Management Management in in Parkinson Parkinson ’ ’ s s Disease Disease Apichart Pisarnpong Apichart Pisarnpong , , M M . . D D . . Director of Parkinson Director of Parkinson ’ ’ s Disease Clinic, s Disease Clinic, Siriraj Hospital, Siriraj Hospital, Mahidol Mahidol University University
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Management Management inin
ParkinsonParkinson’’s s DiseaseDisease
Apichart PisarnpongApichart Pisarnpong,, MM..DD..Director of ParkinsonDirector of Parkinson’’s Disease Clinic, s Disease Clinic,
History of ParkinsonHistory of Parkinson’’s Diseases DiseaseClinical manifestation of PDClinical manifestation of PDEtiology and secondary cause of ParkinsonismEtiology and secondary cause of ParkinsonismClassification Classification Treatment : Treatment :
medical medical surgical (new in Thailand)surgical (new in Thailand)
Late complications (motor VS nonLate complications (motor VS non--motor)motor)
overviewoverview
History of ParkinsonHistory of Parkinson’’s Diseases DiseaseClinical manifestation of PDClinical manifestation of PDEtiology and secondary cause of ParkinsonismEtiology and secondary cause of ParkinsonismClassification Classification Treatment : Treatment :
medical medical surgical (new in Thailand)surgical (new in Thailand)
Late complications (motor VS nonLate complications (motor VS non--motor)motor)
History History
18171817: : James Parkinson James Parkinson ““An Essay on the Shaking PalsyAn Essay on the Shaking Palsy””
1961 using IV levodopa to treat PD patients 1961 using IV levodopa to treat PD patients 1966 combine with Decaboxylase inhibitor 1966 combine with Decaboxylase inhibitor (benzerazide) less side effect and more potent(benzerazide) less side effect and more potent
Pathology of ParkinsonPathology of Parkinson’’s Diseases Disease
Normal Basal Ganglia Functional Normal Basal Ganglia Functional AnatomyAnatomy
Cortex
PrefrontalInsular
CingulateSensoryMotor
Suppl. MotorPremotor
PremotorPrefrontal
Striatum
D2 D1ThalamusVA/VL
+ = excitatory- = inhibitory
BrainstemSC
SNc
SNr
GPi
STN
GPe
-
+
+
+-
-
---
-
+
++
+
+
+
Normal
Function Anatomy of ParkinsonFunction Anatomy of Parkinson’’s s DiseaseDisease
Cortex
PrefrontalInsular
CingulateSensoryMotor
Suppl. MotorPremotor
PremotorPrefrontal
Striatum
D2 D1ThalamusVA/VL
+ = excitatory- = inhibitory
BrainstemSC
SNc
SNr
GPi
STN
GPe
-
-
++
++++
-
-----
+
++
+
+
+ - -
Parkinson’s Disease
Cortex
PrefrontalInsular
CingulateSensoryMotor
Suppl. MotorPremotor
PremotorPrefrontal
Striatum
D2 D1ThalamusVA/VL
+ = excitatory- = inhibitory
BrainstemSC
SNc
SNr
GPi
STN
GPe
-
+
+
+-
-
---
-
+
++
+
+
+
NormalCortex
PrefrontalInsular
CingulateSensoryMotor
Suppl. MotorPremotor
PremotorPrefrontal
Striatum
D2 D1ThalamusVA/VL
+ = excitatory- = inhibitory
BrainstemSC
SNc
SNr
GPi
STN
GPe
-
-
++
++++
-
-----
+
++
+
+
+ - -
Parkinson’s Disease
overviewoverview
History of ParkinsonHistory of Parkinson’’s Diseases Disease
Clinical manifestation of PDClinical manifestation of PDEtiology and secondary cause of ParkinsonismEtiology and secondary cause of ParkinsonismClassification Classification Treatment : Treatment :
medical medical surgical (new in Thailand)surgical (new in Thailand)
Late complications (motor VS nonLate complications (motor VS non--motor)motor)
Signs and SymptomsSigns and Symptoms
Cardinal CharacteristicsCardinal Characteristics
Resting tremorResting tremor
BradykinesiaBradykinesia
RigidityRigidity
Later; Postural instability (3Later; Postural instability (3--5 years after 5 years after Dx)Dx)
Gait disturbance esp. dystonic posture of Gait disturbance esp. dystonic posture of feet, fluctuation of symptoms (YOPD)feet, fluctuation of symptoms (YOPD)
Additional Signs and SymptomsAdditional Signs and Symptoms
Difficulty arising from a chairDifficulty arising from a chair
