AUTHOR AND EDITOR INFORMATION

Section 1 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

INTRODUCTION

Section 2 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Background

The term restless legs syndrome (RLS) was used initially in the mid-1940s by Swedish neurologist Karl A. Ekbom to describe a disorder characterized by sensory symptoms and motor disturbances of the limbs, mainly during rest. However, early descriptions date back to the 17th century. It is recognized now as a neurologic movement disorder of the limbs, often associated with a sleep complaint. 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, which are not painful but are distinctly bothersome; this can lead to significant physical and emotional disability. The sensations usually are worse during inactivity and often interfere with sleep, leading to walking discomfort, chronic sleep deprivation, and stress. Once correctly diagnosed, RLS can usually be treated effectively by relieving symptoms; in some secondary cases, it can even be cured.

Pathophysiology

Pathogenesis of RLS is unclear. Ekbom originally proposed that it was mainly the result of accumulation of metabolites in the legs because of venous congestion. Peripheral nerve abnormalities also have been proposed, but no associated structural changes in nerve endings have been identified.

RLS also has been linked to dopaminergic or opiate abnormalities. Centrally acting dopamine receptor antagonists reactivate symptoms when given to patients with the syndrome. Results of single-photon emission computed tomography (SPECT) have suggested deficiency of dopamine D2 receptors. Sympathetic hyperactivity also has been implicated on the basis of observations that sympathetic nerve blockade relieves periodic limb movements of sleep and that alpha-adrenergic blockers improve symptoms of RLS. Studies also have suggested possible underactivity of the serotonin and gamma-aminobutyric acid (GABA) neurotransmitter systems.

Frequency

United States

RLS affects about 10-15% of the general population, with men and women affected equally. It is often unrecognized or misdiagnosed. Many patients are not diagnosed until 10-20 years after symptom onset. It may begin at any age, even as early as infancy, but most patients who are affected severely are middle-aged or older. Symptoms progress over time in about two thirds of patients and may be severe enough to be disabling.

International

Although the exact prevalence is uncertain, limited studies have indicated that 2-15% of the population may experience symptoms of RLS.

Mortality/Morbidity

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 daily severe disruption of sleep leading to decreased daytime alertness. RLS is associated with reduced quality of life in cross-sectional analysis.

Sex

Although males and females are generally believed to be affected equally, a 2004 study by Berger et al showed that RLS affects women more frequently than men. In this specific study, parity was shown to be a major factor in explaining the sex difference and may guide further clarification of the etiology of the disease.

Age

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. It usually progresses slowly to daily, severe disruption of sleep, typically after age 50.

• A childhood-onset restless legs syndrome has also been described. A study published in Dec 2004 by Kotagal and Silber concluded that iron deficiency and a strong family history were characteristic of this childhood-onset presentation.

CLINICAL

Section 3 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

History

Diagnosis of RLS is based primarily on the clinical history. Often, patients do not bring RLS symptoms to the attention of the physician; therefore, including a few general sleep questions in the review of systems can be helpful. RLS patients typically report dysesthetic sensations described as "pins and needles," an "internal itch," or "a "creeping" or "crawling" sensation.

• The criteria for diagnosis of RLS are based on those developed by the International Legs Syndrome Study Group in 1995; 4 basic elements must be present to make the diagnosis. They are as follows:
• • A compelling urge to move the limbs, usually associated with paresthesias/dysesthesias
  • Motor restlessness, as seen in activities such as floor pacing, tossing and turning in bed, and rubbing the legs
  • Symptoms worse or exclusively present at rest (ie, lying, sitting) with variable and temporary relief on activity
  • Circadian variation of symptoms, which are present in the evening and at night. Often, symptoms are relieved after 5:00 am. In more severe cases, symptoms can be present throughout the day without circadian variation.
• Other features commonly associated with RLS but not required for diagnosis include sleep disturbances and daytime fatigue; normal neurologic exam in primary RLS; and involuntary, repetitive, periodic, jerking limb movements, either in sleep or while awake and at rest.
• Approximately 85% of patients with RLS have periodic leg movements of sleep (PLMS), usually involving the legs. PLMS is characterized by involuntary forceful dorsiflexion of the foot lasting 0.5-5 seconds and occurring every 20-40 seconds throughout sleep.
• A large majority of patients (85%) with RLS report difficulty falling asleep at night because of RLS, and they may experience excessive daytime somnolence because of poor sleep quality due to multiple PLMS-induced arousals.

