INTRODUCTION — Restless legs syndrome (RLS), also called Willis-Ekbom disease (WED), is a common sleep-related movement disorder characterized by an often unpleasant or uncomfortable urge to move the legs that occurs during periods of inactivity, particularly in the evenings, and is transiently relieved by movement. During sleep, most patients with RLS have characteristic limb movements, called periodic limb movements of sleep (PLMS), which may or may not be associated with arousal from sleep.
Periodic limb movement disorder (PLMD) is characterized by a clinical sleep disturbance attributed to an increased number of PLMS, in the absence of alternative causes of the sleep complaints. It usually manifests as daytime somnolence. PLMD and RLS are distinct, mutually exclusive diagnoses.
This topic will discuss the epidemiology, pathophysiology, clinical features, and diagnosis of RLS and PLMD in adults. Treatment of RLS and PLMD in adults, RLS during pregnancy and lactation, and RLS and PLMD in children are reviewed separately. (See "Management of restless legs syndrome and periodic limb movement disorder in adults" and "Restless legs syndrome during pregnancy and lactation" and "Restless legs syndrome and periodic limb movement disorder in children".)
EPIDEMIOLOGY — Restless legs syndrome (RLS) of any severity occurs in 5 to 15 percent of adults in studies that include primarily European and North American populations [1-3]. Estimates of clinically significant RLS are lower (2 to 3 percent), and studies that rely exclusively on questionnaires may overestimate prevalence.
The prevalence of RLS varies by region, ethnicity, sex, and age .
●Region and ethnicity – Northern European countries tend to have the highest prevalence estimates, followed by Germanic/Anglo-Saxon countries, and then Mediterranean countries. The prevalence declines in regions further south and east. Studies in Turkey and India have found a 2 to 3 percent prevalence of RLS; estimates are even lower in East Asia (eg, <1 percent in Singapore). RLS appears to be rare in Africa (<0.1 percent) .
●Sex – Females have higher rates of RLS than males in many studies. Most of the difference appears to be related to a rise in RLS prevalence during pregnancy, and sex differences are minimal when comparing nulliparous females with males [6,7].
●Age – RLS can occur throughout the lifespan, and most studies show increasing prevalence with advancing age . Rates of RLS in children are about 50 percent lower than in adults . (See "Restless legs syndrome and periodic limb movement disorder in children", section on 'Epidemiology'.)
Periodic limb movement disorder (PLMD) is thought to be uncommon, but the exact prevalence is not known . By contrast, periodic limb movements of sleep (PLMS) are common in healthy older adults and in association with RLS and other sleep disorders such as obstructive sleep apnea and narcolepsy. (See 'Periodic limb movements of sleep' below.)
PATHOPHYSIOLOGY — The pathophysiologic basis of restless legs syndrome (RLS) remains incompletely understood, although studies have identified a variety of both central and peripheral nervous system abnormalities in patients with the disorder. There is no evidence that neurodegeneration plays a role .
Central nervous system correlates — The most consistently implicated central nervous system (CNS) alteration in patients with RLS is reduced central iron stores; alterations in dopaminergic systems, circadian physiology, thalamic function, and other neurotransmitters such as glutamate and gamma-aminobutyric acid (GABA) have also been implicated.
●Iron – Reduced CNS iron stores are a robust and consistent finding in RLS, even in the setting of normal systemic iron studies. This finding has been demonstrated in several ways:
•Cerebrospinal fluid (CSF) ferritin is lower in RLS cases compared with controls , and advanced magnetic resonance imaging (MRI) studies show reduced iron stores in the striatum, thalamus, and red nucleus [11-14].
•CNS ultrasonography has identified reduced iron echogenicity in the substantia nigra of patients with RLS [15,16]. Additionally, mitochondrial ferritin is increased in neurons in the substantia nigra but not the putamen .
•Autopsy specimens of patients with RLS show reduced ferritin and iron staining, increased transferrin staining, and reduced transferrin receptors . The reduced transferrin receptor finding is especially important since globally reduced iron stores would normally upregulate transferrin receptors, suggesting a more complicated process than simple lack of iron availability.
Taken together, these data suggest that reduced intracellular iron indices in primary RLS are associated with a perturbation of homeostatic mechanisms that regulate iron influx and/or efflux from the cell.
●Dopaminergic systems – The relationship between RLS and CNS dopaminergic systems is complex and not fully understood. Although the observation that RLS symptoms improve with dopaminergic therapy strongly implicates CNS dopamine in the pathogenesis of RLS, there is little pathologic evidence to suggest an actual dopaminergic deficiency in the striatum or substantia nigra of patients with the disorder [19-21].
Similarly, numerous brain dopamine imaging studies have yielded inconsistent results, generally showing either modest or no abnormalities in various aspects of dopaminergic neurotransmission [22-25]. Dopamine precursor studies have shown normal or reduced dopamine levels; dopamine transporter studies have shown levels to be normal or reduced; and dopamine receptor studies have shown reduced, normal, or increased activity.
