Restless Legs Syndrome 

Updated: Feb 22, 2017
Author: Ali M Bozorg, MD; Chief Editor: Selim R Benbadis, MD 

Overview

Practice Essentials

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

Signs and symptoms

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 paritally 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, or habitual foot tapping.

Approximately 85% of patients with RLS have periodic movements of sleep, usually involving the legs (periodic leg movements of sleep [PLMS]).[2] PLMS is characterized by involuntary, forceful dorsiflexion of the foot lasting 0.5-5 seconds and occurring every 20-40 seconds throughout sleep.

Other features commonly associated with RLS but not required for diagnosis include the following:

  • Sleep disturbances

  • Daytime fatigue

  • Involuntary, repetitive, periodic, jerking limb movements: Either during sleep or while awake and at rest

See Presentation for more detail.

Diagnosis

All patients with symptoms of RLS should be tested for iron deficiency.[3, 4] At a minimum, a ferritin level should be obtained, although a complete iron panel, including the following, is preferable, since ferritin can be falsely elevated in acute inflammatory states:

  • Iron levels

  • Ferritin

  • Transferrin saturation

  • Total iron binding capacity

If a secondary cause of RLS is suspected on the basis of history, abnormal findings on neurologic examination, or poor response to treatment, other laboratory tests should be done. These include a complete blood count (CBC) and measurement of levels of the following:

  • Blood urea nitrogen (BUN)

  • Creatinine

  • Fasting blood glucose

  • Magnesium

  • Thyroid-stimulating hormone (TSH)

  • Vitamin B-12

  • Folate

Other studies include the following:

  • Needle electromyography and nerve conduction studies: Should be considered if polyneuropathy or radiculopathy is suspected on clinical grounds, even if the results of the neurologic examination are apparently normal[5]

  • Polysomnography: May be necessary to quantify PLMS or to characterize sleep architecture, especially in children and in patients who continue to have significant sleep disturbances despite relief of RLS symptoms with treatment

See Workup for more detail.

Management

Pharmacologic therapy

Drug therapy for primary RLS is largely symptomatic, since cure is possible only in secondary disease. Medications used in the treatment of RLS include the following:

  • Dopaminergic agents

  • Benzodiazepines

  • Opioids

  • Anticonvulsants

  • Presynaptic alpha2-adrenergic agonists

  • Iron salt

Nonpharmacologic treatment

  • Sleep hygiene measures

  • Avoidance of caffeine, alcohol, and nicotine in patients with mild RLS who are sensitive to these substances

  • Discontinuation, when possible, of medications that cause or exacerbate RLS, such as selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinepherine reuptake inhibitors (SNRIs), diphenhydramine, and dopamine antagonists

  • Exercise

  • Physical modalities before bedtime, such as a hot or cold bath, whirlpool bath, limb massage, and vibratory or electrical stimulation of the feet and toes

See Treatment and Medication for more detail.

Background

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, 2nd Edition (ICSD-2) are similar but do not include a criterion specifying the frequency or duration of symptoms.

Pathophysiology

The pathogenesis of 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]

Etiology

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

Epidemiology

United States and international statistics

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]

Prognosis

In about two thirds of 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]

Patient Education

Education of patients with 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.

 

Presentation

History and Physical Examination

The diagnosis of restless legs syndrome (RLS) is based primarily on the patient’s clinical history. Often, patients do not bring RLS symptoms to the attention of the physician; accordingly, it can be helpful to include a few general sleep questions in the review of systems. RLS patients typically report dysesthetic sensations variously described as “pins and needles,” an “internal itch,” or a “creeping or crawling” sensation.

Approximately 85% of patients with RLS have periodic movements of sleep, usually involving the legs (periodic leg movements of sleep [PLMS]).[2] PLMS are 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 as a consequence of the condition, and they may experience excessive daytime somnolence because of poor sleep quality resulting from multiple PLMS-induced arousals. PLMS noted on polysomnography (PSG) alone do not warrant treatment. Clinicians should consider treating PLMS if they are causing frequent arousals.

Other features commonly associated with RLS but not required for diagnosis include sleep disturbances, daytime fatigue, and involuntary, repetitive, periodic, jerking limb movements (either while the patient is asleep or while he or she is awake and at rest). A positive family history also aids in the diagnosis of RLS, especially in children.

