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Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is generally a long-term disorder that causes a strong urge to move one's legs. There is often an unpleasant feeling in the legs that improves somewhat by moving them. This is often described as aching, tingling, or crawling in nature. Occasionally, arms may also be affected. The feelings generally happen when at rest and therefore can make it hard to
sleep Sleep is a sedentary state of mind and body. It is characterized by altered consciousness, relatively inhibited sensory activity, reduced muscle activity and reduced interactions with surroundings. It is distinguished from wakefulness by a de ...
. Due to the disturbance in sleep, people with RLS may have daytime sleepiness, low energy, irritability and a
depressed mood Depression is a mental state of low mood and aversion to activity, which affects more than 280 million people of all ages (about 3.5% of the global population). Classified medically as a mental and behavioral disorder, the experience of ...
. Additionally, many have limb twitching during sleep. RLS is not the same as habitual foot tapping or leg rocking. Risk factors for RLS include low iron levels,
kidney failure Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
,
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
,
diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
,
rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
, pregnancy and
celiac disease Coeliac disease (British English) or celiac disease (American English) is a long-term autoimmune disorder, primarily affecting the small intestine, where individuals develop intolerance to gluten, present in foods such as wheat, rye and barle ...
. A number of medications may also trigger the disorder including
antidepressants Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
,
antipsychotics Antipsychotics, also known as neuroleptics, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but ...
,
antihistamines Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides re ...
, and calcium channel blockers. There are two main types. One is early onset RLS which starts before age 45, runs in families and worsens over time. The other is late onset RLS which begins after age 45, starts suddenly, and does not worsen. Diagnosis is generally based on a person's symptoms after ruling out other potential causes. Restless legs syndrome may resolve if the underlying problem is addressed. Otherwise treatment includes lifestyle changes and medication. Lifestyle changes that may help include stopping alcohol and tobacco use, and
sleep hygiene Sleep hygiene is a behavioral and environmental practice developed in the late 1970s as a method to help people with mild to moderate insomnia. Clinicians assess the sleep hygiene of people with insomnia and other conditions, such as depression, ...
. Medications used include a
dopamine agonist A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the ...
such as
pramipexole Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipex ...
. RLS affects an estimated 2.5–15% of the American population. Females are more commonly affected than males, and it becomes increasingly common with age.


Signs and symptoms

RLS sensations range from pain or an 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. It is a "
spectrum A spectrum (plural ''spectra'' or ''spectrums'') is a condition that is not limited to a specific set of values but can vary, without gaps, across a continuum. The word was first used scientifically in optics to describe the rainbow of colors i ...
" disease with some people experiencing only a minor annoyance and others having major disruption of sleep and impairments in quality of life. 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. 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. * "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 a hard time describing them, using words or phrases such as uncomfortable, painful, 'antsy', electrical, creeping, itching,
pins and needles ''Pins and Needles'' (1937) is a musical revue with a book by Arthur Arent, Marc Blitzstein, Emmanuel Eisenberg, Charles Friedman, David Gregory, Joseph Schrank, Arnold B. Horwitt, John Latouche, and Harold Rome, and music and lyrics by Rome. ...
, pulling, crawling, buzzing, and numbness. It is sometimes described 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 legs, followed by arms. Some people have little or no sensation, yet 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 having to walk. 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, duration of the inactivity, etc. * "Variability over the course of 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 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.


Primary and secondary

RLS is categorized as either primary or secondary. * Primary RLS is considered
idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparent wikt:spontaneous, spontaneous origin. From Ancient Greek, Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approxi ...
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. RLS in children is often misdiagnosed as
growing pains ''Growing Pains'' is an American television sitcom created by Neal Marlens that aired on ABC from September 24, 1985, to April 25, 1992. The show ran for seven seasons, consisting of 166 episodes. The series followed the misadventures of the Se ...
. * 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 the use of certain drugs (see below).


