Anda di halaman 1dari 12

Review

Comorbidities, treatment, and pathophysiology in restless


legs syndrome
Claudia Trenkwalder, Richard Allen, Birgit Högl, Stefan Clemens, Stephanie Patton, Barbara Schormair, Juliane Winkelmann

Restless legs syndrome, also known as Willis-Ekbom disease, is a common neurological condition whose manifestation Lancet Neurol 2018
is affected by complex environmental and genetic interactions. Restless legs syndrome can occur on its own, mostly Published Online
at a young age, or with comorbidities such as cardiovascular disease, diabetes, and arterial hypertension, making it a September 20, 2018
http://dx.doi.org/10.1016/
difficult condition to properly diagnose. However, the concept of restless legs syndrome as being two entities, primary
S1474-4422(18)30311-9
or secondary to another condition, has been challenged with genetic data providing further insight into the
Department of Neurosurgery,
pathophysiology of the condition. Although dopaminergic treatment was formerly the first-line therapy, prolonged University Medical Center,
use can result in a serious worsening of symptoms known as augmentation. Clinical studies on pregabalin, gabapentin Goettingen, Germany
enacarbil, oxycodone–naloxone, and iron preparations have provided new treatment options, but most patients still (Prof C Trenkwalder MD);
Paracelsus-Elena Hospital,
report inadequate long-term management of symptoms. Studies of the hypoxic pathway activation and iron deficiency
Kassel, Germany
have provided valuable information about the pathophysiology of restless legs syndrome that should now be translated (Prof C Trenkwalder); Sleep
into new, more effective treatments for restless legs syndrome. Disorders Center, Johns
Hopkins Bayview Medical
Introduction symptoms with longer-term dopaminergic treatment.12 Center, Baltimore, MD, USA
(Prof R Allen PhD); Department
The recognition of restless legs syndrome as a disease Although iron preparations have not received regulatory of Neurology, Johns Hopkins
with substantial effects on quality of life is still low among approval, guidelines for this type of treatment have been University, Baltimore, MD, USA
neurologists. Consequently, when patients present with published.13 Considering novel risk loci for restless legs (Prof R Allen); Department of
Neurology, Medical University
either sensory symptoms in their legs (with or without syndrome by use of genome-wide association studies of Innsbruck, Innsbruck,
pain), an urge to move at rest mostly in the evening, and (GWAS) could also lead to new therapeutic approaches.14 Austria (B Högl MD);
sleep disturbances,1 they are often undiagnosed and left These achievements are important in harmonising Department of Physiology,
untreated for years.2,3 restless legs syndrome evidence-based management Brody School of Medicine, East
Carolina University, Greenville,
To address this problem, new diagnostic criteria among physicians and in avoiding augmentation, but NC, USA (S Clemens PhD);
(appendix) have been established by a consensus of more work is needed to understand the pathophysiology Department of Neurosurgery,
restless legs syndrome experts from the International of the disease and provide the best care for patients. Penn State Hershey Medical
Restless Legs Syndrome Study Group (IRLSSG),4 and a This Review aims to specifically address the improved Center, Hershey, PA, USA
(S Patton PhD); Institute of
slightly modified version has been published by the diagnosis of restless legs syndrome, including in patients Neurogenomics, Helmholtz
American Academy of Sleep Medicine5 in their with comorbidities since these patients are the most Zentrum München, Munich,
International Classification of Sleep Disorders (ICSD-3). difficult to treat. We also review evidence-based treatments Germany (B Schormair PhD,
Although most research refers to the IRLSSG diagnostic that seek to avoid augmentation, which is particularly Prof J Winkelmann MD);
Institute of Human Genetics,
criteria,4 there are independent and somewhat different warranted given the dose-dependent asso­ciation between Technical University, Munich,
diagnostic criteria proposed by the American Psychiatric dopaminergic drugs and augmentation, derived Germany (Prof J Winkelmann);
Association published in their Diagnostic and Statistical from interactions of D1 and D3 receptors and their and Munich Cluster for Systems
Manual of Mental Disorders (DSM-5). The DSM-5 overstimulation that contribute to the pathophysiology of Neurology (SyNergy), Munich,
Germany (Prof J Winkelmann)
criteria do not differentiate between intermittent and augmentation. We examine new insights from genetics,
Correspondence to:
chronic persistent restless legs syndrome, which is and iron and hypoxic pathways to elucidate the strong Prof Claudia Trenkwalder,
essential for clinical practice and therapeutic long-term biological component of this disease. Paracelsus-Elena Hospital, Center
management.6 of Parkinsonism and Movement
The strong familial component, observed many years Comorbidities Disorders, Kassel 34128,
Germany
ago in clinical practice, led to decades of genetic research In the past 5 years, an increasing number of studies claudia.trenkwalder@med.uni-
in restless legs syndrome and showed the genetic describe possible conditions whereby patients with goettingen.de
heterogeneity of the condition, now considered a common medical or neurological diseases could also have restless
complex genetic disease.7 However, comorbidities are legs syndrome. In the past, the term secondary restless See Online for appendix
considered as environmental factors8 that can complicate legs syndrome was used in these instances (appendix).
diagnosis and treatment, and iron deficiency anaemia, The overall quality of these studies, however, limits the
renal insufficiency (when leading to dialysis),9 and proven association with restless legs syndrome to only a
pregnancy10 are all conditions in which restless legs few diseases, such as iron deficiency anaemia and
syndrome can severely affect both the health condition uraemia. However, by looking into the phenomenology of
and quality of life. these cases of secondary restless legs syndrome, it is
Therapeutics have been assessed by use of evidence- apparent that there is no difference in the clinical
based medicine techniques,11 and algorithms have been symptomatology or therapeutic response compared with
created for initiating restless legs syndrome therapy and primary forms of the disorder, with the one exception that
managing augmentation, a serious worsening of oral iron treatment works only for patients with restless

www.thelancet.com/neurology Published online September 20, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30311-9 1