RLS can be difficult to diagnose in children, especially younger ones.[22] For a definite diagnosis, patients must endorse the diagnostic criteria and be able to describe leg symptoms in their own language.[23] Alternatively, they must have the diagnostic criteria plus sleep disturbances, a sibling or parent with RLS, and a PLMS index higher than 5 on PSG.[22] For a possible diagnosis, a PLMS index higher than 5 on PSG and a first-degree family member with RLS are required. These strict criteria are intended to prevent overdiagnosis of RLS in children.

The physical examination is usually normal in patients with RLS; it is performed to identify secondary causes and to exclude other disorders. In particular, the patient should be evaluated for neuropathy, radiculopathy, and parkinsonism.

 

DDx

Diagnostic Considerations

Conditions to consider in the differential diagnosis of restless legs syndrome (RLS) include the following:

  • Akathisia

  • Neuropathy

  • Nocturnal leg cramps

  • Painful legs and moving toes

  • Vascular disease

  • Radiculopathy

Akathisia is characterized by an inner urge to move all or part of the 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 selective serotonin reuptake inhibitors (SSRIs), neuroleptics, or other dopamine-blocking agents.[24]

Patients with neuropathy can have symptoms similar to those of RLS.[25] Typical sensory complaints include numbness, tingling, and pain. However, neuropathic symptoms also differ from RLS symptoms in that they usually are not associated with motor restlessness or helped by movement, nor do they worsen in the evening or at night. Neuropathy and RLS may coexist. RLS occurs more frequently in patients with hereditary neuropathies but not in patients with acquired neuropathies, such as diabetic neuropathy.[25]

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

Patients with painful legs and moving toes exhibit involuntary, spontaneous flexion and extension of the toes, which is usually secondary to spinal cord injury or root lesions.[21] Unlike RLS, this condition is not associated with a focal urge to move the limbs, and it does not show a clear circadian pattern.

Vascular disease (including deep vein thrombosis and claudication) must be considered. Patients with RLS have intact peripheral pulses and typically do not have edema or cool extremities. Also, vascular disease does not exhibit a circadian pattern and usually worsens with activity, not with rest.

Differential Diagnoses

 

Workup

Laboratory Studies

All patients with symptoms of restless legs syndrome (RLS) should be tested for iron deficiency.[3, 4] At a minimum, a ferritin level should be obtained. A complete iron panel, including iron levels, ferritin, transferrin saturation, and total iron binding capacity, is preferable because the ferritin level can be falsely elevated in acute inflammatory states.

Patients whose RLS is well controlled but who develop reemergence or augmentation of symptoms should undergo repeat evaluation of their iron status. Augmentation is defined the presence of 1 or more of the following:

  • Earlier onset of symptoms during the evening or after assumption of a restful position

  • Increased intensity of symptoms in the morning

  • Extension of symptoms to the upper part of the body

If a secondary cause of RLS is suspected on the basis of the history, abnormal findings on neurologic examination, or a poor response to treatment, other laboratory tests should be done. These include a complete blood count (CBC) and measurement of levels of the following:

  • Blood urea nitrogen (BUN)

  • Creatinine

  • Fasting blood glucose

  • Magnesium

  • Thyroid-stimulating hormone (TSH)

  • Vitamin B-12

  • Folate

Other Studies

Needle electromyography (EMG) and nerve conduction studies should be considered if polyneuropathy or radiculopathy is suspected on clinical grounds, even if the results of the neurologic examination are apparently normal.[5]

Polysomnography (PSG) may be necessary to quantify periodic leg movements of sleep (PLMS) or to characterize sleep architecture, especially in children and in patients who continue to have significant sleep disturbances despite relief of RLS symptoms with treatment. PSG should also be used in patients with other suspected sleep comorbidities.

Imaging studies are not routinely used in the diagnosis of patients with RLS and are currently investigational in this setting.

 

Treatment

Approach Considerations

Treatment for restless legs syndrome (RLS) may not be necessary for patients with mild or sporadic symptoms or for those without significant impairment.[4] Treatment should be tailored to the patient’s specific symptoms and may involve pharmacotherapy and nonpharmacologic measures.[4] Patients should be monitored by a neurologist or their primary care provider for development of adverse events, augmentation, or rebound.

