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J Neurol (2008) 255 [Suppl 4]:32–4I 10.1007 s00415-008-4006-

J O N 4

0 0 6

Francesca Del Sorbo

Alberto Albanese

Levodopa-induced dyskinesias

and the r management

Why do PD patients develop dyskinesias?

Following a period of stable response to dopaminer-

gic medication (the “honeymoon” period), Parkinson’sdisease (PD) patients gradually develop two progres-sive clinical phenomena requiring changes in the clin-ical management: motor fluctuations and dyskinesias.These two phenomena are intrinsically interconnected,but often require opposite treatment attitudes, becauseincreases of dopaminergic treatment often improvefluctuations, but worsen dyskinesias. A possible solutionto this dilemma resides in the administration of addi-tional anti-dyskinetic medication; unfortunately, how-

ever, drugs with enough anti-dyskinetic potency havenot yet been developed.

Epidemiology

Dyskinesias are a central side effect of dopaminergictherapy and represent a major clinical problem in the

anagement of patients with PD. Early studies per-ormed before the levodopa era did not describe theresence of motor fluctuation or dyskinesias [32]. Dys-inesias were first observed following the introduction

of levodopa monotherapy. In his seminal paper on le-vodopa treatment of PD, Cotzias [20] first observed “the

F. Del Sorbo · A. Albanese ()Fondazione IRCCS Istituto NeurologicoCarlo Besta

Via G. Celoria, 1120133 Milano, Italy Tel.: +39-02/2394-2552Fax: +39-02/2394-2539E-Mail: [email protected]

A. AlbaneseUniversità Cattolica del Sacro CuoreMilano, Italy

of disability. Their precise etiologyis still poorly understood, althoughit is recognized that dopaminer-

gic pre-synaptic and post-synap-tic mechanisms are involved to-gether with extra-dopaminergicfactors. The phenomenology ofdyskinesias encompasses a vari-able mixture of two prevalent fea-tures: dystonia and chorea. We havestudied their time course follow-ing a single acute levodopa chal-lenge and have found that dysto-nia occurs throughout the durationof the on period, whereas chorei-form movements occur only at the

peak of therapeutic dopaminer-gic motor responses. This allows aschematic relationship to be drawnbetween a short duration motor re-sponse and the occurrence of dys-tonia and chorea. There is currentlyno satisfactory treatment for dys-

kinesias. Managing the therapeuticwindow does not provide an ade-quate solution due to the appear-

ance of a dyskinesia threshold dosethat narrows the therapeutic mar-gin. High frequency stimulation ofthe subthalamic nucleus probably

as some specific anti-dyskineticaction, but is limited by the smallnumber of patients who are candi-dates for this treatment. Researchefforts are currently focused on thedevelopment of specific anti-dys-kinetic medications. Their avail-ability will certainly change thecurrent clinical practice and will

widen again the therapeutic win-dow of dopaminergic medicationshat has now become too narrow.

Key words Parkinson’s disease ·dyskinesias · levodopa · dopamineagonists

Abstract This paper reviewsthe epidemiology, pathophysiol-ogy, clinical features and ratio-

nale for managing dyskinesias as-sociated with Parkinson’s disease.These are a common clinical prob-lem occurring in up to 90% of pa-tients and more frequently affectthose with early-onset. Dyskinesiashave a negative impact on qualityof life and are an important cause



33

reversible induction of athetoid movements, which havebeen observed thus far only in patients with PD and onlywhen the therapeutic effect was significant”. Later ob-servations clearly identified dyskinesias as a side-effectof levodopa treatment [4, 5]. It was later recognized thatdyskinesias can also be caused by dopamine agonists,particularly if short-acting and of adequate potency [22,

35]. It became thus clear that any type of exogenous do-paminergic stimulation in a denervated striatum cancause dyskinesias [46], but pulsatile stimulation pro-duced by short-acting drugs (as typically occurs withlevodopa) particularly favors their occurrence [67]. Theexpression “levodopa-induced dyskinesias” is still cur-rently used, although levodopa is not the only drug caus-ing dyskinesias in PD patients [55].

