JURNAL: Neuro L-Dopa-Induced Dyskinesias in Parkinson s Disease

EUROPEAN NEUROLOGICAL JOURNAL REVIEW ARTICLE

L-dopa-Induced Dyskinesias in Parkinson’s DiseaseIciar Aviles-Olmos*, Raul Martinez-Fernandez*, and Thomas Foltynie

Affiliation: Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London,United Kingdom

A B S T R A C T

Levodopa (L-dopa) is the most effective treatment for the relief of the motor symptoms of Parkinson’s disease (PD). Its use is limited bythe development of drug-induced involuntary movements known as dyskinesias, which can appear in approximately 40% of the PD patientsafter 5 years of treatment. In recent years we have learned a great deal about the processes involved in the appearance of L-dopa-induceddyskinesia (LID). Non-physiological pulsatile stimulation of dopamine receptors that occurs as a consequence of the use of short-lasting drugs,dysfunctional dopamine release, and abnormal postsynaptic dopamine receptor internalization together with disrupted synaptic plasticity allappear to have direct effects on LID development. Avoiding or delaying dyskinesia development and treating patients in this “advanced”stage of PD is a challenge and requires considerable expertise and individualization of therapy. The aim of this review is to outline the clinicalphenomenology of LID, describe an overview of what is known about their pathophysiology, and provide guidance in the range of therapeuticapproaches that can be tailored to the individual patient.

Keywords: levodopa-induced dyskinesia (LID), Parkinson’s disease (PD), synaptic plasticity, dysfunctional dopamine release, dopamine receptorsupersensitivity

Correspondence: Iciar Aviles-Olmos, Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and MovementDisorders, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom. Tel: +44-08451555000 Ext. 18739; e-mail:[email protected]

INTRODUCTIONThe introduction of levodopa (L-dopa) for the treatment of

Parkinson’s disease (PD) in the 1960s dramatically changed theclinical management and prognosis of PD patients.1–2 L-dopacrosses the blood–brain barrier and is converted to dopaminethrough the action of aromatic-L-amino-acid decarboxylasein surviving dopaminergic terminals, and is the most potentsymptomatic agent against the motor symptoms of the disor-der. Inmost patients, L-dopa treatment leads to a “honeymoon”period during which the motor symptoms are well controlled.However, after 5 years of treatment, approximately 40% ofthe patients will develop fluctuations in symptom control inresponse to the drug, as well as involuntary movements knownas “L-dopa-induced dyskinesia” (LID).3 These complicationsaffect as many as 89% of PD patients after 10 years of L-dopatreatment.4

Many PD clinicians delay using L-dopa following diagnosis,in view of concerns that the basal ganglia become “primed”for LID development even following brief exposure to the drug.Although the use of alternative treatments has certainly reducedthe frequency with which severe LID are seen, there has alsobeen an evolution of an “L-dopa phobia” among some clini-cians and patients, resulting in some instances in unnecessarydisability through the undertreatment of symptoms.5 This arti-cle will review the clinical subtypes of LID, the current under-standing of their pathogenesis and will outline the evidence

∗ These 2 authors contributed equally to this work.

basis for preventing/delaying their development and currentand future possible options for their treatment.

TYPES OF DYSKINESIAThe effectiveness of L-dopa treatment decreases as the dis-

ease progresses because of the progressive loss of nigrostriatalneurons. Typically the first sign of this is the gradual return ofPD symptoms before the next dose of medication is due. Thisis called “wearing off” and it generally necessitates increases inL-dopa dosage or frequency. This phase is frequently accompa-nied by the onset of involuntary LID.

LID are involuntary choreiform or dystonic (hyperkinetic)movements. They can affect any part of the body but the legsand neck are most frequently involved. There are three mainsubtypes of LID:

• Peak-dose dyskinesias: these are the most common and earlyappearing LID and occurwhen L-dopa levels are at their high-est. These usually consist of stereotypic, choreic, or ballisticmovements but occasionally dystonia can also be present.They tend to be more easily manageable by patients becausethey occur during periods of good motor control, that is, inthe “on” motor state.6

• Off-period dyskinesias: these emerge when L-dopa levels are attheir lowest. These often present with painful leg cramps or

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European Neurological Journal

abnormal postures (dystonia) typically in the foot, and mostcommonly in the early morning.

• Diphasic dyskinesias: these are the least common and occurwith the rise and fall of L-dopa concentration, disappear-ing when drug levels achieve a certain threshold, and thenrecurring as the drug level falls, before resolving again asparkinsonism returns. These usually present as short-lasting(5–10 minutes) choreiformmovements or akathisia.

Risk Factors for LID DevelopmentSeveral risk factors have been established for the earlier onsetof LID:

Age of the patient: Young-onset PD patients develop LID earlierthan older-onset PD patients.7,8 However, far greater num-bers of young-onset patients have genetic factors contribut-ing to the development of PD, and therefore distinguishingthe effect of age at the onset of PD from the direct effectsof genetic influences on LID risk is difficult even amongpatients with genetically defined PD.9,10

Dose of L-dopa: In the ELLDOPA study, it was shown that patientstreated with L-dopa over a 40-week period were signifi-cantly less impaired than patients treated with placebo evenafter a 2- to 3-week washout period.11 However, dyskinesiaswere seen in 16.5% of patients receiving the highest dose ofL-dopa even over this short follow-up period compared with2–3% of patients on lower doses or placebo, demonstrat-ing that the dose of L-dopa is critical in terms of risk ofdyskinesia development.

Pattern of L-dopa administration: Intermittent administration ofL-dopa has been shown to increase the risk of LID com-pared with continuous dopaminergic stimulation (CDS)in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)primates12 and in advanced PD patients.13 LID eventually caneven occur in normal primates if administered in pulsatiledoses of L-dopa.12 It is now widely accepted that strategiesto reduce the pulsatility of L-dopa stimulation will reducethe risk of triggering the mechanisms that underlie thedevelopment of LID.

Stage of disease: The onset of clinical symptoms of PD likelydenotes the point of failure of compensatory mechanisms.14

Advanced nigrostriatal denervation in animal models andadvanced disease in PD patients are both associated withfaster onset and more severe LID following the initiation ofL-dopa treatment.15–19

PATHOPHYSIOLOGY OF LIDThe neural mechanisms that underlie LID in PD are not com-

pletely understood, but our current insights have been greatlyhelped through the detailed study of basal ganglia anatomyand physiology in the normal and dopamine-depleted states.Dopamine activates the direct striatal output pathway throughD1-type receptors and inhibits the indirect striatal output path-way through D2-type receptors (Figure 1A). In PD, the progres-sive death of SNc neurons upsets the equilibrium between the

direct and indirect pathways, resulting in abnormal GPi activ-ity. It was originally thought that the clinical features of PDwere representative of simple increases in the “rate” of activ-ity of the GPi, which consequently acted as a brake to activityin the supplementary motor area by inhibiting the motor tha-lamus (Figure 1B). Using the same logic, it was suggestedtherefore that excessive L-dopa stimulation might induce dysk-inesia by reduction of the inhibition of thalamocortical neuronsand overactivity of motor cortical areas.20

This model however is inconsistent with several clinical andexperimental findings. For example, in the nonhuman pri-mate model of PD, metabolic activity in the ventral anteriorand ventrolateral thalamic nuclei, regions of the thalamus thatreceive input from the GPi, is significantly decreased ratherthan increased in LID.21 Furthermore among patients with PDand LID, creation of a lesion within the GPi (pallidotomy) isassociated with a reduction in LID rather than a deteriorationin LID that would have been predicted by the rate model.22

The pathophysiological changes that underlie the develop-ment of LID are evidently far more complex. The striataldopaminergic inputs are closely associated with glutamater-gic corticostriatal projections that synapse onto medium spinyneurons that form the direct striatal output pathway. Furthermodulation of the dopaminergic input onto these cells is medi-ated through adenosine A2a inputs and metabotropic gluta-mate receptors.23 These medium spiny striatal neurons appearto be central to LID development. Overlapping inter-relatedmechanisms appear to trigger abnormal functioning of theseneurons, namely, dysfunctional dopamine release, postsynap-tic dopamine receptor internalization, and disrupted synapticplasticity.

