Restless Legs Syndrome

Author: Dr Daniel Tarsy Harvard Medical School 2008-07-28

Clinical features of restless legs syndrome

• Restless legs syndrome (RLS) is a neurological disorder characterized by a very unpleasant discomfort in the legs that occurs when the affected individual is at rest and causes an uncontrollable urge to move the legs to relieve the symptoms. The diagnosis is based exclusively on the patient’s description of their symptoms since a physical and neurological examination of the patient shows no abnormalities.
• The condition is a relatively common cause of insomnia, as well as daytime drowsiness, which very often goes undiagnosed in mild cases. Daytime drowsiness can be severe enough to interfere with work or other daytime functions
• The abnormal feelings are typically hard for patients to describe. Nevertheless, the symptoms are usually deep-seated, located in the calves or lower legs, and bilateral – though sometimes they affect one leg more than the other. Occasionally, the arms may also be involved. Though most patients struggle to provide a precise description of their discomfort, they usually distinguish the feelings from pain or tingling although these symptoms can also occur. Vivid descriptive terms that patients use include crawling, creeping, pulling, drawing, insects crawling, or stretching sensations localized to the muscles, tendons, or bones.
• Characteristically, these feelings are present only when the patient is at rest and are promptly relieved by moving the legs. Symptoms usually become worse late in the day and evening and are at their worst about 15-30 minutes after the patient gets into bed at night. In severe cases the discomfort may occur earlier in the day while the patient is seated for an extended period of time such as during car trips, at a restaurant, in a theatre, or in an airplane. In milder cases patients fidget, move, and kick their legs in bed. Patients with more severe symptoms spend much of the night pacing the floor to gain relief. Relief is usually only temporary with a return of symptoms shortly after returning to bed. In severe cases, this cycle may repeat itself throughout the night. In addition to generating leg movements to ease their discomfort while awake, patients with RLS often have sudden, large bending movements of their legs only while asleep. These are called periodic leg movements of sleep (PLMS) and can also cause sleep interruptions severe enough to cause insomnia and excessive daytime drowsiness.

Diagnosis of restless legs syndrome

The diagnosis of RLS is based on the presence of the uncomfortable symptoms described above, prompt relief of symptoms by moving the legs, the absence of any other neurological symptoms, and a normal physical and neurological examination. A National Institutes of Health (NIH) restless legs study group has proposed the following features as criteria for diagnosis:

• An urge to move the legs, usually accompanied by uncomfortable and unpleasant sensations in the legs. Sometimes the urge to move is present without definite uncomfortable sensations, and sometimes the arms or other body parts are involved in addition to the legs.
• The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting.
• The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues.
• The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night.

There are other conditions that must be differentiated from RLS. The most important of these is painful peripheral neuropathy. Peripheral neuropathy is a physical disorder of the peripheral nerves in the legs or hands due to a variety of medical conditions such as diabetes, chronic renal failure, vitamin deficiencies, immune mediated nerve disorders, genetic causes, and many other medical conditions. Peripheral neuropathy is distinguished from RLS by being more constant throughout the day, being painful, causing tingling sensations in the feet and legs, not being as easily relieved by moving the legs, and being accompanied by loss of sensation and reflexes in the legs. However some patients with peripheral neuropathy also experience symptoms of RLS. RLS should also be differentiated from akathisia which is motor restlessness caused by antipsychotic drugs, certain antinausea medications such as metoclopramide and prochlorperazine, and antidepressants of the serotonin reuptake inhibitor type. Akathisia, which in Greek means “not to sit,” is a more generalized whole body restlessness that is present throughout the day; it is often associated with anxiety, and moving the legs does not relieve the restlessness. A much rarer disorder that resembles RLS is a condition called “painful legs and moving toes.” This condition causes constant, involuntary movements of the toes associated with leg pain while reclining. Muscle cramp disorders also often occur at night, but cause painful muscle cramps or muscle twitching in the calves and other muscles; the cramps and twitching are visible and not as easily responsive to moving the legs. PLMS, which is mentioned above, often occurs in patients with RLS but also occurs in a number of other sleep disorders. PLMS is considerably different from RLS in that it causes large movements of the legs while the patient is asleep rather than when awake and is not associated with discomfort of the legs.