There is indirect evidence that dopamine turnover may actually be increased in RLS . As an example, one study found that CSF 3-ortho-methyldopa (3-OMD) levels were increased in RLS subjects, suggesting either a general increase in dopamine metabolism or increased monoamine oxidase B (MAO-B) activity, which metabolizes dopamine to 3-OMD . These data have led some to speculate that RLS is a disease of hyperdopaminergic function. However, this model cannot easily explain the dramatic and immediate benefit of dopaminergic therapy in RLS.
Several studies have observed that the normal circadian dopaminergic variation is augmented in patients with RLS [28,29]. The specific dopaminergic anatomy has been hypothesized to involve the diencephalospinal dopaminergic tract, originating in the hypothalamus. This dopaminergic tract is involved in anti-nociception and also originates near circadian control centers.
●Other neurotransmitters – Preliminary data have implicated a variety of other neurotransmitter abnormalities in the pathogenesis of RLS, including endogenous opioids , glutamate and glutamine , adenosine , histamine , and gamma-aminobutyric acid (GABA) .
●Thalamic correlates – Thalamic abnormalities have been frequently reported in association with RLS [19,35-38]. In one small pathologic study, numbers of thalamic beta-endorphin positive cells and met-enkephalin positive cells were reduced in RLS patients compared with controls . Voxel-based MRI studies have inconsistently shown increased pulvinar size, and sometimes decreased cortical gray matter, in patients with RLS [35,36]. Others have shown reduced metabolite activity (reduced N-acetylaspartate to creatine ratio) in the medial thalamus .
●Network connectivity – A number of resting state connectivity studies show abnormalities in RLS, most commonly impacting the thalamus and pons, some of which change with treatment [39-42]. Functional MRI studies show increased activity in the red nucleus and brainstem near the reticular formation during active RLS .
Peripheral pathophysiology — The peripheral afferent nervous system has also been implicated in the pathogenesis of RLS. In a series of studies, pinprick pain ratings (ie, static hyperalgesia) in patients with RLS were significantly elevated in the leg, whereas pain in response to light touch (ie, dynamic mechanical hyperalgesia or allodynia) was normal [44,45]. The authors concluded that this type of hyperalgesia was probably mediated by central sensitization to A-delta fiber high-threshold mechanoreceptor input, a hallmark sign of hyperalgesic neuropathic pain.
Abnormalities of microvascular function in the legs have also been demonstrated in individuals with RLS, including altered leg intramuscular blood flow [46,47], peripheral hypoxia , and reduced endothelial function [49,50].
RISK FACTORS — Despite considerable attention given to restless legs syndrome (RLS) genetics, many patients who suffer from RLS do not have an identifiable or highly penetrant genetic pattern. Patients without a positive family history are classified as either primary RLS, if no other explanation is found, or secondary RLS, if they have a comorbid condition known to be associated with RLS.
The most common conditions associated with RLS include systemic iron deficiency, renal failure, neuropathy, spinal cord pathology, pregnancy, multiple sclerosis, and possibly Parkinson disease (PD) and essential tremor; each of these is discussed in more detail below.
Family history and genetics — With careful questioning, a family history of RLS is present in 40 to 60 percent of cases . Twin studies also show a very high concordance rate [52,53]. Most pedigrees suggest an autosomal dominant pattern , although an autosomal recessive pattern with a very high carrier rate is also possible.
Despite many positive linkage studies, however, no specific gene mutations have been identified to date . Numerous candidate genes have been explored, including those involved with dopamine metabolism, Parkinson disease, neurodegeneration, and systemic iron regulation. Results have generally been unrevealing, although the alpha-synuclein promoter Rep1 allele 2, which is a risk factor for Parkinson disease, seems to protect against RLS [56-58]. Whole exome sequencing of an RLS family suggested PCDHA3 as a candidate gene, but this finding remains preliminary .
Genome-wide association studies have found 19 potential risk factor genes that have been replicated in multiple populations, including MEIS1, BTBDP, MAP2K5/LBOXCOR1, PRPRD, and TOX3 [60-66]. Next-generation sequencing of coding sequences has confirmed some of these loci and identified other novel genes . Function analysis of these genes and causative variants within these loci is ongoing. Several of the candidates are thought to be developmental genes, several are involved axonal and synaptic regulation, and several are involved in DNA repair; at least one has been associated with iron regulation . As with other common conditions, the genetics of RLS are complex and probably involve the presence of multiple risk alleles.
Low iron stores — Reduced central nervous system (CNS) iron is a consistent finding in RLS (see 'Central nervous system correlates' above). It follows intuitively that reduced body iron stores could translate into low CNS intracellular iron and thereby cause or exacerbate RLS symptoms; clinical observations largely bear this out.
In multiple studies, low serum ferritin levels (<45 to 50 ng/mL) correlate with RLS [10,11,69-72]. The association seems to be strongest in patients with older-onset RLS and in those who lack a family history [73,74]. Importantly, anemia has not been independently associated with RLS; although frequent blood donors often develop RLS symptoms, this phenomenon is likely due to depletion of iron stores rather than decreased hemoglobin/hematocrit [70,75]. Among patients with RLS and iron deficiency, most are not anemic .
Decreased serum ferritin is the best indicator of low iron stores and the only serum measure to consistently correlate with RLS. However, ferritin is an acute phase reactant and "normal" levels increase with age. Therefore, a "normal" range ferritin does not exclude iron deficiency, and calculation of transferrin saturation (TSAT) may be helpful when clinical suspicion is high. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Progressive iron depletion' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Iron studies (list of available tests)'.)
