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Restless legs syndrome

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Restless legs syndrome
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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.

WED/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 WED/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]

Some controversy surrounds the marketing of drug treatments for WED/RLS. It is a "spectrum" disease with some people experiencing only a minor annoyance and others suffering major disruption of sleep and significant impairments in quality of life.[6]

Signs and symptoms

The sensations—and the need to move—may return immediately after ceasing movement or at a later time. WED/RLS may start at any age, including childhood, and is a progressive disease for some, while the symptoms may remit in others.[7] 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.[8]

  • "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 WED/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 WED/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 WED/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 WED/RLS who responded reported driving while drowsy more than patients without WED/RLS. These daytime difficulties can translate into safety, social and economic issues for the patient and for society.

NIH criteria

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 WED/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 WED/RLS show a clear circadian rhythm to their symptoms, with an increase in sensory symptoms and restlessness in the evening and into the night.

Primary and secondary WED/RLS

WED/RLS is categorized as either primary or secondary.

  • Primary WED/RLS is considered idiopathic or with no known cause. Primary WED/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. WED/RLS in children is often misdiagnosed as growing pains.
  • Secondary WED/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).

Research into causes and contributing factors

Disease mechanism

Most research on the disease mechanism of Willis-Ekbom Disease/restless legs syndrome has focused on the dopamine and iron system.[9][10] 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.[11] Differences in dopamine- and iron-related markers have also been demonstrated in the cerebrospinal fluid of individuals with RLS.[12] 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.[13]

Associated medical conditions, medications and life style factors

The most commonly associated medical condition is iron deficiency (specifically blood ferritin below 50 µg/L[14]), which accounts for 20% of all cases of WED/RLS. A study published in 2007 noted that WED/RLS features were observed in 34% of patients having iron deficiency as against 6% of controls.[15] 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 diseaseand POTS and certain auto-immune disorders such as Sjögren's syndrome, celiac disease, and rheumatoid arthritis. RLS can also worsen in pregnancy.[16] In a 2007 study, RLS was detected in 36% of patients attending a phlebology (vein disease) clinic, compared to 18% in a control group.[17]

An association has been observed between ADHD, and WED/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.[18] 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.[19] 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 WED/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 WED/RLS, or cause it secondarily, including:

Both primary and secondary WED/RLS can be worsened by surgery of any kind; however, back surgery or injury can be associated with causing RLS.[24]

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 WED/RLS could cause the conditions, or medication used to treat a condition could cause WED/RLS.[25][26]

Genetics

More than 60% of cases of WED/RLS are familial[27] and are inherited in an autosomal dominant fashion with variable penetrance.

No one knows the exact cause of WED/RLS. Research and brain autopsies have implicated both dopaminergic system and iron insufficiency in the substantia nigra (study published in Neurology, 2003).[28] Iron is 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, the remainder 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.[29][30] 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.[31]
  2. The second WED/RLS locus maps to chromosome 14q and was discovered in one Italian family.[32] Evidence for this locus was found in one French Canadian family.[33] Also, an association study in a large sample 159 trios of European descent showed some evidence for this locus.[34]
  3. This locus maps to chromosome 9p and was discovered in two unrelated American families.[35] Evidence for this locus was also found by the TDT in a large Bavarian family,[36] in which significant linkage to this locus was found.[37]
  4. This locus maps to chromosome 20p and was discovered in a large French Canadian family with WED/RLS.[38]
  5. This locus maps to chromosome 2p and was found in three related families from population isolated in South Tyrol.[39]
  6. The sixth locus is located on chromosome 16p12.1 and was discovered by Levchenko et al. in 2008.[40]

Three genes, MEIS1, BTBD9 and MAP2K5, were found to be associated to WED/RLS.[41] Their role in RLS pathogenesis is still unclear. More recently, a fourth gene, PTPRD was found to be associated to RLS[42]

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.