Difficulty turning in bedDifficulty turning in bed
Hypophonic speechHypophonic speech
SialorrheaSialorrhea
Loss of the sense of smellLoss of the sense of smell
Foot dystoniaFoot dystonia
OtherOther
MicrographiaMicrographia
Masked faceMasked face
Slowing of ADLsSlowing of ADLs
Stooped, shuffling gaitStooped, shuffling gait
Decreased arm swing when walkingDecreased arm swing when walking
Early symptomatic postural hypotensionEarly symptomatic postural hypotension
Criteria for DiagnosisCriteria for Diagnosis
At least two of three: At least two of three: rest tremor, bradykinesia, rigidityrest tremor, bradykinesia, rigidity
Absence of a secondary cause; drugs, Absence of a secondary cause; drugs, metabolic, etc.metabolic, etc.Definitive diagnosis can only be made Definitive diagnosis can only be made by autopsyby autopsy
overviewoverview
History of ParkinsonHistory of Parkinson’’s Diseases DiseaseClinical manifestation of PDClinical manifestation of PD
Etiology and secondary cause of Etiology and secondary cause of ParkinsonismParkinsonismClassification Classification Treatment : Treatment :
medical medical surgical (new in Thailand)surgical (new in Thailand)
Late complications (motor VS nonLate complications (motor VS non--motor)motor)
Cause of PDCause of PD
Unknown in most casesUnknown in most cases
10% associated with genetic10% associated with genetic
ParkinsonParkinson’’s Disease s Disease Risk FactorsRisk Factors
DefiniteDefinite: Old age: Old ageHighly likelyHighly likely: MZ co: MZ co--twin with earlytwin with early--onset PDonset PDProbableProbable: Positive family history: Positive family historyPossiblePossible: Herbicides, pesticides, heavy metals, proximity : Herbicides, pesticides, heavy metals, proximity to industry, rural residence, well water, repeated head to industry, rural residence, well water, repeated head trauma, etc.trauma, etc.Possible protective effectPossible protective effect: Smoking: Smoking
overviewoverview
History of ParkinsonHistory of Parkinson’’s Diseases DiseaseClinical manifestation of PDClinical manifestation of PDEtiology and secondary cause of PDEtiology and secondary cause of PD
Abrupt onset, usually unilateralAbrupt onset, usually unilateralStepStep--wise or no progressionwise or no progressionOther signsOther signs——hemiparesis, aphasia, hyperreflexiahemiparesis, aphasia, hyperreflexiaInfarcts on neuroimaging helpful in confirming Infarcts on neuroimaging helpful in confirming diagnosisdiagnosis
Age of onset : 12Age of onset : 12--90 y (mean 55.6 y)90 y (mean 55.6 y)age > 40 yr age > 40 yr = 82.3% = 82.3% age 20age 20--40 yr 40 yr = 15.9%= 15.9%age < 20 yr age < 20 yr = 1.8% = 1.8% (age < 40 yr (age < 40 yr = 17.7%)= 17.7%)
Modified Hoehn and Yahr Modified Hoehn and Yahr Clinical staging of PDClinical staging of PD
StageStage00 no signs of diseaseno signs of disease11 Unilateral diseaseUnilateral disease1.51.5 Unilateral plus axial involvementUnilateral plus axial involvement2 2 Bilateral disease, without impairment of balanceBilateral disease, without impairment of balance2.52.5 Mild Bilateral disease, with recovery on pull testMild Bilateral disease, with recovery on pull test33 Mild to moderate bilateral disease: some postural instability: Mild to moderate bilateral disease: some postural instability:
physical independentphysical independent44 Severe disability: still able to walk or stand unassistedSevere disability: still able to walk or stand unassisted55 Wheelchair bound or bedridden unless aided Wheelchair bound or bedridden unless aided
Current concept in treating PDCurrent concept in treating PD(continuous dopaminergic (continuous dopaminergic
stimulation)stimulation)
Tonic and continuous dopaminergicstimulation occurs in normal
promote more dopaminergic cell lost promote more dopaminergic cell lost (post synaptic change) resulting in (post synaptic change) resulting in
