Download Restless Legs Syndrome

Restless Legs Syndrome
Learning Objectives
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
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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-tramtrackbric-a-brac-domain 9.
Introduction
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
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
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.
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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-athe)

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.
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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
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
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
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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?
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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.
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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
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


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)
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
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
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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.
Background
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 gammaaminobutyric 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.
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
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.
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
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.
D 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
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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,
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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 Name
Levodopa with carbidopa (Sinemet) -- Can
improve sensory symptoms and PLMS in primary
RLS and in secondary RLS due to uremia. Most
patients experience benefits with doses of 25/100
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(in mild cases), with maximum dose of 50/200
mg/d. Doses >50/200 mg accompanied by marked
augmentation of symptoms in 85% of patients.
Augmentation defined as earlier onset during
evening or after assuming restful position; as
increased intensity in morning; or as extension of
symptoms to upper part of body. Adjunctive
therapy with reduction of levodopa dose or
discontinuation of levodopa and substitution with
dopamine agonist drug may help.
Adult Dose
Pediatric Dose
Contraindications
25/100-50/200 mg PO qd
Not established
Documented hypersensitivity; narrow-angle
glaucoma; MAOI use within last 14 d; melanoma
Interactions
Hydantoins, pyridoxine, phenothiazine, and
hypotensive agents may decrease effects of
levodopa; levodopa toxicity increases with
antacids and MAOIs
Pregnancy
C - Safety for use during pregnancy has not been
established.
Precautions
Certain adverse CNS effects (e.g., dyskinesias)
may occur at lower dosages and earlier in therapy
with sustained release form; caution in patients
with history of MI, arrhythmias, asthma, or
peptic ulcer disease; sudden discontinuation of
levodopa may cause worsening of Parkinson
disease; high-protein diets should be distributed
throughout day to avoid fluctuations in levodopa
absorption
Drug Name
Pergolide mesylate (Permax) -- Pergolide was
withdrawn from the US market March 29, 2007,
because of heart valve damage resulting in
cardiac valve regurgitation. It is important not to
abruptly stop pergolide. Health care professionals
should assess patients' need for dopamine agonist
(DA) therapy and consider alternative treatment.
If continued treatment with a DA is needed,
another DA should be substituted for pergolide.
For more information, see FDA MedWatch
Product Safety Alert and Medscape Alerts:
Pergolide Withdrawn From US Market.
Potent, long-acting dopamine D1 and D2 receptor
agonist that has been shown to be effective in RLS,
even in patients who are unresponsive to levodopa.
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Adult Dose
Pediatric Dose
Contraindications
0.1-0.5 mg/d PO am and hs
Not established
Documented hypersensitivity
Interactions
Dopamine antagonists such as neuroleptics,
phenothiazines, butyrophenones, thioxanthines,
or metoclopramide may diminish effectiveness;
because drug is more than 90% bound to plasma
proteins, exercise caution if coadministered with
other drugs known to affect protein binding
Pregnancy
B - Usually safe but benefits must outweigh the
risks.
Precautions
May cause valvular heart disease (yearly
echocardiograms recommended for patients on
chronic therapy); inhibits secretion of prolactin;
causes transient rise in serum concentrations of
growth hormone and decrease in serum
concentrations of luteinizing hormone; adverse
effects include nausea, hypotension,
hallucinations, and somnolence; use caution in
patients who have been treated for cardiac
dysrhythmias; may cause or exacerbate
preexisting states of confusion and hallucinations
or dyskinesia
Drug Name
Bromocriptine mesylate (Parlodel) -- Dopamine
D2 receptor agonist that has been found to be
