Restless legs syndrome (RLS) is a common, underdiagnosed and treatable condition. A neurologic movement disorder, RLS is often associated with a sleep complaint.1 Patients with RLS may suffer an almost irresistible urge to move the legs, usually due to disagreeable leg sensations that are worse during inactivity and often interfere with sleep.2 RLS may be described as an agitated inability to rest that can have a negative impact on quality of life by causing waking discomfort, chronic sleep deprivation and stress. This article provides science-based information about RLS and its assessment and management in the primary care setting.
Consequences of RLS
Direct adverse effects of RLS include discomfort, sleep disturbances and fatigue.3 These consequences have a secondary impact on functioning by affecting occupational activities, social activities and family life. Disrupted sleep and an inability to tolerate sedentary activities can lead to job loss, a compromised ability to enjoy life and problems with relationships.
RLS is a central nervous system disorder.9 It is not caused by psychiatric factors or by stress but may contribute to or be exacerbated by these conditions. There is a high incidence of familial cases of RLS, suggesting a genetic origin for primary RLS.8 The exact mode of inheritance is unknown.8,10
SECONDARY CAUSES OF RLS
Iron Deficiency. RLS may be associated with iron deficiency. A patient's iron stores may be deficient without significant anemia. Recent studies have shown that decreased iron stores (indicated by serum ferritin levels below 50 ng per mL [50 μg per L] can exacerbate RLS symptoms.11,12 Patients with newly diagnosed RLS or RLS patients with a recent exacerbation of symptoms should have their serum ferritin levels measured.
Neurologic Lesions. RLS has been reported in association with spinal cord and peripheral nerve lesions, although an exact pathologic mechanism has not been identified. RLS also may occur in patients with vertebral disk disease.8
Pregnancy. RLS affects up to 19 percent of women during pregnancy.13 Symptoms can be severe but usually subside within a few weeks postpartum.
Drug-Induced. Some evidence from published case reports indicates that RLS symptoms may be induced or exacerbated by medications such as tricyclic antidepressants,17 selective serotonin reuptake inhibitors (SSRIs),18 lithium19 and dopamine antagonists.20 Caffeine also has been implicated in the worsening of RLS symptoms.21
Assessment and Diagnosis
The diagnosis of RLS is based primarily on the patient's history. Often, patients do not bring RLS symptoms to the physician's attention; therefore, it can be helpful to include general sleep questions in the review of systems (Table 1). When RLS is suspected, more specific questions should be asked (Table 2).
|How has the patient been sleeping recently? (Ask the patient and bed partner.)
|Suggested questions following a sleep complaint
|When did the problem begin? (To determine acute vs. chronic insomnia)
|Does the patient have a psychiatric or medical condition that may cause insomnia?
|Is the sleep environment conducive to sleep? (Relates to noise, interruptions, temperature, light)
|Does the patient report “creeping, crawling or uncomfortable, difficult-to-describe feelings” in the legs or arms that are relieved by moving them? (Relates to restless legs syndrome)
|Does the bed partner report that the patient's legs or arms jerk during sleep? (Relates to periodic limb movements of sleep)
|Does the patient snore loudly, gasp, choke or stop breathing during sleep? (Relates to obstructive sleep apnea)
|Is the patient a shift worker? What are the work hours? (Relates to circadian sleep disorders/sleep deprivation)
|What times does the patient go to bed and get up on weekdays and weekends? (Relates to poor sleep hygiene and sleep deprivation)
|Does the patient use caffeine, tobacco or alcohol? Does the patient take over-the-counter or prescription medications, such as stimulating antidepressants, steroids, decongestants or beta-blockers? (Relates to substance-induced insomnia)
|Signs of sleepiness
|What daytime consequences, such as fatigue, sleepiness, confusion or difficulty concentrating, does the patient report?
|Does the patient report dozing off or have difficulty staying awake during routine tasks, especially while driving?