Awareness of these levodopa complications has in-fluenced treatment strategies for PD. In modern series,dyskinesias occur later than in earlier series, with an ap-proximate risk of dyskinesias just short of 40 % follow-ing 4–6 years of levodopa monotherapy [1]. The intro-

duction of dopamine agonists since early disease stageshas further reduced and delayed the occurrence of dys-kinesias [80]. Based on published series, it has been esti-mated that PD patients treated for less than 5 years havean 11 % risk of dyskinesias, those treated for 6–9 yearshave a risk of 32 %, whereas patients treated for morethan 10 years have a risk of 89 % [23]. However, thesefigures are likely to decrease due to the widespread useof dopamine agonists, COMT and MAO inhibitors in theearly disease stages.

The three most important risk factors positively as-sociated with increased occurrence of dyskinesias areyounger age at disease onset [40, 79], longer disease du-

ration [70, 73] and longer duration of pulsatile dopami-nergic treatment (typically, levodopa) [23, 80]. The firsttwo factors are interrelated and almost all patients withearly onset disease [81] develop dyskinesias, whereasthey are less frequent in patients with late onset PD [43].PD patients with early disease onset have a high proba-bility to carry mutations for monogenic PD forms andtherefore early onset and genetic predisposition are twooverlapping and possibly interrelated risk factors. Otherrisk factors associated with increased risk of dyskinesiasare female gender [50, 86] and the occurrence of spe-

cific polymorphisms for dopamine receptors or dopa-ine transporters [29, 36, 68].Monogenic forms of PD offer a unique viewpoint to

appreciate the role played by genetic factors on the oc-currence of dyskinesias. Dyskinesias occur in all pa-ients with parkin disease (PARK2) [38], whereas only

84% of patients with PINK1 disease (PARK6) present

dyskinesias [2]. Parkin disease patients have an earlierean age at disease onset (24 years, compared to 31.6)

indicating that genetic make-up influences both vari-ables. The role played by genetic factors is better high-ighted in PINK1 patients by comparing those with one

utated allele to patients with two mutated alleles orwith wild-type PD [52]. Heterozygous carrier PINK1 pa-tients overlap to wild-type PD patients for age at onsetand disease duration, but have a higher incidence of dys-

inesias approaching that of PINK1 patients with bothalleles affected [52] (Table1).

Dyskinesias are an important cause of disability inPD and can reduce the patients’ quality of life. Mild, non-

disabling dyskinesias that occur in early disease stagesdo not impact significantly on quality of life [53]. How-ever, in patients with advanced disease, more severe dys-

inesias may cause poor quality of life, depression andincreased health care costs [71]. It has been observedthat peak-dose dyskinesias are better accepted by pa-tients than off-period morning dystonia and diphasicdyskinesias [15]. Hence, the patients tolerate on statedyskinesias better than those occurring in the off or par-tial-off periods, because of the associated good motorstate and lack of pain or discomfort. The quality of lifeof patients with advanced PD is not only limited by theoccurrence of dyskinesias, but also by insufficient do-

aminergic medication secondary to a low dyskinesiathreshold [80] (see Fig.6).

Pathophys ology

Levodopa and dopamine agonists do not induce dyski-nesias in PD patients (or in experimental animals) that

ave never been previously treated with dopaminergicedications. The process by which the brain becomes

sensitized such that each administration of dopaminer-

Number o alleles a ected

um er o pat ents : ) : ) : ) : )

ge at onset years) . .

sease urat on years) . . .

um er o pat ents w t yston a at onset ) )

um er o pat ents w t motor uctuat ons ) ) ) )

Number o patients with dyskinesias (%) 151 (47 ) 1 (55 %) ** (9 %)

* Significantly different from wild-type patients (p 0.05) and from patients with one affected allele (p 0.05),** Significantly different from wild-type patients (p 0.01)

Table Comparison o dyskinesias in wild-type PD

patients (no allele a ected), PINK1 single heterozy-gote patients (1 allele a ected), and PINK 1 patientscarrying two mutate a e es. From [52



34

gic therapy modifies the response to subsequent dopa-minergic treatments, is called priming. In this way, withrepeated treatment over time, the chance of dopaminer-gic stimulation eliciting dyskinesias is increased andonce dyskinesias have been established, their severityincreases. The priming process, which is responsible forthe insidious evolution of dyskinesias over time of treat-

ment, is associated with changes in receptors for dopa-mine or other neurotransmitters [27, 59].

