Restless legs syndrome

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Restless legs syndrome
Classification and external resources
RLS sleep patterns diagram - en.svg
Sleep pattern of a restless legs syndrome patient (red) vs. a healthy sleep pattern (blue).
ICD-10 G25.8
ICD-9 333.94
OMIM 102300 608831
DiseasesDB 29476
MedlinePlus 000807
eMedicine neuro/509
MeSH D012148

Restless legs syndrome (RLS) also known as Willis-Ekbom disease (WED)[1] or Wittmaack-Ekbom syndrome, is a neurological disorder characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations.[2] It most commonly affects the legs, but can affect the arms, torso, head, and even phantom limbs.[3] Moving the affected body part modulates the sensations, providing temporary relief.

RLS sensations range from pain or an aching in the muscles, to "an itch you can't scratch", an unpleasant "tickle that won't stop", or even a "crawling" feeling. The sensations typically begin or intensify during quiet wakefulness, such as when relaxing, reading, studying, or trying to sleep.[4] Additionally, most individuals with RLS suffer from periodic limb movement disorder (limbs jerking during sleep), which is an objective physiologic marker of the disorder and is associated with sleep disruption.[5] It can be caused by low iron levels.[6]

Treatment is often with levodopa or a dopamine agonist such as pramipexole.[6] Some controversy surrounds the marketing of drug treatments for RLS. It is a "spectrum" disease with some people experiencing only a minor annoyance and others having major disruption of sleep and impairments in quality of life.[7]

Signs and symptoms[edit]

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.[8] In a survey among members of the Willis-Ekbom Disease Foundation, it was found that up to 45% of patients had their first symptoms before the age of 20 years.[9]

  • "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 like: uncomfortable, painful, 'antsy', electrical, creeping, itching, pins and needles, pulling, crawling, 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 sufferers 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 recent poll shows the presence of significant daytime difficulties resulting from this condition. These problems range from being late for work, and 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.

Primary and secondary[edit]

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. 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 the use of certain drugs (see below).

Causes[edit]

The most commonly associated medical condition is iron deficiency (specifically blood ferritin below 50 µg/L[10]), which accounts for 20% of all cases of RLS. A study published in 2007 noted that RLS features were observed in 34% of patients having iron deficiency as against 6% of controls.[11] Conversely, 75% of individuals with RLS symptoms may have increased iron stores. Other associated conditions include varicose vein or venous reflux, folate deficiency, magnesium deficiency, fibromyalgia, sleep apnea, uremia, diabetes, thyroid disease, peripheral neuropathy, Parkinson's disease and POTS and certain auto-immune disorders such as Sjögren's syndrome, celiac disease, and rheumatoid arthritis. RLS can also worsen in pregnancy.[12] In a 2007 study, RLS was detected in 36% of patients attending a phlebology (vein disease) clinic, compared to 18% in a control group.[13]

An association has been observed between ADHD, and RLS or periodic limb movement disorder. 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.[14] A 2005 study suggested that up to 44% of ADHD sufferers had comorbid (i.e. coexisting) RLS, and up to 26% of RLS sufferers had confirmed ADHD or symptoms of the condition.[15] A 2009 study updated this to report that 39% of RLS sufferers also might have ADHD compared to 14% of controls and that those showing signs of both had more severe RLS, suggesting that perhaps either the difficulties of RLS and low sleep quality caused ADHD-like distraction or that dopamine was a possible common factor and its improvement helped both, and that RLS sufferers might wish to consider ADHD testing as well, but cautioned that neither condition was proven as the cause of the other.

Certain medications may cause or worsen RLS, or cause it secondarily, including:

Both primary and secondary RLS can be worsened by surgery of any kind; however, back surgery or injury can be associated with causing RLS.[20]

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.[21][22]

Genetics[edit]

More than 60% of cases of RLS are familial and are inherited in an autosomal dominant fashion with variable penetrance.[23]

Research and brain autopsies have implicated both dopaminergic system and iron insufficiency in the substantia nigra.[24] Iron is well-understood to be an essential co-factor 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 model of inheritance.

  1. The first genetic locus was discovered in one large French Canadian family and maps on chromosome 12q.[25][26] This locus was discovered, however, using an autosomal recessive inheritance model. Evidence for this locus was also found using a transmission disequilibrium test (TDT) in 12 Bavarian families.[27]
  2. The second RLS locus maps to chromosome 14q and was discovered in one Italian family.[28] Evidence for this locus was found in one French Canadian family.[29] Also, an association study in a large sample 159 trios of European descent showed some evidence for this locus.[30]
  3. This locus maps to chromosome 9p and was discovered in two unrelated American families.[31] Evidence for this locus was also found by the TDT in a large Bavarian family,[32] in which significant linkage to this locus was found.[33]
  4. This locus maps to chromosome 20p and was discovered in a large French Canadian family with RLS.[34]
  5. This locus maps to chromosome 2p and was found in three related families from population isolated in South Tyrol.[35]
  6. The sixth locus is located on chromosome 16p12.1 and was discovered by Levchenko et al. in 2008.[36]

Three genes, MEIS1, BTBD9 and MAP2K5, were found to be associated to RLS.[37] Their role in RLS pathogenesis is still unclear. More recently, a fourth gene, PTPRD was found to be associated to RLS[38]

There is also some evidence that periodic limb movements in sleep (PLMS) are associated with BTBD9 on chromosome 6p21.2.[5] The presence of a positive family history suggests that there may be a genetic involvement in the etiology of RLS.

