Elsevier

Progress in Neurobiology

Volume 77, Issue 3, October 2005, Pages 139-165
Progress in Neurobiology

The restless legs syndrome

https://doi.org/10.1016/j.pneurobio.2005.10.007Get rights and content

Abstract

The restless legs syndrome (RLS) is one of the commonest neurological sensorimotor disorders at least in the Western countries and is often associated with periodic limb movements (PLM) during sleep leading to severe insomnia. However, it remains largely underdiagnosed and its underlying pathogenesis is presently unknown. Women are more affected than men and early-onset disease is associated with familial cases. A genetic origin has been suggested but the mode of inheritance is unknown. Secondary causes of RLS may share a common underlying pathophysiology implicating iron deficiency or misuse. The excellent response to dopaminegic drugs points to a central role of dopamine in the pathophysiology of RLS. Iron may also represent a primary factor in the development of RLS, as suggested by recent pathological and brain imaging studies. However, the way dopamine and iron, and probably other compounds, interact to generate the circadian pattern in the occurrence of RLS and PLM symptoms remains unknown. The same is also the case for the level of interaction of the two compounds within the central nervous system (CNS). Recent electrophysiological and animals studies suggest that complex spinal mechanisms are involved in the generation of RLS and PLM symptomatology. Dopamine modulation of spinal reflexes through dopamine D3 receptors was recently highlighted in animal models. The present review suggests that RLS is a complex disorder that may result from a complex dysfunction of interacting neuronal networks at one or several levels of the CNS and involving numerous neurotransmitter systems.

Introduction

The restless legs syndrome (RLS) remains one of the most intriguing and commonest chronic sensorimotor disorders, yet it is still a poorly recognized condition in primary care settings as physicians are frequently unaware of the condition and misdiagnosis is common (Allen et al., 2005, Hening, 2004, Tison et al., 2005, Van De Vijver et al., 2004, Walters et al., 1996). Even though RLS was first identified and characterized in the forties (Ekbom, 1945), it is only recently that the International Restless Legs Syndrome Study Group (IRLSSG) outlined its clinical features (Allen et al., 2003). The underlying neurophysiological and biochemical mechanisms are currently being investigated and recent animal and molecular studies have also begun to elucidate the still uncertain nature of the basic pathophysiology of RLS.

In the present review, we have attempted to summarize the most relevant and recent clinical, epidemiological and genetic aspects of RLS. Much of the manuscript also concerns the secondary forms of RLS as we believe that some may share a similar pathophysiology. The latter has been discussed in separate sections devoted to major biochemical and neurotransmitter systems, brain structures and particularly to spinal mechanisms thought to be involved in the pathophysiology of RLS. Finally, the article concludes with a summary of certain major animal models with pathophysiological significance which have emerged over recent years and which are likely to influence future research in this field.

Despite extensive literature on the topic, RLS appears increasingly to be a complex disorder whose underlying pathophysiology is still unraveled. However, this should not impede clinical and fundamental research efforts for better recognition of the disease.

Section snippets

Clinical presentation

RLS is a common and treatable chronic sensorimotor disorder clinically characterized by a compelling urge to move the limbs, accompanied by uncomfortable and unpleasant sensations in the extremities. Typically, the legs are mostly affected but arm involvement has also been reported (Ekbom, 1960, Michaud et al., 2000, Montplaisir et al., 1997, Ondo and Jankovic, 1996). The diagnosis of RLS is clinical and is based on the patient's description. Subjective symptoms, which are the hallmark of the

Epidemiology

Prevalence rates of RLS, at least in Western countries, clearly identify this disorder as one of the most common neurological movement disorders. However, prevalence estimates in general populations do not overlap across studies even when the IRLSSG criteria are strictly applied. The subjective nature of the complaints, the fluctuating and intermittent course of initial symptoms, different targeted patient populations, and the various methodological tools used such as mailed questionnaires,

Genetics

A positive family history of RLS is supportive of the diagnosis of RLS (Allen et al., 2003). Clinical surveys have shown that in idiopathic forms of the disease, 40.9–92% of patients report having a family history of RLS, suggesting the contribution of genetic factors to the development of this condition (Bjorvatn et al., 2005, Lavigne and Montplaisir, 1994, Montplaisir et al., 1997, Ondo and Jankovic, 1996, Tison et al., 2005, Walters et al., 1996, Winkelmann et al., 2000, Winkelmann et al.,

Periodic limb movements

Another feature of RLS seen in most patients is the presence of unilateral or bilateral recurring movements of the lower limbs referred to as PLM (Coleman et al., 1980). This condition is characterized by periodic episodes of involuntary repetitive and highly stereotyped extension of the big toe and dosiflexion of the ankle with occasional flexion of the knee and hip. The movements usually involve the legs, but in severely affected RLS patients, the arms may also be involved (Chabli et al., 2000

Circadian rhythm of RLS and PLM

Even if sleep deprivation increases the degree of subjective discomfort through a homeostatic process, the striking diurnal fluctuation of RLS symptoms suggests that independent circadian mechanisms play an essential role in the pathophysiology of the disorder. Worsening of both sensory and motor symptoms in RLS has been shown to follow a circadian pattern that parallels core body temperature rhythm, independently from the general level of activity, sleep deprivation, drowsiness or fatigue.

