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•	Introduction
•	Causes
•	Risk Factors
•	Complications
•	Diagnosis
•	Treatment
•	Medications
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Restless legs syndrome and related disorders

Highlights

Periodic Limb Movement Disorder (PLMD)

Periodic limb movements are very common in elderly women, according to a 2006 study in the Journal of Clinical Sleep Medicine. In a study of 455 women with an average age of 83 years, researchers found that 66% of the women experienced 5 or more leg movements per hour, and 52% had 15 or more leg movements. Due to PLMD, over a quarter of the women awoke from sleep 5 or more times an hour. The researchers recommend that people with PLMD consult a sleep specialist.

Restless Legs Syndrome (RLS) and Depression

Depression is common in patients with RLS, but the reverse may also be true, suggests a review in Sleep. Researchers found a significant overlap between depressive and RLS symptoms in several studies. In addition, selective serotonin reuptake inhibitors (SSRIs), a common type of antidepressant medication, can cause RLS symptoms.

RLS and Quality of Life

Patients with RLS have many physical and emotional conditions that interfere with their quality of life, indicates research presented at the annual meeting of the American College of Chest Physicians. Researchers analyzed data from a National Sleep Foundation poll. Poll results suggested that people with RLS are more likely to:

• Have depression and anxiety
• Be overweight
• Be unemployed
• Smoke every day
• Have problems with work attendance and performance
• Miss social events

Drug Treatments

• Ropinirole (Requip), the only approved drug treatment for RLS, reduces RLS symptoms and improves quality of life and anxiety, according to a study in Mayo Clinic Proceedings. In the study, patients received ropinirole once a day for 12 weeks.
• Pramipexole (Mirapex) and cabergoline (Dostinex), two drugs that are related to ropinirole, are showing promising results in clinical trials. In studies published in Neurology, both drugs improved RLS symptoms, sleep, and quality of life.

Introduction

Restless legs syndrome (RLS) is an unsettling and poorly understood movement disorder affecting 3 - 15% of the general population. RLS can affect both children and adults. Although effective treatments are available, the condition frequently remains undiagnosed.

Symptoms of RLS. The core symptom of RLS is an irresistible urge to move the legs (medically known as akathisia ). It is sometimes described as a sense of unease and weariness in the lower leg that is aggravated by rest and relieved by movement. Specific characteristics of RLS include:

• Patients describe their RLS symptoms as "pulling, searing, drawing, tingling, bubbling, or crawling" beneath the skin, usually in the calf area, causing an irresistible urge to move the legs. These sensations can occur not only in the lower legs, but they can also affect the thighs, feet, and even the upper body. In fact, a small 2000 study suggested that nearly half of patients experience RLS-type symptoms in the arms. Furthermore, restless arms may be the first symptom of RLS in some people.
• About 80% of patients with RLS also experience semi-rhythmic movements called periodic limb movement disorder, or PLMD.
• Itching and pain, particularly aching pain, may be present.
• Patients experience symptoms when the legs are at rest and they feel most comfortable. (Conversely, movement brings relief.) Symptoms occur most often at night when lying down or sometimes during the day while sitting.
• Episodes of RLS most often occur between 10 PM and 4 AM at night, being at their worst right after midnight. They typically occur at 30 - 60 second intervals. They usually ebb by morning, although as the condition progresses, people may begin to experience symptoms during the day. They are always worse at night, however.
• At night the unpleasant sensations and the resulting uncontrollable urge to move the legs can often disturb sleep. Ignoring the need to move the legs usually only builds up tension until they jerk uncontrollably. If patients experience symptoms during the day, they usually feel compelled to move their legs in order to relieve the symptoms, making it difficult to sit during air or car travel or through classes or meetings.

Late- and Early Onset Forms. Some experts now believe there are two forms of RLS, early- and late-onset, and that each has different characteristics:

• People with onset of RLS in adolescence or earlier tend to have a family history of the disorder and to have RLS without accompanying pain.
• Those with later onset tend not to have a family history of RLS. Their condition is more likely to have a neurologic basis and symptoms are more like to include pain in the lower extremities.

Periodic Limb Movement Disorder (PLMD)

Periodic limb movement disorder (PLMD) is also called nocturnal myoclonus. PLMD symptoms include:

• As with RLS, episodes usually occur during the night, peaking at around midnight.
• Leg muscles involuntarily and repetitively contract and jerk every 20 - 40 seconds during sleep. Such movements may last less than 1 second, or as long as 10 seconds.
• Unlike RLS, contractions in PLMD usually do not arouse patients.(PLMD is distinct from so-called hypnic jerks, which are brief and sudden movements that occur just as people are falling asleep and jolt them awake.)

Although 80% of RLS sufferers experience PLMD, only about 30% of people with PLMD also have RLS. Although the two conditions can be treated similarly, there are some differences. PLMD, then, is considered to be a separate syndrome. PLMD is also very common in narcolepsy, a sleep disorder that causes people to suddenly fall asleep.

Nocturnal Leg Cramps

Cramps that awaken people during sleep are very common. They can be very painful and may cause a person jump out of bed in the middle of the night. They typically affect a specific area of the calf or the sole of the foot.

The hypothalamus is a highly complex structure in the brain that regulates many important brain chemicals. Malfunction of this area of the brain may give rise to cluster headaches.

Causes

The primary cause of restless legs syndrome is not known. Researchers are investigating neurologic problems that may arise either in the spinal cord or the brain. One current theory on the cause of restless legs syndrome involves a deficiency in a brain chemical called dopamine. RLS probably has a genetic basis in many cases, particularly those that develop before age 40. When the onset of the condition occurs in older adults, it most likely due to some neurologic problem.

The central nervous system is comprised of the brain and spinal cord. The peripheral nervous system includes all peripheral nerves.

Genetic Factors

People with restless legs syndrome often have a family history of the disorder. Researchers have detected specific genetic locations or factors that might be responsible for this condition. Much of the research is based on studies of families with a strong history of RLS-related conditions. In 2005, researchers confirmed that a location on chromosome 12 is definitely linked to RLS. They named this genetic marker RLS1. Locations on chromosomes 14 and 9 may also be associated with hereditary forms of RLS.

