Restless Legs Syndrome

Restless legs syndrome (RLS) is a neurologic movement disorder of the limbs that is often associated with a sleep complaint. ^[6] Patients with RLS have a characteristic difficulty in trying to depict their symptoms. They may report sensations, such as an almost irresistible urge to move the legs, that are not painful but are distinctly bothersome. RLS can lead to significant physical and emotional disability. (See Prognosis and Presentation.)

RLS is often unrecognized or misdiagnosed. ^{[3, 7]} Many patients are not diagnosed until 10-20 years after symptom onset. RLS may begin at any age, even as early as infancy, but most patients who are affected severely are middle-aged or older. (See Epidemiology, Presentation, and Workup.)

The sensations of RLS usually are worse during inactivity and often interfere with sleep, leading to chronic sleep deprivation and stress. ^[8] Once correctly diagnosed, RLS can usually be treated effectively, and in some secondary cases, it can even be cured. (See Treatment and Medication.)

Diagnostic criteria

Diagnostic criteria from the International RLS Study Group (IRLSSG) are as follows: ^[1]

• An urge to move the legs usually but not always accompanied by or felt to be caused by uncomfortable and unpleasant sensations in the legs.
• The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting.
• The urge to move the legs and any accompanying 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 the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day.
• The occurrence of the preceding features are not soley accounted for as symptoms primary to another medical or behavioral condition such as myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, and habitual foot tapping.

In the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the specific criteria for RLS are as follows: ^[9]

• An urge to move the legs that is usually accompanied by or occurs in response to uncomfortable and unpleasant sensations in the legs, characterized by all of the following: (1) the urge to move the legs begins or worsens during periods of rest or inactivity; (2) the urge is partially or totally relieved by movement; and (3) the urge to move legs is worse in the evening or at night than during the day or occurs only in the evening or at night

• Symptoms occur at least 3 times per week and have persisted for at least 3 months

• Symptoms cause significant distress or impairment in social, occupational, educational, academic, behavioral or other areas of functioning

• The symptoms cannot be attributed to another mental disorder or medical condition (e.g., leg edema, arthritis, leg cramps) or behavioral condition (e.g. positional discomfort, habitual foot tapping)

• The disturbance cannot be explained by the effects of a drug of abuse or medication

The diagnostic criteria for RLS in the International Classification of Sleep Disorders, 2^nd Edition (ICSD-2) are similar but do not include a criterion specifying the frequency or duration of symptoms.

The pathogenesis of restless legs syndrome (RLS) is unclear. ^{[2, 10, 11, 12]} Currently, the most widely accepted mechanism involves a genetic component, along with abnormalities in the central subcortical dopamine pathways and impaired iron homeostasis. ^{[13, 14]}

When centrally acting dopamine receptor antagonists are administered to patients with the syndrome, symptoms are reactivated. Results of single-photon emission computed tomography (SPECT) have suggested a deficiency of dopamine D2 receptors. Iron homeostasis abnormalities have been implicated through cerebrospinal fluid (CSF) iron profile measures.

In addition, investigators have shown an increased severity of RLS with decreasing availability of serotonin transporter in the brainstem, which supports the hypothesis that increasing serotonin transmission in the brain may exacerbate RLS. ^[15]

RLS can also be genetic and run in families. ^[16] Various chromosomes have been implicated so far, including 12q, 14q, 9p, 20p, 4q, and 17p, in autosomal dominant and recessive fashion. ^[13]

Restless legs syndrome (RLS) can be either primary or secondary. In most cases, RLS is a primary, idiopathic central nervous system (CNS) disorder. Such idiopathic disease can be familial in 25-75% of cases. In the familial cases, RLS appears to follow a pattern of autosomal dominant or recessive inheritance.

Patients with familial RLS tend to have an earlier age of onset (< 45 years) and slower disease progression. In some families, a progressive decrease in age of onset with successive generations (ie, genetic anticipation) has been described. Psychiatric factors, stress, and fatigue can exacerbate symptoms of RLS.

