Restless legs syndrome

Restless legs syndrome (RLS), also known as Willis–Ekbom disease (WED), is a neurological disorder, usually chronic, that causes an overwhelming urge to move one's legs.<ref name="NIH2010What">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="NIH2019">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> There is often an unpleasant feeling in the legs that improves temporarily by moving them.<ref name="NIH2010What" /> This feeling is often described as aching, tingling, or crawling in nature.<ref name="NIH2010What" /> Occasionally, arms may also be affected.<ref name="NIH2010What" /> The feelings generally happen when at rest and therefore can make it hard to sleep.<ref name="NIH2010What" /> Sleep disruption may leave people with RLS sleepy during the day, with low energy, and irritable or depressed.<ref name="NIH2010What" /> Additionally, many have limb twitching during sleep, a condition known as periodic limb movement disorder.<ref name="NIH2010Sym">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> RLS is not the same as habitual foot-tapping or leg-rocking.<ref name=":5" />

Signs and symptoms

RLS sensations range from pain or aching in the muscles, to "an itch you can't scratch", a "buzzing sensation", an unpleasant "tickle that won't stop", a "crawling" feeling, or limbs jerking while awake. The sensations typically begin or intensify during quiet wakefulness, such as when relaxing, reading, studying, or trying to sleep.<ref name="pmid14592341">Template:Cite journal</ref>

The sensations—and the need to move—may return immediately after ceasing movement or at a later time. RLS may start at any age, including childhood, and is a progressive disease for some, while the symptoms may remit in others.<ref name=":0">Template:Cite journal</ref> In a survey among members of the Restless Legs Syndrome Foundation, it was found that up to 45% of patients had their first symptoms before the age of 20 years.<ref>Template:Cite journal</ref>

• "An urge to move, usually due to uncomfortable sensations that occur primarily in the legs, but occasionally in the arms or elsewhere." The sensations are unusual and unlike other common sensations. Those with RLS have difficulty describing them, using words or phrases such as uncomfortable, painful, 'antsy', electrical, creeping, itching, pins and needles, pulling, crawling, buzzing, and numbness. It is sometimes described as similar to a limb 'falling asleep' or an exaggerated sense of positional awareness of the affected area. The sensation and the urge can occur in any body part; the most cited location is the legs, followed by the arms. Some people have little or no sensation but still have a strong urge to move.
• "Motor restlessness, expressed as activity, which relieves the urge to move." Movement usually brings immediate relief, although temporary and partial. Walking is most common; however, stretching, yoga, biking, or other physical activity may relieve the symptoms. Continuous, fast up-and-down movements of the leg, and/or rapidly moving the legs toward then away from each other, may keep sensations at bay without walking. Specific movements may be unique to each person.
• "Worsening of symptoms by relaxation." Sitting or lying down (reading, plane ride, watching TV) can trigger the sensations and urge to move. Severity depends on the severity of the person's RLS, the degree of restfulness, the duration of the inactivity, etc.
• "Variability throughout the day-night cycle, with symptoms worse in the evening and early in the night." Some experience RLS only at bedtime, while others experience it throughout the day and night. Most people experience the worst symptoms in the evening and the least in the morning.
• "Restless legs feel similar to the urge to yawn, situated in the legs or arms." These symptoms of RLS can make sleeping difficult for many patients and a 2005 National Sleep Foundation poll<ref name="chest">Template:Cite journal</ref> shows the presence of significant daytime difficulties resulting from this condition. These problems range from being late for work to missing work or events because of drowsiness. Patients with RLS who responded reported driving while drowsy more than patients without RLS. These daytime difficulties can translate into safety, social and economic issues for the patient and for society.

RLS may contribute to higher rates of depression and anxiety disorders in RLS patients.<ref name=":2">Template:Cite journal</ref>

Primary and secondary forms

RLS is categorized as either primary or secondary.

• Primary RLS is considered idiopathic or with no known cause. Primary RLS usually begins slowly, before approximately 40–45 years of age, and may disappear for months or even years. It is often progressive and gets worse with age.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref> RLS in children is often misdiagnosed as growing pains.

