We searched the MEDLINE database for articles published in any language between Jan 1, 2013, and May 10, 2018, using the following terms: ((“restless legs syndrome” OR “willis ekbom disease”) AND (augment* OR pathophysiol* OR pathway* OR imag* OR genetic* OR dopamine* OR comorbid* OR dopamine receptor*)). We identified 728 articles. We also included articles that we were aware of being in press. We generated the final reference list on the basis of relevance to the topics covered in this Review.
ReviewComorbidities, treatment, and pathophysiology in restless legs syndrome
Introduction
The recognition of restless legs syndrome as a disease with substantial effects on quality of life is still low among neurologists. Consequently, when patients present with either sensory symptoms in their legs (with or without pain), an urge to move at rest mostly in the evening, and sleep disturbances,1 they are often undiagnosed and left untreated for years.2, 3
To address this problem, new diagnostic criteria (appendix) have been established by a consensus of restless legs syndrome experts from the International Restless Legs Syndrome Study Group (IRLSSG),4 and a slightly modified version has been published by the American Academy of Sleep Medicine5 in their International Classification of Sleep Disorders (ICSD-3). Although most research refers to the IRLSSG diagnostic criteria,4 there are independent and somewhat different diagnostic criteria proposed by the American Psychiatric Association published in their Diagnostic and Statistical Manual of Mental Disorders (DSM-5). The DSM-5 criteria do not differentiate between intermittent and chronic persistent restless legs syndrome, which is essential for clinical practice and therapeutic long-term management.6
The strong familial component, observed many years ago in clinical practice, led to decades of genetic research in restless legs syndrome and showed the genetic heterogeneity of the condition, now considered a common complex genetic disease.7 However, comorbidities are considered as environmental factors8 that can complicate diagnosis and treatment, and iron deficiency anaemia, renal insufficiency (when leading to dialysis),9 and pregnancy10 are all conditions in which restless legs syndrome can severely affect both the health condition and quality of life.
Therapeutics have been assessed by use of evidence-based medicine techniques,11 and algorithms have been created for initiating restless legs syndrome therapy and managing augmentation, a serious worsening of symptoms with longer-term dopaminergic treatment.12 Although iron preparations have not received regulatory approval, guidelines for this type of treatment have been published.13 Considering novel risk loci for restless legs syndrome by use of genome-wide association studies (GWAS) could also lead to new therapeutic approaches.14 These achievements are important in harmonising restless legs syndrome evidence-based management among physicians and in avoiding augmentation, but more work is needed to understand the pathophysiology of the disease and provide the best care for patients.
This Review aims to specifically address the improved diagnosis of restless legs syndrome, including in patients with comorbidities since these patients are the most difficult to treat. We also review evidence-based treatments that seek to avoid augmentation, which is particularly warranted given the dose-dependent association between dopaminergic drugs and augmentation, derived from interactions of D1 and D3 receptors and their overstimulation that contribute to the pathophysiology of augmentation. We examine new insights from genetics, and iron and hypoxic pathways to elucidate the strong biological component of this disease.
Section snippets
Comorbidities
In the past 5 years, an increasing number of studies describe possible conditions whereby patients with medical or neurological diseases could also have restless legs syndrome. In the past, the term secondary restless legs syndrome was used in these instances (appendix). The overall quality of these studies, however, limits the proven association with restless legs syndrome to only a few diseases, such as iron deficiency anaemia and uraemia. However, by looking into the phenomenology of these
Periodic limb movements
Periodic limb movements (PLMs) are present in most patients with restless legs syndrome, but are also highly prevalent in those without, and are associated with some of the same risk polymorphisms as restless legs syndrome, suggesting a shared genetic risk.32 The ICSD-3 diagnosis5 of PLM disorder requires that PLMs are not due to other sleep disorders. Since 2006, several PLM scoring criteria have been established and were revised in 2016 by a joint task force commissioned by the International
Pharmacological therapies
In the first trials of restless legs syndrome, dopaminergic drugs were administered once daily at night, and daytime symptoms were largely ignored.35 Since the 1990s, dopaminergic therapies have been considered the first-line treatment for adults with restless legs syndrome, both for sleep disturbance and for daytime symptoms. In the past 5 years, treatment efficacy of dopamine agonists (such as pramipexole, ropinirole, and rotigotine) approved by the US Food and Drug Administration and the
Pathophysiology
Restless legs syndrome is a disorder based on motor and sensory symptoms; the latter involve signal processing in the sensory neurons of the dorsal part of the spinal cord. By contrast, PLMs are motor events that have their final control in the motor neurons of the ventral part of the spinal cord. Both sensory and motor circuits, and their interplay in sensorimotor integration, are under descending control from monoaminergic clusters in the brain. These clusters with spinal cord projections are
Conclusions and future directions
The past 5 years have seen a remarkable convergence of clinical and laboratory studies of restless legs syndrome. Clinical studies have shown the need, and provided the data, for refinements to diagnostic criteria and the definition of the restless legs syndrome motor sign—ie, PLMs. The observation of brain iron deficiency in patients with restless legs syndrome has provided a basis for exploring multiple research areas. Studies of spinal cord dopamine system and the effects of brain iron
Search strategy and selection criteria
References (97)
- et al.
Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health
Sleep Med
(2003) - et al.
Allocating provider resources to diagnose and treat restless legs syndrome: a cost-utility analysis
Sleep Med
(2017) - et al.
Restless legs syndrome: a common disorder, but rarely diagnosed and barely treated—an Indian experience
Sleep Med
(2012) - et al.
Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria—history, rationale, description, and significance
Sleep Med
(2014) - et al.
Consensus clinical practice guidelines for the diagnosis and treatment of restless legs syndrome/Willis-Ekbom disease during pregnancy and lactation
Sleep Med Rev
(2015) - et al.
Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation
Sleep Med
(2016) - et al.
Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report
Sleep Med
(2018) - et al.
Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis
Lancet Neurol
(2017) - et al.
Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women
Blood
(2015) - et al.
Prevalence of restless legs syndrome and associated factors in an otherwise healthy population: results from the Danish Blood Donor Study
Sleep Med
(2017)
Response to intravenous iron in patients with iron deficiency anemia (IDA) and restless leg syndrome (Willis-Ekbom disease)
Sleep Med
Prevalence of restless legs syndrome in Parkinson's disease: a systematic review and meta-analysis of observational studies
Sleep Med
Prediagnostic presentations of Parkinson's disease in primary care: a case-control study
Lancet Neurol
Restless legs syndrome and cardiovascular disease: a research roadmap
Sleep Med
World Association of Sleep Medicine (WASM) 2016 standards for recording and scoring leg movements in polysomnograms developed by a joint task force from the International and the European Restless Legs Syndrome Study Groups (IRLSSG and EURLSSG)
Sleep Med
Diagnostic accuracy of the standard and alternative periodic leg movement during sleep indices for restless legs syndrome
Sleep Med
Prolonged release oxycodone-naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an open-label extension
Lancet Neurol
The appropriate use of opioids in the treatment of refractory restless legs syndrome
Mayo Clin Proc
Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study
Lancet Neurol
Polysomnographic findings in restless legs syndrome (RLS) patients with severe augmentation
Sleep Med
Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study
Sleep Med
Management of treatment failure in restless legs syndrome (Willis-Ekbom disease)
Sleep Med Rev
Effects of exercise training on restless legs syndrome, depression, sleep quality, and fatigue among hemodialysis patients: a systematic review and meta-analysis
J Pain Symptom Manage
Effects of transcutaneous spinal direct current stimulation in idiopathic restless legs patients
Brain Stimul
Complementary and alternative therapies for restless legs syndrome: an evidence-based systematic review
Sleep Med Rev
Increased excitability of spinal pain reflexes and altered frequency-dependent modulation in the dopamine D3-receptor knockout mouse
Exp Neurol
Aging-related morphine tolerance in dopamine D3 receptor knockout mice reveresed by block of D1 receptor function
Neuroscience
Long-term treatment with dopamine D3 receptor agonists induces a behavioral switch that can be rescued by blocking the dopamine D1 receptor
Sleep Med
Brain iron deficiency in idiopathic restless legs syndrome measured by quantitative magnetic susceptibility at 7 tesla
Sleep Med
In search of alternatives to dopaminergic ligands for the treatment of restless legs syndrome: iron, glutamate, and adenosine
Sleep Med
Genetics of restless legs syndrome
Sleep Med
Genetic associations of periodic limb movements of sleep in the elderly for the MrOS sleep study
Sleep Med
Activity-induced DNA breaks govern the expression of neuronal early-response genes
Cell
Animal models of RLS phenotypes
Sleep Med
Altered brain iron homeostasis and dopaminergic function in restless legs syndrome (Willis-Ekbom disease)
Sleep Med
Lower molecular weight intravenous iron dextran for restless legs syndrome
Sleep Med
High prevalence of restless legs syndrome/Willis Ekbom Disease (RLS/WED) among people living at high altitude in the Indian Himalaya
Sleep Med
Iron and restless legs syndrome: treatment, genetics and pathophysiology
Sleep Med
Influence of high altitude on periodic leg movements during sleep in individuals with restless legs syndrome and healthy controls: a pilot study
Sleep Med
The international classification of sleep disorders: diagnostic & coding manual (ICSD-3)
Diagnostic and statistical manual of mental disorders
Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions
Nat Genet
Restless legs syndrome associated with major diseases: a systematic review and new concept
Neurology
Restless legs syndrome is contributing to fatigue and low quality of life levels in hemodialysis patients
World J Nephrol
Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice
Mov Disord
The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia
Am J Hematol
A prospective study of the cumulative incidence and course of restless legs syndrome in de novo patients with Parkinson's disease during chronic dopaminergic therapy
J Neurol
Association of restless legs syndrome with incident Parkinson's disease
Sleep
Cited by (162)
Redefining the role of the cerebellum in restless legs syndrome
2023, Sleep MedicineRestless legs syndrome: From clinic to personalized medicine
2023, Revue NeurologiqueCorrelates of Restless Legs Syndrome in Older People
2024, Journal of Clinical Medicine