DYSFUNCTIONAL DOPAMINE RELEASEAs the striatum is progressively denervated in PD, the surviv-

ing dopaminergic neurons sprout branches that successfullycompensate for the neurodegenerative process until approxi-mately 60% of neurons are lost. Until this point, the admin-istration of L-dopa does not alter the concentration of stri-atal dopamine, but beyond the 60% deficit, the administrationof L-dopa leads to a 3-fold increase in the concentration ofdopamine in the striatum.24 As soon as the striatum cannotsufficiently buffer exogenously administered and endogenousDA levels, DA synaptic availability starts to mirror the shortplasma half-life of L-dopa, and non-physiological dopaminereceptor stimulation follows, contributing to the occurrence ofpeak-dose LID. Furthermore, 18F-dopa PET scans have demon-strated greater impairments in dopamine synthesis, storage,and release in younger-onset patients, leading to larger swingsin synaptic DA levels, which may contribute to the more com-mon occurrence of LID in younger-onset PD patients.25

Although L-dopa administration will continue to enhancedopamine synthesis and release by the surviving dopamin-ergic neurons, exogenous L-dopa is also decarboxylated andreleased as dopamine by serotonergic terminals, striatal capil-laries, noradrenrgic neurons, and non-aminergic striatal


L-dopa-induced dyskinesias in Parkinson’s disease

SNPars compacta

STRIATUM

Thalamus

STNGPe

CEREBRAL CORTEX

Nigro striataldopaminergic

pathway

D1

D2

GPiSN

Pars reticulata

SNPars compacta

STRIATUM

Thalamus

STNGPe

CEREBRAL CORTEX

Nigro-striataldopaminergic

pathway

D1

D2

GPiSN

Pars reticulata

Indirect ptw

Direct ptw

Indirect ptw

Direct ptw

Figure 1. A) Direct and indirect pathways in normal physiological conditions. B) Rate model of PD: It was originally proposed that with SN pars compactaneuronal loss, overexcitability of the direct pathway compared with the indirect would lead to hyperactivity of GPi and STN, and increased inhibitory basalganglia outflow toward the thalamus. The reality of basal ganglia dysfunction in PD is far more complex. SN pars compacta, substantia nigra pars compacta;Gpe, globus pallidus pars externa; STN, subthalamic nucleus; Gpi, globus pallidus pars interna; SN pars reticulata, substantia nigra pars reticulata; Ptw, pathway.

interneurons.24,26–28 The chaotic unregulated release of dopa-mine as a false neurotransmitter from these non-dopaminergicterminals leads to further non-physiological dopamine recep-tor stimulation contributing to LID appearance.29

DOPAMINE RECEPTOR SUPERSENSITIVITYChronic denervation of dopamine receptors also leads to

receptor supersensitivity and increased expression of receptorson the postsynaptic membrane of medium spiny neurons.30,31

A direct relationship between D1 receptor (D1R) supersensi-tivity and LID severity has been identified.32 Persistent stim-ulation of dopamine receptors leads to their desensitization

and induces receptor internalization, and it is hypothesizedthat in LID, this desensitization and internalization process isimpaired.33

Upon persistent stimulation, D1Rs undergo desensitizationthrough a two-step process: activation-dependent receptorphophorylation by G-protein-coupled receptor kinases (GRKs)followed by the binding of uncoupling proteins called arrestinsthat induce internalization. The D1 receptor–arrestin interac-tion promotes the recruitment of an endocytic complex andconsequently the internalization of the receptor in an endocyticvesicle (Figure 2). This is modified in LID, and D1R expressionis increased and their subcellular distribution is modified. Thishas been proven in dyskinetic animals, as there aremore D1R at

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L-dopa

DA

CEREBRAL CORTEX

Striatal Medium Spiny

Neuron

BG output

D1RAC

cAMP

PKA

DARPP-32

PP

GRK

D1RP

Arrestin

D1R

P Arrestin

Figure 2. Upper part of figure: desensitization process of D1R. D1R is phosphorylated by GRKs and once phosphorylated binds to arrestin. This inducesthe formation of an endocytic complex. GRK, G protein receptor kinase. Bottom part of figure: Loss of depotentiation after chronic non-physiological D1receptor stimulation. L-dopa, levodopa; DA, dopamine; D1R, D1 receptor; AC, adenylyl cyclase; PKA, protein kinase A; DARPP-32, dopamine- and cAMP-regulatedphosphoprotein of molecular weight 32 KDa: PP, protein phosphatase; LTD, long-term depotentiation; LTP, long-term potentiation; BG, basal ganglia.

the plasma membrane.34,35 However, it is clear that LID do notoccur simply as a result of abnormal D1 receptor expression orsensitivity alone because D2-selective agonists can also provokedyskinesia.36

SYNAPTIC PLASTICITYTwo main output pathways arise from the striatal medium

spiny neurons: the direct pathway that projects from the stria-tum to globus pallidus pars interna (GPi) and substantia nigrapars reticulata (SNr), and the indirect one that projects toGPi/SNr through the globus pallidus pars externa (GPe) andsubthalamic nucleus (STN) (Figure 1). Physiological dopamin-ergic input from nigrostriatal neurons onto the striatal mediumspiny neurons plays an important role in the potentiationand de-potentiation of synapses of the corticostriatal pathway.Repetitive stimulation can cause either a long-lasting increasein synaptic strength, known as long-term potentiation (LTP), oran enduring decrease, known as long-term depression (LTD),a phenomenon known as synaptic plasticity.37,38 This processallows the strengthening of desirable motor programs and thedeletion of unwanted or unnecessary connections.

The striatal neurons of the direct pathway express D1R andproduce dynorphin and substance P, and the medium spinyneurons of the indirect pathway are richer in D2R and expressenkephalin. The stimulation of D1R and D2R after L-dopa ther-apy induces the activation or inhibition of adenylyl cyclase(AC), respectively, inducing opposite effects on the intracellu-lar levels of cAMP.39 The increase in cAMP activates proteinkinase A (PKA) which in turn phosphorylates DA and cAMP-regulated phospoprotein 32 kDa (DARPP-32) which acts as apotent inhibitor of protein-phosphatase-1(PP-1). This cascade

of processes culminates in the phosphorylation of intracellularproteins and glutamatergic receptors40 (Figure 2).

LTP and LTD are fully abolished after the genetic disruption ofDARPP-32.41 It is hypothesized that the disruptedmotor controlunderlying dyskinesia is attributable to specific changes occur-ring along the D1/PKA/DARPP-32 signaling pathway leadingto the inhibition of PP-1 activity and loss of synaptic depotentia-tion at corticostriatal synapses.37 Disruption of normal synapticplasticity is strongly linked to the appearance of dyskinesia.42–46

The loss of synaptic depotentiation at corticostriatal synapsesleads to synaptic saturation and to the development of non-physiological motor circuits within the basal ganglia.37

L-dopa can restore normal synaptic plasticity among individ-uals free of dyskinesia, but not when dyskinesias are alreadydeveloped.47 It has been proposed that patients with LID havelost the ability to depotentiate synapses normally, that is, theyhave lost the mechanism that underlies “synaptic forgetting,”leading to the pathological storage of information that wouldnormally be erased and the development of abnormal motorpatterns, that is, LID.43,48

GENETIC INFLUENCES ON LID DEVELOPMENTAlthough much of the variation in LID risk can be attributed

to L-dopa dose and pattern of administration, based on thepreceding data, it is likely that genetic polymorphisms thatinfluence dopaminergic transmission or changes in synapticplasticity may also contribute to susceptibility in developingdyskinesia.49–51 Genetic variations of the dopamine receptorgenes, DRD2, DRD3, and DRD4, have been studied but do notseem to influence the occurrence of L-dopa -induced adverseeffects. However, there is limited evidence in support of a



specific allele of the dopamine transporter gene (VNTR-DAT)being a predictor of LID in L-dopa-treated patients.52 In linewith the evidence that LID develop because of abnormal synap-tic plasticity (which is in turn influenced by the release ofbrain-derived neurotrophic factor (BDNF)),53 a functional poly-morphism in the BDNF gene (val66met) has also been pro-posed to influence time of onset of LID in one cohort of PDpatients.54 These preliminary observations need to be replicatedin further large cohorts of PD patients.

