NONMOTOR SERIES: REVIEW

The Hidden Sister of Motor Fluctuations in Parkinsons Disease:

A Review on Nonmotor Fluctuations
ndez, MD,1* Emmanuelle Schmitt, MSc,2 Pablo Martinez-Martin, MD, PhD,3 and Paul Krack, MD, PhD4
Raul Martnez-Ferna

1
CINAC-Hospital Universitario HM Puerta del Sur, CEU-San Pablo University, Madrid, Spain
2
Movement Disorders Unit, Department of Psychiatry and Neurology, CHU de Grenoble, Universite  de Grenoble Alpes and Grenoble Institut des
Neurosciences, INSERM U386, Grenoble, France
3
National Center of Epidemiology, Carlos III Institute of Health and CIBERNED, Madrid, Spain
4
Neurology Division, Department of Clinical Neurosciences, University Hospital of Geneva, Geneva, Switzerland

A B S T R A C T : Only a few years after the introduction
of levodopa, the first descriptions of motor fluctuations
and dyskinesia related to dopaminergic therapy
appeared. In PD, attention turned to their management,
that had dampened the euphoria of the levodopa
miracle. It soon became clear that neuropsychiatric,
autonomic, and sensory features also tend to develop
fluctuations after chronic exposure to L-dopa. The diver-
sity of fluctuating nonmotor symptoms, their largely sub-
jective nature, coupled with a frequent lack of insight led
to difficulties in identification and quantification. This
may explain why, despite the high impact of nonmotor
symptoms on patient autonomy and quality of life, evalu-
ation of nonmotor fluctuations is not part of clinical rou-
tine. In view of the lack of specific validated assessment
presynaptic pharmacokinetic and postsynaptic pharma-
codynamic mechanisms with the classical motor compli-
cations, but involve different neural pathways. Although
symptoms fluctuate with dopaminergic treatment, sero-
tonine and norepinephrine denervation, as well as inter-
actions between neurotransmitter systems, probably
contribute to their diversity. The lack of validated tools
for assessment of these phenomena explains the almost
complete absence of treatment studies. Management,
largely resulting from expert opinion, includes psychiatric
follow-up, nondopaminergic drugs, and advanced dopa-
minergic treatment, including drug delivery pumps and
DBS. This review aims to provide a starting point for the
understanding, diagnosis, and management of nonmotor
fluctuations. VC 2016 International Parkinson and Move-

tools, detailed anamnesis should ideally be coupled with ment Disorder Society
an evaluation in both ON and OFF drug conditions. The
mechanisms of nonmotor fluctuations are not well under- K e y W o r d s : Parkinsons disease; nonmotor fluctua-
stood. It is thought that they share dopaminergic tions; nonmotor symptoms; dopamine

Motor signs, such as tremor, slowness of movement,
and gait disturbance, caught the attention of the Brit-
ish physician, James Parkinson, in 1817 when he
------------------------------------------------------------
This article was published online on 19 July 2016. After online publica-
tion, revisions were made to the author line and text. This notice is
included in the online and print versions to indicate that both have been
corrected on 29 July 2016.
*Correspondence to: Dr. Raul Martnez-Fernandez, CINAC-HM Puerta
stoles, 28937, Madrid, Spain;
del Sur, Avenida Carlos V 70, Mo
E-mail: rmf.neuro@hotmail.com
Relevant conflicts of interest/financial disclosures: R.M.-F. has
received honorarium from UCB for speaking in a symposium.
Full financial disclosures and author roles may be found in the online ver-
sion of this article.
Received: 22 October 2015; Revised: 13 June 2016; Accepted: 19
June 2016
Published online 19 July 2016 in Wiley Online Library
(wileyonlinelibrary.com). DOI: 10.1002/mds.26731
described the disease that would later bear his name.1
He also noted the presence of other manifestations,
such as sleep disorder, pain, and bowel dysfunction.2
Despite observation of such symptoms, motor features
have dictated clinical management and monopolized
research in Parkinsons disease (PD) for a long time.
However, in the last few decades, physicians have
gradually become more aware of the relevance and
frequency of nonmotor symptoms (NMS).3,4 NMS are
highly prevalent and can be present in 60% to 97%
of PD patients,5-7 covering a wide spectrum of differ-
ent manifestations. The relationship between motor
and nonmotor symptoms is unclear, but it has been
shown that, in the context of long-term levodopa
treatment, many of the NMS can fluctuate like motor
features and therefore present as nonmotor fluctua-
tions (NMF).8,9 The earliest indications of NMF

1080 Movement Disorders, Vol. 31, No. 8, 2016

 A R E V I E W
appeared at the beginning of the levodopa era, when Bar-
beau and Yahr noticed cognitive and behavioral changes
associated with chronic dopaminergic treatment, but they
did not mention their shifting nature.10-12 It took the sharp
eye of Marsden to note mood swings associated with
what he called motor fluctuations in PD patients treated
with L-dopa: . . .the patient is mobile, active, and happy
but shows florid dyskinesias(. . .)and then(. . .)the patient
reverts to profound akinesia often with fear, sweating,
flushing and confusion.13 Subsequent assessments showed
that up to two thirds of motor fluctuating PD patients also
presented mood swings.8,14,15 These initial works stimulat-
ed interest in NMF16 and resulted in a first subdivision of
NMF into categories of autonomic, neuropsychiatric, and
sensory-/pain-related symptoms.17 Subsequently, a few
studies found a dose-responsive correlation between intra-
venous L-dopa administration and emotional manifesta-
tions,18,19 and, Importantly, a discordance between
bradykinesia severity and mood shifting,20 pointing out
that, contrary to what had been believed previously,8,18
motor status alone could not account for mood changes.
NMF are known to impact on patient independence
and quality of life, frequently to a greater extent than
motor fluctuations (MF),21-24 and seem to represent a
largely underestimated clinical problem. Over the last
few years, hypodopaminergic neuropsychiatric symp-
toms, such as apathy, depression, and anxiety, have been
established as an integral part of PD.25 Reversely,
patients may also present with neuropsychiatric side
effects of dopaminergic treatment, such impulse control
disorders (ICDs) or behavioral addictions, and addiction
to dopamine replacement therapy.26,27 Patients suffering
from ICDs may typically shift several times a day from a
hyperactive ON state related to psychotropic effect of
dopamine therapy, featuring impulsive seeking of plea-
surable activities, to an OFF drug condition with acute
drug withdrawal symptoms, consisting of disabling anxi-
ety, sadness, apathetic behavior, pain, and drenching
sweats. In other words, they present with NMF.21,28
Despite the scarce amount of data on the topic, in
the last decade an increasing number of publications
have focused on NMF, shedding light on different
aspects, such as its prevalence,21,29-32 clinical presenta-
tion,21,23,29,31 mechanisms, and potential therapeutic
approaches.33-36 The aim of the present work is to
review the existing literature, with a particular focus
on fluctuations in neuropsychiatric symptoms, and
draw neurologists attention to a hitherto neglected
and disabling complication of L-dopa treatment.
Search Strategy and
Selection Criteria
The authors searched in PubMed for peer-reviewed
articles published in English before May 2016.
O N N O N M O T O R F L U C T U A T I O N S
The search terms Parkinsons disease, non-
motor symptoms, motor fluctuations, motor
complications, non-motor fluctuations, apathy,
depression, pathogenesis, deep brain stim-
ulation, apomorphine, and levodopa-carbidopa
intrajejunal were used. The steps to select relevant
articles for this review were as follows: (1) reading of
the title; (2) reading of the abstract; (3) those with
abstract including the type of information looked for
were read in detail; and (4) information from these
articles that was related with the objectives of the study
was compiled for elaborating the respective synopsis.
For a further source of information on the reviewed
topics, additional articles were found by searching in
the reference list of previously identified articles.
Clinical Presentation and
Epidemiology of NMF
Distinguishing and assessing the fluctuating nature
of NMS poses a new challenge for clinicians. The
identification of NMF has important therapeutic
implications, given that fluctuating symptoms may be
treated by adjusting dopaminergic therapies whereas
specific symptomatic treatment would be the first-line
option for nonfluctuating NMS.37
Overall, previous studies provide very heterogeneous
data on the frequency and clinical presentation of
NMF. NMF typically occur alongside MF, and disen-
tangling the two on the basis of subjective reports
from patients can be tricky. Prevalence of NMF in
patients who suffer from MF varies from 17% to
100%, depending on the evaluation tools and patient
population,21,23,32,38-42 neuropsychiatric fluctuations
being most common. NMS occurrence is much more
frequent in the OFF than in the ON motor condition
(Table 1).42 It is worth noting that some patients may
present with NMF in the absence of MF.40,41
It has been shown that throughout disease evolu-
tion, some NMS increase in frequency whereas others
diminish, differing from the more linear progression of
motor features.43 However, NMS that improve are
those responding to dopaminergic therapy,43,44 and
thus it can be assumed that optimizing dopaminergic
therapy improves a range of NMS and, in conse-
quence, NMF. However, as dopamine depletion wor-
sens with disease progression, physiological
stimulation with pharmacological means becomes
more difficult, and, in the same way than for MF,
NMF tend to progressively increase in frequency and
severity.
Pathophysiology of NMF
Whereas fluctuations in motor features have been
robustly defined in the literature and their underlying
Movement Disorders, Vol. 31, No. 8, 2016 1081
M A R T I N E Z - F E R N A
 N D E Z E T A L

