Restless legs syndrome

Definition

Restless legs syndrome (RLS) is a neurological disorder characterized by uncomfortable sensations in the legs and, less commonly, the arms. These sensations are exacerbated (heightened) when the person with RLS is at rest. The sensations are described as crawly, tingly, prickly and occasionally painful. They result in a nearly insuppressible urge to move around. Symptoms are often associated with sleep disturbances.

Description

Restless legs syndrome is a sensory-motor disorder that causes uncomfortable feelings in the legs, especially during periods of inactivity. Some people also report sensations in the arms, but this occurs much more rarely. The sensations occur deep in the legs and are usually described with terms that imply movement such as prickly, creepy-crawly, boring, itching, achy, pulling, tugging and painful. The symptoms result in an irrepressible urge to move the leg and are relieved when the person suffering from RLS voluntarily moves. Symptoms tend to be worse in the evening or at night.

Restless legs syndrome is associated with another disorder called periodic limb movements in sleep (PLMS). It is estimated that four out of five patients with RLS also suffer from PLMS. PLMS is characterized by jerking leg movements while sleeping that may occur as frequently as every 20 seconds. These jerks disrupt sleep by causing continual arousals throughout the night.

People with both RLS and PLMS are prone to abnormal levels of exhaustion during the day because they are unable to sleep properly at night. They may have trouble concentrating at work, at school or during social activities. They may also have mood swings and difficulty with interpersonal relationships. Depression and anxiety may also result from the lack of sleep. RLS affects people who want to travel or attend events that require sitting for long periods of time.

Demographics

As much as 10% of the population of the United States and Europe may suffer from some degree of restless legs syndrome. Fewer cases are indicated in India, Japan and Singapore, suggesting racial or ethnic factors play a role in the disorder. Although the demographics can vary greatly, the majority of people suffering from RLS are female. The age of onset also varies greatly, but the number of people suffering from RLS increases with age. However, many people with RLS report that they had symptoms of the disorder in their childhood. These symptoms were often disregarded as growing pains or hyperactivity.

Causes and symptoms

Restless legs syndrome is categorized in two ways. Primary RLS occurs in the absence of other medical symptoms, while secondary RLS is usually associated with some other medical disorder. Although the cause of primary RLS is currently unknown, a large amount of research into the cause of RLS is taking place. Researchers at Johns Hopkins University published a study in July 2003 suggesting that iron deficiencies may be related to the disorder. They dissected brains from cadavers of people who suffered from RLS and found that the cells in the midbrain were not receiving enough iron. Other researchers suggest that RLS may be related to a chemical imbalance of the neurotransmitter dopamine in the brain. There is also evidence that RLS has a genetic component. RLS occurs three to five times more frequently in an immediate family member of someone who has RLS than in the general population. A site on a chromosome that may contain a gene for RLS has been identified by molecular biologists.

In many people, other medical conditions play a role in RLS and the disorder is therefore termed secondary RLS. People with peripheral neuropathies (injury to nerves in the arms and legs) may experience RLS. Such neuropathies may result from diabetes or alcoholism. Other chronic diseases such as kidney disorders and rheumatoid arthritis may result in RLS. Iron deficiencies and blood anemias are often associated with RLS and symptoms of the disease usually decrease once blood iron levels have been corrected. Attention deficit/hyperactivity disorder has also been implicated in RLS. Pregnant women often suffer from RLS, especially in the third trimester. Some people find that high levels of caffeine intake may result in RLS.

The symptoms of RLS are all associated with unpleasant feelings in the limbs. The words used to describe these feelings are various, but include such adjectives as deep-seated crawling, jittery, tingling, burning, aching, pulling, painful, itchy or prickly. They are usually not described as a muscle cramp or numbness. Most often the sensations occur during periods of inactivity. They are characterized by an urge to get up and move. Such movements include stretching, walking, jogging or simply jiggling the legs. The feelings worsen in the evening.

A variety of symptoms are associated with RLS, but may not be characteristic of every case. Some people with RLS report involuntary arm and leg movements during the night. Others have difficulty falling asleep and are sleepy or fatigued during the day. Many people with RLS have leg discomfort that is not explained by routine medical exams.