Review

legs syndrome with low peripheral iron (serum ferritin managed appropriately; their treatment differs from
<50 µg/L) because increased iron concentrations block patients without iron deficiency since correcting iron
iron uptake into the blood.15 A model of gene–environment deficiency with iron supplementation usually improves or
interaction has, therefore, been proposed to explain the eliminates restless legs syndrome symptoms in most
increasing number of such cases of secondary restless people.18
legs syndrome.8 Although the prevalence of restless legs Patients with Parkinson’s disease who receive
syndrome in both peripheral iron deficiency and in increasing dopaminergic doses over their disease course
patients with iron deficiency anaemia in clinical trials has could show an increased prevalence of restless legs
been reported to be higher than in the general population,16 syndrome (14 [15%] of 92 patients with Parkinson’s
this higher prevalence has not been confirmed in disease19), compared with patients with newly diagnosed
population-based, cross-sectional studies.8 Even in a Parkinson’s disease who have similar frequencies of
registry study17 of 13 448 healthy blood donors in Denmark, restless legs syndrome to healthy controls (11 [12%] of
the prevalence of restless legs syndrome was not related to 92, odds ratio 2·86, 95% CI 2·10–3·90).20 Population-
plasma ferritin concentrations. Nevertheless, patients based studies21,22 from the USA reported restless legs
with restless legs syndrome with iron deficiency need to syndrome to be increased in individuals who are later
be identified in the clinical setting so that they can be diagnosed with Parkinson’s disease compared with
those who are not diagnosed with Parkinson’s disease,
indicating that the condition is p ossibly mediated, or
Panel: Case study unmasked, by sleep disturbance in this population.
A 62-year-old woman was referred by a neurologist to the restless legs syndrome Restless legs syndrome, however, is not a risk factor for
outpatient clinic in Kassel, Germany, as a result of severe restless legs syndrome with Parkinson’s disease, but in a case-control study23 of 8166
treatment failure. The patient described severe burning and painful symptoms in both legs people with Parkinson’s disease and 46  755 people
starting every day in the late afternoon when relaxing and worsening when she lay down, without it in the UK, increased insomnia 2 years before
resulting in severe sleep disturbance, and walking and eating during the night, with only a a diagnosis of Parkinson’s disease was reported.
few hours of disrupted sleep and daytime sleepiness. She had a body-mass index of 29, was Therefore, the restless legs syndrome phenotype might
diagnosed with insufficiently controlled type 2 diabetes, bilateral sensory polyneuropathy be more likely to manifest in patients with prodromal
with numbness in the toes, a swollen knee due to gonarthrosis, arterial hypertension with Parkinson’s disease with sleep disorders than in healthy
night-time peaks of up to 200/110 mm Hg, and hypercholesterolaemia. Because of controls of equivalent age.
depressive symptoms and sleep disruption, she was given an antidepressant, mirtazapine The frequency of restless legs syndrome increases
(15 mg at night). Restless legs syndrome was treated with pramipexole (0·35 mg three substantially if at least three medical comorbidities, such
times a day) and pregabalin (25 mg twice a day). Additionally, without notifying her as cardiovascular disease, diabetes, arterial hypertension,
neurologist, she continued to take up to 3 pills of levodopa (100 mg) plus benserazide or depression, are present,24 which can make diagnosis
(25 mg), which she had previously been prescribed by her general practitioner. She was difficult (panel). Restless legs syndrome is associated
severely bothered by her restlessness and had called in sick for several months because of with cardiovascular disease, and one study25 in
restless legs syndrome and sleep deprivation, and had asked for early retirement. 2823 community-dwelling men (mean age 76·3 years)
Polysomnography showed an additional obstructive sleep apnoea syndrome with arterial enrolled in six clinical centres in the USA showed that
nocturnal hypertension and periodic limb movements (PLMs) in sleep index of 65/h, with the syndrome was specifically associated with the
42/h PLM during wakefulness and a sleep efficacy of 45%. The patient was taking additional incidence of myocardial infarction. In a large prospective
medication for arterial hypertension, diabetes, and hypercholesterolaemia: enalapril study26 in 57 417 women (mean age 67 years) in the USA,
(15 mg), metoprolol (47·5 mg), metformin (500 mg three times a day), simvastatin restless legs syndrome was shown to significantly
(20 mg), and ibuprofen (400 mg) on demand. This patient was diagnosed with increase the risk of cardiovascular disease mortality.26
augmentation induced by pramipexole and levodopa with possible worsening of restless These findings might be explained by several shared
legs syndrome with mirtazapine, and obstructive sleep apnoea syndrome. This patient had mechanisms of both restless legs syndrome and
a typical diagnosis of restless legs syndrome with associated diseases such as arterial cardiovascular disease, such as increased sympathetic
hypertension, diabetes, and polyneuropathy, which could intensify the symptoms of activity, oxidative stress, metabolic factors, and
restless legs syndrome. Because of the polyneuropathy, restless legs syndrome was not inflammation,27 but the data showing that cardiovascular
diagnosed until several years after symptom onset. Sleep disturbance had been attributed risk factors and diseases predict the subsequent
to depression and the painful sensations in the patient’s legs to diabetic neuropathy. The development of restless legs syndrome are controversial.28
diagnosis of restless legs syndrome was managed by reducing the dose of pramipexole In large population-based studies, cardiovascular
over 1 week to 0·18 mg, discontinuation of levodopa and pregabalin, and additional diseases as risk factors for restless legs syndrome, which
oxycodone–naloxone (10 mg twice a day); because of the low dose and possible weight have been reported in patients with restless legs
gain with dose increase, mirtazapine was also stopped. The patient was started on syndrome who developed cardiovascular disease and
continuous positive airway pressure, and pramipexole was finally switched to rotigotine patients with cardiovascular disease who developed
(2 mg), and oxycodone–naloxone uptitrated to 15 mg at night, which resulted in a restless legs syndrome, could only partly be confirmed
sufficient relief of the symptoms of restless legs syndrome. Diabetes control, blood pressure (ie, for subpopulations of women). Methodological
control, weight reduction, and physical activity were strongly recommended. differences both for restless legs syndrome diagnostic
assessments and diagnosis of cardiovascular disease

2 www.thelancet.com/neurology Published online September 20, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30311-9


Review

could explain these controversial findings. Regardless, Dorsal horn Ascending sensory pathways
the association between the two could further support
the need for monitoring of patients with restless legs
Dorsal root
syndrome for cardiovascular disease and vice versa. ganglion Afferent (sensory)
The few studies that have examined the contribution of neurons
known genetic risk variants for restless legs syndrome in
people with single comorbidities such as renal disease,29,30
Efferent (motor)
or multiple comorbidities, have found either no Grey matter neurons
association with restless legs syndrome or association of
single genes with small effect size.29,31 Finally, some
High D3 receptor
comorbidities (eg, depression or arterial nocturnal Ventral root
Low D1 receptor
hypertension) might arise because of ongoing restless
legs syndrome,31 or the expression of restless legs Descending dopamine
projection fibres High D1 receptor
syndrome might be influenced by the presence or Ventral horn Low D3 receptor
treatment of a comorbidity (eg, dopaminergic treatment
Figure 1: Proposed modulation of dopamine D1 receptors and D3 receptors in the spinal cord
in Parkinson’s disease). Both possibilities are likely but Schematic cross-section of spinal cord highlighting the interplay between ascending and descending signals and their
the data definitively arguing for one over the other are hypothesised modulation by dopamine D1 (green) and D3 receptors (red). Afferent (sensory) neurons (red line) enter
few, partly because restless legs syndrome is as common the spinal cord through the dorsal horn and their signals are integrated, modulated by D3 receptors, and forwarded via
ascending sensory pathways to supraspinal centres in the brain (black line). The spinal cord also receives information
as some of its comorbidities (eg, depression or arterial
from descending premotor pathways that are modulated by D1 receptors and in conjunction with motor neurons can
nocturnal hypertension). In clinical practice, however, generate leg movements (blue line). Descending dopamine fibres from the A11 region project throughout the spinal
patients presenting with a number of comorbidities are grey matter, providing each receptor area with its required substrate (red dashed lines). The scale on the right indicates
very likely to have restless legs syndrome if they report how D3 and D1 receptors in the spinal cord could be acting in a region-specific manner to modulate sensory and motor
symptoms of restless legs syndrome, respectively. Regions with an abundance of D3 receptors (red) indicate potential
one or more key symptoms,23 even if they do not have a treatment targets for sensory symptoms that cause an urge to move. Regions with an abundance of D1 receptors
high genetic risk for the syndrome.30 (green) indicate potential treatment targets for motor symptoms that cause periodic limb movements.

Periodic limb movements


Periodic limb movements (PLMs) are present in most restless legs syndrome has been further confirmed in
patients with restless legs syndrome, but are also highly analyses of the drugs in randomised controlled trials.11,36
prevalent in those without, and are associated with some of However, improved polysomnography-measured sleep
the same risk polymorphisms as restless legs syndrome, efficacy has only been found with ropinirole and not with
suggesting a shared genetic risk.32 The ICSD-3 diagnosis5 any of the other dopamine agonists.36 Levodopa and
of PLM disorder requires that PLMs are not due to other dopamine receptor agonists that target the inhibitory
sleep disorders. Since 2006, several PLM scoring criteria D3 receptor subtype, such as pramipexole and ropinirole,
have been established and were revised in 2016 by a joint produce a pulsatile stimulation of the dopaminergic
task force commissioned by the International and system. This stimulation leads to a sudden and efficient
European Restless Legs Syndrome Study Groups with only relief of symptoms for 2–12 h that targets several relevant
slight changes of the cutoff value for PLMs associated with systems, including sensory pathways in the spinal cord
restless legs syndrome (13/h vs 15/h).33,34 Unfortunately, that mediate some clinical manifestations of restless
sleep physicians or even neurologists interpreting legs syndrome (figure 1). Continuous dopaminergic
polysomnographic results can confuse PLMs with a stimulation (eg, with rotigotine transdermal application)
diagnosis of restless legs syndrome, and mistakenly treat also activates D3 receptors and improves daytime and
patients who are sleep-disturbed and have these PLM cutoff night-time symptoms, but both approaches can induce
values with dopaminergic drugs (expert opinion of the augmentation over time (appendix).
authors BH and CT). Alternative therapeutics include α2δ ligands,37 opioids,38
and iron preparations (although no iron preparations
Treatment have received regulatory approval).13 An overview of
Pharmacological therapies therapies, including efficacy and dosage, is shown in the
In the first trials of restless legs syndrome, dopaminergic table. In the opioid class of drugs, oxycodone–naloxone is
drugs were administered once daily at night, and daytime efficacious when used at low doses twice a day for
symptoms were largely ignored.35 Since the 1990s, improving both daytime and night-time symptoms in
dopaminergic therapies have been considered the first- patients with severe or refractory restless legs syndrome.
line treatment for adults with restless legs syndrome, However, the commonly occurring adverse effects of
both for sleep disturbance and for daytime symptoms. In fatigue, constipation, nausea, induction or worsening of
the past 5 years, treatment efficacy of dopamine agonists sleep-disordered breathing, and the potential for misuse
(such as pramipexole, ropinirole, and rotigotine) should be taken into account.11,38 Oxycodone–naloxone is
approved by the US Food and Drug Administration and licensed for severe restless legs syndrome as second-line
the European Medicines Agency for the treatment of therapy in Europe.39 In the USA, in addition to prolonged

www.thelancet.com/neurology Published online September 20, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30311-9 3