effective in RLS. However, usually poorly
tolerated because of nausea and orthostatic
hypotension.
Other dopamine agonists such as pergolide or
pramipexole preferred.
Adult Dose
7.5 mg PO qd am and hs
Pediatric Dose
Not established
Contraindications
Documented hypersensitivity; ischemic heart
disease; peripheral vascular disorders
Interactions
Ergot alkaloids may increase toxicity;
amitriptyline, butyrophenones, imipramine,
methyldopa, phenothiazines, reserpine may
decrease effects
Pregnancy
C - Safety for use during pregnancy has not been
established.
Precautions
Caution in renal or hepatic disease
Drug Name
Pramipexole (Mirapex) -- D2 and D3 receptor
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agonist recently approved by FDA for treating
Parkinson disease; also used effectively in patients
with RLS.
Adult Dose
Pediatric Dose
Contraindications
0.125-1.0 mg PO pm or hs
Not established
Documented hypersensitivity
Interactions
Cimetidine may increase toxicity; increases
levodopa levels
Pregnancy
C - Safety for use during pregnancy has not been
established.
Precautions
Caution in renal insufficiency and pre-existing
dyskinesias; cases of rhabdomyolysis have been
reported in patients with advanced Parkinson
disease treated with pramipexole
Drug Name
Ropinirole hydrochloride (Requip) -- Dopamine
D2 receptor agonist recently approved by FDA
for treating Parkinson disease; also has been used
in patients with RLS. It is a nonergoline,
nonphenolic indolone derivative.
0.5-5.0 mg PO am or hs
Adult Dose
For treatment of moderate-to-severe primary RLS, a
dose titration recommended; doses should be titrated,
when appropriate, based upon clinical response and
tolerability; all doses are once daily 1-3 h before
bedtime (product information Requip, ropinirole
hydrochloride tablets, 2005):
0.25 mg for days 1 and 2
0.5 mg for days 3-7
1 mg for wk 2
1.5 mg for wk 3
2 mg for wk 4
2.5 mg for wk 5
3 mg for wk 6
4 mg for wk 7
Doses >4 mg qd have not been adequately studied in
patients with RLS; ropinirole has been discontinued
without a taper in clinical trials involving patients
with RLS
Pediatric Dose
Contraindications
Interactions
Not established
Documented hypersensitivity
May potentiate dopaminergic side effects of
levodopa and may cause or exacerbate pre19
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existing dyskinesia (decreasing dose of levodopa
may ameliorate this effect); estrogens may reduce
clearance by 36% (dose adjustment may be
required if estrogen therapy stopped or started
during treatment with ropinirole); potential exists
for substrates or inhibitors of CYP1A2 to alter
clearance—if therapy with potent CYP1A2
inhibitor stopped or started during ropinirole
treatment, dose adjustments may be necessary;
dopamine antagonists such as phenothiazines,
butyrophenones, thioxanthenes, and
metoclopramide may diminish effectiveness
Pregnancy
C - Safety for use during pregnancy has not been
established.
Precautions
Monitor for signs and symptoms of orthostatic
hypotension; cases of retroperitoneal fibrosis,
pulmonary infiltrates, pleural effusion, and
pleural thickening have occurred in some patients
treated with ergot-derived dopaminergic agents—
these complications do not always resolve
completely when drug discontinued; because of
possible additive sedative effects by CNS
depressants, caution when administering
ropinirole concomitantly
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 Name
Clonazepam (Klonopin) -- No controlled trials
have demonstrated that clonazepam or any other
GABAergic sedative hypnotic actually reduces
symptoms of RLS. Therapeutic benefit appears to
arise from sleep-promoting properties such that
patient continues to sleep despite disturbances
from RLS symptoms.
Adult Dose
0.25 mg PO qhs initially; increase daily dose by
0.25 mg each wk; not to exceed 2.0 mg/d
Pediatric Dose
Contraindications
Not established
Documented hypersensitivity; severe liver disease;
acute narrow-angle glaucoma
Interactions
Phenytoin and barbiturates may reduce effects;
CNS depressants increase toxicity
Pregnancy
C - Safety for use during pregnancy has not been
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established.
Precautions
Major adverse effects include daytime drowsiness
and confusion, unsteadiness leading to falls, and
aggravation of sleep apnea; caution in chronic
respiratory disease or impaired renal function;
withdrawal symptoms can result from abrupt
discontinuation of medication
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 (LevoDromoran), 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.
Drug Name
Codeine -- This and other opioids can be helpful
in decreasing symptoms of RLS as treatment of
second choice when other treatments have failed
or caused augmentation problems.
Adult Dose
15 mg PO qhs prn
Pediatric Dose
Contraindications
Not established
Documented hypersensitivity; HACE; elevated
ICP
Interactions
Tricyclic antidepressants, MAOIs, neuromuscular
blockers, CNS depressants, phenothiazines, and
narcotic analgesics increase toxicity
Pregnancy
C - Safety for use during pregnancy has not been
established.
Precautions
Use to treat cough in patients with HACE only if
absolutely necessary; may depress hypoxic
ventilatory rate and respiratory drive during
sleep
Drug Category: Anticonvulsants -- These agents are used to manage severe muscle spasms.
Drug Name
Gabapentin (Neurontin) -- Indicated for patients