development of motor fluctuation and development of motor fluctuation and dyskinesia dyskinesia
((Mouradian MM. pathogenesis of dyskinesia in ParkinsonMouradian MM. pathogenesis of dyskinesia in Parkinson’’s Disease. Ann neurol 1989)s Disease. Ann neurol 1989)
Lost of striatal dopamine receptor that occurs Lost of striatal dopamine receptor that occurs with disease progression results in a diminished with disease progression results in a diminished capacity of these terminal to buffer in capacity of these terminal to buffer in fluctuation in plasma levodopafluctuation in plasma levodopa
Continuous delivery of dopaminergic agents can Continuous delivery of dopaminergic agents can prevent or attenuate the development of prevent or attenuate the development of
dyskinesiadyskinesia
Motor complications associated with levodopa Motor complications associated with levodopa therapy include motor fluctuations and therapy include motor fluctuations and dyskinesia aredyskinesia areparticular problems in younger patientsparticular problems in younger patientsLess likely to occur in those whose symptoms Less likely to occur in those whose symptoms begin after the age of 70 years begin after the age of 70 years
(Golbe LI, neurology 1991, Quinn N, Mov Disord 1987)(Golbe LI, neurology 1991, Quinn N, Mov Disord 1987)
overviewoverview
History of ParkinsonHistory of Parkinson’’s Diseases DiseaseClinical manifestation of PDClinical manifestation of PDEtiology and secondary cause of ParkinsonismEtiology and secondary cause of ParkinsonismClassification Classification
Treatment : Treatment : medical medical
surgical (new in Thailand)surgical (new in Thailand)Late complications (motor VS nonLate complications (motor VS non--motor)motor)
When to start treatmentWhen to start treatmentDetermine whether the patients haveDetermine whether the patients havefunctional impairment or notfunctional impairment or not
1.1. Whether the symptoms effect the dominant or nonWhether the symptoms effect the dominant or non--dominant handdominant hand
2.2. Whether the patient is employed or employableWhether the patient is employed or employable3.3. The type of parkinsonian symptoms that are present The type of parkinsonian symptoms that are present
(e.g. bradykinesia tends to be more disabling than (e.g. bradykinesia tends to be more disabling than tremor)tremor)
4.4. Individual patient sentimentIndividual patient sentiment5.5. The philosophy of treating physicianThe philosophy of treating physician
Sites of action for two types of Sites of action for two types of medical therapies to treat PDmedical therapies to treat PD
Decision tree for early management of PDDecision tree for early management of PDAmerican Academy of Neurology, 2001American Academy of Neurology, 2001
Olanow CW et al. Neurology. 2001:56(suppl 5):S4.
LevodopaLevodopa
MostMost effectiveeffective symptomatically symptomatically antiparkinsonian drugantiparkinsonian drugAll PD patients respondAll PD patients respondImproves disability and prolongs capacity Improves disability and prolongs capacity to maintain employment and independent to maintain employment and independent activities of daily livingactivities of daily livingimproveimprovess mortality ratemortality rate
0
10
20
30
40
50
60
70
80
90
100
0 2 4 6 8 10 12 14 16
Control Group
Years after 1st presentation
Per
cent
Sur
viva
l
P < 0.0001 with control group
P = 0.024 with treated group
Levodopa treated Group N = 565
Levodopa non-treated Group N = 215
P < 0.0292 with control group
Adapt from A.H. Rajput/ Parkinson and related Disorders 8 (2001) 95-100
Levodopa prolongs life expectancy Levodopa prolongs life expectancy and nonand non--toxic to sunstantia nigratoxic to sunstantia nigra
Is Levodopa Toxic?Is Levodopa Toxic?
