When patients describe sensations in their legs like burning, electricity, itching, things crawling under the skin, soda bubbling in the veins, or throbbing, restless legs syndrome (RLS) should come to mind. This sensorimotor disorder is characterized primarily by an urge to move limbs (focal akathisia) because of unpleasant sensations; only movement relieves symptoms.¹ Up to one third of patients with RLS experience pain. While legs are mostly affected, arms may be involved; axial muscles are rarely affected. Symptoms are quiescegenic (occurring only during resting) and usually bilateral.^2,3

RLS was first described in 1945, but practitioners have only recognized it as a clinically significant and common disorder in the past 10 years. RLS is frequently associated with sleep difficulties and nocturnal awakenings, leading to daytime fatigue and inability to concentrate.³ Because sleep deprivation worsens RLS symptoms, a vicious cycle ensues.⁴ Depression and anxiety are common and appear to be consequences of the disorder. One study, for example, identified depression or other affective diagnoses in 43.7% of RLS males and 46.1% of RLS females.⁵ Increased prevalence of hypertension and heart disease accompanies RLS, and RLS patients tend to have poorer overall health.³ Among children, RLS is associated with attention-deficit/hyperactivity disorders.⁶

Adult RLS prevalence is estimated at 7% to 10%, with increased frequency in females. Onset usually occurs between ages 35 and 70, with symptoms worsening with age. Peripheral neuropathy and radiculopathy accompany late onset.⁷ Between 50% and 70% of victims have a first-degree relative with RLS.^2,3 Environmental contributors include smoking, caffeine, and lack of exercise. Some, but not all studies, report an association with alcohol intake and body mass index.^2,3

Etiology

RLS etiology is either primary or secondary. Primary RLS, which is generally idiopathic, involves the central nervous system. The dopaminergic pathways' role is well documented, demonstrated by RLS symptom resolution with dopaminergic agonists and symptom exacerbation with dopamine antagonists.²

Iron deficiency is common, and an inverse relationship exists between iron stores and RLS symptom severity.¹ Both dopamine and iron vary with the circadian cycle, both reaching nadirs when maximum RLS symptoms occur. Because dopamine synthesis requires iron, serum ferritin levels and iron percent saturation assessment should be routine in RLS.⁷

RLS may be secondary to other causes, and clinicians should approach RLS as a potential marker for underlying comorbidities. Secondary causes include iron deficiency (with or without anemia), renal failure, diabetes, rheumatoid arthritis, fibromyalgia, vitamin deficiency (folate, B₁₂), hypothyroidism, and pregnancy.³ Up to 23% of pregnant women, for example, report RLS.² Often, treatment of the underlying condition resolves RLS.

Diagnostic Criteria

Four essential criteria are required for diagnosis. In their absence, a probable RLS diagnosis is made based on supporting clinical features (Table 1). In the cognitively impaired elderly, behavioral manifestations guide diagnosis (Table 2).

RLS assessment should rule out secondary causes and mimicking conditions, especially nighttime cramps and periodic limb movement (PLM) disorders. The latter is especially important. While PLM is common in RLS patients, an important distinction exists: PLM is involuntary, whereas RLS patients move limbs voluntarily to relieve sensations. Other conditions with leg discomfort include arterial and venous insufficiencies, myopathies, small fiber neuropathies, arthritis, neuroleptic-induced akathisia, and positional discomfort or ischemia.³ Table 3 highlights RLS's differentiating characteristics.

Treatment

Symptom frequency (intermittent RLS with occurrence 2-3 times weekly vs daily RLS) and severity (mild, moderate, refractory) dictate treatment. While treatment for secondary RLS focuses on underlying etiology, treatment for RLS relief is the same for all patients. Nonpharmacologic interventions include:

• Eliminating or reducing agents known to precipitate RLS (dopamine-blocking agents, antidepressants, antihistamines, caffeine, alcohol, and nicotine)
• Improving sleep hygiene (eg, regular sleep and wake times, warm baths before bedtime)³

Levodopa is effective in the short term, but its therapeutic effects are confined to the first 4 to 6 hours in bed.¹ Studies reveal that up to 82% of patients experience symptom augmentation with daily levodopa use and/or doses greater than 200 mg daily.⁸ Augmentation is an iatrogenic worsening of RLS with decreased responsiveness to the medication, accompanied by earlier daily symptom onset and symptom progression to previously uninvolved areas. Augmentation resolves with medication cessation.⁸

Because of augmentation, dopamine agonists are preferred as first-line agents, but augmentation still occurs in 10% to 35% of treated patients.³ Dopaminergic agents include ergot derivatives (pergolide) and non-ergot dopamine agonists (pramipexole, ropinirole).¹ Ropinirole is the only FDA-approved agent for RLS. Because ergot-related dopamine agonists have been linked to fibrotic and cardiac valvular problems, nonergoline agonists are preferred.^9,10 Dopamine agonists should be titrated from minimal dose until symptom relief is achieved. Severe daytime sleepiness has been reported in Parkinson's disease patients on dopamine agonists.¹

Second-line agents include the use of opioids (oxycodone, propoxyphene, codeine) for relief when first-line agents are ineffective. Benzodiazepines may be used for their sedative effects for sleep deprivation. Oral iron is recommended for patients with serum ferritin levels <45 to 50 μg/L.²

Consensus is lacking for refractory RLS treatment, but consideration may be given to changing dopamine agonists, switching to an opioid or anticonvulsant, and adding a second medication, possibly with a reduced agonist dose (Table 4).^1,3

Dr. Zanni is a psychologist and health-systems consultant based in Alexandria,Va.

References

1. Hening WA, Allen RP, Earley CJ, Picchietti DL, Silber MH. Restless Legs Syndrome Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 2004;27:560-583.

2. Chahine LM, Chemali ZN. Restless legs syndrome: a review. CNS Spectr. 2006;11(7):511-520.

3. Hening WA. The diagnosis and management of restless legs syndrome. Available at: www.medscape.com/viewprogram/5101. Accessed October 24, 2006.

4. Zarcone VP Jr. Sleep hygiene. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 3rd ed. Philadelphia, Pa: WB Saunders; 2000: 657-661.

5. Banno K, Delaive K, Walld R, Kryger MH. Restless legs syndrome in 218 patients: associated disorders. Sleep Med. 2000;1:221-229.

6. Picchietti DL, England SJ, Walters AS, Willis K, Verrico T. Periodic limb movement disorder and restless legs syndrome in children with attention-deficit hyperactivity disorder. J Child Neurol. 1998;13:588-594.

7. Allen RP, Picchietti D, Hening WA, et al. 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. 2003;4:101-119.

8. Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep. 1996;19:205-213.

9. Shaunak S, Wilkins A, Pilling JB, Dick DJ. Pericardial, retroperitoneal, and pleural fibrosis induced by pergolide. J Neurol Neurosurg Psychiatry. 1999;66:79-81.

10. Horvath J, Fross RD, Kleiner-Fisman G, et al. Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists. Mov Disord. 2004;19:656-662.