Following priming, the development of dyskinesiaslargely depends on two additional factors, the pulsatileadministration of levodopa (or another short-acting do-paminergic agent) and the degree of dopaminergic de-nervation in the striatum. The latter plays an importantrole in setting the threshold required for dyskinesias todevelop [9]. A direct relationship between the degree ofstriatal denervation and the time required to developdyskinesias has been demonstrated in monkeys ren-dered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tet-rahydropyridine [78]. The same observation has also

been replicated in PD patients [42] and has been indi-rectly confirmed by the finding that patients with dopa-responsive dystonia, who have parkinsonism withoutnigrostriatal denervation, uncommonly develop dyski-nesias [21].

Dopaminergic denervation and dopaminergic prim-ing induce a series of anatomical and functional changesin the striatum leading to further and more persistentdysfunction. Dyskinesias are probably generated by apersistent enhancement of the responsiveness of stria-tal medium sized spiny neurons to dopaminergic treat-ment. This is an aftermath of dopamine depletion and isassociated with over-expression of specific components

of the signal transduction machinery. If protracted, thiscondition may ultimately lead to long-term changes ingene expression, which will permanently affect the func-tion of striatal medium spiny neurons [77].

Pre-synaptic dopaminergic changes provide a first-level explanation for the occurrence of both motor com-plications and dyskinesias. The occurrence of severedopaminergic denervation implies the loss of compen-satory mechanism in the nigrostriatal system, and al-ters the routes of levodopa uptake and metabolism inthe brain. When the dopaminergic system is not severelycompromised, the processing of exogenous levodopa oc-curs primarily in nigrostriatal neurons, where levodopa

is converted to dopamine, stored in synaptic vesicles,and released by physiological stimuli into the extracellu-lar space, where clearance of dopamine is ensured frompresynaptic reuptake mechanism. In the striatum of pa-tients with mild PD, levodopa levels may be buffered bythe compensatory effort of surviving nigrostriatal neu-rons providing more or less constant dopamine receptoractivation. This is clinically evidenced by the occurrenceof long-duration anti-parkinsonian responses whichoutlasts the half-life of levodopa, enabling a stable mo-

tor state. Studies have shown that in more advanced PD,with severe lesions of the nigrostriatal pathway, exoge-nous levodopa might be decarboxylated to dopamine atnon-dopaminergic sites, especially serotoninergic neu-rons, glia and endothelial cells, that are not equippedto store, release and reuptake dopamine in a controlledashion [12, 47, 55]. As a result, intrasynaptic dopamine

evels no longer remain constant, but mirror the broadluctuation in plasma levodopa levels that occur after

each dose, causing dopamine receptors to be exposedto alternating high and low concentrations of dopa-

ine [61]. The clinical counterpart of this condition isthe observation of short-duration motor responses to le-vodopa administration (Fig.1). The combination of do-

amine depletion and the administration of short-liveddopaminergic drugs, causing a pulsatile stimulation ofstriatal dopamine receptors in contrast to the tonic stim-ulation that occurs under physiologic circumstances, re-sults in the development of dyskinesias.

Post-synaptic dopaminergic changes are also crucial

to the development of dyskinesias in PD. Loss of dopa-inergic terminals in the striatum and non-physiologi-

cal dopaminergic stimulation can cause plastic changesaltering the normal functioning of the striatum, furthercontributing to pulsatile dopamine stimulation. The de-velopment of dyskinesias is not correlated with any con-sistent variations in the density of dopamine receptors[8, 55], but rather to downstream signal transduction

athways causing post-synaptic changes in proteins andgene expression [7, 26, 28]. Dopaminergic priming andbehavioral sensitization must cause molecular changesat the post-synaptic level in order to cause dyskinesias.