Uremia — Uremia secondary to renal failure is strongly associated with symptoms of RLS. The reported prevalence of RLS ranges from 20 to 73 percent in renal dialysis patients . Some of this variability may be due to the fact that only a minority of uremic patients volunteer RLS symptoms unless specifically queried. Patients with renal impairment not yet requiring dialysis have normal to moderately elevated risk of RLS .
Potential risk factors for RLS in this population include anemia, iron deficiency, diabetes mellitus, high parathyroid hormone, high homocysteine, female sex, younger age, and elevated beta-2 microglobulin. Of these, only low hemoglobin/iron (statistically combined) and diabetes were significantly associated with RLS risk in a meta-analysis of 23 studies in dialysis patients . In one study, genetic factors associated with idiopathic RLS were not found in patients with uremia .
The symptoms of RLS in patients on dialysis are often severe, and patients tend to have high periodic limb movements of sleep (PLMS) indices. Both RLS and PLMS have been associated with increased mortality in the dialysis population [81-84]. Correction of uremia with successful kidney transplant usually leads to improvement in RLS symptoms within days to weeks [85-87], but symptoms do not improve with dialysis . (See "Sleep disorders in end-stage kidney disease", section on 'Restless legs syndrome and periodic limb movement disorder'.)
Neuropathy — Neuropathy related to a variety of underlying causes, including diabetes, alcohol, amyloid, motor neuron disease, poliomyelitis, and radiculopathy have been observed with increased frequency in patients presenting with RLS compared with expected rates in the general population [51,89-95]. The reverse association has been less consistent. Studies evaluating the prevalence of RLS in patients presenting with neuropathy have found RLS rates ranging from 5 to 10 percent, similar to that of the general population [93,94].
In some cases, the prevalence of RLS may be overestimated in patients with neuropathy due to an overlap in symptomatology. This was demonstrated by a case-control study in which nearly 500 individuals were screened for RLS with a standardized phone questionnaire based on RLS diagnostic criteria . While a larger percentage of neuropathy patients endorsed RLS on screening questionnaires compared with controls (18 versus 6 percent), this difference narrowed when individuals underwent a confirmatory diagnostic evaluation (12 versus 8 percent) .
In general, axonal neuropathies have a stronger association with RLS than demyelinating neuropathies.
Spinal cord disease — The spinal cord is implicated in the pathogenesis of RLS , and cases of RLS and PLMS are seen after transient or permanent spinal cord lesions. Traumatic spinal cord lesions [98,99], spinal cord tumors , demyelinating or postinfectious lesions [101-103], and syringomyelia  can all precipitate RLS and PLMS.
Spinal cord blocks used for anesthesia also frequently cause or exacerbate RLS [105,106]. In one prospective study that included 161 subjects without a history of RLS, 9 percent of subjects developed RLS symptoms immediately following spinal anesthesia .
Pregnancy — RLS affects up to one-quarter of individuals during the course of pregnancy. Symptoms tend to escalate over the course of pregnancy, peaking during the third trimester, and remit shortly after delivery. RLS during pregnancy and lactation is discussed in detail separately. (See "Restless legs syndrome during pregnancy and lactation".)
Multiple sclerosis — RLS occurs more commonly in patients with multiple sclerosis compared with the general population. Prevalence estimates range from 10 to 60 percent [107,108]. Risk factors for RLS among individuals with multiple sclerosis include increased disease severity, the chronic progressive form of the disease, and spinal cord lesions [109-111]. Similar findings have been described in patients with neuromyelitis optica spectrum disorder .
Parkinson disease — The reported prevalence of RLS in patients with PD is about 15 to 20 percent in populations with European ancestry [74,113-119]; however, at least some of these cases may represent a less specific "leg restlessness" rather than true RLS . Asian populations, which have less RLS in general, also have lower rates of RLS in patients with PD, but still more than control populations [121,122]. The association is more robust for PD than for other parkinsonian syndromes . One meta-analysis reported that within PD populations, lower ferritin levels were associated with RLS symptoms .
There are several caveats that tend to lessen the clinical significance of RLS in patients with PD. First, RLS symptoms in these patients are often ephemeral, usually not severe, and can be confused with symptoms of PD such as wearing off dystonia, akathisia, or internal tremor. In addition, RLS symptoms do not correlate with daytime sleepiness in patients with PD, and PD precedes the onset of RLS in most cases.
Although PD and RLS both respond to dopaminergic therapies, the underlying pathology and pathophysiology of the two diseases are distinct and, at least with regard to iron accumulation, seemingly opposite . There is no evidence that RLS is a precursor of PD; one study found that young-onset idiopathic RLS was associated with a delayed onset of PD when it did occur .
Others — Limited data support an association between essential tremor and RLS . Patients with both disorders usually present first with tremor, which is often severe. Interestingly, they also have family histories of both disorders, suggesting a common genetic origin.
There are additional reports supporting an association of RLS with some genetic ataxias [119,127,128], fragile X associated tremor ataxia syndrome , fibromyalgia , rheumatologic diseases [131-133], and migraine [134-136]. A number of other conditions have less consistent associations.