Early patients develop motor fluctuations, but may be a Early patients develop motor fluctuations, but may be a function of neuronal cell lossfunction of neuronal cell lossIncreased life expectancy with LD introduction Increased life expectancy with LD introduction LDLD--naive advanced PD patients develop fluctuations naive advanced PD patients develop fluctuations almost immediately with LD inductionalmost immediately with LD inductionNo LD neuronal dropout in laboratory animalsNo LD neuronal dropout in laboratory animalsRecent data suggest possible neuroprotectionRecent data suggest possible neuroprotectionSome believe continuous infusion may be safer than Some believe continuous infusion may be safer than pulsatile therapypulsatile therapy
ELLDOPA studyELLDOPA study
360 never360 never--treated PD patients randomized to treated PD patients randomized to placebo or carbidopa/levodopa (37.5/150, placebo or carbidopa/levodopa (37.5/150, 75/300, 150/600 mg/day)75/300, 150/600 mg/day)No evidence that levodopa had any deleterious No evidence that levodopa had any deleterious effect on disease progression and failed to effect on disease progression and failed to support the notion of levodopa toxicitysupport the notion of levodopa toxicityLevodopa is not harmful to Levodopa is not harmful to SNcSNc neuron in PDneuron in PD
Manifestation of excessive dopaminergic stimulationManifestation of excessive dopaminergic stimulationTypically late effect, and with higher dosesTypically late effect, and with higher dosesNarrowing of therapeutic windowNarrowing of therapeutic windowRare in LDRare in LD--naive patients on DA monotherapy naive patients on DA monotherapy Most common is Most common is ““peak dosepeak dose”” dyskinesiadyskinesia
disappears with dose reductiondisappears with dose reduction
Choreiform, ballistic and dystonic movementsChoreiform, ballistic and dystonic movementsMost patients prefer some dyskinesias over the Most patients prefer some dyskinesias over the alternative of akinesia and rigidityalternative of akinesia and rigidity
Onset DurationImmediate Release 20-40 min 2-4 hr10/100, 25/100, 25/250
Controlled Release 30-60 min 3-6 hr25/100, 50/200
“Fast acting” 10-20 min 0.5-1 hr(dissolved tablets)
Levodopa taking alone without DDC Levodopa taking alone without DDC inhinh. only 1 . only 1 % reach the brain% reach the brainWith DDC With DDC inhinh. 10% reach the brain. 10% reach the brain
Prospective, double blind trial in 618 Prospective, double blind trial in 618 levodopalevodopa--nanaïïve patientsve patients
After 5 years there is no difference in the prevalence After 5 years there is no difference in the prevalence of motor complications between two groupsof motor complications between two groups
Similar result with Madopar HBSSimilar result with Madopar HBS
(Block G. Multicenter 5 years study.Eur Neurol 1997)(Block G. Multicenter 5 years study.Eur Neurol 1997)
Up to 80% of Parkinson’s disease patients suffer from motor fluctuations and dyskinesias after approximately 5 to 10 years of treatment with levodopa4
50% to 75% of patients develop motor fluctuations 3 to 6 years after initiating therapy1-3
1. Fahn S. Adv Neurol. 1996;69:477-486.2. Poewe WH, Wenning GK. Neurology. 1996;47(suppl 3):S146-S152.3. Parkinson Study Group. Ann Neurol. 1996;39:37-45.4. Olanow CW, Stocchi F. Eur J Neurol. 2000;7(suppl 1):3-8.
DykinesiasDykinesias and motor fluctuations in and motor fluctuations in a communitya community--based study of PDbased study of PD
SchragSchrag et al, 2000et al, 2000
DykinesiasDykinesias in 28% of the patients in 28% of the patients Motor fluctuations in 40% of the patientsMotor fluctuations in 40% of the patientsPredictors for the evolution of motor fluctuation:Predictors for the evolution of motor fluctuation:
Mechanism of developing dyskinesiaMechanism of developing dyskinesia
Risk factorsRisk factors1.1. Chronic exogenous exposure to dopaminergic Chronic exogenous exposure to dopaminergic
drugs (mainly when given intermittently); drugs (mainly when given intermittently); dopamine receptor dopamine receptor supersensitivitysupersensitivity
2.2. Severe dopamine depletion resulting from Severe dopamine depletion resulting from nigrostriatal nigrostriatal denervationdenervation
3.3. The required presence of anatomically intact The required presence of anatomically intact striatal neuronsstriatal neurons