Clinical ImplicationsFor some patients dyskinesias are an acceptable inconve-

nience, whereas for others dyskinesias can become severe,exhausting, and disabling, interfering with the daily activi-ties and producing gait disturbances or postural instability.55,56

Delaying the onset or reducing the severity of LID, while main-taining effective relief of PD symptoms, represents a vital com-ponent of contemporary PD treatment.

REDUCING THE RISK OF DYSKINESIADEVELOPMENT

CDSIn the healthy state, dopamine release occurs in both a tonic

and a phasic manner57; however, in PD patients receiving short-acting drugs, the stimulation of dopamine receptors becomesdiscontinuous and pulsatile. Pulsatile administration of L-dopahas been shown to increase the development of LID in MPTPprimates12 and in human studies13 and have led to the devel-opment of therapies to maximize “Continuous DopaminergicStimulation.” “Dopaminergic agonists” have been successfullyused for the control of motor symptoms of PD since their avail-ability in the 1970s.58 These drugs were developed with theexpectation that on the basis of a longer plasma half-life lead-ing to amore physiological pattern of CDS, and as a substitutiveor concomitant treatment with L-dopa, PD symptoms could berelieved while reducing the risk of long-term motor fluctua-tions and dyskinesias.59 There is no doubt that the dopamineagonists have lower efficacy than L-dopa and more trouble-some short-term side effects, and although these drugs canthemselves lead to the development of involuntary dyskineticmovements, this is generally to a lesser extent thanwith L-dopa.

There is still debate about the magnitude of any advantageof using dopamine agonists rather than L-dopa as initial ther-apy in PD. The ELLDOPA study clearly demonstrated that highdoses of L-dopa lead to dyskinesia development early on intreatment. The recent 10-year follow-up of PD patients initi-ated with Ropinirole versus L-dopa36 showed a significantlylower incidence of dyskinesia in the Ropinirole group and asignificantly longer median time to dyskinesia, but no signif-icant difference in “disabling” dyskinesias. Furthermore by 10years, 93% of patients initiated on Ropinirole were also tak-ing L-dopa, almost identical to the percentage in the groupinitiated on L-dopa, and having started on Ropinirole did nottranslate to any significant advantage in activities of daily living.Similar results have also been shown with Pramipexole60 versusL-dopa as the initial treatment choice. Ergot-derived dopamine

agonists are generally to be avoided in view of long-term risksof pulmonary and valvular fibrosis,61,62 notwithstanding the factthat no long-term (14-year) difference in dyskinesia inductionhas been reported comparing Bromocriptine versus L-dopa asinitial treatment.63

CDS using a long-acting transdermally administered agonist,Rotigotine, has shown reduced dyskinesia induction comparedwith pulsatile administration of the same drug and far lessdyskinesia than pulsatile administration of L-dopa alone indrug-naïve MPTP-treated animal models.64 Whether there isany advantage of one dopamine agonist over another has yetto be studied, but the additional development of slow-releasepreparations of Ropinirole and Pramipexole, in addition toRotigotine, provides the opportunity to explore whether thesedrug formulations might confer long-term benefits on dyski-nesia risk.

The monoamine-oxidase B inhibitors, Selegiline and Rasa-giline, have been the subject of extensive research specificallystudying whether they possess any disease-modifying prop-erties. They irreversibly inhibit MAO-B, the main dopamine-metabolizing enzyme in the brain, and enhance dopaminebioavailability, thus potentially leading to CDS. Both have beenshown to improve PD symptoms65,66 and recently a small butsustained advantage has been reported as a result of the ear-lier initiation of treatment,67–69 but any advantage of long-termLID risk is currently unproven. In the long-term follow-up ofthe TEMPO trial the time for 25% of subjects to develop dysk-inesia showed no difference between the early-start group andthe delayed-start group.70

Another theoretical way of improving CDS is throughthe use of catechol-O-methyl transferase (COMT) inhibitors.This enzyme is the main mechanism of peripheral L-dopametabolism.71 COMT inhibition slows L-dopa plasma degrada-tion and increases its bioavailability without increasing max-imal concentration, allowing a L-dopa dose reduction by upto 30%.72 Entacapone and Tolcapone are selective COMTinhibitors that were developed for clinical use for the treat-ment of PD. Tolcapone should be reserved for patients whohave inadequate benefit from Entacapone in view of rare butpotentially fatal hepatotoxicity.73 Animal models showed thatearly coadministration of Entacapone with L-dopa allows goodmotor control while decreasing the severity of all dyskine-sia subtypes and delaying their onset.74,75 However, this sup-posed preventive effect has not been replicated in human clin-ical trials.76 The unpublished STRIDE-PD trial unfortunatelyshowed that the time to dyskinesia was shorter in Carbidopa/L-dopa /Entacapone-treated patients, possibly because ofexcessive L-dopa dosage among patients receiving COMTinhibitors.

Any strategy that reduces the pulsatility of dopaminergic stim-ulation is likely to be an effective way of delaying time to onsetof LID. The effectiveness and tolerability of any drug will varyfrom one patient to the next, emphasizing the need to tai-lor the drug regime to the individual. Combination therapiesthat afford symptom relief while keeping the dose of L-doparelatively low represent the optimal way of reducing pulsatiledopaminergic receptor stimulation.



TREATING LID ONCE THEY HAVE DEVELOPEDFollowing the onset of LID, the general principles of CDS

already outlined should be continued where possible to preventincreases in LID frequency or severity. Beyond this, in order toimplement effective treatment strategies for the treatment ofexisting LID, it is important to establish which type of dyski-nesia the patient is describing, through a careful history of thetype, distribution, and timing of the involuntary movements.

Modification of Oral L-dopaAdministration/MetabolismA short-term approach to reduce peak dose dyskinesias

when they appear for the first time is to diminish the dose ofdopaminergic agents to coincide with the time of day of LIDoccurrence. However, this strategy may be counter-productivebecause of increases in “off” time and dose failures.77

Increasing the frequency of smaller doses of L-dopa can helpin the early stages but with continuing disease progression,recurrence of fluctuations between the off state and the onstate with accompanying dyskinesia demands further therapychanges. Long-acting L-dopa preparations were developed totry and ameliorate fluctuations,78 but these preparations canlead to increased numbers of “dose failures” and unpredictableL-dopa accumulation that further compounds the problem.79

Patients describing off-period dystonia, for example, painfulposturing of a foot in the early morning prior to their medica-tion, can be helpedwith the prescription of dispersible forms ofL-dopa, but these should not be used throughout the day as theyare likely to increase the pulsatility of dopaminergic receptorstimulation.

