Upon successful completion of this course, you will be able to:

• Define the term “restless legs syndrome” (RLS)
• Identify the causes of this syndrome
• List the signs and symptoms of RLS
• Identify the available treatments and medications related to this syndrome

News Item from the New York Times

July 19, 2007

Scientists Find Genetic Link for a Disorder (Next, Respect?)
By NICHOLAS WADE

Imagine you keep waking up with a fierce urge to move your legs, each time further eroding your sleep quota and your partner’s patience. You have restless legs syndrome, a quaintly named disorder whose sufferers may get more respect now that its genetic basis has been identified.

Two independent teams, one in Germany and one in Iceland, have identified three variant sites on the human genome which predispose people to the condition. The advance should help scientists understand the biological basis of the disorder, which could lead to new ideas for treatment.

The new findings may also make restless legs syndrome easier to define, resolving disputes about how prevalent it really is. The disorder is a “case study of how the media helps make people sick,” two researchers at Dartmouth Medical School, Steven Woloshin and Lisa Schwartz, wrote recently in the journal PLoS Medicine. They argued that its prevalence had been exaggerated by pharmaceutical companies and uncritical newspaper articles, and that giving people diagnoses and powerful drugs were serious downsides of defining the elusive syndrome too broadly.

Discovery of the genetic basis of the disorder “puts restless legs syndrome on a firmer footing,” said Dr. Christopher Earley, a physician at Johns Hopkins University who treats the malady.

Dr. Woloshin said that he “wouldn’t change a thing” in his article. He fears the new reports “will be used to validate restless legs syndrome as a highly prevalent disease,” he said.

The two groups of researchers have both used the latest method in trawling the human genome for disease genes. Called Whole Genome Association, the method depends on the use of powerful chips to detect up to 500,000 genetic variants at a time. By comparing patients’ genomes with those of unaffected people, researchers can pinpoint the variants associated with the disease.

One research team, led by Juliane Winkelmann and Thomas Meitinger at the Institute of Human Genetics in Munich, reports in Nature Genetics today that it has found variants in three genes that confer risk for restless syndrome. They detected the variants in a German patient population and confirmed the findings in French-Canadians.

Independently, a team led by Hreinn Stefansson of Decode Genetics in Reykjavik, Iceland, says today in The New England Journal of Medicine that it has found one of the same genetic variants associated with restless legs syndrome in Icelanders and in Americans recruited at Emory University in Atlanta.

Dr. Winkelmann said the three genes implicated in her study had come as a complete surprise because they had never been suspected of involvement in the syndrome. “Now we have for the first time the prerequisite to study the biological basis of restless legs syndrome,” she said.

Kari Stefansson, chief executive of Decode Genetics, said his company had linked variations in the gene known as BTBD9 with periodic leg movements during sleep and with low iron levels in the blood, two clinical features already associated with the syndrome. He said Decode had missed, but subsequently confirmed, the two other genes identified in Dr. Winkelmann’s study.

Experts find it hard to assess how common restless legs syndrome is because it covers a broad spectrum of symptoms, the milder forms of which are harmless, and is also mimicked by several other diseases, like nocturnal cramps. Dr. Stefansson said he believed restless legs syndrome occurred in 5 percent to 15 percent of European populations. Dr. Woloshin said the “most credible” estimate is 3 percent. Still, even that proportion could mean that a lot of spouses are getting kicked out of bed every night.

The variant form of BTBD9 is very common but in most people causes no symptoms. But it accounts for 50 percent of cases of restless leg syndrome in European populations, Decode Genetics calculates. The prevalence of the disease varies widely between ethnic groups, being found in only 0.1 percent of Singaporeans and 2 percent of Ecuadoreans.

Many human genes were first described by geneticists who identified counterpart genes in the laboratory fruitfly. Fruitfly researchers consider it a matter of pride to give genes colorful names, but these are often moderated or disguised by medical researchers who feel absurd names will not help attract research funds. BTBD9, the gene in today’s two studies, stands for broad complex-tramtrack-bric-a-brac-domain 9.

What Is Restless Legs Syndrome?

Restless legs syndrome (RLS) is a sensory disorder causing an almost irresistible urge to move the legs. The urge to move is usually due to unpleasant feelings in the legs that occur when at rest. People with RLS use words such as creeping, crawling, tingling, or burning to describe these feelings. Moving the legs eases the feelings, but only for a while. The unpleasant feelings may also occur in the arms.