Diagnosis

There are no specific tests for WED/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:[43]

  • 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

Prevention

Other than preventing the underlying causes, generally no method of preventing WED/RLS has been established or studied. If WED/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

Treatment of Willis-Ekbom Disease/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 WED/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.[44]

An algorithm created by Mayo Clinic researchers and endorsed by the Willis-Eckbom Disease Foundation[45] provides guidance to the treating physician and patient, including non-pharmacological and pharmacological treatments.[46] 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 WED/RLS may be cured if precipitating medical conditions (anemia, venous disorder) are managed effectively. Secondary conditions causing WED/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.[47][48]

Nonpharmacologic treatments may also reduce the symptoms or their severity. For example, since fatigue may worsen the symptoms, then relaxation techniques, soaking in a warm bath, or massaging the legs can all help aid in relaxation and relief of WED/RLS symptoms. Some other techniques are avoiding caffeine, alcohol, and tobacco; exercising every day; maintaining a schedule of relaxation; and avoiding heavy meals before bed. These techniques can be used with medication or by themselves for those who do not want medication. For symptoms that occur in the evening, patients may find that activities that alert the mind, such as crossword puzzles and video games, may reduce symptoms. Many patients may also benefit from WED/RLS support groups.[49]

Stretching, shaking legs and other methods of relief

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 WED/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. Hot[51] or cold showers or baths have also been known to improve symptoms[52] as has lying on one's front on the floor for approximately half an hour.[53]

Monochromatic near-infrared light treatment has also been shown to decrease symptoms associated with WED/RLS. A study showed there was a steady decrease in symptoms over the four weeks in the treatment group, and after four weeks of treatment, the treatment group had a significantly greater improvement in RLS symptoms than the control group.[54]

Iron supplements

According to some guidelines,[46][55] all people with WED/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 WED/RLS. Oral iron supplements, taken under a doctor's care, 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 sufferers 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 WED/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

Pharmaceuticals

For those whose WED/RLS disrupts or prevents sleep or regular daily activities, medication may be required. Many doctors currently use, and the Mayo Clinic algorithm includes,[46] medication from five categories: [citation needed]

  1. Dopamine agonists such as ropinirole, pramipexole, carbidopa/levodopa or pergolide.

These drugs are effective in reducing symptoms, and improve sleep quality and overall quality of life for those with RLS.[56]

Ropinirole (Requip) was first approved In 2005 by the US Food and Drug Administration (FDA) to treat moderate to severe Willis-Ekbom Disease/Restless Legs Syndrome. The drug was first approved for Parkinson's disease in 1997. Pramipexole (Mirapex, Sifrol, Mirapexen in the EU) received a positive recommendation by the EU Scientific Committee in February 2006. The FDA approved Mirapex for sale in the US in 2006. Rotigotine (Neupro), which is delivered by a transdermal patch was approved by the FDA in May 2007 for early stage Parkinson's disease, but at that time had not yet been approved for WED/RLS in the US. The Neupro patch was withdrawn from the US market shortly after initial introduction due to problems with the medication delivery system. Rotigotine (Neupro), was approved for sale in the EU in 2007 for not only advanced stage Parkinson's disease but also for WED/RLS. Rotigotine (Neupro) patches were reintroduced to the U.S. market in mid-2012 after modifications, extensive trials, and subsequent FDA approval, at doses up to 3 mg/day for RLS and up to higher doses for Parkinson's.

There are, however, issues with the use of dopamine agonists. Dopamine agonists have caused 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 Willis-Ekbom Disease/restless leg syndrome patients can lead to an increase in compulsive gambling.[57] Dopamine agonists are used as a treatment because WED/RLS symptoms coincide with that of dopamine levels, with the majority of symptoms occurring late at night when dopamine levels are at their lowest.[citation needed]

  1. Gabapentin enacarbil, a non-dopaminergic treatment for moderate to severe primary WED/RLS was approved by the FDA in April 2011.
  2. Opioids, particularly methadone, is especially effective in the treatment for the symptoms of severe WED/RLS and do not have the negative side-effects (augmentation and rebounding) of dopamine agonists.[58] However, they have numerous other side-effects.[59][60][61][62]
  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.[63]