MAO-B inhibitors have only mild effects on motor symptomsin advanced PD but can allow a decrease in required L-dopadosage without deterioration in “off-time.” Entacapone hasalso demonstrated its efficacy in prolonging the L-dopa clinicalresponse in patients with motor fluctuations.80,81 Neverthelessdyskinesia increase can occur because of the accumulating lev-els of plasma L-dopa necessitating careful titrated reductionof L-dopa dose.82,83 The LARGO trial revealed a significantbut slight increase in daily-on time without troublesome dysk-inesia in both Rasagiline and Entacapone groups comparedwith placebo in adjunct treatment with L-dopa. No differencesbetween Rasagiline and Entacapone were reported.84

Adding or Increasing an Oral AgonistWhether shifting therapy toward the dopamine agonists can

reverse dyskinesia severity without worsening “off time” isyet to be convincingly established. Among the MPTP-treatedmarmosets with established dyskinesias provoked by pulsatileRotigotine or L-dopa, continuous Rotigotine administrationled to reversal in dyskinesia.85 In the same animal models,switching to Ropinirole86 or adding Pramipexole87 to L-dopa(with its dosage disminution) has also significantly reducedpre-existing LID while maintaining therapeutic benefit.

From the practical perspective, most patients suitable fordopamine agonist treatment have already been prescribed

these drugs prior to L-dopa prescription. Adding a dopamineagonist to a patient on L-dopa therapy generally increasespeak dose dyskinesia unless the L-dopa dose is reduced.88

However, this strategy has been successfully demonstratedwithboth Ropinirole89 and Pramipexole.90,91 The addition of theRotigotine patch has been shown to increase “on” time with-out exacerbating dyskinesia in advanced PD patients althoughreduction in pre-existing dyskinesia has not been reported.92

Patients with painful off-period dystonia in the early morningcan be helped by supplementary prescriptions of long-actingdopamine agonists taken the preceding night. Patients withdiphasic dyskinesias need to maintain sufficient dopaminer-gic medication levels (L-dopa or agonist) throughout the day toreduce the regularity of their occurrence. However, care needsto be taken when using this strategy to ensure that symptomsof dopa-dysregulation do not supervene.

Adding AmantadineThis drug was used originally as an antiviral agent, and it

was only through serendipity that it was observed to moder-ately alleviate PD symptoms.93 Its mechanism of action is stillnot clear, but it is thought to be mediated through the N-methyl-D-aspartate receptor antagonist effect seen with highdoses (300–400 mg/day). Amantadine still remains the onlydrug proven to have direct anti-dyskinetic effects, with improve-ments demonstrated of up to 50%.94–96 Efficacy has been shownfor up to 1 year97; however, loss of efficacy after 3–8 monthshas also been reported in a double-blind evaluation.98 Althoughefficacy is most clearly demonstrated at higher dose levels, itis wise to try and keep the dose to the lowest useful level par-ticularly among elderly patients or individuals with evidence ofcognitive impairment because of cognitive side effects.

Switching to ApomorphineApomorphine is the most potent dopamine agonist used

in clinical practice and has a very fast onset (5–15 minutes)but short duration of effect (∼40 minutes).99 It can be used,through intermittent subcutaneous administration, as a suc-cessful rescue treatment of severe unpredictable “off” periodsin advanced PD patients with motor fluctuations.100 It has alsobeen used as a continuous infusion through a pump since1995,101 and there is robust data to demonstrate good control ofPD symptoms together with the reduction of peak-dose dysk-inesia, by using this therapy as a means of lowering L-doparequirements.102–105 Cognitive side effects, nausea, hypersom-nolence, and skin nodules may occur as well as a rare hemolyticanemia and these factors may limit the number of patients thattolerate its use over the long term.

Ablative NeurosurgeryCreating lesions in the thalamus and globus pallidum for

the treatment of PD was pioneered in the 1950s but thendisplaced for the treatment of PD with the introduction of L-dopa. A major renaissance of surgery followed the publicationthat posteroventral pallidotomy could improve not only the



main PD symptoms, but LID as well,106,107 and this has beendemonstrated as part of randomized trials.108,109 Bilateral pal-lidotomy causes swallowing difficulties,110 and with the adventof implantable pulse generators to enable delivery of chronicstimulation, lesioning techniques are now rarely performed.

Deep Brain StimulationDeep brain stimulation has become a widely used, safe, and

effective technique for the treatment of the cardinal motorsymptoms of advanced PD.111,112 When dyskinesia is the mainproblem, the choice of targets lies between the STN and theGPi.113 There is general acceptance that dyskinesia reductionis greatest following GPi-deep brain stimulation (DBS), withimprovement rates of up to 89% following GPi-DBS comparedwith 62% in the STN.114,115 The improvement in “off” symptomshowever tends to be less with GPi-DBS, and therefore medica-tion requirements usually remain high postoperatively.114,115 Itseems therefore that dyskinesia improvement following GPi-DBS is directly related to the stimulation effect by interferingwith pallidal outflow.

In contrast, STN-DBS frequently leads to reduction in the doseof L-dopa required and this is certainly one explanation whydyskinesia severity has been shown to decrease.116,117 Over a 5-year follow-up period, reduction in both peak-dose dyskinesia,biphasic dyskinesia, and off dystonia has been reported withSTN-DBS,118 and it has been shown that the response of thepatient to a L-dopa challenge also changes implying that thereis possibly also a direct effect of chronic STN stimulation.119

This may perhaps be mediated by changes in synaptic plas-ticity downstream from the STN,120 although this may equallybe related to the stimulation of adjacent local pallidothalamic,pallidosubthalamic, and subthalamopallidal fiber projectionsrather than STN neurons per se.117,121

Intra-Jejunal L-dopaThe best evidence that CDS can relieve LID comes from the

use of the enteral L-dopa infusion. A L-dopa -Carbidopa gel isadministered directly into the duodenum or the upper jejunum,bypassing the stomach (and thus its irregular pattern of empty-ing and drug absorption), with a delivery controlled by an exter-nal portable pump. The systemhas demonstrated a reduction inplasma L-dopa fluctuations comparedwith oral treatment.122–125

This therapy is limited by the need for the patient to have apermanent gastrostomy tube with jejunal extension, the con-sequent risk of local complications,126 and its considerablefinancial cost. At the current time, it is considered as a goodalternative for those patients unsuitable to DBS or intolerant ofApomorphine. No randomized controlled trials have been per-formed to directly compare the efficacy and tolerability of thesethree therapies, and it is likely that any advantage in the meanoutcome of one therapy against another127–130 needs to be con-sidered very carefully in the context of tailoring treatment to theindividual patient.

ClozapineTraditional antipsychotic drugs should not be used in the

treatment of PD patients because of the inevitable deteriora-tion in parkinsonism. The atypical antipsychotic clozapine has

however been shown to improve dyskinesia control in up to50% without worsening of motor symptoms.131–133 The dis-advantage of this drug is the need for regular blood testingbecause of the risk of agranulocytosis.

FUTURE THERAPIESFurther trials are underway to evaluate novel approaches to

reduce LID in PD. These include putative antidyskinetic drugssuch as D2/D3 receptor “partial” agonists, adenosine A2aantagonists, andmetabotropic glutamate receptor antagonists.In addition, there are four major gene therapy programs beingconducted to evaluate whether the complications of PD canbe ameliorated through growth factor administration,134 GADenzyme delivery to the STN,135 or attempts to improve upon stri-atal CDS.136,137 Furthermore there are renewed attempts to applycell therapies to patients with PD before LID development in anattempt to allow restoration of normal physiological dopamin-ergic stimulation and avoid the long-term complications ofpharmacological dopaminergic replacement.

CONCLUSIONSAfter more than 40 years of use and despite the develop-

ment of a wide range of newer treatments, L-dopa remainsthe most efficacious agent to treat the motor symptoms of PD.Nevertheless the disabling motor complications, particularlydyskinesias, can be disabling and limit its long-term thera-peutic use. The issue regarding whether and when to initiatetreatmentwith L-dopa has been the topic of frequent discussionto avoid long-term motor complications but without depriv-ing patients the most effective treatment for the relief of theirmotor symptoms. PD is a heterogeneous disease and individualpatients will respond and tolerate prescribed drugs in differ-ent ways with variable risks of dyskinesia development. L-dopashould not be feared but when required should be used wherepossible in combination with the range of other available thera-pies unless or until alternative (more physiological) treatmentsbecome available.