Diagnosis

Restless legs syndrome cannot currently be diagnosed using any laboratory tests or via a routine physical examination. Diagnosis is based on information given to a doctor by the patient regarding his or her symptoms. Usually the doctor takes a complete medical history as well as a family history. The International Restless Legs Syndrome Study group has proposed a set of criteria that can be used while taking a medical history in order to diagnose RLS:

• a compelling urge to move the arms and legs
• restlessness that manifests itself in pacing, tossing and turning and/or rubbing the legs
• symptoms that worsen when the patient is resting and are relieved when the patient is active
• symptoms that worsen at the end of the day

In addition, a physical examination will be made to identify if there are any other medical conditions, such as neurological disorders or blood disorders that may be causing secondary RLS. A doctor who suspects a patient has RLS may suggest that the person spend the night in a sleep clinic to determine whether the patient also suffers from PLMS.

Treatment

Treatment for restless legs syndrome is generally twopronged, consisting of making lifestyle changes and using medications to relieve some of the symptoms. Lifestyle changes involve making changes to the diet, exercising and performing other self-directed activities, and practicing good sleep hygiene. Although the United States Food and Drug Administration has not yet approved any drugs for treating RLS, four classes of pharmaceuticals have been found effective for treating RLS: dopaminergic agents, benzodiazepines , opioids and anticonvulsants .

Lifestyle changes

Simple changes to the diet have proven effective for some people suffering from RLS. Vitamin deficiencies are a common problem in RLA patients. In patients with RLS, most physicians will check the levels of blood serum ferritin, which can indicate low iron storage. If these levels are below 50 mcg/L, then supplemental iron should be added to the diet. Other physicians have found that supplements of vitamin E, folic acid and B vitamins, and magnesium provide relief to symptoms or RLS. Reducing or eliminating caffeine and alcohol consumption has been effective in other patients.

Many who suffer from RLS find that exercise and massage help reduce symptoms. Walking or stretching before bed, taking a hot bath and using massage or acupressure help improve sleep. Practicing relaxation techniques such as mediation, yoga and biofeedback have also been found to be useful.

Good sleep hygiene includes having a restful, cool sleep environment and sleeping during consistent hours every night. Often people who suffer from RLS find that going to sleep later at night and sleeping later into the morning result in a better sleep.

Pharmaceuticals

Dopaminergic agents are the first type of drug prescribed in the treatment of RLS. Most commonly doctors prescribe dopamine-receptor agonists that are used to treat Parkinson's disease such as Mirapex (pramipexole), Permax (pergolide) and Requip (ropinirole). Sinemet (carbidopa/levodopa), which is a drug that adds dopamine to the nervous system, is also commonly prescribed. Sinemet has been used the more frequently than other drugs in treating RLS, but recently a problem known as augmentation has been associated with its use. When augmentation develops, symptoms of RLS will return earlier in the day and increasing the dose will not improve the symptoms.

Benzodiazepines are drugs that sedate and are typically taken before bedtime so that a patient with RLS can sleep more soundly. The most commonly prescribed sedative in RLS is Klonopin (clonazepam).

Opioids are synthetic narcotics that relieve pain and cause drowsiness. They are usually taken in the evening. The most commonly used opioids prescribed for RLS include Darvon or Darvocet (propoxyphene), Dolophine (methadone), Percocet (oxycodone), Ultram (Tramadol) and Vicodin (hydrocodone). One danger associated with opioids is that they can be addicting.

Anticonvulsants are drugs that were developed to prevent seizures in patients with epilepsy and stroke . Some RLS patients who report pain in their limbs have reported that these drugs, particularly Gabapentin (neurontin), are useful for relieving symptoms.

A few drugs have been found to worsen symptoms of RLS and they should be avoided by patients exhibiting RLS symptoms. These include anti-nausea drugs such as Antivert, Atarax, Compazine and Phenergan. Calcium channel blockers that are often used to treat heart conditions should be avoided. In addition, most anti-depressants tend to exacerbate symptoms of RLS. Finally, antihistamines such as Benadryl have been found to aggravate RLS symptoms in some people.

Clinical trials

A broad spectrum of clinical trials are currently underway to study RLS. The Restless Legs Syndrome Foundation maintains a website that lists a variety of studies throughout the United States that are currently recruiting volunteers. The studies test the effects of a variety of treatments including intravenous iron supplements, exercise and sleeping aids on RLS. More information can be found at <http://www.rls.org/frames/home_frame.htm>.