|Does the patient report “creeping, crawling or uncomfortable, difficult-to-describe feelings” in the legs or arms that are relieved by moving or rubbing them?
|Is there a correlation between RLS symptoms and time of day? Do the symptoms worsen with rest or inactivity?
|Do sensations interfere with sleep onset or returning to sleep?
|What daytime consequences does the patient report (e.g., fatigue, sleepiness, confusion, lack of attention)?
|Does the bed partner report that the patient's legs or arms jerk during sleep? (Relates to periodic limb movements of sleep.)
|Does the patient have secondary causes of RLS, such as low iron stores, diabetes mellitus, kidney disease or pregnancy?
|Are neurologic symptoms or diagnoses present?
|Is there a relationship between symptoms and medications, such as tricyclic antidepressants or selective serotonin reuptake inhibitors?
|Was the onset of symptoms correlated with a change in medication?
|Do family members report similar symptoms? Have any family members been diagnosed with RLS?
Symptoms are described by patients in many ways, with descriptions ranging from “mild” to “intolerable” (Table 3).22 Although most patients experience the sensations in their legs, the 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. RLS must be distinguished from sleep-related leg conditions such as nocturnal leg cramps.
|Like water flowing
|Like worms or bugs crawling under the skin
|Like an electric current
The involuntary, repetitive, periodic, jerking movements refer to periodic limb movements (PLM), also known as PLMS (periodic limb movements of sleep)23 or nocturnal myoclonus,24 which may be associated with RLS. PLMS are stereotyped, repetitive flexions of the limbs (legs alone or legs more than arms) usually occurring during sleep. They occur periodically on an average of every 20 seconds. The most common movement is a dorsiflexion of the ankles and flexion of the knees or hips.
|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 that are worse or exclusively present at rest (i.e., lying, sitting) with variable and temporary relief by activity
|Symptoms that are worse in the evening and at night
|Sleep disturbance and daytime fatigue
|Normal neurologic examination (in patients with primary RLS)
|Involuntary, repetitive, periodic, jerking limb movements, either in sleep or while awake and at rest
The physical examination is usually normal in patients with RLS and is performed to identify secondary causes and to rule out other disorders. The following are areas of particular importance:
A neurologic examination with emphasis on spinal cord and peripheral nerve function.
A vascular examination to rule out vascular disorders.
The following laboratory tests can identify possible secondary causes of RLS:
Serum ferritin level of <50 ng per mL (<50 μg per L).
Serum chemistry to rule out uremia and diabetes.
A sleep study (polysomnography) is not routinely indicated in the work-up of RLS,25 because RLS is diagnosed on the basis of history and clinical findings.
Differential diagnoses may include the following:
Nocturnal leg cramps are typically painful, palpable, involuntary muscle contractions, often focal, with a sudden onset; they are usually unilateral.26
Akathisia is excessive movement, without specific sensory complaints; it often does not correlate with rest or time of day and usually results from medication such as neuroleptics or other dopamine blocking agents.27
Peripheral neuropathy can cause leg symptoms that are different from RLS; they are usually not associated with motor restlessness or helped by movement, and do not worsen in the evening or nighttime. Sensory complaints are typically numbness, tingling or pain. Small fiber sensory neuropathies, as seen in diabetes, are often confused with RLS. Patients with neuropathies may have neuropathic and RLS symptoms.
Vascular disease, such as deep venous thrombosis.
The severity of RLS varies from patient to patient. Although pharmacologic treatment is helpful for many patients with RLS, those with mild symptoms may not need medications. Because no single medication or combination of medications will work predictably for all patients, treatment must be individualized. Physicians and patients may need to work together over time to find the medication or combination of medications and the dosages that will work best. Table 5 lists appropriate pharmacologic agents and their advantages and disadvantages. Therapy for RLS constitutes an “off-label” use of these pharmacologic agents.
|Dopamine precursor combinations such as carbidopa-levodopa
|Can be used on a “one-time” basis or as circumstances may require. Useful for persons with intermittent RLS because dopamine agonists take longer to have an effect.
