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Augmentation and impulsive behaviors in restless legs syndrome: Coexistence or association?

Authors:
Beatrice Heim at Medizinische Universität Innsbruck
Beatrice Heim
Atbin Djamshidian at University of London
Atbin Djamshidian
Anna Heidbreder at Johannes Kepler University Linz
Anna Heidbreder
Ambra Stefani at Medizinische Universität Innsbruck
Ambra Stefani
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Objectives: To assess the frequency of impulse control disorders (ICDs) in patients with restless legs syndrome (RLS) with and without augmentation under dopaminergic therapy in a case-control study. Augmentation and ICDs are both serious complications of dopaminergic treatment of RLS but little is known about possible associations between these drug-induced disorders. Methods: In total, 58 patients with idiopathic RLS diagnosed according to the International Restless Legs Syndrome Study Group criteria were recruited. Of these, 35 patients had augmentation. The frequency of ICD symptoms was assessed using semi-structural interviews. Results: Demographic variables did not differ between patients with RLS with and without augmentation but those with augmentation took higher dopaminergic medication than patients without augmentation. Twenty-three patients with RLS (39.7%) had ICD symptoms, with 12 patients (20.7%) having definitive ICDs. Patients with augmentation had an increased risk of expressing ICD symptoms (p = 0.007, odds ratio 5.64, 95% confidence interval 1.59-20.02). Conclusions: Patients with RLS with augmentation have an almost 6-fold increased risk of exhibiting ICD symptoms. This implies that augmentation and ICDs are related and may share a common pathophysiology. Moreover, our results have clinical implications, suggesting that patients with RLS with augmentation should be screened for ICD symptoms.
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Beatrice Heim, MD
Atbin Djamshidian, MD,
PhD
Anna Heidbreder, MD
Ambra Stefani, MD
Laura Zamarian, PhD
Marie-Theres Pertl, MA
Elisabeth Brandauer, MD
Margarete Delazer, PhD
Klaus Seppi, MD
Werner Poewe, MD
Birgit Högl, MD
Correspondence to
Dr. Djamshidian:
atbin.djamshidian-tehrani@i-med.
ac.at
Editorial, page 15
Supplemental data
at Neurology.org
Augmentation and impulsive behaviors in
restless legs syndrome
Coexistence or association?
ABSTRACT
Objectives: To assess the frequency of impulse control disorders (ICDs) in patients with restless
legs syndrome (RLS) with and without augmentation under dopaminergic therapy in a case-control
study. Augmentation and ICDs are both serious complications of dopaminergic treatment of RLS
but little is known about possible associations between these drug-induced disorders.
Methods: In total, 58 patients with idiopathic RLS diagnosed according to the International Rest-
less Legs Syndrome Study Group criteria were recruited. Of these, 35 patients had augmenta-
tion. The frequency of ICD symptoms was assessed using semi-structural interviews.
Results: Demographic variables did not differ between patients with RLS with and without aug-
mentation but those with augmentation took higher dopaminergic medication than patients with-
out augmentation. Twenty-three patients with RLS (39.7%) had ICD symptoms, with 12 patients
(20.7%) having definitive ICDs. Patients with augmentation had an increased risk of expressing
ICD symptoms (p50.007, odds ratio 5.64, 95% confidence interval 1.59–20.02).
Conclusions: Patients with RLS with augmentation have an almost 6-fold increased risk of exhib-
iting ICD symptoms. This implies that augmentation and ICDs are related and may share a com-
mon pathophysiology. Moreover, our results have clinical implications, suggesting that patients
with RLS with augmentation should be screened for ICD symptoms. Neurology
®
2016;87:36–40
GLOSSARY
DA 5dopamine agonist; ICD 5impulse control disorder; IRLS 5International RLS Study Group Rating Scale; LEU 5
levodopa equivalent unit; OR 5odds ratio; QUIP 5Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease;
RLS 5restless legs syndrome.
Restless legs syndrome (RLS) is a common neurologic disorder affecting up to 10% of the North
American and European population, with clinically relevant symptoms in 1.5%–3%.
1–3
The
clinical diagnosis is based on recently revised criteria.
4
Dopaminergic drugs, especially dopamine
agonists (DA), are considered first-line therapies.
5
However, long-term dopaminergic treatment
may induce augmentation, which is a worsening of symptom severity such as earlier onset of
symptoms at rest, spread to different body parts, increased intensity of RLS severity, and shorter
effect of medication.
6–8
Augmentation occurs in up to 60%–85% of levodopa-treated patients
and in 11%–24% of patients treated with DA.
6,9
A recent cohort study revealed that 56% of all
patients with RLS showed possible augmentation, while only 24% were free of this problem.
10
Impulse control disorders (ICDs), such as gambling disorder, compulsive sexual behavior,
compulsive shopping, binge eating, or punding, are also common in patients with RLS treated
with DA, with prevalence rates ranging between 7% and 16%.
11,12
However, the actual prev-
alence may be even higher as patients often conceal their addiction due to shame, denial, or poor
insight.
While both augmentation and ICDs are relatively common in patients with RLS, it is unclear
whether these 2 behaviors are related or independent complications of dopaminergic therapy.
The purpose of this case-control study was to compare the frequency and severity of ICDs in
patients with RLS with and without augmentation.
From the Departments of Neurology (B. Heim, A.D., A.H., A.S., L.Z., M.-T.P., E.B., M.D., K.S., W.P., B. Högl) and Psychology (M.-T.P.),
Medical University Innsbruck, Austria; and Department of Molecular Neuroscience and Reta Lila Weston Institute for Neurological Studies (A.D.),
University of London, UK.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
36 © 2016 American Academy of Neurology
METHODS Standard protocol approvals, registrations,
and patient consents. The study was approved by the Research
Ethics Committee of Innsbruck Medical University, Austria,
before study initiation. All participants provided written
informed consent according to the Declaration of Helsinki.
Participants. A total of 61 patients diagnosed with idiopathic RLS,
who attended the sleep disorders outpatient clinic and sleep labora-
tory of the Department of Neurology, Innsbruck Medical
University, were consecutively and prospectively screened between
September 2014 and August 2015. Eight patients refused to
participate for various reasons, such as no interest or time to partake.