In 2014, the US Food and Drug Administration (FDA) gave commercial clearance to the first device (Relaxis) for improvement of sleep quality in patients with primary RLS. The device, a vibrating pad, delivers vibratory counterstimulation to the patient’s legs as an individual lies in bed. Approval was based on 2 randomized studies that showed greater improvements in sleep quality with the device than with a placebo pad.[26]

Pharmacologic Therapy

Drug therapy for primary RLS is largely symptomatic; cure is possible only for secondary RLS. In some patients, RLS symptoms occur sporadically, with spontaneous remissions lasting weeks or months. The use of pharmacotherapy on an irregular basis is warranted in such cases. Continuous pharmacologic treatment should be considered if patients complain of having RLS symptoms at least 3 nights each week.

Medications used in the treatment of restless legs syndrome (RLS) include the following:

  • Dopaminergic agents (eg, pramipexole,[27] ropinirole,[28, 29] bromocriptine, levodopa-carbidopa, and rotigotine[30] )

  • Benzodiazepines (eg, clonazepam)

  • Opioids (eg, codeine)

  • Anticonvulsants (eg, gabapentin[31] and pregabalin)

  • Presynaptic alpha2 -adrenergic agonists (eg, clonidine)

  • Iron salt

A Task Force of the International Restless Legs Syndrome Study Group (IRLSSG) has developed evidence-based guidelines for long-term pharmacologic treatment of RLS.[32] The Task Force reviewed the results of 61 studies and arrived at the following conclusions with respect to available medications:

· Pregabalin - Effective for up to 1 year in treating RLS (evidence level, A).

· Pramipexole, ropinirole, and rotigotine - Effective for up to 6 months in treating RLS (evidence level, A)

· Gabapentin enacarbil (1 year), pramipexole (1 year), ropinirole (1 year), levodopa (2 years), and rotigotine (5 years) - Probably effective in treating RLS for durations ranging from 1 to 5 years (evidence level, B)

· Pergolide and cabergoline - Because of associated safety concerns, not to be used in treating RLS unless the benefits clearly outweigh the risks

The IRLSSG Task Force recommends either a dopamine-receptor agonist or an alpha2-delta calcium-channel ligand as first-line treatment therapy for RLS in most patients, with the choice of medication depending on symptom severity, cognitive status, history, and comorbid conditions.[32]

All patients with low iron levels (ferritin < 50 ng/mL) should receive supplemental iron therapy.[4] In iron deficiency, 325 mg of ferrous sulfate 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. Parenteral iron may also have a role in the treatment of RLS secondary to iron deficiency anemia.[33]

Anecdotal evidence from Japan suggests that yokukansan (an herbal remedy) may be effective in the treatment of RLS.[34] Oral corticosteroids have also been used to treat RLS in exceptional circumstances.[35] Currently, steroids and yokukansan are not approved by the US Food and Drug Administration (FDA) as therapy for RLS.

No specific recommendations or FDA-approved medications exist for the treatment of RLS in children. Children with low serum ferritin (< 50 ng/mL) should be treated with supplemental iron therapy. Dopaminergic therapy was found to be effective in small series in children with RLS.

Nonpharmacologic Therapy

Sleep hygiene measures should be recommended to all patients. Moreover, patients with mild RLS who are sensitive to caffeine, alcohol, or nicotine should avoid these substances. Offending medications (eg, selective serotonin reuptake inhibitors [SSRIs], diphenhydramine, and dopamine antagonists) also should be discontinued when it is possible to do so.

Exercise may be helpful for some patients[36] ; however, this potential benefit has not been systematically studied. In general, physical measures are only partially or temporarily helpful and should be avoided before bedtime. Some patients benefit from different physical modalities before bedtime, such as a hot or cold bath, a whirlpool bath, limb massage, or vibratory or electrical stimulation of the feet and toes.

Nonpharmacologic management and sleep hygiene measures are the treatments of choice in children. A regular sleep/wake schedule and the elimination of stimulating activity and caffeine before bedtime are important measures.