Causes

While the cause is generally unknown, it is believed to be caused by changes in the nerve transmitter dopamine resulting in an abnormal use of iron by the brain. RLS is often due to
iron deficiency Iron deficiency, or sideropenia, is the state in which a body lacks enough iron to supply its needs. Iron is present in all cells in the human body and has several vital functions, such as carrying oxygen to the tissues from the lungs as a key ...
(low total body iron status). Other associated conditions may include
end-stage kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...
and
hemodialysis Hemodialysis, also spelled haemodialysis, or simply dialysis, is a process of purifying the blood of a person whose kidneys are not working normally. This type of dialysis achieves the extracorporeal removal of waste products such as creatinin ...
,
folate deficiency Folate deficiency, also known as vitamin B9 deficiency, is a low level of folate and derivatives in the body. Signs of folate deficiency are often subtle. A low number of red blood cells (anemia) is a late finding in folate deficiency and folate ...
,
magnesium deficiency Magnesium deficiency is an electrolyte disturbance in which there is a low level of magnesium in the body. It can result in multiple symptoms. Symptoms include tremor, poor coordination, muscle spasms, loss of appetite, personality changes, an ...
,
sleep apnea Sleep apnea, also spelled sleep apnoea, is a sleep disorder in which pauses in breathing or periods of shallow breathing during sleep occur more often than normal. Each pause can last for a few seconds to a few minutes and they happen many times ...
,
diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
,
peripheral neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
,
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, and certain
autoimmune disease An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s, such as
multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
. RLS can worsen in pregnancy, possibly due to elevated
estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...
levels. Use of alcohol,
nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
products, and
caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
may be associated with RLS. 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.


ADHD

An association has been observed between
attention deficit hyperactivity disorder Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...
(ADHD) and RLS or
periodic limb movement disorder Periodic limb movement disorder (PLMD) is a sleep disorder where the patient moves limbs involuntarily and periodically during sleep, and has symptoms or problems related to the movement. PLMD should not be confused with restless legs syndrome (RL ...
. Both conditions appear to have links to dysfunctions related to the
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
, and common medications for both conditions among other systems, affect dopamine levels in the brain. A 2005 study suggested that up to 44% of people with ADHD had
comorbid In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...
(i.e. coexisting) RLS, and up to 26% of people with RLS had confirmed ADHD or symptoms of the condition.


Medications

Certain medications may cause or worsen RLS, or cause it secondarily, including: * certain
antiemetic An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may ...
s (antidopaminergic ones) * certain
antihistamines Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides re ...
(especially the sedating, first generation H1 antihistamines often in
over-the-counter Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...
cold medications) * many
antidepressants Antidepressants are a class of medication used to treat major depressive disorder, anxiety disorders, chronic pain conditions, and to help manage addictions. Common side-effects of antidepressants include dry mouth, weight gain, dizziness, hea ...
(both older TCAs and newer
SSRI Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs increase the extracellul ...
s) *
antipsychotic Antipsychotics, also known as neuroleptics, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but ...
s and certain
anticonvulsant Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...
s * a
rebound effect The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued, or reduced in dosage. In the case of re ...
of sedative-hypnotic drugs such as a
benzodiazepine withdrawal syndrome Benzodiazepine withdrawal syndrome often abbreviated to benzo withdrawal or BZD withdrawal is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines, either medically or recreationally develops a p ...
from discontinuing benzodiazepine tranquilizers or sleeping pills *
alcohol withdrawal Alcohol withdrawal syndrome (AWS) is a set of symptoms that can occur following a reduction in alcohol use after a period of excessive use. Symptoms typically include anxiety, shakiness, sweating, vomiting, fast heart rate, and a mild fever. M ...
can also cause restless legs syndrome and other movement disorders such as akathisia and parkinsonism usually associated with antipsychotics *
opioid withdrawal Opioid withdrawal is a set of symptoms (a syndrome) arising from the sudden withdrawal or reduction of opioids where previous usage has been heavy and prolonged. Signs and symptoms of withdrawal can include drug craving, anxiety, restless legs, ...
is associated with causing and worsening RLS Both primary and secondary RLS can be worsened by surgery of any kind; however, back surgery or injury can be associated with causing RLS. 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.