• Secondary RLS often has a sudden onset after age 40 and may be daily from the beginning. It is most associated with specific medical conditions or certain drugs (see below).

Causes

While the cause is generally unknown, it is believed to be caused by changes in the neurotransmitter dopamine<ref name="St. Louis 2014">Template:Cite journal</ref> resulting in an abnormal use of iron by the brain.<ref name="NINDS2019Fact" /> RLS is often due to iron deficiency (low total body iron status)<ref name="NINDS2019Fact" /> and could be a sign of anemia caused by internal bleeding or bone marrow issues. Other associated conditions may include end-stage kidney disease and hemodialysis, folate deficiency, magnesium deficiency, sleep apnea, diabetes, peripheral neuropathy, Parkinson's disease, and certain autoimmune diseases, such as multiple sclerosis.<ref name="mlp2017">Template:MedlinePlusEncyclopedia</ref> RLS can worsen in pregnancy, possibly due to elevated estrogen levels.<ref name="NINDS2019Fact" /><ref name="Gupta">Template:Cite journal</ref> Use of alcohol, nicotine products, and caffeine may be associated with RLS.<ref name="NINDS2019Fact" /> A 2014 study from the American Academy of Neurology also found that reduced leg oxygen levels were strongly associated with restless legs syndrome symptom severity in untreated patients.<ref name="St. Louis 2014" />

ADHD

An association has been observed between attention deficit hyperactivity disorder (ADHD) and RLS or periodic limb movement disorder.<ref name=":6">Template:Cite journal</ref> Both conditions appear to have links to dysfunctions related to the neurotransmitter dopamine, and common medications for both conditions among other systems, affect dopamine levels in the brain.<ref name=":8">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A 2005 study suggested that up to 44% of people with ADHD had comorbid (i.e. coexisting) RLS, and up to 26% of people with RLS had confirmed ADHD or symptoms of the condition.<ref name=":9">Template:Cite journal</ref>

Medications

Certain medications may cause or worsen RLS, or cause it secondarily, including the following:<ref name="NINDS2019Fact" />

• certain antiemetics (antidopaminergic ones)<ref name="Buchfuhrer2012" />
• certain antihistamines (especially the sedating, first generation H₁ antihistamines often in over-the-counter cold medications)<ref name="Buchfuhrer2012">Template:Cite journal</ref>
• many antidepressants (both older TCAs and newer SSRIs)<ref name="NINDS2019Fact" /><ref name="Buchfuhrer2012" />
• Antipsychotics.
• a rebound effect of sedative-hypnotic drugs such as a benzodiazepine withdrawal syndrome from discontinuing benzodiazepine tranquilizers or sleeping pills<ref name="NINDS2019Fact" />
• alcohol withdrawal can also cause restless legs syndrome and other movement disorders such as akathisia and parkinsonism usually associated with antipsychotics<ref name=":10">Template:Cite journal</ref>
• opioid withdrawal is associated with causing and worsening RLS<ref name="Trenkwalder17">Template:Cite journal</ref>

Both primary and secondary RLS can be worsened by surgery of any kind; however, back surgery or injury can be associated with causing RLS.<ref name="pmid15830971">Template:Cite book</ref>

The cause vs. effect of certain conditions and behaviors observed in some patients (ex. excess weight, lack of exercise, depression, or other mental illnesses) is not well established. Loss of sleep due to RLS could cause the conditions, or medication used to treat a condition could cause RLS.<ref name=":11">Template:Cite journal</ref><ref>Template:Cite journal</ref>

Genetics

More than 60% of cases of RLS are familial and are inherited in an autosomal dominant fashion with variable penetrance.<ref>Template:Cite journal</ref>

Research and brain autopsies have implicated both the dopaminergic system and iron insufficiency in the substantia nigra.<ref>Template:Cite journal</ref> Iron is well understood to be an essential cofactor for the formation of L-DOPA, the precursor of dopamine.