Recently, several major pharmaceutical companies are reported to be marketing drugs without an explicit approval for WED/RLS, which are "off-label" applications for drugs approved for other diseases. The Restless Legs Syndrome Foundation[64] received 44% of its $1.4 million in funding from these pharmaceutical groups.[65]

Cannabis may help people who experience WED/RLS sensations fall asleep much faster than normal, eliminate nausea caused from medication, and relieve pain. Although still restricted by some governments, many states do consider WED/RLS a medical condition for Medical Marijuana.  (A pill form, marketed under the name Marinol and Sativex, contains the cannabinoid Tetrahydrocannabinol eliminates the primary health hazards associated with marijuana use, such as smoking. However, it should be noted that the medically beneficial pharmacological effects of cannabinoids found in cannabis are due in majority to unique combinatorial effect of numerous cannabinoids, not simply THC or CBD alone. )[citation needed]

Quinine is frequently used off label to treat WED/RLS but is not recommended by the FDA due to its risk of serious hematological side effects.[66]

Ropinirole vs. pramipexole

A meta-analysis published November 2007 combined previous 6–12 week long placebo-controlled studies done for ropinirole, which was the first medication to receive FDA-approved labeling for use in WED/RLS, and pramipexole to indirectly compare adverse reactions and efficacy. It found that while both drugs had the same efficacy, pramipexole had significantly lower incidences of nausea, vomiting, and dizziness. This led the authors to conclude: "differences in efficacy and tolerability favouring pramipexole over ropinirole can be observed."[67]

Vitamins C and E and their combination

In a randomized double-blind placebo controlled trial by Sagheb, et al., vitamins C, E and their combination were found to be effective in the treatment of WED/RLS in hemodialysis patients compared to the placebo. Moreover, these medications were found to be safe and without major side effects.[68]

Prognosis

WED/RLS symptoms may gradually worsen with age, though more slowly for those with the idiopathic form of WED/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

Claims about the prevalence of Willis-Ekbom Disease/restless legs syndrome can be confusing because its severity and frequency varies enormously between individual sufferers. WED/RLS affects an estimated 7% to 10% of the general population in North America and Europe.[69][70][71] A minority of sufferers (around 2.7% of the population) experience daily or severe symptoms.[70] RLS is twice as common in women as in men,[72] and Caucasians are more prone to WED/RLS than people of African descent.[69] WED/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.[69][73] With age, RLS becomes more common, and RLS diagnosed at an older age runs a more severe course.[50]

WED/RLS is even more common in individuals with iron deficiency, pregnancy and end-stage renal disease.[74][75] Neurologic conditions linked to RLS include Parkinson disease, spinal cerebellar atrophy, spinal stenosis,[specify] lumbosacral radiculopathy and Charcot-Marie-Tooth disease type 2.[69] 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 WED/RLS during the third trimester.[76]

History

The first known medical description of WED/RLS was by Sir Thomas Willis in 1672.[77] 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.[78] His contributions to the understanding of the human brain and medical science were extensive and revolutionary at the time.[79] 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 WED/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).[77][80] 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.[81] 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.[82][83]

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][84] 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

As with many diseases with diffuse symptoms, there is controversy among physicians as to whether WED/RLS is a distinct syndrome. The U.S. National Institute of Neurological Disorders and Stroke publishes an information sheet[85] characterizing the syndrome but acknowledging it as a difficult diagnosis. Some physicians consider it a real entity that has specific diagnostic criteria.[86]

Many doctors express the view that the incidence of Willis-Ekbom Disease/restless leg syndrome is exaggerated by manufacturers of drugs used to treat it.[87] Others believe it is an underrecognized and undertreated disorder.[69] Some of the controversy results from the fact that certain pharmaceutical companies used medical representatives (i.e., salespeople) to perform investigations into the treatment of WED/RLS even though those companies had no licensed treatments for the condition. Further, GlaxoSmithKline ran advertisements that, while not promoting off-license use of their drug (ropinirole) for treatment of WED/RLS, did link to the Ekbom Support Group website. That website contained statements advocating the use of ropinirole to treat WED/RLS. The ABPI ruled against GSK in this case.[88]

Another point of confusion is that Willis-Ekbom Disease/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.[89]

See also

References

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