Review

Recommended initial daily dose Highest recommended daily dose Efficacy outcomes Major side-effects Duration of longest
(mean effective dose in clinical double-blind randomised
trials) controlled study (n)
Levodopa plus a 100 mg of levodopa and 25 mg of Maximum recommended dose not IRLSSG rating scale, PLMI Augmentation, nausea 30 weeks11 (n=361)
dopamine decarboxylase dopamine decarboxylase defined (200–300 mg)11
inhibitor  inhibitor*
Dopamine agonists
Ropinirole 0·25 mg†‡ 4 mg12 (2 mg)11 IRLSSG rating scale, PLMI, other Augmentation, nausea, 26 weeks11 (n=404)
objective sleep measures (total somnolence, impulse
sleep time, sleep efficacy), control disorders
depression and anxiety
Pramipexole 0·125 mg (of salt)†‡ 0·75 mg (mean 0·5 mg in the USA; IRLSSG rating scale, PLMI, Augmentation, nausea, 52 weeks11 (n=719)
(0·088 mg of base) three doses of US formulation subjective sleep measures, somnolence, impulse
reported effective: 0·25 mg, depression and anxiety control disorders
0·5 mg, and 0·75 mg). Three doses
of European formulation reported
effective: 0·088 mg, 0·18 mg, and
0·35 mg. Maximum dose 0·54 mg
(mean 0·35 mg) in Europe
Rotigotine 1 mg†‡ 3 mg12 (2 mg)11 IRLSSG rating scale, PLMI, Application site skin 26 weeks11 (n=505)
subjective sleep measures, reactions, augmentation,
daytime symptoms nausea, somnolence,
impulse control disorders
Opioids
Prolonged release Two doses 5–10 mg oxycodone, Two doses of 40 mg oxycodone, IRLSSG rating scale, subjective Constipation, nausea, 12 weeks plus 1 year open
oxycodone–naloxone 2·5–5 mg naloxone‡ 20 mg naloxone12 (22 mg sleep measures sedation, depression, trial11 (n=306)
oxycodone, 11 mg naloxone)11 drug withdrawal
α2δ ligands
Gabapentin enacarbil 600 mg† (300 mg for patients 600 mg (1200 mg)36 IRLSSG rating scale, objective Somnolence, dizziness 12 weeks11 (n=325 or
>65 years) sleep measures other than 469 depending on study)
PLMI, subjective sleep measures
Pregabalin 75 mg§ (50 mg for patients Maximum recommended dose not IRLSSG rating scale, PLMI, other Unsteadiness, somnolence 52 weeks11 (n=719)
>65 years) defined (150–450 mg)11 objective sleep measures,
subjective sleep measures
Gabapentin 300 mg§ (100 mg for patients Maximum recommended dose not IRLSSG rating scale, objective Somnolence, dizziness 6 weeks11 (n=24)
>65 years) defined, (800 mg [200 mg for sleep measures other than
patients with uraemia])11 PLMI, subjective sleep measures
Iron supplementation
Intravenous ferric 1000 mg§ administered in one Not defined IRLSSG rating scale Nausea, headache Assessment at 12 weeks13
carboxymaltose infusion in patients with serum (n=110)
ferritin ≤100 µg/L and transferrin
saturation < 45%13
Intravenous iron 200 mg§ administered in five Not shown to be effective in IRLSSG rating scale Dysaesthesia, oedema in Assessment at 1 year13
sucrose infusions in patients with serum clinical trials, but considered hands and feet, nausea, (n=38)
ferritin ≤100 μg/L and transferrin effective by expert consensus13 vomiting, taste perversion
saturation <45%13

IRLSSG=International Restless Legs Syndrome Study Group. PLMI=periodic limb movement index. *According to national guidelines in Germany, Austria, and Switzerland. †According to US Food and Drug
Administration guidelines. ‡According to European Medicines Agency guidelines. §Not approved by regulatory agencies, but recommended by expert consensus.

Table: Therapies and doses for treatment of adult patients with restless legs syndrome

release oxycodone–naloxone, methadone is used in indications of intravenous iron see the table). In adult
refractory restless legs syndrome at considerably lower patients with restless legs syndrome with iron deficiency
doses than those used for the treatment of chronic pain. or serum ferritin less than 100 µg/L, intravenous ferric
Sensible precautions should be taken to monitor the carboxymaltose is considered a first-line treatment option
treatment of restless legs syndrome with opioids.40 (table).13,41 Expert, consensus-based guidelines13 consider
Treatment with oral iron with vitamin C is recom­ all available intravenous formulations with a carbohydrate
mended for all adult patients with restless legs syndrome bond prolonging the iron release likely to be useful, even
with iron deficiency or with serum ferritin of less than if these preparations have not received regulatory
75 µg/L unless medically contraindicated.13,36 Ferrous approval for the treatment of restless legs syndrome.
forms (eg, ferrous sulphate) are required for uptake in High molecular weight iron dextran is not an option
the gut, with possible gastrointestinal adverse effects (for because it could cause severe anaphylaxis.13 Iron glucose

4 www.thelancet.com/neurology Published online September 20, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30311-9


Review

should be avoided because it produces high restless legs syndrome being treated with dopamine
concentrations of toxic free iron and requires an excessive agonists,46 and patients should be actively questioned in
number of repeated intravenous infusions to obtain the this regard.
desired amount of iron sufficiency.13 α2δ ligands improve both restless legs syndrome
symptoms and sleep, without producing augmentation.
Augmentation For these reasons, and the fact that evidence-based
Augmentation—the intensifying of symptoms or reviews11,36 have confirmed the efficacy of α2δ ligands,
manifestation earlier in the day after a period of consensus guidelines recommend starting pharma­co­
successful dopaminergic treatment—remains a major logical therapy with α2δ ligands (gabapentin, gabapentin
challenge in treating patients with restless legs syndrome enacarbil, or pregabalin) instead of dopaminergics, as
(appendix). The absence of prospective studies evaluating the first-line treatment for restless legs syndrome.12
the treatment of restless legs syndrome augmentation Both gabapentin enacarbil and pregabalin are efficacious
makes it impossible to establish evidence-based for treating restless legs syndrome symptoms and
guidelines for managing the condition. Therefore, initiating and maintaining sleep.37,47 The reported
special monitoring for augmentation has been recom­ common side-effects of dizziness, drowsiness, and
mended when initiating dopaminergic treatment;11 tiredness and the less common but important adverse
clinicians should consider the possibility of augmentation effects of weight gain and cognitive confusion (so-called
when a patient who has been on stable treatment for at brain fog) have to be taken into account.11,36 A 52-week
least 6 months complains of symptom worsening or randomised comparative trial37 of pramipexole,
requests an increase in medication.12 The clinical pregabalin, and placebo, including a cross-over of
knowledge about dopaminergic treatment of restless legs patients in the placebo group to the pregabalin group
syndrome gained in the past 5 years indicates that the after 12 weeks, in a total of 712 patients with restless legs
lowest efficient doses should be used and the maximum syndrome in specialist sleep or movement disorder
recommended limits respected to avoid the development centres in the USA, reported that pregabalin was equally
of augmentation (table).42 Some studies have even effective as pramipexole for treatment of restless legs
suggested that the appearance of daytime symptoms (so- syndrome but induced significantly more augmentation
called breakthrough symptoms) during dopaminergic than pregabalin at effective doses. In the same trial, the
therapy could reflect the first symptoms of dropout rate for adverse events over 1 year of treatment
augmentation.12 The phenotype of augmentation, how­ for effective doses was 28% in the group that started
ever, indicates iatrogenic development of a more severe pregabalin, slightly higher than the 24% in the
form of restless legs syndrome rather than natural pramipexole group. Neither pregabalin nor gabapentin
disease progression or insufficient control of symptoms: has been approved for treatment of restless legs
in 99 consecutive augmented and 84 non-augmented syndrome. Gabapentin enacarbil is approved for first-
patients with restless legs syndrome treated at a line treatment of restless legs syndrome in the USA and
specialised movement disorder hospital in Germany, Japan.
there was no difference in polysomnographic
characteristics between insufficiently treated patients Non-pharmacological therapies
with severe restless legs syndrome and those with Non-pharmacological strategies, including optimising
severely augmented restless legs syndrome.43 general health conditions, physical therapy,48 and
When monitoring a patient for augmentation, magnetic or electrical stimulation techniques,49 are of
withdrawing dopaminergic drugs is necessary because increasing interest for patients and physicians and could
high doses—resulting either from the prescription of serve as an alternative to drugs or in case of treatment
doses that are too high or by self-dosing by patients— failure. Two systematic evidence-based reviews11,50 on
could result in a highly dangerous situation in which complementary and alternative treatments for restless
patients have severe sleep deprivation and continuous legs syndrome identified 18 trials that used the IRLSSG
restlessness. After augmentation, several approaches for rating scale as an endpoint and both reviews suggested
withdrawal of dopaminergic drugs are suggested,12,35 that exercise training and pneumatic compression devices
including changing from pulsatile dopaminergic could be efficacious in restless legs syndrome. In
treatment to a more continuous stimulation,44 or adding patients receiving haemodialysis, a meta-analysis48 of
opioids while slowly reducing dopaminergic doses. 15 randomised controlled trials suggested that exercise
Adding an α2δ ligand to treat augmentation might or was beneficial for restless legs syndrome, depression, and
might not be beneficial.45 With increased sympathetic fatigue.
tone, daytime PLMs when awake and severe restlessness
might occur, blood pressure could rise, and elderly Treatment in specific populations
patients are at risk of cardiac decompensation.12 Further In 2015, an IRLSSG task force developed the first
side-effects such as impulse control disorders (ie, guidelines for the diagnosis and treatment of restless legs
nocturnal eating) might even occur in patients with syndrome during pregnancy and lactation.10 Despite the

