Restless legs syndrome (RLS, Wittmaack-Ekbom's syndrome, or sometimes, but inaccurately, referred to as Nocturnal myoclonus) is a condition that is characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs, but can also be in the arms and torso. Moving the affected body part modulates the sensations, providing temporary relief. RLS causes a sensation in the legs or arms that can most closely be compared to a burning, itching, or tickling sensation in the muscles. Some controversy surrounds the marketing of drug treatments for RLS.
Signs and symptoms
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 early childhood, and is a progressive disease for a certain portion of those afflicted, although the symptoms have disappeared permanently in some sufferers.
- "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, and those with RLS have a hard time describing them. People use words such as: uncomfortable, "antsy", electrical, creeping, painful, itching, pins and needles, pulling, creepy-crawly, ants inside the legs, and many others. 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. While an RLS sufferer may be unable to qualify the sensations to a non-sufferer, someone else with RLS understands the indescribable nature of the unpleasant sensations.
- "Motor restlessness, expressed as activity, that relieves the urge to move."
- Movement will usually bring immediate relief, however, often only temporary and partial. Walking is most common; however, doing stretches, yoga, biking, or other physical activity may relieve the symptoms. Constant and fast up-and-down movement of the leg, coined "sewing machine legs" by at least one RLS sufferer, is often done to keep the sensations at bay without having to walk. Sometimes a specific type of movement will help a person more than another.
- "Worsening of symptoms by relaxation."
- Any type of inactivity involving sitting or lying—reading a book, a plane ride, watching TV or a movie, taking a nap—can trigger the sensations and urge to move. This depends on several factors: the severity of the person’s RLS, the degree of restfulness, the 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."
- While some only experience RLS at bedtime and others experience it throughout the day and night, most sufferers experience the worst symptoms in the evening and the least in the morning.
In 2003, a National Institutes of Health
(NIH) consensus panel modified their criteria to include the following:
- an urge to move the limbs with or without sensations
- improvement with activity
- worsening at rest
- worsening in the evening or night.
RLS is either primary or secondary.
- Primary RLS is considered idiopathic, or with no known cause. Primary RLS usually begins before approximately 40 to 45 years of age, and can even occur as early as the first year of life. In primary RLS, the onset is often slow. The RLS may disappear for months, or even years. It is often progressive and gets worse as the person ages. RLS in children is often misdiagnosed as growing pains.
- Secondary RLS often has a sudden onset and may be daily from the very beginning. It often occurs after the age of 40, however it can occur earlier. It is most associated with specific medical conditions or the use of certain drugs (see below).
Most research on the disease mechanism of restless legs syndrome has focused on the dopamine
and iron system
. These hypotheses are based on the observation that levodopa
and iron can be used to treat RLS, but also on findings from functional brain imaging (such as positron emission tomography
and functional magnetic resonance imaging
series and animal experiments
. Differences in dopamine- and iron-related markers have also been demonstrated in the cerebrospinal fluid
of individuals with RLS. 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.
The most commonly associated medical condition is iron deficiency
(specifically blood ferritin
below 50µg/L), which accounts for just over 20% of all cases of RLS. Other conditions associated with RLS include pregnancy
, varicose vein
or venous reflux, folate deficiency
, sleep apnea
, thyroid disease
, peripheral neuropathy
, Parkinson's disease
and certain auto-immune disorders
such as Sjögren's syndrome
, celiac disease
, and rheumatoid arthritis
. RLS can also worsen in pregnancy
. In a recent study, RLS was detected in 36% of patients attending a phlebology
(vein disease) clinic, compared to 18% in a control group.
Certain medications may worsen RLS in those who already have it, or cause it secondarily. These include: anti-nausea drugs, certain antihistamines (often in over-the-counter cold medications), drugs used to treat depression (both older tricyclics and newer SSRIs), antipsychotic drugs, and certain medications used to control seizures. Treatment of underlying conditions, or cessation of use of the offending drug, often eliminates the RLS.
Hypoglycemia has also been found to worsen RLS symptoms. Opioid detoxification has also recently been associated with provocation of RLS-like symptoms during withdrawal. For those affected, a reduction or elimination in the consumption of simple and refined carbohydrates or starches (for example, sugar, white flour, white rice and white potatoes) or some hard fats, such as those found in beef or biscuits, is recommended. Some doctors believe it is caused by irregular electrical impulses from the brain.