Six genetic loci found by linkage are known and listed below. Other than the first one, all of the linkage loci were discovered using an autosomal dominant inheritance model.

• The first genetic locus was discovered in one large French Canadian family and maps to chromosome 12q.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> This locus was discovered using an autosomal recessive inheritance model. Evidence for this locus was also found using a transmission disequilibrium test (TDT) in 12 Bavarian families.<ref>Template:Cite journal</ref>
• The second RLS locus maps to chromosome 14q and was discovered in one Italian family.<ref>Template:Cite journal</ref> Evidence for this locus was found in one French Canadian family.<ref>Template:Cite journal</ref> Also, an association study in a large sample 159 trios of European descent showed some evidence for this locus.<ref>Template:Cite journal</ref>
• This locus maps to chromosome 9p and was discovered in two unrelated American families.<ref>Template:Cite journal</ref> Evidence for this locus was also found by the TDT in a large Bavarian family,<ref>Template:Cite journal</ref> in which significant linkage to this locus was found.<ref>Template:Cite journal</ref>
• This locus maps to chromosome 20p and was discovered in a large French Canadian family with RLS.<ref>Template:Cite journal</ref>
• This locus maps to chromosome 2p and was found in three related families from population isolated in South Tyrol.<ref>Template:Cite journal</ref>
• The sixth locus is located on chromosome 16p12.1 and was discovered by Levchenko et al. in 2008.<ref>Template:Cite journal</ref>

Three genes, MEIS1, BTBD9 and MAP2K5, were found to be associated to RLS.<ref>Template:Cite journal</ref> Their role in RLS pathogenesis is still unclear. More recently, a fourth gene, PTPRD was found to be associated with RLS.<ref>Template:Cite journal</ref>

There is also some evidence that periodic limb movements in sleep (PLMS) are associated with Template:Gene on chromosome 6p21.2,<ref name="pmid17634447">Template:Cite journal</ref><ref name="moore2014">Template:Cite journal</ref> MEIS1, MAP2K5/SKOR1, and PTPRD.<ref name="moore2014" /> The presence of a positive family history suggests that there may be a genetic involvement in the etiology of RLS.

Mechanism

Although it is only partly understood, pathophysiology of restless legs syndrome may involve dopamine and iron system anomalies.<ref name="pmid15222997">Template:Cite journal</ref><ref name="pmid16832090">Template:Cite journal</ref> There is also a commonly acknowledged circadian rhythm explanatory mechanism associated with it, clinically shown simply by biomarkers of circadian rhythm, such as body temperature.<ref>Template:Cite journal</ref> The interactions between impaired neuronal iron uptake and the functions of the neuromelanin-containing and dopamine-producing cells have roles in RLS development, indicating that iron deficiency might affect the brain dopaminergic transmissions in different ways.<ref name=":3">Template:Cite journal</ref>

Medial thalamic nuclei may also have a role in RLS as part as the limbic system modulated by the dopaminergic system<ref>Template:Cite journal</ref> which may affect pain perception.<ref name=":4">Template:Cite journal</ref> Improvement of RLS symptoms occurs in people receiving low-dose dopamine agonists.<ref>Template:Cite journal</ref>

Diagnosis

Diagnosis of RLS is generally based on a person's symptoms after ruling out other potential causes.<ref name="NIH2010Diag">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Risk factors include low iron levels, kidney failure, Parkinson's disease, diabetes mellitus, rheumatoid arthritis, pregnancy and celiac disease.<ref name="NIH2010What" /><ref name="AFP2013" /><ref name="ZisHadjivassiliou2019">Template:Cite journal</ref> A number of medications may also trigger the disorder including antidepressants, antipsychotics, antihistamines, and calcium channel blockers.<ref name="NIH2010Ca">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

RLS may either be of early onset, occurring before age 45, or late-onset, occurring after age 45. Early-onset cases tend to progress more slowly and involve fewer comorbidities, while cases in older patients may progress suddenly and alongside other conditions.<ref>Template:Cite journal</ref>

There are no specific tests for RLS, but non-specific laboratory tests are used to rule out other causes such as vitamin deficiencies. Five symptoms are used to confirm the diagnosis:<ref name="NINDS2019Fact" />

• A strong urge to move the limbs, usually associated with unpleasant or uncomfortable sensations.
• It starts or worsens during inactivity or rest.
• It improves or disappears (at least temporarily) with activity.
• It worsens in the evening or night.
• These symptoms are not caused by any medical or behavioral condition.