mechanisms progressively elucidated,45 NMF have not TABLE 1. NMS reported to manifest as NMF
yet been unanimously clinically established and their
Distribution in
pathophysiology remains poorly understood. The Category Symptom Motor State
development of MF has been linked to the effect of
pulsatile nonphysiological dopaminergic stimulation46- Neuropsychiatric Depression/sadness OFF > ONa
48 Apathy OFF > ONa
combined with the natural progression of the dis-
Fatigue OFF > ONa
ease.49 Cell death of dopamine-containing neurons in Anxiety OFF > ONa
the mesencephalic SNc is the pathological substrate of Panic attack OFF
motor features in idiopathic PD.50 Progressive dopa- Attention problems OFF > ONa
minergic denervation of SNc projections51 lead to a Forgetfulness OFF > ONa
Slowness of thinking OFF > ON
reduction of endogenous dopamine synthesis and a Mental emptiness OFF>ON
decreasing capability of presynaptic dopaminergic ter- Elevated mood ON > OFFa
minals to store dopamine.52 Consequently, dopamine Hallucination OFF < ON
synaptic levels are fluctuating, depending on L-dopa Mental hyperactivity OFF < ON
concentrations in the blood, and as a result, postsyn- Mutism OFF
Irritability OFF > ON
aptic striatal dopaminergic stimulation becomes errat- Aggressive behavior OFF > ON
ic.53 This results in an imbalance between the direct Moaning and screaming OFF
and indirect pathways. In addition, postsynaptic plas- Confusion OFF
tic changes in response to both the disease and its Drowsiness OFF
Autonomic Light-headedness OFF > ONa
treatment occur. Ultimately, the combination of
Limb edema OFF > ON
pathology and pharmacokinetic and pharmacodynam- Abdominal pain OFF
ic mechanisms leads to motor complications, the Abdominal bloating OFF > ON
patients oscillating between parkinsonian and dyski- Constipation OFF > ON
netic states.45 Nausea OFF > ON
Pyrosis OFF > ON
Changes in NMS are not always time-locked to Hunger OFF
those of motor manifestations,8,20,39,54,55 and fluctua- Sexual disorders OFF > ONa
tions in NMS do not always correlate with motor Drenching sweats OFF > ONa
function.42,54,56 This finding suggests the possible exis- Facial flushing OFF > ON
Bladder dysfunction OFF > ONa
tence of different pathophysiological mechanisms in
Belching OFF > ON
the genesis of MF and NMF. However, a relationship Drooling OFF > ON
appears between dopaminergic therapy intake and Swallowing trouble OFF > ON
improvement in fluctuating NMS, such as apathy or Chilling OFF > ON
pain.14,20,35,57,58 The risk of developing NMF Cough OFF > ON
Stridor OFF
increases in patients with early-onset PD, who have Visual disorder OFF > ON
longer disease duration and receive higher doses of L- Sensory Diffuse pain OFF > ONa
dopa37,39 and female sex,32 which are also risk factors Neuralgic pain OFF > ON
for MF.59 The frequency and severity of both motor Dysesthesia OFF
and NMF increase with PD progression. From an elec- Akathisia OFF > ONa
Burning sensation OFF > ON
trophysiological perspective, a link between motor and Sensory dyspnea OFF
NMF has been suggested. Thus, whereas loss of the Restless legs OFF
ability to synchronize neuronal activity in the -band
in the primary motor cortex is the pathological hall- a
Significant difference in the frequency of presentation between the ON
and the OFF state according to Storch and colleagues.
mark of akinesia, the same mechanism in prefrontal
areas might hold true for bradyphrenia and apathy-
abulia. On the contrary, excessive synchronization in that are potentially involved in the genesis of PD
primary motor areas caused by overstimulation with NMS.61,62 In addition, the degeneration of these neu-
dopamine replacement treatment induces dyskinesias, rotransmitter systems results in complex interactions
and excessive gamma synchronization in the cognitive between both the dopaminergic and nondopaminergic
and limbic loops may cause dopaminergic psychosis factors that ultimately underlie NMF.42
with cognitive impulsivity and flight of ideas as well
as euphoric mood.60 Overall, substantial evidence sug- Neuropsychiatric Fluctuations
gests that, as for MF, dopaminergic mechanisms are
the key factor in NMF occurrencealthough, in the In PD, the neuropsychiatric aspects of NMS, such as
latter, dopamine would act either as a neurotransmit- cognitive impairment, anxiety, depression, apathy, and
ter or as a neuromodulator of other neurotransmitters, fatigue, have received particular attention because of
such as serotonin, acetylcholine, or norepinephrine, their high prevalence and major impact on

1082 Movement Disorders, Vol. 31, No. 8, 2016

 A R E V I E W O N N O N M O T O R F L U C T U A T I O N S

FIG. 1. Neuropsychiatric nonmotor fluctuations that can lead to dopaminergic addiction in a subgroup of patients who attempt to maintain ON
euphoric and avoid OFF dysphoric states. Behavioral addictions, such as gambling, hypersexuality, and shopping, induced by dopamine agonists
are also frequent. Adapted from Lhommee 2012.

disability25,63 and quality of life.64-66 Patients present-
ing with motor complications frequently report
fatigue, decrease in motivation, low mood and slow-
ness of thought, or bradyphrenia during OFF states
and, on the contrary, a sensation of well-being, high
motivation, logorrhea with easy flow of ideas, and
good attention span and liveliness during the ON con-
dition (Fig. 1). These fluctuations in motivation,
mood, and cognition, which occur in parallel to
changes in motor state, have frequently been described
in the literature,8,13,14,29,54,67 with a prevalence rang-
ing from 15% to 100%.21,38,39 Whereas apathy is a
key feature of PD, with a prevalence rate of 20% to
36% in de novo patients,65,68-70 excessive motivation
and ICDs in treated patients can be considered as its
opposite disorder.71 Neuropsychiatric symptoms pre-
sent mainly during OFF periods (82%), with anxi-
ety,21 tiredness, and slowness of thinking being the
most frequent.30 However, features such as impulsivi-
ty, hyperactivity, and a feeling of euphoria that can
reach the manic state are observed more frequently
and exclusively in the ON motor condition.21,42 Hal-
lucinations, which have been classically associated
with the ON state, can also occur in the OFF state of
demented patients and even in de novo untreated
patients, and therefore they would be related to a par-
ticular disease endophenotype rather than to a real
fluctuation in perception.72 Neuropsychiatric fluctua-
tions are reported to be the most frequent and dis-
abling NMF and have been observed in 50% of
patients presenting with neuropsychiatric NMS,40 with
fluctuations in anxiety and mood having the greatest
negative impact on quality of life.23
A more widespread degeneration of mesocortical,
mesolimbic, and mesostriatal dopaminergic projec-
tions, originating in the ventral tegmental area and
SNc, is likely to be involved in motivational and affec-
tive manifestations of PD.73-77 Dopaminergic involve-
ment in neuropsychiatric NMF has been supported by
several studies that demonstrate mood changes related
to L-dopa infusion14,78 in a dose-dependent fashion20
and dopamine modulation of cognitive functions in
nondemented PD patients.79,80 Just as denervation of
the motor loop is a key factor in the development of
MF, the pathological basis of mood symptoms and the
appearance of neuropsychiatric NMF appear to rely

Movement Disorders, Vol. 31, No. 8, 2016 1083

M A R T I N E Z - F E R N A
 N D E Z E T
on degeneration of the mesocorticolimbic dopaminer-
gic pathway.77,81,82 Because of the reduction in both
dopamine storage capability and synaptic dopaminer-
gic release resulting from denervation,52 when meso-
limbic dopamine concentration is at its lowest, a
marked behavioral OFF state with neuropsychiatric
hypoactivity appears.83 Conversely, the increase in
mesolimbic dopamine concentration after L-dopa
intake and the stimulation of dopamine receptors with
dopamine agonists84 may predispose to hyperdopami-
nergic behaviors.85 Importantly, D3 receptors are
those of greater density in limbic areas with very high
expression in the ventral striatum that embraces the
nucleus accumbens,86 whereas D1 are mainly
expressed in the dorsolateral-motor striatum. There-
fore, dopaminergic drugs with high affinity to D2/D3
receptors will act on the mesoaccumbal system and
eventually induce loss of control on appetitive behav-
iors, that is, ICDs, whereas D1/D2 overstimulation
will elicit hyperactivity in the nigrostriatal pathway
leading to motor stereotyped behaviors, such as pund-
ing.71,87 The change between the low-dose hypoac-
tive condition and the peak-dose hyperactive state
clinically presents as neuropsychiatric NMF. They
share with substance addictions clinical features, such
as tendency to self-medication, the kicking in of a
high in the ON phase, and withdrawal symptoms
and craving in the OFF state.83 Both, NMF and addic-
tion, also have certain common mechanisms, as indi-
cated by the choice of the term of dopamine
dysregulation syndrome that has been borrowed
from research into the mechanisms of addiction.88-92
Fluctuations in cognition are complex and, whereas
OFF-state bradyphrenia or slowed thinking improve in
the ON state,18,93 negative effects of L-dopa on execu-
tive functions have been also observed.94 Patients with
MF exhibit greater oscillations in cognitive perfor-
mance than stable L-dopa responders after L-dopa
administration,79 suggesting that, as with motor per-
formance and mood, fluctuations in cognition mainly
rely on dopaminergic mechanisms and are influenced
by the degree of dopaminergic denervation.95
Structural neuroimaging studies have linked altera-
tions in limbic areas, such as gray matter density and
cortical thinning,96-98, reduction in fractional anisotro-
py,99,100 or white matter loss,101 to mood symptoms
in PD.75,81,102 Functional neuroimaging studies have
demonstrated correlations between depression severity
and hypometabolism in the caudate nucleus and the
orbital-inferior frontal cortex,103 lower binding in the
limbic system of the combined dopamine and nor-
adrenaline transporter ligand [11C]RTI-32 in PD
depressed patients,61 abnormal dopaminergic modula-
tion of limbic areas in PD patients with mood fluctua-
tions,104 and an association between apathy and
decreased activity in some limbic cortical areas.105
1084 Movement Disorders, Vol. 31, No. 8, 2016
A L
Finally, in a STN-DBS series, patients with NMF
showed more-severe dopaminergic denervation of the
ventral tegmental area (VTA).77 On the other hand,
several functional MRI studies have also revealed
abnormalities in the limbic frontostriatal network,
such as increased release of dopamine in the ventral
striatum or lower dopamine transporter availability
(in both the dorsal and the ventral striatum) of
patients with ICDs, compared to those without impul-
sivity.71 In addition, pathology-based evidence has
correlated a history of depression and dementia in PD
with the severity of dopaminergic neuron degeneration
in the VTA.106
In summary, all of this evidence suggests that neuro-
psychiatric NMF are essentially linked to dopaminer-
gic denervation of limbic and associative areas,
emphasizing the importance of the role of dopamine
compared to other neurotransmitters such as seroto-
nine or noradrenaline.107
Autonomic Fluctuations
Autonomic symptoms are frequent in PD, attaining
a prevalence of over 80% in some series.108 Although
their fluctuating nature remains controversial, they
were included in Riley and Langs first classification of
NMF.17 Prevalence of autonomic fluctuations is diffi-
cult to specify because of the lack of studies and meth-
odological differences. Between 29% and 94% of
patients with NMF present with autonomic symp-
toms.38-41 Clinical data show associations of certain
autonomic symptoms, such as dyspnea, sweating, car-
diovascular abnormalities, constipation, and urinary
urgency, to the wearing-OFF state,9,21,30,38,39,109-114
and improvement parallel to that of motor features
after L-dopa intake,109,110,115 and therefore provide
evidence of their fluctuating nature. However, chronic
L-dopa treatment has been shown to have no effect on
autonomic symptoms in some series,116,117 and, in
addition, a recent study found that autonomic NMS
did not fluctuate in conjunction with MF and only
changed mildly in severity, calling into question the
occurrence of autonomic NMF.23
The suggested mechanisms underlying autonomic
symptoms in PD are complex and include involvement
of both the central autonomic nucleus and the periph-
eral postganglionic nervous system.4 Dopaminergic
involvement in autonomic symptoms is unclear.37
However, muscular disturbance induced by dopami-
nergic mechanisms are thought to partially underlie
certain autonomic features: detrusor hyper-reflexia,118
explaining urinary urgency and akinesia of specific
muscle groups resulting in dysphagia or drooling.114
Consistent with this, an improvement in voiding
difficulty subsequent to acute L-dopa intake,119 ano-
rectal manometry parameter normalization with
 A R E V I E W
apomorphine,120 and improvement in constipation
and bowel symptoms with continuous L-dopa/carbi-
dopa intestinal gel infusion34 have all been demon-
strated. It has also been suggested that, in addition to
nigral degeneration, dopamine modulation of other
neurotransmitter systems, such as the noradrenergic
system, may also be involved in autonomic NMF.4,112
Sensory Disturbances/Pain
Complaints of pain and sensory disturbances are
common NMS in PD and can affect up to 65% of
patients,58,65,121-125 and a few studies have reported
that PD patients may have a lower pain threshold.126
Importantly, the impact of their presence on quality of
life can be greater than that of motor features,127,128
with pain as the sensory NMF with the greatest nega-
tive impact.23 Pain is more frequently associated with
the OFF motor state21,38,39,129-132 and improves after
administration of L-dopa or apomorphine,129,133,134
manifesting more rarely in the ON state.23 The chang-
ing nature of pain and other sensory symptoms and
their association with dopaminergic treatment allow
them to be considered as part of the NMF spec-
trum9,39,129,131,132,135 and suggest dopamine-mediated
augmentation in their genesis.133,136,137 Reported rates
of sensory disturbances and pain associated with MF
vary widely among studies. They have been found to
represent 24% of nonmotor complaints in the OFF
state38 and to fluctuate in 39% to 45% of patients
who suffer from sensory symptoms.39,40 Among
patients with MF, RLS or akathisia appears as the
most frequent sensitive fluctuating symptom (54%).21
Finally, 25% of nonmotor fluctuators suffered from
sensory symptoms.41 OFF-related pain is heteroge-
neous in body distribution. It can be either diffuse or
restricted to almost any body part. Chest and abdomi-
nal pain are very typical for OFF-period pain and may
have autonomic mechanisms in origin, but the most
frequent localizations are the limbs and the trunk.133
Two different nonmutually exclusive pathophysio-
logical mechanisms explain pain in PD. First, a
peripheral muscular component involving rigidity-
and dystonia-related pain occurring in the OFF motor
state. Dopaminergic treatment relieves such muscular
pain by reducing either rigidity or OFF-state dystonia.
Second, a central spontaneous pain attributed to a
disorder in striatal selection of sensory cortical affer-
ents caused by dopamine depletion.136,138 The exis-
tence of projections from parietal somatosensory
cortices to the striatum139 suggests that the functional
integration of sensory information takes place at this
level/in this area,136 just as the basal ganglia filter and
integrate cortical signals from motor and premotor
cortices to perform motor actions, and modulate
behavior and emotional expression through
O N N O N M O T O R F L U C T U A T I O N S
projections coming from limbic cortices.140 Imaging
and electrophysiological studies have shown that
dopamine is involved in nociceptive processing,139,141
and that L-dopa administration can increase the pain
threshold in PD patients.141 Therefore, a state of
dopamine depletion would result in abnormal sensory
perception and pain, whereas L-dopa intake would
compensate for the dysfunction and normalize sensory
processing. The switching between both conditions
leads to sensory NMF.
Sleep Disorders
Sleep disorders are common in PD, and dopamine
participates in the sleep-wake cycle through complex
mechanisms.37 However, it is somewhat difficult to
define clinical fluctuations in sleep-related problems.
Sleep quality can be improved by both dopamine ago-
nists142 and L-dopa.143 This improvement is likely to be
related to an effect on nocturnal akinesia, nocturia, and
RLS rather than to a specific effect on sleep. A frequent
side effect clinically observed in patients on long-acting
dopamine agonists is nocturnal hyperactivity.144 Day-
time somnolence may be considered a direct side effect
of dopaminergic treatments (on blood pressure, for
instance) or a narcolepsy-like syndrome related to noc-
turnal sleep fragmentation rather than a direct dopami-
nergic effect per se, and, in fact, dopaminergic drugs
can also trigger an excessive wakefulness in the ON
state attributed to the psychotropic amphetamine-like
effects. In addition, daytime sleepiness is more depen-
dent on circadian rhythms and vigilance is more fluctu-
ating with external stimuli than linked to dopamine-
related fluctuations. Sleep disorders may not therefore
be considered to be fluctuating symptoms and indeed
have not been included in any NMF classification.17
Management of NMF
Current Evaluation Tools
Tools for the assessment of NMF are insufficient.
Only one instrument that specifically measures NMF
is available: the NOn-MOtor Fluctuation Assessment
(NOMOFA). However, this was developed recently
and has not yet been validated or used in any
study.145 The authors presented a list of different
NMS to fluctuating PD patients and ranked their
importance according to the frequency and severity
reported by participants.
In the last few years, a number of scales aimed at
identifying wearing-OFF phenomena have been devel-
oped. Wearing-OFF is sometimes difficult to detect in
clinical practice because of its variable presentation.
Initially, the 32-item Wearing-OFF Questionnaire
(WOQ-32) demonstrated its efficacy in the screening
of wearing-OFF.30 Shorter, more easily applicable
Movement Disorders, Vol. 31, No. 8, 2016 1085
M A R T I N E Z - F E R N A
 N D E Z E T A L