Effects of RLS

RLS can make it hard to fall asleep and stay asleep. People with RLS often don’t get enough sleep and may feel tired and sleepy during the day. This can make it difficult to:

• Concentrate, making it harder to learn and remember things
• Work
• Carry out other usual daily activities
• Take part in family and social activities

Not getting enough sleep can also make you feel depressed or have mood swings.

RLS can range from mild to severe, based on:

• How much discomfort there is in the legs and arms
• Whether there is the need to move around
• How much relief there is from moving around
• How much sleep disturbance there is
• How tired or sleepy the person is during the day
• How often the symptoms occur
• How severe the symptoms are on most days
• How well the person is able to carry out daily activities
• How angry, depressed, sad, anxious, or irritable the person feels

Types of RLS

There are two types of RLS:

• Primary RLS is the most common type of RLS. It is also called idiopathic RLS. “Primary” means the cause is not known. Primary RLS, once it starts, usually becomes a lifelong condition. Over time, symptoms tend to get worse and occur more often, especially if they began in childhood or early in adult life. In milder cases, there may be long periods of time with no symptoms, or symptoms may last only for a limited time.
• Secondary RLS is RLS that is caused by another disease or condition or, sometimes, from taking certain medicines. Symptoms usually go away when the disease or condition improves, or if the medicine is stopped.

Periodic Limb Movement Disorder

Most people with RLS also have a condition called periodic limb movement disorder (PLMD). PLMD is a condition in which a person’s legs twitch or jerk uncontrollably about every 10 to 60 seconds. This usually happens during sleep. These movements cause repeated awakenings that disturb or reduce sleep. PLMD usually affects the legs but can also affect the arms.

Outlook

RLS can be unpleasant and uncomfortable. However, there are some simple self-care approaches and lifestyle changes that can help in mild cases. RLS symptoms often improve with medical treatment. Research is ongoing to better understand the causes of RLS and to develop better treatments.

What Causes Restless Legs Syndrome?

Primary RLS

In most cases of restless legs syndrome (RLS), no cause can be found. When no cause can be found, the condition is called primary RLS. It is known, however, that primary RLS tends to run in families. People whose parents have RLS are more likely to develop the disorder. This suggests that there may be a genetic link that increases the chance of getting RLS.

Secondary RLS

Secondary RLS is RLS that is caused by another disease or condition, or as a side effect of certain medications. Some of the diseases and conditions that can cause RLS are:

• Iron deficiency (with or without anemia)
• Kidney failure
• Diabetes
• Parkinson’s disease
• Damage to the nerves in the hands or feet (peripheral neuropathy) (pe-RIF-e-ral noo-ROP-a-the)
• Rheumatoid arthritis (ROO-ma-toyd ar-THRI-tis)
• Pregnancy

RLS is common in pregnant women. It usually occurs during the last 3 months of pregnancy and usually improves or disappears within a few weeks after delivery. However, some women may continue to have symptoms after giving birth or may develop RLS again later in life.

Some of the types of medicines that can cause RLS are:

• Antiseizure medicines
• Antinausea medicines
• Antidepressants
• Some cold and allergy medicines

RLS symptoms usually go away when the medicine is stopped.

Certain substances can trigger RLS symptoms or make them worse. These substances include:

• Caffeine
• Alcohol
• Tobacco

Who Is At Risk for Restless Legs Syndrome?

Restless legs syndrome (RLS) may affect as many as 12 million people in the United States.

Gender

RLS affects both men and women. The disorder occurs more often in women than in men.

Age

The number of cases of RLS rises with age. Many people with RLS are diagnosed in middle age. But in up to two out of every five cases, the symptoms of RLS begin before age 20. People who develop RLS early in life usually have a family history of the disorder.

Race/Ethnic Group

RLS can affect people of any race or ethnic group. The disorder is more common in persons of northern European descent.

Pregnancy

RLS is common in pregnant women. It usually occurs during the last 3 months of pregnancy and usually improves or disappears within a few weeks after delivery.

What Are the Signs and Symptoms of Restless Legs Syndrome?