The National Institutes of Health support three clinical trials to gain information about RLS. The first study investigates the effects of the drug Ropinirole, a dopamine-receptor agonist, on spinal cord reflexes and on symptoms of restless legs syndrome. A second study is testing whether or not sensorimotor gating (the brain's ability to filter multiple stimuli) is deficient in patients who suffer from RLS. The goal of the third study is to improve understanding of neurological conditions associated with RLS by taking careful histories and following the treatment provided by primary car physicians. Information on all three trials can be found at <http://clinicaltrials.gov/search/term=Restless%20Legs%20Syndrome> or by calling the Patient Recruitment and Public Liaison Office at 1-800-411-1222 or sending an electronic message to prpl@mail.cc.nih.gov.

Prognosis

RLS is usually compatible with an active, healthy life when symptoms are controlled and nutritional deficits are corrected.

Resources

BOOKS

Cunningham, Chet. Stopping Restless Legs Syndrome. United Research Publishers, 2000.

OTHER

"Do You have Restless Legs Syndrome?" Restless Leg Syndrome Foundation. (January 23, 2003). <http://www.rls.org/frames/home_frame.htm>.

"Facts about Restless Legs." National Sleep Foundation. (June 2003). <http://www.sleepfoundation.org/publications/fact_rls.cfm>.

"Facts About Restless Legs Syndrome (RLS)." National Heat Blood and Lung Institute. (October 1996). <http://www.nhlbi.nih.gov/health/public/sleep/rls.htm>.

Mayo Clinic Staff. "Restless Legs Syndrome." (July 23, 2002). <http://www.mayoclinic.com/invoke.cfm?objectid=3E2E9266-6525-4125-923345C17FB0E20F>.

National Institute of Neurological Disorders and Stroke. NINDS Restless Legs Syndrome Information Page. (July 1, 2001). <http://www.ninds.nih.gov/health_and_medical/disorders/restless_doc.htm>.

ORGANIZATIONS

RLS Foundation, Inc. 819 Second Street SW, Rochester, MN 55902. (507) 287-6465; Fax: (507) 287-6312. rlsfoundation@rls.org. <http://www.rls.org>.

National Center on Sleep Disorders Research (NCSDR). Two Rockledge Center, Suite 7024, 6701 Rockledge Drive, MSC 7920, Bethesda, MD 20892. (301) 435-0199; Fax: (301) 480-3451.

Juli M. Berwald, PhD

Restless Legs Syndrome

Definition

Restless legs syndrome (RLS) is characterized by unpleasant sensations in the limbs, usually the legs, that occur at rest or before sleep and are relieved by activity such as walking. These sensations are felt deep within the legs and are described as creeping, crawling, aching, or fidgety.

Description

Restless legs syndrome, also known as Ekbom syndrome, Wittmaack-Ekbom syndrome, anxietas tibiarum, or anxietas tibialis, affects up to 10-15% of the population. Some studies show that RLS is more common among elderly people. Almost half of patients over age 60 who complain of insomnia are diagnosed with RLS. In some cases, the patient has another medical condition with which RLS is associated. In idiopathic RLS, no cause can be found. In familial cases, RLS may be inherited from a close relative, most likely a parent.

Causes and symptoms

Most people experience mild symptoms. They may lie down to rest at the end of the day and, just before sleep, will experience discomfort in their legs that prompts them to stand up, massage the leg, or walk briefly. Eighty-five percent of RLS patients either have difficulty falling asleep or wake several times during the night, and almost half experience daytime fatigue or sleepiness. It is common for the symptoms to be intermittent. They may disappear for several months and then return for no apparent reason. Two-thirds of patients report that their symptoms become worse with time. Some older patients claim to have had symptoms since they were in their early 20s, but were not diagnosed until their 50s. Suspected under-diagnosis of RLS may be attributed to the difficulty experienced by patients in describing their symptoms.

More than 80% of patients with RLS experience periodic limb movements in sleep (PLMS). These random movements of arms or legs may result in further sleep disturbance and daytime fatigue. Most patients have restless feelings in both legs, but only one leg may be affected. Arms may be affected in nearly half of patients.

There is no known cause for the disorder, but recent research has focused on several key areas. These include:

• Central nervous system (CNS) abnormalities. Several types of drugs have been found to reduce the symptoms of RLS. Based on an understanding of how these drugs work, theories have been developed to explain the cause of the disorder. Levodopa and other drugs that correct problems with signal transmission within the central nervous system (CNS) can reduce the symptoms of RLS. It is therefore suspected that the source of RLS is a problem related to signal transmission systems in the CNS.
• Iron deficiency. The body stores iron in the form of ferritin. There is a relationship between low levels of iron (as ferritin) stored in the body and the occurrence of RLS. Studies have shown that older people with RLS often have low levels of ferritin. Supplements of iron sulfate have been shown to significantly reduce RLS symptoms for these patients.

