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Copyright 2014 American Medical Association. All rights reserved.

Pharmacological Treatment of Parkinson Disease

A Review

Barbara S. Connolly, MD;AnthonyE. Lang, MD

IMPORTANCE Parkinsondisease is the second most commonneurodegenerative disease

worldwide. Although no available therapies alter the underlying neurodegenerative process,

symptomatic therapies can improve patient quality of life.

OBJECTIVE To provide an evidence-based review of the initial pharmacological management

of theclassic motor symptoms of Parkinson disease; describe management of

medication-related motor complications (suchas motor fluctuations and dyskinesia), and

other medicationadverse effects (nausea, psychosis, and impulse control disorders and

related behaviors); and discuss themanagement of selected nonmotor symptoms of

Parkinson disease, includingrapid eye movement sleep behavior disorder, cognitive

impairment, depression, orthostatic hypotension, and sialorrhea.

EVIDENCE REVIEW Referenceswere identified usingsearches of PubMed between January1985 and February 2014 for English-language human studies andthe full database of the

Cochrane Library. Theclassificationof studies by quality (classes I-IV) was assessed using the

levelsof evidence guidelines from the American Academy of Neurology and the

highest-quality data for each topic.

RESULTS Although levodopa is the most effectivemedication available for treatingthe motor

symptoms of Parkinsondisease,in certain instances (eg, mild symptoms,tremoras the only

or most prominentsymptom, aged

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Parkinson disease is a chronic, progressive disease affecting

1%of thepopulation olderthan60 years1 (Table1).Thedis-

easecoursevariesconsiderably, withthosediagnosedearly

inadulthoodlivinglongerwiththediseasethanthosediagnosedlater

in life.3

Lossofdopamine-secretingneuronswithinthesubstantianigra

andpresenceof Lewy bodiesare the major pathologicalfindings in

Parkinson disease. Early in the disease course, dopamine defi-ciency is the predominant neurochemical abnormality. As the dis-

ease progresses, involve-

ment of nondopaminergic

brain regions results in le-

vodopa-resistantmotorand

nonmotor symptoms.

AlthoughParkinsondis-

ease is incurable, therapies

canimprovequalityoflifefor

many years. We discuss the

pharmacological manage-

ment of important motor

and nonmotor features of Parkinsondisease (Table 2) andadverse

effects of therapy (Table 3). The Box provides definitionsfor com-monly used terms.

Methods

Search

References were identified using searches of PubMed between

January 1985 and February 2014 for English-language human

studies and the full database of the Cochrane Library. The search

strategy and search results are provided in the eAppendix in the

Supplement.

Study ClassificationStudies were classified using theAmericanAcademy of Neurology

(AAN) Classification Scheme Requirements for Therapeutic Ques-

tions and rated on quality of evidence: class I (CI) and class II (CII)

relatetorandomizedclinicaltrials(RCTs),classIII(CIII)indicatesother

controlled trials, andclass IV (CIV) indicates other7 (eTable 1 in the

Supplement). The AAN Classification of Recommendations

guidelines8 (eTable2intheSupplement)wereusedtoprovidealevel

of recommendation(A = established effective; B = probably effec-

tive; C = possibly effective; U = data inadequate or conflicting) for

eachtherapy.Randomizedclinicaltrialswerearbitrarilyclassifiedby

size: those with 50 or fewer participants were considered small,

those with 51to 200were intermediate, and thosewithmore than

200 participants were designated as large.

Study Inclusion

Meta-analyses and individual RCTs fulfilling criteria for the highest

quality of evidence (CI and CII) were primarily included, but if few

ornonewereidentifiedforatopic,thenlower-qualityevidencewas

reviewed. Published guidelines for management of Parkinson dis-

ease were also included. All nonpharmacological studies and stud-

ies on ergot dopamine agonists (bromocriptine, cabergoline, li-

suride, anddihydroergocryptine)andpiribedil(unavailablein North

America) were excluded.

Results

Initiation of Therapy forMotor Symptoms

in Early Parkinson Disease

There are no established disease-modifying or neuroprotective

therapies.9 Medicationshould be initiatedwhen patientsexperience

functional impairment or social embarrassment from their symp-

toms. Figure 1 illustrates mechanisms of action of available medica-

tions. Initial therapy selection typically depends on a patient’s spe-

cific symptoms andage (Table 4; Figure2, Figure3, Figure4).

Ifmotorsymptomsaremildbutrequiretherapy,beforemovingtomore potent treatment such as a dopamine agonist or levodopa, a

monoamineoxidase typeB inhibitor(MAOBI;selegilineor rasagiline)

maybetried.Ameta-analysisofMAOBIsinearlyParkinsondiseasedem-

onstratedasmallsymptomaticbenefit.10Apotentialdisease-modifying

effectofrasagiline(1mg-dose)hasbeenreported 11(1largeCIstudy)but

notconfirmed by additionalclinicaltrial evidence.

A2003Cochranereviewinvolving9heterogeneousstudiesde-

termined that anticholinergic medications are more effective than

placebofor improving motor functionin Parkinson disease, butdata

on their benefits for tremor (generally considered their main indi-

cation) were inconclusive.12,13 Lower-quality, older studies suggest

thatβ-blockers may improve parkinsonian tremor and motorfunc-

tion.Propranololisusedmostoften.

12,14-17

Clozapinehasbeenshownto improve Parkinson disease tremor (1 CII, 2 CIII, and 2 CIV

studies)12,18; this is used exclusively for bothersome or disabling

tremor resistant to other therapies.

EvidencesupportingamantadinefortreatmentofParkinsondis-

ease (6 small CIII RCTs) is mixed. A 2009 Cochrane review con-

cludedthatthereisinsufficientevidenceforitsefficacyduetopoor

study quality,19 whereas expert opinion from the International

Parkinson and Movement Disorder Society and European Federa-

tionof NeurologicalSocietiesconcludedthatamantadineis likely ef-

ficacious for symptomatic monotherapy and adjunct therapy.12,20

COMTI catechol-O-

methyltransferase inhibitor

DDS dopamine dysregulation

syndrome

ICD impulsecontrol disorders

LCIG levodopa-carbidopa intestinal

gel

MAOBI monoamine oxidase type B

inhibitors

PDD Parkinson disease dementia

Table 1. Epidemiology of Parkinson Disease

Epidemiological Features Details

Mean age of onset, y124 65

Men:women125 1.5:1

Incidence, per 1000 person-years125

Patients aged 55-65 y 0.3

Patients ≥85 y 4.4

Prevalence, %123

Total population 0.3

Patients >60 y 1

Idiopathic:hereditary, %126 90:10

Life expectancy2 Varies with age of onset andoccurrence of dementia

Clinical subgroups, %127

Tremor-dominant 8

Akinetic-rigid 26

Mixed 66

Parkinson disease protective factors128 Cigarette smoking, highcoffee consumption

Parkinson disease risk factors2 Family history of Parkinsondisease, pesticide exposure,head injury, constipationa

a Constipationmay actually be anearlysymptomrather than a riskfactor.

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For those withmore severely impaired activities of daily living,

levodopa or a dopamine agonist is usually initiated. Multiple large

CI trials demonstrate thatlevodopa provides the greatest sympto-

maticbenefitforParkinsondisease12andisassociatedwithlessfreez-

ing, somnolence, edema, hallucinations, and risk of impulse con-

trol disorders (ICDs) thandopamine agonists. However, dopamine

agonistsarealsoefficaciousinearlyParkinsondisease21andareless

likely than levodopa to cause dopaminergic motor complications,particularly dyskinesia.22,23 Because younger age-of-onset of Par-

kinson disease is a risk factor for dyskinesia,24 dopamine agonists

areusuallyintroducedasinitialtreatmentforpatientsyoungerthan

60 years. However, there is increasing evidence in open-label, ob-

servational, naturalistic follow-up studies thatthe early advantage

ofdopamineagonistsoverlevodopadiminishesovertime(approxi-

mately 10 years).25-27

Ourexperiencesupportstheapproachesoutlinedaboveandin

Figure2, Figure3, and Figure4. Inpatients with mild symptoms, we

begin with a lower potency medication, such as an MAOBI, which

may have a milder adverse effect profile and often a less frequent

dosingregimen. Serotoninsyndromeis a theoreticalrisk when using

MAOBIsconcurrentlywithanotherserotonergicmedication.AsPar-

kinson disease progresses, medication should be adjusted to ob-tain optimal symptom control. In addition to the diminishing ben-

efitsof initialdopamineagonist therapyin delayingdyskinesia after

age60, greater predisposition to cognitiveand psychiatric adverse

effects with age also influences treatment choices. Elderly pa-

tients, especially those with preexisting cognitive dysfunction, are

atgreaterriskofdevelopingpsychiatricadverseeffects.Thus,inolder

patients, the risk to benefit ratio favors levodopa compared with

dopamine agonists and alternative therapies.

