Introduction

Restless legs syndrome (RLS), also called Willis-Ekbom disease (WED), is a common sleep-related movement disorder associated with an unpleasant or uncomfortable urge to move the legs that occurs during periods of inactivity, particularly in the evenings, and is transiently relieved by movement. Many patients with RLS have characteristic limb movements during sleep, called periodic limb movements of sleep (PLMS), of which they may or may not be aware.  Between 5-15% of adults may experience RLS symptoms. 

The precise mechanisms underlying RLS are not completely understood.  The disorder is likely associated with multiple factors including reducing iron stores in the brain, alterations in the transmission of dopamine in the brain, and peripheral nerve dysfunction.  Many individuals with RLS symptoms have a family history of RLS and genetics are suspected to play an important role in some cases.   Other systemic factors that increase the risk of RLS include iron deficiency, kidney failure, neuropathy, spinal cord pathology, pregnancy, multiple sclerosis, and possibly Parkinson’s disease.

Symptoms

The essential symptom of RLS is an unpleasant or uncomfortable urge to move the legs (less frequently the arms).  The symptoms are most noticeable during sedentary periods and are most disruptive in the evenings.  The sensations are felt deep within the legs between the knee and the ankle.  The sensations are transiently relieved by movement including stretching and walking.  It is challenging for patients with RLS to describe their symptoms but they are frequently described as: a need to move, restlessness, tingling, electric shock, tension, cramp, pulling, soreness, or spasm. 

Several medications may cause or exacerbate RLS symptoms including:

• Antihistamines (diphenhydramine, hydroxyzine, chlorpheniramine)
• Dopamine antagonists (prochlorperazine, chlorpromazine, metoclopramide)
• Antidepressants (mirtazapine, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors)

Diagnosis

RLS is a clinical diagnosis that is made based on a comprehensive history and physical exam.  It is suspected in patients who complain of an urge to move the legs when lying in bed or sitting down in the evening.  Diagnostic criteria published by the International Restless Legs Syndrome Group include all the key clinical features of the disorder and all 5 of the following features are required for the diagnosis:

• An urge to move the legs, 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 severe, the worsening at night may not be noticeable but must have been previously present.
• Symptoms are not solely accounted for by another medical or behavioral condition, such as leg cramps or habitual foot tapping.

Blood work to evaluate iron stores (serum ferritin) can be helpful.  Occasionally, symptoms of RLS cannot be distinguished from those of a neuropathy by history alone or there are risk factors for neuropathy with signs of a peripheral neuropathy on physical examination.  In these cases, an EMG (electromyogram) with nerve conduction studies is useful to determine whether further evaluation for a peripheral neuropathy is necessary.  A polysomnogram (PSG) may also be considered if periodic limb movements in sleep are suspected in addition to RLS.

Treatment

RLS is a treatable disorder and responds well to medication therapy.  The selection of therapy depends on a several factors, including disease severity, age, comorbidities (pain, depression, anxiety, history of impulse control disorders), drug side effects, and patient preferences.  Individuals with frequent or disruptive symptoms may consider one of the following approaches:

1. Iron replacement with oral or intravenous iron can be helpful in individuals with a serum ferritin level less than 75 mcg/L.  Oral supplementation with 325 mg of ferrous sulfate twice daily is recommended with 100-200 mg of vitamin C to optimize absorption.  Iron should not be taken at the same time as calcium supplements or significant amounts of dairy products.
2. Behavioral/complementary strategies including reduced caffeine and alcohol intake, moderate regular exercise, medication modification, yoga, acupuncture, and massage.
3. Relaxis, a prescription device that delivers vibratory stimulation to legs, is available though there are no compelling studies to support its benefit.
4. Medications (side effects include in parentheses):
   • Dopamine agonists:
     • Pramipexole and ropinorole (nausea, lightheadedness, and fatigue; these usually resolve within 10 to 14 day, nasal stuffiness, constipation, insomnia, leg edema, daytime sleepiness, impulse control disorders, augmentation or worsening of RLS symptom severity)
     • Rotigotine patch (Neupro) (skin rash, nausea, lightheadedness, fatigue, impulse control, augmentation)
   • Alpha-2-delta calcium channel ligands:
     • Gabapentin (dizziness, sleepiness, suicidal thoughts)
     • Gabapentin enacarbil (Horizant) (sleepiness, dizziness, weight gain)
     • Pregabalin (sleepiness, dizziness, swelling in the legs, weight gain)

Useful links:

Restless Legs Syndrome Foundation