TABLE 2. Clinical cohorts specifically assessing NMF

Type of Sample Rate of Specific NMF (%)a

No. of Patients Rate of Rate of Most Frequent Neuropsychiatric Autonomic
Author(s)/year (n) MF (%) NMF (%) NMF Sensory Evaluation Tool

Hillen and Sage Patients present- 100 17 Autonomic 32 44 24 Open

1996 ing MF 130 questionnaire
Raudino 2001 Consecutive 80.8 60 Autonomic 20.3 62.9 16.6 Open
patients 47 questionnaire
Witjas et al. Patients present- 100 100 Neuropsychiatric 100 94 90 Structured
2002 ing MF 50 questionnaire
Gunal et al. 2002 Consecutive 84.7 NA Sensory/pain 15.3 29.2 38.3 Open
patients 85 (pain 27%) questionnaire
Storch et al. Patients present- 100 NA Neuropsychiatric NA None NA NMSQuest,
2013 ing MF 100 (fatigue 88%) WOQ9
Seki et al. 2013 Consecutive 69 40 Neuropsychiatric 49 32 45 WOQ19
patients 464
Brun et al. 2014 Consecutive NA 19 Autonomic 44 49 44 Open
patients 303 questionnaire
Storch et al. Patients present- 100 100 Neuropsychiatric NA NA NA NMSS
2015 ing MF 73
Picillo et al. De novo drug 38.3 55.3 Neuropsychiatric NA NA NA WOQ19
2016 nave patients
(prospective 4-
year follow-up)
47

a
Differences in prevalence are partially attributed to methodological issues. Hillen and Sage and Raudino calculated the prevalence for each category (neuro-
psychiatric, autonomic, and sensory) of symptoms among all reported NMS. Witjas and colleagues reported the proportion of patients with fluctuating NMS
among a sample of motor-fluctuating patients. Gunal and colleagues and Seki and colleagues reported the number of patients in whom presentation or
change in NMS were associated to motor fluctuations. Brun and colleagues detailed the percentage of patients with each type of NMS among those patients
with NMF. Storch reported the presence or absence of each NMS in the respective ON or OFF motor state. Finally, Picillo and colleagues asked patients to
answer whether NMS where present and whether they improved after dopaminergic treatment.
NA, not available.

versions of this tool, such as the WOQ-19/Quick,146-
148
WOQ-9,149 and Q10,150 were subsequently devel-
oped without loss of sensitivity. However, these ques-
tionnaires cannot be specifically used for nonmotor
wearing-OFF given that they encompass both motor
and nonmotor symptoms. The Movement Disorders
Task Force recommended the WOQ-19 and WOQ-9
questionnaires for the screening of wearing-OFF in
PD, but they acknowledged that these scales focus
mainly on motor evaluation.151
In order to investigate the prevalence and severity of
NMF, a few studies have assessed the presence of
NMS during motor fluctuations using open question-
naires,21,38,39,41 the self-completed Non-Motor Symp-
toms Questionnaire for PD (NMSQuest),23,152 the
WOQ-19,32,40 the WOQ-9,23 and, more recently, the
Non-Motor Symptoms Scale (NMSS).42,56 The
Ardouin Scale for Behavioral Assessment in Parkin-
sons Disease evaluates hypo- and hyperdopaminergic
behaviors and allows to detect and quantify neuropsy-
chiatric fluctuations by evaluating OFF-drug dysphoria
and ON-drug euphoria.144,153 It has been shown that
self-administered questionnaires (providing the patient
the vocabulary required) are more sensitive than semi-
structured interviews (dependent on insight by the
patient and interpretation of symptoms by the evalua-
tor) in the detection of both motor and NMF.30
Overall, there is a lack of specific and validated
tools for an accurate assessment of NMF.
Treatment
In spite of the increasing number of therapeutic clin-
ical trials for NMS in PD,4,154 their level of scientific
evidence is low,155 and they do not differentiate
between NMS intrinsic to PD or related to dopaminer-
gic therapy. Management of NMF therefore has not
yet been established. However, as previously men-
tioned, NMF are directly or indirectly linked to dopa-
minergic dysfunction. NMS being described mainly in
the OFF-drug condition (Table 1), improvement in
OFF periods will lead to improvement in both NMS
and NMF. For this reason, the approach should be
similar to management of MF, aiming at continuous,
nonpulsatile dopaminergic stimulation.156 There is, as
yet, very little literature evaluating the response of
NMF to specific treatments.
First-Line Treatment
Fluctuating NMS in PD generally respond to dopa-
minergic therapeutic adjustments in the same way as
motor manifestations.35 NMF should therefore be ini-
tially approached with the common therapeutic strate-
gies used in the treatment of motor complications157-
159
: L-dopa dose fragmentation,38 use of long-acting L-

1086 Movement Disorders, Vol. 31, No. 8, 2016

 A R E V I E W O N N O N M O T O R F L U C T U A T I O N S

TABLE 3. Available evidence of the effect of advanced treatments on fluctuating NMS in PD

Fluctuating NMS STN-DBS GPi-DBS Apomorphine Pump L-dopa-Carbidopa Pump

Neuropsychiatric
Depression Improvement200-205 Improvement208 Improvement182 Improvement182,193,209
Worsening77,206,207
Anxiety Improvement200,201,203,205 NA NA Improvement193,194
Worseninga,207,210
Fatigue Improvement205,211 NA Improvement181,182 Improvement34,182,193,209
Apathy Improvement197,212 NA Improvement182 Improvement182
Worseninga,77,105,173,195,201,213,214
Attention/cognition Improvement212 NA Improvement182 Improvement34,182
ICD/hyperdopaminergic Improvementa,90,195,196,215-219 NA Improvement182 Improvement182,193,226
behaviors Worsening/onset201,210,220-225
Hallucination Improvementa,227 Worsening227 NA Improvement182 Improvement182
Autonomic
Cardiovascular Improvement228 NA NA Improvement182
Worsening
Constipation Improvement211,229 NA Improvement182 Improvement34,182,193,208
Worsening Worsening
Drenching sweats Improvement230 NA Improvement181 Improvement193
Bladder dysfunction Improvement231-235 NA Improvement181,182 Improvement34,182,209
Swallowing Improvement236,237 Worsening238 NA NA NA
Sexual disorders Improvement239 NA NA Improvement182
Sensory/pain
Pain Improvement211,240-242 Improvement243 NA Improvement193,209
Dysesthesia NA Improvement243 NA NA
Restless legs Improvement244,245 Worseninga,246 NA NA NA

a
Attributed to either stimulation itself or to reduction in dopaminergic drugs.
GPi-DBS, globus pallidus internus DBS; NA, not available; STN-DBS, subthalamic nucleus DBS.

