Restless Legs Syndrome 

Restless legs syndrome (RLS) is a neurologic movement disorder of the limbs that is often associated with a sleep complaint.^[1] 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.)

The sensations of RLS usually are worse during inactivity and often interfere with sleep, leading to walking discomfort, chronic sleep deprivation, and stress.^[2] Once correctly diagnosed, RLS can usually be treated effectively and, in some secondary cases, it can even be cured. (See Treatment and Medication.)

The term RLS was used initially in the mid-1940s by Swedish neurologist Karl A. Ekbom. However, descriptions of the disorder date back to the 17th century.

RLS is often unrecognized or misdiagnosed.^{[3, 4]} 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.)

Patient education

The education of patients and their families should focus on providing a better understanding of the disease and on the importance of compliance in improving 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.

The pathogenesis of RLS is unclear.^{[5, 6, 7, 8]} Currently, the most widely accepted mechanism involves a genetic component, along with abnormalities in the central, subcortical dopamine pathways and impaired iron homeostasis.^{[9, 10]} When centrally acting dopamine receptor antagonists are administered to patients with the syndrome, symptoms are reactivated. Results of single-photon emission computed tomography (SPECT) scanning have suggested 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, supporting the hypothesis that increasing serotonin transmission in the brain may exacerbate RLS.^[11]

The genetic component of RLS tends to run to in families.^[12] Various chromosomes have been implicated so far, including 12q, 14q, 9p, 20p, 4q, and 17p, in autosomal dominant and recessive fashion.^[9]

Primary RLS

RLS can be 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 y) 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 ^[1]

RLS can develop as a result of certain conditions or factors, particularly iron deficiency and peripheral neuropathy.^[3] These 2 conditions should be excluded before RLS is labeled as primary.^[3] Because of the prevalence of these conditions in the general population, their association with RLS needs to 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, with the disorder thought 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.^[13]

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 great degree of emotion-oriented coping with stress were independently related to the presence of RLS in patients with uremia who were taking hemodialysis therapy.^[6] RLS may improve after kidney transplantation.

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

• Antidopaminergic medications (such as neuroleptics)
• Diphenhydramine
• Tricyclic antidepressants (TCAs)
• Selective serotonin reuptake inhibitors (SSRIs)
• Alcohol
• Caffeine
• Lithium
• Beta blockers

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.^[1]

Race-, sex-, and age-related demographics

RLS affects African Americans less commonly than Caucasians; this applies even to secondary RLS caused by hemodialysis.^[14]

Women are affected more commonly than men at 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 when compared with age-matched men.^[15] Although the prevalence of RLS increases 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.

The symptoms of RLS progress over time in about two thirds of patients. The severity of symptoms in patients with RLS ranges from mild to intolerable. Although patients experience the sensations in their legs, they also may occur in the arms or elsewhere. RLS symptoms are generally worse in the evening and night and less severe in the morning.

While RLS may present early in adult life with mild symptoms, usually by age 50 it 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.^{[15, 16]}

Morbidity

Patients with RLS and periodic leg movements of sleep (PLMS) may be at an increased risk of developing hypertension. PLMS is associated with an autonomic surge and an increase in blood pressure.^[17]

Patients may also be prone to more headaches, which are migraine and tension-type in nature. 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.^[17]