Neurologic Abnormalities

Dopamine and Neurologic Abnormalities in the Brain. Other research suggests that neurologic abnormalities involved with RLS and PLMD originate in the brain. A variety of studies support the hypothesis that an imbalance in neurotransmitters (chemical messengers in the brain), notably dopamine and serotonin, may play a part in RLS. Dopamine and serotonin unleash an array of nerve impulses that affect muscle movement. A similar effect is seen in Parkinson's disease, and indeed, drugs that increase dopamine are used for both disorders. However, Parkinson's disease itself does not seem to increase the risk for RLS. Nor does RLS early in life predispose to Parkinson's later on.

Neurologic Abnormalities in the Spine. Some research suggests that restless legs syndrome may be due to nerve impairment in the spinal cord. It had been thought that such abnormalities were likely to originate from nerve pathways in the lower spine. However, some patients with RLS commonly have symptoms in the arms suggesting that the upper spine may be involved as well. One 2001 study suggested that in patients with RLS and PLMD there is an abnormal overexcitable response along the entire spinal cord, which is triggered by sleep-related factors.

Neuropathy. Some experts suggest that RLS, particularly if it occurs in older adults, may be a form of neuropathy, which is an abnormality in the nervous system outside the spine and brain. Nevertheless, there is no evidence of a causal relationship.

Deficiencies in Iron Metabolism

Iron deficiency, even at a level too mild to cause anemia, has been linked to RLS in some people. Studies suggest, in fact, that RLS in some people may be due to impaired iron acquisition in cells that regulate dopamine in the brain. (Dopamine abnormalities are known to play a role in RLS.) Some studies have reported RLS in 25 - 30% of people with low iron levels. (In fact, the common connection between RLS and Parkinson's disease may derive from iron deficiencies in these patients.)

Causes of Periodic Limb Movement Disorder (PLMD)

The cause or causes of PLMD are not clear. Some research suggests that it may be due to abnormalities in the autonomic nervous system, which regulates the involuntary actions of the smooth muscles, heart, and glands.

Risk Factors

Restless legs syndrome may affect between 2.5 - 15% of the general population. It is more common in women than in men, and its prevalence increases with age. An estimated 10 - 28% of adults older than age 65 are affected by the disorder. In about 40% of patients, RLS begins in adolescence, though it is uncommon in young children.

Family History

Up to two-thirds of people with RLS have a family history of the disorder. In such cases, it is more likely to occur before age 40. (A family history of RLS is less likely in people who develop it as older adults.) It is also more common in populations from northern and western Europe, giving added support for a genetic basis for some cases.

Attention Deficit Activity Disorder (ADHD)

RLS and periodic limb movement disorder in children are strongly associated with inattention and hyperactivity. One study suggested that a quarter of children diagnosed with attention-deficit hyperactivity disorder (ADHD) also have RLS or PLMD, and this may actually contribute to inattentiveness and hyperactivity. The disorders have much in common, including poor sleep habits, twitching, and the need to get up suddenly and walk about frequently. A 2001 study also reported an association between adult attention deficit disorder and RLS. Some evidence suggests that the link between the diseases may be a deficiency in the brain chemical dopamine.

Pregnancy

About 20% of pregnant women report RLS, which in most cases goes away about a month after delivery. RLS in this population has been strongly associated with deficiencies in iron and with B vitamin folate (which in turn reduce iron levels).

Dialysis

Between 20 - 62% of people undergoing dialysis report restless legs syndrome. Symptoms often dissipate after a kidney transplant.

Anxiety Disorders

Anxiety can cause restlessness and agitation at night that can cause or strongly resemble restless legs syndrome.

Other Conditions Associated with RLS

The following medical conditions are also associated with RLS, although the relationships are not clear. In some cases, these conditions may contribute to RLS or they may have a common cause. In some cases, they may simply often coexist because of other risk factors:

• Osteoarthritis. About 72% of patients with RLS also have osteoarthritis.
• Varicose veins occur in 14% of patients with RLS. Sclerotherapy treatments, in which medications are injected into affected veins, may relieve symptoms in such cases.
• Obesity
• Diabetes
• Hypertension
• Hypothyroidism
• Fibromyalgia
• Rheumatoid arthritis
• Emphysema
• Chronic alcoholism
• Sleep apnea and snoring
• Chronic headaches
• Brain or spinal injuries
• Many muscle and nerve disorders. Hereditary ataxia, a group of genetic diseases that affect the central nervous system and cause loss of motor control, is of particular interest. Some experts believe that hereditary ataxia may supply clues for genetic causes of RLS.

Osteoarthritis is a chronic disease of the joint cartilage and bone, often thought to result from "wear and tear" on a joint, although there are other causes such as congenital defects, trauma, and metabolic disorders. Joints appear larger, are stiff and painful, and usually feel worse the more they are used throughout the day.

Click the icon to see an image of hypothyroidism.

Click the icon to see an image of fibromyalgia.

Click the icon to see an image of rheumatoid arthritis.

Click the icon to see an image of emphysema.

Environmental and Dietary Factors

Several environmental and dietary factors can worsen or provoke RLS:

• Iron deficiencies. People who are deficient in iron are at risk for restless legs syndrome even if they don't have anemia.
• Folic acid or magnesium deficiencies
• Smoking
• Alcohol abuse
• Caffeine (coffee drinking is specifically associated with PLMD)
• Stress
• Fatigue
• Prolonged exposure to cold

Medications

Drugs that worsen or provoke the condition include:

• Antidepressants
• Antipsychotic drugs
• Anti-nausea drugs
• Beta blockers
• Antihistamines
• Oral decongestants
• Diuretics
• Asthma drugs
• Spinal anesthesia (anesthesia-induced RLS typically resolves on its own within several months)

Risk Factors for Periodic Limb Movement Disorder (PLMD)

About 6% of the general population has periodic limb movement disorder. Among the elderly, the prevalence increases to 25 – 58%. Studies suggest that PLMD may be especially common in elderly women. As with RLS, numerous conditions are associated with PLMD. They include sleep apnea, spinal cord injuries, stroke, narcolepsy, and degenerative neurological diseases. Certain medications, including some antidepressants and anti-seizure medications, may also contribute to PLMD.