Mechanism[edit]

Most research on the disease mechanism of restless legs syndrome has focused on the dopamine and iron system.[39][40] These hypotheses are based on the observation that iron and levodopa, a pro-drug of dopamine that can cross the blood–brain barrier and is metabolized in the brain into dopamine (as well as other mono-amine neurotransmitters of the catecholamine class) can be used to treat RLS, levodopa being a medicine for treating hypodopaminergic (low dopamine) conditions such as Parkinson's disease, and also on findings from functional brain imaging (such as positron emission tomography and functional magnetic resonance imaging), autopsy series and animal experiments.[41] Differences in dopamine- and iron-related markers have also been demonstrated in the cerebrospinal fluid of individuals with RLS.[42] A connection between these two systems is demonstrated by the finding of low iron levels in the substantia nigra of RLS patients, although other areas may also be involved.[43]

Diagnosis[edit]

There are no specific tests for RLS, but non-specific laboratory tests are used to rule out other causes such as vitamin deficiencies. According to the National Institutes of Health's National Institute of Neurological Disorders and Stroke, four symptoms are used to confirm the diagnosis:[44]

  • The symptoms are more severe at night and do not occur, or are negligible, in the morning (although in extreme cases, symptoms may occur in the daytime)
  • An irresistible urge to move the legs and/or arms, often associated with a sensation of pain, burning, pricking, tingling, numbness, or other unpleasant or unusual sensations
  • The sensations begin following relaxation or a period of staying still, and during sleep
  • Temporary relief from these sensations during movement of the affected legs and/or arms

NIH criteria[edit]

In 2003, a US National Institutes of Health (NIH) panel modified their criteria to include the following:

  1. An urge to move the limbs with or without sensations.
  2. Improvement with activity. Many patients find relief when moving and the relief continues while they are moving. In more severe RLS this relief of symptoms may not be complete or the symptoms may reappear when the movement ceases.
  3. Worsening at rest. Patients may describe being the most affected when sitting for a long period of time, such as when traveling in a car or airplane, attending a meeting, or watching a performance. An increased level of mental awareness may help reduce these symptoms.
  4. Worsening in the evening or night.[4] Patients with mild or moderate RLS show a clear circadian rhythm to their symptoms, with an increase in sensory symptoms and restlessness in the evening and into the night.

Prevention[edit]

Other than preventing the underlying causes, generally no method of preventing RLS has been established or studied. If RLS is due to specific treatable causes (specific medications or treatable conditions), then treatment of those causes may also remove or reduce RLS. Otherwise medical responses focus on treating the condition, either symptomatically or by targeting lifestyle changes and bodily processes capable of modifying its expression or severity.[citation needed]

Treatment[edit]

Treatment of restless legs syndrome involves identifying the cause of symptoms when possible. The treatment process is designed to reduce symptoms, including decreasing the number of nights with RLS symptoms, the severity of RLS symptoms and nighttime awakenings. Improving the quality of life is another goal in treatment. This means improving overall quality of life, decreasing daytime somnolence, and improving the quality of sleep. Pharmacologic treatment involves dopamine agonists or gabapentin enacarbil as first line drugs for daily restless legs syndrome, and opioids for treatment of resistant cases.[45]

An algorithm created by Mayo Clinic researchers and endorsed by the Willis-Eckbom Disease Foundation[46] provides guidance to the treating physician and patient, including non-pharmacological and pharmacological treatments.[47] Treatment of primary RLS should not be considered until possible precipitating medical conditions are ruled out, especially venous disorders. RLS drug therapy is not curative and has side effects such as nausea, dizziness, hallucinations, orthostatic hypotension, or daytime sleep attacks.

Secondary RLS may be cured if precipitating medical conditions (anemia, venous disorder) are managed effectively. Secondary conditions causing RLS include iron deficiency, varicose veins, and thyroid problems. Karl-Axel Ekbom, in his 1945 doctoral thesis on RLS, suspected venous disease in about 12.5% of cases. But due to the unavailability of Doppler ultrasound imaging technology (the diagnostic tool that detects abnormal blood flow in the veins – "venous reflux" – the pathological basis for varicose veins) at that time, Ekbom may have underestimated the role of venous disease. In uncontrolled prospective series, improvement of RLS was achieved in a high percentage of patients presenting with a combination of RLS and venous disease and had sclerotherapy or other treatment for the correction of venous insufficiency.[48][49]

Stretching[edit]

Stretching the leg muscles can bring temporary relief.[4][50] Walking and moving the legs, as the name "Restless Legs" implies, brings temporary relief. In fact, those suffering from 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.