Managing Motor Fluctuations

Managing Symptom Reemergence Between MedicationDoses

Strategiesforreducingthetimethatmedicationisnotoptimallyef-

fective (“off” time) include increasing the dosage of dopaminergicmedication, adding anotherdopaminergicmedication,dividing the

levodopa dosage into smaller but more frequent doses (levodopa

dose fractionation), or adding a catechol-O-methyltransferase in-

hibitor(COMTI)orMAOBItoinhibitthebreakdownoflevodopaand

dopamine and prolong their effects.28 Few trials have compared

these therapeutic options. Rasagiline (an MAOBI) and entacapone

(a COMTI) were not significantly different in reducing off time in 1

largeCI study,29andasubsequentsubstudyprovidedevidencethat

Table 2. MainMotor and NonmotorSymptoms of Parkinson Disease

Features Timing Frequency, %a

Primary motor symptoms

Rest tremorb At diagnosis or later ~ 70 at diagnosis

Bradykinesia At diagnosis Allc

Rigidity At diagnosis or later ~ 90

Early nonmotor symptoms

Hyposmia May precedediagnosis

25-97

Fatigue May precedediagnosis

~ 60

Depression May precedediagnosis

~ 25

Rapid eye movement sleepbehavior disorder (RBD)

May precede diag-nosis by 15 y ormore4

~ 30

Constipation May precedediagnosis

~ 30

Late symptoms

Treatment-resistant axialsymptoms

5-10 y after symp-tom onset

Freezing/posturalinstability/falls

. ~ 90 by 15 y

Dysphagia ~ 50 by 15 y

Psychiatric disturbances 5-10 y after symp-tom onset

Anxiety ~ 55

Autonomic disturbances 5-10 y after symp-tom onset

Postural lightheadedness ~ 15

Sialorrhea ~ 30

Urinary urgency ~ 35

Nocturia ~ 35

Sexual dysfunction ~ 20

Cognitive impairment: Likelihood increaseswith time sincesymptom onset

Mild cognitive impairment ~ 35 at diagnosis, 50after 5 y

Dementia >80 at 20 y afterdiagnosis

a Frequencyof symptoms areestimated froma compositeof studies.129-133

bSomepatientscan present withan isolated parkinsonianrest tremor,butwithout bradykinesia thediagnosis of Parkinson disease cannotbe madeclinically.

c Basedon theUK ParkinsonDisease Society BrainBank Clinical DiagnosticCriteria, bradykinesia is essential for the diagnosis of Parkinson disease.

Table 3. AdverseEffects of DopaminergicTreatmenta

Symptom Adverse EffectTime to Onset AfterTre atme nt I ni ti ation Fr equ en cy, %b

Motor complications

Motor fluctuations 3-5 y ~ 40 by 4-6 y; ~ 70 by≥9-15 y

Dyskinesia 3-5 y ~ 35 by 4-6 y; >85 by≥9-15 y

Impulsive and compulsivebehaviors

Impulse control disorders Any time ~ 15

Dopamine dysregulationsyndrome

Any time Up to 4

Punding Any time Up to ~ 15

Nausea Immediate ~ 15

Hallucinations Generally later in diseasecourse; earlier in olderpatients

>70 by 20 y

a SeeBoxfor definitions of uncommon terms.

bFrequencyof symptoms estimatedfroma compositeof studies.133-136

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adjunctrasagiline ismore effective than entacapone atreducing the

severityofmotorsymptomsintheofftime.30A CII,open-label trial

showedno significantdifference in reduced offtime, rate of motor

complications, or daily levodopa dose with entacapone compared

with levodopa dose fractionation.31

In most available CI (2 large) and CII (2 large and 3 intermedi-

ate) studies, entacapone and tolcapone (COMTIs) significantly re-

duced off time compared with placebo andbaselineand had simi-laradverseeffects, suchas nausea,diarrhea, orthostatic hypotension,

and dyskinesia.28,32,33 These2COMTIshavenotbeendirectlycom-

pared,but a “switching” study34 (adouble-blindstudy in whichpa-

tients taking entacapone were randomized to stay on entacapone

or switch to tolcapone)and uncontrolled evidence support greater

efficacy of tolcapone.35,36 However, hepatic monitoring is neces-

sary due to rare cases of fatalhepatotoxicitywith tolcapone.37

There is extensive, conflicting evidence for use of selegiline (a

MAOBI) to reduce off time.21,38 Orally disintegrating selegiline sig-

nificantly reduced off time compared with placebo in 1 intermedi-

ate CII study,39 but not in an intermediate CI study.40 Adjunct

rasagiline decreased daily offtime in 2 large CI studies.29,41

Dopamine agonists may be added to levodopa to reduce off

time. Adjunctive pramipexole, ropinirole (including their ex-tended-andprolonged-releaseformulations),andtransdermalroti-

gotine (24-hourcontinuous delivery)significantlyreducedoff time

compared with placebo (inat least1 largeCI studyeach and several

intermediate CII studies)20,21,28. Prolonged-release ropinirole was

moreefficaciousinmaintaininga20%ormorereductioninofftime

comparedwithimmediate-releaseropinirole (1largeCI study)42and

therewasnosignificantdifferenceinbenefitbetweenrotigotineand

pramipexole for the outcome of wearing-off–type motor fluctua-

tions(1largeCIstudy).43 Intermittent,asneeded,subcutaneousapo-

morphine provides rapid delivery to reduce bothersome off peri-

ods(1smallCIIstudy),butmayincreasedyskinesia. 28Aretrospective

review of patients receiving continuous subcutaneous apomor-

phineinfusionalsodemonstratedasignificantreductioninofftimecompared with the patients’ baseline.44

Controlled-releaselevodopa-carbidopadoesnotreduceofftime

more than immediate-release levodopa-carbidopa (4 small CIII

trials).28However,anewextended-release,levodopa-carbidopafor-

mulationreducedofftimecomparedwiththeimmediate-releasefor-

mulationin1largeCIstudy.45AnintermediateCIstudyoflevodopa-

carbidopa intestinal gel (LCIG), administered directly into the

duodenum by pump through a gastrostomy catheter, confirmed

early, small, open-label studies showing a marked reduction in off

time.21,46,47

Managementof Dyskinesia

It is unnecessary to treat mild nontroublesome dyskinesia. Dopa-minergicmedicationreductionstrategieswill reduce dyskinesia but

typicallyworsenparkinsonism.48Amantadineisfrequentlyusedfor

reducingdyskinesiaseverityandduration(1smallCI,1smallCII,and

several lower-quality studies),28,49-51 and is usually well tolerated.

Clozapinehasbeenshowntoimprovedyskinesia(1smallCIIIstudy). 21

Levodopa-carbidopa intestinal gel may be useful in the future, and

exploratory trialsof other agents areongoing.

In our experience, levodopa-related wearing-off–type motor

fluctuationsrespond,toavariableextent,toallofthereviewedthera-

peutic options, and, when 1 is suboptimally effective, 1 or more al-

ternatives may be combined with greater success. Some patients

requirea combinationof 3 or4 differenttypesof medications.Aman-

tadinecan be extremely effective in managing dyskinesia and effi-

cacy is generally retained in the long-term despite common con-

cernsabout tachyphylaxis.52 It is important to regularly reevaluate

the ongoing efficacy and need for various drugs, although le-

vodopa remains the mainstay of treatment for all patients. We do

not routinely use controlled-release levodopa-carbidopa and usu-

ally discontinue this in patients with motor complications given itsunreliable pharmacokinetics, although when administered at bed-

time it may provide better overnight Parkinson disease symptom

control when nighttime symptoms are problematic. Levodopa-

carbidopa intestinal gel appears promising in the management of

carefully selected patients with disabling motor fluctuations.

Management of Other Medication Adverse Effects

Nausea

Nauseaisafrequent,generallytransientadverseeffectofdopamin-

ergic therapy. Slow titration of dopaminergic therapy and medica-

tion administration with food can reduce nausea. However, in the

long-term,foodmaydelaygastricemptying,anddietaryproteinmay

interfere with levodopa absorption.

53

The dopa decarboxylase in-hibitors carbidopa and benserazide prevent peripheral conversion

of levodopa to dopamine.An additional dose of carbidopa30 min-

utesbeforetheregularlevodopapreparationmayabolishlevodopa-

induced (but not dopamine agonist–induced) nausea.54 Domperi-

done,aperipheraldopamineD2-receptorantagonist(unavailablein

the United States), reduced nausea from dopaminergic medica-

tions in several small CIII andCIV studies.55,56Trimethobenzamide

has also been used for the same purpose.57 Metoclopramide,

prochlorperazine,andpromethazine canworsenparkinsoniansymp-

toms and should be avoided.

Box. Definitions of Common Parkinson Disease–Related Terms

“On”period: Periodswhenthepatientexperiencesagoodresponseto medication

“Off”period:Periods whenbenefit fromParkinson disease medica-tions wears off and symptoms reemerge (wearing-off–type motor

fluctuations)

Motor fluctuations: Alterations between on andoff periodsDyskinesia:Involuntary,nonrhythmicchoreicorchoreo-dystonicmove-

mentsmostoften relatedto peakdopamine levels;theycanlead tosocial embarrassment,impairedmotorfunction, injury, andweightloss

Rapid eye movement (REM) sleep behavior disorder: Character-ized by the loss of muscle atonia during REM sleep resulting in act-

ingout of dreams, often with aggressive or violent behavior, some-times resultingin injuryto thepatient or his/her bedpartner

Impulse control disorders: Include pathological gambling, hyper-

sexuality, bingeeating, and compulsiveshopping

Dopamine dysregulation syndrome: A form of addictive behavior

with the compulsive overuse of dopaminergic medications (typi-cally shorter-acting medications, such as levodopa and apomor-

phine)impairingphysical, social, and occupationalfunctioning5

Punding: Repetitive,often purposeless,stereotypedbehaviors, suchas sorting or disassembling6





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Impulsive and CompulsiveBehaviorsIncludingICDs, Dopamine

Dysregulation Syndrome, and Punding

Impulse control disorders are typically, but not exclusively, associ-

ated with dopamine agonist use.58 A history of obsessive-

compulsive disorder, impulsive personality, or addictive behaviors

increases the likelihood of ICDs.59 Given the effect of ICDs, these

need to be discussedon initiation ofa dopamine agonistand moni-

tored regularly. Dopamine agonist dose reduction or discontinua-

tion,potentially offset by increasing levodopa, is a generally effec-

tivetreatmentofICDs.

60-62

Withdrawalsymptomsincludinganxiety,depression, fatigue, pain, orthostatic hypotension, and drug crav-

ings(the dopamineagonistwithdrawal syndrome)unresponsive to

increasing levodopa may occur in 15%to 20%of patients.63

Zonisamidemarkedlyreducedtheseverityofimpulsivebehav-

iors and global impulsiveness refractory to dopaminergic medica-

tion dose reduction in a small CIII study.64 Amantadine improved

pathological gambling resistant to dopamine agonist dose reduc-

tion or withdrawal or behavioral strategies in 1 small CII study.65 In

small case series (1 CIV study each), topiramate66 and valproate67

were effective.