 

Guidelines

Guidelines Summary

The following organizations have released guidelines for the management of RLS:

  • American Academy of Sleep Medicine (AASM)

  • European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society (EFNS/ENS/ESRS)

  • Willis-Ekbom Disease Foundation (Restless Legs Syndrome Foundation)

  • International Restless Legs Syndrome Study Group (IRLSSG)

The 2013 IRLSSG guidelines for the long-term treatment of RLS recommends either a dopamine-receptor agonist or an alpha2-delta calcium-channel ligand as first-line treatment therapy for RLS in most patients, with the choice of medication depending on symptom severity, cognitive status, history, and comorbid conditions.[37]

The use of alpha2-delta calcium-channel ligand should be considered for initial treatment of patients with any of the following:

  • Severe sleep disturbance (disproportionate to other symptoms)

  • Comorbid insomnia, anxiety, pain

  • A previous history of an impulse control disorder (ICD) or comorbid generalized anxiety disorder

The use of a dopamine-receptor agonist should be considered for initial treatment of patients with any of the following:

  • Very severe symptoms

  • Excessive weight

  • Comorbid depression

  • Increased risk of falls

  • Cognitive impairment

Other IRLSSG recommendations include the following:

  • Patients with clinically significant daytime symptoms should be treated with a long-acting agent; multiple daily doses of a short-acting agent can also be tried

  • Considerable caution should be exercised with all dopaminergic agents, with frequent monitoring for loss of efficacy or the development or progression of augmentation

  • Treatment with the combination of a dopamine-receptor agonist and an alpha2-delta calcium-channel ligand should be considered for patients with symptoms that cannot be controlled with low-dose monotherapy of either drug class

 

Medication

Medication Summary

Medications used in the treatment of restless legs syndrome (RLS) include the following:

  • Dopaminergic agents

  • Benzodiazepines

  • Opioids

  • Anticonvulsants

  • Alpha2 -adrenergic agonists

  • Iron salt

Antiparkinson Agents, Dopamine Agonists

Class Summary

Dopamine agonists may improve sensory symptoms associated with RLS. Agents such as pramipexole, ropinirole, and bromocriptine are less likely to produce augmentation or rebound than the combination of levodopa and carbidopa is. These agents can be used alone or along with levodopa.

Pramipexole (Mirapex, Mirapex ER)

Pramipexole is a dopamine D2- and D3-receptor agonist that has been approved by the US Food and Drug Administration (FDA) for the treatment of Parkinson disease. It is also used effectively in patients with RLS.

Ropinirole (Requip, Requip XL)

Ropinirole is a dopamine D2-receptor agonist that has been approved by the FDA for the treatment of Parkinson disease. It has also has been used in patients with RLS. Ropinirole is a nonergoline, nonphenolic indolone derivative.

Levodopa with carbidopa (Sinemet, Parcopa)

Levodopa with carbidopa can improve sensory symptoms and periodic leg movements of sleep (PLMS) in primary RLS and in secondary RLS due to uremia. Most patients experience benefits with doses of 25/100 mg (in mild cases), with a maximum dosage of 50/200 mg/day.

Dosages higher than 50/200 mg/day are accompanied by marked augmentation of symptoms in 85% of patients. Adjunctive therapy with reduction of levodopa dose or discontinuance of levodopa and substitution with a dopamine agonist drug may help. Sinemet is preferred for patients with occasional and mild symptoms.

Bromocriptine mesylate (Parlodel, Cycloset)

Bromocriptine mesylate is a dopamine D2-receptor agonist that has been found to be effective in RLS. However, it is usually poorly tolerated because of nausea and orthostatic hypotension. Other dopamine agonists, such pramipexole, are preferred.

Rotigotine (Neupro)

Rotigotine is a dopamine agonist stimulating D3, D2, and D1 receptors. It is indicated for treatment of moderate-to-severe primary RLS. It is available as a transdermal patch that provides continuous delivery for 24 hours.

Anxiolytics, Benzodiazepines

Class Summary

A benzodiazepine may be used as monotherapy in patients with mild or intermittent symptoms of RLS or as a component of combination therapy in severe cases. Clonazepam has been shown to ease sensory symptoms and PLMS in RLS. Other benzodiazepines, such as temazepam and alprazolam, also can be effective.