Symptoms — The hallmark symptom of restless legs syndrome (RLS) is an often unpleasant or uncomfortable urge to move the legs (and occasionally the arms). The symptom emerges during periods of inactivity, is most prominent in the evening, and is transiently relieved by movement. It is usually felt deep within the legs, often between the knee and ankle.
The sensation may be difficult for individuals to characterize, and subjective descriptions can be quite varied and suggestible. Common terms used by individuals with RLS to describe their symptoms include: "need to move," "crawling," "tingling," "restless," "cramping," "creeping," "pulling," "electric," "tension," "discomfort," "soreness," and "itching" [51,76]. Typically the sensations are deep rather than superficial.
For patients who have difficulty describing their symptoms, it can be helpful to ask questions that target other key aspects of RLS symptomatology:
●Does the symptom make you want to move your legs?
●Is the symptom better while moving?
●Are symptoms worse in the evening or at night?
The sensation of RLS is unpleasant, but not necessarily painful. Patients usually deny that the symptom has a burning or pins and needles quality, commonly experienced in neuropathies or nerve entrapments, although neuropathic pain and RLS can coexist. (See 'Neuropathy' above.)
Essentially all patients report that walking and other movements or maneuvers provide transient symptomatic improvement. These include rubbing or pressure, stretching, and application of hot or cold water. As a general rule, harsh sensory stimuli, as well as cognitive or emotionally activating circumstances, tend to mitigate symptoms of RLS.
Common consequences of RLS include sleep-onset insomnia, nocturnal awakenings, depression, and anxiety. Other clinical features typical of RLS include the tendency for symptoms to gradually worsen with age, improvement with dopaminergic treatments, a positive family history, and a description from a bed partner or sleep study of periodic limb movements while asleep.
Arm symptoms are common in severe RLS, usually following many years of isolated leg involvement. Rare clinical variants involving unpleasant perineal and lower abdominal sensations, termed restless bladder syndrome and restless genital syndrome, have been described [137,138].
Exacerbating factors — Several medications are known to exacerbate existing RLS or possibly precipitate RLS. These include:
●Antihistamines, particularly the centrally-acting (sedating), first-generation drugs such as diphenhydramine, chlorpheniramine, and hydroxyzine. Many patients with RLS will have experienced this, since sedating antihistamines like diphenhydramine are commonly used as over-the-counter sleep aids.
●Dopamine receptor antagonists, including antipsychotic medications and many anti-nausea medications (eg, prochlorperazine, chlorpromazine, metoclopramide).
●Certain antidepressants, including mirtazapine and possibly tricyclic antidepressants, selective serotonergic reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs) . SSRIs, however, are more consistently associated with periodic limb movements of sleep than RLS . Many non-SSRI antidepressants have histamine receptor affinities, which could be implicated in RLS exacerbation.
Natural history — Early and moderate RLS tends to wax and wane but when more severe, RLS symptoms are persistent. In longitudinal cohort studies, the spontaneous remission rate ranges from 30 to 60 percent [141-143]. In addition to symptom severity, factors that increase the likelihood of chronicity include a positive family history and older age at onset.
Association with adverse health outcomes — RLS is associated with multimorbidity and poor health in general [144,145]. In several large observational studies, prevalent or incident RLS has been identified as a risk factor for cardiovascular disease, stroke, cardiovascular mortality, and all-cause mortality, independent of vascular risk factors and comorbidities such as heart disease and chronic kidney disease [146-151]. Others have found that the association is no longer significant after controlling for potential confounders [152,153].
Meta-analyses support an association with hypertension, but other cardiovascular disease associations are less clear [154-156]. That said, at least one observational study has suggested that treating RLS may reduce risk of multiple cardiovascular disease outcomes .
RLS may also be associated with an increased risk of suicide and self-harm. In a United States insurance claims database study spanning six years of follow-up among nearly 170,000 adults age 20 to 65 years, a diagnosis of RLS was associated with a two- to threefold higher risk of suicide and self-harm (adjusted hazard ratio [HR] 2.66, 95% CI 1.7-4.15) . The multivariable model included adjustment for multiple potential confounders by diagnosis code, including depression, alcohol consumption, insomnia, and use of antidepressant medication. Patients with RLS are known to have an increased prevalence of depression and other psychiatric comorbidities, but this study would suggest that risk of self-harm may be conferred by additional unknown factors.
Periodic limb movements of sleep — Periodic limb movements of sleep (PLMS) are defined as periodic episodes of repetitive and highly stereotyped limb movements that occur during sleep. Specifically, polysomnography demonstrates repetitive movements that are 0.5 to 10 seconds in duration, typically separated by an interval of 20 to 40 seconds (range 5 to 90 seconds) .
Formal criteria for PLMS developed by the American Academy of Sleep Medicine (AASM) include the following :
●The minimum number of consecutive limb movement (LM) events needed to define a PLMS series is 4 LMs.
●The minimum period length between LM (defined as the time between the onsets of consecutive LMs) to include them as part of a PLMS series is 5 seconds.
●The maximum period length between LMs to include them as part of a PLM series is 90 seconds.