Non-dopaminergic neurons are also considered to

contribute to the pathophysiology of PD dyskinesias. Adysregulation of medium sized striatal spiny neuronscan contribute to the pathogenesis of dyskinesias [10,18]. Non-physiological stimulation of dopamine recep-tors on striatal spiny neurons leads to changes in sub-unit phosphorylation pattern of coexpressed ionotropic

MDA and AMPA glutamatergic receptors [17]. Resul-tant sensitization of these receptors augments corticalexcitatory input to the spiny efferent neurons, thus al-tering striatal output in ways that compromise motorunction [14]. Consistent with this possibility is the ob-

servation that drugs that block glutamate receptors tendto diminish motor complications in both parkinsonian

odels and patients [19]. In addition, enhancement ofetabotropic glutamatergic receptors may also contrib-ute to the pathogenesis of dyskinesias [76]. Other recep-tor types located in the basal ganglia also make an im-

ortant contribution to the functional state of striataloutput neurons and are targets for novel anti-dyskinetictreatments. They include: cannabinoid CB1, adenosine

2A, serotonergic 5HT A, 5HT1A, -2 adrenergic and opi-oid receptors [11].



35

Clinical features

The perception of dyskinesias may differ between doc-tors and PD patients (Table2). It is not uncommon toobserve that patients stand dyskinesias in the on-pe-riod when they are mobile and try to avoid unsatisfac-

tory partial-on periods, particularly if dystonic dyski-nesias occur.The phenomenology of dyskinesias is variable; they

can occur at different times following intake of a dopa-minergic medication and variably combine dystonic andchoreic movements. The dystonic nature of dyskinesiasin PD was recognized early, when the expressions “im-provement-dystonia-improvement” (I-D-I) and “dysto-nia-improvement-dystonia” (D-I-D) were used [58] todescribe what was otherwise called “diphasic” [6] and“peak-dose” [54] dyskinesias (Fig. 2). At the same time it

was also noted that choreic features are characteristic ofdyskinesias occurring in the on-period [45]. On-periodand off-period dyskinesias differ in several ways: theirst are mainly choreic and dystonic whereas the latter

are purely dystonic. Tremor and pain (likely related torigidity) may be present in the off-period and decreasewith improving motor condition [49, 51] (Fig.3). This

gradient provides a clinical continuum between a hyper-dopaminergic and a hypo-dopaminergic state [51].

Dysk nes as follow ng acute levodopa challenge

The clinical phenomenology of dyskinesias (namely,their choreiform or dystonic appearance) has been cor-related to the motor response elicited by an acute le-vodopa challenge.

Ten PD patients (three men and seven women) witha diagnosis according to the Queen Square Brain Bankcriteria [33] were evaluated. They had disabling motor

luctuations with prolonged and, at least occasionally,unpredictable off-periods (patients spent 25% or moreof the waking day in the off-state) and on-state dyskine-sias. Their Hoehn-Yahr stage was ≥ III in the practicallydefined off-condition [44].

All patients were on dopaminergic therapy with le-vodopa and one dopamine agonist at the moment of en-rollment and gave their written informed consent. Theincluded patients were assessed in the morning, in the

ractically defined off-condition [44]. The clinical eval-

days

P o s t - s y n a p t i c n e u r o n

lial cell

L e v o d o

p a

P o s t - s y n a p t i c n e u r o n

L e v o d o

p a

Early stage PD Late stage PD

hours

Long-duration response

us stror or atumus str

l l ell

Short-duration response

Fig.1 ong-duration responses depend on the availability of functionaldopaminergic nigrostriatal terminals,whereas short-duration responses aregenerate y evo opa pro uce outside nigrostriatal dopaminergic termnals, once these are degenerated. Inear y isease stages, ong- uration responses allow or a continuous clinical

benefit (“honey moon” period); lateron, short-duration responses appearand long-duration responses graduallywane. Super-sensitive post-synaptic opaminergic receptors are schematicallys own in ye ow

