Elsevier

The Lancet Neurology

Volume 17, Issue 11, November 2018, Pages 994-1005
The Lancet Neurology

Review
Comorbidities, treatment, and pathophysiology in restless legs syndrome

https://doi.org/10.1016/S1474-4422(18)30311-9Get rights and content

Summary

Restless legs syndrome, also known as Willis-Ekbom disease, is a common neurological condition whose manifestation is affected by complex environmental and genetic interactions. Restless legs syndrome can occur on its own, mostly at a young age, or with comorbidities such as cardiovascular disease, diabetes, and arterial hypertension, making it a difficult condition to properly diagnose. However, the concept of restless legs syndrome as being two entities, primary or secondary to another condition, has been challenged with genetic data providing further insight into the pathophysiology of the condition. Although dopaminergic treatment was formerly the first-line therapy, prolonged use can result in a serious worsening of symptoms known as augmentation. Clinical studies on pregabalin, gabapentin enacarbil, oxycodone–naloxone, and iron preparations have provided new treatment options, but most patients still report inadequate long-term management of symptoms. Studies of the hypoxic pathway activation and iron deficiency have provided valuable information about the pathophysiology of restless legs syndrome that should now be translated into new, more effective treatments for 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

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.

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