|As many as 80 percent of patients who take carbidopa-levodopa may develop augmentation.* Therapeutic effect may be reduced if taken with high-protein food. Can cause insomnia, sleepiness and gastrointestinal problems.
|Dopamine agonists such as pergolide, pramipexole, ropinirole
|Useful in moderate to severe RLS. Recent reports indicate high efficacy of dopamine agonists, but the role of their long-term use is unknown.29
|Can cause severe sleepiness,30 which may limit its use during daytime.
|Agonists can cause nausea. To avoid this, slow dosage increase is important, especially for pergolide.
|Opioids such as codeine, hydrocodone, oxycodone, propoxyphene, tramadol Benzodiazepines such as clonazepam, temazepam
|Can be used on an intermittent basis. Can also be used successfully for daily therapy. Helpful in some patients when other medications are not tolerated and may help improve sleep.
|Can cause constipation, urinary retention, sleepiness or cognitive changes. Tolerance and dependence possible with higher doses of stronger agents. Can cause daytime sleepiness and cognitive impairment, particularly in the elderly.
|Anticonvulsants such as carbamazepine, gabapentin
|Can be considered when dopamine agonists have failed. May be useful in those with coexisting peripheral neuropathy and/or when RLS discomfort is described as pain.
|Vary, depending on agent. Gastrointestinal disturbance such as nausea, sedation, dizziness.
|Iron (ferrous sulfate)
|Use in patients with serum ferritin levels < 50 ng per mL (< 50 μg per L).
|Ideal means of administration has not been established. Oral treatment may take several months to be effective and may be poorly tolerated.
|May be useful in hypertensive patients.
|Has the potential to cause hypotension, dermatitis and sleepiness.
The selection of pharmacologic agents is influenced by a number of factors, including:
Age of the patient. For example, benzodiazepines may cause cognitive impairment in the elderly.
Severity of symptoms. Some patients with mild symptoms may elect not to use medications; others may benefit from levodopa or a dopamine agonist. Patients with severe symptoms may require a strong opioid.
Frequency or regularity of symptoms.
Patients with infrequent symptoms may benefit from a single effective dose of a medication such as an opioid or levodopa, taken as needed.
Presence of pregnancy or comorbid illnesses. No controlled clinical trials have assessed the safety and efficacy of medications for RLS or PLMS during pregnancy.28
Renal failure. In patients with renal failure, pharmacologic agents are generally safe, but less frequent doses may be needed if drugs are renally excreted. In addition, for dialysis patients, some medications, such as gabapentin, are dialyzable and others, such as propoxyphene, are not.28
Dopaminergic agents are the first-line drugs for most RLS patients. It is important for primary care physicians to educate patients about the nature and actions of the drugs that are prescribed, including side effects and the uncertainty of long-term effects. For example, when dopaminergic agents are prescribed, patients should be informed that although these medications are usually used to treat Parkinson's disease, they also help to relieve RLS symptoms.
RLS medications have received approval from the U.S. Food and Drug Administration for other uses. In many cases, the therapeutic dosages to treat RLS are much lower than those required for the original uses. The starting dose is usually very low and is gradually increased until effective. In addition to the medications listed in Table 5, agents such as vitamin E, folate and magnesium may be useful. Although many nonpharmacologic treatments have been reported by patients to be helpful, there is no scientific evidence that they are useful in the treatment of RLS.
When to Consider Referral
Most cases of RLS can be effectively managed by primary care physicians. If the primary care physician encounters difficulty managing RLS symptoms in a patient, referral to or consultation with a movement disorders specialist or a sleep specialist may be helpful.
The primary care physician plays a central role in the identification and treatment of RLS. Incorporating sleep- and RLS-related questions into the general review of systems can be helpful in diagnosing RLS. An important aspect of treatment is listening to and supporting patients and carefully evaluating their symptoms. Most patients with RLS can obtain symptomatic relief with commonly prescribed medications and support.