The symptoms below are not essential, like the ones above, but occur commonly in RLS patients:<ref name="NINDS2019Fact" /><ref>Template:Citation</ref>

• genetic component or family history with RLS
• good response to dopaminergic therapy
• periodic leg movements during the day or sleep
• most strongly affected are people who are middle-aged or older
• other sleep disturbances are experienced
• decreased iron stores can be a risk factor and should be assessed

According to the International Classification of Sleep Disorders (ICSD-3), the main symptoms have to be associated with a sleep disturbance or impairment to support RLS diagnosis.<ref name="ICSD2014">Template:Cite journal</ref> As stated by this classification, RLS symptoms should begin or worsen when being inactive, be relieved when moving, should happen exclusively or mostly in the evening and at night, not be triggered by other medical or behavioral conditions, and should impair one's quality of life.<ref name="ICSD2014" /><ref name="Breen2018">Template:Cite journal</ref> Generally, both legs are affected, but in some cases there is an asymmetry.

Differential diagnosis

The most common conditions that should be differentiated with RLS include leg cramps, positional discomfort, local leg injury, arthritis, leg edema, venous stasis, peripheral neuropathy, radiculopathy, habitual foot tapping/leg rocking, anxiety, myalgia, and drug-induced akathisia.<ref name=":5">Template:Cite journal</ref>

Peripheral artery disease and arthritis can also cause leg pain but this usually gets worse with movement.<ref name="NIH2010Sym" />

There are less common differential diagnostic conditions included myelopathy, myopathy, vascular or neurogenic claudication, hypotensive akathisia, orthostatic tremor, painful legs, and moving toes.<ref name=":5" />

Treatment

RLS may resolve if the underlying problem is addressed.<ref name="NIH2010Tx">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Otherwise treatment includes lifestyle changes and medication.<ref name="NIH2010What" /> Lifestyle changes that may help include stopping alcohol and tobacco use, and sleep hygiene.<ref name="NIH2010Tx" /> Medications used to treat RLS include dopamine agonists like pramipexole and gabapentinoids (α₂δ ligands) like gabapentin.<ref name="AFP2013" /><ref name="pmid27448465">Template:Cite journal</ref><ref>Template:Cite journal</ref> RLS affects an estimated 2.5–15% of the American population.<ref name="AFP2013">Template:Cite journal</ref> Females are more commonly affected than males, and RLS becomes increasingly common with age.<ref name="NIH2010Age">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="NINDS2019Fact" />

If RLS is not linked to an underlying cause, its frequency may be reduced by lifestyle modifications such as adopting improving sleep hygiene, regular exercise, and stopping smoking.<ref name="nhs">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Medications used may include dopamine agonists and gabapentinoids in those with daily restless legs syndrome.<ref name="NINDS2019Fact" /><ref name="Trenkwalder17" /><ref name="pmid27448465" /><ref name="pmid34218864">Template:Cite journal</ref> In severe or refractory cases, opioids have been used.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Treatment of RLS should not be considered until possible medical causes are ruled out. Secondary RLS may be cured if precipitating medical conditions (anemia) are managed effectively.<ref name="NINDS2019Fact" />

Physical measures

Stretching the leg muscles can bring temporary relief.<ref name="pmid14592341" /><ref name="pmid11435804">Template:Cite journal</ref> Walking and moving the legs, as the name "restless legs" implies, brings temporary relief. In fact, those with RLS often have an almost uncontrollable need to walk and therefore relieve the symptoms while they are moving. Unfortunately, the symptoms usually return immediately after the moving and walking ceases.

