EUROPEAN NEUROLOGICAL JOURNAL REVIEW ARTICLE

L-dopa-Induced Dyskinesias in Parkinson’s Disease

Iciar 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 by
the development of drug-induced involuntary movements known as dyskinesias, which can appear in approximately 40% of the PD patients
after 5 years of treatment. In recent years we have learned a great deal about the processes involved in the appearance of L-dopa-induced
dyskinesia (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 all
appear 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 clinical
phenomenology of LID, describe an overview of what is known about their pathophysiology, and provide guidance in the range of therapeutic
approaches that can be tailored to the individual patient.

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

Correspondence: Iciar Aviles-Olmos, Unit of Functional Neurosurgery, Sobell Department of Motor Neuroscience and Movement
Disorders, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom. Tel: +44-08451555000 Ext. 18739; e-mail:
i.olmos@ion.ucl.ac.uk

INTRODUCTION basis for preventing/delaying their development and current

The introduction of levodopa (L-dopa) for the treatment of
Parkinson’s disease (PD) in the 1960s dramatically changed the
clinical management and prognosis of PD patients.1–2 L-dopa
crosses the blood–brain barrier and is converted to dopamine
through the action of aromatic-L-amino-acid decarboxylase
in surviving dopaminergic terminals, and is the most potent
symptomatic agent against the motor symptoms of the disor-
der. In most 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% of
the patients will develop fluctuations in symptom control in
response to the drug, as well as involuntary movements known
as “L-dopa-induced dyskinesia” (LID).3 These complications
affect as many as 89% of PD patients after 10 years of L-dopa
treatment.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 reduced
the frequency with which severe LID are seen, there has also
been an evolution of an “L-dopa phobia” among some clini-
cians and patients, resulting in some instances in unnecessary
disability 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
and future possible options for their treatment.
TYPES OF DYSKINESIA
The effectiveness of L-dopa treatment decreases as the dis-
ease progresses because of the progressive loss of nigrostriatal
neurons. Typically the first sign of this is the gradual return of
PD symptoms before the next dose of medication is due. This
is called “wearing off” and it generally necessitates increases in
L-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 legs
and neck are most frequently involved. There are three main
subtypes of LID:
• Peak-dose dyskinesias: these are the most common and early
appearing LID and occur when L-dopa levels are at their high-
est. These usually consist of stereotypic, choreic, or ballistic
movements but occasionally dystonia can also be present.
They tend to be more easily manageable by patients because
they occur during periods of good motor control, that is, in
the “on” motor state.6
• Off-period dyskinesias: these emerge when L-dopa levels are at
their lowest. These often present with painful leg cramps or

∗
These 2 authors contributed equally to this work.