Patients with secondary RLS, renal or hepatic dysfunction, or
only sporadic RLS symptoms were not included. Furthermore,
mild cognitive impairment (defined as a score less than 25 points
on the Montreal Cognitive Assessment),
13
major depression, or
treatment with a neuroleptic drug were exclusion criteria. Three
of the 61 patients were excluded based on their performance on
cognitive testing. Diagnosis of RLS was made according to the
International Restless Legs Syndrome Study Group criteria.
4
Mild or severe augmentation was defined according to the
recently published guidelines.
7
ICDs were assessed by using
semi-structural interviews based on the Questionnaire for
Impulsive-Compulsive Disorders in Parkinson’s Disease
(QUIP).
14
In contrast to definitive ICDs, ICD symptoms were
classified as a positive screen on the QUIP without causing a sig-
nificant impairment in social or occupational functioning. These
symptom-positive patients sometimes had difficulties controlling
their thoughts or urges in relation to their addictive behaviors.
Levodopa equivalent units (LEU) were calculated as described
elsewhere.
15
Statistics. Parametric tests, nonparametric tests, and the Fisher
exact test were used for statistical analyses depending on the scale
type of the variables. The Shapiro-Wilk test was used to test for
normal distribution of continuous nonordinal variables. Data
were analyzed with parametric statistics where normality
assumptions were met. Otherwise, nonparametric tests were
used. To assess the frequency of ICD symptoms in patients
with RLS with and without augmentation, we used the Fisher
exact test and calculated the odds ratio (OR). We also applied
a logistic regression model with ICDs (yes/no) as dependent
variable and augmentation as independent variable corrected for
the International RLS Study Group Rating Scale (IRLS) score,
LEU, age, sex, and disease duration. All potential risk factors
were treated as continuous and categorical variables. OR of
continuous variables were calculated for a 1 SD unit change of
the respective variable in order to render odds comparable. All
variables having a significance level of p#0.2 in the
unadjusted univariate logistic regression analysis (model A) as
well as in the logistic regression analysis adjusted for age and
sex (model B) were entered in a multivariate logistic regression
model (model C).
RESULTS Eight patients were on levodopa mono-
therapy while 4 patients were taking levodopa in com-
bination with a DA (2 patients were on pramipexole
and one patient each was on rotigotine and ropinirole).
A further 34 patients were taking pramipexole mono-
therapy and 7 patients were on rotigotine and 2
on ropinirole monotherapy. Three patients had
pramipexole-induced fatigue and 2 of them had in
addition augmentation and were recently switched to
an opioid receptor agonist.
Patients with ICD symptoms. Altogether, 23 (39.7%)
out of 58 patients with RLS had at least one ICD
symptom, with 12 patients (20.7%) fulfilling the cri-
teria of definitive ICDs. All 12 patients with
definitive ICDs had augmentation in addition. Sub-
sequent analysis was performed with these 23 patients
with ICD symptoms vs the 35 patients who were
screened negative on the QUIP. Augmentation was
more common in these 23 patients with ICD symp-
toms (p50.006, table 1). The LEU dose was higher
in the 23 patients with RLS screened positive for an
Table 1 Demographic and clinical data of patients with RLS with and without
ICD symptoms
RLS with ICD
symptoms
RLS without ICD
symptoms
p
Value
No. 23 35
Augmentation
a
0.006
b
Yes 19 16
No 419
Male:female
a
13:10 15:20 0.42
MoCA
c
27.9 61.4 28.0 61.4 0.82
Age, y
d
61.2 611.5 62.9 612.1 0.60
Years of education
c
10.73 63.1 10.7 62.4 0.84
Disease duration, y
d
19.0 613.4 14.8 612.3 0.15
IRLS
d
23.4 68.8 20.3 68.8 0.27
LEU, mg
c
123.3 6167.5 58.3 667.9 0.05
DA monotherapy 16 (69.6) 27 (77.1) 0.37
Pramipexole 12 (52.2) 22 (62.9) 0.30
Rotigotine 3 (13.0) 4 (11.4) 0.31
Ropinirole 1 (4.4) 1 (2.9) 0.49
Opioid receptor agonists 2 (8.7) 1 (2.9) 0.34
Levodopa 5 (21.7) 7 (20.0) 0.15
Levodopa monotherapy 4 (17.4) 4 (11.4) 0.24
Levodopa plus DA 1 (4.4) 3 (8.6) 0.36
ICD symptom (male:female) 23 (13:10)
Binge eating 10 (3:7)
Punding 7 (4:3)
Gambling 2 (2:0)
Compulsive sexual disorder 8 (7:1)
Shopping 6 (4:2)
Hoarding 2 (0:2)
Two or more ICD symptoms 10 (6:4)
Abbreviations: DA 5dopamine agonist; ICD 5impulse control disorder; IRLS 5International
RLS Study Group Rating Scale; LEU 5levodopa equivalent units; MoCA 5Montreal
Cognitive Assessment; RLS 5restless legs syndrome.
Values are mean 6SD or n (%).
a
Fisher exact test.
b
Significant difference.
c
Mann-Whitney Utest.
d
Unpaired ttest.
Neurology 87 July 5, 2016 37
ICD symptom than in those screened negative on the
QUIP, although this difference was just not signifi-
cant (Z521.9, p50.053). None of the patients
exhibited signs of dopamine dysregulation syndrome.
Otherwise, there were no differences on any other
demographic variables (table 1).
ICD symptoms are listed in table 1. Ten out of these
23 patients (43.5%) had 2 or more ICD symptoms.
Patients with augmentation. Thirty-five patients (60.3%)
of our cohort had augmentation, of whom 21
(36.2%) fulfilled diagnostic criteria of mild augmen-
tation and 14 (24.1%) had severe augmentation.
7
As
expected, patients with RLS with augmentation
took significantly higher LEU doses than patients
without augmentation (Z522.67, p50.003)
and had higher scores on the IRLS (Z522.6,
p50.004) (table 2).
Furthermore, there was a significant association
between ICD symptoms and augmentation (p5
0.007, OR 5.64, 95% confidence interval 1.59–
20.02). Thus, patients with RLS with augmentation
had an almost 6-fold risk of ICD symptoms com-
pared to patients without augmentation.
