23. 23. GENERAL APPROACH TO ADVANCING PARKINSON’S DISEASE1) “Wearing off” effecta) Most common type of motor fluctuation in advancing diseaseb) Recurrence of parkinsonian symptoms and clinical deteriorationbefore next dosec) If response to levodopa during the “on” phase is adequate, movenext dose to an earlier time and shorten the time between dosesd) If response to levodopa during the “on” phase is inadequate,increase individual levodopa dose before making any adjustment intiming of next dosee) Addition of dopamine agonist after adjustments to levodoparegimen has been made reduces motor fluctuationsf) Addition of COMT inhibitors may also increase the “on” phase butpredispose to levodopa-induced adverse effects (e.g., dyskinesias)
  24. 24. 2) Dyskinesiasa) Dystonic in absence of chorea: usually parkinsonian (mostcommonly, early morning or nocturnal dystonia such as painful footcramps)b) Choreiform with or without dystonia: usually levodopa-inducedc) Usually peak-dose (Off-On-Dyskinesia-On-Off) and rarely biphasic(Off-Dyskinesia-On- Dyskinesia-Off)TTT1) Peak-dose dyskinesias: reduce amount of levodopa IR andconsider discontinuing adjunctive selegiline or COMT inhibitors,Consider addition of amantadine2) Rapid motor fluctuations with alternating dyskinesias and “off”states, consider addition of an agonist (use adequate dose and avoidrapid titration of dose)3) Biphasic dykinesias (true biphasic dyskinesias are rare):shortening the time between doses
  25. 25. 3) “On-Off” phenomenona) Unpredictable, abrupt episodes of parkinsonismb) Usually treated with increasing levodopa dose or addition ofdopamine agonists4) Freezinga) Usually occurs because of rigidity and bradykinesia,representsdifficulty with initiating movements (walking, getting up from aseated position, etc.)b) “Off” phase, end-dose freezing responds to shortening the timebetween levodopa doses and taking the next dose at earlier time,addition of a COMT inhibitor or agonistc) If clinical response to levodopa is inadequate, treatment is toincrease the respective levodopa dosed) Liquid levodopa as “rescue therapy” can be effective givenrelatively short onset of symptoms
  27. 27. THALAMOTOMYa) Now obsoleteb) Alleviates or abolishes contralateral rest tremor or rigidity in80% to 90% of patientsc) Also effective for contralateral dyskinesiasd) No effect on bradykinesia, postural instability, or other axialsymptomse) Complications: weakness, numbness, paresthesias, dysarthria,delayed-onset dystonia (more common with bilateral procedurespreviously done)
  28. 28. UNILATERALPALLIDOTOMYa) Improves rigidity, postural instability, and bradykinesia (asopposed to thalamotomy), although not much greater benefitover L-dopa treatment.b) Most important benefit: dyskinesias (both levodopa-induced chorea type and parkinsonian dystonic type)c) Complications: hemiparesis, aphasia, facial weakness(more common with bilateral procedures)
  29. 29. DEEP BRAIN STIMULATIONa) Electrodes implanted in ventralis intermedius nucleus of thalamus,subthalamic nucleus, globus pallidus interna, and other subcorticalnucleib) Components: lead, power source (implantable pulse generator),and extension wire connecting the twoc) Implantable pulse generator is usually subcutaneous ininfraclavicular aread) Stimulator implanted in thalamus, usually unilaterallye) Stimulator implanted in subthalamic nucleus and globus pallidusinterna, usually bilaterallyf) Mechanism of action thought to involvei) Depolarization inhibition and blockii) Activation of inhibitory pathwaysiii) Desynchronization of tremor-causing intrinsic pacemaker activityof excitatory neurons
  30. 30. Generally, good surgical candidates: younger than 75;multiple antiparkinsonian agents, including combinations,have been tried; no dementia, behavioral problems, or mooddisorders
  31. 31. OTHER PARKINSONIANSYNDROMESThis is a group of parkinsonian syndromes distinguishedfrom IPD by the presence of additional prominentneurologic abnormalities. In these conditions, there may becerebellar, autonomic, pyramidal, oculomotor, corticalsensory, bulbar, cognitive, and psychiatric dysfunction, aswell as apraxia and movement disorders not typically seenin untreated IPD such as myoclonus, dystonia, or chorea.Despite the apparent clinical differences between IPD andthe Parkinson-plus syndromes,differentiation between thetwo can be difficult.