Both primary and secondary RLS can be worsened by surgery of any kind, however back surgery or injury can be associated with causing RLS.
Some experts believe RLS and periodic limb movement disorder are strongly associated with ADHD in some children. Dopamine appears to factor into both conditions. In addition, many types of medication for the treatment of both conditions affect dopamine levels in the brain.
The cause vs. effect of certain conditions and behaviors that are observed in some patients (ex. carrying excess weight, lack of exercise, suffering from depression or other mental illnesses) does not appear to be well established. The loss of sleep due to RLS could be the cause of the conditions, or the medication used to treat a condition could be the cause of an individual's RLS.
More than 60% of cases of RLS are familial and are inherited in an autosomal dominant
fashion with variable penetrance
No one knows the exact cause of RLS at present. Research and brain autopsies have implicated both dopaminergic system and iron insufficiency in the substantia nigra (study published in Neurology, 2003). Iron is an essential cofactor for the formation of L-dopa, the precursor of dopamine.
Five genetic loci found by linkage are currently known. Other than the first, the remainder of the linkage loci were discovered using an autosomal dominant model of inheritance.
- The first genetic locus was discovered in one large French Canadian family and maps on chromosome 12q. 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.
- The second RLS locus maps to chromosome 14q and was discovered in one Italian family. Evidence for this locus was found in one French Canadian family. Also, an association study in a large sample 159 trios of European descent showed some evidence for this locus.
- The third locus maps to chromosome 9p and was discovered in two unrelated American families. Evidence for this locus was also found by the TDT in a large Bavarian family, as well as in a German family, in which significant linkage to this locus was found.
- The next locus maps to chromosome 20p and was discovered in a large French Canadian family with RLS.
- The fifth locus maps to chromosome 2p and was found in three related families from population isolate in Bolzano-Bozen.
Three genes, MEIS1, BTBD9 and MAP2K5, were found to be associated to RLS.
Their role in RLS pathogenesis is still unclear.
There is also some evidence that periodic limb movements in sleep (PLMS) are associated with on chromosome 6p21.2.
The diagnosis of RLS relies essentially on a good medical history
and physical examination
. Sleep registration in a laboratory (polysomnography
) is not necessary for the diagnosis. Peripheral neuropathy
and leg cramps
should be considered in the differential diagnosis
; in these conditions, pain is often more pronounced than the urge to move. Akathisia
, a side effect of several antipsychotics
, is a more constant form of leg restlessness without discomfort. Duplex Ultrasound
evaluation of the vascular system is essential in all cases to rule out venous disorders which is common etiology of RLS. A rare syndrome of painful legs and moving toes
has been described, with no known cause.
Restless legs can only be prevented by preventing the underlying causes. No other ways of prevention have been studied.
An algorithm for treating primary RLS (i.e., RLS that is not the result of another medical condition) was created by leading researchers at the Mayo Clinic
and is endorsed by the Restless Legs Syndrome Foundation. This document provides guidance to both the treating physician and the patient, and includes both nonpharmacological and pharmacological treatments. Treatment of primary RLS should not be considered until possible precipitating medical conditions are ruled out, especially venous disorders. Drug therapy in RLS is not curative and is known to have significant side effects; expensive (about $100-150 per month for life), and thus it needs to be considered with caution.
Secondary RLS has the potential for cure if the precipitating medical conditions, anaemia, venous disorder, etc., are managed effectively. In many instances the alleged secondary conditions might be the only conditions causing the RLS; these include iron deficiency, varicose veins, and thyroid problems. Karl Ekbom in his original thesis on RLS in 1945 had suspected of venous disease in about 12.5% of the cases he studied. But due to the unavailability of Duplex ultrasound imaging technology (the diagnostic tool that detects the 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 who had presented with a combination of RLS and venous disease and had sclerotherapy or other treatment for the correction of venous insufficiency.
According to some guidelines , all people with RLS should have their ferritin
levels tested; ferritin levels should be at least 50 µg for those with 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 is not sufficient for some sufferers and increasing the level to 80 µg may greatly 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 dangerous to take 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 can cause iron overload disorder
, potentially a very dangerous condition.