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European Neurological Journal
abnormal postures (dystonia) typically in the foot, and most
commonly in the early morning.
• Diphasic dyskinesias: these are the least common and occur
with the rise and fall of L-dopa concentration, disappear-
ing when drug levels achieve a certain threshold, and then
recurring as the drug level falls, before resolving again as
parkinsonism returns. These usually present as short-lasting
(5–10 minutes) choreiform movements or akathisia.
Risk Factors for LID Development
Several risk factors have been established for the earlier onset
of LID:
Age of the patient: Young-onset PD patients develop LID earlier
than 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 distinguishing
the effect of age at the onset of PD from the direct effects
of genetic influences on LID risk is difficult even among
patients with genetically defined PD.9,10
Dose of L-dopa: In the ELLDOPA study, it was shown that patients
treated with L-dopa over a 40-week period were signifi-
cantly less impaired than patients treated with placebo even
after a 2- to 3-week washout period.11 However, dyskinesias
were seen in 16.5% of patients receiving the highest dose of
L-dopa even over this short follow-up period compared with
2–3% of patients on lower doses or placebo, demonstrat-
ing that the dose of L-dopa is critical in terms of risk of
dyskinesia development.
Pattern of L-dopa administration: Intermittent administration of
L-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 can
even occur in normal primates if administered in pulsatile
doses of L-dopa.12 It is now widely accepted that strategies
to reduce the pulsatility of L-dopa stimulation will reduce
the risk of triggering the mechanisms that underlie the
development of LID.
Stage of disease: The onset of clinical symptoms of PD likely
denotes the point of failure of compensatory mechanisms.14
Advanced nigrostriatal denervation in animal models and
advanced disease in PD patients are both associated with
faster onset and more severe LID following the initiation of
L-dopa treatment.15–19
PATHOPHYSIOLOGY OF LID
The neural mechanisms that underlie LID in PD are not com-
pletely understood, but our current insights have been greatly
helped through the detailed study of basal ganglia anatomy
and physiology in the normal and dopamine-depleted states.
Dopamine activates the direct striatal output pathway through
D1-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
ENJ 2010; 2:(2). August 2010
direct and indirect pathways, resulting in abnormal GPi activ-
ity. It was originally thought that the clinical features of PD
were representative of simple increases in the “rate” of activ-
ity of the GPi, which consequently acted as a brake to activity
in the supplementary motor area by inhibiting the motor tha-
lamus (Figure 1B). Using the same logic, it was suggested
therefore that excessive L-dopa stimulation might induce dysk-
inesia by reduction of the inhibition of thalamocortical neurons
and overactivity of motor cortical areas.20
This model however is inconsistent with several clinical and
experimental findings. For example, in the nonhuman pri-
mate model of PD, metabolic activity in the ventral anterior
and ventrolateral thalamic nuclei, regions of the thalamus that
receive input from the GPi, is significantly decreased rather
than increased in LID.21 Furthermore among patients with PD
and LID, creation of a lesion within the GPi (pallidotomy) is
associated with a reduction in LID rather than a deterioration
in 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 striatal
dopaminergic inputs are closely associated with glutamater-
gic corticostriatal projections that synapse onto medium spiny
neurons that form the direct striatal output pathway. Further
modulation 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 appear
to be central to LID development. Overlapping inter-related
mechanisms appear to trigger abnormal functioning of these
neurons, namely, dysfunctional dopamine release, postsynap-
tic dopamine receptor internalization, and disrupted synaptic
plasticity.
DYSFUNCTIONAL DOPAMINE RELEASE
As the striatum is progressively denervated in PD, the surviv-
ing dopaminergic neurons sprout branches that successfully
compensate 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 administration
of L-dopa leads to a 3-fold increase in the concentration of
dopamine in the striatum.24 As soon as the striatum cannot
sufficiently buffer exogenously administered and endogenous
DA levels, DA synaptic availability starts to mirror the short
plasma half-life of L-dopa, and non-physiological dopamine
receptor stimulation follows, contributing to the occurrence of
peak-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 swings
in 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 enhance
dopamine synthesis and release by the surviving dopamin-
ergic neurons, exogenous L-dopa is also decarboxylated and
released as dopamine by serotonergic terminals, striatal capil-
laries, noradrenrgic neurons, and non-aminergic striatal
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 L-dopa-induced dyskinesias in Parkinson’s disease

CEREBRAL CORTEX

STRIATUM D2
D1 Thalamus

Indirect ptw

Direct ptw
GPe STN
Nigro striatal
dopaminergic GPi
pathway SN
Pars reticulata
SN
Pars compacta

CEREBRAL CORTEX

STRIATUM D2
D1 Thalamus

Indirect ptw
Direct ptw

GPe STN
Nigro-striatal
dopaminergic GPi
pathway SN
Pars reticulata

SN
Pars compacta

Figure 1. A) Direct and indirect pathways in normal physiological conditions. B) Rate model of PD: It was originally proposed that with SN pars compacta
neuronal loss, overexcitability of the direct pathway compared with the indirect would lead to hyperactivity of GPi and STN, and increased inhibitory basal
ganglia 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-dopaminergic
terminals leads to further non-physiological dopamine recep-
tor stimulation contributing to LID appearance.29
DOPAMINE RECEPTOR SUPERSENSITIVITY
Chronic denervation of dopamine receptors also leads to
receptor supersensitivity and increased expression of receptors
on 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 hypothesized
that in LID, this desensitization and internalization process is
impaired.33
Upon persistent stimulation, D1Rs undergo desensitization
through a two-step process: activation-dependent receptor
phophorylation by G-protein-coupled receptor kinases (GRKs)
followed by the binding of uncoupling proteins called arrestins
that induce internalization. The D1 receptor–arrestin interac-
tion promotes the recruitment of an endocytic complex and
consequently the internalization of the receptor in an endocytic
vesicle (Figure 2). This is modified in LID, and D1R expression
is increased and their subcellular distribution is modified. This
has been proven in dyskinetic animals, as there are more D1R at