Complications

Restless legs syndrome rarely results in any serious consequences. But in some cases, severe and persistent symptoms can cause considerable mental distress, chronic insomnia, and daytime sleepiness.

Sleep Deprivation

Sleep deprivation, and the daytime sleepiness that follows, is increasingly recognized as a cause of mood disruption and a contributor to industrial errors and motor vehicle crashes.

Effect on Daily Performance and Activities. Studies suggest that sleeplessness worsens many waking behaviors. These include:

• Avoidance of passive activities. Since RLS is worse when resting, people with severe RLS may avoid activities that involve long periods of sitting, such as going to movies or traveling long distances.
• Reduced concentration. Some experts report that deep sleep deprivation impairs the brain's ability to process information.
• Impaired task performance. Missing several hours of nightly sleep over the course of a week can negatively affect performance levels and mood. In fact, sleep deprivation can cause impaired performance levels comparable to those of intoxicated people.
• Effect on learning. Whether sleeplessness significantly impairs learning is unclear. Some studies have reported problems in memorization, although others have found no differences in test scores between people with temporary sleep loss and those with full sleep.

Psychiatric Effects

Some experts believe that many cases of RLS are due to underlying anxiety or depression. Other experts think it more likely that emotional issues stem from RLS rather than the other way around.

Studies in Swedish working-aged men and women reported that those with RLS were more apt to be socially isolated, to have frequent daytime headaches or depression, and to complain of reduced libido or problems related to sleepiness. Similarly, research presented at the 2005 meeting of the American College of Chest Physicians indicated that adults at risk of RLS were more likely than healthy peers to have psychiatric conditions such as depression and anxiety. They were also more likely to be overweight, unemployed, chronic smokers, and have trouble with work attendance and performance.

RLS can contribute to insomnia. Insomnia itself can increase the activity of hormones and pathways in the brain that produce emotional problems. Even modest alterations in waking and sleeping patterns can have significant effects on a person's mood. Persistent insomnia may even predict the future development of mood disorders in some cases.

It is not clear if RLS is responsible for negative mood states or if anxiety or depression contributes to RLS. Anxiety can cause agitation and leg restlessness that resemble RLS, and depression and RLS symptoms also overlap. In addition, certain types of antidepressant drugs -- such as serotonin reuptake inhibitors (SSRIs) -- can increase periodic limb movements during sleep.

Diagnosis

A diagnosis of restless legs syndrome or nocturnal leg cramps often relies solely on the patient's description of symptoms. In general, the recommended approach is first to take a sleep and personal history. The doctor may conduct an interview that includes the following questions:

• How would the sleep problem be described?
• How long has the sleep problem been experienced?
• How long does it take to fall asleep?
• How many times a week does it occur?
• How restful is sleep?
• What are the leg problems like (cramps, twitching, crawling feelings)?
• What is the sleep environment like? Noisy? Not dark enough?
• What medications are being taken (including the use of antidepressants and self-medications for insomnia, such as herbs, alcohol, and over-the-counter or prescription drugs)?
• Is the patient taking or withdrawing from stimulants, such as coffee or tobacco?
• How much alcohol is consumed per day?
• What stresses or emotional factors may be present?
• Has the patient experienced any significant life changes?
• Does the patient snore or gasp during sleep (an indication of sleep apnea, a condition in which breathing stops for short periods many times during the night and which may worsen symptoms of restless legs syndrome or insomnia)?
• If there is a bed partner, is his or her behavior distressing or disturbing?
• Is the patient a shift worker?

Keeping a Record of Sleep. To help answer these questions, the patient may need to keep a sleep diary. Every day for 2 weeks, the patient should record all sleep-related information, including responses to questions listed above described on a daily basis. Recording sleep behavior using an extended-play audio or videotape can be very helpful in diagnosing sleep apnea.

A bed partner can help by adding his or her observations of the patient's sleep behavior.

Sleep Disorders Centers

In some cases of an uncertain diagnosis, high-risk patients may need to consult a sleep specialist or go to a sleep disorders center. At most centers, patients undergo an in-depth analysis, usually supervised by a multi-disciplinary team of consultants who can provide both physical and psychiatric evaluations. Centers should be accredited by the American Academy of Sleep Medicine.

Among the signs that may indicate a need for a sleep disorders center are:

• Insomnia due to psychological disorders
• Sleeping problems due to substance abuse
• Snoring and sudden awakening with gasping for breath (possible sleep apnea)
• Severe restless legs syndrome
• Persistent daytime sleepiness
• Sudden episodes of falling asleep during the day (possible narcolepsy)
• At most sleep disorders centers, patients undergo an in-depth analysis, usually supervised by a multidisciplinary team of consultants who can provide both physical and psychiatric evaluations.

Polysomnography

Overnight polysomnography involves several tests to measure different functions during sleep. It is typically performed in a sleep center and may help rule out sleep apnea or confirm the effectiveness of RLS treatments.

The patient arrives about 2 hours before bedtime without having made any changes in daily habits. Polysomnography electronically monitors the patient as he or she passes, or fails to pass, through the various sleep stages. Polysomnography tracks the following:

• Brain waves
• Body movements
• Breathing
• Heart rate
• Eye movements
• Changes in breathing and blood levels of oxygen

Actigraphy

Actigraphy uses a small wristwatch-like device (e.g., Actiwatch) to monitor sleep quality in people with suspected RLS, periodic limb movement disorder (PLMD), insomnia, sleep apnea, and other sleep-related conditions. The device can be applied to the wrists or ankles. It measures muscle movements and records them during sleep. For example, with PLMD, it can provide information on total duration of movements, the number of occurrences, whether PLMD occurs simultaneously in both legs, and the effects on sleep.

It is not as accurate as polygraphy because it cannot measure all the biologic effects of sleep. It is more accurate than a sleep log, however, and very helpful for recording long periods of sleep.