Genetics

More than 60% of cases of RLS are familial and are inherited in an
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
fashion with
variable penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype). In medical genetics, the penetrance of a disease-causing mutation is t ...
. Research and brain autopsies have implicated both dopaminergic system and iron insufficiency in the
substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra app ...
. 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 Linkage may refer to: * ''Linkage'' (album), by J-pop singer Mami Kawada, released in 2010 *Linkage (graph theory), the maximum min-degree of any of its subgraphs *Linkage (horse), an American Thoroughbred racehorse * Linkage (hierarchical cluster ...
are known and listed below. Other than the first one, all of the linkage loci were discovered using an autosomal dominant model of inheritance. * The first genetic locus was discovered in one large
French Canadian French Canadians (referred to as Canadiens mainly before the twentieth century; french: Canadiens français, ; feminine form: , ), or Franco-Canadians (french: Franco-Canadiens), refers to either an ethnic group who trace their ancestry to Fren ...
family and maps to
chromosome 12 Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the to ...
q. This locus was discovered using an
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...
inheritance model. Evidence for this locus was also found using a
transmission disequilibrium test The transmission disequilibrium test (TDT) was proposed by Spielman, McGinnis and Ewens (1993) as a family-based association test for the presence of genetic linkage between a genetic marker and a trait. It is an application of McNemar's test. A ...
(TDT) in 12
Bavaria Bavaria ( ; ), officially the Free State of Bavaria (german: Freistaat Bayern, link=no ), is a state in the south-east of Germany. With an area of , Bavaria is the largest German state by land area, comprising roughly a fifth of the total lan ...
n families. * The second RLS locus maps to chromosome 14q and was discovered in one
Italian Italian(s) may refer to: * Anything of, from, or related to the people of Italy over the centuries ** Italians, an ethnic group or simply a citizen of the Italian Republic or Italian Kingdom ** Italian language, a Romance language *** Regional Ita ...
family. Evidence for this locus was found in one French Canadian family. Also, an
association Association may refer to: *Club (organization), an association of two or more people united by a common interest or goal *Trade association, an organization founded and funded by businesses that operate in a specific industry *Voluntary associatio ...
study in a large sample 159 trios of
European European, or Europeans, or Europeneans, may refer to: In general * ''European'', an adjective referring to something of, from, or related to Europe ** Ethnic groups in Europe ** Demographics of Europe ** European cuisine, the cuisines of Europe ...
descent showed some evidence for this locus. * This locus maps to chromosome 9p and was discovered in two unrelated
American American(s) may refer to: * American, something of, from, or related to the United States of America, commonly known as the "United States" or "America" ** Americans, citizens and nationals of the United States of America ** American ancestry, pe ...
families. Evidence for this locus was also found by the TDT in a large Bavarian family, in which significant linkage to this locus was found. * This locus maps to chromosome 20p and was discovered in a large French Canadian family with RLS. * This locus maps to chromosome 2p and was found in three related families from population isolated in
South Tyrol it, Provincia Autonoma di Bolzano – Alto Adige lld, Provinzia Autonoma de Balsan/Bulsan – Südtirol , settlement_type = Autonomous province , image_skyline = , image_alt ...
. * The sixth locus is located on chromosome 16p12.1 and was discovered by Levchenko et al. in 2008. Three genes,
MEIS1 Homeobox protein Meis1 is a protein that in humans is encoded by the MEIS1 gene. Function Homeobox genes, of which the most well-characterized category is represented by the HOX genes, play a crucial role in normal development. In addition, se ...
, BTBD9 and MAP2K5, were found to be associated to RLS. Their role in RLS
pathogenesis Pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from Greek πάθος ''pat ...
is still unclear. More recently, a fourth gene,
PTPRD Receptor-type tyrosine-protein phosphatase delta is an enzyme that, in humans, is encoded by the ''PTPRD'' gene. Function The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signa ...
was found to be associated with RLS. There is also some evidence that
periodic limb movements in sleep Periodic limb movement disorder (PLMD) is a sleep disorder where the patient moves limbs involuntarily and periodically during sleep, and has symptoms or problems related to the movement. PLMD should not be confused with restless legs syndrome (RL ...
(PLMS) are associated with on chromosome 6p21.2,
MEIS1 Homeobox protein Meis1 is a protein that in humans is encoded by the MEIS1 gene. Function Homeobox genes, of which the most well-characterized category is represented by the HOX genes, play a crucial role in normal development. In addition, se ...
, MAP2K5/SKOR1, and
PTPRD Receptor-type tyrosine-protein phosphatase delta is an enzyme that, in humans, is encoded by the ''PTPRD'' gene. Function The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signa ...
. 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 Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
and iron system anomalies. There is also a commonly acknowledged
circadian rhythm A circadian rhythm (), or circadian cycle, is a natural, internal process that regulates the sleep–wake cycle and repeats roughly every 24 hours. It can refer to any process that originates within an organism (i.e., Endogeny (biology), endogeno ...
explanatory mechanism associated with it, clinically shown simply by
biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...
s of circadian rhythm, such as
body temperature Thermoregulation is the ability of an organism to keep its body temperature within certain boundaries, even when the surrounding temperature is very different. A thermoconforming organism, by contrast, simply adopts the surrounding temperature ...
. The interactions between impaired neuronal iron uptake and the functions of the
neuromelanin Neuromelanin (NM) is a dark pigment found in the brain which is structurally related to melanin. It is a polymer of 5,6-dihydroxyindole monomers. Neuromelanin is found in large quantities in catecholaminergic cells of the substantia nigra pars com ...
-containing and dopamine-producing cells have roles in RLS development, indicating that
iron deficiency Iron deficiency, or sideropenia, is the state in which a body lacks enough iron to supply its needs. Iron is present in all cells in the human body and has several vital functions, such as carrying oxygen to the tissues from the lungs as a key ...
might affect the brain dopaminergic transmissions in different ways. Medial
thalamic nuclei This traditional list does not accord strictly with human thalamic anatomy. Nuclear groups of the thalamus include: *anterior nuclear group ** anteroventral nucleus ** anterodorsal nucleus ** anteromedial nucleus **superficial ("lateral dorsal" ...
may also have a role in RLS as part as the
limbic system The limbic system, also known as the paleomammalian cortex, is a set of brain structures located on both sides of the thalamus, immediately beneath the medial temporal lobe of the cerebrum primarily in the forebrain.Schacter, Daniel L. 2012. ''Ps ...
modulated by the
dopaminergic system Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% o ...
which may affect pain perception. Improvement of RLS symptoms occurs in people receiving low-dose
dopamine agonist A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the ...
s.