Acknowledgments: Dr Foltynie is supported by grants from theParkinson’s Appeal and Parkinson’s UK.

Disclosure: Dr Foltynie has received honoraria for speaking at meet-ings from Teva, UCB, GSK, and Orion Pharma.

REFERENCES1. Cotzias GC, Van Woert MH, Schiffer LM. Aromatic amino acids and

modification of parkinsonism. N Engl J Med. 1967;276(7):374–379.2. Hornykiewicz OD. Physiologic, biochemical, and pathological back-

grounds of levodopa and possibilities for the future. Neurology.1970;20(12):1–5.

3. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias andmotor fluctuations as estimated from the cumulative literature.Mov Disord.2001;16(3):448–458.

4. Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson’sdisease. A community-based study. Brain. 2000;123(Pt. 11):2297–2305.

5. Kurlan R. “Levodopa phobia”: a new iatrogenic cause of disability inParkinson disease. Neurology. 2005;64(5):923–924.

6. Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F. Impact of the motorcomplications of Parkinson’s disease on the quality of life. Mov Disord.2005;20(2):224–230.



7. Kostic V, Przedborski S, Flaster E, Sternic N. Early development oflevodopa-induced dyskinesias and response fluctuations in young-onsetParkinson’s disease. Neurology. 1991;41(2(Pt. 1)):202–205.

8. Wagner ML, Fedak MN, Sage JI, Mark MH. Complications of disease andtherapy: a comparison of younger and older patients with Parkinson’sdisease. Ann Clin Lab Sci. 1996;26(5):389–395.

9. Lucking CB, Durr A, Bonifati V, et al. Association between early-onsetParkinson’s disease and mutations in the parkin gene. N Engl J Med.2000;342(21):1560–1567.

10. Khan NL, Graham E, Critchley P, et al. Parkin disease: a phenotypic studyof a large case series. Brain. 2003;126(Pt. 6):1279–1292.

11. Fahn S, Oakes D, Shoulson I, et al. Levodopa and the progression ofParkinson’s disease. N Engl J Med. 2004;351(24):2498–2508.

12. Smith LA, JacksonMJ, Hansard MJ, Maratos E, Jenner P. Effect of pulsatileadministration of levodopa on dyskinesia induction in drug-naive MPTP-treated common marmosets: effect of dose, frequency of administration,and brain exposure.Mov Disord. 2003;18(5):487–495.

13. Nutt JG, Obeso JA, Stocchi F. Continuous dopamine-receptor stimula-tion in advanced Parkinson’s disease. Trends Neurosci. 2000;23(10 Suppl.):S109–S115.

14. Bezard E, Brotchie JM, Gross CE. Pathophysiology of levodopa-induceddyskinesia: potential for new therapies. Nat Rev Neurosci. 2001;2(8):577–588.

15. Rodriguez M, Barroso-Chinea P, Abdala P, Obeso J, Gonzalez-HernandezT. Dopamine cell degeneration induced by intraventricular administrationof 6-hydroxydopamine in the rat: similarities with cell loss in parkinson’sdisease. Exp Neurol. 2001;169(1):163–181.

16. Marin C, Aguilar E, Mengod G, Cortes R, Obeso JA. Effects of early vs. lateinitiation of levodopa treatment in hemiparkinsonian rats. Eur J Neurosci.2009;30(5):823–832.

17. Bezard E, Gross CE. Compensatory mechanisms in experimental andhuman parkinsonism: towards a dynamic approach. Prog Neurobiol.1998;55(2):93–116.

18. Langston JW, Ballard P. Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP): implications for treatmentand the pathogenesis of Parkinson’s disease. Can J Neurol Sci. 1984;11(1 Suppl.):160–165.

19. Kuoppamaki M, Al-Barghouthy G, Jackson MJ, Smith LA, Quinn N,Jenner P. L-dopa dose and the duration and severity of dyskine-sia in primed MPTP-treated primates. J Neural Transm. 2007;114(9):1147–1153.

20. Wichmann T, DeLong MR. Pathophysiology of Parkinson’s disease:the MPTP primate model of the human disorder. Ann N Y Acad Sci.2003;991:199–213.

21. Mitchell IJ, Boyce S, Sambrook MA, Crossman AR. A 2-deoxyglucosestudy of the effects of dopamine agonists on the parkinsonianprimate brain. Implications for the neural mechanisms that medi-ate dopamine agonist-induced dyskinesia. Brain. 1992;115(Pt. 3):809–824.

22. Laitinen LV, Bergenheim AT, Hariz MI. Ventroposterolateral pallido-tomy can abolish all parkinsonian symptoms. Stereotact Funct Neurosurg.1992;58(1–4):14–21.

23. Conn PJ, Battaglia G, Marino MJ, Nicoletti F. Metabotropic gluta-mate receptors in the basal ganglia motor circuit. Nat Rev Neurosci.2005;6(10):787–798.

24. Lee J, Zhu WM, Stanic D, et al. Sprouting of dopamine terminals andaltered dopamine release and uptake in Parkinsonian dyskinaesia. Brain.2008;131(Pt. 6):1574–1587.

25. Sossi V, de la Fuente-Fernandez R, Schulzer M, Adams J, Stoessl J. Age-related differences in levodopa dynamics in Parkinson’s: implications formotor complications. Brain. 2006;129(Pt. 4):1050–1058.

26. Melamed E, Hefti F, Pettibone DJ, Liebman J, Wurtman RJ. AromaticL-amino acid decarboxylase in rat corpus striatum: implications for actionof L-dopa in parkinsonism. Neurology. 1981;31(6):651–655.

27. Ng KY, Chase TN, Colburn RW, Kopin IJ. L-dopa-induced release ofcerebral monoamines. Science. 1970;170(953):76–77.

28. Carta M, Carlsson T, Munoz A, Kirik D, Bjorklund A. Involvement of theserotonin system in L-dopa-induced dyskinesias. Parkinsonism Relat Disord.2008;14(Suppl. 2):S154–S158.

29. Carta M, Carlsson T, Munoz A, Kirik D, Bjorklund A. Serotonin-dopamineinteraction in the induction andmaintenance of L-DOPA-induced dyskine-sias. Prog Brain Res. 2008;172:465–478.

30. Lee T, Seeman P, Rajput A, Farley IJ, Hornykiewicz O. Receptorbasis for dopaminergic supersensitivity in Parkinson’s disease. Nature.1978;273(5657):59–61.

31. Shinotoh H, Hirayama K, Tateno Y. Dopamine D1 and D2 receptors inParkinson’s disease and striatonigral degeneration determined by PET.Adv Neurol. 1993;60:488–493.

32. Aubert I, Guigoni C, Hakansson K, et al. Increased D1 dopamine recep-tor signaling in levodopa-induced dyskinesia. Ann Neurol. 2005;57(1):17–26.

33. Guigoni C, Bezard E. Involvement of canonical and non-canonical D1dopamine receptor signalling pathways in L-dopa-induced dyskinesia.Parkinsonism Relat Disord. 2009;15(Suppl. 3):S64–S67.

34. Berthet A, Porras G, Doudnikoff E, et al. Pharmacological analysisdemonstrates dramatic alteration of D1 dopamine receptor neuronal dis-tribution in the rat analog of L-DOPA-induced dyskinesia. J Neurosci.2009;29(15):4829–4835.

35. Guigoni C, Doudnikoff E, Li Q, Bloch B, Bezard E. Altered D(1) dopaminereceptor trafficking in parkinsonian and dyskinetic non-human primates.Neurobiol Dis. 2007;26(2):452–463.