Physical

The physical examination is usually normal in patients with RLS; it is performed to identify secondary causes and to exclude other disorders.

Causes

RLS can be primary or secondary.

• Primary RLS
• • In most cases, RLS is an idiopathic CNS disorder. Such idiopathic disease can be familial in 25-75% of cases. In the familial cases, it appears to follow a pattern of autosomal dominant inheritance.
  • Progressive decrease in age at onset with subsequent generations (ie, genetic anticipation) has been described in some families. Patients with familial RLS tend to have an earlier age at onset (< 45) and slower progression.
  • Psychiatric factors, stress, and fatigue can exacerbate symptoms of RLS.
• Secondary RLS
• • RLS can develop as a result of certain conditions or factors, particularly iron deficiency and peripheral neuropathy. These 2 conditions should be excluded before RLS is labeled as primary. Because of the prevalence of these conditions in the general population, their association with RLS needs to be interpreted with caution.
  • Other causes are folate or magnesium deficiency, polyneuropathy (either idiopathic or caused by alcohol abuse), amyloidosis, diabetes mellitus, lumbosacral radiculopathy, Lyme disease, monoclonal gammopathy of undetermined significance, rheumatoid arthritis, Sjögren syndrome, uremia, or vitamin B-12 deficiency.
  • Women can be affected by RLS during pregnancy, and the syndrome usually subsides within a few weeks after delivery. It affects 25-40% of pregnant women.
  • RLS also occurs in as many as 25-50% of patients who have end-stage renal disease and find their symptoms particularly bothersome during hemodialysis. Hyperphosphatemia, anxiety, and a great degree of emotion-oriented coping with stress were independently related to the presence of RLS in uremic patients taking hemodialysis therapy.
  • RLS symptoms occur in 25-50% of patients with iron deficiency.
  • Other conditions associated with RLS are anemia; Parkinson disease; gastric surgery; chronic obstructive pulmonary disease (COPD); some tumors; chronic venous insufficiency or varicose veins; medications or certain substances, such as alcohol, caffeine, anticonvulsants (eg, methsuximide, phenytoin), antidepressants (eg, amitriptyline, paroxetine), beta-blockers, histamine-H2 antagonists, lithium, neuroleptics, withdrawal from vasodilators, sedatives, or imipramine; cigarette smoking; myelopathy or myelitis; hypothyroidism or hyperthyroidism; acute intermittent porphyria; fibromyalgia; and cholesterol peripheral microemboli.
• The pathogenesis of RLS seems to involve more than one mechanism, which leads to restless legs as the final common pathway.

DIFFERENTIALS

Section 4 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Other Problems to be Considered

Nocturnal leg cramps: These are typically unilateral, painful, palpable, involuntary muscle contractions, often local, with a sudden onset. Like RLS, they may have a circadian pattern and often occur at rest. However, the leg cramps have physical changes including a muscle hardening not seen in RLS.

Akathisia: It is characterized by excessive urge to move the entire body, without a focal sensory complaint in the limbs; often it does not correlate with rest or show circadian variation, and it usually results from medications such as neuroleptics or other dopamine-blocking agents. It also may be caused by selective serotonin reuptake inhibitors (SSRIs).