Table yskinesias: patients’ vs. doctors’ viewpoints

octors

ys nes as as a motor p enomenon

There are no tools to evaluate the impact of dyskinesias on the patients’ua ty o e

at ents

May not be aware of dyskinesias (particularly peak-dose dyskinesias)

n erest mate t e r actua preva ence

Estimate the prevalence of fluctuations and dyskinesias that areclinically significant



3

uation of each patient was carried out using the follow-ing outcome measures: parkinsonian motor disabilitywas assessed using the Unified Parkinson’s Disease Rat-ing Scale motor score (UPDRS) [24], upper limb speed

as an index of bradikinesia was assessed by the tappingtest (TT) [62]; the evaluation of topography, type andseverity of dyskinesias was performed while the patientwas sitting, walking and performing TT, by using items11 and 12 of the Unified Huntington’s Rating Scale [34],applied to face, mouth, trunk, upper and lower limbs.Following baseline assessment of all the measured vari-

ables, the patients received an acute levodopa/carbidopa250/25 mg) challenge followed by TT and dyskinesias

rating every 15 min and by UPDRS motor assessmentevery 7 min. The complete clinical evaluation was car-ried out until the TT score returned <15% better thanbaseline TT score.

The patients had a mean age of 61.2 (±10.4) yearsand a disease duration of 12.3 (±5) years. They had beentreated with levodopa for 10.6 (± 5.1) years, had motorluctuations for the last 4.1 (±2.3) years and dyskine-

sias for 3.9 (± 2.5) years. At the time of evaluation the to-tal levodopa equivalent dose was 1,086.5(±529) mg. Allthe patients had an excellent response to levodopa with

an average improvement of 53.4 % following the acutechallenge.

The drug challenge produced appreciable short-du-ration motor responses in every patient, as shown by thetime-dependent decrease of UPDRS motor score and in-crease of TT scores (Fig.4 ). Onset of motor improve-

ent occurred between 15 and 45 min following theevodopa challenge and averaged 28.5± 8.5min. The on-eriod lasted for a minimum of 130 and a maximum of

240 min (on average 179.5 ± 41.3 min). Dyskinesias oc-curred in all patients during the on-period, with dys-tonic, choreic or combined features (Fig.4 B).

At baseline evaluation, fixed dystonia was present in

ive patients. In two of them it exclusively involved thetrunk, whereas in the other three the distribution wasgeneralized. All patients had on-period dystonia withthe features of mobile or fixed dystonia. Two patients

resented chorea and dystonia in combination duringthe entire on-period. Dystonia was more commonly de-tected in the mouth (9 patients), in the upper limbs (9

atients), in the lower limbs (9 patients), in the trunk8 patients) and in the face (5 patients). Dystonia se-

verity was ranked in decreasing order from the trunkmean score 2.0± 1.6, legs 1.5± 1.5, arms 1.4± 1.3, mouth

0.8±1.0 and to the face 0.6±1.0).Chorea was not observed at baseline and only oc-

curred in the on-period. It was detected in nine patientsstarting 41.7± 26.8 min following levodopa challenge. Inthree patients, limb chorea preceded the observable onstate by an average of 13.5± 9.5 min. On-period choreaoccurred in decreasing frequency from the upper limbs8 patients), to the lower limbs (7 patients), the trunk2 patients), and the mouth or face (1 patient). Cho-

rea severity was maximal in the trunk (0.6±1.1), andilder in the legs and arms (0.4 ± 0.7), or face and mouth

0.1±0.2).

Peak-dose

quare wave

Diphasic

b

F g. 2 ea - ose ys inesias (correspon ing to I-D-I) are t e typica on-periodyskinesias observed in PD ( ); diphasic dyskinesias (corresponding to D-I-D) occur when patients are in the transitional state from the off- to the on-period );square-wave dyskinesias encompass a combination o both types C)

Fig. The transition rom peak-dose to diphasic dyskinesias and o -period dys-tonia is associated with increasing pain and dystonia and the occurrence o tremor.

is p enomeno ogica gra ient appears as a c inica continuum etween a yper-opaminergic an a ypo- opaminergic state in patients wit comp icate P



37

When patients returned to the of state, off-perioddystonia recurred at the same degree and characteris-tics in all of five patients who had it at baseline, whereasit was not observed in the remaining patients. No cho-reic movements were detected in the off-period.