Counter-stimulation from massage, a hot or cold compress, or a vibratory counter-stimulation device has been found to help some people with primary RLS to improve their sleep.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Iron

There is some evidence that intravenous iron supplementation moderately improves restlessness for people with RLS.<ref name="iron">Template:Cite journal</ref>

Medications

For those whose RLS disrupts or prevents sleep or regular daily activities, medication may be useful. Evidence supports the use of dopamine agonists including pramipexole, ropinirole, rotigotine, cabergoline, and pergolide.<ref name="pmid27448465" /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> They reduce symptoms, improve sleep quality and quality of life.<ref>Template:Cite journal</ref> Levodopa is also effective.<ref>Template:Cite journal</ref> However, pergolide and cabergoline are less recommended due to their association with increased risk of valvular heart disease.<ref>Template:Cite journal</ref> Ropinirole has a faster onset with shorter duration.<ref name=":7">Template:Cite journal</ref> Rotigotine is commonly used as a transdermal patch which continuously provides stable plasma drug concentrations, resulting in its particular therapeutic effect on patients with symptoms throughout the day.<ref name=":7" /> A 2008 meta-analysisTemplate:Update inline found pramipexole to be better than ropinirole.<ref>Template:Cite journal</ref>

There are, however, issues with the use of dopamine agonists including augmentation. This is a medical condition where the drug itself causes symptoms to increase in severity and/or occur earlier in the day. Dopamine agonists may also cause rebound when symptoms increase as the drug wears off. In many cases, the longer dopamine agonists have been used, the higher the risk of augmentation and rebound as well as the severity of the symptoms. Patients may also develop dopamine dysregulation syndrome, meaning that they can experience an addictive pattern of dopamine replacement therapy.Template:Cn

Pramipexole and ropinirole, both dopamine agonists, along with aripiprazole, a dopamine modulator, have been linked to an elevated risk of problematic gambling.<ref name="Wolfschlag">Template:Cite journal</ref> The excessive activation of the dopaminergic reward and reinforcement system is one potential mechanism by which dopaminergic drugs may contribute to increased gambling behavior.<ref name="Wolfschlag" /> Patients may also exhibit other impulse-control disorders such as compulsive shopping and compulsive eating.<ref name="Aurora Kristo Bista Rowley et al 2012">Template:Cite journal</ref> There are some indications that stopping the dopamine agonist treatment has an impact on the resolution or at least improvement of the impulse-control disorder, even though some people can be particularly exposed to dopamine agonist withdrawal syndrome.<ref name="Aurora Kristo Bista Rowley et al 2012" />

Gabapentinoids (α₂δ ligands), including gabapentin, pregabalin, and gabapentin enacarbil, are also widely used in the treatment of RLS.<ref name="pmid27448465" /><ref name="pmid34764852" /> They are used as first-line treatments similarly to dopamine agonists, and as of 2019, guidelines have started to recommend gabapentinoids over dopamine agonists as initial therapy for RLS due to higher known risks of symptom augmentation with long-term dopamine agonist therapy.<ref name="pmid31229171" /> Gabapentin enacarbil is approved by regulatory authorities for the treatment of RLS, whereas gabapentin and pregabalin are used off-label.<ref name="pmid27448465" /> Data on gabapentinoids in the treatment of RLS are more limited compared to dopamine agonists.<ref name="pmid36692194">Template:Cite journal</ref> However, based on available evidence, gabapentinoids are similarly effective to dopamine agonists in the treatment of RLS.<ref name="pmid31229171">Template:Cite book</ref><ref name="pmid28888061">Template:Cite journal</ref><ref name="pmid34764852">Template:Cite journal</ref>