Risk factors associated with the presence of ICD
symptoms. Augmentation was associated with the
presence of ICD symptoms in an unadjusted univar-
iate regression analysis (model A). This association re-
mained significant after correction for age and sex
(model B). The strong association of augmentation
with ICD symptoms remained significant after enter-
ing IRLS, LEU, and disease duration (model C)
(table 3). Three patients were not treated with dopa-
minergic medication at the time of the assessment.
Therefore, the regression analyses were repeated
excluding those individuals, which did not change
the results (table e-1 on the Neurology
®
Web site at
Neurology.org).
DISCUSSION In an unbiased sample of 58 patients
with RLS, 23 individuals had at least one ICD symp-
tom, with 12 of these patients fulfilling the criteria of
definitive ICDs. These results are consistent with the
prevalence rate of ICDs reported in larger studies.
12
Furthermore, almost half of the patients with ICDs
had 2 or more addictive behaviors, which is also in
line with previous reports.
11
Thirty-five patients of this sample had augmenta-
tion. These patients were taking higher doses of DA
and also had higher IRLS scores compared to patients
with RLS without augmentation. Of these 35 pa-
tients, 21 were screened positive for at least one ques-
tion for augmentation and were considered as having
mild augmentation, while 14 individuals fulfilled the
criteria of severe augmentation.
7
The prevalence of
augmentation presented here is higher than in pre-
vious reports.
6,9,10
This may be because we applied the
newly proposed diagnostic guidelines, which also
identify patients with mild symptoms.
7
Furthermore,
patients were recruited in a tertiary referral center,
where complicated cases including those with aug-
mentation may be overrepresented.
Finally, we found an almost 6-fold risk of ICD
symptoms in patients with RLS with augmentation
as compared to those without augmentation.
Although the LEU dose was higher in patients with
augmentation, the association was also seen in a mul-
tivariate logistic regression analysis entering age, sex,
IRLS, LEU, and disease duration into the model.
The only significant association with the presence
of ICD symptoms was augmentation. This argues
against dopaminergic drug dose as the main triggering
Table 2 Demographic and clinical data in patients with RLS with and without
augmentation
RLS with
augmentation
RLS without
augmentation pValue
No. 35 23
Male:female
a
17:18 11:12 1.00
MoCA
b
28.1 61.4 28.0 61.6 0.49
Age, y
c
64.3 610.5 59.1 613.2 0.12
Years of education
b
10.8 62.7 10.6 62.6 0.70
Disease duration, y
c
17.9 612.9 14.4 612.5 0.38
IRLS
b
24.2 67.9 17.4 68.9 0.006
d
LEU, mg
b
119.1 6145.6 31.6 625.6 0.003
d
DA monotherapy 24 (68.6) 19 (82.6) 0.12
Pramipexole 19 (54.3) 15 (65.2) 0.31
Rotigotine 5 (14.3) 2 (5.7) 0.42
Ropinirole 0 2 (5.7) NA
Opioid receptor agonists 2 (5.7) 1 (2.9) 0.66
Levodopa 9 (25.7) 3 (8.6) 0.17
Levodopa monotherapy 5 (14.3) 3 (8.6) 0.61
Levodopa plus DA 4 (11.4) 0 NA
ICD symptom (male:female) 19 (9:10) 4 (3:1) 0.006
d
Binge eating 8 (2:6) 2 (1:1)
Punding 7 (4:3) 0
Gambling 1 (1:0) 1 (1:0)
Compulsive sexual disorder 7 (6:1) 1 (1:0)
Shopping 5 (3:2) 1 (1:0)
Hoarding 2 (0:2) 0
Two or more ICDs 9 (6:3) 1 (1:0)
Abbreviations: DA 5dopamine agonist; ICD 5impulse control disorder; IRLS 5International
RLS Study Group Rating Scale; LEU 5levodopa equivalent units; MoCA 5Montreal
Cognitive Assessment; NA 5not applicable; RLS 5restless legs syndrome.
Values are mean 6SD or n (%).
a
Fisher exact test.
b
Mann-Whitney Utest.
c
Unpaired ttest.
d
Significant difference.
38 Neurology 87 July 5, 2016
factor for ICDs in patients with RLS of this series,
which is also in line with previous studies.
12
In fact,
ICDs in RLS can also be observed with low doses of
DA,
16,17
suggesting that other factors such as an
increased individual susceptibility for ICDs may be
responsible for developing addictive behaviors.
11
Although the link between ICDs and augmenta-
tion has not been systematically studied before, co-
occurrence has been observed in 3 case reports of
a total of 4 patients.
18–20
Patients with RLS with ICD symptoms and aug-
mentation share several clinical similarities: compul-
sive behavior, poor insight, a tendency to conceal
their behavior, and depression and anxiety are com-
mon for both drug-induced side effects.
18,19
Further-
more, the psychological burden is particularly high in
RLS with augmentation
21
and in patients with
ICDs.
22
However, detailed assessment of the neuro-
psychological profile of patients with RLS with ICDs
and augmentation are pending. Furthermore, dopa-
mine agonist withdrawal symptoms, which have been
described to be refractory to antidepressants and ben-
zodiazepines and improve after restarting the DA
therapy,
23
are common in both conditions.
18,19
There are, however, also important differences
between ICDs and augmentation: While ICDs in pa-
tients with RLS have been associated with a personal
history of addictive behaviors,
11
no such risk factors have
been reported for patients with augmentation. Further-
more, patients with augmentation self-medicate to
alleviate the unpleasant RLS symptoms, which is
uncommon in patients with RLS who have ICDs in
isolation.
There are limitations of our study. We used the
new proposed diagnostic criteria to assess augmenta-
tion,
7
whereby the majority of our patients (n 5
21) did not fulfil criteria for severe augmentation.
Thus, this study mainly correlates mild addictive
behavior in RLS with mild signs of augmentation.
Nevertheless, our results suggest that augmentation
and ICD symptoms share a common underlying neu-
robiologic substrate and may lie on the same spec-
trum of behavioral side effects.
Wefoundinanunbiasedsampleof58treated
patients with RLS that those with augmentation
had an almost 6-fold risk of exhibiting ICD symp-
toms. Although our findings need to be replicated
in larger studies, these results suggest that impulsiv-
ity and augmentation share a common underlying
pathomechanism.