whose symptoms include pain and/or neuropathy.
May be used as single treatment or with other
treatments.
Adult Dose
100-300 mg PO qhs initially; increase by 100-300
mg q3d to maximum 2400 mg/d divided tid
Pediatric Dose
Contraindications
Interactions
Not established
Documented hypersensitivity
Antacids may reduce bioavailability significantly
(administer at least 2 h following antacids); may
increase norethindrone levels significantly
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Pregnancy
C - Safety for use during pregnancy has not been
established.
Precautions
Usually well tolerated, but may cause transient or
mild effects such as somnolence, dizziness, ataxia,
and fatigue; caution in severe renal disease
Drug Category: Presynaptic alpha2-adrenergic agonists -- These agents stimulate alpha2adrenoreceptors in brain stem, activating an inhibitory neuron, which in turn results in reduced
sympathetic outflow.
Drug Name
Clonidine hydrochloride (Catapres) -- May be
effective in primary RLS and that associated with
uremia. However, has no effect on PLMS.
Adult Dose
Initial dose: 0.1 mg PO qhs; can increase daily
dose weekly by 0.1 mg; not to exceed 1 mg/d;
average effective dose is 0.5 mg/d
Pediatric Dose
Contraindications
Not established
Documented hypersensitivity
Interactions
Tricyclic antidepressants inhibit hypotensive
effects; beta-blockers may potentiate
bradycardia; tricyclic antidepressants may
enhance hypertensive response associated with
abrupt clonidine withdrawal; narcotic analgesics
increase hypotensive effects of clonidine
Pregnancy
C - Safety for use during pregnancy has not been
established.
Precautions
Common adverse effects include dry mouth,
decreased cognition, light-headedness, sleepiness,
and constipation; caution in cerebrovascular
disease, coronary insufficiency, sinus node
dysfunction, and renal impairment
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Restless Legs Syndrome: Detection and Management in Primary Care
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE WORKING GROUP ON RESTLESS LEGS SYNDROME
National Institutes of Health, Bethesda, Maryland
Restless legs syndrome (RLS) is a neurologic movement disorder that is often associated with a sleep
complaint. Patients with RLS have an irresistible urge to move their legs, which is usually due to
disagreeable sensations that are worse during periods of inactivity and often interfere with sleep. It is
estimated that between 2 and 15 percent of the population may experience symptoms of RLS. Primary
RLS likely has a genetic origin. Secondary causes of RLS include iron deficiency, neurologic lesions,
pregnancy and uremia. RLS also may occur secondarily to the use of certain medications. The
diagnosis of RLS is based primarily on the patient's history. A list of questions that may be used as a
basis to assess the likelihood of RLS is included in this article. Pharmacologic treatment of RLS
includes dopaminergic agents, opioids, benzodiazepines and anticonvulsants. The primary care
physician plays a central role in the diagnosis and management of RLS. (Am Fam Physician
2000;62:108-14.)
Restless legs syndrome (RLS) is a common, underdiagnosed and treatable condition. A neurologic
movement disorder, RLS is often associated with a sleep complaint.1 Patients with RLS may suffer an
almost irresistible urge to move the legs, usually due to disagreeable leg sensations that are worse
during inactivity and often interfere with sleep.2 RLS may be described as an agitated inability to rest
that can have a negative impact on quality of life by causing waking discomfort, chronic sleep
deprivation and stress. This article provides science-based information about RLS and its assessment
and management in the primary care setting.
Consequences of RLS
Direct adverse effects of RLS include discomfort, sleep disturbances and fatigue.3 These consequences
have a secondary impact on functioning by affecting occupational activities, social activities and family
life. Disrupted sleep and an inability to tolerate sedentary activities can lead to job loss, a compromised
ability to enjoy life and problems with relationships.
Prevalence
RLS is a common disorder. Although the exact prevalence is uncertain, limited studies have indicated
that 2 to 15 percent of the population may experience RLS symptoms.4-6 This wide range of results
may be due to differences in study methodologies.
Although the prevalence of RLS increases with age,6 it has a variable age of onset and can occur in
children.7 In patients with severe RLS, one third to two fifths had their first symptom before 20 years
of age,8 although the precise diagnosis of RLS was made much later.
Etiology
Primary RLS
RLS is a central nervous system disorder.9 It is not caused by psychiatric factors or by stress but may
contribute to or be exacerbated by these conditions. There is a high incidence of familial cases of RLS,
suggesting a genetic origin for primary RLS.8 The exact mode of inheritance is unknown.8,10
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Secondary Causes of RLS
Iron Deficiency. RLS may be associated with iron deficiency.
A patient's iron stores may be deficient without significant
anemia. Recent studies have shown that decreased iron stores
(indicated by serum ferritin levels below 50 ng per mL [50
µg per L] can exacerbate RLS symptoms.11,12 Patients with
newly diagnosed RLS or RLS patients with a recent