Clonazepam (Klonopin)

No controlled trials have demonstrated that clonazepam or any other gamma-aminobutyric acid (GABA)-ergic sedative hypnotic actually reduces the symptoms of RLS. Clonazepam's therapeutic benefit appears to arise from sleep-promoting properties that allow the patient to continue to sleep despite disturbances from RLS symptoms.

Opioid Analgesics

Class Summary

Low-potency opioids (eg, codeine) can benefit patients with mild and intermittent symptoms; higher-potency agents (eg, oxycodone hydrochloride, methadone hydrochloride, and levorphanol tartrate), 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, especially in ones with a prominent pain component.

Codeine

Codeine and other opioids can be helpful in decreasing the symptoms of RLS, serving as a treatment of second choice when other treatments have failed or have caused augmentation problems.

Anticonvulsants, Other

Class Summary

Anticonvulsants are being used more frequently for the treatment of moderate-to-severe RLS. They are particularly helpful in patients with a strong neuropathic symptom component or with comorbid neuropathy.

Gabapentin Enacarbil (Horizant)

A prodrug of gabapentin, gabapentin enacarbil, has been approved by the FDA. In a randomized, placebo-controlled study, 600 mg orally, taken once daily at 5 PM, provided sustained gabapentin exposure and maintained improvements in RLS symptoms in comparison with placebo.[29]

Gabapentin (Neurontin)

Gabapentin is indicated for patients whose symptoms include pain, neuropathy, or both. It may be used as a single treatment or with other treatments.

Pregabalin (Lyrica)

Pregabalin binds with high affinity to the alpha2-delta site (a calcium channel subunit). Its mechanism of action is unknown. In vitro, pregabalin reduces the calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. This agent is FDA-approved for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures. It is not FDA-approved for the treatment of RLS.

Alpha2-Adrenergic Agonists

Class Summary

Presynaptic alpha2 -adrenergic agents stimulate alpha2 adrenoreceptors in the brainstem, activating an inhibitory neuron, which in turn results in reduced sympathetic outflow.

Clonidine hydrochloride (Catapres, Kapvay, Nexiclon XR)

Clonidine hydrochloride may be effective in primary RLS, as well as in RLS associated with uremia. However, it has no effect on PLMS.

Iron Salt

Class Summary

Iron salt is used to correct iron deficiency resulting from chronic hemodialysis.

Iron sucrose (Venofer)

Iron sucrose is used to treat iron deficiency (in conjunction with erythropoietin) due to chronic hemodialysis. Iron sucrose has shown a lower incidence of anaphylaxis than other parenteral iron products. Parenteral iron sucrose has also been shown to improve symptoms of RLS in patients with RLS and low ferritin levels. Parenteral iron sucrose is not FDA-approved for the treatment of RLS.

 

Questions & Answers

Overview

What is restless legs syndrome (RLS)?

What are the IRLSSG diagnostic criteria for restless legs syndrome (RLS)?

How is periodic leg movements of sleep (PLMS) characterized in patients with restless legs syndrome (RLS)?

What are signs and symptoms of restless legs syndrome (RLS)?

What is the role of iron level measurement in the workup of restless legs syndrome (RLS)?

Which lab tests should be performed when a secondary cause of restless legs syndrome (RLS) is suspected?

What is the role of electrodiagnostic testing and polysomnography in the workup of restless legs syndrome (RLS)?

What are the pharmacologic therapy options in the treatment of restless legs syndrome (RLS)?

What are the nonpharmacologic treatment options for restless legs syndrome (RLS)?

What is restless legs syndrome (RLS)?

In which age group is restless legs syndrome (RLS) most often diagnosed?

Which factors exacerbate the sensations of restless legs syndrome (RLS)?

What are the IRLSSG diagnostic criteria for restless legs syndrome (RLS)?

What are the DSM-5 and ICSD-2 diagnostic criteria for restless legs syndrome (RLS)?

What is the pathogenesis of restless legs syndrome (RLS)?

What are the causes of restless legs syndrome (RLS)?

What is the etiology of familial restless legs syndrome (RLS)?

What are the common secondary causes of restless legs syndrome (RLS)?

What are the less common causes of secondary restless legs syndrome (RLS)?

What is the etiology of restless legs syndrome (RLS) during pregnancy?

What is the incidence of restless legs syndrome (RLS) in patients with end-stage renal disease?