●LMs on two different legs separated by <5 seconds between movement onsets are counted as a single movement.
PLMS are seen in more than 80 percent of patients with RLS who undergo polysomnography. The prevalence varies depending on how many nights are evaluated and increases the more nights investigated .
The exact relationship between the two phenotypes is unclear, but genetic studies suggest that they are highly correlated . Conceptually, some authors segregate RLS into a sensory component, manifest by an urge to move, and a motor component, manifest by PLMS and/or periodic limb movements while awake (PLMA) .
PLMS can occur simultaneously in both legs, alternate between legs, or occur unilaterally. The duration of a leg movement is typically between 1.5 and 2.5 seconds; intensity and anatomic distribution vary from slight extension of the great toe to a prominent triple flexion of the entire leg. Frequency of episodes ranges from an average of one every 20 and 40 seconds. (See "Polysomnography in the evaluation of abnormal movements during sleep", section on 'Periodic limb movements of sleep'.)
Movements are most pronounced in stage N1 and stage N2 of sleep, where they are often accompanied by K-complexes on polysomnography and an increase in pulse and blood pressure . PLMS may result in arousals but are not generally associated with insomnia . Dopaminergic drugs attenuate both the leg movements and the associated blood pressure spike [164,165] but not necessarily the K-complexes and arousals that usually precede PLMS .
The blood pressure lability that occurs during leg movements  has been increasingly scrutinized as a mechanism that might explain the association between PLMS/RLS and an increased risk of cardiovascular disease and mortality that has been reported in several studies. (See 'Association with adverse health outcomes' above.)
Although PLMS accompany most cases of RLS, they are not specific to the disorder. In other words, most people with RLS have PLMS, but many people with PLMS do not have RLS. One study found that only 17 percent of subjects with PLMS on polysomnography endorsed symptoms of RLS . The prevalence of PLMS in the general population increases with age and is reported to occur in as many as 57 percent of older adults without other neurological illnesses [169,170]. Other conditions associated with PLMS include narcolepsy, obstructive sleep apnea, and Parkinson disease .
DIFFERENTIAL DIAGNOSIS — Restless legs syndrome (RLS) and periodic limb movements of sleep (PLMS) must be distinguished from a variety of other causes of abnormal sensations or movements in the legs (table 1). In most cases, this can be accomplished by a history and physical examination.
●Volitional movements – A variety of semivolitional movements, including foot tapping and bouncing, leg rocking, and isolated stereotypic movements of the leg, may be confused with RLS. Usually these lack a circadian pattern and do not bother the patient, are not necessarily associated with any "urge," and are easily suppressed. These are not generally considered to be pathologic and may be an alerting activity.
●Akathisia – Akathisia represents an inner sense of restlessness accompanied by an intense desire to move. The restlessness is usually generalized but may be most prominent in the legs; in such cases it may be confused with RLS. Unlike in RLS, however, patients with akathisia do not typically complain of limb paresthesias or other unpleasant sensory phenomena. In addition, there is less relief from voluntary movement and less circadian rhythmicity compared with RLS. Akathisia is usually associated with the use of neuroleptic (dopamine blocking) drugs. It can also be associated with orthostatic hypotension. (See "Schizophrenia in adults: Maintenance therapy and side effect management", section on 'Extrapyramidal symptoms'.)
●Nocturnal leg cramps – Nocturnal leg cramps are a common, multifactorial disorder manifested by paroxysmal, disorganized spasms that usually involve muscles of the feet or calf. Unlike the symptoms of RLS, nocturnal leg cramps are sudden in onset, short in duration, and usually associated with a palpable muscle contraction. (See "Nocturnal leg cramps", section on 'Clinical manifestations'.)
●Positional discomfort – Body positional discomfort often arises with prolonged sitting or lying in the same position. Although the discomfort is usually relieved by a simple change in position, some patients may complain that they simply cannot find a comfortable position. Other characteristic features of RLS are lacking.
●Leg pain – Pain or other discomfort in the legs secondary to vascular claudication, radiculopathy, and peripheral neuropathy can sometimes be confused with RLS, even though RLS is rarely described as being frankly painful. Unlike RLS, symptoms are not accompanied by an urge to move and are not relieved by movement; in the case of vascular claudication, symptoms may actually worsen with movement or walking.
Painful legs and moving toes is a rare symptom complex that sometimes complicates trauma to the spinal cord or cauda equina, lumbar root lesions, or peripheral neuropathy. Patients present with neuropathic leg pain associated with persistent, semirhythmic toe movements that cannot easily be reproduced volitionally, and may be only partly suppressible .
●Physiologic leg movements during sleep – Some normal movements, such as partial or "massive," hypnic myoclonic jerks and periodic movements during phasic rapid eye movement (REM) sleep, may mimic PLMS. Partial myoclonic jerks are usually multifocal and occur in distal muscles. Massive myoclonic jerks are generalized and affect trunk and proximal muscles. (See "Polysomnography in the evaluation of abnormal movements during sleep", section on 'Definitions of specific movements' and "Classification and evaluation of myoclonus", section on 'Jerks associated with sleep'.)