Managementofdopaminedysregulationsyndrome(DDS)typi-

cally involves a gradual reduction of levodopa and immediate dis-

continuation of “booster” doses of medications (such as subcuta-

neous apomorphine boluses and rapid-acting levodopa

formulations).5Nostudieshaveformallyexaminedmanagementof

DDS, but in a small case series of 4 patients (1 CIV study), all 4 re-

sponded to valproate.68

Improvement of punding may follow reduction or cessationof

dopaminergic medication; amantadine and quetiapinemay alsobe

beneficial (1 small open-label, prospective, CIII study).

69

Psychosis

Hallucinationsarebothafeatureoflater-stageParkinsondiseaseand

a consequence of Parkinson diseasemedication,whereas additional

psychotic symptoms are generally drug-related.Clozapine and que-

tiapine have beenmostextensivelystudied forthe treatmentof psy-

chosisinParkinsondiseasegiventhepropensityofotherneuroleptics

toworsenparkinsonism.Clozapineisconsistentlyefficacious(1inter-

mediateCI study and 1 intermediate CIIstudy [both withopen-label

extensions of the study treatment use] and 2 comparative studies

Figure 1. SchematicIllustrationof Neurologic Pathways Affected in Parkinson Diseaseand Sites of Action of Medications for theTreatmentof Motor

Symptoms

Degeneration of

dopamine-producing

neurons

BLOOD VESSEL

STRIATUM

STRIATUM

NIGROSTRIATAL

DOPAMINERGIC

AFFERENT

MEDIUM SPINY

GABAergic

DENDRITE

CHOLINERGIC

AFFERENT

SUBSTANTIA NIGRA

Inhibit breakdown

of dopamine

MAOBIs

Medium spiny

neuron

Corticostriatal

glutamatergic

afferentCaudate

nucleus

Cortex

Striatum

Cholinergic

interneuron

Nigrostriatal

dopaminergic

afferent

Binds to and activates

dopamine receptors

Bind to and activate

dopamine receptors

Bind to and block

acetylcholine

receptors

Binds to and blocks

NMDA glutamate

receptors

Dopamine

agonists

Levodopa Dopamine3-OMD

(Carbidopa, benserazide)

Levodopa

Levodopa

Blood-brain

barrier

(Entacapone, tolcaponea)

ConversionDegradation

Amantadineb

Anticholinergics

DDCIs

Dopamine

COMTIs

Conversion

Conversion

Putamen

PONS

PONS

Midbrain

Substantia nigra

Midbrain

Dopamine

CORTICOSTRIATAL

GLUTAMATERGIC

AFFERENT

2

1

1

2

Availablemedicationsto treat themotor symptoms of Parkinsondiseaseact oncomplex neurologic interactions in thestriatum thataffect motoractivity.Dopaminergicafferents from thesubstantianigra, glutamatergic afferents fromthe cerebral cortexand thalamus, and cholinergicstriatal interneuronsallconverge to influencetheactivityof themainefferentneuronsof thestriatum,the medium spinyGABAergicneurons. Levodopa is transportedfrom theperipheral circulationacross theblood-brain barrier and is converted centrallyto dopamine, replacing theneurotransmitter deficient in Parkinson disease.Outside the blood-brain barrier, in the peripheral circulation,dopaminedecarboxylase inhibitors (DDCIs) blockthe conversionof levodopa todopamine, and catechol-O-methyltransferase inhibitors (COMTIs) blockitsdegradationto 3-0-methyldopa (3-0MD). In thestriatum,levodopa, dopamine

agonists, and monoamineoxidase typeB inhibitors (MAOBIs) all havedopaminergiceffects.Anticholinergicdrugs and amantadineact onpostsynaptic receptors for otherneurotransmitters in thestriatum.Theseneurotransmittersbind to and activate multiple different subtypes of receptorspresent on thevarious presynaptic afferentsin thestriatum,as well as onpostsynaptic efferent mediumspiny neurons. NMDAindicatesN-methyl-D-aspartate.a Tolcapone, unlike entacapone, is able to cross theblood-brainbarrier and

blockdegradationof levodopa and dopamine.bAmantadinehas dopamine releasing effects in addition to affecting NMDA

glutamate receptors.


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[smallCIIandCIII]),whereasresultsforquetiapinearemixed(4nega-

tiveblindedRCTs [1 small CI, 2 small CII,and 1 intermediateCII]and 1

positive blindedRCT[smallCII],andvariedresults incomparative stud-

ieswithclozapine).12,70-73However,quetiapineisoftenprescribedfirst

becauseoftheriskofagranulocytosisandtherequirementforfrequent

blood monitoring withclozapine.

Olanzapine wasfoundin 2 CIIstudies (1 small and1 intermedi-

ate) to be ineffective for hallucinations and may cause motor

deterioration,72 and another study was stopped early for these

reasons74; therefore, olanzapine should notbe used for Parkinson

disease.72 Similar motor deterioration hasbeen observed with ris-

peridone and aripiprazole.75

Table 4. Treatmentof Motor Symptomsof Parkinson Disease

Medication Class Efficacya Dosage

Level of Recommendationb

Indication Adverse EffectsMonotherapyc Adjunct Therapy

Levodopa-PDDI

Levodopa-carbidopa 1 Titrate toinitial doseof100/25 mgthrice daily; max,1500/375mg/dor more basedon symptoms

A A All motorsymptoms

Nausea, orthostatic hypotension,dyskinesia, and hallucinations

Levodopa-benserazide 1 Titrate toinitialdose of100/25 mgthrice daily; max,1500/375mg/dor more basedon symptoms


Same as levodopa-carbidopa

Dopamine agonists

Pramipexole 2 Start 0 .125 m g thrice d aily; m ax,4.5 mg/d


Nausea, orthostatic hypotension,hallucinations, ICDs, edema, andincreased sleepiness(includingsleep attacks)

Pramipexoleextended release

2 0.26 m g, 0 .52 m g, 1 .05 m g, 2 .1mg,or 3.15 mgonce daily


Sameas pramipexole

Ropinirole 2 Start 0.25 mg thrice daily; max, 24mg/d


Sameas pramipexole

Ropinirole pro-longed release

2 6-24 mg once daily A A All motorsymptoms

Sameas pramipexole

Rotigotine 2 Start 2 mg/24 h; max, 16 mg/24 h A A All motorsymptoms

Sameas pramipexole

MAOBIs

Selegiline 3 2.5 mg once daily; max, 5 m g twicedaily

A U Early, mildsymptoms,and MF

Stimulant effect, dizziness, head-ache, confusion, andexacerbationof levodopaadverseeffects

Rasagiline 3 1 mg once daily A A Early, mildsymptoms,and MF

Headache, arthralgia, dyspepsia,depression,flulike syndrome,exacerbation of levodopaadverseeffects, and constipation

COMTIs

Entacapone 3 200 m g with e ach d ose o f levodopa;max,8/d

A MF Dark-colored urine and exacerba-tionof levodopaadverse effects

Tolcapone 3 100-200 mg thrice daily A MF Dark-colored urine, exacerbationof levodopaadverseeffects,andhepatotoxicity

Unspecified

Amantadine 4 Start 100 mg o nce daily; max, 4times daily (thrice daily is typical)

U C Gait dysfunctionand dyskinesia

Hallucinations, confusion,blurredvision, ankle edema,livedo reticularis, nausea, drymouth, andconstipation

β-Blocker

Propranolol 5 Start 4 0 mg t wice d aily; m ax, 3 20mg/d

U U Tremor Fatigue and dizziness

Anticholinergic

Trihexyphenidyl 4 Start1 mgonce daily; typicalmain-tenance dose 2 mgthrice daily

U U Tremor Hallucinations, CI, nausea, drymouth, blurred vision, urinaryretention, and constipation

Benztropine 4 Start 0 .5-1 m g once d aily; u sualdose 1-2mg thricedaily

U U Tremor Same as trihexyphenidyl

Neuroleptic

Clozapine Undeterminedd Start6.25-12.5mg at bedtime;max, 150mg/d

C fortremor;U for dyskinesia

Tremor anddyskinesia

Agranulocytosis, myocarditis,seizures,sedation, andortho-static hypotension

Abbreviations: CI, cognitive impairment;COMTIs,catechol-O-methyltransferaseinhibitors; ICDs,impulse control disorders; MAOBIs,

monoamine oxidase typeB inhibitors;MF, motorfluctuations; PDDI, peripheraldopa decarboxylase inhibitor.a Efficacy scoredfrom 1 (mosteffective) to 5 (least effective).bLevelof recommendation is based onthe numberand strengthof studies (as

defined byAmerican Academy of Neurology classes I-IV as outlined ineTable 1in the Supplement) available: A = established effective;B = probably effective;

C = possibly effective;U = data inadequateor conflicting.137

c Cells areleft emptywhenmedication is notusedas monotherapy.dRefers only to theindeterminateefficacyof clozapinefor tremor(not

hallucinations or dyskinesia).





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The cholinesterase inhibitor donepezil reduced hallucinations

in patients with Parkinson disease without dementia (1 small CIII

study),76and rivastigminereduced hallucinations in those withde-

mentia(1intermediateCIIstudy).77Ziprasidonewaseffectiveforpsy-

chosisin Parkinsondisease in 2 small CIII studies.78,79

Inourexperience,thetreatmentoptionsoutlinedabovewillal-

most always adequately control gastrointestinal intolerance and it

is extremely rare for gastrointestinal symptoms to limit the use of

therapeutically effectivedosesof levodopa.Mostproblematic ICDs

canbe successfullymanaged. Involvementof caregivers, family, and

friends to limit the patient’s access to money, Internet sites, food,

orcasinos,isoftenhelpful.Insomepatients,ICDsarerefractory,es-

pecially when symptoms of dopamine agonist withdrawal syn-

dromeoccur.We do not use amantadine for pathological gambling

becauseICDsmaybemorecommoninpatientstakingthisdrug,and

we have seen them develop as a consequence of adding amanta-

dinetolevodopa.ManagementofDDSisextremelychallengingand

anexpertinaddictionmanagementshouldassistinthecareofthese

patients. Hospital admission may be required if prominent mood

symptoms,hypomania,orpsychoticepisodesdevelop.Inmanypa-

tients,pundingbehaviorcanbemonitoredwithouttreatment;how-

ever, whensymptomsbecome disruptiveand thepatientis onlytak-

inglevodopainadoserequiredtomaintainmotorcontrol,treatment

is often unsatisfactory.