www.thelancet.com/neurology Published online September 20, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30311-9 5


Review

absence of clinical trials with pregnant women with receptor subtype in the spinal cord, which could underlie
restless legs syndrome, a recommendation for non- augmentation.58 The interaction of dopamine receptors
pharmacological therapies and iron supplementation has and μ-opioid receptors occurs in the dorsal horn of the
been agreed upon on the basis of available data and review spinal cord in which D3 receptors might prevent
of specific safety and risk concerns.10 Psychopharmacological antinociceptive effects of morphine when administered
treatments such as levodopa plus a dopamine over the long term.59 One of the genes related to restless
decarboxylase inhibitor, clonazepam, or even oxycodone legs syndrome—MEIS1—influences the development of
in severe cases, can be considered for treatment of the basal ganglia and might alter dopaminergic path­
pregnant women with restless legs syndrome.10 ways in motor control centres. In a heterozygous
Increasing evidence from community-based cohort knockout mouse model, haploinsufficiency of Meis1
studies and cross-sectional patient studies suggests that reduces sensitivity to inhibitory dopamine receptor
depression is closely linked to restless legs syndrome,51 agonists when testing startle reflexes.60 Moreover,
although pathophysiological concepts have yet to be behavioural and immunohistochemical data from two
identified. The prevalence of depressive  symptoms is animal models of restless legs syndrome (the D3 receptor
increased in restless legs syndrome, and antidepressants knockout mouse and the Meis1 knockout mouse) suggest
such as  mirtazapine, selective  serotonin reuptake that the increased excitability of the sensory system
inhibitors, and serotonin and norepinephrine reuptake might stem from an altered D3 receptor system, but the
inhibitors could also exacerbate symptoms.52 Therefore, motor-associated increased activity could be due to an
atypical antidepressants such as bupropion or trazodone increased expression of the D1 receptor system in the
should be used.52 spinal cord.61
Restless legs syndrome and PLMs could, therefore, be
Pathophysiology clinical repercussions of altered spinal circuits in sensory-
Restless legs syndrome is a disorder based on motor and processing and motor-processing areas, respectively.
sensory symptoms; the latter involve signal processing in Because the locomotor central pattern generator is
the sensory neurons of the dorsal part of the spinal cord. contained in the ventral aspect of the thoracolumbar
By contrast, PLMs are motor events that have their final spinal cord,62 and the D1 receptor is more strongly
control in the motor neurons of the ventral part of the expressed in ventral areas than sensory areas of the spinal
spinal cord. Both sensory and motor circuits, and their cord, D1 receptor-mediated actions could predominantly
interplay in sensorimotor integration, are under target motor-related over sensory functions in the spinal
descending control from monoaminergic clusters in the cord. Intriguingly, PLMs in sleep are often associated
brain. These clusters with spinal cord projections are with restless legs syndrome,32,63 and PLMs in sleep scores
dorsal raphe (serotonin), locus coeruleus (noradrenaline), are regularly used to quantify treatment response in
and the A11 region in the dorsal-posterior hypothalamus restless legs syndrome.36 Furthermore, inhibitory D3
(dopamine).53 D3 receptors have a very high affinity for receptors can form functional heterodimers with
dopamine; in the spinal cord, low dopamine excitatory D1 receptors,64 and the D1 receptor in turn can
concentrations tend to predominantly activate inhibitory form heterodimers with adenosine A1 receptors that,
D2-like receptors (D3 over D2) and thus mediate through the heterodimer, can control the efficacy of the
inhibitory actions in the dorsal spinal cord,54 but high D1 receptor.65 Such A1-D1 receptor heterodimers have
dopamine concentrations target excitatory (D1-like) been shown in basal ganglia and are now also established
receptors and can even activate or maintain locomotor- in the spinal cord.66 Moreover, brain iron deficiency
like activity in the isolated spinal cord (figure 1).55,56 This produces a hypoadenosinergic state.67 This process opens
important mechanism could trigger augmentation; a path by which modulation of the A1-receptor system can
restless legs syndrome is more prevalent with ageing, downregulate the D1 receptor and thereby reduce
when D1 receptor but not D3 receptor expression is dopamine-mediated excitability in both basal ganglia and
increased, supporting a causal role for the D1 receptor spinal cord circuits.
in the emergence of restless legs syndrome and
augmentation.57 Genetic factors
Although the efficacy of dopaminergic treatment is well The importance of genetic factors in susceptibility to
documented, the pathophysiology of its mechanism of restless legs syndrome is well documented, and genetic
action is still not sufficiently understood. Dopaminergics studies have strived to identify disease genes to provide
targeting the inhibitory receptor subtype D3 are initially starting points for in-depth functional analyses to dissect
extremely effective in treating the symptoms of restless molecular mechanisms underlying the disease.68 GWAS
legs syndrome but over time cause augmentation. of common genetic variants continue to be a major source
Moreover, D3 receptor dysfunction in animals enhances of genetic associations for restless legs syndrome, with
sensory and motor effects of iron deficiency. Animal data the largest study a meta-analysis14 of three GWAS
suggest that long-term treatment with D3 receptor involving 15 126 patients with restless legs syndrome and
agonists leads to an upregulation of the excitatory D1 95 725 control participants of European ancestry, raising

6 www.thelancet.com/neurology Published online September 20, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30311-9