Restless legs syndrome — Restless legs syndrome (RLS) is a clinical diagnosis that should be suspected in patients who complain of an urge to move the legs when lying in bed or sitting down, particularly if the symptom occurs predominantly in the evenings. The diagnosis is made by history and does not require additional testing, except for an assessment of iron stores in all patients (see 'Low iron stores' above) and blood urea nitrogen and creatinine if uremia is suspected. Any potentially causative or exacerbating medications should be identified.
Diagnostic criteria for RLS published by the International Restless Legs Syndrome Study Group (IRLSSG) reflect all of the key clinical features of the disorder, and all five are required for the diagnosis (table 2) :
●An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs. Sometimes the urge to move is present without the uncomfortable sensations, and sometimes the arms or other body parts are involved in addition to the legs.
●The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting.
●The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues.
●The urge to move or unpleasant sensations are worse in the evening or night than during the day, or only occur in the evening or night. When symptoms are severe, the worsening at night may not be noticeable but must have been previously present.
●Symptoms are not solely accounted for by another medical or behavioral condition, such as leg cramps or habitual foot tapping. (See 'Differential diagnosis' above.)
Diagnostic criteria for RLS in the International Classification of Sleep Disorders, Third Edition (ICSD-3), are similar to those of the IRLSSG and also contain a requirement that symptoms cause concern, distress, sleep disturbance, or impairment in functioning . Neither a minimum frequency nor duration of events is part of the current diagnostic criteria. One study found that clinical distress associated with RLS symptoms increases sharply when symptoms are present at least three days per week .
Diagnostic phone interview , rating scales [175,176], and a quality of life scale  have all been validated based on these features . A single diagnostic question, "When you try to relax in the evening or sleep at night, do you ever have unpleasant, restless feelings in your legs that can be relieved by walking or movement?" has also shown good predictive power to diagnose RLS . Purely written questionnaires without interview tend to overdiagnose RLS.
A polysomnographic evaluation is not required for the diagnosis of RLS. It is usually reserved for patients in whom the diagnosis is in doubt, in cases where periodic limb movements of sleep (PLMS) are suspected to be severe and result in arousals, or if other sleep disorders, such as obstructive sleep apnea, are suspected.
Occasionally, symptoms of RLS cannot be distinguished from those of a neuropathy by history alone (ie, sensations beginning in the feet or superficial pain), or there are risk factors for neuropathy (eg, diabetes) or signs of a peripheral neuropathy on physical examination. In such cases, nerve conduction velocities (NCV) and electromyogram (EMG) are useful to determine whether further etiologic evaluation for a peripheral neuropathy is necessary. Small fiber neuropathy, which is not always identified by NCV/EMG, can also contribute to RLS symptoms.
Periodic limb movement disorder — Periodic limb movement disorder (PLMD) is diagnosed based on a clinical history of sleep disturbance or daytime fatigue, combined with polysomnography (PSG) showing an excessive number of periodic limb movements of sleep (PLMS), and exclusion of alternative causes of the sleep complaints. PLMD is a diagnosis of exclusion and cannot be diagnosed in the context of other sleep disorders known to be associated with PLMS, including RLS, obstructive sleep apnea, and narcolepsy . (See 'Periodic limb movements of sleep' above.)
Diagnostic criteria for periodic limb movement disorder (PLMD) require PLMS of more than 15 periodic limb movements per hour of sleep time in adults (more than 5 in children), causing clinically significant sleep disturbance or impairment in mental, physical, social, occupational, educational, or behavioral wellbeing not explained by some other entity (table 3) [8,159]. Formal scoring criteria for periodic limb movements on PSG are reviewed above. (See 'Periodic limb movements of sleep' above.)
Whether or not to treat isolated PLMS is debated. (See "Management of restless legs syndrome and periodic limb movement disorder in adults", section on 'Periodic limb movement disorder'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Restless legs syndrome".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Restless legs syndrome (The Basics)" and "Patient education: Nocturnal (nighttime) leg cramps (The Basics)")
Online information and support is available for patients with restless legs syndrome through the Restless Legs Syndrome Foundation.
PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Severe restless legs syndrome and associated depression".)
SUMMARY AND RECOMMENDATIONS
●What is RLS? – Restless legs syndrome (RLS) is a disorder characterized by an unpleasant sensation in the legs (and occasionally the arms), accompanied by an urge to move, that emerges during periods of inactivity, is most prominent in the evening, and is transiently relieved by movement. (See 'Symptoms' above.)
●Epidemiology – RLS is common, affecting 5 to 15 percent of adults. Estimates of clinically significant (moderate to severe) RLS are lower (2 to 3 percent). RLS is most common in people of northern European ancestry and less common in certain regions, including East Asia and Africa. (See 'Epidemiology' above.)
●Etiology – The pathophysiologic basis of RLS is incompletely understood. Reduced iron stores are the most consistently implicated central nervous system (CNS) alteration. (See 'Pathophysiology' above.)
●Genetics – A family history of RLS is present in 40 to 60 percent of cases. Although no highly penetrant genes have been identified, many genetic variants can increase risk for RLS. As with other common conditions, the genetics of RLS are complex and probably involve the presence of multiple risk alleles. (See 'Family history and genetics' above.)