  33. 33. Often multiple overlapping clinical features:1)Autonomic features: Shy-Drager syndrome Most common presenting symptoms: orthostatism andurinary incontinence, Postural hypotension,Postprandial hypotension, Anhidrosis, Urinaryincontinence (Detrusor hypofunction and denervation, Detrusorhyperreflexia, Sphincter weakness from involvement of Onuf’s nucleus(sacral cord)), Male impotence, Iris atrophy, Constipation.2)Extrapyramidal features:Most often bradykinesia and rigidity, less often tremor,Severe hypophonia, Postural myoclonus: jerking ofoutstretched hands Up to 30% of patients may respond to levodopa:response is usually brief and limited, Levodopa-induced dyskinesias are usually dystonic
  34. 34. 3)Cerebellar features:olivopontocerebellar atrophya. Presenting feature in only about 5% of patientsb. Eventually develops in up to half of patientsc. Appendicular and axial dysmetria are more common thanoculomotor dysmetria4) Other featuresa. Stridor (as well as sleep apnea and other sleep-relatedbreathing disorders)1) Due to abductor weakness of vocal cords2) May cause sudden nocturnal deathb. Pyramidal features: long-tract signs include spasticity,extensor plantar responses, hyperreflexia
  35. 35. HISTOPATHOLOGYa. Neuronal loss and gliosis in inferior olivary nucleus,pons,cerebellum, intermediolateral cell column of thoracic cord,putamen, and substantia nigrab. Glial and neuronal inclusions
  36. 36. INVESTIGATIONSa. MRI1) Rule out other disorders2) T2 imaging: putaminal hypointensity and atrophyand nigralatrophy—not specific3) Atrophy of cerebellum, cerebellar peduncles, pons(may see “hot-cross-bun sign” with pontine atrophy)b. Functional imaging1) Fluorodopa PET: decreased uptake in striatonigral projections,reduced metabolism in putamen and caudatec. Thermoregulatory sweat test and autonomic testingd. Sleep study for evaluation of stridorE. Electromyography (EMG) of the externalurethra or anal sphincter: long duration, high-amplitudeneurogenic potentials indicating denervation and involvement ofOnuf’s nucleus (segments S2 and S3)
  37. 37. Treatmenta. Orthostatism1) Discontinuation of agents exacerbating orthostatic hypotension2) Increase fluid and salt intake in diet3) Elevate head of bed at 30 degrees (to increase renin secretion)4) Compressive elastic stockings5) Medications ( Fludrocortisone, Midodrine)b. Urinary incontinence1) Bedside urinal or condom catheter (males) for simple urge incontinence2) Intermittent self-catheterization for urinary retention3) Anticholinergic agents (oxybutynin 2.5-5 mg 2-3 times daily) or propantheline bromide (15-60 mgdaily) for detrusor hyperreflexia4) Indwelling catheters5) Surgery (last resort)c. Anhidrosis: patients warned against extreme heat (environmental or during exercise)d. Other measures1) Physical therapy2) Stridor: continuous positive pressure or tracheostomy for refractory vocal cord paresise. Parkinsonism: carbidopa-levodopa (may worsen orthostatic hypotension)
  38. 38. PROGRESSIVESUPRANUCLEAR PALSYClinical featuresa. Supranuclear ophthalmoplegia1) Vertical saccades (especially downward) > horizontalsaccades affected earlier than pursuit movements2) Apraxia of eyelid movements (especially opening)3) Reduced vestibulo-ocular reflex suppression4)Eventually, complete bilateral ophthalmoplegia
  39. 39. b. Parkinsonism and early falls1) Prominent, early axial rigidity and early impairment of axial and postural reflexes with retropulsion2) Prominent hyperextended posture during walking (as compared with antecollis in patients withmultiple system atrophy)3) Symmetric bradykinesia4) Rest tremor is uncommon5) Unresponsive or poor response to levodopac. Pseudobulbar palsy1) “Emotional incontinence”: crying or laughter inappropriate to context of conversation2) Dysarthria: spastic and sometimes hypernasal speech3) Dysphagia4) Drooling5) Increased jaw jerkd. Cognitive disturbance1) Impaired attention and mental slowing2) Frontal-executive dysfunction3) Frontal release signs4) Personality change: apathy, irritability, disinhibitione. Other:hypertension (presumably from degeneration of brainstem adrenergic nuclei)
  40. 40. INVESTIGATIONSa. MRI1) Localized midbrain atrophy (reduced anteroposterior diameter)2) Enlarged third ventricle3) Atrophy of red nucleus4) Possibly frontal or temporal atrophyb. Functional imaging1) Global metabolic reduction, including bilateralfrontal lobes (especially anterior cingulate cortex), basal ganglia,thalamus, upper brainstem2) Fluorodopa PET: reduction of 18F-dopa influx into caudate andputamenc. Polysomnography: diminished total sleep time and REM sleep
  41. 41. HISTOPATHOLOGYa. Atrophy (with neuronal loss and gliosis) of upperbrainstem structures, pallor of substantia nigra and locusceruleusb. Other areas may be affected: periaqueductal gray matter,superior colliculus, substantia nigra, subthalamic nucleus,red nucleus, dentate nucleus, basal ganglia (globus pallidus> putamen), hippocampal structuresc. Abnormal tau deposition, including neuropil threads(tau-positive fibers) and tau-positive tufted astrocytesd. Iron pigmentation of globus pallidus
  42. 42. TREATMENTa. Few patients have response to dopaminergic agents:minimal response may be appreciated with bradykinesia andrigidityb. Trials of NMDA receptor antagonists (e.g., amantadine) andacetylcholinesterase inhibitors have been disappointing
