The restless legs syndrome
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
References (403)
- et al.
Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections
Brain Res.
(2001) - et al.
State dependent excitability changes of spinal flexor reflex in patients with restless legs syndrome secondary to chronic renal failure
Sleep Med.
(2002) Dopamine and iron in the pathophysiology of restless legs syndrome (RLS)
Sleep Med.
(2004)- et al.
Defining the phenotype of the restless legs syndrome (RLS) using age-of-symptom-onset
Sleep Med.
(2000) - 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.
Spontaneous motor activity in human infants with iron-deficiency anemia
Early Hum. Dev.
(2002) - et al.
Nutritional iron and dopamine binding sites in the rat brain
Pharmacol. Biochem. Behav.
(1982) - et al.
Assessment of spontaneously occurring periodic limb movements in sleep in the rat
J. Neurol. Sci.
(2002) - et al.
Tapping into spinal circuits to restore motor function
Brain Res. Brain Res. Rev.
(1999) - et al.
Initiation and modulation of the locomotor pattern in the adult chronic spinal cat by noradrenergic, serotonergic and dopaminergic drugs
Brain Res.
(1991)
Altered monamine metabolism in caudate-putamen of iron-deficient rats
Pharmacol. Biochem. Behav.
Antidromic discharges in dorsal roots of decerebrate cats. I. Studies at rest and during fictive locomotion
Brain Res.
Antidromic discharges in dorsal roots of decerebrate cats. II. studies during treadmill locomotion
Brain Res.
Differential effects of SKF 38393 and LY 141865 on nociception and morphine analgesia
Life Sci.
A preliminary study of the effects of correction of anemia with recombinant human erythropoietin therapy on sleep, sleep disorders, and daytime sleepiness in hemodialysis patients (The SLEEPO study)
Am. J. Kidney Dis.
Restless legs syndrome in hemodialysis patients in India: a case controlled study
Sleep Med.
Prevalence, severity and risk factors of restless legs syndrome in the general adult population in two Scandinavian countries
Sleep Med.
Endogenous opiates and behavior: 2003
Peptides
Dopamine D3 receptor agonists produce similar decreases in body temperature and locomotor activity in D3 knock-out and wild-type mice
Neuropharmacology
Monoaminergic control of the release of calcitonin gene-related peptide- and substance P-like materials from rat spinal cord slices
Neuropharmacology
Dopamine receptor-mediated depression of spinal monosynaptic transmission
Brain Res.
Brain iron, transferrin and ferritin concentrations are altered in developing iron-deficient rats
J. Nutr.
Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p
Am. J. Hum. Genet.
Reliability of a questionnaire screening restless legs syndrome in patients on chronic dialysis
Am. J. Kidney Dis.
Reversal of the circadian expression of tyrosine-hydroxylase but not nitric oxide synthase levels in the spinal cord of dopamine D(3) receptor knockout mice
Neuroscience
Clinical and biochemical findings in uremic patients with and without restless legs syndrome
Am. J. Kidney Dis.
The measurement of serum transferrin receptor
Am. J. Med. Sci.
Identification of a major susceptibility locus for restless legs syndrome on chromosome 12q
Am. J. Hum. Genet.
Increased nigral iron content in postmortem parkinsonian brain
Lancet
Opioid antagonists and spinal reflexes in the anaesthetized cat
Brain Res.
Neural control of locomotion: the central pattern generator from cats to humans
Gait Posture
The treatment of restless legs syndrome with intravenous iron dextran
Sleep Med.
Repeated IV doses of iron provides effective supplemental treatment of restless legs syndrome
Sleep Med.
Relative potency of epidural to intrathecal clonidine differs between acute thermal pain and capsaicin-induced allodynia
Pain
A targeted mutation of the D3 dopamine receptor gene is associated with hyperactivity in mice
Proc. Natl. Acad. Sci. U.S.A.
Treatment of restless legs syndrome with gabapentin
Clin. Neuropharmacol.
Olfactory function in restless legs syndrome
Mov. Disord.
Restless legs syndrome treatment with dopaminergic drugs
Clin. Neuropharmacol.
Organization of central nervous system dopaminergic pathways
J. Neural Transm. Suppl.
MRI measurement of brain iron in patients with restless legs syndrome
Neurology
Restless legs syndrome prevalence and impact: REST general population study
Arch. Intern. Med.
Periodic limb movements in sleep in community-dwelling elderly
Sleep
Circadian modulation of dopamine receptor responsiveness in Drosophila melanogaster
Proc. Natl. Acad. Sci. U.S.A.
Control of locomotion in vitro. II. Chemical stimulation
Somatosens Mot. Res.
The importance of formal serum iron studies in the assessment of restless legs syndrome
Neurology
Periodic limb movements in sleep: state-dependent excitability of the spinal flexor reflex
Neurology
Dopamine receptor-mediated spinal antinociception in the normal and haloperidol pretreated rat: effects of sulpiride and SCH 23390
Br. J. Pharmacol.
Responses of motoneurones to electrophoretically applied dopamine
Br. J. Pharmacol.
Neuromodulation of the locomotor network by dopamine in the isolated spinal cord of newborn rat
Eur. J. Neurosci.
Sex and the risk of restless legs syndrome in the general population
Arch. Intern. Med.
Cited by (92)
Restless legs syndrome: Clinical changes in nervous system excitability at the spinal cord level
2019, Sleep Medicine ReviewsCitation Excerpt :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].
Complementary and alternative therapies for restless legs syndrome: An evidence-based systematic review
2018, Sleep Medicine ReviewsRestless Leg Syndrome in Neurologic and Medical Disorders
2015, Sleep Medicine ClinicsNeurological Insights into Sleep Disorders in Parkinson’s Disease
2023, Brain Sciences