●Risk factors – Although most cases of RLS are considered to be primary or idiopathic, certain comorbid conditions are commonly associated with RLS, including systemic low iron stores, uremia, neuropathy, spinal cord disease, and pregnancy. (See 'Risk factors' above.)
●Differential diagnosis – The most common mimics of RLS are volitional movements such as foot tapping, akathisia, nocturnal leg cramps, positional discomfort, and leg pain from a variety of causes (table 1). In most cases, these can be distinguished from RLS by history and physical examination. (See 'Differential diagnosis' above.)
●Diagnosis – RLS is a clinical diagnosis that should be suspected in patients who complain of an urge to move the legs when lying in bed or sitting down, particularly if the symptom occurs predominantly in the evenings. Diagnostic criteria are provided in the table (table 2). (See 'Restless legs syndrome' above.)
The diagnosis is made by history and does not require additional testing, except for an assessment of iron stores in all patients and blood urea nitrogen and creatinine if uremia is suspected. Any potentially causative or exacerbating medications should be identified. (See 'Low iron stores' above and 'Exacerbating factors' above.)
Diagnostic criteria for periodic limb movement disorder (PLMD) require more than 15 periodic limb movements per hour of sleep time in adults (more than 5 in children), causing clinically significant sleep disturbance or impairment in function or wellbeing not explained by some other entity (table 3). (See 'Periodic limb movement disorder' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Daniel Tarsy, MD, and Robert Sheon, MD, who contributed to earlier versions of this topic review.
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4 : Achievements, challenges, and future perspectives of epidemiologic research in restless legs syndrome (RLS).
9 : Neuropathology of primary restless leg syndrome: absence of specific tau- and alpha-synuclein pathology.
13 : Low brain iron content in idiopathic restless legs syndrome patients detected by phase imaging.
14 : Brain iron deficiency in idiopathic restless legs syndrome measured by quantitative magnetic susceptibility at 7 tesla.
15 : Brain parenchyma sonography differentiates RLS patients from normal controls and patients with Parkinson's disease
19 : Does the endogenous opiate system play a role in the Restless Legs Syndrome? A pilot post-mortem study.
20 : Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome.
22 : Nocturnal myoclonus syndrome (periodic movements in sleep) related to central dopamine D2-receptor alteration.
24 : Striatal dopaminergic function in restless legs syndrome: 18F-dopa and 11C-raclopride PET studies.
25 : Normal striatal D2 receptor binding in idiopathic restless legs syndrome with periodic leg movements in sleep.
27 : Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis.
28 : Circadian variation in neuroendocrine response to L-dopa in patients with restless legs syndrome.
31 : Thalamic glutamate/glutamine in restless legs syndrome: increased and related to disturbed sleep.
32 : Adenosine mechanisms and hypersensitive corticostriatal terminals in restless legs syndrome. Rationale for the use of inhibitors of adenosine transport.
34 : Restless legs syndrome and central nervous system gamma-aminobutyric acid: preliminary associations with periodic limb movements in sleep and restless leg syndrome symptom severity.
36 : Cortical grey matter alterations in idiopathic restless legs syndrome: An optimized voxel-based morphometry study.
40 : Increased Gray Matter Density and Functional Connectivity of the Pons in Restless Legs Syndrome.
41 : Functional connectivity and topology in patients with restless legs syndrome: a case-control resting-state functional magnetic resonance imaging study.
42 : Differential functional connectivity in thalamic and dopaminergic pathways in restless legs syndrome: a meta-analysis.
44 : Static mechanical hyperalgesia without dynamic tactile allodynia in patients with restless legs syndrome.
46 : Reduced daytime intramuscular blood flow in patients with restless legs syndrome/Willis-Ekbom disease.
47 : Novel assessment of microvascular changes in idiopathic restless legs syndrome (Willis-Ekbom disease).
49 : Impaired vascular endothelial function in patients with restless legs syndrome: a new aspect of the vascular pathophysiology.
54 : Family study of restless legs syndrome in Quebec, Canada: clinical characterization of 671 familial cases.
55 : Phenocopies in families with essential tremor and restless legs syndrome challenge Mendelian laws. Epigenetics might provide answers.
56 : The PD-associated alpha-synuclein promoter Rep1 allele 2 shows diminished frequency in restless legs syndrome.
62 : PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome.
63 : Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions.
64 : Association studies of variants in MEIS1, BTBD9, and MAP2K5/SKOR1 with restless legs syndrome in a US population.
65 : Family-based and population-based association studies validate PTPRD as a risk factor for restless legs syndrome.
66 : Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis.
68 : Restless legs syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon.
70 : Multiple blood donations associated with iron deficiency in patients with restless legs syndrome.
71 : Saphenous nerve entrapment caused by pes anserine bursitis mimicking stress fracture of the tibia.
73 : Prevalence and characteristics of restless legs syndrome (RLS) in the elderly and the relation of serum ferritin levels with disease severity: hospital-based study from Istanbul, Turkey.
76 : Clinical features and subtypes of restless legs syndrome in Chinese population: a study of 359 patients.
77 : Epidemiology, impact, and treatment options of restless legs syndrome in end-stage renal disease patients: an evidence-based review.
80 : Association of candidate genetic variants with restless legs syndrome in end stage renal disease: a multicenter case-control study in Taiwan.