Non ergotamineNon ergotamineRopiniroleRopinirolePramipexolePramipexolePiribedilPiribedil
Dopamine agonistDopamine agonist (3)(3)
Reduced motor complication compare Reduced motor complication compare with levodopawith levodopaAntiparkinsonian effect superior to Antiparkinsonian effect superior to placebo in earlyplacebo in early--stage PDstage PDAntiparkinsonian effect comparable to Antiparkinsonian effect comparable to levodopa in earlylevodopa in early--stage PDstage PDCan use as monotherary up to several yearsCan use as monotherary up to several years
Dopamine agonistDopamine agonist (4)(4)
Supplementation with levodopa Supplementation with levodopa provides clinical benefits comparable provides clinical benefits comparable to levodopa alone but with reduced to levodopa alone but with reduced motor complicationsmotor complications? Neuroprotective effects? Neuroprotective effects
DAs: Common Adverse EffectsDAs: Common Adverse Effects
Association of Association of effusionseffusions and and fibrosisfibrosis withwithergot vs.ergot vs. nonnon--ergotergot dopaminedopamine agonistsagonists
Cabergoline
1997
12
1
0
13
DHEC
1989
1
0
1
2
Lisuride
1968
6
0
1
7
Pergolide
1988
104
8
19
131
Pramipexole
1997
0
0
0
0
Müller T, Fritze J. Clinical Neuropharmacol 2003; 26: 109-111
Pergolide 0.05 qd 0.75-6 Pramipexole 0.125 tid 0.75-3 Ropinirole 0.25 tid 9-24 Cabergoline 0.25 qd 0.5-5 Peribedil 50 qd 50-250
Dopamine agonistDopamine agonist
Drug T ½ (h) Carbidopa/levodopa 1-1.5 Pergolide 12-27 Pramipexole 8-12 Cabergoline 65+ Ropinirole Bromocriptine
4 6
Dopamine Agonists in Dopamine Agonists in comparisoncomparison
As As monotherapy monotherapy and adjunctive and adjunctive
to levodopato levodopa
As adjunctive As adjunctive to levodopa to levodopa
onlyonly
Not being Not being approvedapproved
As As monotherapy monotherapy
and and adjunctive to adjunctive to
levodopalevodopa
US FDA approvalUS FDA approval(http://(http://www.accewww.accessdata.fda.gov/scrissdata.fda.gov/scripts/cder/drugsatfpts/cder/drugsatfda/index.cfmda/index.cfm))
Assessment of Dopamine Agonists for the Assessment of Dopamine Agonists for the treatment of PD according totreatment of PD according to Evidence Based Evidence Based
MedicineMedicine**
Efficacious (maximum strength of evidence)± Likely efficacious ? Insufficient evidence0 No studies
(*adapted from Rascol O. et al. Lancet 2002; 359: 1589-1598)
Monotherapyin early PD ± ? ± ?Combination therapy with L-Dopa in late PD ± ? ?Treatment of motor fluctuations ± ± ? ?Prevention of motor complications ± ? ? ?Imaging indicates slowed loss of 0 0 0 0 0dopaminergic neurons
Dopamine agonistDopamine agonist
Start lowStart low,, go slow go slow ((gradually titrated over several weeks or monthsgradually titrated over several weeks or months))
Improved motor and ADL scoresImproved motor and ADL scoresDecreases Decreases ““offoff”” timetimeprovided a levodopa sparing effectprovided a levodopa sparing effect
Treatment of unpredictable, frequent motor Treatment of unpredictable, frequent motor fluctuationsfluctuations
continuous s.c. infusion via minicontinuous s.c. infusion via mini--pumppump
SE: nausea, vomiting, hypotensionSE: nausea, vomiting, hypotensiontrimethobenzamide 250 mg t.i.d.trimethobenzamide 250 mg t.i.d.domperidone 20 mg t.i.d.; not available in U.S.domperidone 20 mg t.i.d.; not available in U.S.
COMT inhibitorCOMT inhibitor
No titration easy to administerNo titration easy to administerDecreased Decreased ““offoff”” timetime,, increased increased ““onon”” time and time and enhanced motor responses in patients with enhanced motor responses in patients with levodopa motor fluctuationlevodopa motor fluctuationImproved motor and ADL scores in stable Improved motor and ADL scores in stable levodopa responderslevodopa respondersMay reduce risk for motor complications if used May reduce risk for motor complications if used from onset of levodopa therapyfrom onset of levodopa therapy
COMT inhibitorCOMT inhibitor
Entacapone Entacapone 200200 mg with each dose of mg with each dose of levodopalevodopaTalcapone Talcapone 100100--200200 mg tidmg tidSide effect Side effect ;; discoloration of urinediscoloration of urine,, increase increase dyskinesiadyskinesia,, diarrheadiarrhea
COMT inhibitorCOMT inhibitor