Diagnosis

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: * 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. These symptoms are not essential, like the ones above, but occur commonly in RLS patients: * genetic component or family history with RLS * good response to dopaminergic therapy * periodic leg movements during 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 The International Classification of Sleep Disorders (ICSD) is "a primary diagnostic, epidemiological and coding resource for clinicians and researchers in the field of sleep and sleep medicine". The ICSD was produced by the American Academy of Slee ...
(ICSD-3), the main symptoms have to be associated with a sleep disturbance or impairment in order to support RLS diagnosis. 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. 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 Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...
,
venous stasis Venostasis, or venous stasis, is a condition of slow blood flow in the veins, usually of the legs. Presentation Complications Potential complications of venous stasis are: * Venous ulcers * Blood clot formation in veins (venous thrombosis), that ...
, peripheral
neuropathy Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or o ...
,
radiculopathy Radiculopathy, also commonly referred to as pinched nerve, refers to a set of conditions in which one or more nerves are affected and do not work properly (a neuropathy). Radiculopathy can result in pain (radicular pain), weakness, altered sens ...
, habitual foot tapping/leg rocking,
anxiety Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
, myalgia, and drug-induced
akathisia Akathisia is a movement disorder characterized by a subjective feeling of inner restlessness accompanied by mental distress and an inability to sit still. Usually, the legs are most prominently affected. Those affected may fidget, rock back a ...
.
Peripheral artery disease Peripheral artery disease (PAD) is an abnormal narrowing of arteries other than those that supply the heart or brain. When narrowing occurs in the heart, it is called coronary artery disease, and in the brain, it is called cerebrovascular dis ...
and
arthritis Arthritis is a term often used to mean any disorder that affects joints. Symptoms generally include joint pain and stiffness. Other symptoms may include redness, warmth, swelling, and decreased range of motion of the affected joints. In som ...
can also cause leg pain but this usually gets worse with movement. There are less common differential diagnostic conditions included
myelopathy Myelopathy describes any neurologic deficit related to the spinal cord. The most common form of myelopathy in humans, ''Spinal cord compression, cervical spondylotic myelopathy (CSM)'', also called ''degenerative cervical myelopathy'', results fro ...
,
myopathy In medicine, myopathy is a disease of the muscle in which the muscle fibers do not function properly. This results in muscular weakness. ''Myopathy'' means muscle disease (Greek : myo- ''muscle'' + patheia '' -pathy'' : ''suffering''). This meani ...
, vascular or neurogenic
claudication Claudication is a medical term usually referring to impairment in walking, or pain, discomfort, numbness, or tiredness in the legs that occurs during walking or standing and is relieved by rest. The perceived level of pain from claudication can be ...
,
hypotensive akathisia Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dias ...
,
orthostatic tremor A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving oscillations or twitching movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, f ...
, painful legs, and moving toes.