Our approach to new-onset or increased hallucinations

includes initial exclusion of systemic illness (such as infection) or

other medication use.80 We then reduce or discontinue antipar-

kinsonian drugs in order from lowest efficacy, starting with anti-

cholinergics, amantadine, and MAOBIs, followed by dopamine

agonists and COMTIs.81 Finally, the levodopa dose is cautiously

reduced and the patient is monitored for a disabling increase in

parkinsonism, including the rareoccurrence of a neuroleptic malig-

nantlike state. Quetiapine and clozapine can help to avoid these

outcomes; clozapine clearly has the highest efficacy for hallucina-

tions and psychosis. Cholinesterase inhibitors may reduce halluci-

Figure 2. Algorithm for theTreatmentof Parkinson Disease WithTremor-Dominant Motor Symptoms

Monitorb

Yes

Yes

Age ≥60y

Add or change todopamine agonist25

Add dopamineagonist or COMTIor MOABI

None orsuboptimal benefitc



Add or changeto levodopa

If excellent tremorcontrol, discontinueanticholinergic drugor β-blocker

YesIf excellent tremorcontrol, discontinueanticholinergic drugor β-blocker

Benefit?

Benefit?

Benefit?

Patient with Parkinson disease

Postural instabilityand/or gait impairment

TremorTremor

See Figure 4See Figure 3

Bradykinesia with slownessand impaired dexterity

MonitorbYes

Benefit?


Anticholinergic drug12,a

or β-blocker12,14-17

Initial treatment

Monitorb


Add or change to levodopa,anticholinergic drug, orβ-blocker

Add clozapine12,18

Consider surgery to treatrefractory tremord

Add clozapine12,18

Consider surgery to treatrefractory tremor

Add clozapine12,18

Consider surgery to treatrefractory tremor

Benefit?Yes Monitorb

Yes

None orsuboptimal

benefitc

Good butmotorfluctuations

Benefit?

Dopamine agonist12,22,23Initial treatment

Age

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nations, but generally not other psychotic symptoms. A very

recent intermediate CI study showing efficacy for the selective

serotonin 5-HT2A inverse agonist pimavanserin for psychotic

symptoms82 provides new promise for future therapies not requir-

ing extensive monitoring.

Management of Selected Nonmotor Symptoms

RapidEye Movement Sleep Behavior Disorder

Clonazepam is a first-line therapy for rapid eye movement sleep

behavior disorder (RBD),83 but only case reports and case series

are available on its use in Parkinson disease patients.84 Similarly,

there is little evidence for melatonin specifically in patients with

Parkinson disease, but 1 small CI RCT showed benefit in patients

with RBD who were not diagnosed with Parkinson disease.84,85

Rivastigmine improved the frequency of RBD episodes in 1 small CI

study.86

We prescribemelatonin forpatients whodo nottolerateclon-

azepam or as a first-line therapy for patientswith relative contrain-

dications to clonazepam (such as dementia, obstructive sleep ap-

nea, and extreme frailty with an increased risk of falls).84

Depression

The literature on treatment of depression in Parkinson disease is

mixed.A 2013systematicreviewand meta-analysisassessed6 RCTs

(2 small CI, 1 intermediate CI, 1 intermediate CII, 2 small CIII) of an-

tidepressantsfordepressioninpatientswithParkinsondisease(in-

volving sertraline, citalopram, paroxetine, venlafaxine, desipra-

mine, and nortriptyline).87 There was no statistically significant

superiority of antidepressants compared with placebo, as a group

or by class,but tricyclicantidepressants were superior to selective

serotoninreceptorinhibitors(SSRIs;2studies 88,89).However,asen-

sitivityanalysisthatexcludedstudieswithquestionableresults,high

risk of bias (3 of 6 studies),or both found antidepressants to be ef-

ficacious. Two other recent meta-analyses showed no significant

pooled effect of antidepressants and insufficientevidence to sup-port use of SSRIs, serotonin-norepinephrine reuptake inhibitors

(SNRIs), or pramipexole, but tricyclic antidepressants were found

more efficacious thanplacebo.90,91All3 studies (largeCI, interme-

diateCII,smallCIII)92-94assessingpramipexolefordepressioninpa-

tientsnotrequiringfurthertreatmentofmotorsymptomswereposi-

tive,but only the largest was placebo-controlled.

Although evidence is lacking for the use of specific SSRIs and

SNRIsto treatpatients withParkinson disease–relateddepression,

in our experience, both can be effective for this indication. Sertra-

line,escitalopram,citalopram,andextended-releasevenlafaxineare

commonly used due to familiarity and low likelihood of major ad-

verseeffects.Althoughwefindtricyclicantidepressants,inparticu-

lar nortriptyline anddesipramine,effective, they are used less fre-quentlyduetoconcernsaboutadverseeffectsinolderpatientswho

arecognitivelyimpaired.Pramipexoleisanoption,especiallywhen

both motor and mood symptoms arebeingtargeted.

Cognitive Impairment

Patients with Parkinson disease often develop mild cognitive im-

pairment andmay progress to Parkinson disease dementia (PDD).

Fewstudieshave assessedtreatment of mildcognitive impairment

in patients with Parkinsondisease.A small CIVpilotstudy of atom-

oxetine in patients with Parkinson disease and executive dysfunc-

tion demonstrated a clinically significant improvement and a small

CIIstudy ofatomoxetinefor treatmentof depressionin patientswith

Parkinson disease reported improvements in global cognitive

performance.

95,96

Cholinergicdysfunctionmaybepartiallyresponsibleforthecog-

nitiveimpairmentseeninthemajorityofpatientswithParkinsondis-

ease over time.97 There are no published studies of cholinesterase

inhibitors for Parkinson disease–related mild cognitive impair-

ment,butaphase4RCToftherivastigminetransdermalpatchiscur-

rently under way (NCT01519271) and a study of donepezil for pa-

tientswithParkinsondisease–relatedmildcognitiveimpairmentand

PDD is planned (NCT01014858). Rasagiline improved some mea-

suresofattentionandverbalfluencyinpatientswithParkinsondis-

easeand mildcognitive impairment (1 intermediate CII study), sug-

Figure 3. Algorithm for theTreatmentof Parkinson Disease With

Predominant Bradykinesia and Impaired Dexterity

Monitorb

Monitorb Monitorb

Age

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gesting a favorable benefit on executive function.98 A longer-term

study is ongoing (NCT013823420).

A recent Cochrane review foundthat cholinesterase inhibitors

are associated with improvements in global assessment, cognitive

function, behavioral disturbance, and activities of daily living in pa-

tientswithPDD.99Fiveplacebo-controlledtrialshaveassessedcho-

linesterase inhibitors for PDD.70,100 Rivastigmine moderately im-

provedmeasuresofdementia,cognition,andbehavioralsymptoms

(1 large CII trial). Three small studies of donepezil (2 CI and 1 CII)

showed variable benefit, whereas 1 large CII study did not achieve

its predefined primary end points, but secondary outcomes sug-

gested that donepezil may improve cognition, executive function,and global status in PDD.100 There are no blinded RCTs of galan-

tamine for PDD, but 1 small, open-label CIII study suggested ben-

efit. Conflicting data exist forthe useof memantine, a N-methyl-D-

aspartate receptor antagonist, in PDD.70

In our experience, achievingclinically meaningful benefit with

cholinesteraseinhibitors in PDD is variableand unpredictable. Still,

theresponsein somepatients canbe striking;therefore,a trialis war-

ranted. However, exacerbation of tremor can limit their use. Gas-

trointestinal symptoms can also be problematic and the rivastig-

mine transdermal patch is generally better tolerated than the oral

formulation. Response to memantine has been disappointing.

Orthostatic Hypotension

Orthostatic hypotension can be a major problem in Parkinson dis-easeandshouldberegularlyevaluated.Orthostatichypotensioncan

be an inherent componentof Parkinsondisease as a manifestation

ofautonomicdysfunction,butitcanalsobeanadverseeffectofdo-

paminergic medication. One small CII study reported improve-

mentin symptoms of orthostatichypotension andclinicalglobalim-

pression, focusing on orthostasis with use of fludrocortisone or

domperidone compared with nonpharmacological measures; al-

though notall participantshad orthostatic hypotensionatbaseline.101

Midodrinewasevaluatedfortreatingneurogenicorthostatichy-

potension in 3 studies (2 intermediate CI and 1 small CII) that in-

cluded patients with Parkinson disease,102-104 and a small CIII trial

of pyridostigmine for orthostatic hypotension included 3 patients

withParkinson disease.105

Results were positive,but patientswithParkinsondisease were not analyzed separately. A small crossover

trial of yohimbinefor orthostatic hypotension in patients with Par-

kinsondiseasewasnegative,106whereasasmallCIIcomparisonstudy

of yohimbine and pyridostigmine vs placebo involving some pa-

tients with Parkinsondisease demonstrated a significant improve-

ment only for yohimbine.107

InasmallCIIIstudy,indomethacinsignificantlyreducedorthostatic

symptomsanddropinbloodpressurewithstanding. 108Droxidopa,a

syntheticprecursorof norepinephrine,caused an objectiveimprove-

ment in orthostatic hypotension but not of orthostatic hypotension

symptomsin a placebo-controlled RCTin Parkinsondiseaseand mul-

tiplesystematrophy (publishedin abstractform only).109

Inourexperience,domperidone(notuniformlyavailableintheUnitedStates)controlsdopamineagonist–inducedhypotension,es-

peciallywhenitoccursontheintroductionofdopamineagonisttreat-

ment.It can also improve orthostatic hypotension worsened by le-

vodopa. Before or in concert with trials of fludrocortisone and

midodrine,weusenonpharmacologicaltechniquesformanagingor-

thostatic hypotension, includingincreasingsalt andfluid consump-

tion, elevating the head of the bed, and compression stockings.