Both the 2021 algorithm for the treatment of RLS published by members of the Scientific and Medical Advisory Board of the RLS Foundation in the Mayo Clinic Proceedings,<ref name=":2" /> and the 2024 American Academy of Sleep Medicine Practice Guidelines<ref name=":6" /> recommend the use of low-dose opioids for the treatment of refractory RLS, with the caveat that, although opioids are highly effective, “reasonable precautions should be taken in light of the opioid epidemic.<ref name=":0" />" Among the opioids and their suggested doses are tramadol, codeine, morphine, oxycodone, hydrocodone, methadone (all of which are schedule II), and buprenorphine (a schedule III partial opioid-receptor agonist with a lower risk of causing respiratory depression or dependence, compared with the full-agonist opioids.<ref name=":9" /><ref name=":10" /> The only data publicly available on the use of buprenorphine in the treatment of RLS are two posters presented at the 2019 and 2023 Associated Professional Sleep Society’s meetings. In the first, Forbes et al<ref name=":8" /> presented preliminary open-label data from five men and two women, with an average age of 68 years, who had experienced RLS symptoms for a mean of 30+ years and been treated for 10+ years using a mean of nine drugs. The severity of both RLS and insomnia decreased significantly according to the IRLSSG Rating Scale scores and Insomnia Severity Index (31.1 ± 6.7 at baseline to 4 ± 8 and 19.8 ± 6.1 to 1.3 ± 1.9, respectively). In the second study, Berkowsi<ref name=":11" /> and colleagues presented data from a retrospective study of 55 patients who had been started on buprenorphine for the treatment of severe RLS. Mean IRLSSG severity scores decreased from 27.8 at baseline to 11.4 at 1 year and allowed most of those patients on dopamine receptor agonists who had developed augmentation to discontinue the dopamine receptor agonists.

Benzodiazepines, such as diazepam or clonazepam, are not generally recommended,<ref name="trenk">Template:Cite journal</ref> and their effectiveness is unknown or contradictory.<ref name="pmid28319266">Template:Cite journal</ref><ref name="pmid36692194" /> They, however, are sometimes still used as a second-line treatment,<ref>Template:Cite journal</ref> as add-on agents.<ref name="pmid28319266" /> Other treatments have also been explored, such as valproate, carbamazepine, perampanel, and dipyridamole, but are either not effective or have insufficient data to support their use.<ref name="pmid36692194" />

Placebo

Placebos provide a large benefit in reducing RLS symptoms.<ref name="pmid17932100">Template:Cite journal</ref> This is thought to be due to positive expectancy effects and conditioning, which activate dopamine and opioid pathways in the brain.<ref name="pmid17932100" /> Both dopamine agonists and opioids are used in and effective for the treatment of RLS, which is thought to be related to the effectiveness of placebos for the condition.<ref name="pmid17932100" /> More than half of the benefit of RLS medications such as pramipexole and gabapentin enacarbil appears to be due to the placebo component based on clinical trial data.<ref name="MirapexLabel">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="HorizantLabel">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Prognosis

RLS symptoms may gradually worsen with age, although more slowly for those with the idiopathic form of RLS than those with an associated medical condition.<ref name="factsheet">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Current therapies can control the disorder, minimizing symptoms and increasing periods of restful sleep. In addition, some people have remissions, periods in which symptoms decrease or disappear for days, weeks, or months, although symptoms usually eventually reappear.<ref name="factsheet" /> Being diagnosed with RLS does not indicate or foreshadow another neurological disease, such as Parkinson's disease.<ref name="factsheet" /> RLS symptoms can worsen over time when dopamine-related drugs are used for therapy, an effect called augmentation which may represent symptoms occurring throughout the day and affect movements of all limbs.<ref name="factsheet" /> There is no cure for RLS.<ref name="factsheet" />

Epidemiology

RLS affects an estimated 2.5–15% of the American population.<ref name="AFP2013" /><ref name="ChestReview2006">Template:Cite journal</ref> A minority (around 2.7% of the population) experience daily or severe symptoms.<ref name="allen2005">Template:Cite journal</ref> RLS is twice as common in women as in men,<ref name="pmid14744844">Template:Cite journal</ref> and Caucasians are more prone to RLS than people of African descent.<ref name="ChestReview2006" /> RLS occurs in 3% of individuals from the Mediterranean or Middle Eastern regions, and in 1–5% of those from East Asia, indicating that different genetic or environmental factors, including diet, may play a role in the prevalence of this syndrome.<ref name="ChestReview2006" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> RLS diagnosed at an older age runs a more severe course.<ref name="pmid11435804" /> RLS is even more common in individuals with iron deficiency, pregnancy, or end-stage kidney disease.<ref name="pmid11445024">Template:Cite journal</ref><ref>Template:Cite journal</ref> The National Sleep Foundation's 1998 Sleep in America poll showed that up to 25 percent of pregnant women developed RLS during the third trimester.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Poor general health is also linked.<ref>Template:Cite journal</ref>