Review

the number of risk loci for restless legs syndrome to 19 studies, two CSF studies, and clinical studies showing
(figure 2). Candidate genes in these loci are not directly intravenous iron treatment benefit for patients with
implicated as key molecules in dopaminergic neuro­ restless legs syndrome with or without peripheral iron
transmission or brain iron metabolism, the systems deficiency.13,80 Seven of the ten imaging studies (three in
predominantly studied in restless legs syndrome the past 5 years81–83) and all three ultrasound studies
pathophysiology. Instead, enrichment analyses of the found decreased iron in the substantia nigra. Three
19 risk loci support the previously posited concept of imaging studies (two in the past 5 years that used more
deranged neurodevelopmental processes playing a part in sensitive measures appropriate for the low iron
restless legs syndrome.14,71 These analyses also highlight concentration reported in patients with restless legs
related pathways such as neurogenesis, axon guidance, syndrome63,83) also found decreased iron in the thalamus.
and synaptogenesis, which are important in the formation Two imaging studies,84,85 however, did not find brain iron
and maintenance of neural circuits in the CNS. Another deficiency, possibly because of methodological reasons or
highlighted pathway—DNA damage repair—also contri­ different patient selection.
butes to correct functioning of the CNS.14,72 GWAS have Brain iron deficiency has provided an impetus for
led to, and continue to foster, the development of animal the development of iron treatments of restless legs
models and cellular assays for studying the underlying syndrome.13 Brain iron deficiency effects also reveal
pathomechanisms in restless legs syndrome. Different important biological mechanisms in restless legs
animal models for MEIS1, BTBD9, and PTPRD—risk syndrome; for example, CNS hypoadenosinergic state,
genes discovered in 2007–08—have been established and activation of CNS hypoxic pathways, and altered
are being used to study the function of these genes and dopaminergic systems. These processes produce
their interaction with dopaminergic neuro-​transmission potential feedback interactions, expanding our under­
and iron metabolism.60,61,73,74 standing of restless legs syndrome pathophysiology and
The neurodevelopmental aspect in restless legs providing opportunities for new treatments.
syndrome is supported by a study71 that used transgenic A putative role of hypoxia increasing prevalence and
mouse embryos to show an effect of risk variants in severity of restless legs syndrome was described in a
MEIS1 during early embryonic development in the study86 done in the Himalayas with five untreated patients
ganglionic eminences, which give rise to the cells of the with restless legs syndrome and five people in the control
basal ganglia.71 GWAS can also suggest candidates for group residing at high altitudes. Furthermore, restless
follow-up studies to address a possible repurposing or legs syndrome has a higher prevalence in people with
modification of existing drugs. Three risk loci contain diseases that cause decreased peripheral oxygen
genes encoding potential therapeutic targets: PTPRD, concentrations, such as chronic obstructive pulmonary
CRBN, and MEIS2. Illudalic acid analogues were shown disease and obstructive sleep apnoea, than in
to inhibit PTPRD phosphatase activity in in-vitro trials,75,76 healthy people.87–89 Indications of peripheral oxygen
making them candidates for future drug development. dysregulation include alterations in skeletal muscle
CRBN and MEIS2 provide a link to the drug thalidomide, morphology and lower limb microvascular circulation,90
since CRBN is targeted by thalidomide and MEIS2 is an and also decreased oxygen partial pressure in the legs of
endogenous ligand of CRBN.14,77 Studying thalidomide patients with restless legs syndrome.91 In a small Austrian
and thalidomide-like substances, with due attention to case-control study,92 PLMs increased in both 15 patients
their teratogenicity, could result in new treatment with restless legs syndrome and 14 people in the control
options. group after one night in a hypoxic environment.
Shared genetic association signals between different An autopsy study93 indicating activation of the CNS
disorders can point to overlapping pathomechanisms, hypoxic pathway showed upregulation of hypoxia-
suggesting pleiotropy of the genes involved. However, inducible factor (HIF)-1α in the substantia nigra in
these signals could also be indicators of phenotypic brains from six patients with restless legs syndrome
heterogeneity in the study populations. GWAS have compared with six control brains. Additionally, both
identified an association of known restless legs syndrome HIF-2α and vascular endothelial growth factor were
risk variants in MEIS1 with insomnia symptoms, upregulated in cortical microvasculature of four patients
suggesting a role for this gene in both conditions.78,79 Two with restless legs syndrome compared with four control
factors appear to drive this asso­ ciation—a pleiotropic individuals. Furthermore, β-haemoglobin, which has
role of MEIS1 and phenotypic heterogeneity (ie, presence been shown to be upregulated as a result of hypoxia, was
of patients with restless legs syndrome in the insomnia upregulated in CSF from six patients with restless legs
cohort). To what extent each factor contributes has not syndrome compared with six control individuals.94 HIF-
been resolved. 1α activation in cerebral microvascular endothelial cells
increases blood–brain barrier permeability,95 suggesting
Iron and peripheral and central hypoxic pathways that hypoxic pathway activation in restless legs syndrome
Brain iron deficiency has been documented in restless could also affect the regulatory mechanisms of iron
legs syndrome with ten imaging studies, three ultrasound across the blood–brain barrier. Similarly, HIF-2α

www.thelancet.com/neurology Published online September 20, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30311-9 7


Review

rs12046503
chr1
0 20 40 60 80 100 120 140 160 180 200 220 240

1
T6
NG
M
NT
PR
rs113851554
rs10208712 rs1820989 rs80319144
chr2
0 20 40 60 80 100 120 140 160 180 200 220 240

1
1

8
2C

D
LF

P4
AA

NC
EIS

14
C1
AP
DC

PK
DC
ET

TA
M
DC

CC
rs1848460 rs35987657
chr3
0 20 40 60 80 100 120 140 160 180
4

C1

1
BN
TN

TE
P2
CR

AS
CN

AT
rs61192259
rs17636328
chr6
0 20 40 60 80 100 120 140 160
ZF 1
D3
1

9
CM 8

O1
7
A
TR

BD
F

16
DG
AN
RN

GL
BT
DC
M
CC

rs10952927
chr7
Figure 2: GWAS-derived risk 0 20 40 60 80 100 120 140
loci for restless legs
C7 P4
ZN 62

B
ST 2

04
2
EA

f
AM

or

syndrome and periodic limb


F8
AD

movements rs1836229
Ideograms of all chromosomes rs62535767
containing risk loci (red and chr9
0 20 40 60 80 100 120 140
blue text) for restless legs
syndrome. Genomic
D
PR
PT

coordinates are given in mega


base pairs. The loci are defined
by the respective lead single rs340561
nucleotide polymorphism chr13
0 20 40 60 80 100
found in a meta-analysis14
with the respective reference
1
S3
CH
DI
DA

single nucleotide
polymorphism cluster
identifier (rsID) given above rs996064 rs111652004 rs868036
each chromosome. Red text chr15
0 20 40 60 80 100
refers to loci solely associated
1

CA S1
CH

with restless legs syndrome.


K5
2

L4
D
H6

rf6
EIS

OR
A6

PIA
2
IQ

LM
DP

5o
AP
M

SK
M

Blue text indicates loci for


B
C1

M
SE

GA
AA

which an association to
restless legs syndrome and rs45544231
periodic limb movements has chr16
0 20 40 60 80
been shown in GWAS or
focused association
CA 3
16
X
TO

SC

studies.14,32,69,70 For each risk


locus tagged by a lead single
nucleotide polymorphism, rs12450895
protein-coding candidate risk chr17
0 20 40 60 80
genes in the genomic
XB C1

region are listed below the


ste
HO PRA
clu

ideogram in black text.


The gene list is not exhaustive
and might not contain all rs12962305
candidate genes or the true chr18
0 20 40 60
causal gene because the
1

association signals in GWAS


P
TB
SE

pinpoint genomic regions


(linkage disequilibrium
blocks), which in most cases rs365032
contain more than one gene. chr20
0 20 40 60
GWAS=genome-wide
1

association study.
RL
YT
OP

chr=chromosome.

8 www.thelancet.com/neurology Published online September 20, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30311-9


Review

Contributing factors Iron deficiency Nitric oxide Adenosine MEIS1

Stabilisation and nuclear translocation of HIF-1α

Increased tyrosine Increased transferrin Increased erythropoietin Increased VEGF


Experimental observations
hydrolase in putamen receptor in lymphocytes in lymphocytes
in restless legs syndrome
and substantia nigra

Treatment efficacy with Alterations in central and Decreased oxygen Vascular changes in the
Clinical observations evident dopamine agonists peripheral iron concentrations in the legs legs of patients with
in restless legs syndrome homoeostasis of patients with restless restless legs syndrome
legs syndrome

Figure 3: Proposed intracellular pathways of hypoxia in restless legs syndrome


Intracellular factors such as iron deficiency, nitric oxide, adenosine, or MEIS1 allelic variations can potentially act alone (solid lines) or in concert (dashed lines) to
contribute to restless legs syndrome pathophysiology and clinical presentation. These intracellular signals activate the hypoxic pathway by stabilisation and
translocation of HIF-1α to the nucleus of the cell and result in upregulation of proteins that are regulated by HIF-1α, such as erythropoietin, VEGF, tyrosine
hydroxylase, and transferrin receptor. The transcriptional activation of the hypoxic pathway could result in vascular changes,59 decreased oxygen concentrations in
the legs of patients with restless legs syndrome,50 elevated tyrosine hydroxylase,59 and alterations in central and peripheral iron homoeostasis that are observed in
patients with restless legs syndrome,59 whereas iron deficiency alone can directly alter dopaminergic and iron homoeostasis. HIF-1α=hypoxia-inducible factor-1α.
VEGF=vascular endothelial growth factor.