Sleepiness Scale

The Epworth sleepiness scale uses a simple questionnaire to measure excessive sleepiness during eight situations.

Diagnosing Iron Deficiency Anemia and Its Causes

Because of the high association between restless legs syndrome and iron deficiency, a test for low iron stores should be part of the diagnostic work-up in RLS. There are two steps in making this diagnosis:

• The first step is to determine if a person is actually deficient in iron.
• If iron stores are low, the second step is to diagnose the cause of the iron deficiencies, which will help determine treatment.

Determining if Iron Stores are Low: The following findings are important in determining that a person is iron deficient:

• Blood cells viewed under the microscope are pale (hypochromic) and abnormally small (microcytic). They are also mostly uneven in shape. (These findings suggest iron deficiency, they but can also appear in anemia of chronic disease and thalassemia.)
• Hemoglobin and iron levels are low. (These findings further suggest iron deficiency, but they can also occur in cases due to anemia due to chronic disease.)
• Ferritin levels are low. Ferritin is a protein that binds to iron and low levels typically mean reduced iron stores. (However, high levels in the blood do not always mean sufficient iron stores. For example, pregnant women may have high ferritin levels into their third trimester but still be iron deficient. Ferritin levels may also be normal or even elevated in patients with inflammation from anemia of chronic disease, even if they also have low iron stores.)
• A test that measures a factor called serum transferrin receptor (TfR) is proving to be very sensitive in identifying iron deficiency in problematic patients, including the elderly with chronic diseases and possibly pregnant women.

Determining Causes of Iron Deficiency. When iron deficiency anemia is diagnosed, the next step is to determine what causes the iron deficiency itself.

• Dietary iron deficiency is most common in children and infants. It is rare in adults.
• Heavy menstrual or abnormal uterine bleeding is usually the cause of iron deficiencies in young women. Increased need for iron during pregnancy is also a common cause in this population.
• If internal bleeding is suspected as the cause, the gastrointestinal tract is usually the first suspect as the source. A diagnosis in such cases can be often be made if the patient has noticed blood in the stools, which can be black and tarry or red-streaked. Often, however, bleeding may be present but not visible. In such cases, stool tests for this hidden (occult ) blood are required. Additional tests may then be needed to diagnose the precipitating condition. Endoscopy, in which a fiber optic tube is used to view into the gastrointestinal tract, may be used, particularly when the source of bleeding is unclear.

If the patient's diet suggests low iron intake and other causes cannot be established, then a monthly trial of iron supplements may be given. If the patient fails to respond, further evaluation is needed.

Other Laboratory Tests

Certainly laboratory tests may be helpful in determining causes of RLS or conditions that rule it out. They include:

• Blood glucose tests for diabetes
• Tests for kidney problems
• Possibly tests for thyroid hormone and magnesium and folate levels

Ruling Out Other Leg Disorders

In addition to other sleep-related leg disorders, a number of other medical conditions may have features that resemble restless leg syndrome. The doctor will need to consider these disorders in making a diagnosis.

Peripheral Neuropathies. Peripheral neuropathies are nerve disorders in the legs or feet. They can be caused by several conditions and can produce pain, burning, tingling, or shooting sensations in the extremities. Diabetes is a very common cause of painful peripheral neuropathies. Other causes include alcoholism, rheumatoid arthritis, systemic lupus erythematosus, amyloidosis, HIV infection, kidney failure, and certain vitamin deficiencies. Symptoms of peripheral neuropathies may mimic RLS. However, unlike RLS they are not usually associated with restlessness, nor are they relieved by movement, and they do not worsen at bedtime.

Deep Vein Thrombosis. Deep vein thrombosis is caused by a blood clot deep in the leg, usually in the thigh or calf. It may cause pain, swelling and aching in the leg where the clot has developed. It can occur in people with heart disease, with varicose veins, during pregnancy, in women from hormonal treatments, from injury to the leg, or from inactivity (such as after surgery or during long flights). Left untreated, this can be a very serious and even life-threatening condition.

This picture shows a red and swollen thigh and leg caused by a blood clot (thrombus) in the deep veins in the groin (iliofemoral veins), which prevents normal return of blood from the leg to the heart.

Intermittent Claudication and Peripheral Artery Disease. Peripheral artery disease (PAD) occurs when atherosclerosis (commonly called hardening of the arteries) affects the feet and legs. In such cases, the arteries become blocked, obstructing oxygen-rich blood flow. Intermittent claudication is an important symptom of PAD and occurs in between a third and half of these patients. Claudication is taken from the Latin word "to limp". The name is used to describe the pain that occurs in PAD patients when they exercise, particularly during walking. In intermittent claudication, blood flow is sufficient to meet the needs of the person at rest. The result is leg pain during exercise, which is relieved by rest.

Click the icon to see an image of peripheral artery disease.

Akathisia. Akathisia is a state of restlessness or agitation and feelings of muscle quivering. A condition called hypotensive akathisia is caused by failure in the autonomic nervous system. Unlike RLS, it occurs at any time of the day and usually only when the patient is sitting -- not lying down. Akathisia itself can also be caused by drugs used to treat schizophrenia and other psychoses, with anti-nausea drugs, or when drugs to treat Parkinson's disease are withdrawn.

Painful Legs and Moving Toes Syndrome. A rare disorder affecting one or both legs, painful legs and moving toes syndrome is marked by a constant deep, throbbing ache in the limbs and involuntary toe movements. The discomfort may be mild or severe. It intensifies with activity and usually ceases during sleep. In most cases the cause is unknown, though it may arise from spinal injuries or herpes zoster infection. The condition is difficult to treat, although the drug baclofen, combined with either clonazepam or carbamazepine, has shown some success. Other therapies that may help include orthotics for the shoes and transcutaneous electrical nerve stimulation (TENS).

Meralgia Paresthetica. An uncommon nerve condition, meralgia paresthetic is characterized by numbness, pain, tingling, or burning on the front and side of the thigh. It usually occurs on one side and is thought to be due to compression of the thigh nerve as it passes through the pelvis. It occurs most commonly in people ages 30 - 60 years, but it can affect people of all ages. It often goes away on its own.