This observational study following acute levodopachallenge was designed to evaluate in a controlled settingthe onset and presentation of dyskinesias, from the off

otor condition preceding the acute challenge throughthe complete duration of the on state, until the end ofshort-duration motor response. This allowed the com-

arative features of choreic and dystonic dyskinesias to

be observed through the off and on-periods, and to rec-ognize that chorea is only present during the peak of

otor effect. Dystonia, instead, was observed through-out the observation period and increased during the du-ration of motor response. Diphasic dyskinesias, whichoccurred at the beginning and end of motor response,were mainly dystonic, whereas peak-dose dyskinesiaswere mixed, choreic and dystonic (Fig.5). These dataextend and complete previous suggestions that dyski-nesias constitute a continuum with changing phenome-nology [51] and better specify how PD motor responseis associated to chorea and dystonia.

It has been already observed that dystonia can also

occur in the off motor state [49, 51, 85]. Off-period dys-tonia is mainly fixed and turns into a mobile form dur-ing the on-period. As the motor response induced byacute challenge vanishes, dystonia turns back again toa fixed form.

Rat onale for management

The observation that dyskinesias increase in the on stateas prompted attempts to identify perfectly titrated in-

dividual doses for continuous infusions of levodopa [72,74] or dopamine agonists [65, 66]. This was supposed

Fig. ean motor improvement emonstrate y TT an UPDRS motor score (A),compare to t e mean c orea an ystonia scores B) following an acute challengewith levodopa/carbidopa (250/25 mg). X-axes show time in minutes ollowing theacute a ministration; Y-axes s ow mean scores, as out ine in t e text

Fixed dystonia

Short-duration

motor response

Chorea

Mobile dystonia

dyskinesi

Time

(hours)1

D i p h a s i c d y s k i n e s i a

D i p h a s i

d y s k i n e s i a

state transition threshold

Fig.5 chematic representation of dyskinesias oc-curring in relation with a short-duration motor re-sponse (red line) elicited by levodopa. Dystonia isn icate in ue, c orea in green. Fixe ystonia

occurs throughout the duration o motor response,prevalently in the o state. en t e pat ent turnsn (crossing t e otte re t res o ), mo i e ys-

tonia (hatched blue area) occurs during the on-pe-rio ; c orea ( atc e green area) can a itiona y eobserved at peak dose. This schematic drawing alsondicates that peak-dose dyskinesias are choreic andystonic, w ereas ip asic ys inesias are ystonic,ut not choreic



3

to avoid the occurrence of severe on-state dyskinesias,

yet providing an adequate motor condition for the du-ration of infusion. This historical approach was basedon the observation that motor fluctuations and dys-kinesias coexisted in patients with complicated PD. Itseemed therefore reasonable to address both phenom-ena using a unique treatment strategy [16]. Unfortu-nately, attempts to ameliorate dyskinesias in advancedPD patients by giving smaller, more frequent doses of le-vodopa or a continuous infusion turned out to be coun-ter-productive [56]. Attempts to manage the therapeuticwindow by changing the pharmacokinetics of levodopaor of dopamine agonists were not efficacious in control-ling on-period dyskinesias. The reason why this option

does not provide an efficient solution is highlighted inFig.6 which schematically shows a typical sigmoid dose-effect curve for anti-parkinsonian response to levodopa(or dopamine agonists). In order to elicit maximal anti-parkinsonian effect an optimal dose of levodopa(or dopamine agonist) must be given. There is no advan-tage of further increasing the medication, as this wouldprovide no additional anti-parkinsonian effect (dashedred area). This is a very efficacious treatment in earlydisease stages, when dyskinesias are not present. How-ever, after dyskinesias are established, a threshold med-ication dose for dyskinesias becomes apparent. Oncethe dyskinesia threshold moves to the left of the max-

imal antiparkinsonian dose line

, dyskinesias becomeinevitably associated with the maximal anti-parkinso-nian effect. In practical terms, it becomes necessary toprovide suboptimal treatment to keep the patient freefrom dyskinesias. As PD treatment and disease prog-ress, the dyskinesia threshold moves further to the leftand the therapeutic window narrows, making thethreshold of maximal anti-parkinsonian effect withoutdyskinesias move further down.