AUTHOR CONTRIBUTIONS
Beatrice Heim, MD, was involved in conception, design, organization,
and execution of the study, statistical analysis, and writing of the manu-
script. Atbin Djamshidian, MD, PhD, was involved in conception,
design, organization, and execution of the study, supervision, statistical
analysis, and review and critique of the manuscript. Anna Heidbreder,
MD, was involved in organization, execution, and writing of the manu-
script. Ambra Stefani, MD, was involved in execution, design, writing,
and review of the manuscript. Laura Zamarian, PhD, was involved in
execution, writing of the manuscript, and statistical analysis. Marie-
Theres Pertl, MA, was involved in patient recruitment, execution of
the study, and review of the manuscript. Elisabeth Brandauer, MD,
was involved in patient recruitment and review of the manuscript. Mar-
garete Delazer, PhD, was involved in conception, organization, and writ-
ing of the manuscript and the statistical analysis. Klaus Seppi, MD, was
involved in design, organization, review, and critique of the manuscript
and statistical analysis. Werner Poewe, MD, was involved in conception,
design, and critique of the manuscript. Birgit Hoegl, MD, was involved
in execution of the study and critique of the manuscript.
Table 3 Association of augmentation, LEU dose, disease duration, age, education, and sex with the development of ICDs
Model A
a
Model B
b
Model C
c
OR (95% CI) b(SE) pValue OR (95% CI) b(SE) pValue OR (95% CI) b(SE) pValue
Age 0.9 (0.5–1.5) 21.4 (0.3) 0.6 NA 0.9 (0.9–1.0) 20.03 (0.03) 0.3
Sex 1.7 (0.6–5.0) 0.6 (0.5) 0.3 NA 2.2 (0.6–7.7) 0.8 (0.6) 0.2
LEU 1.9 (0.9–3.9) 0.7 (0.4) 0.07 1.4 (0.7–2.8) 0.4 (0.3) 0.3 1.0 (0.9–1.0) 0.002 (0.003) 0.4
RLS severity
d
1.1 (0.3–3.3) 0.1 (0.6) 0.9 1.1 (0.3–3.5) 0.8 (0.6) 0.9 NA
IRLS 1.5 (0.8–2.5) 0.4 (0.3) 0.20 1.1 (1.0–1.1) 0.04 (0.03) 0.2 1.0 (0.9–1.1) 20.006 (0.4) 0.9
Disease duration 1.4 (0.8–2.4) 0.3 (0.3) 0.20 1.6 (0.9–2.7) 0.4 (0.3) 0.13 1.0 (0.9–1.1) 0.4 (0.03) 0.14
AUGM 5.6 (1.6–20.0) 1.7 (0.6) 0.007 7.3 (1.8–29.5) 2.0 (0.7) 0.005 6.2 (1.1–34.6) 1.8 (0.9) 0.04
Education 1.0 (0.6–1.7) 0.02 (0.3) 0.9 1.1 (0.6–1.9) 0.07 (0.3) 0.8 NA
MoCA 1.0 (0.6–1.7) 0.01 (0.3) 1.0 1.0 (0.6–1.7) 0.03 (0.3) 0.9 NA
Abbreviations: AUGM 5augmentation; CI 5confidence interval; ICD 5impulse control disorder; IRLS 5International RLS Study Group Rating Scale;
LEU 5levodopa equivalent units; MoCA 5Montreal Cognitive Assessment; NA 5not applicable; OR 5odds ratio; RLS 5restless legs syndrome.
a
Model A: Unadjusted univariate analysis.
b
Model B: Adjusted for age and sex.
c
Model C: Joint model with variables age, sex, LEU, IRLS, disease duration, and augmentation.
d
RLS severity is based on the IRLS with IRLS scores $15 reflecting moderate to severe disease vs IRLS scores ,15 reflecting mild disease.
24,25
RLS
severity is not included in model C because (1) it is based on the IRLS and (2) bis higher for the IRLS than for RLS severity in models A and B.
Neurology 87 July 5, 2016 39
ACKNOWLEDGMENT
The authors thank the patients who volunteered to participate in the study.
STUDY FUNDING
No targeted funding reported.
DISCLOSURE
B. Heim reports no disclosures relevant to the manuscript. A. Djamshi-
dian reports honoraria from UCB and Britannia. A. Heidbreder reports
travel support by Habel Medizintechnik and Air Liquide; the article sub-
mitted is not related to this relationship. A. Stefani reports no disclosures
relevant to the manuscript. L. Zamarian reports research support from
TWF-2010-1-993 and MUI-Start 2014-05-001. M. Pertl is supported
by a fellowship granted by the “Vizerektorat fuer Forschung”of the
Leopold-Franzens-University Innsbruck, 2014/3/PSY-15. E. Brandauer
reports personal fees from Inspire. M. Delazer reports no disclosures
relevant to the manuscript. K. Seppi reports grants from Oesterreichische
Nationalbank, FWF Austrian Science Fund, Michael J. Fox Foundation,
International Parkinson and Movement Disorder Society, Boehringer-
Ingelheim, UCB, Lundbeck, and AOP Orphan Pharmaceuticals AG out-
side the submitted work. W. Poewe receives personal fees from AbbVie,
Allergan, AstraZeneca, Boehringer-Ingelheim, Boston Scientific, GlaxoS-
mithKline, Ipsen, Lundbeck, Medtronic, MSD, Merck-Serono, Merz
Pharmaceuticals, Novartis, Orion Pharma, Teva, UCB, and Zambon
(consultancy and lecture fees in relation to clinical drug development
programs for PD) and royalties from Thieme, Wiley Blackwell, Oxford
University Press, and Cambridge University Press. B. Hoegl reports hon-
oraria from Lunbeck, Mundipharma, UCB, Abbvie, and Otsuka, and is
the current chair of the RLS Foundation medical advisory board (since
2014). Go to Neurology.org for full disclosures.
Received October 27, 2015. Accepted in final form February 22, 2016.
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40 Neurology 87 July 5, 2016
DOI 10.1212/WNL.0000000000002803
2016;87;36-40 Published Online before print June 3, 2016Neurology
Beatrice Heim, Atbin Djamshidian, Anna Heidbreder, et al.
Augmentation and impulsive behaviors in restless legs syndrome: Coexistence or association?