36. Hauser RA, Rascol O, Korczyn AD, et al. Ten-year follow-up of Parkinson’sdisease patients randomized to initial therapy with ropinirole or levodopa.Mov Disord. 2007;22(16):2409–2417.

37. Calabresi P, Di Filippo M, Ghiglieri V, Picconi B. Molecularmechanisms underlying levodopa-induced dyskinesia. Mov Disord.2008;23(Suppl. 3):S570–S579.

38. Di Filippo M, Picconi B, Tantucci M, et al. Short-term and long-term plas-ticity at corticostriatal synapses: implications for learning and memory.Behav Brain Res. 2009;199(1):108–118.

39. Greengard P, Allen PB, Nairn AC. Beyond the dopamine recep-tor: the DARPP-32/protein phosphatase-1 cascade. Neuron. 1999;23(3):435–447.

40. Santini E, Valjent E, Usiello A, et al. Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia. J Neurosci. 2007;27(26):6995–7005.

41. Calabresi P, Gubellini P, CentonzeD, et al. Dopamine and cAMP-regulatedphosphoprotein 32 kDa controls both striatal long-term depression andlong-term potentiation, opposing forms of synaptic plasticity. J Neurosci.2000;20(22):8443–8451.

42. LinazasoroG.New ideas on the origin of L-dopa-induced dyskinesias: age,genes and neural plasticity. Trends Pharmacol Sci. 2005;26(8):391–397.

43. Picconi B, Centonze D, Hakansson K, et al. Loss of bidirectionalstriatal synaptic plasticity in L-DOPA-induced dyskinesia. Nat Neurosci.2003;6(5):501–506.

44. Calabresi P, Galletti F, Saggese E, Ghiglieri V, Picconi B. Neuronalnetworks and synaptic plasticity in Parkinson’s disease: beyond motordeficits. Parkinsonism Relat Disord. 2007;13(Suppl. 3):S259–S262.

45. Chase TN. Striatal plasticity and extrapyramidal motor dysfunction.Parkinsonism Relat Disord. 2004;10(5):305–313.

46. Ueki Y, Mima T, Kotb MA, et al. Altered plasticity of the human motorcortex in Parkinson’s disease. Ann Neurol. 2006;59(1):60–71.

47. Morgante F, Espay AJ, Gunraj C, Lang AE, Chen R. Motor cortex plas-ticity in Parkinson’s disease and levodopa-induced dyskinesias. Brain.2006;129(Pt. 4):1059–1069.

48. Picconi B, Paille V, Ghiglieri V, et al. L-DOPA dosage is criticallyinvolved in dyskinesia via loss of synaptic depotentiation. Neurobiol Dis.2008;29(2):327–335.

49. Lin JJ, Yueh KC, Lin SZ, Harn HJ, Liu JT. Genetic polymorphism of theangiotensin converting enzyme and L-dopa-induced adverse effects inParkinson’s disease. J Neurol Sci. 2007;252(2):130–134.

50. Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, Lang AE. A five-year study of the incidence of dyskinesia in patients with early Parkinson’sdisease who were treated with ropinirole or levodopa. 056 Study Group.N Engl J Med. 2000;342(20):1484–1491.

51. Zappia M, Annesi G, Nicoletti G, et al. Sex differences in clinical andgenetic determinants of levodopa peak-dose dyskinesias in Parkinsondisease: an exploratory study. Arch Neurol. 2005;62(4):601–605.



52. Kaiser R, Hofer A, Grapengiesser A, et al. L-dopa-induced adverseeffects in PD and dopamine transporter gene polymorphism. Neurology.2003;60(11):1750–1755.

53. Wardle RA, Poo MM. Brain-derived neurotrophic factor modulation ofGABAergic synapses by postsynaptic regulation of chloride transport.J Neurosci. 2003;23(25):8722–8732.

54. Foltynie T, Cheeran B, Williams-Gray CH, et al. BDNF val66met influ-ences time to onset of levodopa induced dyskinesia in Parkinson’s disease.J Neurol Neurosurg Psychiatry. 2009;80(2):141–144.

55. Marras C, Lang A, KrahnM, Tomlinson G, Naglie G. Quality of life in earlyParkinson’s disease: impact of dyskinesias and motor fluctuations. MovDisord. 2004;19(1):22–28.

56. Sethi KD. The impact of levodopa on quality of life in patients withParkinson disease. Neurologist. 2010;16(2):76–83.

57. Grace AA, Bunney BS. The control of firing pattern in nigral dopamineneurons: single spike firing. J Neurosci. 1984;4(11):2866–2876.

58. Calne DB, Teychenne PF, Claveria LE, Eastman R, Greenacre JK, PetrieA. Bromocriptine in Parkinsonism. Br Med J. 1974;4(5942):442–444.

59. Fahn S. How do you treat motor complications in Parkinson’s disease:medicine, surgery, or both? Ann Neurol. 2008;64(Suppl. 2):S56–S64.

60. Holloway RG, Shoulson I, Fahn S, et al. Pramipexole vs levodopa as initialtreatment for Parkinson disease: a 4-year randomized controlled trial. ArchNeurol. 2004;61(7):1044–1053.

61. Tintner R,Manian P,Gauthier P, Jankovic J. Pleuropulmonary fibrosis afterlong-term treatment with the dopamine agonist pergolide for ParkinsonDisease. Arch Neurol. 2005;62(8):1290–1295.

62. Antonini A, Poewe W. Fibrotic heart-valve reactions to dopamine-agonisttreatment in Parkinson’s disease. Lancet Neurol. 2007;6(9):826–829.

63. Katzenschlager R, Head J, Schrag A, Ben-Shlomo Y, Evans A, Lees AJ.Fourteen-year final report of the randomized PDRG-UK trial comparingthree initial treatments in PD. Neurology. 2008;71(7):474–480.

64. Stockwell KA, Scheller D, Rose S, et al. Continuousadministration of rotigotine to MPTP-treated com-mon marmosets enhances anti-parkinsonian activity andreduces dyskinesia induction. Exp Neurol. 2009;219(2):533–542.

65. Elizan TS, Yahr MD, Moros DA, Mendoza MR, Pang S, Bodian CA.Selegiline as an adjunct to conventional levodopa therapy in Parkinson’sdisease. Experience with this type B monoamine oxidase inhibitor in 200patients. Arch Neurol. 1989;46(12):1280–1283.

66. Parkinson Study Group. A controlled, randomized, delayed-start study ofrasagiline in early Parkinson disease. Arch Neurol. 2004;61(4):561–566.

67. Olanow CW, Hauser RA, Jankovic J, et al. A randomized, double-blind,placebo-controlled, delayed start study to assess rasagiline as a dis-ease modifying therapy in Parkinson’s disease (the ADAGIO study):rationale, design, and baseline characteristics. Mov Disord. 2008;23(15):2194–2201.

68. Palhagen S, Heinonen E, Hagglund J, Kaugesaar T, Maki-Ikola O, Palm R.Selegiline slows the progression of the symptoms of Parkinson disease.Neurology. 2006;66(8):1200–1206.

69. Parkinson Study Group. A controlled trial of rasagiline in early Parkinsondisease: the TEMPO Study. Arch Neurol. 2002;59(12):1937–1943.

70. Hauser RA, Lew MF, Hurtig HI, Ondo WG, Wojcieszek J, Fitzer-Attas CJ.Long-term outcome of early versus delayed rasagiline treatment in earlyParkinson’s disease.Mov Disord. 2009;24(4):564–573.

71. Axelrod J, Tomchick R. Enzymatic O-methylation of epinephrine and othercatechols. J Biol Chem. 1958;233(3):702–705.

72. Nutt JG, Woodward WR, Beckner RM, et al. Effect of peripheral catechol-O-methyltransferase inhibition on the pharmacokinetics and pharmaco-dynamics of levodopa in parkinsonian patients. Neurology. 1994;44(5):913–919.