There are several risk factors for RLS, including old age, family history, and uremia. The prevalence of RLS tends to increase with age, as well as its severity and longer duration of symptoms. People with uremia receiving renal dialysis have a prevalence from 20% to 57%, while those having kidney transplant improve compared to those treated with dialysis.<ref>Template:Cite journal</ref>

RLS can occur at all ages but usually begins in the third or fourth decade.<ref name="Breen2018" /> Genome‐wide association studies have now identified 19 risk loci associated with RLS.<ref>Template:Cite journal</ref> Neurological conditions linked to RLS include Parkinson's disease, spinal cerebellar atrophy, spinal stenosis,Template:Specify lumbosacral radiculopathy and Charcot–Marie–Tooth disease type 2.<ref name="ChestReview2006" />

Nomenclature

In 2013, the Restless Legs Syndrome Foundation renamed itself the Willis–Ekbom Disease Foundation; however, it reverted to its original name in 2015 “to better support its mission”.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

A point of confusion is that RLS and delusional parasitosis are entirely different conditions that have both been called "Ekbom syndrome", as both syndromes were described by the same person, Karl-Axel Ekbom.<ref name="WhoNamedIt">Template:WhoNamedIt</ref> Today, calling WED/RLS "Ekbom syndrome" is outdated usage, as the unambiguous names (WED or RLS) are preferred for clarity.

History

Sir Thomas Willis provided a medical description in 1672.<ref name="pmid15165536">Template:Cite journal</ref> Willis emphasized the sleep disruption and limb movements experienced by people with RLS.

Subsequently, other descriptions of RLS were published, including by Template:Ill (1861) (in relation to whom it is sometimes known as Wittmaack-Ekbom syndrome).<ref>Template:Cite journal</ref>

In 1945, Karl-Axel Ekbom (1907–1977) provided a detailed and comprehensive report of this condition in his doctoral thesis, restless legs: clinical study of hitherto overlooked disease.<ref>Template:Cite journal</ref> Ekbom coined the term "restless legs".

Ekbom's work was largely ignored until it was rediscovered by Arthur S. Walters and Wayne A. Hening in the 1980s. Subsequent landmark publications include 1995 and 2003 papers, which revised and updated the diagnostic criteria.<ref name="pmid14592341" /><ref>Template:Cite journal</ref>

Controversy

Some doctors express the view that the incidence of restless legs syndrome is exaggerated by manufacturers of drugs used to treat it.<ref>Template:Cite journal</ref> Others believe it is an underrecognized and undertreated disorder.<ref name="ChestReview2006"/> Further, GlaxoSmithKline (GSK) ran advertisements that, while not promoting off-license use of their drug (ropinirole) for treatment of RLS, did link to the Ekbom Support Group website. That website contained statements advocating the use of ropinirole to treat RLS. The Association of the British Pharmaceutical Industry (ABPI) ruled against GSK in this case.<ref>Template:Cite news</ref>

Research

Different measurements have been used to evaluate treatments in RLS. Most of them are based on subjective rating scores, such as IRLS rating scale (IRLS), Clinical Global Impression (CGI), Patient Global Impression (PGI), and Quality of Life (QoL).<ref name=":1">Template:Cite journal</ref> These questionnaires provide information about the severity and progress of the disease, as well as the person's quality of life and sleep.<ref name=":1" /> Polysomnography (PSG) and actigraphy (both related to sleep parameters) are more objective resources that provide evidence of sleep disturbances associated with RLS symptoms.<ref name=":1" />