Increase plasma levodopa elimination half life by Increase plasma levodopa elimination half life by 50%50% and area under the curve by and area under the curve by 75%75% without without rising of either the maximal plasma rising of either the maximal plasma concentrationconcentration((CmaxCmax)) or the time to reach or the time to reach maximal plasma concentration maximal plasma concentration ((TmaxTmax))
AnticholinergicsAnticholinergics
Dopaminergic Dopaminergic depletiondepletion→→cholinergiccholinergicoveractivityoveractivityInitially used in the 1950sInitially used in the 1950sEffective mainly for tremor (rigidity)Effective mainly for tremor (rigidity)Common agents (Start low, go slow):Common agents (Start low, go slow):
Irreversible MAOIrreversible MAO--B inhibitorB inhibitorClinically active by inhibiting dopamine Clinically active by inhibiting dopamine metabolism in brainmetabolism in brainMay be neuroprotective (DATATOP, May be neuroprotective (DATATOP, SINDEPAR)SINDEPAR)Dosage: 5 mg at breakfast and lunchDosage: 5 mg at breakfast and lunch
SelegilineSelegiline
Side effects: insomnia, hallucinations, Side effects: insomnia, hallucinations, nausea (rarely), dyskinesianausea (rarely), dyskinesiaPotential interactions with tricyclics and Potential interactions with tricyclics and SSRI antidepressantsSSRI antidepressantsAs adjunct to levodopa, provides reduced As adjunct to levodopa, provides reduced motor fluctuations and increased motor fluctuations and increased ““onon””timetime
DATATOP FollowDATATOP Follow--UpUp
DATATOP: 3 year followDATATOP: 3 year follow--up studies (Ann Neurol up studies (Ann Neurol 1996)1996)
subjects requiring levodopa (n=352)subjects requiring levodopa (n=352)selegiline made no difference with regard to disease selegiline made no difference with regard to disease severity, wearingseverity, wearing--off or dyskinesiasoff or dyskinesias
subjects not requiring levodopa (n=162)subjects not requiring levodopa (n=162)No difference in parkinsonian disability between the two No difference in parkinsonian disability between the two groupsgroups
8 year follow8 year follow--up (Ann Neurol 1998)up (Ann Neurol 1998)No increase in mortalityNo increase in mortality
overviewoverview
History of ParkinsonHistory of Parkinson’’s Diseases DiseaseClinical manifestation of PDClinical manifestation of PDEtiology and secondary cause of ParkinsonismEtiology and secondary cause of ParkinsonismClassification Classification Treatment : Treatment :
medical medical surgical (new in Thailand)surgical (new in Thailand)
Late complications:Late complications:motor VS nonmotor VS non--motormotor
Stages in Decline of Response to LDStages in Decline of Response to LD
I: Patient not aware of effect of individual doseI: Patient not aware of effect of individual doseII: MidII: Mid--afternoon loss of benefitafternoon loss of benefitIII: Loss of sleep benefit; earlyIII: Loss of sleep benefit; early--morning akinesia, morning akinesia, possible foot dystoniapossible foot dystoniaIV: Regular IV: Regular ““wearing offwearing off”” every 4 hours at first, every 4 hours at first, shortens with timeshortens with timeV: Frequent wearing off, abrupt onV: Frequent wearing off, abrupt on--off, unpredictable off, unpredictable dose responsedose response
Central causes:Central causes:pulsatile delivery to striatal receptorspulsatile delivery to striatal receptorsimpaired storage capacityimpaired storage capacityalteration of DA receptorsalteration of DA receptors
reduce LDreduce LDliver function monitoringliver function monitoring
Apomorphine rescueApomorphine rescue
Peak Dose Dyskinesia or DystoniaPeak Dose Dyskinesia or Dystonia
Chorea more common than dystoniaChorea more common than dystoniaMay be worse on more affected sideMay be worse on more affected sideMay not be as disabling as akinesia/rigidityMay not be as disabling as akinesia/rigidityDose adjustments, addDose adjustments, add--ons:ons:
Appears when LD level is low, especially early Appears when LD level is low, especially early AMAMw/ or w/o parkinsonismw/ or w/o parkinsonismDose adjustments, addDose adjustments, add--ons:ons:
more frequent LD dosing to avoid low plasma levelsmore frequent LD dosing to avoid low plasma levelsadd DA, COMT inhibitor, MAOadd DA, COMT inhibitor, MAO--B inhibitorB inhibitor
Wearing OffWearing Off
Regular and predictable decline in response 2Regular and predictable decline in response 2--4 4 hours after LD dosehours after LD doseMost common motor fluctuationMost common motor fluctuationDose adjustments, addDose adjustments, add--ons:ons:
change to LDchange to LD--CR, or increase LD frequencyCR, or increase LD frequencyreduce LD, add DA or COMT inhibitorreduce LD, add DA or COMT inhibitor
OnOn--off Responseoff Response
Sudden and unpredictable off periods unrelated Sudden and unpredictable off periods unrelated to dosing scheduleto dosing scheduleOne of the hardest features to manageOne of the hardest features to manageDose adjustments, addDose adjustments, add--ons:ons:
reduce LD, add DAreduce LD, add DA
Other Motor ComplicationsOther Motor Complications
Diphasic dyskinesiaDiphasic dyskinesiadyskinesia at beginning and end of dosedyskinesia at beginning and end of doseDose adjustments, addDose adjustments, add--ons: add DAons: add DA
Drug failureDrug failurelate afternoon, probably related to poor gastric emptying or late afternoon, probably related to poor gastric emptying or absorptionabsorptionliquid preparations; increase gastric motility; decrease dietaryliquid preparations; increase gastric motility; decrease dietaryproteinproteinapomorphine rescueapomorphine rescue
Freezing and FallsFreezing and Falls
FreezingFreezingmotoric block; at initiation of gait, turning, narrow spacesmotoric block; at initiation of gait, turning, narrow spacesuse auditory, visual, proprioceptive cuesuse auditory, visual, proprioceptive cues
FallsFallsphysical therapy evaluationphysical therapy evaluationcane, scooter, wheelchair may be necessarycane, scooter, wheelchair may be necessary
Change from CR to standard carbidopa/levodopaChange from CR to standard carbidopa/levodopaTry atypical antipsychotic agentsTry atypical antipsychotic agentsTry lowTry low--potency traditional antipsychotic agentspotency traditional antipsychotic agents
DepressionDepression
Reported in 30Reported in 30--90% of PD patients90% of PD patientsDifficult to discern from vegetative symptomsDifficult to discern from vegetative symptomsRequires inquiry into depression symptomsRequires inquiry into depression symptomsUsually responds quickly to medicationsUsually responds quickly to medications
LevodopaLevodopa--related: take with meals, add related: take with meals, add carbidopa, add domperidonecarbidopa, add domperidoneOther antiOther anti--PD medications: same. PD medications: same.
If no improvement: withdraw newest agent, reIf no improvement: withdraw newest agent, re--initiate at minimal doses, slowly increaseinitiate at minimal doses, slowly increase
Excessive SweatingExcessive Sweating
Usually levodopa related, and may be seen at Usually levodopa related, and may be seen at peak or trough dose drug levelspeak or trough dose drug levels
reduce levodopareduce levodopaadd dopamine agonist or COMT inhibitoradd dopamine agonist or COMT inhibitoradd carbidopaadd carbidopaadd Betaadd Beta--blockerblocker
Surgical Treatment Surgical Treatment inin
ParkinsonParkinson’’s Diseases DiseasePart 6 of 7
Surgical Treatments for ParkinsonSurgical Treatments for Parkinson’’s Diseases Disease
TransplantTransplantautologous adrenal, human fetal, xenotransplants, autologous adrenal, human fetal, xenotransplants, genetically engineered transplantsgenetically engineered transplants
ThalamotomyThalamotomy
Significant improvement in contralateral tremorSignificant improvement in contralateral tremordepends on correct placementdepends on correct placement
Minimal improvement in other PD signsMinimal improvement in other PD signsBilateral procedures poorly toleratedBilateral procedures poorly toleratedAEs: bulbar, sensory and motor deficits, gait, AEs: bulbar, sensory and motor deficits, gait, surgical complicationssurgical complicationsGradually being replaced by thalamic DBS Gradually being replaced by thalamic DBS
Deep Brain Stimulation (DBS)Deep Brain Stimulation (DBS)
High frequency, pulsatile, bipolar electrical High frequency, pulsatile, bipolar electrical stimulationstimulationStereotactically placed into target nucleusStereotactically placed into target nucleusCan be activated and deactivated with an Can be activated and deactivated with an external magnetexternal magnetExact physiology unknown, but higher Exact physiology unknown, but higher frequencies mimic cellular ablation, not frequencies mimic cellular ablation, not stimulation stimulation
Movement Disorder SurgeryMovement Disorder Surgery
ศรัณย นันทอารี
Siriraj Movement Disorder Group
อภิชาติ พิศาลพงศ กนกวรรณ บุญญพิสิฎฐ
อรสา ชวาลภาฤทธิ์ นิพนธ พวงวรินทร