Iron[edit]

According to some guidelines,[47][51] all people with RLS should have their serum ferritin level tested. The ferritin level, a measure of the body's iron stores, should be at least 50 µg/L (or ng/mL, an equivalent unit) for those with RLS. Oral iron supplements can increase ferritin levels. For some people, increasing ferritin will eliminate or reduce RLS symptoms; a ferritin level of 50 µg/L is not sufficient for some and increasing the level to 80 µg/L may further reduce symptoms. However, at least 40% of people will not notice any improvement. Treatment with IV iron is being tested at the US Mayo Clinic and Johns Hopkins Hospital. It is not advised to take oral iron supplements without first having ferritin levels tested, as many people with RLS do not have low ferritin and taking iron when it is not called for is unlikely to offer any therapeutic benefit whilst still able to cause adverse events. All parenteral iron treatments require diagnosis with laboratory tests to avoid iron overload

Medications[edit]

For those whose RLS disrupts or prevents sleep or regular daily activities, medication may be useful.

Evidence supports the use dopamine agonists including: pramipexole, ropinirole, rotigotine, and cabergoline.[52] They reduce symptoms, improve sleep quality and quality of life.[53] Levodopa is also effective.[54] One review found pramipexole to be better than ropinirole.[55]

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 are 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 leg syndrome can lead to an increase in compulsive gambling.[56]

  1. Gabapentin, a non-dopaminergic treatment for moderate to severe primary RLS
  2. Opioids are only indicated in severe cases that do not respond to other measures due to their high rate of side effects.[57]
  3. Benzodiazepines, such as diazepam, which not only provide symptom relief but also often assist in staying asleep and reducing awakenings from the movements
  4. Anticonvulsants, such as carbamazepine, help people who experience the RLS sensations as painful.[58]

Quinine is not recommended due to its risk of serious hematological side effects.[59]

Prognosis[edit]

RLS symptoms may gradually worsen with age, though more slowly for those with the idiopathic form of RLS than for patients who also suffer from an associated medical condition. Nevertheless, current therapies can control the disorder, minimizing symptoms and increasing periods of restful sleep. In addition, some patients 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.

Epidemiology[edit]

RLS affects an estimated 2.5 to 15% of the American population .[6][60] A minority (around 2.7% of the population) experience daily or severe symptoms.[61] RLS is twice as common in women as in men,[62] and Caucasians are more prone to RLS than people of African descent.[60] RLS occurs in 3% of individuals from the Mediterranean or Middle Eastern region, and in 1–5% of those from the Far East, indicating that different genetic or environmental factors, including diet, may play a role in the prevalence of this syndrome.[60][63] With age, RLS becomes more common, and RLS diagnosed at an older age runs a more severe course.[50]

RLS is even more common in individuals with iron deficiency, pregnancy and end-stage renal disease.[64][65] Neurologic conditions linked to RLS include Parkinson disease, spinal cerebellar atrophy, spinal stenosis,[specify] lumbosacral radiculopathy and Charcot-Marie-Tooth disease type 2.[60] Approximately 80–90% of people with RLS also have periodic limb movement disorder (PLMD), which causes slow "jerks" or flexions of the affected body part. These occur during sleep (PLMS = periodic limb movement while sleeping) or while awake (PLMW—periodic limb movement while waking).

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.[66]

History[edit]

The first known medical description of RLS was by Sir Thomas Willis in 1672.[67] Willis (1621–1675) is considered to be the founder of clinical neuroscience and is most famous for his description of the Circle of Willis, the arterial circle at the base of the brain.[68] His contributions to the understanding of the human brain and medical science were extensive and revolutionary at the time.[69] Known to be a keen observer of his patients' symptoms, Willis emphasized the sleep disruption and limb movements experienced by sufferers of RLS. Initially published in Latin (De Anima Brutorum, 1672) but later translated to English (The London Practice of Physick, 1685), Willis wrote:

Wherefore to some, when being abed they betake themselves to sleep, presently in the arms and legs, leapings and contractions on the tendons, and so great a restlessness and tossings of other members ensue, that the diseased are no more able to sleep, than if they were in a place of the greatest torture.

Subsequently, other descriptions of RLS were published, including those by Francois Boissier de Sauvages (1763), Magnus Huss (1849), Theodur Wittmaack (1861), George Miller Beard (1880), Georges Gilles de la Tourette (1898), Hermann Oppenheim (1923) and Frederick Gerard Allison (1943).[67][70] 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.[71] 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.[72][73]

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.[4][74] 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.

Controversy[edit]

Some doctors express the view that the incidence of restless leg syndrome is exaggerated by manufacturers of drugs used to treat it.[75] Others believe it is an underrecognized and undertreated disorder.[60] Further, GlaxoSmithKline 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 ABPI ruled against GSK in this case.[76]

Another point of confusion is that RLS and delusional parasitosis are entirely different conditions that share part of the Wittmaack-Ekbom syndrome eponym, as both syndromes were described by the same person, Karl-Axel Ekbom.[77]

The Restless Legs Syndrome Foundation[78] received 44% of its $1.4 million in funding from pharmaceutical groups.[79]

See also[edit]

References[edit]

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