dopa formulations or dopamine agonists, and intro-
duction of dopamine-enhancing therapies, like cate-
chol-O-methyltransferase or monamine oxidase-B
inhibitors.160-163 In a cross-over study of oral L-dopa
challenge with L-dopa/carbidopa controlled-release
formulation versus immediate-release formulation,
only fluctuating patients showed increase in mood and
exclusively with the immediate-release presentation.164
A post-hoc analysis of a double-blind trial of transder-
mal dopamine agonist rotigotine versus placebo in PD
patients with MF165 suggested an improvement in the
NMSS domains of pain, sleep/fatigue and mood/
apathy.166,167 Furthermore, the promising results for
the treatment of motor complications in controlled tri-
als using safinamide,168 a novel drug with dopaminer-
gic and glutamatergic mechanisms, along with the
improvement in depression in the same trial, opens the
door to its possible effectiveness in the treatment of
NMS and NMF. It is worth noting that whereas apo-
morphine injections have been observed to acutely
improve OFF-period symptoms,169 their intermittent,
rapid, and short-acting effect can lead to compulsive
use of the treatment and thus aggravate neuropsychi-
atric NMF170; therefore, its usefulness for controlling
NMF is unlikely. Finally, cognitive-behavioral therapy
has been shown to improve ICD171 and depression in
patients with PD.172 This suggests that it might also
potentially be used in the context of NMF to alleviate
clinical features of both the neuropsychiatric ON
and OFF states. Controlled trials with specific evalua-
tion of these therapies are lacking.
Second-Line Treatment
Patients with advanced PD and motor complications
refractory to medical treatment are candidates for
more-aggressive nonpulsatile therapies, such as subcu-
taneous apomorphine pump, L-dopa/carbidopa intesti-
nal gel infusion (LCIG), or DBS.173-176 In the case of
NMS, the lack of controlled studies means that recom-
mendations are based only on clinical observations
and reports. For this reason, although the presence
and severity of NMS must be taken into account
when considering a more invasive treatment, they do
not constitute an indication per se.159 Table 3 summa-
rizes the literature on the effects of advanced PD ther-
apies on fluctuating NMS.
Subcutaneous Apomorphine Infusion
Subcutaneous apomorphine infusion is highly effec-
tive in reducing MF.177-179 Although data on the effec-
tiveness of subcutaneous apomorphine on NMS are
scarce, observations from clinical practice suggest a
strong beneficial effect.180 Apomorphine has been
shown to improve NMSS total score significant-
ly.181,182 More particularly, it alleviates autonomic
symptoms, such as gastrointestinal problems120,181,183
and urinary dysfunction.184 Whereas apomorphine