activation has been described in microvascular


endothelial cells in patients with restless legs syndrome.93 Search strategy and selection criteria
These findings could explain the variety of peripheral We searched the MEDLINE database for articles published in
hypoxic states associated with restless legs syndrome, any language between Jan 1, 2013, and May 10, 2018, using
such as venous disease, or even the large number of the following terms: ((“restless legs syndrome” OR “willis
cardiovascular diseases27 associated with the condition. ekbom disease”) AND (augment* OR pathophysiol* OR
Improving peripheral hypoxia might alleviate restless pathway* OR imag* OR genetic* OR dopamine* OR
legs syndrome symptoms in these patients, and even comorbid* OR dopamine receptor*)). We identified 728
iron therapy could partially act on this peripheral pathway. articles. We also included articles that we were aware of being
Although hypoxic pathways appear activated in brains in press. We generated the final reference list on the basis of
from patients with restless legs syndrome, the studies do relevance to the topics covered in this Review.
not show actual hypoxia but rather disruption of important
regulatory pathways affecting various aspects of the CNS;
for example, upregulation of tyrosine hydroxylase. Figure 3 and the development of a basis for the sensory symptoms
summarises intracellular factors that can act both and motor signs of restless legs syndrome, major
independently and also through the hypoxic pathway to puzzling features of the condition remain, such as the
result in experimental and clinical features that are manifestation of symptoms only at rest that improve
observed in patients with restless legs syndrome. with activity. The pathophysiology of restless legs
syndrome remains a complex mystery, and although
Conclusions and future directions many pathways have been studied, a single cause for the
The past 5 years have seen a remarkable convergence of clinical manifestation of the very stable phenotype has
clinical and laboratory studies of restless legs syndrome. not been found. Augmentation, a serious challenge in
Clinical studies have shown the need, and provided the treating the disorder, might be better explained by the
data, for refinements to diagnostic criteria and the involvement of the different spinal dopaminergic
definition of the restless legs syndrome motor sign—ie, systems and their upregulation with chronic treatment.
PLMs. The observation of brain iron deficiency in The biggest challenge is finding new treatments since
patients with restless legs syndrome has provided a basis most patients report inadequate treatment over the long
for exploring multiple research areas. Studies of spinal term. More immediately, combination treatments
cord dopamine system and the effects of brain iron that are commonly prescribed should be evaluated.
deficiency converged on a possible important role for Combination therapy clinical trials, which take into
adenosine in the condition. Clinical and animal studies account the pathophysiological knowledge on spinal and
indicate putative associations between some restless legs metabolic pathways and the known side-effects of the
syndrome risk alleles, and both iron68,96 and basal ganglia drugs, are needed. The combinations of low-dose
development.71 Despite these remarkable convergences dopaminergic drugs, opioids, or α2δ ligands could be

www.thelancet.com/neurology Published online September 20, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30311-9 9


Review

safer, more efficient, and cheaper than monotherapy and 10 Picchietti DL, Hensley JG, Bainbridge JL, et al. Consensus clinical
should be urgently explored to increase safety and practice guidelines for the diagnosis and treatment of restless legs
syndrome/Willis-Ekbom disease during pregnancy and lactation.
efficacy in long-term therapy and to reduce costs.97 Sleep Med Rev 2015; 22: 64–77.
Fortunately, combination treatments can be evaluated 11 Winkelmann J, Allen R, Högl B, et al. Treatment of restless legs
because of improved knowledge about the mechanisms syndrome: an evidence-based review and implications for
clinical practice. Mov Disord 2018; published online May 14.
that could underlie restless legs syndrome and because DOI:10.1002/mds.27260.
of new tools and approaches that can translate knowledge 12 Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines
about the condition into new, more effective treatments for the first-line treatment of restless legs syndrome/Willis-Ekbom
disease, prevention and treatment of dopaminergic augmentation:
and perhaps even preventive approaches. a combined task force of the IRLSSG, EURLSSG, and the
Contributors RLS-foundation. Sleep Med 2016; 21: 1–11.
CT, JW, and RA conceptualised and designed the Review. All authors 13 Allen RP, Picchietti DL, Auerbach M, et al. Evidence-based and
were involved in drafting the manuscript and provided critical input and consensus clinical practice guidelines for the iron treatment of
comments on the manuscript. restless legs syndrome/Willis-Ekbom disease in adults and
children: an IRLSSG task force report. Sleep Med 2018; 41: 27–44.
Declaration of interests 14 Schormair B, Zhao C, Bell S, et al. Identification of novel risk loci
CT reports personal fees from Paracelsus-Elena-Klinik Kassel, outside the for restless legs syndrome in genome-wide association studies in
submitted work. RA reports grants and personal fees from Luitpold individuals of European ancestry: a meta-analysis. Lancet Neurol
Pharmaceutical and grants from Amag Pharmaceuticals, outside the 2017; 16: 898–907.
submitted work. BH reports personal fees from Axovant, Benevolent Bio, 15 Moretti D, Goede JS, Zeder C, et al. Oral iron supplements increase
Mundipharma, UCB Pharma, Lundbeck, Abbvie, Janssen Cilag, Lilly, and hepcidin and decrease iron absorption from daily or twice-daily
Nutricia, and grants from UCB Pharma, outside the submitted work. SC doses in iron-depleted young women. Blood 2015; 126: 1981–89.
reports grants from Craig H Neilsen Foundation, North Carolina 16 Allen RP, Auerbach S, Bahrain H, Auerbach M, Earley CJ.
Biotechnology Center, and the National Institute of Neurological The prevalence and impact of restless legs syndrome on patients
Disorders and Stroke, outside the submitted work. SC also has a patent with iron deficiency anemia. Am J Hematol 2013; 88: 261–64.
(Treatment and Management of Augmentation in Restless Legs 17 Didriksen M, Rigas AS, Allen RP, et al. Prevalence of restless legs
Syndrome) pending to East Carolina University and a patent (Methods syndrome and associated factors in an otherwise healthy
population: results from the Danish Blood Donor Study.
and Compositions for Maintaining Opioid Efficacy in the Treatment of
Sleep Med 2017; 36: 55–61.
Chronic Pain) pending to East Carolina University. BS reports personal
18 Mehmood T, Auerbach M, Earley CJ, Allen RP. Response to
fees from Bayer Vital GmbH, outside the submitted work. JW has a
intravenous iron in patients with iron deficiency anemia (IDA) and
patent pending for treatment of restless legs syndrome by use of
restless leg syndrome (Willis-Ekbom disease). Sleep Med 2014;
thalidomide and derivatives. SP declares no competing interests. 15: 1473–76.
Acknowledgments 19 Marchesi E, Negrotti A, Angelini M, Goldoni M, Abrignani G,
The authors thank Anne-Marie Williams for her help in editing the Calzetti S. A prospective study of the cumulative incidence and
manuscript, organising tables, and checking references, and Michael Bartl course of restless legs syndrome in de novo patients with
(Department of Clinical Neurophysiology, University Medical Center, Parkinson’s disease during chronic dopaminergic therapy.
J Neurol 2016; 263: 441–47.
Goettingen, Germany) for his assistance with the literature search.
20 Yang X, Liu B, Shen H, et al. Prevalence of restless legs syndrome
References in Parkinson’s disease: a systematic review and meta-analysis of
1 Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, observational studies. Sleep Med 2018; 43: 40–46.
Montplaisir J. Restless legs syndrome: diagnostic criteria, special 21 Szatmari S Jr, Bereczki D, Fornadi K, Kalantar-Zadeh K,
considerations, and epidemiology. A report from the restless legs Kovesdy CP, Molnar MZ. Association of restless legs syndrome
syndrome diagnosis and epidemiology workshop at the National with incident Parkinson’s disease. Sleep 2017; 40: zsw065.
Institutes of Health. Sleep Med 2003; 4: 101–19.
22 Wong JC, Li Y, Schwarzschild MA, Ascherio A, Gao X. Restless legs
2 Padula WV, Phelps CE, Moran D, Earley C. Allocating provider syndrome: an early clinical feature of Parkinson disease in men.
resources to diagnose and treat restless legs syndrome: a cost-utility Sleep 2014; 37: 369–72.
analysis. Sleep Med 2017; 38: 44–49.
23 Schrag A, Horsfall L, Walters K, Noyce A, Petersen I. Prediagnostic
3 Gupta R, Lahan V, Goel D. Restless legs syndrome: a common presentations of Parkinson’s disease in primary care: a case-control
disorder, but rarely diagnosed and barely treated—an Indian study. Lancet Neurol 2015; 14: 57–64.
experience. Sleep Med 2012; 13: 838–41.
24 Szentkiralyi A, Volzke H, Hoffmann W, Trenkwalder C, Berger K.
4 Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs Multimorbidity and the risk of restless legs syndrome in 2
syndrome/Willis-Ekbom disease diagnostic criteria: updated prospective cohort studies. Neurology 2014; 82: 2026–33.
International Restless Legs Syndrome Study Group (IRLSSG)
25 Winkelman JW, Blackwell T, Stone K, Ancoli-Israel S, Redline S.
consensus criteria—history, rationale, description, and significance.
Associations of incident cardiovascular events with restless legs
Sleep Med 2014; 15: 860–73.
syndrome and periodic leg movements of sleep in older men, for
5 American Academy of Sleep Medicine. The international the Outcomes of Sleep Disorders in Older Men Study (MrOS Sleep
classification of sleep disorders: diagnostic & coding manual Study). Sleep 2017; 40: zsx023.
(ICSD-3), 3rd edn. Darien, IL: American Academy of Sleep
26 Li Y, Li Y, Winkelman JW, et al. Prospective study of restless legs
Medicine, 2014.
syndrome and total and cardiovascular mortality among women.
6 American Psychiatric Association. Diagnostic and statistical manual Neurology 2018; 90: e135–41.
of mental disorders, 5th edn. Arlington, VA: American Psychiatric
27 Gottlieb DJ, Somers VK, Punjabi NM, Winkelman JW. Restless legs
Association, 2013.
syndrome and cardiovascular disease: a research roadmap.
7 Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide Sleep Med 2017; 31: 10–17.
association study of restless legs syndrome identifies common
28 Szentkiralyi A, Volzke H, Hoffmann W, Happe S, Berger K. A time
variants in three genomic regions. Nat Genet 2007; 39: 1000–06.
sequence analysis of the relationship between cardiovascular risk
8 Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J. factors, vascular diseases and restless legs syndrome in the general
Restless legs syndrome associated with major diseases: a systematic population. J Sleep Res 2013; 22: 434–42.
review and new concept. Neurology 2016; 86: 1336–43.
29 Lin CH, Chen ML, Wu VC, et al. Association of candidate genetic
9 Giannaki CD, Hadjigavriel M, Lazarou A, et al. Restless legs variants with restless legs syndrome in end stage renal disease:
syndrome is contributing to fatigue and low quality of life levels in a multicenter case-control study in Taiwan. Eur J Neurol 2014;
hemodialysis patients. World J Nephrol 2017; 6: 236–42. 21: 492–98.