Treatment

The initial approach to a patient who complains of sleeplessness and restless legs syndrome is to try non-drug treatments to improve sleep and eliminate possible causes of RLS. A non-drug approach is a particularly important first step for elderly patients.

• The doctor should first try to treat any underlying medical conditions that may be causing restless legs.
• If medications may be causing RLS, the doctor should try to prescribe alternatives, if possible.
• If the cause cannot be determined, it is best to first try sleep hygiene and relaxation methods. Such approaches provide added benefits, even if drug therapy is later required.

Helpful Tips

Some people report help or relief from RLS with the following behaviors or devices:

• Hot baths or cold compresses.
• Ergonomic measures. For example, patients might find it useful to work at a high stool, where they can dangle their legs. In meetings or during air travel, it is helpful to obtain an aisle seat.
• Changing sleep patterns. Some patients report that symptoms don't occur if they sleep late in the morning, so, if feasible, changing sleep patterns may also be helpful.
• Avoiding caffeine, alcohol, and nicotine.

Alternative treatments that are sometimes advocated for RLS include acupuncture and massage. These treatments, however, have not been rigorously studied.

Vitamins and Minerals

Some people have reported benefits from:

• Vitamin E (800 - 1200 IU per day)
• Calcium, magnesium, or potassium supplements
• Folic acid supplements for people with folate deficiencies

Folate (folic acid) is necessary for the production of red blood cells and for the synthesis of DNA (which controls heredity and is used to guide the cell in its daily activities). Folic acid also helps with tissue growth and cell function. In addition, it helps to increase appetite when needed and stimulates the formation of digestive acids.

Dietary Iron

Because RLS is associated with iron insufficiency, people with the condition should be sure they have a diet that provides iron. [For more information, see In-Depth Report #57: Anemia.] Iron found in foods is either in the form of heme or non-heme iron:

• Heme Iron. Foods containing heme iron are the best for increasing or maintaining healthy iron levels. Such foods include (in decreasing order of iron-richness) clams, oysters, organ meats, beef, pork, poultry, and fish.
• Non-Heme Iron. Non-heme iron is less well absorbed. About 60% of the iron in meat is non-heme (although meat itself helps absorb non-heme iron). Eggs, dairy products, and iron-containing vegetables have only the non-heme form. Vegetable include dried beans and peas, iron-fortified cereals, bread, and pasta products, dark green leafy vegetables (chard, spinach, mustard greens, kale), dried fruits, nuts, and seeds.

The Effects of Food on Iron Absorption. The absorption of non-heme iron often depends on the food balances in meals. The following are foods that enhance absorption of non-heme iron.

• Meat and fish not only contain heme iron, the best form for maintaining stores, but they also help absorb non-heme iron.
• Increasing intake of vitamin-C rich foods can enhance absorption of non-heme iron during a single meal. In any case, vitamin-C rich foods are healthful and include broccoli, cabbage, citrus fruits, melon, tomatoes, and strawberries. One orange or 6 ounces of orange juice can double the amount of iron your body absorbs from plant foods. (Taking vitamin C supplements does not appear to have any significant effect on iron stores.)
• Foods containing riboflavin (vitamin B2) may help enhance the formation of hemoglobin from iron. Sources include liver, dried fortified cereals, and yogurt.

Certain nutrients impede the body's absorption of dietary iron. They include:

• Polyphenols (found in tea, coffee, red wine, berries, apples).
• Phytates (found in foods such as seeds, dried beans, soy, and bran). Such foods are typically high in fiber. (It is often believed that fiber itself impedes iron absorption, but researchers report that it has little or no effect.)
• Calcium. Calcium impairs the absorption of heme and non-heme iron. However, calcium intake must be quite high to cause any significant problems. For example, a 2002 study reported that cheese had no effect on iron absorption from meals rich in heme and non-heme iron.

The Effects of Cooking Methods on Iron. Cooking methods can enhance iron stores. Cooking in cast iron pans and skillets is well-known to increase the iron content of food. According to one study, boiling, steaming, or stir-frying in utensils composed of any material significantly increased the release of non-heme iron stored in vegetables.

Iron Supplements

In people with RLS who are also iron deficient, iron supplements can produce a significant reduction in symptoms. They should be used in these patients, however, only when dietary measures have failed. They do not appear to be useful for patients with normal or above normal iron levels.

Supplement Forms. To replace iron, the preferred forms of iron tablets are ferrous salts, usually ferrous sulfate (Feosol, Fer-In-Sol, Mol-Iron). Other forms include ferrous fumarate (Femiron, FerroSequels, Feostat, Fumerin, Hemocyte, Ircon), ferrous gluconate (Fergon, Ferralet, Simron), polysaccharide-iron complex (Niferex, Nu-Iron), and carbonyl iron (Elemental Iron, Feosol Caplet, Ferra-Cap). Specific brands and forms may have certain advantages. The following are some examples:

• Prolonged-release ferrous sulfate (Slow Fe) may enhance iron absorption with fewer side effects than standard ferrous sulfate pills.
• FerroSequels contains a stool softener, which helps prevent constipation.
• Polysaccharide-iron complex has fewer side effects and equal absorption rates compared to ferrous salts. It is very expensive, however.
• Carbonyl iron is composed of very fine tiny uniform spheres of iron powder and may prove to be less toxic than ferrous iron.
• Coated or combination pills do not appear to offer any additional advantages and may hinder absorption of the iron.

Regimen. A reasonable approach for patients with RLS is to take 65 mg of iron (or 325 mg of ferrous sulfate) along with 100 mg of vitamin C on an empty stomach three times a day.

IMPORTANT: As few as three adult iron tablets can poison, and even kill, children. This includes any form of iron pill. No one, even adults, should take a double dose of iron if one is missed.