Movement Disorders, Vol. 31, No. 8, 2016 1087

M A R T I N E Z - F E R N A
 N D E Z E T
showed no effect on increasing pain threshold or
changing pain-induced cerebral activity in a functional
imaging study,185 according to some reports, subcuta-
neous injections are highly effective for OFF-period
pain.129,134 Data on apomorphines role on neuropsy-
chiatric symptoms are scarce and controversial.180 To
the best of our knowledge, there are no reports specifi-
cally addressing the impact of apomorphine infusion
on NMF, but because of its effect on MF and NMS,
its use should be considered.
Levodopa/Carbidopa Intestinal Gel Infusion
LCIG avoids the irregular absorption of oral L-dopa
caused by impaired gastric emptying and by providing
more-stable L-dopa plasma concentrations results in
continuous dopaminergic stimulation.186,187 In view of
dopamines role in the genesis of NMF, stabilizing
dopamine concentrations should, in theory, improve
their presentation. The efficacy of LCIG in controlling
motor complications and reducing OFF-time motor
state has strong support.187-189 However, only a few
open-label trials34,190-194 and a very recent multicen-
ter, observational study182 have demonstrated that it
significantly improves NMS either measured by the
NMSS34,190-192,194 or based on clinical interview.193
Moreover, LCIG resulted in significantly greater
NMSS improvement than subcutaneous apomorphine
infusion.182 Overall, studies have shown a significant
improvement in total NMSS score, particularly in
sleep/fatigue and gastrointestinal subdomains. This
improvement in NMS correlated with improvement in
quality of life.34,182,190 To the best of our knowledge,
there are no reports specifically addressing the impact
of LCIG on NMF.
Deep Brain Stimulation
Very few studies have specifically addressed the
effects of STN-DBS on NMF. One series found a 58%
total reduction in NMF postsurgery using the NMF
scale of Witjas and colleagues, with pain/sensory fluc-
tuations showing the greatest reduction (84%) and
neuropsychiatric fluctuations the smallest (30%).33
Additionally, the overall number of fluctuating symp-
toms decreased. More recently, it was demonstrated
that STN-DBS significantly reduces rates and severity
of preoperative OFF dysphoria and ON euphoria 1
year postsurgery.195 After surgery, patients presented a
significantly lower prevalence and severity of both
chronic neuropsychiatric NMF and acute NMF
assessed during the L-dopa test. However, this
improvement came at the expense of an overall
increase in apathy. Furthermore, in the more recent
randomized, controlled Earlystim study, neuropsychi-
atric NMF improved after STN-DBS whereas they
tend to worsen in the best medical treatment group.196
The acute stimulant psychotropic effect of STN-DBS
1088 Movement Disorders, Vol. 31, No. 8, 2016
A L
has been established.197 However, in the long term,
reduction of antiparkinsonian medication can unmask
mesolimbic hypodopaminergic behaviors.77,198,199
Reintroduction of a dopamine agonist drug has been
shown to reverse this condition.57 Finally, in a 2-year
follow-up cohort, STN-DBS significantly reduced the
number and severity of autonomic and psychiatric
NMF in the OFF medication state whereas sensory
NMF completely disappeared in the ON medication
condition.36
To sum up, there is growing evidence suggesting the
efficacy of advanced PD treatments for NMS, but very
little specifically addressing their effect on NMF. Stud-
ies with larger samples comparing these therapies
are required to optimize patient selection and
management.
Conclusion
NMF are currently underevaluated, and few thera-
peutic studies are available. The amount of evidence
on the topic remains low, and many elements regard-
ing its pathological and clinical nature are still miss-
ing. The impact of NMF on patient autonomy and
quality of life make them an entity that deserves as
much attention as classic motor fluctuations. A vali-
dated and accepted clinical scale for specific assess-
ment of NMF emerges as an unmet need in order to
improve clinical management and promote research.
Hopefully, the increasing awareness of NMS in PD
will contribute to take NMF out of hiding and turn
them into a central issue of patient care in PD.
Acknowledgment: We thank Mrs. Cate Dal Molin for English cor-
rection and Eugenie Lhommee for providing Figure 1.
References
1. Parkinson J. An essay on the shaking palsy. London: Sherwood
Neely & Jones; 1817.
2. Fahn S. The medical treatment of Parkinson disease from James
Parkinson to George Cotzias. Mov Disord 2015;30:4-18.
3. Schrag A, Jahanshahi M, Quinn N. What contributes to quality
of life in patients with Parkinsons disease? J Neurol Neurosurg
Psychiatry 2000;69:308-312.
4. Chaudhuri KR, Healy DG, Schapira AH. Non-motor symptoms
of Parkinsons disease: diagnosis and management. Lancet Neurol
2006;5:235-245.
5. Martinez-Martin P, Schapira AH, Stocchi F, et al. Prevalence of
nonmotor symptoms in Parkinsons disease in an international
setting; study using nonmotor symptoms questionnaire in 545
patients. Mov Disord 2007;22:1623-1629.
6. Shulman LM, Taback RL, Bean J, Weiner WJ. Comorbidity of
the nonmotor symptoms of Parkinsons disease. Mov Disord
2001;16:507-510.
7. Martinez-Martin P. Nonmotor symptoms and health-related qual-
ity of life in early Parkinsons disease. Mov Disord 2014;29:166-
168.
8. Nissenbaum H, Quinn NP, Brown RG, Toone B, Gotham AM,
Marsden CD. Mood swings associated with the on-off phenome-
non in Parkinsons disease. Psychol Med 1987;17:899-904.
9. Quinn NP. Classification of fluctuations in patients with Parkin-
sons disease. Neurology 1998;51(2 Suppl 2):S25-S29.
 A R E V I E W
10. Barbeau A. Long-term side-effects of levodopa. Lancet 1971;1:
395.
11. Barbeau A. L-dopa therapy in Parkinsons disease: a critical
review of nine years experience. Can Med Assoc J 1969;101:59-
68.
12. Yahr MD, Duvoisin RC, Schear MJ, Barrett RE, Hoehn MM.
Treatment of parkinsonism with levodopa. Arch Neurol 1969;21:
343-354.
13. Marsden CD, Parkes JD. On-off effects in patients with Parkin-
sons disease on chronic levodopa therapy. Lancet 1976;1:292-
296.
14. Cantello R, Gilli M, Riccio A, Bergamasco B. Mood changes
associated with end-of-dose deterioration in Parkinsons dis-
ease: a controlled study. J Neurol Neurosurg Psychiatry 1986;49:
1182-1190.
15. Hardie RJ, Lees AJ, Stern GM. On-off fluctuations in Parkinsons
disease. A clinical and neuropharmacological study. Brain 1984;
107(Pt 2):487-506.
16. Lees AJ. The on-off phenomenon. J Neurol Neurosurg Psychiatry
1989;Suppl:29-37.
17. Riley DE, Lang AE. The spectrum of levodopa-related fluctua-
tions in Parkinsons disease. Neurology 1993;43:1459-1464.
18. Menza MA, Sage J, Marshall E, Cody R, Duvoisin R. Mood
changes and on-off phenomena in Parkinsons disease. Mov
Disord 1990;5:148-151.
19. Maricle RA, Nutt JG, Carter JH. Mood and anxiety fluctuation
in Parkinsons disease associated with levodopa infusion: prelimi-
nary findings. Mov Disord 1995;10:329-332.
20. Maricle RA, Nutt JG, Valentine RJ, Carter JH. Dose-response
relationship of levodopa with mood and anxiety in fluctuating
Parkinsons disease: a double-blind, placebo-controlled study.
Neurology 1995;45:1757-1760.
21. Witjas T, Kaphan E, Azulay JP, et al. Nonmotor fluctuations in
Parkinsons disease: frequent and disabling. Neurology 2002;59:
408-413.
22. Muller B, Assmus J, Herlofson K, Larsen JP, Tysnes OB. Impor-
tance of motor vs. non-motor symptoms for health-related quality
of life in early Parkinsons disease. Parkinsonism Relat Disord
2013;19:1027-1032.
23. Storch A, Schneider CB, Wolz M, et al. Nonmotor fluctuations in
Parkinson disease: severity and correlation with motor complica-
tions. Neurology 2013;80:800-809.
24. Rieu I, Houeto JL, Pereira B, et al. Impact of mood and behavior-
al disorders on quality of life in Parkinsons disease. J Parkinsons
Dis 2016;6:267-277.
25. Weintraub D, Moberg PJ, Duda JE, Katz IR, Stern MB. Effect of
psychiatric and other nonmotor symptoms on disability in Parkin-
sons disease. J Am Geriatr Soc 2004;52:784-788.
26. Weintraub D, David AS, Evans AH, Grant JE, Stacy M. Clinical
spectrum of impulse control disorders in Parkinsons disease.
Mov Disord 2015;30:121-127.
27. Beaulieu-Boire I, Lang AE. Behavioral effects of levodopa. Mov
Disord 2015;30:90-102.
28. Evans AH, Strafella AP, Weintraub D, Stacy M. Impulsive and
compulsive behaviors in Parkinsons disease. Mov Disord 2009;
24:1561-1570.
29. Racette BA, Hartlein JM, Hershey T, Mink JW, Perlmutter JS,
Black KJ. Clinical features and comorbidity of mood fluctuations
in Parkinsons disease. J Neuropsychiatry Clin Neurosci 2002;14:
438-442.
30. Stacy M, Bowron A, Guttman M, et al. Identification of motor
and nonmotor wearing-off in Parkinsons disease: comparison of
a patient questionnaire versus a clinician assessment. Mov Disord
2005;20:726-733.
31. Bayulkem K, Lopez G. Nonmotor fluctuations in Parkinsons dis-
ease: clinical spectrum and classification. J Neurol Sci 2010;289:
89-92.
32. Picillo M, Palladino R, Moccia M, et al. Gender and non motor
fluctuations in Parkinsons disease: a prospective study. Parkin-
sonism Relat Disord 2016;27:89-92.
33. Witjas T, Kaphan E, Regis J, et al. Effects of chronic subthalamic
stimulation on nonmotor fluctuations in Parkinsons disease. Mov
Disord 2007;22:1729-1734.
O N N O N M O T O R F L U C T U A T I O N S
34. Honig H, Antonini A, Martinez-Martin P, et al. Intrajejunal levo-
dopa infusion in Parkinsons disease: a pilot multicenter study of
effects on nonmotor symptoms and quality of life. Mov Disord
2009;24:1468-1474.
35. Stacy MA, Murck H, Kroenke K. Responsiveness of motor and
nonmotor symptoms of Parkinson disease to dopaminergic thera-
py. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:57-61.
36. Ortega-Cubero S, Clavero P, Irurzun C, et al. Effect of deep brain
stimulation of the subthalamic nucleus on non-motor fluctuations
in Parkinsons disease: two-years follow-up. Parkinsonism Relat
Disord 2013;19:543-547.
37. Chaudhuri KR, Schapira AH. Non-motor symptoms of Parkin-
sons disease: dopaminergic pathophysiology and treatment. Lan-
cet Neurol 2009;8:464-474.
38. Hillen ME, Sage JI. Nonmotor fluctuations in patients with Par-
kinsons disease. Neurology 1996;47:1180-1183.
39. Gunal DI, Nurichalichi K, Tuncer N, Bekiroglu N, Aktan S. The
clinical profile of nonmotor fluctuations in Parkinsons disease
patients. Can J Neurol Sci 2002;29:61-64.
40. Seki M, Takahashi K, Uematsu D, et al. Clinical features and
varieties of non-motor fluctuations in Parkinsons disease: a Japa-
nese multicenter study. Parkinsonism Relat Disord 2013;19:104-
108.
41. Brun L, Lefaucheur R, Fetter D, et al. Non-motor fluctuations in
Parkinsons disease: prevalence, characteristics and management
in a large cohort of parkinsonian outpatients. Clin Neurol Neuro-
surg 2014;127:93-96.
42. Storch A, Schneider CB, Klingelhofer L, et al. Quantitative assess-
ment of non-motor fluctuations in Parkinsons disease using the
Non-Motor Symptoms Scale (NMSS). J Neural Transm (Vienna)
2015;122:1673-1684.
43. Antonini A, Barone P, Marconi R, et al. The progression of non-
motor symptoms in Parkinsons disease and their contribution to
motor disability and quality of life. J Neurol 2012;259:2621-
2631.
44. Zis P, Rizos A, Martinez-Martin P, et al. Non-motor symptoms
profile and burden in drug naive versus long-term Parkinsons dis-
ease patients. J Parkinsons Dis 2014;4:541-547.
45. Obeso JA, Rodriguez-Oroz M, Marin C, et al. The origin of
motor fluctuations in Parkinsons disease: importance of dopami-
nergic innervation and basal ganglia circuits. Neurology 2004;
62(1 Suppl 1):S17-S30.
46. Chase TN, Baronti F, Fabbrini G, Heuser IJ, Juncos JL,
Mouradian MM. Rationale for continuous dopaminomimetic
therapy of Parkinsons disease. Neurology 1989;39:7-10; discus-
sion, 9.
47. Nutt JG, Obeso JA, Stocchi F. Continuous dopamine-receptor
stimulation in advanced Parkinsons disease. Trends Neurosci
2000;23(10 Suppl):S109-S115.
48. Olanow CW, Obeso JA, Stocchi F. Continuous dopamine-