exacerbation of symptoms should have their serum ferritin
levels measured.
Secondary causes of restless legs
syndrome include iron deficiency,
spinal cord and peripheral nerve
lesions, pregnancy, uremia and
some medications.
Neurologic Lesions. RLS has been reported in association with spinal cord and peripheral nerve
lesions, although an exact pathologic mechanism has not been identified. RLS also may occur in
patients with vertebral disk disease.8
Pregnancy. RLS affects up to 19 percent of women during pregnancy.13 Symptoms can be severe but
usually subside within a few weeks postpartum.
Uremia. RLS occurs in up to 50 percent of patients with end-stage renal failure and may be particularly
bothersome during dialysis when the patient is confined to a resting position.14,15 Improvement in
symptoms of RLS has been seen after renal transplantation.16
Drug-Induced. Some evidence from published case reports indicates that RLS symptoms may be
induced or exacerbated by medications such as tricyclic antidepressants,17 selective serotonin reuptake
inhibitors (SSRIs),18 lithium19 and dopamine antagonists.20 Caffeine also has been implicated in the
worsening of RLS symptoms.21
Assessment and Diagnosis
The diagnosis of RLS is based primarily on the patient's history. Often, patients do not bring RLS
symptoms to the physician's attention; therefore, it can be helpful to include general sleep questions in
the review of systems (Table 1). When RLS is suspected, more specific questions should be asked
(Table 2).
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TABLE 1
Sleep/Wake Profile
TABLE 2
Questions That May Aid in the Diagnosis
of Restless Legs Syndrome (RLS)
How has the patient been sleeping recently?
(Ask the patient and bed partner.)
Suggested questions following a sleep
complaint
When did the problem begin? (To
determine acute vs. chronic
insomnia)
Does the patient have a psychiatric
or medical condition that may cause
insomnia?
Is the sleep environment conducive
to sleep? (Relates to noise,
interruptions, temperature, light)
Does the patient report "creeping,
crawling or uncomfortable,
difficult-to-describe feelings" in the
legs or arms that are relieved by
moving them? (Relates to restless
legs syndrome)
Does the bed partner report that the
patient's legs or arms jerk during
sleep? (Relates to periodic limb
movements of sleep)
Does the patient snore loudly, gasp,
choke or stop breathing during
sleep? (Relates to obstructive sleep
apnea)
Is the patient a shift worker? What
are the work hours? (Relates to
circadian sleep disorders/sleep
deprivation)
What times does the patient go to
bed and get up on weekdays and
weekends? (Relates to poor sleep
hygiene and sleep deprivation)
Does the patient use caffeine,
tobacco or alcohol? Does the patient
take over-the-counter or
prescription medications, such as
Does the patient report "creeping, crawling or
uncomfortable, difficult-to-describe feelings"
in the legs or arms that are relieved by moving
or rubbing them?
Is there a correlation between RLS symptoms
and time of day? Do the symptoms worsen
with rest or inactivity?
Do sensations interfere with sleep onset or
returning to sleep?
What daytime consequences does the patient
report (e.g., fatigue, sleepiness, confusion,
lack of attention)?
Does the bed partner report that the patient's
legs or arms jerk during sleep? (Relates to
periodic limb movements of sleep.)
Does the patient have secondary causes of
RLS, such as low iron stores, diabetes
mellitus, kidney disease or pregnancy?
Are neurologic symptoms or diagnoses
present?
Is there a relationship between symptoms and
medications, such as tricyclic antidepressants
or selective serotonin reuptake inhibitors?
Was the onset of symptoms correlated with a
change in medication?
Do family members report similar symptoms?
Have any family members been diagnosed
with RLS?
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stimulating antidepressants,
steroids, decongestants or betablockers? (Relates to substanceinduced insomnia)
Signs of sleepiness
What daytime consequences, such
as fatigue, sleepiness, confusion or
difficulty concentrating, does the
patient report?
Does the patient report dozing off or
have difficulty staying awake
during routine tasks, especially
while driving?
Symptoms are described by patients in many ways, with descriptions ranging from "mild" to
"intolerable" (Table 3).22 Although most patients experience the sensations in their legs, the sensations
also may occur in the arms or elsewhere. RLS symptoms are generally worse in the evening and night
and less severe in the morning. RLS must be distinguished from sleep-related leg conditions such as
nocturnal leg cramps.
Clinical Criteria
The criteria for the diagnosis of RLS are based on those developed by the International Restless Legs
Syndrome Study Group (Table 4).3
The involuntary, repetitive, periodic, jerking movements refer to periodic limb movements (PLM), also
known as PLMS (periodic limb movements of sleep)23 or nocturnal myoclonus,24 which may be
associated with RLS. PLMS are stereotyped, repetitive flexions of the limbs (legs alone or legs more
than arms) usually occurring during sleep. They occur periodically on an average of every 20 seconds.
The most common movement is a dorsiflexion of the ankles and flexion of the knees or hips.
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TABLE 3
Terms Used to Describe
Sensations of Restless Legs
Syndrome