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European Neurological Journal
Striatal Medium Spiny
Neuron
D1R
Arrestin
D1R
P P Arrestin
GRK
cAMP
D1R
DA AC
PKA
DARPP-32
L-dopa
Figure 2. Upper part of figure: desensitization process of D1R. D1R is phosphorylated by GRKs and once phosphorylated binds to arrestin. This induces
the formation of an endocytic complex. GRK, G protein receptor kinase. Bottom part of figure: Loss of depotentiation after chronic non-physiological D1
receptor stimulation. L-dopa, levodopa; DA, dopamine; D1R, D1 receptor; AC, adenylyl cyclase; PKA, protein kinase A; DARPP-32, dopamine- and cAMP-regulated
phosphoprotein 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 not
occur simply as a result of abnormal D1 receptor expression or
sensitivity alone because D2-selective agonists can also provoke
dyskinesia.36
SYNAPTIC PLASTICITY
Two 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 nigra
pars reticulata (SNr), and the indirect one that projects to
GPi/SNr through the globus pallidus pars externa (GPe) and
subthalamic nucleus (STN) (Figure 1). Physiological dopamin-
ergic input from nigrostriatal neurons onto the striatal medium
spiny neurons plays an important role in the potentiation
and de-potentiation of synapses of the corticostriatal pathway.
Repetitive stimulation can cause either a long-lasting increase
in synaptic strength, known as long-term potentiation (LTP), or
an enduring decrease, known as long-term depression (LTD),
a phenomenon known as synaptic plasticity.37,38 This process
allows the strengthening of desirable motor programs and the
deletion of unwanted or unnecessary connections.
The striatal neurons of the direct pathway express D1R and
produce dynorphin and substance P, and the medium spiny
neurons of the indirect pathway are richer in D2R and express
enkephalin. 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 protein
kinase A (PKA) which in turn phosphorylates DA and cAMP-
regulated phospoprotein 32 kDa (DARPP-32) which acts as a
potent inhibitor of protein-phosphatase-1(PP-1). This cascade
ENJ 2010; 2:(2). August 2010 94
CEREBRAL CORTEX
PP
BG output
of processes culminates in the phosphorylation of intracellular
proteins and glutamatergic receptors40 (Figure 2).
LTP and LTD are fully abolished after the genetic disruption of
DARPP-32.41 It is hypothesized that the disrupted motor control
underlying dyskinesia is attributable to specific changes occur-
ring along the D1/PKA/DARPP-32 signaling pathway leading
to the inhibition of PP-1 activity and loss of synaptic depotentia-
tion at corticostriatal synapses.37 Disruption of normal synaptic
plasticity is strongly linked to the appearance of dyskinesia.42–46
The loss of synaptic depotentiation at corticostriatal synapses
leads 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 already
developed.47 It has been proposed that patients with LID have
lost the ability to depotentiate synapses normally, that is, they
have lost the mechanism that underlies “synaptic forgetting,”
leading to the pathological storage of information that would
normally be erased and the development of abnormal motor
patterns, that is, LID.43,48
GENETIC INFLUENCES ON LID DEVELOPMENT
Although much of the variation in LID risk can be attributed
to L-dopa dose and pattern of administration, based on the
preceding data, it is likely that genetic polymorphisms that
influence dopaminergic transmission or changes in synaptic
plasticity may also contribute to susceptibility in developing
dyskinesia.49–51 Genetic variations of the dopamine receptor
genes, DRD2, DRD3, and DRD4, have been studied but do not
seem to influence the occurrence of L-dopa -induced adverse
effects. However, there is limited evidence in support of a
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specific allele of the dopamine transporter gene (VNTR-DAT)
being a predictor of LID in L-dopa-treated patients.52 In line
with the evidence that LID develop because of abnormal synap-
tic plasticity (which is in turn influenced by the release of
brain-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 PD
patients.54 These preliminary observations need to be replicated
in further large cohorts of PD patients.
Clinical Implications
For 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 DYSKINESIA
DEVELOPMENT
CDS
In 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 becomes
discontinuous and pulsatile. Pulsatile administration of L-dopa
has been shown to increase the development of LID in MPTP
primates12 and in human studies13 and have led to the devel-
opment of therapies to maximize “Continuous Dopaminergic
Stimulation.” “Dopaminergic agonists” have been successfully
used for the control of motor symptoms of PD since their avail-
ability in the 1970s.58 These drugs were developed with the
expectation that on the basis of a longer plasma half-life lead-
ing to a more physiological pattern of CDS, and as a substitutive
or concomitant treatment with L-dopa, PD symptoms could be