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November 2016
Beatrice Heim · Atbin Djamshidian · Anna Heidbreder · Ambra Stefani · Birgit Högl
... To the best of our knowledge, there has been only one cross-sectional study evaluating ICD disorders in PD patients with RLS, concluding long-term Dopaminergic treatment leading to the emergence of both RLS and ICD in PD patients. [20] This highlights the continuous neurodegenerative process is an underlying factor for the occurrence of both behavioral disorders seen in the later part of the PD disease. Studies have shown that RLS might precede the onset of PD or be noted during the disease as a non-motor manifestation. ...
... Another confounding factor for the association between RLS and ICD is the augmentation phenomenon. Heim et al. [20] reported 6 fold increased risk of exhibiting ICD symptoms in patients with RLS with augmentation. [22] But unlike our study, this was conducted among idiopathic RLS patients only. ...
Impulse-Control Disorders and Restless Leg Syndrome in Parkinson's Disease: Association or Coexistence
Article
Full-text available
  • Mar 2023
Background: Both Impulse-control disorders and related behaviours (ICD-RB) and restless leg syndrome (RLS) are relatively common in patients with Parkinson's disease, but little is known are they related or independent complications of dopaminergic therapy. The aim of this study was to determine the correlation between ICD-RBs and RLS and also, to determine the associated significant psycho-behavioural profile of RLS patients in presence of ICD-RBs. Methods: PD who visited neurology OPD were screened for the presence of addictive behaviors, alcohol and substance abuse, ICDs including Impulse control disorders not elsewhere classified with the help of a QUIP questionnaire. RLS was evaluated by diagnostic criteria set by the International RLS study group. To evaluate the association of RLS and ICDs, cohort was divided into groups of patients who had both ICD and RLS, ICD with no RLS, RLS with no ICD and no ICD or RLS. Results: Among 122 PD patients who visited OPD, 95 eligible were included in the study. Out of these 95 patients, 51 (53.6%) had at least one ICD-RB and 18 (18.9%) had RLS. ICD-RB in decreasing order of frequency were compulsive medication (47.4%), compulsive eating (29.4%), compulsive buying (17.6%), gambling (11.7%), hypersexuality (3.9%), and others (29.8%). Among 18 patients with RLS, 12 (66.7%) were associated with at least one ICD-RB. The compulsive behaviours significantly associated with PD-RLS group were gambling (27.8%), followed by compulsive eating (44.2%). While comparing disease characteristics, PD-ICD/RLS patients had statistically significant disease duration (p 0.007) and higher LEDD (p 0.004). Other demographic and socioeconomic features did not reveal any differences between the groups. Conclusion: 11% of PwPD can have co-occurrence of RLS and ICD-RBs. Circadian fluctuation in levels of dopamine release on the background of hyper-dopaminergic state produces waves of crest and trough, which may be possible for this behavioral profile. Long-term dopaminergic treatment or degenerative process itself may be the cause leading to emergence of both RLS and ICD-RBs in PD patients.
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... Formerly used DA medications were included in consideration of the earlier years of the study period. Most notably, carbidopa/levodopa is now limited to intermittent use or for mild/infrequent RLS due to long-term risks of augmentation, which is a paradoxical worsening of RLS symptoms and severity over time associated with long-term dopaminergic treatment [12,22,23]. ...
... Ropinirole and pramipexole maintained prescribing preference by far throughout the study period, although the annual treatment prevalence showed a slight decrease in the later years and an increase in gabapentin. This trend was expected given a recent shift in preference for gabapentinoids over DAs in light of the long-term risk of augmentation associated with chronic dopaminergic treatment [22]. Recent guidelines recommend starting initial treatment with non-dopaminergic therapies, i.e., gabapentinoids, in most cases [16]. ...
Treatment initiation and utilization patterns of pharmacotherapies for early-onset idiopathic restless legs syndrome
Article
  • May 2022
  • SLEEP MED
Objective/background Restless legs syndrome (RLS) is a complex condition associated with circadian rhythm that disrupts sleep and can cause multisystemic consequences. This study assesses pharmacotherapy treatment initiation, estimates annual treatment prevalence, and assesses treatment patterns for early-onset idiopathic RLS. Methods We used the MarketScan Commercial Claims Database from 2012 to 2019 to conduct a new user retrospective cohort study. Annual treatment prevalence was calculated from a cross-sectional sample. Newly diagnosed adults with early-onset (18–44 years) idiopathic RLS who initiated on and off-label gabapentinoids, dopamine agonists, or levodopa/carbidopa were included. Among monotherapy users who had one year of insurance enrollment, treatment patterns (single fill, continuous use of initiated therapy, switching, and add-on therapy) were examined and mean time on the initial treatment (as a measure of persistence) was calculated. Results In total, 6, 828 patients were initiated on monotherapy treatment for early-onset idiopathic RLS in which 4,638 met all inclusion criteria. In 2019, annual prevalence of monotherapy treatment of diagnosed patients for ropinirole was 171.3/1,000 patients; 85.0/1,000 patients for pramipexole; and 132.1/1,000 patients for gabapentin. Overall, 22.3% (n = 1,033) of patients maintained their initiated pharmacotherapy for the entire year. Rotigotine had the longest persistence (mean 185.4 [161.4 SD] days) but this user group was the smallest (n = 29). Gabapentin enacarbil, pregabalin, and rotigotine use was low (2.8% total). Conclusion Ropinirole, pramipexole, and gabapentin were initiated most often for early-onset idiopathic RLS. FDA-approved agents for RLS, including gabapentin enacarbil and rotigotine, were used less frequently. In general, persistence was low for all RLS study drugs examined.
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... Impulse control disorders and related disorders are seen as comorbidities in neurodegenerative diseases, such as progressive supranuclear palsy [4,5], multiple system atrophy [6,7] and frontotemporal dementia [8], and are most common in patients with idiopathic Parkinson's disease (PD) [9]. Moreover, addictive behaviours can also occur in patients without clear evidence of neuronal/ nigrostriatal degeneration as a direct consequence of dopamine agonist therapy in patients with fibromyalgia [10], patients with restless legs syndrome (particularly in those who have in addition augmentation) [11] and in patients with endocrine diseases (such as pituitary adenomas) [12]. Furthermore, ICDs and related disorders have been described in patients with frontal lobe dysfunction such as Gilles de la Tourette syndrome [13], and in patients with attention-deficit hyperactivity syndrome [14]. ...