Treatment

If RLS is not linked to an underlying cause, its frequency may be reduced by lifestyle modifications such as adopting improving
sleep hygiene Sleep hygiene is a behavioral and environmental practice developed in the late 1970s as a method to help people with mild to moderate insomnia. Clinicians assess the sleep hygiene of people with insomnia and other conditions, such as depression, ...
, regular exercise, and stopping smoking. Medications used may include
dopamine agonists A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and th ...
or
gabapentin Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is a first-line medication for the treatment of neuropathic pain caused by diabeti ...
in those with daily restless legs syndrome, and opioids for treatment of resistant cases. Treatment of RLS should not be considered until possible medical causes are ruled out. Secondary RLS may be cured if precipitating medical conditions (
anemia Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
) are managed effectively.


Physical measures

Stretching the leg muscles can bring temporary relief. 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. A vibratory counter-stimulation device has been found to help some people with primary RLS to improve their sleep.


Iron

There is some evidence that intravenous iron supplementation moderately improves restlessness for people with RLS.


Medications

For those whose RLS disrupts or prevents sleep or regular daily activities, medication may be useful. Evidence supports the use of
dopamine agonist A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the ...
s including:
pramipexole Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipex ...
,
ropinirole Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In PD the dose needs to be adjusted to the effect and treatment should not be suddenly stopped. ...
,
rotigotine Rotigotine, sold under the brand name Neupro among others, is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson's disease and restless legs syndrome. It is formulated as a once-daily transdermal ...
, and
cabergoline Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth. Cabergoline is an e ...
. They reduce symptoms, improve sleep quality and quality of life. Levodopa is also effective. However, pergolide and cabergoline are less recommended due to their association with increased risk of valvular heart disease. Ropinirole has a faster onset with shorter duration. 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. One 2008 review found pramipexole to be better than ropinirole. 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. Also, a recent study indicated that dopamine agonists used in restless legs syndrome can lead to an increase in
compulsive gambling Problem gambling or ludomania is repetitive gambling behavior despite harm and negative consequences. Problem gambling may be diagnosed as a mental disorder according to ''DSM-5'' if certain diagnostic criteria are met. Pathological gambling is ...
. *
Gabapentin Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is a first-line medication for the treatment of neuropathic pain caused by diabeti ...
or
pregabalin Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic and anxiolytic medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal and generalized anxiety diso ...
, a non-dopaminergic treatment for moderate to severe primary RLS *
Opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid us ...
s are only indicated in severe cases that do not respond to other measures due to their very high abuse liability and high rate of
side effect In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequence ...
s, which may include
constipation Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...
, fatigue and
headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...
. One possible treatment for RLS is dopamine agonists, unfortunately patients can develop
dopamine dysregulation syndrome Dopamine dysregulation syndrome (DDS) is a dysfunction of the reward system observed in some individuals taking dopaminergic medications for an extended length of time. It typically occurs in people with Parkinson's disease (PD) who have taken dop ...
, meaning that they can experience an addictive pattern of dopamine replacement therapy. Additionally, they can exhibit some behavioral disturbances such as impulse control disorders like pathologic gambling, compulsive purchasing and compulsive eating. 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.
Benzodiazepine Benzodiazepines (BZD, BDZ, BZs), sometimes called "benzos", are a class of depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat conditions such as anxiety disorders, ...
s, such as
diazepam Diazepam, first marketed as Valium, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is commonly used to treat a range of conditions, including anxiety, seizures, alcohol withdrawal syndrome, muscle spasms, insomnia, a ...
or
clonazepam Clonazepam, sold under the brand names Klonopin and Rivotril, is a medication used to prevent and treat seizures, panic disorder, anxiety disorders, and the movement disorder known as akathisia. It is a tranquilizer of the benzodiazepine class ...
, are not generally recommended, and their effectiveness is unknown. They however are sometimes still used as a second line, as add on agents.
Quinine Quinine is a medication used to treat malaria and babesiosis. This includes the treatment of malaria due to '' Plasmodium falciparum'' that is resistant to chloroquine when artesunate is not available. While sometimes used for nocturnal le ...
is not recommended due to its risk of serious side effects involving the blood.


