Restless Legs Syndrome

A Practical Guide to Diagnosis and Management

Introduction
Restless legs syndrome (RLS), a sensorimotor disorder with a profound impact on sleep, has been called the "most common disorder that you've never heard of." Although prevalence studies indicate that up to 12% of people have RLS, many physicians lack awareness of the disorder, impeding patients' ability to obtain relief from the dysesthesias and compelling urge to move that characterize RLS. As the primary precipitating event leading patients to seek treatment, the negative impact of RLS on sleep is at least partially responsible for the reduced quality of life in patients with RLS.

Features of RLS

Essential Diagnostic Criteria

An urge to move the legs is present, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs. Sometimes the urge to move is present without the uncomfortable sensations, and sometimes the arms or other body parts are involved in addition to the legs.

The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting.

The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues.

The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur in the evening or night. When symptoms are very severe, the worsening at night may not be noticeable but must have been previously present.

Modified from Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. Mar 2003;4(2):101-119.

Primary And Secondary RLS
The onset of symptoms in primary RLS is more insidious and occurs at an earlier age (before 40 years), as compared with secondary RLS; patients with primary RLS are more likely to have affected family members than are people in the general population or even those patients with secondary forms of RLS. Secondary RLS occurs in relationship to other conditions, such as pregnancy, end-stage renal disease, and iron deficiency, or with exposure to certain medications.

Pathophysiology
The pathophysiology of RLS is not known; however, multiple etiologies likely have been proposed.

• Major susceptibility loci have been identified on three chromosomes, although no evidence has been found of candidate genes.
• Almost universal response to treatment with dopaminergic agents supports a dopaminergic dysfunction as a causal factor of RLS.
• An inverse relationship has been identified between symptom severity and serum ferritin levels (< 40-50 ng/dL), and a decrease in ferritin levels and an increase in transferrin levels have been found in the cerebrospinal fluid of patients with RLS, as compared with that of controls.

Prevalence
Although epidemiologic studies show a wide variation in the prevalence of RLS, the disorder appears to affect approximately 7% to 12% of people of European extraction, with lower rates in people of African and Asian descent.

Diagnosis
The supportive clinical features of RLS may assist the physician in establishing a diagnosis in cases that are ambiguous.

Supportive Clinical Features of Restless Legs Syndrome

• More than 50% of patients with primary RLS have affected family members.

• A positive response to dopaminergic therapy is almost universal.

• Up to 85% of people with RLS have periodic limb movements during wakefulness or sleep.

The Most Commonly Encountered Conditions in the Differential Diagnosis of RLS
Akathisia	Polyneuropathy
Intermittent claudication	Positional discomfort
Nocturnal leg cramps	Radiculopathy
Pathophysiologic insomnia	Tardive dyskinesia

Rating Scales
The International RLS Study Group and the Johns Hopkins Rating Scale may be used to quantify the severity of RLS symptoms for research purposes and to measure treatment efficacy in clinical settings.

Treatment
The goal of treatment is to minimize associated symptoms and increase normal functioning, thereby improving overall quality of life. Based on a review of the medical literature and expert opinion, the Medical Advisory Board of the Restless Legs Syndrome Foundation developed "An algorithm for the management of restless legs syndrome," which is available in PDF format from the web site of the Mayo Clinic Proceedings (http://www.mayoclinicproceedings.com/pdf/7907/7907Crc.pdf).

Pharmacologic Therapy
The clearly established therapies for RLS are pharmacologic; currently the only drug approved by the U. S. Food and Drug Administration with labeling for RLS is ropinirole (Requip®).

Key Points to Achieving Optimal Pharmacologic Treatment of RLS

• Treatment of comorbid conditions may alter the pharmacologic treatment of RLS.
• Drugs should be initiated at the lowest possible dosage and gradually upwardly titrated.
• Drugs are often given at lower doses in RLS than in the treatment of the condition for which the drug is indicated.
• Intractable RLS may require the use of more than one drug.
• Effective long-term therapy may be difficult; when one drug loses its effectiveness, another drug in the same or a different class may prove to be effective.