receptor treatment of Parkinsons disease: scientific rationale and
clinical implications. Lancet Neurol 2006;5:677-687.
49. Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era
of Parkinsons disease: insights into motor complications from
sub-Saharan Africa. Brain 2014;137:2731-2742.
50. Hirsch E, Graybiel AM, Agid YA. Melanized dopaminergic neu-
rons are differentially susceptible to degeneration in Parkinsons
disease. Nature 1988;334:345-348.
51. Kordower JH, Olanow CW, Dodiya HB, et al. Disease duration
and the integrity of the nigrostriatal system in Parkinsons disease.
Brain 2013;136:2419-2431.
52. Stocchi F, Jenner P, Obeso JA. When do levodopa motor fluctua-
tions first appear in Parkinsons disease? Eur Neurol 2010;63:
257-266.
53. de la Fuente-Fernandez R, Sossi V, Huang Z, et al. Levodopa-
induced changes in synaptic dopamine levels increase with pro-
gression of Parkinsons disease: implications for dyskinesias. Brain
2004;127:2747-2754.
54. Richard IH, Justus AW, Kurlan R. Relationship between mood
and motor fluctuations in Parkinsons disease. J Neuropsychiatry
Clin Neurosci 2001;13:35-41.
55. Chaudhuri KR, Yates L, Martinez-Martin P. The non-motor
symptom complex of Parkinsons disease: a comprehensive assess-
ment is essential. Curr Neurol Neurosci Rep 2005;5:275-283.
Movement Disorders, Vol. 31, No. 8, 2016 1089
M A R T I N E Z - F E R N A
 N D E Z E T A L
56. Ossig C, Sippel D, Fauser M, et al. Assessment of non-motor fluc-
tuations using a diary in advanced Parkinsons disease.
J Parkinsons Dis 2016 May 31. doi: 10.3233/JPD-150764. [Epub
ahead of print]
57. Thobois S, Lhommee E, Klinger H, et al. Parkinsonian apathy
responds to dopaminergic stimulation of D2/D3 receptors with
piribedil. Brain 2013;136:1568-1577.
58. Defazio G, Berardelli A, Fabbrini G, et al. Pain as a nonmotor
symptom of Parkinson disease: evidence from a case-control
study. Arch Neurol 2008;65:1191-1194.
59. Hauser RA, McDermott MP, Messing S. Factors associated with
the development of motor fluctuations and dyskinesias in Parkin-
son disease. Arch Neurol 2006;63:1756-1760.
60. Brown P, Marsden CD. What do the basal ganglia do? Lancet
1998;351:1801-1804.
61. Remy P, Doder M, Lees A, Turjanski N, Brooks D. Depression in
Parkinsons disease: loss of dopamine and noradrenaline innerva-
tion in the limbic system. Brain 2005;128:1314-1322.
62. Halliday GM, Leverenz JB, Schneider JS, Adler CH. The neurobi-
ological basis of cognitive impairment in Parkinsons disease.
Mov Disord 2014;29:634-650.
63. Riedel O, Dodel R, Deuschl G, et al. Depression and care-
dependency in Parkinsons disease: results from a nationwide
study of 1449 outpatients. Parkinsonism Relat Disord 2012;18:
598-601.
64. Schrag A. Quality of life and depression in Parkinsons disease.
J Neurol Sci 2006;248:151-157.
65. Barone P, Antonini A, Colosimo C, et al. The PRIAMO study: A
multicenter assessment of nonmotor symptoms and their impact
on quality of life in Parkinsons disease. Mov Disord 2009;24:
1641-1649.
66. Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM,
Chaudhuri KR. The impact of non-motor symptoms on health-
related quality of life of patients with Parkinsons disease. Mov
Disord 2011;26:399-406.
67. Friedenberg DL, Cummings JL. Parkinsons disease, depression,
and the on-off phenomenon. Psychosomatics 1989;30:94-99.
68. Aarsland D, Bronnick K, Alves G, et al. The spectrum of neuro-
psychiatric symptoms in patients with early untreated Parkinsons
disease. J Neurol Neurosurg Psychiatry 2009;80:928-930.
69. Dujardin K, Sockeel P, Carette AS, Delliaux M, Defebvre L.
Assessing apathy in everyday clinical practice with the short-form
Lille Apathy Rating Scale. Mov Disord 2013;28:2014-2019.
70. Santangelo G, Barone P, Cuoco S, et al. Apathy in untreated, de
novo patients with Parkinsons disease: validation study of Apa-
thy Evaluation Scale. J Neurol 2014;261:2319-2328.
71. Sierra M, Carnicella S, Strafella AP, et al. Apathy and impulsive
control disorders: yin & yang of dopamine dependent behaviors.
J Parkinsons Dis 2015;5:625-636.
72. Pagonabarraga J, Martinez-Horta S, Fernandez de Bobadilla R,
et al. Minor hallucinations occur in drug-naive Parkinsons dis-
ease patients, even from the premotor phase. Mov Disord 2016;
31:45-52.
73. Favier M, Duran T, Carcenac C, Drui G, Savasta M, Carnicella
S. Pramipexole reverses Parkinsons disease-related motivational
deficits in rats. Mov Disord 2014;29:912-920.
74. Drui G, Carnicella S, Carcenac C, et al. Loss of dopaminergic
nigrostriatal neurons accounts for the motivational and affective
deficits in Parkinsons disease. Mol Psychiatry 2014;19:358-367.
75. Pagonabarraga J, Kulisevsky J, Strafella AP, Krack P. Apathy in
Parkinsons disease: clinical features, neural substrates, diagnosis,
and treatment. Lancet Neurol 2015;14:518-531.
76. Bjorklund A, Dunnett SB. Dopamine neuron systems in the brain:
an update. Trends Neurosci 2007;30:194-202.
77. Thobois S, Ardouin C, Lhommee E, et al. Non-motor dopamine
withdrawal syndrome after surgery for Parkinsons disease: predictors
and underlying mesolimbic denervation. Brain 2010;133:1111-1127.
78. Maricle RA, Valentine RJ, Carter J, Nutt JG. Mood response to
levodopa infusion in early Parkinsons disease. Neurology 1998;
50:1890-1892.
79. Kulisevsky J, Avila A, Barbanoj M, Antonijoan R, Berthier ML,
Gironell A. Acute effects of levodopa on neuropsychological per-
formance in stable and fluctuating Parkinsons disease patients at
1090 Movement Disorders, Vol. 31, No. 8, 2016
different levodopa plasma levels. Brain 1996;119(Pt 6):2121-
2132.
80. Cools R, Stefanova E, Barker RA, Robbins TW, Owen AM.
Dopaminergic modulation of high-level cognition in Parkinsons
disease: the role of the prefrontal cortex revealed by PET. Brain
2002;125:584-594.
81. Tang J, Strafella AP. The frontostriatal circuitry and behavioral
complications in PD. Parkinsonism Relat Disord 2012;18(Suppl
1):S104-S106.
82. Obeso JA, Rodriguez-Oroz MC, Benitez-Temino B, et al. Func-
tional organization of the basal ganglia: therapeutic implications
for Parkinsons disease. Mov Disord 2008;23(Suppl 3):S548-
S559.
83. Acquas E, Di Chiara G. Depression of mesolimbic dopamine
transmission and sensitization to morphine during opiate absti-
nence. J Neurochem 1992;58:1620-1625.
84. Di Chiara G, Imperato A. Drugs abused by humans preferentially
increase synaptic dopamine concentrations in the mesolimbic sys-
tem of freely moving rats. Proc Natl Acad Sci U S A 1988;85:
5274-5278.
85. Bodi N, Keri S, Nagy H, et al. Reward-learning and the novelty-
seeking personality: a between- and within-subjects study of the
effects of dopamine agonists on young Parkinsons patients. Brain
2009;132:2385-2395.
86. Murray AM, Ryoo HL, Gurevich E, Joyce JN. Localization of
dopamine D3 receptors to mesolimbic and D2 receptors to meso-
striatal regions of human forebrain. Proc Natl Acad Sci U S A
1994;91:11271-11275.
87. Canales JJ, Graybiel AM. A measure of striatal function predicts
motor stereotypy. Nat Neurosci 2000;3:377-383.
88. Koob GF, Le Moal M. Drug abuse: hedonic homeostatic dysregu-
lation. Science 1997;278:52-58.
89. Evans AH, Lawrence AD, Cresswell SA, Katzenschlager R, Lees
AJ. Compulsive use of dopaminergic drug therapy in Parkinsons
disease: reward and anti-reward. Mov Disord 2010;25:867-876.
90. Cilia R, Siri C, Canesi M, et al. Dopamine dysregulation syn-
drome in Parkinsons disease: from clinical and neuropsychologi-
cal characterisation to management and long-term outcome.
J Neurol Neurosurg Psychiatry 2014;85:311-318.
91. Weintraub D, Koester J, Potenza MN, et al. Impulse control dis-
orders in Parkinson disease: a cross-sectional study of 3090
patients. Arch Neurol 2010;67:589-595.
92. Evans AH, Lawrence AD, Potts J, Appel S, Lees AJ. Factors
influencing susceptibility to compulsive dopaminergic drug use in
Parkinson disease. Neurology 2005;65:1570-1574.
93. Stacy MA, Murck H, Kroenke K. Responsiveness of motor and
nonmotor symptoms of Parkinson disease to dopaminergic thera-
py. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:57-61.
94. Cools R. Dopaminergic modulation of cognitive function-
implications for L-DOPA treatment in Parkinsons disease. Neu-
rosci Biobehav Rev 2006;30:1-23.
95. Nieoullon A. Dopamine and the regulation of cognition and
attention. Prog Neurobiol 2002;67:53-83.
96. Reijnders JS, Scholtissen B, Weber WE, Aalten P, Verhey FR,
Leentjens AF. Neuroanatomical correlates of apathy in Parkin-
sons disease: a magnetic resonance imaging study using voxel-
based morphometry. Mov Disord 2010;25:2318-2325.
97. Tinaz S, Courtney MG, Stern CE. Focal cortical and subcortical
atrophy in early Parkinsons disease. Mov Disord 2011;26:436-
441.
98. Feldmann A, Illes Z, Kosztolanyi P, et al. Morphometric changes
of gray matter in Parkinsons disease with depression: a voxel-
based morphometry study. Mov Disord 2008;23:42-46.
99. Matsui H, Nishinaka K, Oda M, et al. Depression in Parkinsons
disease. Diffusion tensor imaging study. J Neurol 2007;254:1170-
1173.
100. Li W, Liu J, Skidmore F, Liu Y, Tian J, Li K. White matter
microstructure changes in the thalamus in Parkinson disease with
depression: a diffusion tensor MR imaging study. AJNR Am J
Neuroradiol 2010;31:1861-1866.
101. Kostic VS, Agosta F, Petrovic I, et al. Regional patterns of brain
tissue loss associated with depression in Parkinson disease. Neu-
rology 2010;75:857-863.
 A R E V I E W
102. Kostic VS, Filippi M. Neuroanatomical correlates of depression
and apathy in Parkinsons disease: magnetic resonance imaging
studies. J Neurol Sci 2011;310:61-63.
103. Mayberg HS, Starkstein SE, Sadzot B, et al. Selective hypometab-
olism in the inferior frontal lobe in depressed patients with Par-
kinsons disease. Ann Neurol 1990;28:57-64.
104. Black KJ, Hershey T, Hartlein JM, Carl JL, Perlmutter JS. Levo-
dopa challenge neuroimaging of levodopa-related mood fluctua-
tions in Parkinsons disease. Neuropsychopharmacology 2005;30:
590-601.
105. Le Jeune F, Drapier D, Bourguignon A, et al. Subthalamic nucleus
stimulation in Parkinson disease induces apathy: a PET study.
Neurology 2009;73:1746-1751.
106. Torack RM, Morris JC. The association of ventral tegmental area
histopathology with adult dementia. Arch Neurol 1988;45:497-
501.
107. Lim SY, Fox SH, Lang AE. Overview of the extranigral aspects
of Parkinson disease. Arch Neurol 2009;66:167-172.
108. Jost WH. Autonomic dysfunctions in idiopathic Parkinsons dis-
ease. J Neurol 2003;250(Suppl 1):I28-I30.
109. Goetz CG, Lutge W, Tanner CM. Autonomic dysfunction in Par-
kinsons disease. Neurology 1986;36:73-75.
110. Pursiainen V, Korpelainen JT, Haapaniemi TH, Sotaniemi KA,
Myllyla VV. Blood pressure and heart rate in parkinsonian
patients with and without wearing-off. Eur J Neurol 2007;14:
373-378.
111. Pursiainen V, Haapaniemi TH, Korpelainen JT, Sotaniemi KA,
Myllyla VV. Sweating in Parkinsonian patients with wearing-off.
Mov Disord 2007;22:828-832.
112. Baratti M, Calzetti S. Fluctuation of arterial blood pressure dur-
ing end-of-dose akinesia in Parkinsons disease. J Neurol Neuro-
surg Psychiatry 1984;47:1241-1243.
113. Swinn L, Schrag A, Viswanathan R, Bloem BR, Lees A, Quinn N.
Sweating dysfunction in Parkinsons disease. Mov Disord 2003;
18:1459-1463.
114. Raudino F. Non motor off in Parkinsons disease. Acta Neurol
Scand 2001;104:312-315.
115. Quadri R, Comino I, Scarzella L, et al. Autonomic nervous func-
tion in de novo parkinsonian patients in basal condition and after
acute levodopa administration. Funct Neurol 2000;15:81-86.
116. Muller B, Assmus J, Larsen JP, Haugarvoll K, Skeie GO, Tysnes
OB. Autonomic symptoms and dopaminergic treatment in de
novo Parkinsons disease. Acta Neurol Scand 2013;127:290-294.
117. Goldstein DS, Eldadah BA, Holmes C, et al. Neurocirculatory
abnormalities in Parkinson disease with orthostatic hypotension:
independence from levodopa treatment. Hypertension 2005;46:
1333-1339.
118. Kaufmann H, Goldstein DS. Autonomic dysfunction in Parkinson
disease. Handb Clin Neurol 2013;117:259-278.