• As already stated, the diagnosis of RLS is made on the basis of a characteristic group of symptoms and a normal neurologic examination. There are no specific laboratory tests for the diagnosis of RLS. A test has been devised which requires the patient to sit or lie down without moving for a fixed period of time while the legs are monitored with electromyography. However, such tests are not usually necessary for diagnosis and are not widely done. Laboratory tests, including a serum iron and ferritin level (see below), should be done to rule out secondary forms of RLS. An overnight sleep laboratory evaluation is not necessary to diagnose RLS but, if such a test is done, sleep studies will usually show the presence of PLMS (see above) which is a different symptom but often occurs in patients with RLS and also interferes with sleep. Electromyography and nerve conduction studies are tests of the nerves and muscles; they should be done if peripheral neuropathy is suspected or the patient has a medical condition such as diabetes or renal failure that commonly causes peripheral neuropathy.

Epidemiology of restless legs syndrome

If mild cases are included, RLS appears to be a very common disorder with various surveys showing that 5-15 % of the US population is affected by it. Women are affected twice as often as men. Although it is more common in patients above age 50 it may occur at any age. RLS also occurs in about 2% of children under age 18 in whom incorrect diagnoses such as “growing pains” or attention deficit hyperactivity disorder are common.

Causes of restless legs syndrome

• Primary RLS refers to RLS that occurs in isolation and is not related to an underlying medical disorder. The specific cause of primary RLS is not known. A genetic basis was originally suggested by the positive family history which occurs in more than 40% of cases with a pattern suggesting a dominant form of inheritance. Several large families have since been identified with an even higher family occurrence of RLS. Finally, RLS has been associated with several abnormal genes, which adds additional weight to a genetic cause for RLS.
• Many neurophysiologic research studies of the brain, spinal cord, and peripheral nerve reflexes have been carried out in patients with RLS. Several abnormalities in the transmission of signals in the nervous system have been found but so far these have not led to an explanation for the cause of RLS. Despite these inconclusive findings it is currently believed that RLS is probably due to a central brain or spinal cord disorder rather than a disorder of the peripheral nerves.
• Recent experimental brain imaging studies have shown that there is a mild reduction in brain dopamine concentrations in patients with RLS, although much less than in Parkinson’s disease in which dopamine deficiency is a central feature. The possibility of a deficit in dopamine function in the spinal cord has also been suggested.
• Secondary forms of RLS are believed to be due to an underlying medical disorder. When RLS was first reported in the Swedish medical literature more than 60 years ago it was believed that iron deficiency was the underlying cause for most cases and treatment with iron was recommended. Recent scientific studies have once again examined the possible importance of iron deficiency in RLS. A protein called ferritin which binds to iron and transports it the body has been found to be lower in RLS patients compared to normal individuals, even in the absence of iron deficiency anemia. Concentrations of iron and proteins that transport iron have also been found to be reduced in certain brain regions in individuals with RLS.
• Patients with chronic kidney failure who are being treated with dialysis commonly have symptoms identical to primary RLS. Symptoms of RLS are also increased in patients with diabetes who have the complication of diabetic peripheral neuropathy. In both of these cases, symptoms of neuropathy such as pain, tingling, and numbness of the feet and legs usually accompany the symptoms of RLS. There are other miscellaneous conditions reported to cause or aggravate RLS such as other peripheral neuropathies, Parkinson’s disease, pregnancy, vitamin deficiencies, rheumatoid arthritis, chronic venous insufficiency of the legs and, very rarely, a compressed lumbar nerve root that may cause symptoms limited to one leg.

Treatment of restless legs syndrome

RLS is a very common disorder that varies widely in its severity and not all patients have symptoms severe enough to warrant treatment. The first treatment proposed for RLS was iron since iron deficiency anemia appeared to occur in patients with RLS. However, iron deficiency is an uncommon cause for RLS and currently is recommended for those patients who have iron deficiency or a deficiency of its binding and transport protein ferritin or who have failed to respond to other treatments. Vasodilators and vitamins were once popularly used for treatment but with little scientific evidence that they were effective.

The following drugs are currently used for the treatment of RLS in patients symptomatic enough to require treatment. These are listed in order of usefulness with the understanding that medication selection should be tailored to the individual patient.

• Dopamine agonists are currently considered first-line treatment for RLS. These drugs directly stimulate dopamine receptors in the brain and have been used for many years in much larger doses for the treatment of Parkinson’s disease in which dopamine deficiency causes tremor, rigidity and slowness of movement. Pramipexole and ropinirole are the drugs of first choice for treatment of the vast majority of patients with RLS and are FDA approved for this purpose. Cabergoline is a long acting dopamine agonist which is available in Europe for treatment of RLS. All have been shown to be safe and effective in controlled trials that compared these drugs to placebo. They have the advantage of having a prolonged duration of effect, which makes them convenient for use before going to sleep. Side effects at the low doses used for RLS are uncommon, mild, and usually temporary. These include nausea, lightheadedness, drowsiness, and ankle swelling. When used in much higher doses in patients with Parkinson’s disease, more serious side effects include confusion, visual hallucinations, pathologic gambling, compulsive eating, and hypersexuality. These are all exceedingly rare or have not occurred in patients with RLS receiving lower doses of these medications. However, recently several cases of pathological gambling have been reported in patients with RLS being treated with these drugs.