ไพรัช สายวิรุณพร
วรพรรณ เสนาณรงค
นันทศักดิ ์ทิศาวิภาค
VIM Thalamic DBSVIM Thalamic DBS
80% reduction in contralateral arm and leg tremor80% reduction in contralateral arm and leg tremorPossible mild improvement in bradykinesia and rigidityPossible mild improvement in bradykinesia and rigidityNo functional improvement (UPDRS part II), but No functional improvement (UPDRS part II), but significant improvement based upon global scoressignificant improvement based upon global scoresNo effect: gait and bulbar symptomsNo effect: gait and bulbar symptomsAEs: bulbar, gait, paresthesia, surgicalAEs: bulbar, gait, paresthesia, surgical
Effects tend to mimic those of pallidotomyEffects tend to mimic those of pallidotomySignificant improvement in dyskinesiaSignificant improvement in dyskinesiaModerate improvement in cardinal Moderate improvement in cardinal ““offoff”” signssignsNo comparison between unilateral and bilateral No comparison between unilateral and bilateral Bilateral DBS may be better tolerated than bilateral Bilateral DBS may be better tolerated than bilateral pallidotomypallidotomy
Bilateral placement appears to be superior to Bilateral placement appears to be superior to unilateral placementunilateral placementTheorized neuroprotective mechanism, but no Theorized neuroprotective mechanism, but no clinical evidence supporting this clinical evidence supporting this AE: confusion and hallucinations, increased AE: confusion and hallucinations, increased dyskinesia before medication adjustments, eyelid dyskinesia before medication adjustments, eyelid opening apraxia, weight gain, surgical opening apraxia, weight gain, surgical complicationscomplications
Patient Diary Data Subthalamic Nucleus
Patient Diary Data Patient Diary Data Subthalamic NucleusSubthalamic Nucleus
Clinical Results
Asleep27%
“on” time23%
“off” time35%
“on” withDyskinesia
14%
Asleep33%
“on” time53%
“off” time11%“on” with
Dyskinesia3%
Asleep33%
“on” time53%
“off time”12%“on” with
Dyskinesia2%
Pre-Implant 6 Months 12 Monthsn = 39
L-dopa equiv. = 1325 mg
n = 25
L-dopa equiv. = 1016 mg
n = 12
L-dopa equiv. = 988 mg
Subthalamic DBSSubthalamic DBS
All cardinal features of PD noted to improve All cardinal features of PD noted to improve in open label trialsin open label trials““OffOff”” UPDRS improved 60%UPDRS improved 60%““OnOn”” UPDRS improved 10%UPDRS improved 10%Dyskinesia tends to improve but this is Dyskinesia tends to improve but this is probably due to decreased levodopa doseprobably due to decreased levodopa dose
Activa® Parkinson’s Control SystemActivaActiva®® ParkinsonParkinson’’s Control Systems Control System
Genetically engineered cellsGenetically engineered cellsResearch ongoing Research ongoing
Human Fetal TransplantsHuman Fetal Transplants
EfficacyEfficacyEncouraging preliminary results in young PD ptsEncouraging preliminary results in young PD ptsPET studies consistent with cell functioningPET studies consistent with cell functioningAutopsies (2) show cell survivalAutopsies (2) show cell survival
Speech/language therapySpeech/language therapyDiet and nutritionDiet and nutritionPsychosocial interventionsPsychosocial interventions
Current management in Current management in Young Young ––onset Parkinsononset Parkinson’’s Disease patientss Disease patients
Start with Dopamine agonistStart with Dopamine agonistAdd levodopa when disability can not overcome Add levodopa when disability can not overcome by DAby DAAdd COMT inhibitor when developing motor Add COMT inhibitor when developing motor fluctuationsfluctuationsConsider start with anticholinergic or Consider start with anticholinergic or amantadine if tremor is the prominent symptomamantadine if tremor is the prominent symptom
Current management in Current management in LateLate––onset Parkinsononset Parkinson’’s Disease patientss Disease patients
Start with dopamine agonist if no Start with dopamine agonist if no contraindication and add on levodopa later contraindication and add on levodopa later Or start with levodopa when reaching dosage of Or start with levodopa when reaching dosage of 400400-- 600 mg add on dopamine agonist600 mg add on dopamine agonistConsidering COMT inhibitor when developing Considering COMT inhibitor when developing motor fluctuationsmotor fluctuations? Start with triple combinations (L? Start with triple combinations (L--dopa+ dopa+ DDC+ COMT inhibitor)DDC+ COMT inhibitor)