Creeping

Crawling

Itching

Burning

Searing

Tugging

Indescribable

Pulling

Drawing

Aching

Like water flowing

Like worms or bugs
crawling under the skin

Like an electric current

Restless

Painful
TABLE 4
Clinical Criteria and Associated Features of Restless
Legs Syndrome (RLS)
Minimal criteria
A compelling urge to move the limbs, usually
associated with paresthesias/dysesthesias
Motor restlessness as seen in activities such as
floor pacing, tossing and turning in bed and
rubbing the legs
Symptoms that are worse or exclusively
present at rest (i.e., lying, sitting) with variable
and temporary relief by activity
Symptoms that are worse in the evening and at
night
Associated features
Sleep disturbance and daytime fatigue
Normal neurologic examination (in patients
with primary RLS)
Involuntary, repetitive, periodic, jerking limb
movements, either in sleep or while awake and
at rest
Information from Waters AS. Toward a better
definition of the restless leg syndrome. Mov Disord
1995; 10:634-42.
Physical Examination
The physical examination is usually normal in patients with RLS and is performed to identify
secondary causes and to rule out other disorders. The following are areas of particular importance:

A neurologic examination with emphasis on spinal cord and peripheral nerve function.

A vascular examination to rule out vascular disorders.
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Laboratory Tests
The following laboratory tests can identify possible secondary causes of RLS:

Serum ferritin level of <50 ng per mL (<50 µg per L).

Serum chemistry to rule out uremia and diabetes.
A sleep study (polysomnography) is not routinely indicated in the work-up of RLS,25 because RLS is
diagnosed on the basis of history and clinical findings.
Differential Diagnosis
Differential diagnoses may include the following:
Periodic limb movements of sleep
(PLMS), also known as nocturnal
myoclonus, may be associated with
restless legs syndrome.

Nocturnal leg cramps are typically painful,
palpable, involuntary muscle contractions, often
focal, with a sudden onset; they are usually
unilateral.26

Akathisia is excessive movement, without specific
sensory complaints; it often does not correlate with rest or time of day and usually results
from medication such as neuroleptics or other dopamine blocking agents.27

Peripheral neuropathy can cause leg symptoms that are different from RLS; they are
usually not associated with motor restlessness or helped by movement, and do not worsen
in the evening or nighttime. Sensory complaints are typically numbness, tingling or pain.
Small fiber sensory neuropathies, as seen in diabetes, are often confused with RLS.
Patients with neuropathies may have neuropathic and RLS symptoms.

Vascular disease, such as deep venous thrombosis.
Treatment
The severity of RLS varies from patient to patient. Although pharmacologic treatment is helpful for
many patients with RLS, those with mild symptoms may not need medications. Because no single
medication or combination of medications will work predictably for all patients, treatment must be
individualized. Physicians and patients may need to work together over time to find the medication or
combination of medications and the dosages that will work best. Table 5 lists appropriate
pharmacologic agents and their advantages and disadvantages. Therapy for RLS constitutes an "offlabel" use of these pharmacologic agents.
The selection of pharmacologic agents is influenced by a
number of factors, including:

Age of the patient. For example, benzodiazepines
may cause cognitive impairment in the elderly.

Severity of symptoms. Some patients with mild
symptoms may elect not to use medications; others
may benefit from levodopa or a dopamine agonist.
Patients with severe symptoms may require a
strong opioid.
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Although many nonpharmacologic
treatments have been reported by
patients to be helpful, there is no
scientific evidence to show that they
are useful in the treatment of
restless legs syndrome.