For those whose RLS disrupts or prevents sleep or regular daily activities, medication may be required. Many doctors currently use, and the Mayo Clinic algorithm
includes, medication from four categories:
- Dopamine agonists such as ropinirole, pramipexole, carbidopa/levodopa or pergolide. Ropinirole (Requip) was first approved In 2005 by the US Food and Drug Administration (FDA) to treat moderate to severe 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. It was approved for sale in the EU in 2007. There are some issues with the use of dopamine augmentation. Dopamine agonists may cause 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. Also, a recent study indicated that dopamine agonists used in restless leg patients can lead to an increase in compulsive gambling.
- Opioids such as propoxyphene, oxycodone, or methadone, etc.
- Benzodiazepines, which often assist in staying asleep and reducing awakenings from the movements
- Anticonvulsants, which often help people who experience the RLS sensations as painful, such as carbamazepine
Recently, several major pharmaceutical companies are reported to be marketing drugs without an explicit approval for RLS, which are "off-label" applications for drugs approved for other diseases. The Restless Legs Syndrome Foundation received 44% of its $1.4 million in funding from these pharmaceutical groups
Ropinirole vs. Pramipexole
published November 2007 compared previous 6-12 week long studies done for ropinirole and pramipexole for 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."
While a 52 week open label study
found that "ropinirole treatment for RLS over 52 weeks was found to be well tolerated and appropriate for long-term use."
The non drug musculoskeletal approach
The non-drug musculoskeletal approach has been developed by a small group of doctors working at the London College of Osteopathic Medicine, London, UK and appears to produces relief of symptoms in 80–90% of patients. A small pilot study carried out at the London College of Osteopathic Medicine, using a specific form of manipulation, showed successful relief of symptoms in more that 80% of sufferers . This followed the empirical observation that a large proportion of RLS sufferers have a "somatic dysfunction" at the lowermost level of the lumbar spine, and that a specific type of gentle manipulation could relieve their symptoms. One study has shown that RLS patients have increased rather than the normal decreased spinal cord excitability during sleep and this fits with the osteopathic concept of spinal facilitation postulated by Korr. Specific types of manipulation appear to reduce this excessive sensory input and relieve symptoms. This non drug treatment approach is free of the side effects associated with many of the drug treatments outlined above.
Claims about the prevalence of restless legs syndrome can be confusing because its severity and frequency varies enormously between individual sufferers. RLS affects an estimated 7% to 10% of the general population in North America and Europe. Only a minority of sufferers (around 2.7% of the population) experience daily or severe symptoms. RLS is twice as common in women as in men, and whites are more prone to RLS than African Americans. 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. With age, RLS becomes more common, and RLS diagnosed at an older age runs a more severe course.
RLS is even more common in individuals with iron deficiency, pregnancy and end-stage renal disease. Neurologic conditions linked to RLS include Parkinson disease, spinal cerebellar atrophy, spinal stenosis, lumbar sacral radiculopathy and Charcot-Marie-Tooth disease type 2. 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 15 percent of pregnant women developed RLS during the third trimester.
Earlier studies were done by Thomas Willis
(1622–1675) and by Theodor Wittmaack
. Another early description of the disease and its symptoms were made by George Miller Beard
(1839-1883). In a 1945 publication titled 'Restless Legs', Swedish neurologist Karl-Axel Ekbom
(1907-1977) described the disease and presented eight cases used for his studies.
As with many diseases with diffuse symptoms, there is controversy among physicians as to whether RLS is a distinct syndrome. The U.S. National Institute of Neurological Disorders and Stroke
publishes an information sheet characterizing the syndrome but acknowledging it as a difficult diagnosis. Some physicians doubt that RLS actually exists as a legitimate clinical entity, but believe it to be a kind of "catch-all" category, perhaps related to a general heightened sympathetic nervous system
response that could be caused by any number of physical or emotional factors . Other physicians consider it a real entity that has specific diagnostic criteria.
The U.K. support group for RLS calls itself the "Ekbom support group" and explains that RLS and "Ekbom's Syndrome" are two names for the same condition. However, 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.
Many doctors express the view that the incidence of restless leg syndrome is exaggerated by manufacturers of drugs used to treat it. Others believe it is an underrecognized and undertreated disorder.