Diagnosis

A careful history enables the physician to distinguish RLS from similar types of disorders that cause night time discomfort in the limbs, such as muscle cramps, burning feet syndrome, and damage to nerves that detect sensations or cause movement (polyneuropathy).

The most important tool the doctor has in diagnosis is the history obtained from the patient. There are several common medical conditions that are known to either cause or to be closely associated with RLS. The doctor may link the patient's symptoms to one of these conditions, which include anemia, diabetes, disease of the spinal nerve roots (lumbosacral radiculopathy), Parkinson's disease, late-stage pregnancy, kidney failure (uremia), and complications of stomach surgery. In order to identify or eliminate such a primary cause, blood tests may be performed to determine the presence of serum iron, ferritin, folate, vitamin B₁₂, creatinine, and thyroid-stimulating hormones. The physician may also ask if symptoms are present in any close family members, since it is common for RLS to run in families and this type is sometimes more difficult to treat.

In some cases, sleep studies such as polysomnography are undertaken to identify the presence of PLMS that are reported to affect 70-80% of people who suffer from RLS. The patient is often unaware of these movements, since they may not cause him to wake. However, the presence of PLMS with RLS can leave the person more tired, because it interferes with deep sleep. A patient who also displays evidence of some neurologic disease may undergo electromyography (EMG). During EMG, a very small, thin needle is inserted into the muscle and electrical activity of the muscle is recorded. A doctor or technician usually performs this test at a hospital outpatient department.

Treatment

The first step in treatment is to treat existing conditions that are known to be associated with RLS and that will be identified by blood tests. If the patient is anemic, iron (iron sulfate) or vitamin supplements (folate or vitamin B₁₂) will be prescribed. If kidney disease is identified as a cause, treatment of the kidney problem will take priority.

Prescription drugs

In some people whose symptoms cannot be linked to a treatable associated condition, drug therapy may be necessary to provide relief and restore a normal sleep pattern. Prescription drugs that are normally used for RLS include:

• Benzodiazepines and low-potency opioids. These drugs are prescribed for use only on an "as needed" basis, for patients with mild RLS. Benzodiazepines appear to reduce nighttime awakenings due to PLMS. The benzodiazepine most commonly used to treat RLS is clonazepam (Klonopin, Rivotril). The main disadvantage of this drug type is that it causes daytime drowsiness. It also causes unsteadiness that may lead to accidents, especially for an elderly patient. Opioids are narcotic pain relievers. Those commonly used for mild RLS are low potency opioids, such as codeine (Tylenol #3) and propoxyphene (Darvocet). Studies have shown that these can be successfully used in the treatment of RLS on a long-term basis without risk of addiction. However, narcotics can cause constipation and difficulty urinating.
• Levodopa (L-dopa) and carbidopa (Sinemet). Levodopa is the drug most commonly used to treat moderate or severe RLS. It acts by supplying a chemical called dopamine to the brain. It is often taken in conjunction with carbidopa to prevent or decrease side effects. Although it is effective against RLS, levodopa may also causes a worsening of symptoms during the afternoon or early evening in 50-80% of patients. This phenomenon is known as "restless legs augmentation," and if it occurs, the physician will probably discontinue Levodopa for a brief period while an alternate drug is used. Levodopa can often be reintroduced after a short break.
• Pergolide (Permax). Pergolide acts on the same part of the brain as Levodopa. It is less likely than Levodopa to cause daytime worsening of symptoms (occurs in about 25% of patients). However, it is not recommended as the first choice in drug therapy since it causes a high rate of minor side effects. Pergolide is often used only if Levodopa has been discontinued.
• High potency opioids. If the symptoms of RLS are difficult to treat with the above medication, higher dose opioids will be used. These include methadone (Dolophine), oxycodone, and clonidine (Catapres, Combipres, Dixarit). A significant disadvantage of these drugs is risk of addiction.
• Anticonvulsants. Some cases of RLS may be improved by anticonvulsant drugs, such as carbamazepine (Tegretol).
• Combination therapy. Some patients respond well to combinations of drugs such as a benzodiazepine and Levodopa.