Frequency or regularity of symptoms. Patients with infrequent symptoms may benefit
from a single effective dose of a medication such as an opioid or levodopa, taken as
needed.

Presence of pregnancy or comorbid illnesses. No controlled clinical trials have assessed
the safety and efficacy of medications for RLS or PLMS during pregnancy.28

Renal failure. In patients with renal failure, pharmacologic agents are generally safe, but
less frequent doses may be needed if drugs are renally excreted. In addition, for dialysis
patients, some medications, such as gabapentin, are dialyzable and others, such as
propoxyphene, are not.28
Dopaminergic agents are the first-line drugs for most RLS patients. It is important for primary care
physicians to educate patients about the nature and actions of the drugs that are prescribed, including
side effects and the uncertainty of long-term effects. For example, when dopaminergic agents are
prescribed, patients should be informed that although these medications are usually used to treat
Parkinson's disease, they also help to relieve RLS symptoms.
RLS medications have received approval from the U.S. Food and Drug Administration for other uses.
In many cases, the therapeutic dosages to treat RLS are much lower than those required for the original
uses. The starting dose is usually very low and is gradually increased until effective. In addition to the
medications listed in Table 5, agents such as vitamin E, folate and magnesium may be useful. Although
many nonpharmacologic treatments have been reported by patients to be helpful, there is no scientific
evidence that they are useful in the treatment of RLS.
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TABLE 5
Pharmacologic Treatment for Patients with Restless Legs Syndrome (RLS)
Agent
Advantages
Disadvantages
Dopamine
precursor
combinations
such as
carbidopalevodopa
Can be used on a "one-time"
basis or as circumstances may
require. Useful for persons with
intermittent RLS because
dopamine agonists take longer to
have an effect.
As many as 80 percent of
patients who take carbidopalevodopa may develop
augmentation.* Therapeutic
effect may be reduced if taken
with high-protein food. Can
cause insomnia, sleepiness and
gastrointestinal problems.
Dopamine
agonists such
as pergolide,
pramipexole,
ropinirole
Useful in moderate to severe
RLS. Recent reports indicate
high efficacy of dopamine
agonists, but the role of their
long-term use is unknown.29
Can cause severe sleepiness,30
which may limit its use during
daytime.
Agonists can cause nausea. To
avoid this, slow dosage increase
is important, especially for
pergolide.
Opioids such as
codeine,
hydrocodone,
oxycodone,
propoxyphene,
tramadol
Can be used on an intermittent
basis. Can also be used
successfully for daily therapy.
Can cause constipation, urinary
retention, sleepiness or cognitive
changes. Tolerance and
dependence possible with higher
doses of stronger agents.
Benzodiazepines
such as
clonazepam,
temazepam
Helpful in some patients when
other medications are not
tolerated and may help improve
sleep.
Can cause daytime sleepiness
and cognitive impairment,
particularly in the elderly.
Anticonvulsants
such as
Can be considered when
dopamine agonists have failed.
Vary, depending on agent.
Gastrointestinal disturbance
Dopaminergic
agents
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carbamazepine,
gabapentin
May be useful in those with
coexisting peripheral
neuropathy and/or when RLS
discomfort is described as pain.
such as nausea, sedation,
dizziness.
Iron (ferrous
sulfate)
Use in patients with serum
ferritin levels <50 ng per mL
(<50 µg per L).
Ideal means of administration
has not been established. Oral
treatment may take several
months to be effective and may
be poorly tolerated.
Clonidine
May be useful in hypertensive
patients.
Has the potential to cause
hypotension, dermatitis and
sleepiness.
*--Augmentation is a worsening of RLS symptoms in the course of therapy. Symptoms may
be more severe and start earlier in the day (e.g., afternoon rather than evening) than before
treatment began and may spread to different parts of the body. Augmentation, which can
start soon after therapy is begun or not until months or years later, has also been reported
with dopamine agonists and may occur with other medications.
When to Consider Referral
Most cases of RLS can be effectively managed by primary care physicians. If the primary care
physician encounters difficulty managing RLS symptoms in a patient, referral to or consultation with a
movement disorders specialist or a sleep specialist may be helpful.
Conclusion
The primary care physician plays a central role in the identification and treatment of RLS.
Incorporating sleep- and RLS-related questions into the general review of systems can be helpful in
diagnosing RLS. An important aspect of treatment is listening to and supporting patients and carefully
evaluating their symptoms. Most patients with RLS can obtain symptomatic relief with commonly
prescribed medications and support.
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