73. Assal F, Spahr L, Hadengue A, Rubbia-Brandt L, Burkhard PR. Tolcaponeand fulminant hepatitis. Lancet. 1998;352(9132):958.

74. Marin C, Aguilar E, Obeso JA. Coadministration of entacapone with lev-odopa attenuates the severity of dyskinesias in hemiparkinsonian rats.MovDisord. 2006;21(5):646–653.

75. Smith LA, Jackson MJ, Al-Barghouthy G, et al. Multiple small doses oflevodopa plus entacapone produce continuous dopaminergic stimulationand reduce dyskinesia induction in MPTP-treated drug-naive primates.

Mov Disord. 2005;20(3):306–314.76. Hauser RA, Panisset M, Abbruzzese G, Mancione L, Dronamraju

N, Kakarieka A. Double-blind trial of levodopa/carbidopa/entacaponeversus levodopa/carbidopa in early Parkinson’s disease. Mov Disord.2009;24(4):541–550.

77. Metman LV, van den Munckhof P, Klaassen AA, Blanchet P, MouradianMM, Chase TN. Effects of supra-threshold levodopa doses on dyskinesiasin advanced Parkinson’s disease. Neurology. 1997;49(3):711–713.

78. Pacchetti C, Martignoni E, Sibilla L, Bruggi P, Turla M, Nappi G.Effectiveness of Madopar HBS plus Madopar standard in patients withfluctuating Parkinson’s disease: two years of follow-up. Eur Neurol.1990;30(6):319–323.

79. Koller WC, Hutton JT, Tolosa E, Capilldeo R. Immediate-releaseand controlled-release carbidopa/levodopa in PD: a 5-year random-ized multicenter study. Carbidopa/Levodopa Study Group. Neurology.1999;53(5):1012–1019.

80. Rinne UK, Larsen JP, Siden A, Worm-Petersen J. Entacapone enhances theresponse to levodopa in parkinsonian patients with motor fluctuations.Nomecomt Study Group. Neurology. 1998;51(5):1309–1314.

81. Entacapone improves motor fluctuations in levodopa-treated Parkinson’sdisease patients. Parkinson Study Group. Ann Neurol. 1997;42(5):747–755.

82. Linazasoro G, Kulisevsky J, Hernandez B. Should levodopa dose bereduced when switched to stalevo? Eur J Neurol. 2008;15(3):257–261.

83. Gordin A, Kaakkola S, Teravainen H. Clinical advantages of COMTinhibition with entacapone—a review. J Neural Transm. 2004;111(10–11):1343–1363.

84. Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct tolevodopa in patients with Parkinson’s disease and motor fluctuations(LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Oncedaily, study): a randomised, double-blind, parallel-group trial. Lancet.2005;365(9463):947–954.

85. Stockwell KA, Scheller DK, Smith LA, et al. Continuous rotigotineadministration reduces dyskinesia resulting from pulsatile treatment withrotigotine or L-DOPA in MPTP-treated common marmosets. Exp Neurol.2010;221(1):79–85.

86. Jackson MJ, Smith LA, Al-Barghouthy G, Rose S, Jenner P. Decreasedexpression of L-dopa-induced dyskinesia by switching to ropini-role in MPTP-treated common marmosets. Exp Neurol. 2007;204(1):162–170.

87. Tayarani-Binazir KA, Jackson MJ, Rose S, Olanow CW, Jenner P.Pramipexole combined with levodopa improves motor function butreduces dyskinesia in MPTP-treated common marmosets. Mov Disord.2010;25(3):377–384.

88. Talati R, Baker WL, Patel AA, Reinhart K, Coleman CI. Adding adopamine agonist to preexisting levodopa therapy vs. levodopa therapyalone in advanced Parkinson’s disease: a meta analysis. Int J Clin Pract.2009;63(4):613–623.

89. Cristina S, Zangaglia R, Mancini F, Martignoni E, Nappi G, Pacchetti C.High-dose ropinirole in advanced Parkinson’s disease with severe dyski-nesias. Clin Neuropharmacol. 2003;26(3):146–150.

90. GuttmanM. Double-blind comparison of pramipexole and bromocriptinetreatment with placebo in advanced Parkinson’s disease. InternationalPramipexole-Bromocriptine Study Group. Neurology. 1997;49(4):1060–1065.

91. Brodsky MA, Park BS, Nutt JG. Effects of a dopamine agonist onthe pharmacodynamics of levodopa in Parkinson disease. Arch Neurol.2010;67(1):27–32.

92. Rektor I, Babic T, Boothmann B, Polivka J, Boroojerdi B, Randerath O.High doses of rotigotine transdermal patch: results of an open-label,dose-escalation trial in patients with advanced-stage, idiopathic Parkinsondisease. Clin Neuropharmacol. 2009;32(4):193–198.

93. Schwab RS, England AC, Jr., Poskanzer DC, Young RR. Amantadine in thetreatment of Parkinson’s disease. JAMA. 1969;208(7):1168–1170.

94. Luginger E, Wenning GK, Bosch S, Poewe W. Beneficial effects of aman-tadine on L-dopa-induced dyskinesias in Parkinson’s disease.Mov Disord.2000;15(5):873–878.

95. VerhagenMetman L, Del Dotto P, van denMunckhof P, Fang J, MouradianMM, Chase TN. Amantadine as treatment for dyskinesias and motor



fluctuations in Parkinson’s disease. Neurology. 1998;50(5):1323–1326.96. Rajput AW, Rajput AH. 18 month prospective study of amantadine for

levodopa induced dyskinesia in Parkinson’s Disease. Can J Neurol Sci.1997;24:S23.

97. Metman LV, Del Dotto P, LePoole K, Konitsiotis S, Fang J, Chase TN.Amantadine for levodopa-induced dyskinesias: a 1-year follow-up study.Arch Neurol. 1999;56(11):1383–1386.

98. Thomas A, Iacono D, Luciano AL, Armellino K, Di Iorio A, Onofrj M.Duration of amantadine benefit on dyskinesia of severe Parkinson’s dis-ease. J Neurol Neurosurg Psychiatry. 2004;75(1):141–143.

99. Duby SE, Cotzias GC, Papavasiliou PS, Lawrence WH. Injected apomor-phine and orally administered levodopa in Parkinsonism. Arch Neurol.1972;27(6):474–480.

100. Chen JJ, Obering C. A review of intermittent subcutaneous apomorphineinjections for the rescue management of motor fluctuations associatedwith advanced Parkinson’s disease. Clin Ther. 2005;27(11):1710–1724.

101. Gancher ST, Nutt JG, Woodward WR. Apomorphine infusional therapyin Parkinson’s disease: clinical utility and lack of tolerance. Mov Disord.1995;10(1):37–43.

102. Manson AJ, Turner K, Lees AJ. Apomorphine monotherapy in the treat-ment of refractory motor complications of Parkinson’s disease: long-termfollow-up study of 64 patients.Mov Disord. 2002;17(6):1235–1241.

103. Stocchi F, Vacca L, De Pandis MF, Barbato L, Valente M, Ruggieri S.Subcutaneous continuous apomorphine infusion in fluctuating patientswith Parkinson’s disease: long-term results. Neurol Sci. 2001;22(1):93–94.

104. Colzi A, Turner K, Lees AJ. Continuous subcutaneous waking day apo-morphine in the long term treatment of levodopa induced interdose dysk-inesias in Parkinson’s disease. J Neurol Neurosurg Psychiatry. 1998;64(5):573–576.

105. Katzenschlager R, Hughes A, Evans A, et al. Continuous subcuta-neous apomorphine therapy improves dyskinesias in Parkinson’s dis-ease: a prospective study using single-dose challenges. Mov Disord.2005;20(2):151–157.