10 www.thelancet.com/neurology Published online September 20, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30311-9


Review

30 Schormair B, Plag J, Kaffe M, et al. MEIS1 and BTBD9: 49 Heide AC, Winkler T, Helms HJ, et al. Effects of transcutaneous
genetic association with restless leg syndrome in end stage renal spinal direct current stimulation in idiopathic restless legs patients.
disease. J Med Genet 2011; 48: 462–66. Brain Stimul 2014; 7: 636–42.
31 Szentkiralyi A, Volzke H, Hoffmann W, Winkelmann J, Berger K. 50 Xu XM, Liu Y, Jia SY, Dong MX, Cao D, Wei YD.
Lack of association between genetic risk loci for restless legs Complementary and alternative therapies for restless legs
syndrome and multimorbidity. Sleep 2016; 39: 111–15. syndrome: an evidence-based systematic review. Sleep Med Rev 2018;
32 Moore Ht, Winkelmann J, Lin L, Finn L, Peppard P, Mignot E. 38: 158–67.
Periodic leg movements during sleep are associated with 51 Cho CH, Kim L, Lee HJ. Individuals with restless legs syndrome
polymorphisms in BTBD9, TOX3/BC034767, MEIS1, tend to have severe depressive symptoms: findings from a
MAP2K5/SKOR1, and PTPRD. Sleep 2014; 37: 1535–42. community-based cohort study. Psychiatry Investig 2017;
33 Ferri R, Fulda S, Allen RP, et al. World Association of Sleep 14: 887–93.
Medicine (WASM) 2016 standards for recording and scoring leg 52 Becker PM, Sharon D. Mood disorders in restless legs syndrome
movements in polysomnograms developed by a joint task force (Willis-Ekbom disease). J Clin Psychiatry 2014; 75: e679–94.
from the International and the European Restless Legs Syndrome 53 Koblinger K, Fuzesi T, Ejdrygiewicz J, Krajacic A, Bains JS,
Study Groups (IRLSSG and EURLSSG). Sleep Med 2016; Whelan PJ. Characterization of A11 neurons projecting to the spinal
26: 86–95. cord of mice. PLoS One 2014; 9: e109636.
34 Ferri R, Rundo F, Zucconi M, et al. Diagnostic accuracy of the 54 Keeler BE, Baran CA, Brewer KL, Clemens S. Increased excitability
standard and alternative periodic leg movement during sleep of spinal pain reflexes and altered frequency-dependent modulation
indices for restless legs syndrome. Sleep Med 2016; 22: 97–99. in the dopamine D3-receptor knockout mouse. Exp Neurol 2012;
35 Trenkwalder C, Winkelmann J, Inoue Y, Paulus W. Restless legs 238: 273–83.
syndrome—current therapies and management of augmentation. 55 Clemens S, Belin-Rauscent A, Simmers J, Combes D.
Nat Rev Neurol 2015; 11: 434–45. Opposing modulatory effects of D1- and D2-like receptor activation
36 Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline on a spinal central pattern generator. J Neurophysiol 2012;
summary: treatment of restless legs syndrome in adults: report of 107: 2250–59.
the Guideline Development, Dissemination, and Implementation 56 Sharples SA, Humphreys JM, Jensen AM, et al. Dopaminergic
Subcommittee of the American Academy of Neurology. Neurology modulation of locomotor network activity in the neonatal mouse
2016; 87: 2585–93. spinal cord. J Neurophysiol 2015; 113: 2500–10.
37 Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of 57 Samir S, Yllanes AP, Lallemand P, Brewer KL, Clemens S.
pregabalin with pramipexole for restless legs syndrome. Aging-related morphine tolerance in dopamine D3 receptor
N Engl J Med 2014; 370: 621–31. knockout mice reveresed by block of D1 receptor function.
38 Trenkwalder C, Beneš H, Grote L, et al. Prolonged release Neuroscience 2017; 349: 87–97.
oxycodone-naloxone for treatment of severe restless legs syndrome 58 Dinkins M-L, Lallemand P, Clemens S. Long-term treatment with
after failure of previous treatment: a double-blind, randomised, dopamine D3 receptor agonists induces a behavioral switch that can
placebo-controlled trial with an open-label extension. Lancet Neurol be rescued by blocking the dopamine D1 receptor. Sleep Med 2017;
2013; 12: 1141–50. 40: 47–52.
39 National Institute for Health and Care Excellence. Restless legs 59 Brewer KL, Baran CA, Whitfield BR, Jensen AM, Clemens S.
syndrome: oxycodone/naloxone prolonged release (evidence Dopamine D3 receptor dysfunction prevents anti-nociceptive effects
summary [ESNM67]). December, 2015. https://www.nice.org.uk/ of morphine in the spinal cord. Front Neural Circuits 2014; 8: 62.
advice/esnm67/chapter/full-evidence-summary (accessed 60 Salminen AV, Garrett L, Schormair B, et al. Meis1: effects on motor
May 27, 2018). phenotypes and the sensorimotor system in mice. Dis Model Mech
40 Silber MH, Becker PM, Buchfuhrer MJ, et al. The appropriate use 2017; 10: 981–91.
of opioids in the treatment of refractory restless legs syndrome. 61 Meneely S, Dinkins M-L, Kassai M, et al. Differential dopamine D1
Mayo Clin Proc 2018; 93: 59–67. and D3 receptor modulation and expression in the spinal cord of
41 Trenkwalder C, Winkelmann J, Oertel W, et al. Ferric two mouse models of restless legs syndrome. Front Behav Neurosci
carboxymaltose in patients with restless legs syndrome and 2018; published online Sept 4. DOI:10.3389/fnbeh.2018.00199.
nonanemic iron deficiency: a randomized trial. Mov Disord 2017; 62 Kiehn O. Decoding the organization of spinal circuits that control
32: 1478–82. locomotion. Nat Rev Neurosci 2016; 17: 224–38.
42 Oertel W, Trenkwalder C, Beneš H, et al. Long-term safety and 63 Li X, Allen RP, Earley CJ, et al. Brain iron deficiency in idiopathic
efficacy of rotigotine transdermal patch for moderate-to-severe restless legs syndrome measured by quantitative magnetic
idiopathic restless legs syndrome: a 5-year open-label extension susceptibility at 7 tesla. Sleep Med 2016; 22: 75–82.
study. Lancet Neurol 2011; 10: 710–20.
64 Guitart X, Navarro G, Moreno E, et al. Functional selectivity of
43 Steinke SS, Trenkwalder C, Zimmermann J, Sixel-Döring F, allosteric interactions within G protein-coupled receptor oligomers:
Muntean M-L. Polysomnographic findings in restless legs the dopamine D1-D3 receptor heterotetramer. Mol Pharmacol 2014;
syndrome (RLS) patients with severe augmentation. Sleep Med 2018; 86: 417–29.
48: 79–85.
65 Fuxe K, Guidolin D, Agnati LF, Borroto-Escuela DO.
44 Trenkwalder C, Canelo M, Lang M, et al. Management of Dopamine heteroreceptor complexes as therapeutic targets in
augmentation of restless legs syndrome with rotigotine: a 1-year Parkinson’s disease. Expert Opin Ther Targets 2015; 19: 377–98.
observational study. Sleep Med 2017; 30: 257–65.
66 Rivera-Oliver M, Moreno E, Álvarez-Bagnarol Y, et al. Adenosine
45 Garcia-Borreguero D, Cano-Pumarega I, Marulanda R. A1-dopamine D1 receptor heteromers control the excitability of the
Management of treatment failure in restless legs syndrome spinal motoneuron. Mol Neurobiol 2018; published online May 24.
(Willis-Ekbom disease). Sleep Med Rev 2018; 41: 50–60. DOI:10.1007/s12035-018-1120-y.
46 Heim B, Djamshidian A, Heidbreder A, et al. Augmentation and 67 Ferre S, Earley C, Gulyani S, Garcia-Borreguero D. In search of
impulsive behaviors in restless legs syndrome: coexistence or alternatives to dopaminergic ligands for the treatment of restless
association? Neurology 2016; 87: 36–40. legs syndrome: iron, glutamate, and adenosine. Sleep Med 2017;
47 Bogan RK, Lee DO, Buchfuhrer MJ, Jaros MJ, Kim R, Shang G. 31: 86–92.
Treatment response to sleep, pain, and mood disturbance 68 Winkelmann J, Schormair B, Xiong L, Dion PA, Rye DB,
and their correlation with sleep disturbance in adult patients Rouleau GA. Genetics of restless legs syndrome. Sleep Med 2017;
with moderate-to-severe primary restless legs syndrome: pooled 31: 18–22.
analyses from 3 trials of gabapentin enacarbil. Ann Med 2015;
69 Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for
47: 269–77.
periodic limb movements in sleep. N Engl J Med 2007;
48 Song YY, Hu RJ, Diao YS, Chen L, Jiang XL. Effects of exercise 357: 639–47.
training on restless legs syndrome, depression, sleep quality, and
70 Winkelman JW, Blackwell T, Stone K, et al. Genetic associations of
fatigue among hemodialysis patients: a systematic review and
periodic limb movements of sleep in the elderly for the MrOS sleep
meta-analysis. J Pain Symptom Manage 2018; 55: 1184–95.
study. Sleep Med 2015; 16: 1360–65.