Dopaminergic Agents*
*Dopaminergic drugs were developed and have been approved for the treatment of Parkinson's disease. Their safety and efficacy have been established in this population.

Dopamine-Receptor Agonists
Dopaminergic-receptor agonists are first-line therapy in the treatment of moderate to severe RLS and are effective in treating mild or intermittent RLS that is not responsive to nonpharmacologic intervention. The medications studied most thoroughly for use in RLS include the nonergot derivatives pramipexole dihydrochloride (Mirapex®) and ropinirole hydrochloride (Requip®). Cabergoline, an ergot derivative is used in Europe, but it is only packaged for the treatment of hyperprolactinemia in the United States. Recent reports of cardiac valvulopathy in patients taking ergot-derived dopamine agonists may limit the use of these drugs.

Dopaminergic Agents
Drug	Typical starting dose, mg	Usual therapeutic range, mg	Half-life, h	Side effects
Dopamine receptor agonists
Nonergot dopamine receptor agonists				Mild N/V; sedation; orthostatic hypotension;
Pramipexole	0.125	0.25-1.0	8-12
Ropinirole	0.25	0.5-8.0	6
Dopamine precursor				Augmentation; N/V; headache
Carbidopa-levodopa	12.5/50	12.5/50-75/300	1.5-2.0
Carbidopa-levodopa CR	25/100	25/100-100/400	3-8

N/V refers to nausea and vomiting; OH, orthostatic hypotension; CR, continuous release.

Dopamine Precursor
Levodopa combined with a decarboxylase inhibitor (typically, carbidopa in the United States) is effective in relieving the sensory and motor symptoms of RLS. However, because of its short half-life and the potential for augmentation to occur at higher doses (in up to 80% of patients), the use of levodopa is typically reserved for those patients who have intermittent or very occasional symptoms of RLS that require treatment.

Patients should be cautioned that if augmentation occurs, they should not increase their dosage of a dopaminergic medication. They should return to the prescribing physician for consultation. The treatment of augmentation may involve adjusting the timing or the dose of the medication or switching to another agent.

Key Features of Augmentation
• Temporal relationship exists between
↑ daily medication	↑ symptom intensity
↓ daily medication	↓ symptom intensity
• Sensations spread to previously uninvolved parts of the body.
• The duration of treatment effect is shorter than with initial therapeutic response.
• Symptoms of RLS occur at least two hours earlier than the time they occurred before the initiation of drug therapy.
• The time from onset of quiescence to onset of symptoms is typically shorter.
• Periodic limb movements while awake either occur for the first time or are worse than with initial therapeutic response or before treatment was instituted.

Benzodiazepines
The use of benzodiazepines may improve sleep and reduce arousals due to periodic limb movements of sleep, may be less effective in eliminating motor and sensory abnormalities, and are usually administered shortly before bedtime. They are used most often for mild or intermittent RLS and may be combined with dopaminergic agents in the management of severe RLS symptoms.

Drug	Usual therapeutic range, mg/day	Half-life, h
Clonazepam	0.5-2.0	18-40
Temazepam	7.5-30.0	1.5-5.5
Diazepam	5-15	30-60
Triazolam	0.125-0.5	8-15

Opioids
In clinical studies, with small numbers of patients, the use of opioids has been shown to alleviate paresthesias or dysesthesias, motor restlessness, and associated sleep disturbances. The use of opioids is typically reserved for patients with severe unrelenting symptoms of RLS.

Anticonvulsants
Of the anticonvulsant agents, carbamazepine and gabapentin have been used most often in the treatment of RLS; gabapentin is particularly useful for patients who describe their symptoms as painful.

Summary
With an increased awareness of this commonly occurring yet uncommonly diagnosed condition—and an understanding of the effective treatments—physicians can easily recognize RLS and improve the quality of life of the millions of people affected by RLS.