Quickly drinking 2 8-ounce glasses of cold water can have a rapid

ameliorative effect on orthostatic hypotension. Monitoring for su-

pinehypertension is importantwhen using antihypotensive drugs.

Figure 4. Algorithmfor theTreatmentof Parkinson DiseaseWith

Predominant Postural Instability and GaitImpairment

Monitorb

Monitorb

Age

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Table 5. Treatment of Nonmotor Symptomsof Parkinson Disease

Nonmotor Symptom Medication DosageLevel of

Recommendationa Adverse Effects

Nausea Domperidoneb 10 mg thrice daily; max,20mg 4 times daily

U Cardiac arrhythmia, suddencardiac death,breastpain, drowsiness, dry mouth, headache, hot flashes,andnausea

RBDClonazepam 0.25-2 mg at bedtime U Sedation and confusion

Melatonin 3-15 mg at bedtime U Daytime sleepiness, dizziness, and headache

Depression

Citalopram 10-20 mg once daily U Akathisia, anorexia, nausea, drowsiness, and sexualdysfunction

Fluoxetine 10-50 mg once daily C Same as citalopram

Paroxetine 20-40 mg once daily U Same as citalopram

Sertraline 25-200 mg once daily(rarely >100mg)

U Same as citalopram

Venlafaxine extendedrelease

37.5-225 m go nce d aily B Drowsiness, i nsomnia, s exual d ysfunction, a nd gas-trointestinal symptoms

Nortriptyline 25-150 m g/d s ingle o rdivided

C Anticholinergic e ffectsd, orthostatichypotension,ventricular arrhythmias, heartblock, drowsiness,sexual dysfunction, andweight gain

Desipramine 25-150 m g/d single o rdivided

B Same as nortriptyline

Hallucinations

Clozapine 6.25-150 mg at bedtimeor divided (often effectiveinvery lowdoses)

B Agranulocytosis,seizure, myocarditis,cardiomyo-pathy,and sedation

Quetiapine 12.5-400 mg at bedtimeor divided C Extrapyramidalsymptoms andsedation

Rivastigminec 1.5-6mg twicedaily;transdermal patch, 4.5-9.8mg/24 h

C Gastrointestinalsymptoms,bradycardia, vividdreams, andexacerbationof resttremor

PD-MCI Atomoxetine Target dose, 80 mg oncedaily

U Alopecia, dry mouth,sexualdysfunction,gastroin-testinalsymptoms, dizziness, andincreased heartrateand bloodpressure

PDD

Rivastigmine 1.5-6 m g twice d aily;transdermal patch, 4.5-9.8mg/24 h

B Same as rivastigmine

Donepezil 5-10 mg once daily B Same as rivastigmine

Galantamine 4-12 mg twice daily U Same as rivastigmine

OrthostaticHypotension

Fludrocortisone 0.05-0.1mg onceortwicedaily

C Hypertension, metabolic abnormalities (includinghypokalemia), gastrointestinal symptoms, andmyopathy

Domperidoneb 10 mg thrice daily; max,

20mg 4 times daily

C Same as domperidone

Midodrine 2.5-10 mg thrice daily U Hypertension, nausea, weakness, heartburn, head-ache, scalp tingling, and chills

Pyridostigmine 50 m g thrice d aily U Hypertension, g astrointestinal symptoms, s weating,and increased salivation/bronchialsecretions

Indomethacin 50 mg t hrice daily U Hypertension, edema, metabolic abnormalities,gastrointestinal symptoms,headache, and renaldamage

Yohimbine 2 mg thrice daily U Blood pressure changes, sexual dysfunction, halluci-nations, seizure, andrenal failure

Droxidopa 300 mg thrice daily U Hypertension, tachycardia, nausea, vomiting, andheadache

Sialorrhea

Glycopyrrolate 1 mg thrice daily B Anticholinergic effectsd

Atropine 1-2 drops of 1% concen-tration up to 4 times daily

U Same a s glycopyrrolate

Ipratropium bromide 1-2 sprays(21 μg);max,4 timesdaily

U Same a s glycopyrrolate

BTA Varies by formulation B Dysphagia, dry mouth, and injection-associateddiscomfort

BTB Varies by formulation B Same as BTA

Abbreviations: BTA,botulinumtoxin typeA; BTB,botulinum toxintype B; PDD,Parkinson disease dementia;PD-MCI, Parkinson disease mild cognitiveimpairment;RBD, rapideye movementsleep behavior disorder.a Levelof recommendation is based onthe numberand strength(as defined by

American Academy of Neurology classes I-IVas outlinedin eTable 1 intheSupplement)of studies available: A = establishedeffective;B = probablyeffective;C = possibly effective;U = data inadequateorconflicting.137

bDomperidone hasa black boxwarningin theUnited States.c Rivastigmine for hallucinations in patients withdementia.dAnticholinergic effects include cognitive impairment,hallucinations,blurred

vision, dry mouth, urinaryretention, and constipation.





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Sialorrhea

Atropine drops were effective forsialorrhea in 6 patients with Par-

kinsondisease,but systemic adverseeffects,includingdelirium and

hallucinations, occurred (1 small CIII study).2 Ipratropium bromide

spraydid not improve objective or subjectivemeasuresof drooling

following2weeksoftreatment(1smallCIstudy), 110whereas glyco-

pyrrolate significantly improved mean sialorrhea scores (1 small CI

study).

111

Although a pilot study (small CI) of intraoral tropicamidefilm112 failed toshowbenefit,a phase2 studyis currentlyunder way

(NCT01844648).

Treatment with botulinum toxin type A (BTA) injections signifi-

cantly improvedanobjective measure of saliva quantity, measuresof

socialembarrassment, anddrooling frequency in a small CIIstudy.113

Benefits were alsoreported in2 small RCTs (1CI and 1 CIII) ofBTAfor

sialorrhea in mixed populations including patients with Parkinson

disease.4,114 Botulinum toxin type B (BTB) injections reduced drool-

ing, disability, and embarrassment related to sialorrhea (1 intermedi-

ate CI, 1 small CII, and 1 small CIV studies).115-117 Injections of BTA and

of BTB hadsimilareffectivenessand safetyin a small CIIpilot study of

patientswithamyotrophiclateralsclerosisorParkinsondisease.118Dys-

phagiais a potentialadverse effectand maylimituse.

Inour experience,anticholinergicdrugswithrelativelylowcentralactivitymaybeusefulbutarepoorlytoleratedinolderpatientswithcog-

nitivedysfunction,whereasglycopyrrolatemaybeveryeffectiveand

better tolerateddue tolimited blood-brainbarrierpenetration. Injec-

tionsof BTA canbe effectiveand arewell tolerated; standard parotid

injectionscanbe supplementedwithsubmandibularinjectionsfor im-

proved efficacy but havepotentiallymorecomplications.

Discussion

Inthisreviewwehave summarizedtheevidencefromthe literaturead-

dressing initial treatment and management of various disease- and

treatment-relatedsymptoms.OurrecommendationsareinagreementwithseveralrecentlypublishedguidelinesonthemanagementofPar-

kinson disease (eTable3 in theSupplement).High-quality evidenceis

available for some treatment recommendations, for example initial

therapy,butforotherissues,suchasmanagementofdyskinesia,nau-

sea,RBD,andorthostatichypotension,dataarelimited.Fortheseprob-

lemswehavemaderecommendationsbasedonourreviewofpublished

evidence andour experience.

Levodopa is the most effective treatment for Parkinson dis-

ease. Figure 2, Figure 3, and Figure 4 provide a treatment algo-

rithm for Parkinson disease motor symptoms based on age, symp-

tomcharacteristics,andresponsestotreatment.Table4summarizes

treatmentoptions for motorsymptomsincluding indications,level

of recommendation for efficacy, doses, and adverse effects.

Many patients incorrectly believe thatlevodopa loses efficacy

after 5 years or that it is toxic to dopamine neurons. These con-

cerns,andafearofdevelopingmotorcomplications,especiallydys-

kinesia, oftenresult in a “levodopa phobia.” However, dyskinesiaisoften mild and can usually be successfully treated.119 Age is espe-

cially important because younger patients develop dyskinesia ear-

lier and more frequently following the initiation of levodopa, and

older patients are more prone to cognitiveand psychiatric adverse

effects withall anti-Parkinsonmedication,requiringcarefulassess-

mentof riskto benefitratios. Dyskinesiaand motor fluctuationsthat

impair quality of life are indications for deep brain stimulation and

thistreatment should be consideredin younger patients(generally

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2. HysonHC, Johnson AM,Jog MS. Sublingualatropine for sialorrhea secondary to parkinsonism:a pilot study. Mov Disord . 2002;17(6):1318-1320.

3. Ishihara LS,CheesbroughA, BrayneC, SchragA.Estimatedlife expectancyof Parkinson’s patientscompared withthe UK population. J Neurol NeurosurgPsychiatry . 2007;78(12):1304-1309.

4. Mancini F, ZangagliaR, Cristina S,et al.Double-blind,placebo-controlled studyto evaluate

theefficacyand safetyof botulinumtoxintypeA inthe treatmentof drooling in parkinsonism. Mov Disord . 2003;18(6):685-688.

5. O’Sullivan SS,Evans AH,LeesAJ.Dopaminedysregulationsyndrome: an overview of itsepidemiology, mechanisms,and management. CNS Drugs. 2009;23(2):157-170.

6. EvansAH, Katzenschlager R, PaviourD, etal.Punding in Parkinson’s disease: its relation to thedopamine dysregulation syndrome. Mov Disord .2004;19(4):397-405.

7. FrenchJ, GronsethG. Lost in a jungleof evidence:we need a compass. Neurology .2008;71(20):1634-1638.

8. Gronseth G, French J. Practice parametersandtechnology assessments: whatthey are, whattheyarenot, andwhy youshould care. Neurology .2008;71(20):1639-1643.