Peripheral neuropathy: It can cause leg symptoms that are different from those of RLS; symptoms usually are neither associated with motor restlessness nor helped by movement and do not worsen in evening or nighttime. Typically, sensory complaints are numbness, tingling, or pain. Small-fiber sensory neuropathies, as seen in diabetes, often are confused with RLS; patients with neuropathies may have both neuropathic symptoms and symptoms of RLS.

Vascular disease (eg, deep vein thrombosis)

Painful legs moving toes: Unlike RLS, this condition is not associated with a focal urge to move the limbs, and it does not show a clear circadian pattern.

RLS must be distinguished from sleep-related leg conditions, such as nocturnal leg cramps. These periodic limb movements, also known as PLMS or nocturnal myoclonus, which may be associated with RLS, are stereotyped, repetitive flexion of the limbs (legs alone or legs more than arms), lasting 0.5-5 seconds and usually occurring every 20-40 seconds.

WORKUP

Section 5 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Lab Studies

• If a secondary cause is suspected on the basis of history, abnormal findings on neurologic examination, or poor response to treatment, a laboratory evaluation should be done. Tests include measurement of levels of BUN, creatinine, fasting blood glucose, ferritin, magnesium, thyroid-stimulating hormone (TSH), vitamin B-12, and folate; Venereal Disease Research Laboratory (VDRL) test; glucose tolerance test; and CBC count.
• In a recent controlled study, Tuisku et al demonstrated that the general lower limb activity measured by 3-channel actometry is a promising objective measure of RLS severity. The same authors further evaluated the method in measuring RLS symptom severity in an open, single-day pramipexole intervention with 15 patients with RLS. They reported that both their standardized actometric parameters (nocturnal lower limb activity and controlled rest activity) decreased significantly during the intervention in parallel with the subjectively reported relief of RLS symptoms.

Other Tests

• Needle electromyography and nerve conduction studies should be considered if polyneuropathy is suspected on clinical grounds, even if results of neurologic examination are apparently normal.
• Polysomnography may be necessary to quantify PLMS or to characterize sleep architecture, especially in patients who continue to have significant sleep disturbances despite relief of RLS symptoms with treatment.
• Because RLS is primarily a subjective disorder, a subjective scale has been proposed as the optimal instrument to meet this need. In March 2003, a study was published after 20 centers from 6 countries participated in an initial reliability and validation study of a rating scale for the severity of RLS designed by the International RLS study group (IRLSSG). This scale, the IRLSSG rating scale, was administered to 196 RLS patients, most of whom were taking some medication, and 209 control subjects. The results of this study showed that the IRLSSG scale had high levels of internal consistency, interexaminer reliability, test-retest reliability over a 2-4 week period, and convergent validity. This scale is an interesting tool and should be considered for its value as a brief, patient-completed instrument that can be used to assess RLS severity for clinical assessment, research, or therapeutic trials.

TREATMENT

Section 6 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Medical Care

Therapeutic success is obtained when the physician tailors the treatment on the basis of the patient's specific symptoms and whether the symptoms are bothersome. Therapy should not be withheld if RLS is impairing the patient's quality of life.

• Nonpharmacologic management
• • Patients with mild RLS who are sensitive to caffeine, alcohol, or nicotine should avoid these substances. Offending medications also should be discontinued. Mild exercise is helpful in some patients. In general, physical measures are only partially or temporarily helpful. Behavioral treatments with circadian adjustments permit later sleep times.
  • Some patients benefit from different physical modalities, such as hot or cold baths, whirlpool baths, limb massage, or vibratory or electrical stimulation of the feet and toes before bedtime.
  • Supplementation to correct vitamin deficiencies, electrolytes, or iron may improve symptoms in some patients. In iron deficiency, for example, ferrous sulfate 325 mg may be given with 250 mg of vitamin C. Absorption is increased by taking this on an empty stomach and waiting 60 minutes before eating.
  • Patients with prominent varicose veins in the legs may benefit from Ted hose.
  • Those with uremia or anemia may find relief after kidney transplantation or correction of anemia, respectively.