Secondary RLS can develop as a result of certain conditions or factors, particularly iron deficiency and peripheral neuropathy. ^{[6, 7]} Because of the prevalence of these conditions in the general population, their association with RLS must be interpreted with caution.

Other causes of RLS include the following:

• Folate or magnesium deficiency

• Amyloidosis

• Diabetes mellitus

• Lumbosacral radiculopathy

• Lyme disease

• Monoclonal gammopathy of undetermined significance

• Rheumatoid arthritis

• Sjögren syndrome

• Uremia

• Vitamin B-12 deficiency

• Frequent blood donation

Pregnancy is another causative factor in RLS, which is estimated to affect 25-40% of pregnant women. The syndrome usually subsides within a few weeks after delivery. However, in one long-term, follow-up study, women who developed RLS during pregnancy had a 4-fold increased risk of developing chronic RLS compared with women who did not have RLS when pregnant. ^[17]

RLS also occurs in as many as 25-50% of patients who have end-stage renal disease; these patients find their symptoms to be particularly bothersome during hemodialysis. One study found that hyperphosphatemia, anxiety, and a high degree of emotion-oriented coping with stress were independently related to the presence of RLS in patients with uremia who were undergoing hemodialysis. ^[10] RLS may improve after kidney transplantation.

The following medications have been known to cause or exacerbate the symptoms of RLS:

• Antidopaminergic medications (eg, neuroleptics)

• Diphenhydramine

• Tricyclic antidepressants (TCAs)

• Selective serotonin reuptake inhibitors (SSRIs)

• Serotonin-norepinepherine reuptake inhibitors (SNRIs)

• Alcohol

• Caffeine

• Lithium

• Beta blockers

United States and international statistics

Restless legs syndrome (RLS) affects about 5-15% of the general population of the United States. Although the exact international prevalence of the disease is uncertain, limited studies have indicated that 2-15% of the world’s population may experience symptoms of RLS. ^[6]

Age-, sex-, and race-related demographics

Although RLS becomes more prevalent with age, it has a variable age of onset and can occur in children. In patients with severe RLS, 33-40% had their first symptom before the age of 20 years, although the precise diagnosis of RLS was made much later. RLS usually progresses slowly to daily symptoms and severe disruption of sleep after age 50 years. Individuals with familial RLS tend to have onset of symptoms before age 45 years.

Women are affected more commonly than men, in a ratio of almost 2:1. The increased risk of RLS in women is thought to be related to parity; nulliparous women have the same risk of developing RLS that age-matched men do. ^[18] RLS affects African Americans less commonly than white individuals; this applies even to secondary RLS caused by hemodialysis. ^[19]

In about two thirds of restless legs syndrome (RLS) patients, the symptoms progress over time. The severity of symptoms in patients with RLS ranges from mild to intolerable. In addition to being experienced in the legs, sensations also may occur in the arms or elsewhere. RLS symptoms are generally worse in the evening and night and less severe in the morning.

Whereas RLS may present early in adult life with mild symptoms, by age 50 years it usually progresses to severe, daily disruption of sleep leading to decreased daytime alertness. RLS has been associated with reduced quality of life in cross-sectional analysis. ^{[18, 20]}

Patients with RLS and periodic leg movements of sleep (PLMS) may be at increased risk for hypertension. PLMS is associated with an autonomic surge and an increase in blood pressure. ^[21] Patients may also be more prone to headaches (migraine and tension-type). The headaches are probably secondary to disturbances in sleep associated with RLS and PLMS. Learning and memory difficulties have also been associated with RLS, presumably secondary to disrupted nocturnal sleep. ^[21]

Education of patients with restless legs syndrome (RLS) and their families should focus on providing a better understanding of the disease and on emphasizing the importance of compliance for alleviating the symptoms. (See Treatment and Medication.)

For patient education information, see the Sleep Disorders Center, as well as Restless Legs Syndrome (RLS), Sleep Disorders in Women, and Sleep Disorders and Aging.