Restless legs syndrome (RLS) has several major signs and symptoms:

• An almost irresistible urge to move the legs or arms when sitting or lying down
• An unpleasant feeling in the legs
• Difficulty falling asleep or staying asleep because of the unpleasant feelings in the legs or arms
• Daytime sleepiness, which results from a lack of restful sleep due to the repeated limb movements

Urge To Move

RLS gets its name from the urge to move the legs when sitting or lying down. This urge is due to unpleasant feelings in the legs that are relieved by movement. Typical movements are:

· Pacing and walking
· Jiggling the legs
· Stretching and flexing
· Tossing and turning
· Rubbing the legs

Unpleasant Feelings

The urge to move the legs usually is due to unpleasant feelings in the legs. People with RLS describe these feelings as:

• Creeping
• Crawling
• Pulling
• Itching
• Tingling
• Burning
• Aching
• Painful
• Hard to describe

Children may describe RLS symptoms differently than adults.

The unpleasant feelings in RLS usually occur in the lower leg (calf). But the feelings can occur at any place between the thigh and the ankle and also in the arm. The feelings are worse:

• When lying down or sitting for a long period of time
• During the evening or night, more so than during the day

The unpleasant feelings also:

• Make it hard to fall asleep or stay asleep
• Are not as bad or go away when you move

Duration and Severity

RLS symptoms tend to get worse over time. They may begin in childhood and develop slowly over several years. People with early symptoms are more likely to have other family members with RLS than people who develop RLS later in life.

Symptoms tend to worsen faster when RLS occurs later in life. RLS that occurs later in life is also more likely to result from an underlying condition or illness than RLS that occurs early in life.

People with mild symptoms may only notice them when they are still or awake for a long time, such as on a long airplane trip.

How Is Restless Legs Syndrome Diagnosed?

The way that you describe your symptoms is very important in diagnosing restless legs syndrome (RLS). Your doctor will:

• Take a complete medical history
• Do a complete physical examination
• Order other tests

The diagnosis of RLS usually requires the following four conditions be present:

1. An urge to move the legs due to an unpleasant feeling in the legs.
2. The urge to move the legs, or the unpleasant feelings in the legs, begins or gets worse when you are at rest or not moving around frequently.
3. The urge to move the legs, or the unpleasant feelings in the legs, is partly or completely relieved by movement (such as walking or stretching) for as long as the movement continues.
4. The urge to move the legs, or the unpleasant feelings in the legs, is worse in the evening and at night, or only occurs in the evening or at night.

Medical History

The caregiver will take a medical history and ask questions such as:

• Can you describe your symptoms?
• When did your symptoms first begin?
• When during the day or night do the symptoms usually occur?
• When are your symptoms worse?
• Do symptoms interfere with your sleep?

The caregiver will also ask about your sleep habits, such as:

• The time you go to bed and get up
• Your routine before going to bed
• Noise, light, and interruptions in the room where you sleep
• Whether you snore

The caregiver will ask about how you feel during the day, including whether:

• You are tired and sleepy when you wake up and during the day.
• You have trouble concentrating.
• You doze off or have difficulty staying awake doing routine tasks, especially driving.

The caregiver will ask questions to find out if your symptoms are a result of a possible underlying condition. Questions might include:

• Do members of your family have similar symptoms?
• What medicines (over-the-counter and prescription) do you take?
• Do you snore loudly and frequently?
• Do you gasp for air during sleep?
• Do you use caffeine, tobacco, or alcohol?

Physical Exam

A physical exam is done to:

• Identify any underlying condition that may cause RLS
• Rule out other disorders

The caregiver also will pay special attention to:

• The nerves in your spinal cord (especially) and legs and arms
• The blood flow in your legs and arms

Other Tests

There is no test currently available to diagnose RLS.

However, blood tests can be used to look for underlying conditions that can cause RLS. These tests check for:

• Low iron stores or iron deficiency
• Diabetes
• Kidney disease
• Other vitamin and mineral deficiencies

How Is Restless Legs Syndrome Treated?

The goals of treatment for restless legs syndrome (RLS) are to:

• Relieve symptoms
• Increase the amount and quality of sleep
• Treat or correct any underlying condition that may cause RLS

Types of treatment include:

• Lifestyle changes and other nondrug treatments
• Medicines

Lifestyle Changes and Other Nondrug Treatments

Lifestyle changes can improve and relieve symptoms of RLS. Lifestyle changes may be the only treatment needed for mild RLS. Some lifestyle changes that may help include:

• Avoid things that can make symptoms of RLS worse:
  o Tobacco
  o Alcohol
  o Caffeine—Chocolate, coffee, tea, and some soft drinks contain caffeine. Although it may seem to help overcome daytime sleepiness, caffeine    usually only delays or masks RLS symptoms, and often makes them worse.
  o Some medicines—Some types of over-the-counter and prescription medicines can also make RLS symptoms worse. These include:
     § Antidepressants (most of them)
     § Antinausea medicines
     § Antipsychotic medicines
     § Antihistamines
• Adopt good sleep habits:
  o Keep the bedroom or sleep area cool, quiet, comfortable, and free of unnecessary light.
  o Use the bedroom for sleeping, not for watching TV or using computers or cell phones.
  o Go to bed every night at the same time and wake up at the same time every morning. Some people with RLS find it helpful to go to bed later    in the evening and get up later in the morning. The important thing is to get enough sleep so that you feel rested when you wake up.
• Follow a program of moderate exercise

Other activities that also may help relieve symptoms include:

• Walking or stretching
• Taking a hot or cold bath
• Massaging the leg or arm
• Using heat or ice packs

Medicines

Medicines can help relieve some symptoms of RLS. Doctors prescribe medicines to treat RLS in people:

• With clearly defined symptoms
• Whose symptoms cannot be controlled by lifestyle and nondrug treatments

No single medicine is helpful in all persons with RLS. It may take several changes in medicines and dosages to find the best approach. Sometimes, a medicine will work for a while and then stop working.

Some medicines may not be safe for pregnant women.

Always talk with your doctor before taking any medicines, even over-the-counter medicines.

Specific medicines

Medicines used to treat Parkinson’s disease also are used to treat RLS. Even though these medicines help reduce RLS symptoms, RLS is not a form of Parkinson’s disease. The medicines help reduce the amount of motion in the legs. They include:

• Levodopa (le-vo-DO-pa)
  o Is best used to treat mild cases of RLS
  o Is short-acting
  o Works for a while but does not work long term in most people
• Dopamine agonists (pergolide (PER-go-lid), pramipexole (prah-mih-PEX-ohl), and ropinirole (roh-PIN-ih-roll))
  o Are used to treat moderate and severe cases of RLS
  o Are used to treat mild cases of RLS if levodopa stops working
  o Are long-acting

The U.S. Food and Drug Administration recently approved ropinirole to treat moderate to severe RLS.

Other medicines may be used to treat RLS, including:

• Strong pain-relieving medicines (narcotics).
  o Used most often when symptoms are severe
  o May be used in people who don’t respond to dopamine agonists
• Sedatives (benzodiazepines (BEN-so-di-AZ-e-pens)).
  o Help with falling asleep
  o May cause daytime sleepiness
  o Are not recommended for people with sleep apnea and for older persons
• Medicines used to treat epilepsy (anticonvulsants: gabapentin (gab-ah-PEN-tin), carbamazepine (kar-bam-AZ-e-pen), and valproate (val-PROH-ate)). These types of medicines are:
  o Considered when dopamine agonists fail
  o Most effective in persons with daytime and evening symptoms, as well as sleep-onset symptoms, and in those who describe the unpleasant feelings in the legs as painful.
• Iron supplements, if iron deficiency appears to be contributing to RLS. Iron supplements should only be used if recommended by a doctor.

Living With Restless Legs Syndrome

Restless legs syndrome (RLS) is often a lifelong condition. The symptoms may come and go frequently or disappear completely for long periods of time. They may get worse over time. Lifestyle changes and medicines can help control and relieve the symptoms of RLS. For severe symptoms, ongoing medicines may be needed. Persons affected should talk to their doctor about lifestyle changes and medicines that might help your symptoms. New treatments are being developed as research continues.

RLS that occurs during pregnancy usually improves or disappears within a few weeks after delivery.

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:

• In the US: 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.
• Internationally: 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.

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:
  o A compelling urge to move the limbs, usually associated with paresthesias/dysesthesias
  o Motor restlessness, as seen in activities such as floor pacing, tossing and turning in bed, and rubbing the legs
  o Symptoms worse or exclusively present at rest (i.e., lying, sitting) with variable and temporary relief on activity
  o 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
  o 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.
  o Progressive decrease in age at onset with subsequent generations (i.e., genetic anticipation) has been described in some families. Patients    with familial RLS tend to have an earlier age at onset (< 45) and slower progression.
  o Psychiatric factors, stress, and fatigue can exacerbate symptoms of RLS.
  
  
• Secondary RLS
  o 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 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 (e.g., 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.

IFFERENTIALS

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.

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
  
  o 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.
  o 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.
  o 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.
  o Patients with prominent varicose veins in the legs may benefit from Ted hose.
  o 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.

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.