119. Uchiyama T, Sakakibara R, Hattori T, Yamanishi T. Short-term
effect of a single levodopa dose on micturition disturbance in Par-
kinsons disease patients with the wearing-off phenomenon. Mov
Disord 2003;18:573-578.
120. Edwards LL, Quigley EM, Harned RK, Hofman R, Pfeiffer RF.
Defecatory function in Parkinsons disease: response to apomor-
phine. Ann Neurol 1993;33:490-493.
121. Snider SR, Fahn S, Isgreen WP, Cote LJ. Primary sensory symp-
toms in parkinsonism. Neurology 1976;26:423-429.
122. Hanagasi HA, Akat S, Gurvit H, Yazici J, Emre M. Pain is common
in Parkinsons disease. Clin Neurol Neurosurg 2011;113:11-13.
123. Waseem S, Gwinn-Hardy K. Pain in Parkinsons disease. Com-
mon yet seldom recognized symptom is treatable. Postgrad Med
2001;110:33-4, 940, 46.
124. Rana AQ, Kabir A, Jesudasan M, Siddiqui I, Khondker S. Pain in
Parkinsons disease: analysis and literature review. Clin Neurol
Neurosurg 2013;115:2313-2317.
125. Silva EG, Viana MA, Quagliato EM. Pain in Parkinsons disease:
analysis of 50 cases in a clinic of movement disorders. Arq Neu-
ropsiquiatr 2008;66:26-29.
126. Zambito Marsala S, Tinazzi M, Vitaliani R, et al. Spontaneous
pain, pain threshold, and pain tolerance in Parkinsons disease.
J Neurol 2011;258:627-633.
O N N O N M O T O R F L U C T U A T I O N S
127. Gallagher DA, Lees AJ, Schrag A. What are the most important
nonmotor symptoms in patients with Parkinsons disease and are
we missing them? Mov Disord 2010;25:2493-2500.
128. Roh JH, Kim BJ, Jang JH, et al. The relationship of pain and
health-related quality of life in Korean patients with Parkinsons
disease. Acta Neurol Scand 2009;119:397-403.
129. Lefaucheur R, Berthelot L, Senant J, Borden A, Maltete D. Acute
genital pain during non-motor fluctuations improved by apomor-
phine. Mov Disord 2013;28:687-688.
130. Rana AQ, Depradine J. Abdominal pain: a symptom of levodopa
end of dose wearing off in Parkinsons disease. West Indian Med
J 2011;60:223-224.
131. Quinn NP, Koller WC, Lang AE, Marsden CD. Painful Parkin-
sons disease. Lancet 1986;1:1366-1369.
132. Nebe A, Ebersbach G. Pain intensity on and off levodopa in
patients with Parkinsons disease. Mov Disord 2009;24:1233-
1237.
133. Ford B. Pain in Parkinsons disease. Mov Disord 2010;25(Suppl
1):S98-S103.
134. Factor SA, Brown DL, Molho ES. Subcutaneous apomorphine
injections as a treatment for intractable pain in Parkinsons dis-
ease. Mov Disord 2000;15:167-169.
135. Bayulkem K, Lopez G. Clinical approach to nonmotor sensory
fluctuations in Parkinsons disease. J Neurol Sci 2011;310:82-85.
136. Juri C, Rodriguez-Oroz M, Obeso JA. The pathophysiological
basis of sensory disturbances in Parkinsons disease. J Neurol Sci
2010;289:60-65.
137. Rijsman RM, Schoolderman LF, Rundervoort RS, Louter M.
Restless legs syndrome in Parkinsons disease. Parkinsonism &
related disorders 2014;20(Suppl 1):S5-S9.
138. Tinazzi M, Recchia S, Simonetto S, et al. Muscular pain in Par-
kinsons disease and nociceptive processing assessed with CO2
laser-evoked potentials. Mov Disord 2010;25:213-220.
139. Chudler EH, Dong WK. The role of the basal ganglia in nocicep-
tion and pain. Pain 1995;60:3-38.
140. Prescott TJ, Montes Gonzalez FM, Gurney K, Humphries MD,
Redgrave P. A robot model of the basal ganglia: behavior and
intrinsic processing. Neural Netw 2006;19:31-61.
141. Brefel-Courbon C, Payoux P, Thalamas C, et al. Effect of levodo-
pa on pain threshold in Parkinsons disease: a clinical and posi-
tron emission tomography study. Mov Disord 2005;20:1557-
1563.
142. Poewe WH, Rascol O, Quinn N, et al. Efficacy of pramipexole
and transdermal rotigotine in advanced Parkinsons disease: a
double-blind, double-dummy, randomised controlled trial. Lancet
Neurol 2007;6:513-520.
143. Leeman AL, ONeill CJ, Nicholson PW, et al. Parkinsons disease
in the elderly: response to and optimal spacing of night time dos-
ing with levodopa. Br J Clin Pharmacol 1987;24:637-643.
144. Ardouin C, Chereau I, Llorca PM, et al. [Assessment of hyper-
and hypodopaminergic behaviors in Parkinsons disease]. Rev
Neurol (Paris) 2009;165:845-856.
145. Kleiner-Fisman G, Martine R, Lang AE, Stern MB. Development
of a non-motor fluctuation assessment instrument for Parkinson
disease. Parkinsons Dis 2011;2011:292719.
146. Stacy M, Hauser R. Development of a Patient Questionnaire to
facilitate recognition of motor and non-motor wearing-off in Par-
kinsons disease. J Neural Transm 2007;114:211-217.
147. Altavista MC, Cassetta E, Brusa L, et al. Wearing-off detection in
clinical practice: the wearing off real practice key (WORK-PD)
study in Parkinsons disease. Parkinsonism Relat Disord 2015;21:
95-100.
148. Martinez-Martin P, Tolosa E, Hernandez B, Badia X. Validation
of the QUICK questionnairea tool for diagnosis of wearing-
off in patients with Parkinsons disease. Mov Disord 2008;23:
830-836.
149. Stacy M, Hauser R, Oertel W, et al. End-of-dose wearing off in
Parkinson disease: a 9-question survey assessment. Clin Neuro-
pharmacol 2006;29:312-321.
150. Martinez-Martin P, Hernandez B. The Q10 questionnaire for
detection of wearing-off phenomena in Parkinsons disease. Par-
kinsonism Relat Disord 2012;18:382-385.
Movement Disorders, Vol. 31, No. 8, 2016 1091
M A R T I N E Z - F E R N A
 N D E Z E T A L
151. Antonini A, Martinez-Martin P, Chaudhuri RK, et al. Wearing-
off scales in Parkinsons disease: critique and recommendations.
Mov Disord 2011;26:2169-2175.
152. Chaudhuri KR, Martinez-Martin P, Schapira AH, et al. Interna-
tional multicenter pilot study of the first comprehensive self-
completed nonmotor symptoms questionnaire for Parkinsons dis-
ease: the NMSQuest study. Mov Disord 2006;21:916-923.
153. Rieu I, Martinez-Martin P, Pereira B, et al. International valida-
tion of a behavioral scale in Parkinsons disease without demen-
tia. Mov Disord 2015;30:705-713.
154. Zesiewicz TA, Sullivan KL, Arnulf I, et al. Practice Parameter:
treatment of nonmotor symptoms of Parkinson disease: report of
the Quality Standards Subcommittee of the American Academy
of Neurology. Neurology 2010;74:924-931.
155. Connolly BS, Lang AE. Pharmacological treatment of Parkinson
disease: a review. JAMA 2014;311:1670-1683.
156. Witjas T, Kaphan E, Azulay JP. [Non-motor fluctuations in Par-
kinsons disease]. Rev Neurol (Paris) 2007;163:846-850.
157. Chaudhuri KR, Rizos A, Sethi KD. Motor and nonmotor compli-
cations in Parkinsons disease: an argument for continuous drug
delivery? J Neural Transm 2013;120:1305-1320.
158. Hauser RA, Hsu A, Kell S, et al. Extended-release carbidopa-
levodopa (IPX066) compared with immediate-release carbidopa-
levodopa in patients with Parkinsons disease and motor fluctua-
tions: a phase 3 randomised, double-blind trial. Lancet Neurol
2013;12:346-356.
159. Odin P, Ray Chaudhuri K, Slevin JT, et al.; National Steering
Committees. Collective physician perspectives on non-oral medi-
cation approaches for the management of clinically relevant unre-
solved issues in Parkinsons disease: Consensus from an
international survey and discussion program. Parkinsonism Relat
Disord 2015;21:1133-1144.
160. Nutt JG, Woodward WR, Beckner RM, et al. Effect of peripheral
catechol-O-methyltransferase inhibition on the pharmacokinetics
and pharmacodynamics of levodopa in parkinsonian patients.
Neurology 1994;44:913-919.
161. Rascol O, Brooks DJ, Melamed E, et al. Rasagiline as an adjunct
to levodopa in patients with Parkinsons disease and motor fluc-
tuations (LARGO, Lasting effect in Adjunct therapy with Rasagi-
line Given Once daily, study): a randomised, double-blind,
parallel-group trial. Lancet 2005;365:947-954.
162. Calandrella D, Antonini A. Pulsatile or continuous dopaminomi-
metic strategies in Parkinsons disease. Parkinsonism Relat Disord
2012;18(Suppl 1):S120-S122.
163. Smith KM, Eyal E, Weintraub D. Combined rasagiline and anti-
depressant use in Parkinson disease in the ADAGIO study: effects
on nonmotor symptoms and tolerability. JAMA Neurol 2015;72:
88-95.
164. Kulisevsky J, Pascual-Sedano B, Barbanoj M, Gironell A,
Pagonabarraga J, Garcia-Sanchez C. Acute effects of immediate
and controlled-release levodopa on mood in Parkinsons disease:
a double-blind study. Mov Disord 2007;22:62-67.
165. Trenkwalder C, Kohnen R, Hogl B, et al. Parkinsons disease
sleep scalevalidation of the revised version PDSS-2. Mov Dis-
ord 2011;26:644-652.
166. Ray Chaudhuri K, Martinez-Martin P, Antonini A, et al. Rotigo-
tine and specific non-motor symptoms of Parkinsons disease:
post hoc analysis of RECOVER. Parkinsonism Relat Disord
2013;19:660-665.
167. Kassubek J, Chaudhuri KR, Zesiewicz T, et al. Rotigotine trans-
dermal system and evaluation of pain in patients with Parkinsons
disease: a post hoc analysis of the RECOVER study. BMC Neu-
rol 2014;14:42.
168. Borgohain R, Szasz J, Stanzione P, et al. Two-year, randomized,
controlled study of safinamide as add-on to levodopa in mid to
late Parkinsons disease. Mov Disord 2014;29:1273-1280.
169. Pahwa R, Koller WC, Trosch RM, Sherry JH. Subcutaneous apo-
morphine in patients with advanced Parkinsons disease: a dose-
escalation study with randomized, double-blind, placebo-con-
trolled crossover evaluation of a single dose. J Neurol Sci 2007;
258:137-143.
170. Lawrence AD, Evans AH, Lees AJ. Compulsive use of dopamine
replacement therapy in Parkinsons disease: reward systems gone
awry? Lancet Neurol 2003;2:595-604.
1092 Movement Disorders, Vol. 31, No. 8, 2016
171. Okai D, Askey-Jones S, Samuel M, et al. Trial of CBT for
impulse control behaviors affecting Parkinson patients and their
caregivers. Neurology 2013;80:792-799.
172. Calleo JS, Amspoker AB, Sarwar AI, et al. A pilot study of a
cognitive-behavioral treatment for anxiety and depression in
patients with Parkinson disease. J Geriatr Psychiatry Neurol
2015;28:210-217.
173. Krack P, Batir A, Van Blercom N, et al. Five-year follow-up of
bilateral stimulation of the subthalamic nucleus in advanced Par-
kinsons disease. N Engl J Med 2003;349:1925-1934.
174. Katzenschlager R, Hughes A, Evans A, et al. Continuous subcuta-
neous apomorphine therapy improves dyskinesias in Parkinsons
disease: a prospective study using single-dose challenges. Mov
Disord 2005;20:151-157.
175. Devos D. Patient profile, indications, efficacy and safety of duode-
nal levodopa infusion in advanced Parkinsons disease. Mov Dis-
ord 2009;24:993-1000.
176. Limousin P, Pollak P, Benazzouz A, et al. Bilateral subthalamic
nucleus stimulation for severe Parkinsons disease. Mov Disord
1995;10:672-674.
177. Garcia Ruiz PJ, Sesar Ignacio A, Ares Pensado B, et al. Efficacy
of long-term continuous subcutaneous apomorphine infusion in
advanced Parkinsons disease with motor fluctuations: a multicen-
ter study. Mov Disord 2008;23:1130-1136.
178. Hughes AJ, Bishop S, Kleedorfer B, et al. Subcutaneous apomor-
phine in Parkinsons disease: response to chronic administration
for up to five years. Mov Disord 1993;8:165-170.
179. Manson AJ, Turner K, Lees AJ. Apomorphine monotherapy in
the treatment of refractory motor complications of Parkinsons
disease: long-term follow-up study of 64 patients. Mov Disord
2002;17:1235-1241.
180. Todorova A, Ray Chaudhuri K. Subcutaneous apomorphine and
non-motor symptoms in Parkinsons disease. Parkinsonism Relat
Disord 2013;19:1073-1078.
181. Martinez-Martin P, Reddy P, Antonini A, et al. Chronic subcuta-
neous infusion therapy with apomorphine in advanced Parkin-
sons disease compared to conventional therapy: a real life study
of non motor effect. J Parkinsons Dis 2011;1:197-203.
182. Martinez-Martin P, Reddy P, Katzenschlager R, et al. EuroInf: a
multicenter comparative observational study of apomorphine and
levodopa infusion in Parkinsons disease. Mov Disord 2015;30:
510-516.
183. Mathers SE, Kempster PA, Law PJ, et al. Anal sphincter dysfunc-
tion in Parkinsons disease. Arch Neurol 1989;46:1061-1064.
184. Christmas TJ, Kempster PA, Chapple CR, et al. Role of subcuta-
neous apomorphine in parkinsonian voiding dysfunction. Lancet
1988;2:1451-1453.
185. Dellapina E, Gerdelat-Mas A, Ory-Magne F, et al. Apomorphine