relieved while reducing the risk of long-term motor fluctua-
tions and dyskinesias.59 There is no doubt that the dopamine
agonists have lower efficacy than L-dopa and more trouble-
some short-term side effects, and although these drugs can
themselves lead to the development of involuntary dyskinetic
movements, this is generally to a lesser extent than with L-dopa.
There is still debate about the magnitude of any advantage
of using dopamine agonists rather than L-dopa as initial ther-
apy in PD. The ELLDOPA study clearly demonstrated that high
doses of L-dopa lead to dyskinesia development early on in
treatment. The recent 10-year follow-up of PD patients initi-
ated with Ropinirole versus L-dopa36 showed a significantly
lower incidence of dyskinesia in the Ropinirole group and a
significantly longer median time to dyskinesia, but no signif-
icant difference in “disabling” dyskinesias. Furthermore by 10
years, 93% of patients initiated on Ropinirole were also tak-
ing L-dopa, almost identical to the percentage in the group
initiated on L-dopa, and having started on Ropinirole did not
translate to any significant advantage in activities of daily living.
Similar results have also been shown with Pramipexole60 versus
L-dopa as the initial treatment choice. Ergot-derived dopamine
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L-dopa-induced dyskinesias in Parkinson’s disease
agonists are generally to be avoided in view of long-term risks
of pulmonary and valvular fibrosis,61,62 notwithstanding the fact
that no long-term (14-year) difference in dyskinesia induction
has been reported comparing Bromocriptine versus L-dopa as
initial treatment.63
CDS using a long-acting transdermally administered agonist,
Rotigotine, has shown reduced dyskinesia induction compared
with pulsatile administration of the same drug and far less
dyskinesia than pulsatile administration of L-dopa alone in
drug-naïve MPTP-treated animal models.64 Whether there is
any advantage of one dopamine agonist over another has yet
to be studied, but the additional development of slow-release
preparations of Ropinirole and Pramipexole, in addition to
Rotigotine, provides the opportunity to explore whether these
drug 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 specifically
studying whether they possess any disease-modifying prop-
erties. They irreversibly inhibit MAO-B, the main dopamine-
metabolizing enzyme in the brain, and enhance dopamine
bioavailability, thus potentially leading to CDS. Both have been
shown to improve PD symptoms65,66 and recently a small but
sustained advantage has been reported as a result of the ear-
lier initiation of treatment,67–69 but any advantage of long-term
LID risk is currently unproven. In the long-term follow-up of
the TEMPO trial the time for 25% of subjects to develop dysk-
inesia showed no difference between the early-start group and
the delayed-start group.70
Another theoretical way of improving CDS is through
the use of catechol-O-methyl transferase (COMT) inhibitors.
This enzyme is the main mechanism of peripheral L-dopa
metabolism.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 up
to 30%.72 Entacapone and Tolcapone are selective COMT
inhibitors that were developed for clinical use for the treat-
ment of PD. Tolcapone should be reserved for patients who
have inadequate benefit from Entacapone in view of rare but
potentially fatal hepatotoxicity.73 Animal models showed that
early coadministration of Entacapone with L-dopa allows good
motor 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 unfortunately
showed that the time to dyskinesia was shorter in Carbidopa/
L-dopa /Entacapone-treated patients, possibly because of
excessive L-dopa dosage among patients receiving COMT
inhibitors.
Any strategy that reduces the pulsatility of dopaminergic stim-
ulation is likely to be an effective way of delaying time to onset
of LID. The effectiveness and tolerability of any drug will vary
from one patient to the next, emphasizing the need to tai-
lor the drug regime to the individual. Combination therapies
that afford symptom relief while keeping the dose of L-dopa
relatively low represent the optimal way of reducing pulsatile
dopaminergic receptor stimulation.
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European Neurological Journal
TREATING LID ONCE THEY HAVE DEVELOPED
Following the onset of LID, the general principles of CDS
already outlined should be continued where possible to prevent
increases in LID frequency or severity. Beyond this, in order to
implement effective treatment strategies for the treatment of
existing LID, it is important to establish which type of dyski-
nesia the patient is describing, through a careful history of the
type, distribution, and timing of the involuntary movements.
Modification of Oral L-dopa
Administration/Metabolism
A short-term approach to reduce peak dose dyskinesias
when they appear for the first time is to diminish the dose of