106. Laitinen LV, Bergenheim AT, Hariz MI. Leksell’s posteroventral pallido-tomy in the treatment of Parkinson’s disease. J Neurosurg. 1992;76(1):53–61.

107. Guridi J, Obeso JA, Rodriguez-Oroz MC, Lozano AA, Manrique M.L-dopa-induced dyskinesia and stereotactic surgery for Parkinson’s dis-ease. Neurosurgery. 2008;62(2):311–323;discussion 323–325.

108. de Bie RM, de Haan RJ, Nijssen PC, et al. Unilateral pallidotomy inParkinson’s disease: a randomised, single-blind, multicentre trial. Lancet.1999;354(9191):1665–1669.

109. Vitek JL, Bakay RA, Freeman A, et al. Randomized trial of pallidotomyversus medical therapy for Parkinson’s disease. Ann Neurol. 2003;53(5):558–569.

110. Merello M, Starkstein S, Nouzeilles MI, Kuzis G, Leiguarda R. Bilateralpallidotomy for treatment of Parkinson’s disease induced corticobul-bar syndrome and psychic akinesia avoidable by globus pallidus lesioncombined with contralateral stimulation. J Neurol Neurosurg Psychiatry.2001;71(5):611–614.

111. Limousin P, Pollak P, Benazzouz A, et al. Effect of parkinsonian signsand symptoms of bilateral subthalamic nucleus stimulation. Lancet.1995;345(8942):91–95.

112. Rodriguez-Oroz MC, Obeso JA, Lang AE, et al. Bilateral deep brain stimu-lation in Parkinson’s disease: a multicentre study with 4 years follow-up.Brain. 2005;128(Pt. 10):2240–2249.

113. Deep-brain stimulation of the subthalamic nucleus or the pars interna ofthe globus pallidus in Parkinson’s disease. N Engl J Med. 2001;345(13):956–963.

114. Burchiel KJ, Anderson VC, Favre J, Hammerstad JP. Comparison of pallidaland subthalamic nucleus deep brain stimulation for advanced Parkinson’sdisease: results of a randomized, blinded pilot study. Neurosurgery.1999;45(6):1375–1382;discussion 1382–1384.

115. Anderson VC, Burchiel KJ, Hogarth P, Favre J, Hammerstad JP. Pallidalvs subthalamic nucleus deep brain stimulation in Parkinson disease. ArchNeurol. 2005;62(4):554–560.

116. Moro E, Scerrati M, Romito LM, Roselli R, Tonali P, Albanese A. Chronicsubthalamic nucleus stimulation reduces medication requirements inParkinson’s disease. Neurology. 1999;53(1):85–90.

117. Katayama Y, Oshima H, Kano T, Kobayashi K, Fukaya C, Yamamoto T.

Direct effect of subthalamic nucleus stimulation on levodopa-inducedpeak-dose dyskinesia in patients with Parkinson’s disease. Stereotact FunctNeurosurg. 2006;84(4):176–179.

118. Simonin C, Tir M, Devos D, et al. Reduced levodopa-induced complica-tions after 5 years of subthalamic stimulation in Parkinson’s disease: asecond honeymoon. J Neurol. 2009;256(10):1736–1741.

119. Piboolnurak P, Lang AE, Lozano AM, et al. Levodopa response in long-term bilateral subthalamic stimulation for Parkinson’s disease.Mov Disord.2007;22(7):990–997.

120. Moro E, EsselinkRJ, Benabid AL, Pollak P. Response to levodopa in parkin-sonian patients with bilateral subthalamic nucleus stimulation. Brain.2002;125(Pt. 11):2408–2417.

121. Alterman RL, Shils JL, Gudesblatt M, Tagliati M. Immediate and sustainedrelief of levodopa-induced dyskinesias after dorsal relocation of a deepbrain stimulation lead. Case report. Neurosurg Focus. 2004;17(1):E6.

122. Nyholm D, Askmark H, Gomes-Trolin C, et al. Optimizing levodopa phar-macokinetics: intestinal infusion versus oral sustained-release tablets. ClinNeuropharmacol. 2003;26(3):156–163.

123. Stocchi F, Vacca L, Ruggieri S, Olanow CW. Intermittent vs continuouslevodopa administration in patients with advanced Parkinson disease: aclinical and pharmacokinetic study. Arch Neurol. 2005;62(6):905–910.

124. Antonini A, Isaias IU, Canesi M, et al. Duodenal levodopa infusion foradvanced Parkinson’s disease: 12-month treatment outcome. Mov Disord.2007;22(8):1145–1149.

125. Nyholm D, Nilsson Remahl AI, Dizdar N, et al. Duodenal levodopa infu-sion monotherapy vs oral polypharmacy in advanced Parkinson disease.Neurology. 2005;64(2):216–223.

126. Nyholm D, Lewander T, Johansson A, Lewitt PA, Lundqvist C, AquiloniusSM. Enteral levodopa/carbidopa infusion in advanced Parkinson disease:long-term exposure. Clin Neuropharmacol. 2008;31(2):63–73.

127. DeGaspari D, Siri C, Landi A, et al. Clinical and neuropsychological followup at 12 months in patients with complicated Parkinson’s disease treatedwith subcutaneous apomorphine infusion or deep brain stimulation of thesubthalamic nucleus. J Neurol Neurosurg Psychiatry. 2006;77(4):450–453.

128. Clarke CE, Worth P, Grosset D, Stewart D. Systematic review of apomor-phine infusion, levodopa infusion and deep brain stimulation in advancedParkinson’s disease. Parkinsonism Relat Disord. 2009;15(10):728–741.

129. Nyholm D, Constantinescu R, Holmberg B, Dizdar N, Askmark H.Comparison of apomorphine and levodopa infusions in four patientswith Parkinson’s disease with symptom fluctuations. Acta Neurol Scand.2009;119(5):345–348.

130. Deuschl G, Schade-Brittinger C, Krack P, et al. A randomized trial ofdeep-brain stimulation for Parkinson’s disease. N Engl J Med. 2006;355(9):896–908.

131. Bennett JP, Jr., Landow ER, Schuh LA. Suppression of dyskinesiasin advanced Parkinson’s disease. II. Increasing daily clozapine dosessuppress dyskinesias and improve parkinsonism symptoms. Neurology.1993;43(8):1551–1555.

132. Pierelli F, Adipietro A, Soldati G, Fattapposta F, Pozzessere G, ScoppettaC. Low dosage clozapine effects on L-dopa induced dyskinesias in parkin-sonian patients. Acta Neurol Scand. 1998;97(5):295–299.

133. Durif F, Debilly B, Galitzky M, et al. Clozapine improves dyskinesias inParkinson disease: a double-blind, placebo-controlled study. Neurology.2004;62(3):381–388.

134. Marks WJ, Jr., Ostrem JL, Verhagen L, et al. Safety and tolerability ofintraputaminal delivery of CERE-120 (adeno-associated virus serotype 2-neurturin) to patients with idiopathic Parkinson’s disease: an open-label,phase I trial. Lancet Neurol. 2008;7(5):400–408.

135. Kaplitt MG, Feigin A, Tang C, et al. Safety and tolerability of gene ther-apy with an adeno-associated virus (AAV) borne GAD gene for Parkinson’sdisease: an open label, phase I trial. Lancet. 2007;369(9579):2097–2105.

136. Christine CW, Starr PA, Larson PS, et al. Safety and tolerability of putam-inal AADC gene therapy for Parkinson disease. Neurology. 2009;73(20):1662–1669.

137. Jarraya B, Boulet S, Ralph GS, et al. Dopamine gene therapy forParkinson’s disease in a nonhuman primate without associated dyskine-sia. Sci Transl Med. 2009;1(2):2ra4.


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JURNAL: Neuro L-Dopa-Induced Dyskinesias in Parkinson s Disease