Prognosis

RLS symptoms may gradually worsen with age, although more slowly for those with the
idiopathic An idiopathic disease is any disease with an unknown cause or mechanism of apparent wikt:spontaneous, spontaneous origin. From Ancient Greek, Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approxi ...
form of RLS than for people who also have an associated medical condition. 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. Being diagnosed with RLS does not indicate or foreshadow another neurological disease, such as
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
. RLS symptoms can worsen over time when
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
-related drugs are used for therapy, an effect called "augmentation" which may represent symptoms occurring throughout the day and affect movements of all limbs. There is no cure for RLS.


Epidemiology

RLS affects an estimated 2.5–15% of the American population. A minority (around 2.7% of the population) experience daily or severe symptoms. RLS is twice as common in women as in men, and Caucasians are more prone to RLS than people of African descent. RLS occurs in 3% of individuals from the
Mediterranean The Mediterranean Sea is a sea connected to the Atlantic Ocean, surrounded by the Mediterranean Basin and almost completely enclosed by land: on the north by Western and Southern Europe and Anatolia, on the south by North Africa, and on the e ...
or
Middle East The Middle East ( ar, الشرق الأوسط, ISO 233: ) is a geopolitical region commonly encompassing Arabian Peninsula, Arabia (including the Arabian Peninsula and Bahrain), Anatolia, Asia Minor (Asian part of Turkey except Hatay Pro ...
ern regions, and in 1–5% of those from
East Asia East Asia is the eastern region of Asia, which is defined in both geographical and ethno-cultural terms. The modern states of East Asia include China, Japan, Mongolia, North Korea, South Korea, and Taiwan. China, North Korea, South Korea and ...
, indicating that different genetic or environmental factors, including diet, may play a role in the prevalence of this syndrome. RLS diagnosed at an older age runs a more severe course. RLS is even more common in individuals with
iron deficiency Iron deficiency, or sideropenia, is the state in which a body lacks enough iron to supply its needs. Iron is present in all cells in the human body and has several vital functions, such as carrying oxygen to the tissues from the lungs as a key ...
, pregnancy, or end-stage
kidney disease Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can ...
. The
National Sleep Foundation The National Sleep Foundation (NSF) is an American non-profit, charitable organization. Founded in 1990, it's stated goal is to provide expert information on health-related issues concerning sleep. Research NSF Sleep Duration Recommendations ...
's 1998 ''Sleep in America'' poll showed that up to 25 percent of pregnant women developed RLS during the third trimester. Poor general health is also linked. There are several risk factors for RLS, including old age, family history, and
uremia Uremia is the term for high levels of urea in the blood. Urea is one of the primary components of urine. It can be defined as an excess of amino acid and protein metabolism end products, such as urea and creatinine, in the blood that would be no ...
. 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 Kidney dialysis (from Greek , , 'dissolution'; from , , 'through', and , , 'loosening or splitting') is the process of removing excess water, solutes, and toxins from the blood in people whose kidneys can no longer perform these functions natura ...
have a prevalence from 20% to 57%, while those having
kidney transplant Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantati ...
improve compared to those treated with dialysis. RLS can occur at all ages, although it typically begins in the third or fourth decade. Genome‐wide association studies have now identified 19 risk loci associated with RLS. Neurological conditions linked to RLS include
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
, spinal cerebellar atrophy,
spinal stenosis Spinal stenosis is an abnormal narrowing of the spinal canal or neural foramen that results in pressure on the spinal cord or nerve roots. Symptoms may include pain, numbness, or weakness in the arms or legs. Symptoms are typically gradual i ...
, lumbosacral
radiculopathy Radiculopathy, also commonly referred to as pinched nerve, refers to a set of conditions in which one or more nerves are affected and do not work properly (a neuropathy). Radiculopathy can result in pain (radicular pain), weakness, altered sens ...
and
Charcot–Marie–Tooth disease Charcot–Marie–Tooth disease (CMT) is a hereditary motor and sensory neuropathy of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. This disease is the most ...
type 2.