81 : Periodic limb movements of sleep index (PLMSI): a sensitive predictor of mortality in dialysis patients
84 : Restless legs syndrome is associated with cardio/cerebrovascular events and mortality in end-stage renal disease.
88 : Restless legs syndrome (RLS) in uremic patients is related to the frequency of hemodialysis sessions.
92 : Restless legs syndrome and nocturnal myoclonus: initial clinical manifestation of familial amyloid polyneuropathy.
98 : Incidence of periodic leg movements and of the restless legs syndrome during sleep following acute physical activity in spinal cord injury subjects.
101 : Transverse myelitis associated with restless legs syndrome and periodic movements of sleep responsive to an oral dopaminergic agent but not to intrathecal baclofen.
109 : Restless legs syndrome is a common finding in multiple sclerosis and correlates with cervical cord damage.
110 : Higher prevalence of restless legs syndrome/Willis-Ekbom disease in multiple sclerosis patients is related to spinal cord lesions.
111 : Restless Legs Syndrome/Willis-Ekbom Disease in Multiple Sclerosis Patients with Spinal Cord Lesions.
112 : Increased frequency and severity of restless legs syndrome in patients with neuromyelitis optica spectrum disorder.
114 : Restless legs syndrome in Parkinson's disease patients may improve with subthalamic stimulation.
115 : International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson's disease: the NMSQuest study.
117 : Restless legs syndrome in patients with Parkinson's disease: a comparative study on prevalence, clinical characteristics, quality of life and nutritional status.
118 : Prevalence of restless legs syndrome in Parkinson's disease: a systematic review and meta-analysis of observational studies.
122 : Restless legs syndrome in Korean patients with drug-naïve Parkinson's disease: a nation-wide study.
123 : Prevalence and profile of Restless Legs Syndrome in Parkinson's disease and other neurodegenerative disorders: a case-control study.
124 : Decreased serum ferritin may be associated with increased restless legs syndrome in Parkinson's disease (PD): a meta-analysis for the diagnosis of RLS in PD patients.
125 : Does idiopathic restless legs syndrome delay onset and reduce severity of Parkinson's disease: a pilot study.
128 : Intermediate CAG repeat lengths (53,54) for MJD/SCA3 are associated with an abnormal phenotype.
129 : Prevalence of restless legs syndrome and sleep quality in carriers of the fragile X premutation.
132 : A clinical, serological and neurophysiological study of restless legs syndrome in rheumatoid arthritis.
137 : Restless Bladder in an Elderly Woman: An Unusual Feature or a Variant of Restless Legs Syndrome?
139 : The influence of antidepressants on restless legs syndrome and periodic limb movements: A systematic review.
142 : Prospective survey on the natural course of restless legs syndrome over two years in a closed cohort.
143 : Ten-year natural course of habitual snoring and restless legs syndrome in a population aged 61-63 years at the baseline.
145 : The association between obesity and restless legs syndrome: A systemic review and meta-analysis of observational studies.
146 : Periodic limb movements in sleep contribute to further cardiac structure abnormalities in hemodialysis patients with restless legs syndrome.
148 : Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study.
149 : Association of incident restless legs syndrome with outcomes in a large cohort of US veterans.
150 : Associations of Incident Cardiovascular Events With Restless Legs Syndrome and Periodic Leg Movements of Sleep in Older Men, for the Outcomes of Sleep Disorders in Older Men Study (MrOS Sleep Study).
151 : Prospective study of restless legs syndrome and total and cardiovascular mortality among women.
153 : A time sequence analysis of the relationship between cardiovascular risk factors, vascular diseases and restless legs syndrome in the general population.
154 : Incident Cardiovascular Events and Death in Individuals With Restless Legs Syndrome or Periodic Limb Movements in Sleep: A Systematic Review.
155 : Association between restless legs syndrome and hypertension: a meta-analysis of nine population-based studies.
156 : Restless legs syndrome and cerebrovascular/cardiovascular events: Systematic review and meta-analysis.
157 : Treating Restless Legs Syndrome Was Associated With Low Risk of Cardiovascular Disease: A Cohort Study With 3.4 Years of Follow-Up.
160 : Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria.
161 : Leg movements during wakefulness in restless legs syndrome: time structure and relationships with periodic leg movements during sleep.
163 : An Evidence-based Analysis of the Association between Periodic Leg Movements during Sleep and Arousals in Restless Legs Syndrome.
164 : Effects of acute dopamine-agonist treatment in restless legs syndrome on heart rate variability during sleep.
165 : Rotigotine's effect on PLM-associated blood pressure elevations in restless legs syndrome: An RCT.
167 : Significant association between systolic and diastolic blood pressure elevations and periodic limb movements in patients with idiopathic restless legs syndrome.
173 : Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria--history, rationale, description, and significance.
175 : Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome.
176 : Validation of the self-administered version of the international Restless Legs Syndrome study group severity rating scale - The sIRLS.
177 : Validation of the Restless Legs Syndrome Quality of Life Instrument (RLS-QLI): findings of a consortium of national experts and the RLS Foundation.
178 : Review of diagnostic instruments for the restless legs syndrome/Willis-Ekbom Disease (RLS/WED): critique and recommendations.