dopaminergic agents to coincide with the time of day of LID
occurrence. However, this strategy may be counter-productive
because of increases in “off” time and dose failures.77
Increasing the frequency of smaller doses of L-dopa can help
in the early stages but with continuing disease progression,
recurrence of fluctuations between the off state and the on
state with accompanying dyskinesia demands further therapy
changes. Long-acting L-dopa preparations were developed to
try and ameliorate fluctuations,78 but these preparations can
lead to increased numbers of “dose failures” and unpredictable
L-dopa accumulation that further compounds the problem.79
Patients describing off-period dystonia, for example, painful
posturing of a foot in the early morning prior to their medica-
tion, can be helped with the prescription of dispersible forms of
L-dopa, but these should not be used throughout the day as they
are likely to increase the pulsatility of dopaminergic receptor
stimulation.
MAO-B inhibitors have only mild effects on motor symptoms
in advanced PD but can allow a decrease in required L-dopa
dosage without deterioration in “off-time.” Entacapone has
also demonstrated its efficacy in prolonging the L-dopa clinical
response in patients with motor fluctuations.80,81 Nevertheless
dyskinesia increase can occur because of the accumulating lev-
els of plasma L-dopa necessitating careful titrated reduction
of L-dopa dose.82,83 The LARGO trial revealed a significant
but slight increase in daily-on time without troublesome dysk-
inesia in both Rasagiline and Entacapone groups compared
with placebo in adjunct treatment with L-dopa. No differences
between Rasagiline and Entacapone were reported.84
Adding or Increasing an Oral Agonist
Whether shifting therapy toward the dopamine agonists can
reverse dyskinesia severity without worsening “off time” is
yet to be convincingly established. Among the MPTP-treated
marmosets with established dyskinesias provoked by pulsatile
Rotigotine or L-dopa, continuous Rotigotine administration
led 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 reduced
pre-existing LID while maintaining therapeutic benefit.
From the practical perspective, most patients suitable for
dopamine agonist treatment have already been prescribed
ENJ 2010; 2:(2). August 2010
these drugs prior to L-dopa prescription. Adding a dopamine
agonist to a patient on L-dopa therapy generally increases
peak dose dyskinesia unless the L-dopa dose is reduced.88
However, this strategy has been successfully demonstrated with
both Ropinirole89 and Pramipexole.90,91 The addition of the
Rotigotine patch has been shown to increase “on” time with-
out exacerbating dyskinesia in advanced PD patients although
reduction in pre-existing dyskinesia has not been reported.92
Patients with painful off-period dystonia in the early morning
can be helped by supplementary prescriptions of long-acting
dopamine agonists taken the preceding night. Patients with
diphasic dyskinesias need to maintain sufficient dopaminer-
gic medication levels (L-dopa or agonist) throughout the day to
reduce the regularity of their occurrence. However, care needs
to be taken when using this strategy to ensure that symptoms
of dopa-dysregulation do not supervene.
Adding Amantadine
This 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 still
not clear, but it is thought to be mediated through the N-
methyl-D-aspartate receptor antagonist effect seen with high
doses (300–400 mg/day). Amantadine still remains the only
drug proven to have direct anti-dyskinetic effects, with improve-
ments demonstrated of up to 50%.94–96 Efficacy has been shown
for up to 1 year97 ; however, loss of efficacy after 3–8 months
has also been reported in a double-blind evaluation.98 Although
efficacy is most clearly demonstrated at higher dose levels, it
is wise to try and keep the dose to the lowest useful level par-
ticularly among elderly patients or individuals with evidence of
cognitive impairment because of cognitive side effects.
Switching to Apomorphine
Apomorphine 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” periods
in advanced PD patients with motor fluctuations.100 It has also
been used as a continuous infusion through a pump since
1995,101 and there is robust data to demonstrate good control of
PD symptoms together with the reduction of peak-dose dysk-
inesia, by using this therapy as a means of lowering L-dopa
requirements.102–105 Cognitive side effects, nausea, hypersom-
nolence, and skin nodules may occur as well as a rare hemolytic
anemia and these factors may limit the number of patients that
tolerate its use over the long term.
Ablative Neurosurgery
Creating lesions in the thalamus and globus pallidum for
the treatment of PD was pioneered in the 1950s but then
displaced for the treatment of PD with the introduction of L-
dopa. A major renaissance of surgery followed the publication
that posteroventral pallidotomy could improve not only the
96 www.slm-neurology.com