  44. 44. Clinical. This syndrome can present as a strikingly asymmetric orunilateral akinetic-rigid syndrome associated with limb apraxia,alien limb phenomenon, cortical sensory signs, stimulus sensitivemyoclonus, dystonia, and postural or action tremor. Supranucleargaze palsy, cognitive impairment, and pyramidal tract signs canalso be seen.The alien limb phenomenon is present when a patient manifestsuncontrollable grasping and manipulating of objects. Thisphenomenon may be present in CBD, ischemic strokes, orCreutzfeldt-Jakob disease (CJD).NeuroimagingMRI or CT of the brain are abnormal in some patients and revealasymmetric frontoparietal atrophy
  45. 45. NEUROPATHOLOGYNeuronal loss and gliosis is found in the frontoparietalregions and substantia nigra pars compacta. Swollen achromatic neurons and basophilic nigralinclusions, which represent an overlap with Picks disease,are characteristic.Abundant cytoplasmic inclusions consisting of aggregatedhyperphosphorylated tau protein are found
  46. 46. SECONDARY PARKINSONISMParkinsonism can be induced by a wide spectrum of disease processesaffecting the brain, especially the basal ganglia. These include infection,cerebrovascular disorders, toxins, metabolic disorders, trauma,neoplasm, drugs, hypoxemia, and hydrocephalus. Selected causesinclude:1. Drug-induced parkinsonism. Neuroleptics and metoclopramide blockstriatal D-2 dopamine receptors, whereas reserpine depletes dopaminefrom presynaptic vesicles. The resolution of drug induced parkinsonismmay take several months after discontinuation of the offendingmedication2. Toxic parkinsonisma. Manganese: most common cause of environmental toxinb. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinec. Cyanided. Methanole. Carbon monoxide
  47. 47. 3. Metabolic parkinsonism a. Hepatic encephalopathy: parkinsonism associated with asterixis, myoclonus, chorea, encephalopathy b. Postanoxic parkinsonism: associated with pallidal lesions (as in carbon monoxide poisoning) c. Hypoparathyroidism: associated with basal ganglia calcifications d. Hypothyroidism (not true parkinsonism): slowing of activity may mimic parkinsonism e. Central pontine myelinolysis: associated with extrapontine lesions that occur with rapid correction of hyponatremia4. Vascular parkinsonism a. Multiple small lacunes in deep gray matter b. Parkinsonism primarily affecting gait and presenting as loss of postural stability and falls (primarily lower body involvement); apractic gait with difficulty initiating each step c. Pseudobulbar affect, urinary incontinence with subcortical dementia d. Associated with vascular dementia e. Pyramidal involvement is common: hyperreflexia and extensor plantar responses are more common than upper motor neuron distribution weakness f. Poor response to dopaminergic agents5. Posttraumatic parkinsonism6.Infectious and postencephalitic parkinsonism
  49. 49. • Wilsons disease. An autosomal recessive condition associated with impairment of copper excretion due to a genetic defect in a copper transporting ATPase, resulting in copper accumulation in different organ systems including the central nervous system, liver (cirrhosis), cornea (Kayser- Fleischer ring), heart, and kidney.• Huntingtons disease (HD). progressive autosomal dominant disorder characterized by dementia, psychiatric disturbance, and a variety of movement disorders.• familial calcification of the basal ganglia. (Fahr’s disease)Syndrome of progressive dementia and parkinsonism, schizophrenia-like psychosis extensive calcification of basal ganglia. Usually sporadic but may be inherited as autosomal dominant disorder (locus on chromosome 14)
  51. 51. • Dementia with Lewy bodies, characterized by the presence of Lewy bodies in the cortical and subcortical areas, is now considered the second most common neuropathological cause of dementia after Alzheimer’s disease. Dementia, defined as progressive decline of memory andother cognitive functions causing impairment in functional ability, is an essential feature for the diagnosis. The dementia can have cortical and subcortical characteristics. Other features include fluctuation of symptoms, visual hallucination and spontaneous Parkinsonism. Fluctuation can be defined as a significant variation in a patient’s cognitive or functional abilities, or periods of confusion or decreased responsiveness alternating with reasonable lucidity .This is a distinctive characteristic and can vary in duration from minutes to days or weeks. Fluctuation can present as episodic confusion, inattention, decreased level of arousal, and even speech arrest.• Visual hallucinations are often a prominent feature and have been described in 40 to 75 percent of patients with DLB . The hallucinations are represented by vivid images of animals, people, or children and can be very disturbing to the patient.• Parkinsonian features are also found in DLB, particularly rigidity and bradykinesia and less commonly resting tremor.• Other clinical findings include syncope, loss of muscle tone, transient loss of consciousness, delusions, and so on.• Treatment: The treatment is symptomatic with the use of anticholinesterase and antipsychotic and neuroprotective agents. The response to levodopa is variable among subjects. Hypersensitivity to antipsychotics.