Tips for taking iron are:

• For best absorption, iron should be taken between meals. (Iron may cause stomach and intestinal disturbances, however, and some experts believe that low doses of ferrous sulfate can be taken with food and absorbed without side effects.)
• Always drink a full 8 ounces of fluid with an iron pill.
• Tablets should be kept in a cool place. (Bathroom medicine cabinets may be too warm and humid, which may cause the pills to disintegrate.)

Side Effects. Common side effects of iron supplements include the following:

• Constipation and diarrhea are very common. They are rarely severe, although iron tablets can aggravate existing gastrointestinal problems such as ulcers and ulcerative colitis.
• Nausea and vomiting may occur with high doses, but can be controlled by taking smaller amounts. Switching to ferrous gluconate may help some people with severe gastrointestinal problems.
• Black stools are normal when taking iron tablets. In fact, if they do not turn black, the tablets may not be working effectively. This tends to be a more common problem with coated or long-acting iron tablets.
• If the stools are tarry looking as well as black, if they have red streaks, or if cramps, sharp pains, or soreness in the stomach occur, gastrointestinal bleeding may be causing the iron deficiency and the patient should call the doctor promptly.
• Acute iron poisoning is rare in adults, but can be fatal in children who take adult-strength tablets.

Interactions With Other Drugs. Certain medications, including antacids, can reduce iron absorption. Iron tablets may also reduce the effectiveness of other drugs, including the antibiotics tetracycline, penicillamine, and ciprofloxacin and the anti-Parkinson's disease drugs methyldopa, levodopa, and carbidopa. At least 2 hours should elapse between doses of these drugs and iron supplements.

Supplementary Treatments. The following supplements may improve iron absorption:

• Adding either ascorbic acid (vitamin C) or succinic acid to ferrous sulfate therapy will improve absorption of iron stores. Ascorbic acid added to iron therapy, however, may worsen some of the side effects. Succinic acid added to ferrous sulfate does not appear to increase side effects.
• Some studies have found that the addition of zinc to iron supplements increases hemoglobin levels more than iron alone. (Some evidence for this suggests that zinc affects a hormone called insulin-like growth factor-I (IGF-I), which plays a role in the regulation of red blood cell production.)

Exercise

Exercise earlier in the day may be one of the best ways to achieve healthy sleep. However, vigorous exercise and stimulation (including sexual activity) within 1 - 2 hours of bed time may worsen RLS. A study found that people who engaged in brisk walking for 30 minutes, four times a week, improved minor sleep disturbances after 4 months. Regular, moderate exercise, healthful in any case, may help prevent RLS. Patients report that either bursts of excessive energy or long sedentary periods worsen symptoms.

Medications

The American Academy of Sleep Medicine recommends medications for RLS or periodic limb movement disorder (PLMD) only for persons who fulfill strict diagnostic criteria, and who experience excessive sleepiness that occurs as a result of these conditions. Little is known about the best way to treat RLS, but some experts suggest the following:

• Over-the-counter pain relievers and possibly mineral and vitamin supplements (particularly folic acid in people who might be deficient) should be tried first.
• People with RLS should be tested for iron deficiency and, if they are, treated with oral iron supplements.
• Dopaminergic drugs (drugs that increase levels of dopamine) are the standard drugs for treating severe RLS, PMLD, or both. These drugs include dopamine precursors such as levodopa (L-dopa) as well as dopamine receptor agonists such as pergolide, pramiprexole, and ropinirole. Some experts then recommend regular use of dopamine receptor agonists for patients who experience nightly symptoms and fast-acting L-dopa combinations for those whose symptoms occur only occasionally.
• If dopaminergic drugs fail or for patients who have frequent -- but not nightly -- symptoms, other drugs may be helpful. These include opiates (pain relievers), benzodiazepines (sedative hypnotic drugs), or anticonvulsants. However, benzodiazepines and opiates can become habit forming and addictive.

Tylenol and Non-Steroidal Anti-Inflammatories (NSAIDs)

Before taking stronger medications, people should try over-the-counter pain relievers, such as acetaminophen (Tylenol) or nonsteroidal anti-inflammatory drugs (NSAIDs), which include ibuprofen (Advil, Motrin, Rufen), naproxen (Anaprox, Naprosyn, Aleve), and ketoprofen (Orudis KT, Aktron).

Although NSAIDs work well, long-term use can cause stomach problems, such as ulcers and bleeding, and possible heart problems. In April 2005, the FDA asked drug manufacturers of NSAIDs to include a warning label on their product that alerts users of an increased risk for cardiovascular events and gastrointestinal bleeding.

Levodopa and Other Dopaminergic Drugs

Dopaminergic drugs increase the availability of the brain chemical dopamine and are the first-line treatment for severe RLS and PLMD. These drugs significantly reduce the number of limb movements per hour and improve the subjective quality of sleep. Patients with either condition who take these drugs have experienced up to 100% reduction in symptoms. However, these drugs, which are ordinarily used for Parkinson's disease, can have severe side effects. They do not appear to be as helpful for RLS related to hemodialysis as RLS from other causes. Dopaminergic drugs include dopamine receptor agonists and dopamine precursors.

Dopamine Receptor Agonists. Dopamine receptor agonists (also called dopamine agonists) are increasingly being used as alternatives to L-dopa. Because they have fewer side effects than L-dopa, including rebound effect, and augmentation, these drugs may be used on a daily basis. They have been shown to relieve symptoms in up to 70 - 90% of patients. Dopamine agonists can be categorized as ergot-derived (such as pergolide, cabergoline) or non-ergot derived (such as pramipexole, ropinirole). The newer non-ergotamine derivatives may induce fewer side effects than ergot-derived drugs. Studies on these medications report the following:

• Ropinirole (Requip) is a non-ergotamine dopamine agonist. Approved in 2005, ropinirole is the first and only drug approved specifically for treatment of moderate-to-severe RLS (more than 15 RLS episodes a month). Side effects are generally mild but may include nausea, vomiting, drowsiness, and dizziness.
• Pergolide (Procalamine) is as effective as carbidopa-levodopa and has fewer side effects, though nausea, dizziness, and nasal stuffiness are common. It also seems to produce fewer of the rebound and augmentation effects of levodopa, particularly at higher doses. Benefits persist for at least a year.
• Pramipexole (Mirapex) is showing good results in clinical trials for improving symptoms and quality of life in patients with RLS. A long-term, follow-up study showed the drug continued to be effective for RLS, even after 7 months of use. However, some research suggests that RLS symptoms may rapidly worsen when the drug is discontinued. The most common side effects of pramipexole include nausea, headache, and tiredness.
• Cabergoline (Dostinex) is also showing promise in clinical trials. In one study, cabergoline was used for RLS after levodopa had either failed or resulted in increased symptoms. Patients in the study reported relief or freedom from symptoms after 4 weeks of use. A 2006 study indicated that a single evening dose of cabergoline improved both day and nighttime limb movements, and sleep disturbances.