www.thelancet.com/neurology Published online September 20, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30311-9 11


Review

71 Spieler D, Kaffe M, Knauf F, et al. Restless legs 86 Gupta R, Ulfberg J, Allen RP, Goel D. High prevalence of restless
syndrome-associated intronic common variant in Meis1 alters legs syndrome/Willis Ekbom Disease (RLS/WED) among people
enhancer function in the developing telencephalon. Genome Res living at high altitude in the Indian Himalaya. Sleep Med 2017;
2014; 24: 592–603. 35: 7–11.
72 Madabhushi R, Gao F, Pfenning AR, et al. Activity-induced DNA 87 Connor JR, Patton SM, Oexle K, Allen RP. Iron and restless legs
breaks govern the expression of neuronal early-response genes. syndrome: treatment, genetics and pathophysiology. Sleep Med 2017;
Cell 2015; 161: 1592–605. 31: 61–70.
73 Drgonova J, Walther D, Wang KJ, et al. Mouse model for PTPRD 88 Budhiraja R, Siddiqi TA, Quan SF. Sleep disorders in chronic
associations with WED/RLS and addiction: reduced expression obstructive pulmonary disease: etiology, impact, and management.
alters locomotion, sleep behaviors and cocaine-conditioned place J Clin Sleep Med 2015; 11: 259–70.
preference. Mol Med 2015; published online July 14. 89 Lin SW, Chen YL, Kao KC, et al. Diseases in patients coming to a
DOI:10.2119/molmed.2015.00017. sleep center with symptoms related to restless legs syndrome.
74 Allen RP, Donelson NC, Jones BC, et al. Animal models of RLS PLoS One 2013; 8: e71499.
phenotypes. Sleep Med 2017; 31: 23–28. 90 Oskarsson E, Wahlin-Larsson B, Ulfberg J. Reduced daytime
75 Uhl GR, Drgonova J. Cell adhesion molecules: druggable targets intramuscular blood flow in patients with restless legs
for modulating the connectome and brain disorders? syndrome/Willis-Ekbom disease. Psychiatry Clin Neurosci 2014;
Neuropsychopharmacology 2014; 39: 235. 68: 640–43.
76 Earley CJ, Connor J, Garcia-Borreguero D, et al. Altered brain iron 91 Salminen AV, Rimpila V, Polo O. Peripheral hypoxia in restless legs
homeostasis and dopaminergic function in restless legs syndrome syndrome (Willis-Ekbom disease). Neurology 2014; 82: 1856–61.
(Willis-Ekbom disease). Sleep Med 2014; 15: 1288–301. 92 Stefani A, Heidbreder A, Hackner H, Burtscher M, Hogl B.
77 Fischer ES, Bohm K, Lydeard JR, et al. Structure of the DDB1-CRBN Influence of high altitude on periodic leg movements during sleep
E3 ubiquitin ligase in complex with thalidomide. Nature 2014; in individuals with restless legs syndrome and healthy controls:
512: 49–53. a pilot study. Sleep Med 2017; 29: 88–89.
78 Hammerschlag AR, Stringer S, de Leeuw CA, et al. Genome-wide 93 Patton SM, Ponnuru P, Snyder AM, Podskalny GD, Connor JR.
association analysis of insomnia complaints identifies risk genes Hypoxia-inducible factor pathway activation in restless legs
and genetic overlap with psychiatric and metabolic traits. syndrome patients. Eur J Neurol 2011; 18: 1329–35.
Nat Genet 2017; 49: 1584–92. 94 Patton SM, Cho YW, Clardy TW, Allen RP, Earley CJ, Connor JR.
79 Lane JM, Liang J, Vlasac I, et al. Genome-wide association analyses Proteomic analysis of the cerebrospinal fluid of patients with
of sleep disturbance traits identify new loci and highlight shared restless legs syndrome/Willis-Ekbom disease. Fluids Barriers CNS
genetics with neuropsychiatric and metabolic traits. Nat Genet 2017; 2013; 10: 20.
49: 274–81. 95 Yeh WL, Lu DY, Lin CJ, Liou HC, Fu WM. Inhibition of
80 Cho YW, Allen RP, Earley CJ. Lower molecular weight intravenous hypoxia-induced increase of blood–brain barrier permeability by
iron dextran for restless legs syndrome. Sleep Med 2013; 14: 274–77. YC-1 through the antagonism of HIF-1alpha accumulation and
81 Moon HJ, Chang Y, Lee YS, et al. T2 relaxometry using 3.0-tesla VEGF expression. Mol Pharmacol 2007; 72: 440–49.
magnetic resonance imaging of the brain in early- and late-onset 96 Sorensen E, Grau K, Berg T, et al. A genetic risk factor for low
restless legs syndrome. J Clin Neurol 2014; 10: 197–202. serum ferritin levels in Danish blood donors. Transfusion 2012;
82 Moon HJ, Chang Y, Lee YS, et al. A comparison of MRI tissue 52: 2585–89.
relaxometry and ROI methods used to determine regional brain 97 Jaarsma J, Dauvilliers Y, Ferri R, et al. Early Intervention:
iron concentrations in restless legs syndrome. Med Devices (Auckl) bridging the early diagnosis and tretment gap, policy white paper
2015; 8: 341–50. towards optimizing research and care for brain disorders.
83 Rizzo G, Manners D, Testa C, et al. Low brain iron content in June, 2017. http://www.braincouncil.eu/wp-content/
idiopathic restless legs syndrome patients detected by phase uploads/2017/06/EBC-VoT-White-Policy-Paper.pdf (accessed
imaging. Mov Disord 2013; 28: 1886–90. June 22, 2017).
84 Knake S, Heverhagen JT, Menzler K, Keil B, Oertel WH,
© 2018 Elsevier Ltd. All rights reserved.
Stiasny-Kolster K. Normal regional brain iron concentration in
restless legs syndrome measured by MRI. Nat Sci Sleep 2010;
2: 19–22.
85 Margariti PN, Astrakas LG, Tsouli SG, Hadjigeorgiou GM,
Konitsiotis S, Argyropoulou MI. Investigation of unmedicated
early onset restless legs syndrome by voxel-based morphometry,
T2 relaxometry, and functional MR imaging during the night-time
hours. AJNR Am J Neuroradiol 2012; 33: 667–72.

12 www.thelancet.com/neurology Published online September 20, 2018 http://dx.doi.org/10.1016/S1474-4422(18)30311-9

Anda mungkin juga menyukai