Many drugs have been investigated for treatment of RLS, but it seems as though the perfect therapy has not yet been found. However, careful monitoring of side effects and good communication between patient and doctor can result in a flexible program of therapy that minimizes side effects and maximizes effectiveness.

Alternative treatment

It is likely that the best alternative therapy will combine both conventional and alternative approaches. Levodopa may be combined with a therapy that relieves pain, relaxes muscles, or focuses in general on the nervous system and the brain. Any such combined therapy that allows a reduction in dosage of levodopa is advantageous, since this will reduce the likelihood of unacceptable levels of drug side effects. Of course, the physician who prescribes the medication should monitor any combined therapy. Alternative methods may include:

• Acupuncture. Patients who also suffer from rheumatoid arthritis may especially benefit from acupuncture to relieve RLS symptoms. Acupuncture is believed to be effective in arthritis treatment and may also stimulate those parts of the brain that are involved in RLS.
• Homeopathy. Homeopaths believe that disorders of the nervous system are especially important because the brain controls so many other bodily functions. The remedy is tailored to the individual patient and is based on individual symptoms as well as the general symptoms of RLS.

• Reflexology. Reflexologists claim that the brain, head, and spine all respond to indirect massage of specific parts of the feet.
• Nutritional supplements. Supplementation of the diet with vitamin E, calcium, magnesium, and folic acid may be helpful for people with RLS.

Some alternative methods may treat the associated condition that is suspected to cause restless legs. These include:

• Anemia or low ferritin levels. Chinese medicine will emphasize stimulation of the spleen as a means of improving blood circulation and vitamin absorption. Other treatments may include acupuncture and herbal therapies, such as ginseng (Panax ginseng ) for anemia-related fatigue.
• Late-stage pregnancy. There are few conventional therapies available to pregnant women, since most of the drugs prescribed are not recommended for use during pregnancy. Pregnant women may benefit from alternative techniques that focus on body work, including yoga, reflexology, and acupuncture.

Prognosis

RLS usually does not indicate the onset of other neurological disease. It may remain static, although two-thirds of patients get worse with time. The symptoms usually progress gradually. Treatment with Levodopa is effective in moderate to severe cases that may include significant PLMS. However, this drug produces significant side effects, and continued successful treatment may depend on carefully monitored use of combination drug therapy. The prognosis is usually best if RLS symptoms are recent and can be traced to another treatable condition that is associated with RLS. Some associated conditions are not treatable. In these cases, such as for rheumatoid arthritis, alternative therapies such as acupuncture may be helpful.

Prevention

Diet is key in preventing RLS. A preventive diet will include an adequate intake of iron and the B vitamins, especially B₁₂ and folic acid. Strict vegetarians should take vitamin supplements to obtain sufficient vitamin B₁₂. Ferrous gluconate may be easier on the digestive system than ferrous sulfate, if iron supplements are prescribed. Some medications may cause symptoms of RLS. Patients should check with their doctor about these possible side effects, especially if symptoms first occur after starting a new medication. Caffeine, alcohol, and nicotine use should be minimized or eliminated. Even a hot bath before bed has been shown to prevent symptoms for some sufferers.

Resources

PERIODICALS

Silber, Michael H. "Concise Review for Primary-Care Physicians. Restless Legs Syndrome." Mayo Clinical Proceedings 72 (March 1997): 261-264.

ORGANIZATIONS

Restless Legs Syndrome Foundation. 1904 Banbury Road, Raleigh, NC 27608-4428. (919) 781-4428. 〈http://www.rls.org〉.

KEY TERMS

Anemia— A condition that affects the size and number of red blood cells. It often results from lack of iron or certain B vitamins and may be treated with iron or vitamin supplements.

Insomnia— Trouble sleeping. People who suffer from RLS often lose sleep either because they spend time walking to relieve discomfort or because they have PLMS, which causes them to wake often during the night.

Periodic limb movements in sleep (PLMS)— Random movements of the arms or legs that occur at regular intervals of time during sleep.

restless legs syndrome (Ekbom's syndrome) (rest-lis) n. a condition in which a sense of uneasiness, restlessness, and itching, often accompanied by twitching and pain, is felt in the calves of the legs when sitting or lying down, especially in bed at night. The cause is unknown: it may be inadequate circulation, peripheral neuropathy, deficiency of iron, vitamin B₁₂, or folic acid, or a reaction to antipsychotic or antidepressant drugs.