9. AlDakheelA, Kalia LV, Lang AE.Pathogenesis-targeted, disease-modifyingtherapies in Parkinsondisease. Neurotherapeutics.2014;11(1):6-23.

10. Ives NJ, StoweRL, Marro J,et al.Monoamineoxidase typeB inhibitors in earlyParkinson’sdisease: meta-analysis of 17 randomised trialsinvolving 3525 patients. BMJ . 2004;329(7466):593.

11. OlanowCW,Rascol O,Hauser R, etal; ADAGIOStudyInvestigators.A double-blind, delayed-starttrial of rasagiline in Parkinson’s disease. N EnglJ Med . 2009;361(13):1268-1278.

12. Ferreira JJ, Katzenschlager R, Bloem BR,et al.Summary of the recommendations of theEFNS/MDS-ESreview on therapeutic managementof Parkinson’s disease. EurJ Neurol .2013;20(1):5-15.

13. Katzenschlager R, SampaioC, Costa J,LeesA.Anticholinergics for symptomatic management of Parkinson’s disease. Cochrane Database SystRev .2003;(2):CD003735.

14. KollerWC, HerbsterG. Adjuvanttherapyof parkinsonian tremor. Arch Neurol .1987;44(9):921-923.

15. Foster NL, Newman RP, LeWitt PA,GillespieMM, LarsenTA, ChaseTN. Peripheralβ-adrenergicblockade treatment of parkinsoniantremor. AnnNeurol . 1984;16(4):505-508.

16. Herring AB.Actionof pronethalol onparkinsonian tremor. Lancet . 1964;2(7365):892.

17. Owen DA,MarsdenCD. Effectof adrenergicβ-blockade on parkinsoniantremor.Lancet .1965;2(7425):1259-1262.

18. FriedmanJH, KollerWC, LannonMC,Busenbark K, Swanson-Hyland E, SmithD.Benztropinevs clozapine for the treatmentof tremorin Parkinson's disease. Neurology .1997;48(4):1077-1081.

19. CrosbyN, DeaneKH, ClarkeCE. Amantadine inParkinson’s disease. Cochrane DatabaseSyst Rev .2003;(1):CD003468.

20. FoxSH,KatzenschlagerR, LimSY, Barton B,Seppi K, CoelhoM, etal. Updateon treatments formotorsymptomsof PD. http://www.movementdis-orders.org/UserFiles/file/update-on-treatments-for-motor-symptoms-of-PD.pdf?new.Accessed March27,2014.

21. Fox SH,Katzenschlager R, LimSY, etal. TheMovementDisorder Society Evidence-BasedMedicine Review update: treatmentsfor themotorsymptoms of Parkinson’s disease. Mov Disord .2011;26(suppl 3):S2-S41.

22. RascolO, BrooksDJ,KorczynAD, DeDeynPP,ClarkeCE, Lang AE.A 5-yearstudyof theincidenceof dyskinesia in patients withearly Parkinson’sdisease whoweretreatedwith ropiniroleorlevodopa: 056 studygroup. NEngl JMed .2000;342(20):1484-1491.

23. Holloway RG,ShoulsonI, Fahn S,et al;Parkinson StudyGroup. Pramipexole vs levodopa asinitial treatmentfor Parkinson disease: a 4-yearrandomized controlled trial. Arch Neurol .2004;61(7):1044-1053.

24. Wickremaratchi MM, Ben-Shlomo Y, MorrisHR.Theeffect of onsetage onthe clinical features of Parkinson’s disease. EurJ Neurol .2009;16(4):450-456.

25. Katzenschlager R, Head J,Schrag A,Ben-ShlomoY, Evans A, LeesAJ; Parkinson’sDisease Research Groupof the United Kingdom.Fourteen-year final reportof therandomizedPDRG-UK trial comparing 3 initial treatmentsin PD.Neurology . 2008;71(7):474-480.

26. HauserRA, RascolO, Korczyn AD, etal.Ten-year follow-up of Parkinson’s disease patientsrandomized to initialtherapywith ropinirole orlevodopa. Mov Disord . 2007;22(16):2409-2417.

27. BiglanKM, HollowayR, MarekK, etal;Parkinson StudyGroup CALMCohort Investigators.

Long-termeffect of initiatingpramipexole vslevodopa in earlyParkinsondisease. Arch Neurol .2009;66(5):563-570.

28. PahwaR, Factor SA,Lyons KE,et al;QualityStandards Subcommittee of theAmerican Academyof Neurology.Practiceparameter: treatmentof Parkinson disease withmotor fluctuations anddyskinesia (an evidence-based review): reportof theQuality Standards Subcommittee of theAmerican Academy of Neurology.Neurology .2006;66(7):983-995.

29. RascolO, Brooks DJ, Melamed E, etal; LARGOstudy group.Rasagiline as anadjunct to levodopa inpatients withParkinson’s disease and motorfluctuations(LARGO,Lasting effect in Adjuncttherapy withRasagilineGiven Oncedaily,study):

a randomised,double-blind, parallel-grouptrial.Lancet . 2005;365(9463):947-954.

30. Stocchi F, RabeyJM. Effectof rasagiline asadjunct therapy to levodopa on severityof OFFinParkinson’s disease. EurJ Neurol .2011;18(12):1373-1378.

31. DestéeA, RératK, Bourdeix I. Is thereadifference between levodopa/dopa-decarboxylaseinhibitor and entacaponeand levodopa/dopa-decarboxylase inhibitor dosefractionationstrategiesin Parkinson’s disease patientsexperiencing symptom re-emergence due to

wearing-off? theHoneymoonStudy. Eur Neurol .2009;61(2):69-75.

32. ReichmannH, BoasJ, Macmahon D,Myllyla V,HakalaA, Reinikainen K; ComQol StudyGroup.Efficacy of combining levodopa withentacaponeonqualityof life andactivitiesof daily livingin patientsexperiencing wearing-offtype fluctuations. ActaNeurolScand . 2005;111(1):21-28.

33. MizunoY,KanazawaI, Kuno S,YanagisawaN,

YamamotoM, KondoT. Placebo-controlled,double-blinddose-findingstudy of entacaponeinfluctuating parkinsonianpatients. Mov Disord .2007;22(1):75-80.

34. Entacaponeto TolcaponeSwitchStudyInvestigators. Entacaponeto tolcapone switch:multicenter,do uble-blind, randomized,active-controlled trialin advanced Parkinson’sdisease. Mov Disord . 2007;22(1):14-19.

35. OnofrjM, ThomasA, Iacono D,Di IorioA,Bonanni L. Switch-over from tolcapone toentacaponein severe Parkinson’s disease patients.Eur Neurol . 2001;46(1):11-16.

36. Factor SA,MolhoES, Feustel PJ,BrownDL,Evans SM. Long-termcomparative experiencewithtolcapone and entacaponein advanced Parkinson’s

disease. ClinNeuropharmacol . 2001;24(5):295-299.

37. LewMF, Kricorian G.Results froma 2-yearcentralized tolcapone liverenzyme monitoringprogram. Clin Neuropharmacol . 2007;30(5):281-286.

38. Goetz CG,Koller WC,Poewe W,et al.Managementof Parkinson’s disease: anevidence-based review.Mov Disord . 2002;17(suppl4):S1-S166.

39. Waters CH,Sethi KD, HauserRA, Molho E,Bertoni JM;Zydis SelegilineStudy Group.Zydisselegiline reduces off timein Parkinson’s diseasepatients withmotor fluctuations:a 3-month,randomized, placebo-controlled study.Mov Disord .2004;19(4):426-432.

40. Ondo WG,Sethi KD, Kricorian G.Selegilineorallydisintegratingtablets in patients withParkinson disease and “wearing off” symptoms. ClinNeuropharmacol . 2007;30(5):295-300.

41. Schwid SR,ShoulsonI, Stern M,et al;ParkinsonStudyGroup. A randomizedplacebo-controlledtrialof rasagiline in levodopa-treatedpatients withParkinson disease and motorfluctuations:thePRESTO study. Arch Neurol . 2005;62(2):241-248.

42. Stocchi F, GiorgiL, HunterB, Schapira AH.PREPARED:Comparisonof prolonged andimmediate release ropinirole in advancedParkinson’s disease. Mov Disord . 2011;26(7):1259-1265.

43. Poewe WH, RascolO, Quinn N,et al;SP515Investigators. Efficacy of pramipexole andtransdermalrotigotinein advanced Parkinson’sdisease: a double-blind,double-dummy,randomised controlled trial.LancetNeurol .2007;6(6):513-520.

44. GarcíaRuiz PJ,SesarIgnacioA, AresPensadoB,et al. Efficacy of long-term continuoussubcutaneousapomorphine infusion in advancedParkinson’s disease withmotor fluctuations:a multicenter study. Mov Disord . 2008;23(8):1130-1136.

45. HauserRA, Hsu A,Kell S,et al; IPX066ADVANCE-PDi nvestigators. Extended-release





8/18/2019 A3-PARK1

13/14


carbidopa-levodopa (IPX066) compared withimmediate-releasecarbidopa-levodopain patientswithParkinson’s diseaseand motor fluctuations:a phase3 randomised,double-blindtrial. Lancet Neurol . 2013;12(4):346-356.

46. FernandezHH, OdinP. Levodopa-carbidopaintestinalgel for treatmentof advanced Parkinson’sdisease. Curr MedRes Opin. 2011;27(5):907-919.

47. Boyd JT, FernandezHH, SlevinJT, Espay AJ,

StandaertDG, PritchettY,et al.Efficacy of levodopa-carbidopa intestinalgel compared to orallevodopa-carbidopa in advanced Parkinson'sdisease: sensitivityand responder analyses. Mov Disord . 2013;28(suppl 1):S143.

48. Khan TS.Off spellsand dyskinesias:pharmacologicmanagement of motorcomplications. Cleve Clin J Med . 2012;79(suppl2):S8-S13.