Other Dopamine Agonists. Rotigotine is a unique dopamine agonist that is being developed in patch form for RLS and Parkinson's disease. Other dopamine agonists that have shown some promise in small studies include alpha-dihydroergocryptine, or DHEC (Almirid), and piribedil (Trivastal).

Dopamine Precursors. The dopamine precursor levodopa (L-dopa) is often used for severe RLS. The standard preparations (Sinemet, Atamet) combine levodopa with carbidopa, which improves the action of levodopa and reduces some of its side effects, particularly nausea. Levodopa can also be combined with benserazide (Madopar) with similar results, but Sinemet is almost always used in America. (Levodopa combinations are shown to be well tolerated and safe.)

Patients typically start with a very low dose taken 1 hour before bedtime. The dosage is increased until the patient finds relief. Patients sometimes need to take an extended form or to take it again during the night.

Levodopa has a rapid onset of action, and effectiveness is usually achieved within the first few days of therapy. One study reported that a combination therapy of regular-release L-dopa plus sustained release L-dopa was effective in improving sleep.

Serious common side effects of L-dopa treatment are augmentation and rebound. (See side effects section for more information.) Many studies report that augmentation (worsening of symptoms earlier in the day) occurs in up to 70% of patients who take L-dopa. The risk is highest for patients who take daily doses, especially doses at high levels (greater than 200 mg). For this reason, experts recommend that L-dopa should only be used intermittently (fewer than three times per week) and that the drug should be immediately discontinued if augmentation does occur. Following withdrawal from L-dopa, patients can switch to a dopamine receptor agonist.

Regimens. L-dopa is fast acting and takes only 15 - 30 minutes before it is effective. The dopamine receptor agonists take at least 2 hours to start working. Some experts recommend regular use of dopamine receptor agonists for patients who experience nightly symptoms and L-dopa for those whose symptoms occur only occasionally.

Side Effects. Common side effects of all these drugs vary but may include feeling faint or dizzy (especially when standing up), headaches, abnormal muscle movements, rapid heartbeat, insomnia, bloating, chest pain, and dry mouth. Nausea may be especially common. Adding the drug domperidone may help to relieve this side effect. Because these drugs may also cause daytime drowsiness, special care should be taken when driving. In rare cases, they can cause hallucinations or lung disease.

Dopaminergic drugs may also have the following side effects, which can be limiting factors in the value of these medications for RLS. (They tend to be more severe with L-dopa than the newer dopamine receptor agonists.)

• Rebound Effect. The rebound effect causes increased leg movements at night or in the morning as the dose wears off.
• Augmentation. Long-term use of these drugs may eventually intensify symptoms of restless legs syndrome in the late afternoon or evening. Symptoms of restlessness, in severe cases, extend to the upper part or the whole body and may occur when walking. About 30% of patients who take the dopamine receptor agonists have reported augmentations symptoms compared to 70% who take L-dopa. As the newer drugs are taken for longer periods and at higher doses, however, their augmentation rates may become closer to those of L-dopa. In general, however, occasional use of any drug poses a very a low risk for augmentation.
• Tolerance (Loss of effectiveness). Long-term use can lead to loss of effectiveness. Adding a drug called entacapone (Comtan) may prolong the duration of action of carbidopa-levodopa therapy (Sinemet), but it can cause nausea.

Using the lowest dose possible can minimize these effects.

Withdrawal Symptoms. Patients who withdraw from these drugs typically experience very severe RLS symptoms for the first two days after stopping. RLS eventually returns to pre-treatment levels after about a week. The longer the drugs have been taken, the worse the withdrawal symptoms.

Benzodiazepines

Benzodiazepines, such as clonazepam (Klonopin), are commonly called sedative hypnotics and are used for insomnia and anxiety. They may be helpful for some patients with RLS that disrupts sleep. Clonazepam may be particularly helpful for children with both periodic limb movement disorder and symptoms of attention-deficit hyperactivity disorder. It also appears to be helpful for patients with RLS who are undergoing hemodialysis.

Side Effects. Elderly people are more susceptible to side effects and should usually start at half the dose prescribed for younger people and should not take long-acting forms. Side effects may differ depending on whether the benzodiazepine is long- or short-acting.

• The drugs may increase depression, a common co-condition in any case in many people with insomnia.
• Breathing problems may occur with overuse or with people with pre-existing respiratory illness.
• Long-acting drugs have a very high rate of residual daytime drowsiness compared to others. They have been associated with a significantly increased risk for automobile accidents and falls in the elderly particularly in the first week after taking them. Shorter-acting benzodiazepines do not appear to pose as high a risk.
• Memory loss (so-called traveler's amnesia), sleepwalking, and odd mood states have been reported after taking triazolam (Halcion) and other short-acting benzodiazepines. These effects are rare and probably enhanced by alcohol.
• Because these drugs cross the placenta and enter breast milk, pregnant nursing women should not use them. An association was reported between the use of benzodiazepines in the first trimester of pregnancy and the development of cleft lip in newborns.
• In rare cases, overdoses have been fatal.

Interactions. Benzodiazepines are potentially dangerous when used in combination with alcohol. Some drugs such as the ulcer medication cimetidine can slow the breakdown of the benzodiazepine.