Secondary RLS

Whilst most cases may be idiopathic, RLS may also occur in acquired forms associated with a variety of neurological disorders, including parkinsonian syndromes, and several other medical conditions, some of which involve a possible iron deficiency. Iron deficiency, end-stage renal disease and pregnancy are thus well established secondary causes of RLS. Although diabetes and neuropathy are commonly given as causes for secondary RLS, supporting data are limited and survey studies using full

Dopamine and RLS

The strongest evidence for a primary dopaminergic role in RLS and PLM is to be found in the excellent pharmacological response to low-dose dopaminergic medications (Hening et al., 1999a) and the worsening of symptoms with dopamine release blocker (Kraus et al., 1999, Montplaisir et al., 1991).

Investigation for a potential nigrostriatal dopaminergic dysfunction in patients with idiopathic RLS by means of functional neuroimaging techniques has produced conflicting results and overall no obvious

Opioids and RLS

Successful treatment of RLS and PLM with opioid drugs has led to speculation that the endogenous opiate system may be involved in the pathogenesis of RLS and PLM (Hening et al., 1986, Walters et al., 1986). However, prospective, double-blind, placebo-controlled trials with a significant large sample of RLS patients are scarce (Walters et al., 1993). Many of the studies are small and have yielded contradictory results, while other studies have demonstrated only marginal benefit of opioid agents

Iron and RLS

Based on the evidence of deficient iron storage in RLS patients and marked improvement in some patients with iron supplementation, it is likely that brain iron status plays a role in the pathogenesis of RLS (Allen, 2004). However, although compelling data suggest possible connections between iron and dopamine pathology in RLS, it is still unknown how iron impacts the dopaminergic system to produce RLS symptoms.

In the brain, iron is unevenly distributed with the highest concentrations of iron to

Brain structures

A direct participation of the cerebral cortex in the genesis of RLS seems to be excluded since electroencephalographic back-averaging elicited no cortical pre-potentials in association with PLM in RLS patients (Provini et al., 2001, Trenkwalder et al., 1993), although a preparatory cortical activation was shown to precede leg movements on functional electroencephalography (Rau et al., 2004). Motor descending pathway excitability is also normal, as studied by transcranial magnetic stimulation

Spinal origin of RLS?

In the RLS, clinical and electrophysiological studies have provided evidence for impairment of sensorimotor processing at the level of the spinal cord, suggesting enhanced spinal excitability and/or diminished central inhibition. One recent clinical study demonstrated static mechanical hyperalgesia in patients with RLS and suggested the latter to be a primary pain modulation disorder involving central sensitization probably within the spinal cord (Stiasny-Kolster et al., 2004a). This is in

Animal models of RLS and PLM

The use of animal models is a pillar of the basic neuroscience research conduced into the understanding, prevention and treatment of neurological diseases, particularly in the field of movement disorders. The adequacy of any model is determined by its relevant pathological and behavioral features. This is particularly difficult in RLS as the clinical diagnosis relies exclusively on subjective symptoms, and any pathological features, if present, are so far undetermined. To the best of our

Conclusion

In a dysesthesic context, the involuntary advent of elementary motor programs predominantly in the legs should be subject to relatively simple central mechanisms. On the contrary, the pathophysiology of the RLS is really complex and its primum movens remains unknown. However, the following evidence can be put forward.

  • (1)

    The spontaneous emergence of this abnormal motor activity may depend on an increase in the neuronal excitability of different spinal areas involving the motor sector or even spinal

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      Restless legs syndrome (RLS) is a disorder presenting with both sensory and motor symptoms, which are often manifest as an urge to move and periodic limb movements (PLM) respectively [1]. As the spinal cord is the site of sensory input and motor output it has been considered that the aetiology of RLS may be due to dysfunctions in the spinal cord leading to hyperexcitability [2]. It is possible that RLS patients have reductions in descending spinal inhibition due to subcortical and/or intra-cortical dysfunction [3].

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