History

The first known medical description of RLS was by Sir Thomas Willis in 1672. Willis emphasized the sleep disruption and limb movements experienced by people with RLS. Initially published in
Latin Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally a dialect spoken in the lower Tiber area (then known as Latium) around present-day Rome, but through the power of the ...
(''De Anima Brutorum'', 1672) but later translated to English (''The London Practice of Physick'', 1685), Willis wrote: The term "fidgets in the legs" has also been used as early as the early nineteenth century. Subsequently, other descriptions of RLS were published, including those by
François Boissier de Sauvages François () is a French masculine given name and surname, equivalent to the English name Francis. People with the given name * Francis I of France, King of France (), known as "the Father and Restorer of Letters" * Francis II of France, King o ...
(1763),
Magnus Huss Magnus Huss (22 October 1807 – 22 April 1890) was a Swedish physician and professor, knighted with his name retained. He is known for coining the term ''alcoholism'' in 1849, which he used to refer to the pathological changes in the body due to ...
(1849), Theodur Wittmaack (1861),
George Miller Beard George Miller Beard (May 8, 1839 – January 23, 1883) was an American neurologist who popularized the term neurasthenia, starting around 1869. Biography Beard was born in Montville, Connecticut, on May 8, 1839, to Reverend Spencer F. Beard, ...
(1880),
Georges Gilles de la Tourette Georges Albert Édouard Brutus Gilles de la Tourette (; 30 October 1857 – 22 May 1904) was a French neurologist and the namesake of Tourette syndrome, a neurological condition characterized by tics. His main contributions in medicine were in ...
(1898),
Hermann Oppenheim Hermann Oppenheim (1 January 1858 – 5 May 1919) was one of the leading neurologists in Germany. Life and work Oppenheim is the son of Juda Oppenheim (1824–1891), the long-time rabbi of the Warburg synagogue community , and his wife, Cäcil ...
(1923) and Frederick Gerard Allison (1943). However, it was not until almost three centuries after Willis, in 1945, that 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''. Ekbom coined the term "restless legs" and continued work on this disorder throughout his career. He described the essential diagnostic symptoms, differential diagnosis from other conditions, prevalence, relation to anemia, and common occurrence during pregnancy. 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. ''Journal of Parkinsonism and RLS'' is the first peer-reviewed, online, open access journal dedicated to publishing research about Parkinson's disease and was founded by a Canadian neurologist Dr. Abdul Qayyum Rana.


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”. 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. Today, calling WED/RLS "Ekbom syndrome" is outdated usage, as the unambiguous names (WED or RLS) are preferred for clarity.


Controversy

Some doctors express the view that the incidence of restless legs syndrome is exaggerated by manufacturers of drugs used to treat it. Others believe it is an underrecognized and undertreated disorder. Further,
GlaxoSmithKline GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the ten ...
(GSK) ran advertisements that, while not promoting off-licence use of their drug (
ropinirole Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In PD the dose needs to be adjusted to the effect and treatment should not be suddenly stopped. ...
) 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 The Association of the British Pharmaceutical Industry (ABPI) is the trade association for over 120 companies in the UK producing prescription medicines for humans, founded in 1891.
(ABPI) ruled against GSK in this case.


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). These questionnaires provide information about the severity and progress of the disease, as well as the person's quality of life and sleep.
Polysomnography Polysomnography (PSG), a type of sleep study, is a multi-parameter study of sleep and a diagnostic tool in sleep medicine. The test result is called a polysomnogram, also abbreviated PSG. The name is derived from Greek and Latin roots: the Gre ...
(PSG) and actigraphy (both related to sleep parameters) are more objective resources that provide evidences of sleep disturbances associated with RLS symptoms.


See also

*
Periodic limb movement disorder Periodic limb movement disorder (PLMD) is a sleep disorder where the patient moves limbs involuntarily and periodically during sleep, and has symptoms or problems related to the movement. PLMD should not be confused with restless legs syndrome (RL ...


References


External links

* {{DEFAULTSORT:Restless Legs Syndrome Extrapyramidal and movement disorders Sleep disorders Syndromes Wikipedia medicine articles ready to translate Wikipedia neurology articles ready to translate