Impulse Control Disorders in Parkinson's Disease: An Overview of Risk Factors, Pathogenesis and Pharmacological Management
Article
Full-text available
  • Apr 2024
  • CNS DRUGS
Impulse control disorders in Parkinson’s disease are relatively common drug-induced addictive behaviours that are usually triggered by the dopamine agonists pramipexole, ropinirole and rotigotine. This narrative review aimed to provide a comprehensive overview of the current knowledge of impulse control disorders in Parkinson’s disease. We summarised the prevalence, clinical features, risk factors and potential underlying mechanisms of impulse control disorders in Parkinson’s disease. Moreover, recent advances in behavioural and imaging characteristics and management strategies are discussed. Early detection as well as a tailored multidisciplinary approach, which typically includes careful adjustment of the dopaminergic therapy and the treatment of associated neuropsychiatric symptoms, are necessary. In some cases, a continuous delivery of levodopa via a pump or the dopamine D1 receptor agonist, apomorphine, can be considered. In selected patients without cognitive or speech impairment, deep brain stimulation of the subthalamic nucleus can also improve addictions. Finding the right balance of tapering dopaminergic dose (usually dopamine agonists) without worsening motor symptoms is essential for a beneficial long-term outcome.
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... While impulse control disorders, including compulsive gambling, buying, sexual behavior, and eating disorders, are serious and frequent psychiatric complications in patients with Parkinson's disease [118], their frequency is relatively low in patients with RLS, whether drug naïve or treated with the recommended low dose of dopaminergic agonist [119,120]. Indeed, a high dose of short-acting dopaminergic agonists can lead to impulse control disorders [121], especially in patients at risk and with augmentation syndrome [122]. ...
Restless legs syndrome: From clinic to personalized medicine
Article
  • Sep 2023
  • REV NEUROL-FRANCE
Restless legs syndrome (RLS) is a common neurological sensorimotor disorder that impairs sleep, mood and quality of life. RLS is defined by an urge to move the legs at rest that increases in the evening and at night, and is frequently associated with metabolic and cardiovascular diseases. Symptoms frequency, age at RLS onset, severity, familial history and consequences of RLS vary widely between patients. A genetic susceptibility, iron deficiency, dopamine deregulation, and possible hypo-adenosinergic state may play a role in the pathophysiology of RLS. Polysomnographic recordings found often periodic leg movements during sleep and wakefulness in patients with RLS. RLS can be classified as primary or comorbid with major diseases: iron deficiency, renal, neurological, rheumatological and lung diseases. First-line treatments are low-dose dopamine agonists, and alpha-2-delta ligands depending on the clinical context, and second/third line opiates for pharmacoresistant forms of RLS. Augmentation syndrome is a serious complication of dopamine agonists and should be prevented by using the recommended low dose. Despite an increase in knowledge, RLS is still underdiagnosed, poorly recognized, resulting in substantial individual health burden and socioeconomic coast, and education is urgently needed to increase awareness of this disabling disorder.
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... However, recently, considering the risk of long-term dopamine augmentation, there has been an increased interest in gabapentinoids, which are known to be effective by improving somatosensory symptoms on the RLS. Gabapentin and pregabalin has become one of the first-line treatment options [28,29] Considering the efficacy of vortioxetine on both dopamine and gaba , its may have had a positive effect on RLS symptoms. ...
Potential Effect of Vortioxetine on Restless Leg Syndrome
Article
  • Aug 2023
Restless legs syndrome (RLS) is a chronic progressive movement disorder characterized by abnormal sensations, especially at rest and at night, as the need and urge to move the lower extremity. It has been reported that RLS severity and frequency increase in patients with anxiety and depression. It has been reported that serotonin-noradrenaline reuptake inhibitors such as venlafaxine and selective serotonin reuptake inhibitors such as citalopram, fluoxetine, paroxetine, and sertraline can cause RLS symptoms. No adverse effects of vortioxetine on RLS have been reported in the literature. In this case series, we report the effect of vortioxetine in patients with RLS with symptoms of depression and anxiety. In this case series, the effect of adding vortioxetine to treatment on RLS symptoms is reported in 7 patients (5 female). After the use of vortioxetine, 5 of 7 patients' symptoms regressed without the need to start a separate drug for primary movement disorder. In conclusion, we believe that studies should be conducted to investigate the efficacy of vortioxetine in the treatment of RLS. Therefore, randomized controlled studies are needed to determine the effect and safety of vortioxetine on RLS symptoms.
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... 114 However, medical marijuana as a single treatment option induced serious adverse psychopathologic effects in only about 1% of patients, whereas the rate was around 20% in patients undergoing dopaminergic treatments. 114,117 Cannabis is considered as an alternative to prescription drugs in chronic and neuropathic pain, 118e120 and, whereas the potential benefit of cannabis use in RLS is presently unknown, there are some indications that cannabis is effective and well-tolerated in patients with refractory RLS. 121 Large placebo-controlled and double-blind clinical studies on the efficacy of medical cannabis in RLS patients are urgently needed to test their short/long-term effectiveness and safety. ...
Restless Legs Syndrome
Chapter
  • Jan 2023
Restless Legs Syndrome (RLS) is a sensorimotor disorder that severely affects sleep. It has a high prevalence in the population (between 2% and 10%, depending on severity) and is usually a lifelong condition. The origins of idiopathic RLS remain unclear, but genome-wide association studies (GWAS) have identified several genetic factors involved. In addition, gender, iron homeostasis, and age appear to play an important role. RLS is also a comorbidity to various other disorders. The diagnostic criteria of RLS rely on a patient-reported subjective questionnaire, but RLS is commonly accompanied by periodic leg movements during sleep (PLMS), which can be used as a quantifiable marker of RLS severity. First-line treatment of RLS with dopaminergics is initially highly efficient, but often leads to a worsening of the symptoms (augmentation) over time. Both motor areas in the brain and sensorimotor spinal cord circuits appear to be involved in the pathophysiology of RLS, and animal models point to altered dopamine receptor pathophysiologies and hyperglutamatergic states as a result of brain iron dysfunction. Early identification of the symptoms and careful ongoing titration of pharmacological treatment options are needed to manage the symptoms and their responsiveness to individual drug paradigms.
