Restless legs syndrome
Restless legs syndrome | |
---|---|
Other names | Willis–Ekbom disease (WED), |
Frequency | 2.5–15% (US)[4] |
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.
Risk factors for RLS include
Diagnosis is generally based on a person's symptoms after ruling out other potential causes.[6]
Restless legs syndrome may resolve if the underlying problem is addressed.[15] Otherwise treatment includes lifestyle changes and medication.[2] Lifestyle changes that may help include stopping alcohol and tobacco use, and sleep hygiene.[15] Medications used to treat RLS include dopamine agonists like pramipexole and gabapentinoids (α2δ ligands) like gabapentin.[4][7] RLS affects an estimated 2.5–15% of the American population.[4] Females are more commonly affected than males, and it becomes increasingly common with age.[3][1]
History
Sir Thomas Willis provided a medical description in 1672.[16] Willis emphasized the sleep disruption and limb movements experienced by people with RLS.
Subsequently, other descriptions of RLS were published, including by Theodor Wittmaack (1861) (in relation to whom it is sometimes known as Wittmaack-Ekbom syndrome).[17]
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.[18] 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.[19][20]
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.[19]
It is a "
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.[22] 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.[23]
- "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, 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[24] 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.[25]
Primary and secondary
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.[26] 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
While the cause is generally unknown, it is believed to be caused by changes in the neurotransmitter dopamine
ADHD
An association has been observed between
Medications
Certain medications may cause or worsen RLS, or cause it secondarily, including:[1]
- certain antiemetics (antidopaminergic ones)[33]
- certain antihistamines (especially the sedating, first generation H1 antihistamines often in over-the-counter cold medications)[33]
- many
- Antipsychotics.
- a rebound effect of sedative-hypnotic drugs such as a benzodiazepine withdrawal syndrome from discontinuing benzodiazepine tranquilizers or sleeping pills[1]
- alcohol withdrawal can also cause restless legs syndrome and other movement disorders such as akathisia and parkinsonism usually associated with antipsychotics[34]
- opioid withdrawal is associated with causing and worsening RLS[35]
Both primary and secondary RLS can be worsened by surgery of any kind; however, back surgery or injury can be associated with causing RLS.[36]
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.[37][38]
Genetics
More than 60% of cases of RLS are familial and are inherited in an
Research and brain autopsies have implicated both dopaminergic system and iron insufficiency in the substantia nigra.[40] 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 model of inheritance.
- The first genetic locus was discovered in one large autosomal recessive inheritance model. Evidence for this locus was also found using a transmission disequilibrium test (TDT) in 12 Bavarian families.[43]
- The second RLS locus maps to chromosome 14q and was discovered in one European descent showed some evidence for this locus.[46]
- This locus maps to chromosome 9p and was discovered in two unrelated American families.[47] Evidence for this locus was also found by the TDT in a large Bavarian family,[48] in which significant linkage to this locus was found.[49]
- This locus maps to chromosome 20p and was discovered in a large French Canadian family with RLS.[50]
- This locus maps to chromosome 2p and was found in three related families from population isolated in South Tyrol.[51]
- The sixth locus is located on chromosome 16p12.1 and was discovered by Levchenko et al. in 2008.[52]
Three genes, MEIS1, BTBD9 and MAP2K5, were found to be associated to RLS.[53] Their role in RLS pathogenesis is still unclear. More recently, a fourth gene, PTPRD was found to be associated with RLS.[54]
There is also some evidence that
Mechanism
Although it is only partly understood, pathophysiology of restless legs syndrome may involve
Medial
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:[1]
- 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:[1][64]
- 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 (ICSD-3), the main symptoms have to be associated with a sleep disturbance or impairment in order to support RLS diagnosis.[65] 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.[65][66] 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
Peripheral artery disease and arthritis can also cause leg pain but this usually gets worse with movement.[11]
There are less common differential diagnostic conditions included
Treatment
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.[67] Medications used may include dopamine agonists and gabapentinoids in those with daily restless legs syndrome.[1][35][7][8] In severe or refractory cases, opioids have been used.[68]
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.[1]
Physical measures
Stretching the leg muscles can bring temporary relief.[19][69] 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.[70][71]
Iron
There is some evidence that intravenous iron supplementation moderately improves restlessness for people with RLS.[72]
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.[7][73][74] They reduce symptoms, improve sleep quality and quality of life.[75] Levodopa is also effective.[76] However, pergolide and cabergoline are less recommended due to their association with increased risk of valvular heart disease.[77] Ropinirole has a faster onset with shorter duration.[78] 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.[78] A 2008 meta-analysis[needs update] found pramipexole to be better than ropinirole.[79]
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
Low doses of opioids are used in the treatment of severe and treatment-resistant cases and are recommended by multiple reputable medical guidelines.[7][8][86] The most commonly used agents are prolonged-release oxycodone and methadone, but other opioids, including tramadol, codeine, morphine, and hydrocodone, may also be considered.[7][87][8] Opioids 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 effects, which may include constipation, fatigue, and headache.[88][35] However, opioids are said to be highly effective for severe and refractory RLS, and can be helpful in well-selected individuals.[7][8][87]
Benzodiazepines, such as diazepam or clonazepam, are not generally recommended,[89] and their effectiveness is unknown or contradictory.[90][84] They, however, are sometimes still used as a second-line treatment,[91] as add-on agents.[90] 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.[84]
Placebo
Placebos provide a large benefit in terms of reduction of RLS symptoms.[92] This is thought to be due to positive expectancy effects and conditioning, which activate dopamine and opioid pathways in the brain.[92] 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.[92] 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.[93][94]
Prognosis
RLS symptoms may gradually worsen with age, although more slowly for those with the
Epidemiology
RLS affects an estimated 2.5–15% of the American population.[4][96] A minority (around 2.7% of the population) experience daily or severe symptoms.[97] RLS is twice as common in women as in men,[98] and Caucasians are more prone to RLS than people of African descent.[96] 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.[96][99] RLS diagnosed at an older age runs a more severe course.[69] RLS is even more common in individuals with iron deficiency, pregnancy, or end-stage kidney disease.[100][101] 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.[102] Poor general health is also linked.[103]
There are several risk factors for RLS, including old age, family history, and
RLS can occur at all ages, although it typically begins in the third or fourth decade.[66]
Genome‐wide association studies have now identified 19 risk loci associated with RLS.
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”.[106]
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.[107] 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.
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).[110] These questionnaires provide information about the severity and progress of the disease, as well as the person's quality of life and sleep.[110] Polysomnography (PSG) and actigraphy (both related to sleep parameters) are more objective resources that provide evidences of sleep disturbances associated with RLS symptoms.[110]
See also
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External links
- Restless legs syndrome at Curlie