Restless Legs Syndrome

Restless legs syndrome (RLS), also known as Wittmaack-Ekbom's syndrome or Jimmy Legs 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 affect the arms or torso, and even phantom limbs. 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. It is a 'spectrum' disease with some people experiencing only a minor annoyance and others experiencing major issues.

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, numbness, and many others. It is sometimes described as feeling similar to a limb "falling asleep". See formication. While it may be impossible to describe the sensation to someone without RLS, other RLS sufferers can easily relate to the peculiar sensation. 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, that relieves the urge to move."
• Movement will usually bring immediate relief; however, this relief will often be only temporary and partial. Walking is most common; however, doing stretches, yoga, biking, or other physical activity may relieve the symptoms. Continuous, fast up-and-down movements of the leg, 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 down: reading a book, a plane ride, watching TV or a movie, or 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.

NIH criteria

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

1. an urge to move the limbs with or without sensations
2. improvement with activity
3. worsening at rest
4. 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. 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).

Causes

Disease mechanism

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, and also on findings from functional brain imaging (such as positron emission tomography and functional magnetic resonance imaging), autopsy 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.

Underlying disorders

The most commonly associated medical condition is iron deficiency (specifically blood ferritin below 50 µg/L), which accounts for just over 20% of all cases of RLS. Other conditions associated with RLS include varicose vein or venous reflux, folate deficiency, magnesium deficiency, sleep apnea, uremia, diabetes, 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: some antiemetics (the dopaminergic ones), certain antihistamines (often in over-the-counter cold medications), many antidepressants (both older TCAs and newer SSRIs), antipsychotics, and certain anticonvulsants. Treatment of underlying conditions, or cessation of use of the offending drug, often eliminates the RLS. Restless legs syndrome can occur as a result of the benzodiazepine withdrawal syndrome when discontinuing benzodiazepine tranquillisers or sleeping pills. A sedative hypnotic with a short half life may also induce restless legs syndrome when the dose wears off as part of a rebound effect.

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.

Genetics

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.

Six genetic loci found by linkage are currently known and are listed below. Other than the first one in this list, 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.
• The sixth locus is located on chromosome 16p12.1 and was discovered by Levchenko et al. in 2008.

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

There is also some evidence that periodic limb movements in sleep (PLMS) are associated with BTBD9 on chromosome 6p21.2.

Diagnosis

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, radiculopathy 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 or antidepressants, is a more constant form of leg restlessness without discomfort. Doppler 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.

Prevention

Other than preventing the underlying causes, no method of preventing restless legs has been established or studied.

Treatment

Treatment of restless legs syndrome involves identifying the cause of symptoms when possible. Pharmacotherapy involves dopamine agonists which are first line drugs for daily restless legs syndrome; gabapentin and opioids can be used for treatment resistant cases. The dopamine agonists pergolide, pramipexole, ropinirole, and cabergoline are preferred over levodopa as levodopa has problems of commonly having a rebound effect. 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 side effects such as nausea, dizziness, hallucinations, orthostatic hypotension, and sudden sleep attacks during the daytime. In addition, it can be 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 venous disease in about 12.5% of the cases he studied. But due to the unavailability of Doppler 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.

Stretching and shaking legs

Stretching the muscles in the legs can bring instant and permanent relief, lasting several days or longer. This does not work for everyone: sometimes relief is temporary, and discomfort can return within the span of a few seconds. One stretching method consists of bending over from a standing position and reaching out one's hands to the ground (touching the toes if possible). This position is held for 10 to 20 seconds and repeated 3 times.

Iron supplements

According to some guidelines[citation needed], 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.

Pharmaceuticals

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:

1. 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 for early stage Parkinson's disease; it is not yet approved for RLS in the US. The Neupro patch has been withdrawn from the US market 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 RLS. There are some issues with the use of dopamine agonists. 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.
2. Opioids are sometimes used when restless legs syndrome occurs with neuropathic pain or when other treatments fail to provide relief.
3. Benzodiazepines, such as diazepam, which often in addition to symptom relief assist in staying asleep and reducing awakenings from the movements
4. Anticonvulsants, such as carbamazepine, help people who experience the RLS sensations as painful.

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

A meta-analysis published November 2007 combined previous 6-12 week long placebo-controlled studies done for ropinirole 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."

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 produce 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.

Prognosis

RLS is generally a lifelong condition for which there is no cure. 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. A diagnosis of RLS does not indicate the onset of another neurological disease.