49. SawadaH, Oeda T, Kuno S,et al;AmantadineStudyGroup. Amantadinefor dyskinesiasinParkinson’s disease: a randomizedcontrolledtrial.PLoS One . 2010;5(12):e15298.

50. Wolf E, Seppi K, Katzenschlager R, etal.Long-termantidyskineticefficacy of amantadineinParkinson’s disease. Mov Disord . 2010;25(10):1357-

1363.

51. CrosbyNJ, DeaneKH, ClarkeCE. Amantadinefor dyskinesia in Parkinson’s disease. Cochrane DatabaseSyst Rev . 2003;(2):CD003467.

52. Ory-MagneF,CorvolJC, AzulayJP, etal;NS-Park CIC Network. Withdrawingamantadine indyskinetic patients withParkinsondisease: theAMANDYSK trial. Neurology . 2014;82(4):300-307.

53. ContinM, Martinelli P. Pharmacokineticsof levodopa. J Neurol . 2010;257(suppl 2):S253-S261.

54. Hristova AH, Koller WC. EarlyParkinson’sdisease: what is thebestapproachto treatment.DrugsAging. 2000;17(3):165-181.

55. ParkesJD. Domperidoneand Parkinson’sdisease. Clin Neuropharmacol . 1986;9(6):517-532.

56. BraunM, Cawello W,BoekensH, HorstmannR.Influence of domperidoneon pharmacokinetics,safety, and tolerabilityof the dopamine agonistrotigotine. Br J Clin Pharmacol . 2009;67(2):209-215.

57. Gunzler SA.Apomorphinein thetreatment of Parkinson disease and othermovementdisorders.Expert Opin Pharmacother . 2009;10(6):1027-1038.

58. WeintraubD, Siderowf AD, Potenza MN,et al.Association of dopamine agonist use withimpulsecontrol disorders in Parkinson disease. Arch Neurol .2006;63(7):969-973.

59. Weiss HD, Marsh L. Impulse controldisordersand compulsivebehaviors associatedwithdopaminergictherapiesin Parkinson disease.NeurolClin Pract . 2012;2(4):267-274.

60. EvansAH, StrafellaAP, WeintraubD, Stacy M.Impulsive and compulsive behaviors in Parkinson’sdisease. Mov Disord . 2009;24(11):1561-1570.

61. MamikonyanE, Siderowf AD, Duda JE,et al.Long-termfollow-up of impulse control disorders inParkinson’s disease. Mov Disord . 2008;23(1):75-80.

62. Ávila A, CardonaX, Martín-BaraneraM, Bello J,Sastre F.Impulsiveand compulsive behaviors inParkinson’s disease: a 1-year follow-up study. J Neurol Sci . 2011;310(1-2):197-201.

63. PondalM, MarrasC, Miyasaki J,et al.Clinicalfeatures of dopamine agonist withdrawalsyndromein a movementdisorders clinic. J Neurol NeurosurgPsychiatry . 2013;84(2):130-135.

64. Bermejo PE,Ruiz-HueteC, Anciones B.Zonisamidein managing impulsecontrol disordersin Parkinson’s disease. J Neurol . 2010;257(10):1682-1685.

65. ThomasA, Bonanni L, Gambi F, Di Iorio A,

Onofrj M. Pathological gambling in Parkinsondisease is reduced by amantadine. Ann Neurol .2010;68(3):400-404.

66. Bermejo PE. Topiramate in managing impulsecontrol disorders in Parkinson’s disease.ParkinsonismRelat Disord . 2008;14(5):448-449.

67. HicksCW, PandyaMM, Itin I, Fernandez HH.Valproatefor the treatmentof medication-inducedimpulse-control disorders in 3 patients withParkinson’s disease. ParkinsonismRelat Disord .2011;17(5):379-381.

68. SriramA, Ward HE,Hassan A, etal. Valproateas a treatmentfor dopamine dysregulationsyndrome (DDS)in Parkinson’s disease. J Neurol .2013;260(2):521-527.

69. Fasano A, Ricciardi L, Pettorruso M,BentivoglioAR. Management of punding in Parkinson’s disease:an open-label prospectivestudy. J Neurol .2011;258(4):656-660.

70. Seppi K, WeintraubD, CoelhoM, etal. TheMovementDisorder Society Evidence-BasedMedicine Review Update: treatmentsfor thenonmotor symptoms of Parkinson’s disease. Mov Disord . 2011;26(suppl 3):S42-S80.

71. Shotbolt P, SamuelM, David A. Quetiapine inthetreatmentof psychosisin Parkinson’s disease.Ther AdvNeurol Disord . 2010;3(6):339-350.

72. Miyasaki JM,ShannonK, Voon V, etal; QualityStandards Subcommittee of the American Academyof Neurology. Practice Parameter:evaluation andtreatmentof depression,psychosis, and dementiain Parkinson disease (an evidence-based review):reportof theQuality Standards Subcommittee of theAmerican Academy of Neurology. Neurology .2006;66(7):996-1002.

73. EngML, WeltyTE. Management of hallucinations and psychosisin Parkinson’s disease. Am J Geriatr Pharmacother . 2010;8(4):316-330.

74. Goetz CG,BlasucciLM, LeurgansS, PappertEJ.Olanzapineand clozapine:comparative effects onmotorfunction in hallucinating PD patients.Neurology . 2000;55(6):789-794.

75. GoldmanJG, Vaughan CL,GoetzCG. Anupdateexpert opinionon management and researchstrategiesin Parkinson’s disease psychosis. Expert Opin Pharmacother . 2011;12(13):2009-2024.

76. Fabbrini G, Barbanti P, AuriliaC, Pauletti C,

LenziGL, Meco G.Donepezil in thetreatmentof hallucinations and delusions in Parkinson’s disease.Neurol Sci . 2002;23(1):41-43.

77. Burn D,EmreM, McKeith I, etal. Effects of rivastigminein patients withand without visualhallucinations in dementia associated withParkinson’s disease. Mov Disord . 2006;21(11):1899-1907.

78. PintorL, Valldeoriola F, BaillésE, Martí MJ,Muñiz A, Tolosa E. Ziprasidone vs clozapinein thetreatmentof psychoticsymptoms in Parkinson

disease: a randomizedopen clinical trial.ClinNeuropharmacol . 2012;35(2):61-66.

79. Gómez-Esteban JC,Zarranz JJ, Velasco F, etal.Use of ziprasidonein parkinsonianpatientswithpsychosis. ClinNeuropharmacol . 2005;28(3):111-114.

80. Thomsen TR, Panisset M, SuchowerskyO,GoodridgeA, MendisT,LangAE. Impactof standard of care forpsychosisin Parkinsondisease.

J Neurol Neurosurg Psychiatry . 2008;79(12):1413-1415.

81. DiederichNJ, Fénelon G,StebbinsG, GoetzCG.Hallucinations in Parkinsondisease. NatRev Neurol .2009;5(6):331-342.

82. Cummings J,IsaacsonS, Mills R, etal.Pimavanserin for patients withParkinson’s diseasepsychosis:a randomised,placebo-controlled phase3 trial. Lancet . 2014;383(9916):533-540.

83. Schenck CH,Bundlie SR,Ettinger MG,Mahowald MW.Chronic behavioral disorders of human REMsleep: a newcategoryof parasomnia. Sleep. 1986;9(2):293-308.

84. Aurora RN,Zak RS,MagantiRK, etal;Standards of Practice Committee;AmericanAcademy of SleepMedicine. Best practiceguideforthetreatmentof REMsleepbehaviordisorder(RBD). J Clin Sleep Med . 2010;6(1):85-95.

85. Kunz D,MahlbergR. A 2-part,double-blind,placebo-controlledtrial of exogenousmelatonininREM sleepbehaviour disorder. J Sleep Res.2010;19(4):591-596.

86. Di Giacopo R, Fasano A, Quaranta D,DellaMarca G,Bove F,BentivoglioAR. Rivastigmineasalternativetreatment for refractory REM behaviordisorder in Parkinson’s disease. Mov Disord .2012;27(4):559-561.

87. Rocha FL,MuradMG, StumpfBP, Hara C,Fuzikawa C. Antidepressantsfor depressioninParkinson’s disease: systematicreview andmeta-analysis. J Psychopharmacol .2013;27(5):417-423.

88. Devos D,DujardinK, PoirotI, etal. Comparisonof desipramineand citalopram treatmentsfordepression in Parkinson’s disease: a double-blind,randomized, placebo-controlled study. Mov Disord .2008;23(6):850-857.

89. Menza M,Dobkin RD, MarinH,et al. Acontrolled trial of antidepressants in patients withParkinson disease and depression. Neurology .2009;72(10):886-892.

90. TroeungL, Egan SJ, GassonN. A meta-analysisof randomisedplacebo-controlledtreatment trialsfor depressionand anxiety in Parkinson’s disease.PLoS One . 2013;8(11):e79510.

91. Liu J,Dong J,Wang L,Su Y, YanP, Sun S.Comparativeefficacy and acceptability of

antidepressants in Parkinson’s disease: a networkmeta-analysis. PLoSOne . 2013;8(10):e76651.

92. RektorováI, RektorI, Bares M,et al.Pramipexole and pergolide in thetreatmentof depression in Parkinson’s disease: a nationalmulticentreprospective randomizedstudy.Eur J Neurol . 2003;10(4):399-406.

93. BaroneP,PoeweW, Albrecht S,et al.Pramipexole for the treatmentof depressivesymptoms in patients withParkinson’s disease:a randomised,double-blind, placebo-controlledtrial. LancetNeurol . 2010;9(6):573-580.


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8/18/2019 A3-PARK1

14/14

94. BaroneP,Scarzella L, Marconi R, etal;Depression/Parkinson ItalianStudy Group.Pramipexole vs sertraline in the treatmentof depression in Parkinson’s disease: a nationalmulticenter parallel-grouprandomized study. J Neurol . 2006;253(5):601-607.