effect on pain threshold in Parkinsons disease: a clinical and pos-
itron emission tomography study. Mov Disord 2011;26:153-157.
186. Nilsson D, Nyholm D, Aquilonius SM. Duodenal levodopa infu-
sion in Parkinsons diseaselong-term experience. Acta Neurol
Scand 2001;104:343-348.
187. Nyholm D, Askmark H, Gomes-Trolin C, et al. Optimizing levo-
dopa pharmacokinetics: intestinal infusion versus oral sustained-
release tablets. Clin Neuropharmacol 2003;26:156-163.
188. Kurth MC, Tetrud JW, Tanner CM, et al. Double-blind, placebo-
controlled, crossover study of duodenal infusion of levodopa/car-
bidopa in Parkinsons disease patients with on-off fluctuations.
Neurology 1993;43:1698-1703.
189. Olanow CW, Kieburtz K, Odin P, et al. Continuous intrajejunal
infusion of levodopa-carbidopa intestinal gel for patients with
advanced Parkinsons disease: a randomised, controlled, double-
blind, double-dummy study. Lancet Neurol 2014;13:141-149.
190. Caceres-Redondo MT, Carrillo F, Lama MJ, et al. Long-term
levodopa/carbidopa intestinal gel in advanced Parkinsons disease.
J Neurol 2014;261:561-569.
191. Bellante F, Dethy S, Zegers de Beyl D. Depression, anxiety and
non-motor symptoms on initiation of intrajejunal levodopa/carbi-
dopa therapy. Acta Neurol Belg 201;116:39-41.
192. Antonini A, Yegin A, Preda C, Bergmann L, Poewe W. Global
long-term study on motor and non-motor symptoms and safety
of levodopa-carbidopa intestinal gel in routine care of advanced
 A R E V I E W
Parkinsons disease patients; 12-month interim outcomes. Parkin-
sonism Relat Disord 2015;21:231-235.
193. Buongiorno M, Antonelli F, Camara A, et al. Long-term response
to continuous duodenal infusion of levodopa/carbidopa gel in
patients with advanced Parkinson disease: the Barcelona registry.
Parkinsonism Relat Disord 2015;28:871-876.
194. Eggert K, Schrader C, Hahn M, et al. Continuous jejunal levodo-
pa infusion in patients with advanced parkinson disease: practical
aspects and outcome of motor and non-motor complications.
Clin Neuropharmacol 2008;31:151-166.
195. Lhommee E, Klinger H, Thobois S, et al. Subthalamic stimulation
in Parkinsons disease: restoring the balance of motivated behav-
iours. Brain 2012;135:1463-1477.
196. Lhommee E, Wojtecki L, Czernecki V, et al. EARLYSTIM: STN-
DBS alleviates behavioural side effects of dopamine replacement
therapy when compared to best medical treatment in a 2-year fol-
low-up randomized controlled trial. Movement Disorders Society
International Congress. Berlin: Movement disorders Society;
2016.
197. Funkiewiez A, Ardouin C, Krack P, et al. Acute
psychotropic effects of bilateral subthalamic nucleus stimulation
and levodopa in Parkinsons disease. Mov Disord 2003;18:524-
530.
198. Castrioto A, Lhommee E, Moro E, Krack P. Mood and behaviou-
ral effects of subthalamic stimulation in Parkinsons disease. Lan-
cet Neurol 2014;13:287-305.
199. Castrioto A, Kistner A, Klinger H, et al. Psychostimulant effect of
levodopa: reversing sensitisation is possible. J Neurol Neurosurg
Psychiatry 2013;84:18-22.
200. Deuschl G, Schade-Brittinger C, Krack P, et al. A randomized tri-
al of deep-brain stimulation for Parkinsons disease. N Engl J
Med 2006;355:896-908.
201. Funkiewiez A, Ardouin C, Caputo E, et al. Long term effects of
bilateral subthalamic nucleus stimulation on cognitive function,
mood, and behaviour in Parkinsons disease. J Neurol Neurosurg
Psychiatry 2004;75:834-839.
202. Witt K, Daniels C, Herzog J, et al. Differential effects of L-dopa
and subthalamic stimulation on depressive symptoms and hedonic
tone in Parkinsons disease. J Neuropsychiatry Clin Neurosci
2006;18:397-401.
203. Witt K, Daniels C, Reiff J, et al. Neuropsychological and psychi-
atric changes after deep brain stimulation for Parkinsons disease:
a randomised, multicentre study. Lancet Neurol 2008;7:605-614.
204. Schuepbach WM, Rau J, Knudsen K, et al. Neurostimulation for
Parkinsons disease with early motor complications. N Engl J
Med 2013;368:610-622.
205. Wolz M, Hauschild J, Koy J, et al. Immediate effects of deep
brain stimulation of the subthalamic nucleus on nonmotor symp-
toms in Parkinsons disease. Parkinsonism Relat Disord 2012;18:
994-997.
206. Bejjani BP, Damier P, Arnuslf I, et al. Transient acute depression
induced by high-frequency deep-brain stimulation. N Engl J Med
1999;340:1476-1480.
207. Strutt AM, Simpson R, Jankovic J, York MK. Changes in
cognitive-emotional and physiological symptoms of depression
following STN-DBS for the treatment of Parkinsons disease. Eur
J Neurol 2012;19:121-127.
208. Follett KA, Weaver FM, Stern M, et al. Pallidal versus subthala-
mic deep-brain stimulation for Parkinsons disease. N Engl J Med
2010;362:2077-2091.
209. Antonini A, Yegin A, Preda C, et al. Global long-term study on
motor and non-motor symptoms and safety of levodopa-
carbidopa intestinal gel in routine care of advanced Parkinsons
disease patients; 12-month interim outcomes. Parkinsonism Relat
Disord 2015;21:231-235.
210. Houeto JL, Mesnage V, Mallet L, et al. Behavioural disorders,
Parkinsons disease and subthalamic stimulation. J Neurol Neuro-
surg Psychiatry 2002;72:701-707.
211. Cury RG, Galhardoni R, Fonoff ET, et al. Effects of deep brain
stimulation on pain and other nonmotor symptoms in Parkinson
disease. Neurology 2014;83:1403-1409.
212. Czernecki V, Pillon B, Houeto JL, et al. Does bilateral stimula-
tion of the subthalamic nucleus aggravate apathy in Parkinsons
disease? J Neurol Neurosurg Psychiatry 2005;76:775-779.
O N N O N M O T O R F L U C T U A T I O N S
213. Drapier D, Drapier S, Sauleau P, et al. Does subthalamic nucleus
stimulation induce apathy in Parkinsons disease? J Neurol 2006;
253:1083-1091.
214. Kirsch-Darrow L, Zahodne LB, Marsiske M, Okun MS, Foote
KD, Bowers D. The trajectory of apathy after deep brain stimula-
tion: from pre-surgery to 6 months post-surgery in Parkinsons
disease. Parkinsonism Relat Disord 2011;17:182-188.
215. Bandini F, Primavera A, Pizzorno M, Cocito L. Using STN DBS and
medication reduction as a strategy to treat pathological gambling in
Parkinsons disease. Parkinsonism Relat Disord 2007;13:369-371.
216. Witjas T, Baunez C, Henry JM, et al. Addiction in Parkinsons
disease: impact of subthalamic nucleus deep brain stimulation.
Mov Disord 2005;20:1052-1055.
217. Ardouin C, Voon V, Worbe Y, et al. Pathological gambling in
Parkinsons disease improves on chronic subthalamic nucleus
stimulation. Mov Disord 2006;21:1941-1946.
218. De la Casa-Fages B, Grandas F. Dopamine dysregulation syn-
drome after deep brain stimulation of the subthalamic nucleus in
Parkinsons disease. J Neurol Sci 2012;312:191-193.
219. Eusebio A, Witjas T, Cohen J, et al. Subthalamic nucleus stimula-
tion and compulsive use of dopaminergic medication in Parkin-
sons disease. J Neurol Neurosurg Psychiatry 2013;84:868-874.
220. Romito LM, Raja M, Daniele A, et al. Transient mania with
hypersexuality after surgery for high frequency stimulation of the
subthalamic nucleus in Parkinsons disease. Mov Disord 2002;17:
1371-1374.
221. Ballanger B, van Eimeren T, Moro E, et al. Stimulation of the
subthalamic nucleus and impulsivity: release your horses. Ann
Neurol 2009;66:817-824.
222. Contarino MF, Daniele A, Sibilia AH, et al. Cognitive outcome 5
years after bilateral chronic stimulation of subthalamic nucleus in
patients with Parkinsons disease. J Neurol Neurosurg Psychiatry
2007;78:248-252.
223. Halbig TD, Tse W, Frisina PG, et al. Subthalamic deep brain
stimulation and impulse control in Parkinsons disease. Eur J
Neurol 2009;16:493-497.
224. Lim SY, OSullivan SS, Kotschet K, et al. Dopamine dysregula-
tion syndrome, impulse control disorders and punding after deep
brain stimulation surgery for Parkinsons disease. J Clin Neurosci
2009;16:1148-1152.
225. Moum SJ, Price CC, Limotai N, et al. Effects of STN and GPi
deep brain stimulation on impulse control disorders and dopa-
mine dysregulation syndrome. PLoS One 2012;7:e29768.
226. Todorova A, Samuel M, Brown RG, Chaudhuri KR. Infusion
therapies and development of impulse control disorders in
advanced Parkinson disease: clinical experience after 3 years fol-
low-up. Clin Neuropharmacol 2015;38:132-134.
227. Umemura A, Oka Y, Okita K, Matsukawa N, Yamada K. Sub-
thalamic nucleus stimulation for Parkinson disease with severe
medication-induced hallucinations or delusions. J Neurosurg
2011;114:1701-1705.
228. Stemper B, Beric A, Welsch G, Haendl T, Sterio D, Hilz MJ.
Deep brain stimulation improves orthostatic regulation of patients
with Parkinson disease. Neurology 2006;67:1781-1785.
229. Zibetti M, Torre E, Cinquepalmi A, et al. Motor and nonmotor
symptom follow-up in parkinsonian patients after deep brain stim-
ulation of the subthalamic nucleus. Eur Neurol 2007;58:218-223.
230. Trachani E, Constantoyannis C, Sirrou V, Kefalopoulou Z,
Markaki E, Chroni E. Effects of subthalamic nucleus deep brain
stimulation on sweating function in Parkinsons disease. Clin
Neurol Neurosurg 2010;112:213-217.
231. Winge K, Nielsen KK, Stimpel H, Lokkegaard A, Jensen SR,
Werdelin L. Lower urinary tract symptoms and bladder control
in advanced Parkinsons disease: effects of deep brain stimulation
in the subthalamic nucleus. Mov Disord 2007;22:220-225.
232. Seif C, Herzog J, van der Horst C, et al. Effect of subthalamic
deep brain stimulation on the function of the urinary bladder.
Ann Neurol 2004;55:118-120.
233. Finazzi-Agro E, Peppe A, DAmico A, et al. Effects of subthala-
mic nucleus stimulation on urodynamic findings in patients with
Parkinsons disease. J Urol 2003;169:1388-1391.
234. Shimizu N, Matsumoto S, Mori Y, et al. [Effects of deep brain
stimulation on urodynamic findings in patients with Parkinsons
disease]. Hinyokika Kiyo 2007;53:609-612.
Movement Disorders, Vol. 31, No. 8, 2016 1093
M A R T I N E Z - F E R N A
 N D E Z E T A L
235. Herzog J, Weiss PH, Assmus A, et al. Subthalamic stimulation
modulates cortical control of urinary bladder in Parkinsons dis-
ease. Brain 2006;129:3366-3375.
236. Ciucci MR, Barkmeier-Kraemer JM, Sherman SJ. Subthalamic
nucleus deep brain stimulation improves deglutition in Parkin-
sons disease. Mov Disord 2008;23:676-683.
237. Kulneff L, Sundstedt S, Olofsson K, et al. Deep brain stimula-
tioneffects on swallowing function in Parkinsons disease. Acta
Neurol Scand 2013;127:329-336.
238. Hariz MI, Rehncrona S, Quinn NP, Speelman JD, Wensing C.
Multicenter study on deep brain stimulation in Parkinsons dis-
ease: an independent assessment of reported adverse events at 4
years. Mov Disord 2008;23:416-421.
239. Castelli L, Perozzo P, Genesia ML, et al. Sexual well being in
parkinsonian patients after deep brain stimulation of the subtha-
lamic nucleus. J Neurol Neurosurg Psychiatry 2004;75:1260-
1264.
240. Kim HJ, Paek SH, Kim JY, et al. Chronic subthalamic deep brain
stimulation improves pain in Parkinson disease. J Neurol 2008;
255:1889-1894.
1094 Movement Disorders, Vol. 31, No. 8, 2016
241. Gierthmuhlen J, Arning P, Binder A, et al. Influence of deep brain
stimulation and levodopa on sensory signs in Parkinsons disease.
Mov Disord 2010;25:1195-1202.
242. Surucu O, Baumann-Vogel H, Uhl M, Imbach LL, Baumann CR.
Subthalamic deep brain stimulation versus best medical therapy
for L-dopa responsive pain in Parkinsons disease. Pain 2013;154:
1477-1479.
243. Loher TJ, Burgunder JM, Weber S, Sommerhalder R, Krauss JK.
Effect of chronic pallidal deep brain stimulation on off period
dystonia and sensory symptoms in advanced Parkinsons disease.
J Neurol Neurosurg Psychiatry 2002;73:395-399.
244. Driver-Dunckley E, Evidente VG, Adler CH, et al. Restless legs
syndrome in Parkinsons disease patients may improve with sub-
thalamic stimulation. Mov Disord 2006;21:1287-1289.
245. Chahine LM, Ahmed A, Sun Z. Effects of STN DBS for Parkin-
sons disease on restless legs syndrome and other sleep-related
measures. Parkinsonism Relat Disord 2011;17:208-211.
246. Kedia S, Moro E, Tagliati M, Lang AE, Kumar R. Emergence of
restless legs syndrome during subthalamic stimulation for Parkin-
son disease. Neurology 2004;63:2410-2412.