Which medications cause or exacerbate the symptoms of restless legs syndrome (RLS)?

What is the prevalence of restless legs syndrome (RLS) in the US and globally?

How does the prevalence of restless legs syndrome (RLS) vary among age groups?

How does the prevalence of restless legs syndrome (RLS) vary between males and females and among races?

What is the progression of the symptoms of restless legs syndrome (RLS)?

What are the possible complications of restless legs syndrome (RLS) and periodic leg movements of sleep (PLMS)?

What education should be given to patients with restless legs syndrome (RLS)?

Presentation

What is the basis for a diagnosis of restless legs syndrome (RLS) and what symptoms do patients typically report?

What is the prevalence of periodic leg movements of sleep (PLMS) in patients with restless legs syndrome (RLS)?

When is treatment of periodic leg movements of sleep (PLMS) indicated in patients with restless legs syndrome (RLS)?

What are non-diagnostic symptoms of restless legs syndrome (RLS)?

What is required for a definite diagnosis of restless legs syndrome (RLS) in children?

What is included in the physical exam for restless legs syndrome (RLS)?

DDX

Which conditions should be included in the differential diagnoses of restless legs syndrome (RLS)?

How is akathisia differentiated from restless legs syndrome (RLS)?

How is neuropathy differentiated from restless legs syndrome (RLS)?

How are nocturnal leg cramps differentiated from restless legs syndrome (RLS)?

How are painful legs and moving toes differentiated from restless legs syndrome (RLS)?

How is vascular disease differentiated from restless legs syndrome (RLS)?

What are the differential diagnoses for Restless Legs Syndrome?

Workup

When is iron level testing indicated in the workup of restless legs syndrome (RLS)?

How is augmentation of restless legs syndrome (RLS) defined?

Which lab tests are performed when a secondary cause of restless legs syndrome (RLS) is suspected?

Which studies are performed to exclude polyneuropathy or radiculopathy in the workup of restless legs syndrome (RLS)?

What is the indication for a polysomnography (PSG) in the workup of restless legs syndrome (RLS)?

What is the role of imaging studies in the workup of restless legs syndrome (RLS)?

Treatment

When is treatment indicated for restless legs syndrome (RLS)?

What is the role of vibratory counterstimulation (Relaxis) in the treatment of restless legs syndrome (RLS)?

What are considerations for the use of pharmacotherapy in restless legs syndrome (RLS)?

What medications are used in the treatment of restless legs syndrome (RLS)?

What are the IRLSSG guidelines for long-term pharmacologic treatment of restless legs syndrome (RLS)?

What is the role of supplemental iron therapy in the treatment of restless legs syndrome (RLS)?

Are systemic corticosteroids and yokukansan effective in the treatment of restless legs syndrome (RLS)?

What are the FDA-approved medications in the treatment of children with restless legs syndrome (RLS)?

What are the nonpharmacologic treatment options for restless legs syndrome (RLS)?

Guidelines

Which organizations have released guidelines for the management of restless legs syndrome (RLS)?

What are the IRLSSG recommendations for the long-term treatment of restless legs syndrome (RLS)?

According to the IRLSSG guidelines, what are the indications for alpha2-delta calcium-channel ligand in the treatment of restless leg syndrome (RLS)?

According to the IRLSSG guidelines, when are dopamine-receptor agonists indicated for initial treatment of restless legs syndrome (RLS)?

According to the IRLSSG guidelines, how are patients with restless legs syndrome (RLS) who are treated with dopaminergic agents monitored and when should multidrug therapy be considered?

Medications

Which medications are used in the treatment of restless legs syndrome (RLS)?

Which medications in the drug class Iron Salt are used in the treatment of Restless Legs Syndrome?

Which medications in the drug class Alpha2-Adrenergic Agonists are used in the treatment of Restless Legs Syndrome?

Which medications in the drug class Anticonvulsants, Other are used in the treatment of Restless Legs Syndrome?

Which medications in the drug class Opioid Analgesics are used in the treatment of Restless Legs Syndrome?

Which medications in the drug class Anxiolytics, Benzodiazepines are used in the treatment of Restless Legs Syndrome?

Which medications in the drug class Antiparkinson Agents, Dopamine Agonists are used in the treatment of Restless Legs Syndrome?