NORD gratefully acknowledges Michael H. Silber, MB, ChB, Center for Sleep Medicine and Department of Neurology, Mayo Clinic, Rochester, Minnesota, for assistance in the preparation of this report.
Restless legs syndrome (RLS) is a neurologic and sleep related movement disorder characterized by an irresistible urge to move in the legs that typically occurs or worsens at rest. It is usually accompanied by abnormal, uncomfortable sensations, known as paresthesias or dysesthesias, that are often likened to crawling, cramping, aching, burning, itching, or prickling deep within the affected areas. Although the legs are usually involved, an urge to move with paresthesias or dysesthesias may also sometimes affect the arms or other areas of the body. Those with RLS may vigorously move the affected area, engage in pacing, or perform other, often repetitive movements, such as stretching, bending, or rocking. Symptoms typically worsen in the evening or at night, often resulting in sleep disturbances. Some individuals with RLS may also develop symptoms during other extended periods of inactivity, such as while sitting in a movie theater or traveling in a car. RLS may occur as a primary condition or due to another underlying disorder, certain medications, or other factors (secondary or symptomatic RLS). In primary RLS, the disorder is often genetic in origin or occurs for unknown reasons (idiopathic). Secondary RLS may occur in association with certain conditions, such as iron deficiency, low levels of the oxygen-carrying component of red blood cells (anemia), kidney failure, or pregnancy.
In individuals with restless legs syndrome (RLS), symptoms may become apparent at any age, including childhood. In most cases, the disorder is chronic in nature, often becoming more severe with increasing age. However, in some affected individuals, RLS symptoms may periodically subside and recur with varying levels of severity.
Because RLS symptoms typically occur upon relaxation and inactivity, many with the disorder may have problems falling asleep and/or may often be awakened by symptoms. In addition, the irresistible urge to move often causes affected individuals to get out of bed and walk around or perform other movements, further disrupting the opportunity for restful (restorative) sleep. In some cases, those with severe symptoms may only be able to obtain a few hours of sleep on a nightly basis, resulting in excessive daytime sleepiness.
In many cases, individuals with RLS may also experience repetitive movements of the legs during sleep (periodic limb movements in sleep [PLMS]) in which there is bending of the ankle (i.e., dorsiflexion), extension of the big toe, and, often, associated bending (flexion) of the knee or hip. PLMS tends to occur during non-dreaming periods of sleep (non-REM sleep) and is defined as five or more periodic limb movements per hour. In those with RLS, PLMS may contribute to sleep difficulties.
Some individuals with severe RLS may also experience abnormal, involuntary (dyskinetic) movements while awake that may be characterized by sudden, rapid muscle jerks or more prolonged uncontrolled movements of certain muscles or muscle groups. Although the legs are usually affected, the arms may also be involved in some cases. These involuntary movements, which may appear similar to PLMS, typically cease upon the performance of voluntary movements.
Restless legs syndrome (RLS) may occur as a primary disorder for unknown reasons (primary or idiopathic RLS) or in association with certain underlying conditions or other factors (secondary or symptomatic RLS). Many individuals with primary RLS report a family history of the disorder that may appear to suggest autosomal dominant inheritance. Human traits, including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.
In autosomal dominant disorders, a single copy of the disease gene (received from either the mother or father) may be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disease gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. RLS has been linked to sites on several chromosomes and a number of genes, but the exact genetic basis of the disorder has not been clearly defined.
Secondary RLS may be associated with other conditions, such as iron deficiency, anemia, kidney failure, or peripheral neuropathy. RLS may also occur or become more severe in women who are pregnant. In addition, some medications may appear to cause or aggravate RLS symptoms, such as certain antipsychotic, antidepressant or antinausea drugs.
The exact underlying cause of RLS symptoms is unknown. However, many researchers suggest that abnormalities in a certain neurotransmitter (dopamine) in the brain and spinal cord (central nervous system) plays some causative role. Neurotransmitters, including dopamine, are chemicals that regulate the transmission of nerve impulses. Low iron stores in the brain may also play a role.