Continuous levodopa infusion corrects the phar-

acokinetic causes leading to dyskinesias, as it allows

avoiding the peaks and troughs of repeated oral admin-istration [63]; however, the pharmacodynamic causesof dyskinesias illustrated by Fig.6 remain. This explainswhy dyskinesias are still observed when the patients aretreated enough to reach an adequate on state [3, 60, 64].Similarly, dyskinesias do not disappear when patientsare treated with continuous infusions of dopamine ag-onists [37, 82].

High frequency stimulation of the subthalamic nu-cleus or the globus pallidum provide an alternative ap-

roach to the treatment of dyskinesias in PD [83]. Thetwo targets are considered to reduce dyskinesias by

eans of different anatomofunctional mechanisms

[13]. Globus pallidum stimulation probably has a directanti-dyskinetic effect by interfering with pallidal out-low, whereas subthalamic nucleus stimulation reduces

edication requirements (thus changing the pharma-codynamic dose-effect curve) [57] and in addition mayalso affect pallidal outflow at the level of the ansa len-ticularis, situated just below the subthalamic nucleus.Deep brain stimulation of the subthalamic nucleus hasstriking ameliorative effects on off-period dystonia [41],yielding an average reduction in dyskinesias of approx-imately 70% [39]. It must be remember that the numberof candidate patients for deep brain stimulation repre-sent a minority of the PD population, because strict se-

ection criteria are usually implemented in most centers[75].A third line of treatment is based on the administra-

tion of specific antidyskinetic drugs capable to move tothe right the dyskinesia threshold depicted in Fig.6.

ovel potential therapeutic strategies attempt to act onnon-dopaminergic neurotransmitter systems and re-duce the expression of dyskinesias, once they are estab-ished, without interfering with the anti-parkinsonian

activity of dopaminergic drugs [7, 25]. The first (and

A n t i p a r k i n s o n i a n r e s p o n s e

Levodopa dose

1 Antiparkinsonian threshold

d se (25% motor

improvement)

2 Dyskinesia threshold dos

Therapeutic window

Optimal dos

Maximal antiparkinsonian

effect

6 Slope

7 Maximal antiparkinsonian

effect without dyskinesias

75

6

1

3

2 4

Fig.6 igmoid dose-e ect curve oranti-par insonian response to t e aministration of increasing doses of levodopa (blue). Motor-related thresholdsare re , ys inesia-re a te t res o sare green. See text or an explanation



3

still only) drug with proven anti-dyskinetic efficacy isamantadine, a glutamate antagonist active on NMDA re-ceptors, whose activity lends further support to the glu-tamatergic hypothesis on the pathogenesis of dyskine-sias [31, 69]. The improvement of dyskinesias is around50 % without concomitant worsening of parkinsoniansymptoms [48, 84].

Other potential anti-dyskinetic candidates have beenexcluded or are still under scrutiny. Sarizotan demon-strated potential efficacy in an open label trial, but sub-sequently proved to be ineffective in two double blind

lacebo-controlled studies [30]. Atypical neurolep-tics (particularly clozapine) have also been considered,but presently there is insufficient evidence to supportthe efficacy of clozapine in reducing dyskinesias [69].Other promising anti-dyskinetic drugs act on glutamateNMDA, AMPA or mGluR), serotonin (5HT1A, 5HT1B/D,

5HT2A–2C), adenosine (A2), opiate or other receptors.

Their potential efficacy is currently under scrutiny.

onflict of interest The authors have no conflict of interest to de-clare.

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