Diet

Patients with RLS who are sensitive to caffeine, alcohol, or nicotine should avoid these substances.

MEDICATION

Section 7 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Drug therapy for primary RLS is largely symptomatic, since cure is possible only in secondary disease.

In some patients, RLS symptoms occur sporadically with spontaneous remissions lasting weeks or months. Use of pharmacologic treatment on an irregular basis is warranted in such cases.

Continuous pharmacologic treatment should be considered if patients complain of RLS symptoms at least 3 nights each week.

Drug Category: Dopaminergic agents

These agents may improve sensory symptoms associated with RLS.

Agents like pramipexole, ropinirole, and bromocriptine are less likely than the combination drug levodopa/carbidopa to produce augmentation or rebound and can be used alone or along with levodopa in patients in whom one of these conditions develops. Adverse effects of dopamine agonists include nausea, light-headedness, drowsiness, and postural hypotension.

Drug Category: Benzodiazepines

These agents may be used as monotherapy in patients with mild or intermittent symptoms or as combination therapy in severe cases. Clonazepam (Klonopin) has been shown to ease sensory symptoms and PLMS in RLS. Other benzodiazepines, such as temazepam (Restoril) and alprazolam (Xanax) also can be effective.

Drug Category: Opioids

Low-potency opioids, such as codeine and propoxyphene (Darvon, Dolene), can benefit patients with mild and intermittent symptoms; higher-potency agents, such as oxycodone hydrochloride (Roxicodone), methadone hydrochloride (Dolophine), and levorphanol tartrate (Levo-Dromoran), may have a role in refractory cases. Because of the risk of addiction, these drugs should be used with caution; their use usually is recommended only in refractory cases.

Drug Category: Anticonvulsants

These agents are used to manage severe muscle spasms.

Drug Category: Presynaptic alpha2-adrenergic agonists

These agents stimulate alpha2-adrenoreceptors in brain stem, activating an inhibitory neuron, which in turn results in reduced sympathetic outflow.

FOLLOW-UP

Section 8 of 9  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

Further Outpatient Care

• Patients should be monitored by a neurologist or their primary care provider.

Patient Education

• Education of patients and their families should focus on providing a better understanding of the disease and the importance of compliance in improving the symptoms.
• For excellent patient education resources, visit eMedicine's Sleep Disorders Center. Also, see eMedicine's patient education articles Restless Legs Syndrome, Sleep Disorders in Women, and Sleep Disorders and Aging.

REFERENCES

Section 9 of 9

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• References

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• Berger K, Luedemann J, Trenkwalder C, et al. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med. Jan 26 2004;164(2):196-202. [Medline].
• Ekbom KA. Restless legs syndrome. Neurology. Sep 1960;10:868-73. [Medline].
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• Montplaisir J, Nicolas A, Denesle R. Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology. Mar 23 1999;52(5):938-43. [Medline].
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• Silber MH. Restless legs syndrome. Mayo Clin Proc. Mar 1997;72(3):261-4. [Medline].
• Takaki J, Nishi T, Nangaku M, et al. Clinical and psychological aspects of restless legs syndrome in uremic patients on hemodialysis. Am J Kidney Dis. Apr 2003;41(4):833-9. [Medline].
• Trenkwalder C, Walters AS, Hening W. Periodic limb movements and restless legs syndrome. Neurol Clin. Aug 1996;14(3):629-50. [Medline].
• Tuisku K, Holi MM, Wahlbeck K, et al. Actometry in measuring the symptom severity of restless legs syndrome. Eur J Neurol. May 2005;12(5):385-7. [Medline].
• Walters AS. Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord. Sep 1995;10(5):634-42. [Medline].
• Walters AS, LeBrocq C, Dhar A, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. Mar 2003;4(2):121-32. [Medline].

Article Last Updated: Mar 30, 2007