Restless legs syndrome appears to be about twice as common in women than men. Associated symptoms may become apparent at any age, and the disorder is usually chronic, often becoming more severe with increasing age. However, in some affected individuals, RLS symptoms may periodically subside and recur with varying levels of severity. According to some reports, although most individuals do not bring their symptoms to the attention of physicians until middle age, up to 40 percent may initially experience symptoms before age 20.
The diagnosis of restless legs syndrome (RLS) is based upon a thorough clinical evaluation; a complete patient history, including current medications; family history; and specialized tests. In addition, a clinical assessment scale may be used to help evaluate severity of the disorder. Various laboratory studies may be conducted to help detect or rule out possible associated conditions, including tests to measure iron and ferritin levels in the blood to assess iron stores in the body. In addition, a neurological examination may be conducted if associated neurological abnormalities are suspected (e.g., peripheral neuropathy). In addition, some physicians may recommend specialized sleep studies to evaluate sleep disturbances and possible PLMS, but sleep studies are not needed to diagnose uncomplicated RLS.
Because making certain adjustments in lifestyle may help to alleviate RLS symptoms, physicians may recommend that patients follow a regular sleep routine, regularly engage in moderate exercise, yet avoid excessive exercise that may actually serve to aggravate symptoms. Physicians may also stress that individuals with RLS should refrain from using caffeine, and, if possible, using certain antidepressant, antinausea, or other medications that may aggravate RLS symptoms.
In individuals with secondary RLS, disease management includes appropriate treatment of the underlying disorder or condition, such as iron therapy. Such treatment may alleviate or eliminate symptoms of RLS in some cases. If such treatment does not effectively manage symptoms, certain drug therapies may be prescribed specifically to treat RLS.
Drug therapy may also be considered for many individuals with primary RLS. The main drug classes used for RLS include dopamine precursors or agonists, drugs binding to calcium channels, opioids and benzodiazepines. The specific medication(s) recommended may depend upon various factors, including disease severity, specific symptoms present, and response to therapy.
Dopamine precursors and dopamine agonists are medications that enhance levels or mimic the effects of the neurotransmitter dopamine. Certain of these medications may be recommended as first-line therapies that may be beneficial in improving all characteristic findings of RLS.
Levodopa, also known as L-dopa, is a dopamine precursor that increases concentrations of dopamine in the brain. Because certain enzymes immediately begin to break down available dopamine, a medication (carbidopa) that blocks the activity of such enzymes is often combined with L-dopa (e.g., as a combination drug known as carbidopa/levodopa). Many individuals who take levodopa medications may develop more severe RLS symptoms when the dose begins to wear off, or earlier in the day before treatment was initiated (known as “augmentation”). Because of this, the drug should never be used long-term but should be restricted to intermittent use, not more frequently than twice a week.
Dopamine agonists act like dopamine by stimulating molecules on the surface of certain cells that bind with dopamine (dopamine receptors). In many cases, these medications are recommended as first-line therapies, in place of levodopa preparations. Dopamine agonists used to treat RLS include ropinirole, pramipexole, and the rotigotine patch, all approved by the FDA for the treatment of RLS. Although evidence suggests that, during therapy with such dopamine agonists, augmentation appears to be less severe and less frequent than occurs with use of levodopa preparations, 40-80% of patients may develop augmentation with time. Other potentially serious side-effects include the development of impulse control disorders (compulsive shopping, pathologic gambling, increased sexuality and compulsive eating) in 6-17% of patients and increased sleepiness during the day. These potential side-effects should be discussed with the treating physician before starting therapy.
Drugs binding to calcium channels including gabapentin, pregabalin and gabapentin enacrbil (Horizant) are alternative first-line therapies for RLS. Gabapentin enacarbil is a precursor of gabapentin and has been approved by the FDA for the treatment of RLS as a once daily treatment. These drugs are all effective in RLS treatment but may cause sleepiness, dizziness, unsteadiness, a sense of mental fog, depression and weight gain.
In some cases, recommended treatment may include the use of other medications. Opioids (eg, oxycodone) are highly effective but are usually restricted to patients with RLS refractory to other drugs because of the potential for dependence and other side-effects. Certain benzodiazepine sleeping medications (e.g., clonazepam, temazepam); may be used to enhance sleep.
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