Withdrawal Symptoms. Withdrawal symptoms usually occur after prolonged use and indicate dependence. They can last 1 - 3 weeks after stopping the drug and may include:

• Gastrointestinal distress
• Sweating
• Disturbed heart rhythm
• In severe cases, patients might hallucinate or experience seizures, even a week or more after the drug has been stopped.

Rebound Insomnia. Rebound insomnia, which often occurs after withdrawal, typically includes one to two nights of sleep disturbance, daytime sleepiness, and anxiety. The chances for rebound are higher with the short-acting benzodiazepines than with the longer-acting ones.

Narcotic Pain Relievers

Narcotics are pain-relieving drugs that act on the central nervous system. They are sometimes prescribed for severe cases of RLS. They may be a good choice if pain is a prominent feature. Some evidence also suggests that narcotics reduce the frequency of periodic leg movements.

There are two types of narcotics, both of which have been used in RLS:

• Opiates are derived from natural opium (morphine and codeine). Some patients report relief with the use of the opiate fentanyl (Duragesic), used in skin patch form. An implanted abdominal pump (Isomed) uses morphine and an anesthetic called bupivacaine. Investigate work is showing promise for patients with severe RLS.
• Opioids are synthetic drugs. The most common example is oxycodone (Percodan, Percocet, Roxicodone, Oxycontin). Apomorphine is a morphine derivative. In one study, when it was injected under the skin at night, it reduced nocturnal discomfort and leg movements in some patients.

Although the use of narcotics for severe RLS is controversial, some studies have suggested that they are rarely addictive for pain sufferers except among patients with a history of substance abuse, even when they are prescribed long-term. The use of such drugs may be beneficial when included as part of a comprehensive pain management program. Such a program involves screening prospective patients for possible drug abuse and then regularly monitoring those who are taking it, adjusting the dose as necessary to achieve an acceptable balance between pain relief and side effects. Patients on long-term opiate therapy should also be monitored periodically for sleep apnea, a condition that causes breathing to stop for short periods many times during the night and which may exacerbate symptoms of RLS, insomnia, and other complaints.

Tramadol. Tramadol (Ultram) is a pain reliever that has been used as an alternative to opioids. In one study, tramadol was very effective for RLS and produced few or no side effects. It has opioid-like properties, but is not as addictive. (Dependence and abuse have been reported, however.) Nevertheless, withdrawal after long-term use (longer than a year) can cause intense symptoms, including diarrhea, insomnia, and even restless legs syndrome itself.

Antiseizure Drugs

Antiseizure drugs, such as gabapentin (Neurontin), valproic acid (valproate, divalproex, Depakote, Depakene), and carbamazepine (Tegretol), relax blood vessels and are being tested for RLS. Gabapentin, a newer antiseizure drug, is showing particular promise for mild to moderate RLS. A 2002 study reported that it improved RLS symptoms and sleep, particularly in patients who also experienced pain. It was also effective for periodic leg movement disorder.

Side Effects. All antiseizure drugs have potentially severe side effects and should be tried only after non-drug methods have failed. Side effects of many anti-seizure drugs include nausea, vomiting, heartburn, increased appetite with weight gain, hand tremors, irritability, and temporary hair thinning and loss (taking zinc and selenium supplements may help reduce this effect). Some can also cause birth defects and, in rare cases, liver toxicity. Gabapentin may have fewer of these side effects than valproic acid or carbamazepine.

Other Drugs

Selective Serotonin Reuptake Inhibitors (SSRIs) and Similar Antidepressants. Imbalances in the neurotransmitter serotonin have been associated with RLS. To correct these imbalances, some patients can try the common antidepressants known as SSRIs, which increase serotonin levels in the brain. One study found that SSRIs reduced RLS in 58% of patients and eliminated symptoms in 12%. SSRIs include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), and citalopram (Celexa, Cipramil).

Bupropion (Wellbutrin), a newer so-called designer antidepressant that has slightly different actions, may also be helpful for RLS. These drugs are not addictive and do not have the severe side effects of other RLS drugs, but more research is warranted to determine if they are useful.

Clonidine. Clonidine (Catapres), a drug used for high blood pressure, is helpful for some patients and may be an appropriate choice for patients who have RLS accompanied by hypertension. It also may help patients with RLS who are undergoing hemodialysis.

Baclofen. The anti-spasm drug baclofen (Lioresal) appears to reduce intensity of RLS (although not frequency of movements).

Resources

• www.aasmnet.org -- American Academy of Sleep Medicine
• www.sleepfoundation.org -- National Sleep Foundation
• www.ninds.nih.gov -- National Institute of Neurological Disorders and Stroke
• www.nhlbi.nih.gov/about/ncsdr/ -- National Center on Sleep Disorders Research
• www.rls.org -- Restless Legs Syndrome Foundation
• www.wemove.org -- Worldwide Education and Awareness for Movement Disorders

References

Bogan RK, Fry JM, Schmidt MH, Carson SW, Ritchie SY. Ropinirole in the treatment of patients with restless legs syndrome: a US-based randomized, double-blind, placebo-controlled clinical trial. Mayo Clin Proc. 2006 Jan;81(1):17-27.

Claman DM; Redline S; Blackwell T, Ancoli-Israel S, Surovec S, Scott N, et al. Prevalence and correlates of periodic limb movements in older women. J Clin Sleep Med 2006 Oct;2(4):438-445.

Oertel WH, Benes H, Bodenschatz R, Peglau I, Warmuth R, Happe S, et al. Efficacy of cabergoline in restless legs syndrome: a placebo-controlled study with polysomnography (CATOR). Neurology. 2006 Sep 26;67(6):1040-6.

Partinen M, Hirvonen K, Jama L, Alakuijala A, Hublin C, Tamminen I, et al. Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study--the PRELUDE study. Sleep Med. 2006 Aug;7(5):407-17.

Picchietti D, Winkelman JW. Restless legs syndrome, periodic limb movements in sleep, and depression. Sleep. 2005 Jul 1;28(7):891-8.

Winkelman JW, Sethi KD, Kushida CA, Becker PM, Koester J, Cappola JJ, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology. 2006 Sep 26;67(6):1034-9.

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