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... A more recent smaller study reported a 39.7% frequency of ICD symptoms, and a 20.7% frequency of definitive ICDs in a cohort of people with RLS with and without augmentation. However, patients with augmentation had an almost 6-fold increased risk of exhibiting ICD symptoms (Heim et al., 2016). A further study by the same group suggested that augmentation is associated with poorer decision making, even in the absence of ICD symptoms (Heim et al., 2021). ...
Restless Legs Syndrome: Over 50 Years of European Contribution.
Article
Full-text available
  • Apr 2022
  • J SLEEP RES
Restless legs syndrome (RLS) is a sensorimotor neurological disorder characterized by an urge to move the limbs with a circadian pattern (occurring in the evening/at night), more prominent at rest, and relieved with movements. RLS is one of the most prevalent sleep disorders, occurring in 5-10% of the European population. Thomas Willis first described RLS clinical cases already in the 17th century, and Karl-Axel Ekbom described the disease as a modern clinical entity in the 20th century. Despite variable severity, RLS can markedly affect sleep (partly through the presence of periodic legs movements) and quality of life, with a relevant socio-economic impact. Thus, its recognition and treatment are essential. However, screening methods present limitations and should be improved. Moreover, available RLS treatment options albeit providing sustained relief to many patients are limited in number. Additionally, տհե development of augmentation with dopamine agonists represents a major treatment problem. A better understanding of RLS pathomechanisms can bring to light novel treatment possibilities. With emerging new avenues of research in pharmacology, imaging, genetics, and animal models of RLS, this is an interesting and constantly growing field of research. This review will update the reader on the current state of RLS clinical practice and research, with a special focus on the contribution of European researchers.
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... 114 However, medical marijuana as a single treatment option induced serious adverse psychopathologic effects in only about 1% of patients, whereas the rate was around 20% in patients undergoing dopaminergic treatments. 114,117 Cannabis is considered as an alternative to prescription drugs in chronic and neuropathic pain, 118e120 and, whereas the potential benefit of cannabis use in RLS is presently unknown, there are some indications that cannabis is effective and well-tolerated in patients with refractory RLS. 121 Large placebo-controlled and double-blind clinical studies on the efficacy of medical cannabis in RLS patients are urgently needed to test their short/long-term effectiveness and safety. ...
D3 Receptors and Restless Legs Syndrome
Chapter
  • Apr 2022
Restless Legs Syndrome (RLS) is a sensorimotor disorder that severely affects sleep. It is characterized by an urge to move the legs that is often accompanied by periodic limb movements during sleep (PLMS). RLS has a high prevalence in the population and is usually a life-long condition. While its origins remain unclear, RLS is initially highly responsive to treatment with dopaminergics that target the D3 receptor. However, over time patients often develop a gradual tolerance that can lead to the emergence of adverse effects and the augmentation of the symptoms. While the basal ganglia and the striatum control leg movements, the lumbar spinal cord is the gateway for the sensory processing of the symptoms and critical for the associated leg movements. D3 receptors are highly expressed in nucleus accumbens (NAc) of the striatum and the sensory-processing areas of the spinal dorsal horn. In contrast, D1 receptors are strongly expressed throughout the entire striatum and in the ventral horn of the spinal cord. Long-term treatment with D3 receptor full agonists is associated with an upregulation of the D1 receptor subtype, and D3 and D1 receptors can form functional heteromers, in which the D3R controls the D1R function. It is conceivable that the switch from beneficial treatment to augmentation observed in RLS patients after prolonged D3R agonist exposure may be the result of unmasked D1-like receptor actions.
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Frequency of impulse control behaviours associated with dopaminergic therapy in restless legs syndrome
Article
Full-text available
  • Sep 2011
  • BMC NEUROL
Low doses of dopamine agonists (DA) and levodopa are effective in the treatment of restless legs syndrome (RLS). A range of impulse control and compulsive behaviours (ICBs) have been reported following the use of DAs and levodopa in patients with Parkinson's disease. With this study we sought to assess the cross-sectional prevalence of impulse control behaviours (ICBs) in restless legs syndrome (RLS) and to determine factors associated with ICBs in a population cohort in Germany. Several questionnaires based on validated and previously used instruments for assessment of ICBs were mailed out to patients being treated for RLS. Final diagnoses of ICBs were based on stringent diagnostic criteria after psychiatric interviews were performed. 10/140 RLS patients of a clinical cohort (7.1%) were finally diagnosed with ICBs, 8 of 10 on dopamine agonist (DA) therapy, 2 of 10 on levodopa. 8 of the 10 affected patients showed more than one type of abnormal behaviour. Among those who responded to the questionnaires 6/140 [4.3%] revealed binge eating, 5/140 [3.6%] compulsive shopping, 3/140 [2.1%] pathological gambling, 3/140 [2.1%] punding, and 2/140 [1.4%] hypersexuality in psychiatric assessments. Among those who did not respond to questionnaires, 32 were randomly selected and interviewed: only 1 patient showed positive criteria of ICBs with compulsive shopping and binge eating. ICBs were associated with higher DA dose (p = 0.001), younger RLS onset (p = 0.04), history of experimental drug use (p = 0.002), female gender (p = 0.04) and a family history of gambling disorders (p = 0.02), which accounted for 52% of the risk variance. RLS patients treated with dopaminergic agents and dopamine agonists in particular, should be forewarned of potential side effects. A careful history of risk factors should be taken.