main PD symptoms, but LID as well,106,107 and this has been
demonstrated as part of randomized trials.108,109 Bilateral pal-
lidotomy causes swallowing difficulties,110 and with the advent
of implantable pulse generators to enable delivery of chronic
stimulation, lesioning techniques are now rarely performed.
Deep Brain Stimulation
Deep brain stimulation has become a widely used, safe, and
effective technique for the treatment of the cardinal motor
symptoms of advanced PD.111,112 When dyskinesia is the main
problem, the choice of targets lies between the STN and the
GPi.113 There is general acceptance that dyskinesia reduction
is greatest following GPi-deep brain stimulation (DBS), with
improvement rates of up to 89% following GPi-DBS compared
with 62% in the STN.114,115 The improvement in “off” symptoms
however tends to be less with GPi-DBS, and therefore medica-
tion requirements usually remain high postoperatively.114,115 It
seems therefore that dyskinesia improvement following GPi-
DBS is directly related to the stimulation effect by interfering
with pallidal outflow.
In contrast, STN-DBS frequently leads to reduction in the dose
of L-dopa required and this is certainly one explanation why
dyskinesia 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 with
STN-DBS,118 and it has been shown that the response of the
patient to a L-dopa challenge also changes implying that there
is 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 equally
be related to the stimulation of adjacent local pallidothalamic,
pallidosubthalamic, and subthalamopallidal fiber projections
rather than STN neurons per se.117,121
Intra-Jejunal L-dopa
The best evidence that CDS can relieve LID comes from the
use of the enteral L-dopa infusion. A L-dopa -Carbidopa gel is
administered 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 system has demonstrated a reduction in
plasma L-dopa fluctuations compared with oral treatment.122–125
This therapy is limited by the need for the patient to have a
permanent gastrostomy tube with jejunal extension, the con-
sequent risk of local complications,126 and its considerable
financial cost. At the current time, it is considered as a good
alternative for those patients unsuitable to DBS or intolerant of
Apomorphine. No randomized controlled trials have been per-
formed to directly compare the efficacy and tolerability of these
three therapies, and it is likely that any advantage in the mean
outcome of one therapy against another127–130 needs to be con-
sidered very carefully in the context of tailoring treatment to the
individual patient.
Clozapine
Traditional 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
www.slm-neurology.com
L-dopa-induced dyskinesias in Parkinson’s disease
however been shown to improve dyskinesia control in up to
50% without worsening of motor symptoms.131–133 The dis-
advantage of this drug is the need for regular blood testing
because of the risk of agranulocytosis.
FUTURE THERAPIES
Further trials are underway to evaluate novel approaches to
reduce LID in PD. These include putative antidyskinetic drugs
such as D2/D3 receptor “partial” agonists, adenosine A2a
antagonists, and metabotropic glutamate receptor antagonists.
In addition, there are four major gene therapy programs being
conducted to evaluate whether the complications of PD can
be ameliorated through growth factor administration,134 GAD
enzyme delivery to the STN,135 or attempts to improve upon stri-
atal CDS.136,137 Furthermore there are renewed attempts to apply
cell therapies to patients with PD before LID development in an
attempt to allow restoration of normal physiological dopamin-
ergic stimulation and avoid the long-term complications of
pharmacological dopaminergic replacement.
CONCLUSIONS
After more than 40 years of use and despite the develop-
ment of a wide range of newer treatments, L-dopa remains
the most efficacious agent to treat the motor symptoms of PD.
Nevertheless the disabling motor complications, particularly
dyskinesias, can be disabling and limit its long-term thera-
peutic use. The issue regarding whether and when to initiate
treatment with L-dopa has been the topic of frequent discussion
to avoid long-term motor complications but without depriv-
ing patients the most effective treatment for the relief of their
motor symptoms. PD is a heterogeneous disease and individual
patients will respond and tolerate prescribed drugs in differ-
ent ways with variable risks of dyskinesia development. L-dopa
should not be feared but when required should be used where
possible in combination with the range of other available thera-
pies unless or until alternative (more physiological) treatments
become available.
Acknowledgments: Dr Foltynie is supported by grants from the
Parkinson’s Appeal and Parkinson’s UK.
Disclosure: Dr Foltynie has received honoraria for speaking at meet-
ings from Teva, UCB, GSK, and Orion Pharma.
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