95. MarshL, BiglanK, GerstenhaberM, WilliamsJR. Atomoxetine for thetreatmentof executivedysfunctionin Parkinson’s disease: a pilot

open-label study.Mov Disord . 2009;24(2):277-282.96. WeintraubD, Mavandadi S, MamikonyanE,etal. Atomoxetinefor depressionand otherneuropsychiatricsymptomsin Parkinsondisease.Neurology . 2010;75(5):448-455.

97. PerryEK, McKeith I, ThompsonP,et al.Topography,extent,and clinical relevanceof neurochemical deficits in dementia of Lewybodytype,Parkinson’s disease, and Alzheimer’s disease. Ann N Y Acad Sci . 1991;640:197-202.

98. Hanagasi HA,GurvitH, UnsalanP, etal. Theeffects of rasagiline oncognitivedeficitsinParkinson’s disease patients without dementia:a randomized,double-blind, placebo-controlled,multicenter study. Mov Disord . 2011;26(10):1851-1858.

99. RolinskiM, Fox C,MaidmentI, McShane R.Cholinesterase inhibitors for dementia with Lewybodies,Parkinson’s disease dementia and cognitiveimpairmentin Parkinson’s disease. Cochrane DatabaseSyst Rev . 2012;3:CD006504.

100. DuboisB, Tolosa E, Katzenschlager R, etal.Donepezil in Parkinson’s disease dementia:a randomized,double-blind efficacy and safetystudy. Mov Disord . 2012;27(10):1230-1238.

101. Schoffer KL,Henderson RD, O’MaleyK,O’SullivanJD. Nonpharmacologicaltreatment,fludrocortisone, and domperidonefor orthostatichypotensionin Parkinson’s disease. Mov Disord .2007;22(11):1543-1549.

102. LowPA, GildenJL, Freeman R, Sheng KN,McElligott MA;Midodrine StudyGroup. Efficacy of

midodrine vs placebo in neurogenicorthostatichypotension: a randomized,double-blindmulticenter study. JAMA. 1997;277(13):1046-1051.

103. Jankovic J,Gilden JL,HinerBC, etal.Neurogenic orthostatichypotension:a double-blind,placebo-controlledstudy withmidodrine. Am J Med . 1993;95(1):38-48.

104. WrightRA, KaufmannHC, Perera R, etal. Adouble-blind,dose-response studyof midodrine inneurogenicorthostatichypotension. Neurology .1998;51(1):120-124.

105. Singer W,Opfer-GehrkingTL, McPhee BR, HilzMJ,Bharucha AE, Low PA.Acetylcholinesteraseinhibition: a novelapproachin thetreatmentof neurogenicorthostatichypotension. J Neurol NeurosurgPsychiatry . 2003;74(9):1294-1298.

106. SenardJM, RascolO, RascolA, Montastruc JL.Lack of yohimbineeffect on ambulatorybloodpressure recording: a double-blindcross-overtrialin parkinsonians withorthostatichypotension.Fundam Clin Pharmacol . 1993;7(8):465-470.

107. ShibaoC, Okamoto LE,Gamboa A, etal.Comparativeefficacy of yohimbineagainstpyridostigmine for the treatmentof orthostatichypotensionin autonomic failure. Hypertension.2010;56(5):847-851.

108. AbateG, PolimeniRM, CuccurulloF,PudduP,Lenzi S. Effects of indomethacin on postural

hypotensionin Parkinsonism. BMJ .1979;2(6203):1466-1468.

109. Mathias CJ, SenardJM, CortelliP.Adouble-blind, randomized, placebo-controlledstudy todetermine efficacy andsafety of droxidopain thetreatmentof orthostatichypotensionassociated withmultiple system atrophy orParkinson's disease. Clin Auton Res. 2007;17:272.

110. ThomsenTR, Galpern WR,Asante A,

Arenovich T, FoxSH. Ipratropiumbromide sprayastreatmentfor sialorrhea in Parkinson’s disease. Mov Disord . 2007;22(15):2268-2273.

111. ArbouwME, Movig KL,KoopmannM, etal.Glycopyrrolate for sialorrhea in Parkinson disease:a randomized,double-blind, crossover trial.Neurology . 2010;74(15):1203-1207.

112. LloretSP,NanoG, CarrosellaA, Gamzu E,Merello M. A double-blind,placebo-controlled,randomized, crossoverpilotstudyof thesafetyandefficacy of multiple dosesof intra-oral tropicamidefilms forthe short-term reliefof sialorrheasymptoms in Parkinson’s disease patients. J Neurol Sci . 2011;310(1-2):248-250.

113. LagallaG, Millevolte M,Capecci M, ProvincialiL, Ceravolo MG.Botulinum toxin type A fordrooling

in Parkinson’s disease: a double-blind,randomized,placebo-controlled study. Mov Disord .2006;21(5):704-707.

114. Lipp A, TrottenbergT,Schink T, KupschA,ArnoldG. A randomized trial of botulinumtoxin Afor treatmentof drooling. Neurology .2003;61(9):1279-1281.

115. OndoWG, HunterC, Moore W.A double-blindplacebo-controlledtrial of botulinum toxinB forsialorrhea in Parkinson’s disease. Neurology .2004;62(1):37-40.

116. Lagalla G, MillevolteM, Capecci M,ProvincialiL, Ceravolo MG. Long-lasting benefits of botulinumtoxintype B in Parkinson’s disease-related drooling. J Neurol . 2009;256(4):563-567.

117. ChinnapongseR, Gullo K, NemethP, ZhangY,GriggsL. Safetyand efficacy of botulinum toxintype B fortreatment of sialorrheain Parkinson’sdisease: a prospectivedouble-blindtrial. Mov Disord . 2012;27(2):219-226.

118. Guidubaldi A, Fasano A, Ialongo T, et al.Botulinum toxin A vs B in sialorrhea: a prospective,randomized,double-blind, crossover pilot studyinpatients withamyotrophiclateral sclerosis orParkinson’s disease. Mov Disord . 2011;26(2):313-319.

119. VanGerpen JA,KumarN, Bower JH,WeigandS, Ahlskog JE. Levodopa-associated dyskinesia riskamongParkinsondisease patients in OlmstedCounty,Minnesota, 1976-1990. Arch Neurol .2006;63(2):205-209.

120. Schuepbach WM,Rau J,KnudsenK, etal;EARLYSTIM StudyGroup. Neurostimulation forParkinson’s disease withearly motorcomplications.N EnglJ Med . 2013;368(7):610-622.

121. Deuschl G, Schade-Brittinger C, KrackP,et al;German ParkinsonStudy Group,NeurostimulationSection. A randomized trialof deep-brainstimulationfor Parkinson’s disease. N EnglJ Med .2006;355(9):896-908.

122. WeaverFM, Follett KA,SternM, etal; CSP468Study Group.Randomizedtrialof deep brainstimulationfor Parkinsondisease: 36-monthoutcomes. Neurology . 2012;79(1):55-65.

123. Nussbaum RL, Ellis CE. Alzheimer’s diseaseand Parkinson’s disease. N EnglJ Med .2003;348(14):1356-1364.

124. deRijkMC,Launer LJ, BergerK, etal;Neurologic Diseases in the ElderlyResearchGroup.Prevalenceof Parkinson’s disease in Europe:a collaborativestudy of population-based cohorts.Neurology . 2000;54(11)(suppl 5):S21-S23.

125. deLau LML, Giesbergen PCLM, deRijk MC,

HofmanA, Koudstaal PJ, Breteler MMB.Incidenceof parkinsonismand Parkinsondiseasein a generalpopulation:the RotterdamStudy. Neurology .2004;63(7):1240-1244.

126. SpatolaM, Wider C. Genetics of Parkinson’sdisease: the yield.ParkinsonismRelat Disord .2014;20(suppl 1):S35-S38.

127. RajputAH, Voll A, RajputML, RobinsonCA,RajputA. Coursein Parkinson disease subtypes:a 39-year clinicopathologic study. Neurology .2009;73(3):206-212.

128. Noyce AJ,BestwickJP, Silveira-MoriyamaL,etal. Meta-analysisof early nonmotor features andrisk factors for Parkinson disease. Ann Neurol .2012;72(6):893-901.

129. HughesAJ,Daniel SE,LeesAJ. Theclinicalfeatures of Parkinson’s diseasein 100 histologicallyprovencases. Adv Neurol . 1993;60:595-599.

130. BaroneP,AntoniniA, Colosimo C, etal;PRIAMO studygroup. ThePRIAMO study:a multicenter assessmentof nonmotor symptomsandtheirimpact onquality of life inParkinson’sdisease. Mov Disord . 2009;24(11):1641-1649.

131. Haehner A, BoesveldtS, BerendseHW, etal.Prevalenceof smellloss in Parkinson’s disease—amulticenter study. ParkinsonismRelat Disord .2009;15(7):490-494.

132. HelyMA, Reid WGJ, Adena MA,Halliday GM,MorrisJGL. TheSydneymulticenter studyof Parkinson’s disease: the inevitabilityof dementia at20 years. Mov Disord . 2008;23(6):837-844.

133. BroedersM, de BieRM, Velseboer DC,Speelman JD,MuslimovicD, Schmand B. Evolutionof mild cognitive impairmentin Parkinson disease.Neurology . 2013;81(4):346-352.

134. Ahlskog JE,Muenter MD. Frequencyof levodopa-related dyskinesiasand motorfluctuations as estimated from the cumulativeliterature. Mov Disord . 2001;16(3):448-458.

135. Weintraub D,KoesterJ, Potenza MN,et al.Impulsecontrol disorders in Parkinsondisease:a cross-sectional studyof 3090patients. ArchNeurol . 2010;67(5):589-595.

136. Mestre TA,StrafellaAP, Thomsen T, VoonV,Miyasaki J. Diagnosis and treatment of impulsecontrol disorders in patients withmovementdisorders. Ther AdvNeurol Disord .

2013;6(3):175-188.137. KollerWC, HubbleJP. Levodopa therapy inParkinson's disease. Neurology . 1990;40(10suppl3):suppl 40-47, discussion 47-49.

138. Gross RA,JohnstonKC. Levels of evidence:takingneurologyto thenextlevel. Neurology .2009;72(1):8-10.



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