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Psychological distress of patients suffering from restless legs syndrome: A cross-sectional study
Article
Full-text available
  • Sep 2011
  • HEALTH QUAL LIFE OUT
Restless legs syndrome (RLS) is a chronic disorder with substantial impact on quality of life similar to that seen in diabetes mellitus or osteoarthritis. Little is known about the psychological characteristics of RLS patients although psychological factors may contribute to unfavourable treatment outcome. In an observational cross-sectional design, we evaluated the psychological features of 166 consecutive RLS patients from three outpatient clinics, by means of the Symptom Checklist 90-R (SCL-90-R) questionnaire. Additionally, the Beck Depression Inventory-II (BDI-II) and the International RLS Severity Scale (IRLS) were measured. Both treated and untreated patients were included, all patients sought treatment. Untreated patients (n = 69) had elevated but normal scores on the SCL-90-R Global Severity Index (GSI; p = 0.002) and on the sub-scales somatisation (p < 0.001), compulsivity (p = 0.003), depression (p = 0.02), and anxiety (p = 0.004) compared with a German representative sample. In the treated group, particularly in those patients who were dissatisfied with their actual treatment (n = 62), psychological distress was higher than in the untreated group with elevated scores for the GSI (p = 0.03) and the sub-scales compulsivity (p = 0.006), depression (p = 0.012), anxiety (p = 0.031), hostility (p = 0.013), phobic anxiety (p = 0.024), and paranoid ideation (p = 0.012). Augmentation, the most serious side effect of dopaminergic, i.e. first-line treatment of RLS, and loss of efficacy were accompanied with the highest psychological distress, as seen particularly in the normative values of the sub-scales compulsivity and anxiety. Generally, higher RLS severity was correlated with higher psychological impairment (p < 0.001). Severely affected RLS patients show psychological impairment in multiple psychological domains which has to be taken into account in the treatment regimen.
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Pramipexole in the management of restless legs syndrome: An extended study
Article
  • Apr 2001
Study Objectives: To determine whether pramipexole used over an extended time for restless legs syndrome (RLS) remains effective; whether the dose of the drug needs to be increased; whether augmentation develops; and whether side effects, especially sleepiness, are prominent. Design: Retrospective review of the records of consecutive patients treated with pramipexole for RLS. Setting: Sleep disorders center in an academic hospital. Patients: 60 consecutive patients treated with pramipexole for RLS. Interventions: N/A Measurements and Results: Pramipexole was completely effective in controlling RLS in 67%, partially effective in 27%, and ineffective in 7% of patients. Eleven patients (18%) discontinued pramipexole after less than 4 months; the remainder were followed for a mean of 27.2 months, during which only 4 others stopped the drug. The median daily dose increased from 0.38 mg after stabilization to 0.63 mg at the end of the study. Forty percent experienced mild side effects, most commonly insomnia, nausea or dyspepsia, and dizziness. Only 5% experienced sleepiness, and none experienced sleep attacks while driving. Augmentation developed in 33%, most in the first year and all by 30 months. Augmentation was not predictable by prior augmentation with other dopaminergic agents. Only 1 patient discontinued pramipexole because of augmentation. Conclusions: Pramipexole was effective for RLS with continued response with time. Modest escalations in dose occurred, partly due to additional doses prescribed for augmentation. Side effects were common, but generally mild and tolerated. Sleepiness while driving was not a problem. Augmentation occurred in 33% of patients but was treatable with increased doses earlier in the day.
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An algorithm for the management of restless legs syndrome
Article
  • Jul 2004
Restless legs syndrome (RLS) is a common disorder with a prevalence of 5% to 15%. Primary care physicians must become familiar with management of this disorder. This algorithm for the management of RLS was written by members of the Medical Advisory Board of the Restless Legs Syndrome Foundation and is based on scientific evidence and expert opinion. Restless legs syndrome is divided into intermittent, daily, and refractory types. Nonpharmacological approaches, including mental alerting activities, avoiding substances or medications that may exacerbate RLS, and addressing the possibility of iron deficiency, are discussed. The role of carbidopa/levodopa, dopamine agonists, opioids, benzodiazepines, and anticonvulsants for the different types of the disorder is delineated.
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Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: Updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria - history, rationale, description, and significance
Article
  • Aug 2014
  • SLEEP MED
Background In 2003, following a workshop at the National Institutes of Health, the International Restless Legs Syndrome Study Group (IRLSSG) developed updated diagnostic criteria for restless legs syndrome/Willis–Ekbom disease (RLS/WED). These criteria were integral to major advances in research, notably in epidemiology, biology, and treatment of RLS/WED. However, extensive review of accumulating literature based on the 2003 NIH/IRLSSG criteria led to efforts to improve the diagnostic criteria further. Methods The Clinical Standards Workshop, sponsored by the WED Foundation and IRLSSG in 2008, started a four-year process for updating the diagnostic criteria. That process included a rigorous review of research advances and input from clinical experts across multiple disciplines. After broad consensus was attained, the criteria were formally approved by the IRLSSG executive committee and membership. Results Major changes are: (i) addition of a fifth essential criterion, differential diagnosis, to improve specificity by requiring that RLS/WED symptoms not be confused with similar symptoms from other conditions; (ii) addition of a specifier to delineate clinically significant RLS/WED; (iii) addition of course specifiers to classify RLS/WED as chronic–persistent or intermittent; and (iv) merging of the pediatric with the adult diagnostic criteria. Also discussed are supportive features and clinical aspects that are important in the diagnostic evaluation. Conclusions The IRLSSG consensus criteria for RLS/WED represent an international, interdisciplinary, and collaborative effort intended to improve clinical practice and promote further research.
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Transdermal rotigotine causes impulse control disorders in patients with restless legs syndrome
Article
  • Feb 2012
Dopaminergic drugs are the mainstay of treatment for restless legs syndrome (RLS). We analyzed the frequency and clinical characteristics of impulse control disorders (ICD) in patients with RLS on transdermal rotigotine treatment. Retrospective case series at a university movement disorder clinic (n = 28, 17 women). Symptoms of ICD were assessed via detailed history taking and scoring with the Zurich Screening Questionnaire for ICD (ZICD) prior to and after initiation of treatment. None of the patients had a history of ICD prior to treatment. Baseline mean scores for patients who did (8.0 ± 2.5) and did not (6.2 ± 2.7) develop ICD under treatment did not differ. Six male patients (21%) developed various symptoms of ICD (mean ZICD scores 20.7 ± 10.2) on rotigotine treatment (mean dose: 3.8 mg/d), including binge eating, hypersexuality, compulsive shopping, pathological gambling, and punding, equaling a prevalence rate of 21%. Also in the non-ICD group, ZICD scores increased (7.5 ± 2.8). This is the first report of ICD in patients treated with transdermal rotigotine for RLS. In contrast to literature, even low doses of rotigotine (mean 3.8 mg/d) can cause ICD. Therefore every prescribing physician should be aware that ICD may emerge in both RLS and PD patients on any dopaminergic treatment, and should actively ask for such symptoms. The ZICD questionnaire not only replicated the findings of detailed history taking but also showed an increased tendency towards impulsive behaviour in subjects that did not develop ICD.
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