Either pramipexole or ropinirole should be taken about one to two hours before retiring. The starting dose for pramipexole is 0.125 mg each evening. It is then increased by 0.125mg increments every few days until it is effective. A typical effective dose is 0.25 to 1.0 mg each evening. Ropinirole is begun with 0.25 mg each evening and increased by 0.25 mg increments every few days until effective. A typical effective dose is 2-4 mg each evening. Patients who have symptoms in the daytime require treatment with divided doses during the day according to their pattern of symptoms.

Some patients develop tolerance to dopamine agonists or a withdrawal reaction causing exacerbation of symptoms in the early morning or during the day called “augmentation”. However, this is much less common than after treatment with levodopa which is discussed below.

• Levodopa is a naturally occurring amino acid, similar to the dopamine agonists. It is used in much larger doses for the treatment of Parkinson’s disease. Levodopa has been found to be effective for treatment for RLS in placebo-controlled clinical trials. Side effects are rare at the low doses used for RLS and include nausea or lightheadedness. Nevertheless, tolerance to its effects and augmentation of symptoms as the effects of levodopa wear off are much more common than with the dopamine agonists making this a second-line treatment option. However, levodopa remains an excellent option in patients who develop side effects, tolerance, or augmentation during treatment with a dopamine agonist. Levodopa (LD) is combined in a single tablet with carbidopa (CD) in order to reduce side effects of levodopa. Treatment is begun with LD/CD 25/100 mg taken before retiring in either a regular or sustained release form. Some patients may require additional doses during the night or day according to their pattern of symptoms.

• Benzodiazepines such as diazepam were at one time the most commonly used medications used for treatment of RLS although few controlled clinical trials were ever carried out. Because of tolerance and the possibility of chemical dependence, it is recommended that they should only be used intermittently in patients with intermittent symptoms of RLS. They may also be considered if a patient with RLS also has poor sleep for another reason. Diazepam 2-5 mg is given before sleep. Other benzodiazepines may also be used, such as clonazepam 1.0 mg before sleep or the longer acting benzodiazepine temazepam, 15-30 mg before sleep. Side effects are generally limited to drowsiness.
• Opiates (narcotic analgesic–pain relievers) have been found to be useful for RLS largely in open clinical trials that were not controlled by comparison to a placebo. The drugs sometimes used include codeine, propoxyphene, hydrocodone, and oxycodone. Because of the possibility of chemical dependence they are usually reserved for patients who have responded poorly to other RLS treatments or as adjunctive treatment for patients experiencing an incomplete response to other medications.
• Other medications that appear to be useful in RLS, but have been less formally studied, are the anticonvulsants gabapentin and carbamazepine, the adrenergic blocking agents clonidine and propranolol, and the anti-parkinson drug amantadine.
• Nonpharmacologic treatments are also available. If the serum ferritin is low, iron replacement is recommended by giving ferrous sulphate together with vitamin C to enhance absorption. Anecdotally, it has been found that treatment with iron is sometimes helpful even in the absence of iron deficiency. Some patients report that vigorous exercise or leg stretching before sleep is helpful but this is of inconsistent benefit. Mental alerting activities to prevent boredom while unoccupied during the day have been recommended for patients with daytime symptoms. If possible, drugs sometimes reported to aggravate RLS symptoms such as caffeine, nicotine, alcohol, antidepressants, antipsychotic drugs, and antihistamines should be avoided.
• Refractory RLS refers to RLS in which there is either: a poor response to medication treatment; a declining response to treatment over time (tolerance); intolerable side effects; or shifts in the time of day that symptoms appear (augmentation) which cannot be controlled by changes in frequency of doses or the time of day medications are administered. Attempts to manage refractory RLS may include adding a second or third medication from among those listed above or replacing a poorly effective medication with another drug, including switching from one dopamine agonist to another. In some patients, repeated recycling of different medications every few months may be necessary to control symptoms. Finally, nonpharmacologic approaches should be considered to supplement medications in this situation.

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