Restless Legs Syndrome

by Zhu Zhu, MD, PhD; Saniya Pervin, MBBS; and Daniel O. Lee, MD, FAAN, FAASM

Restless legs syndrome (RLS) is a common sensorimotor neurological disorder characterized by an irresistible urge to move the limbs. The uncomfortable feelings are typically described as “creeping, tingling, pulling, crawling or painful” sensations deep inside the limbs. Of note, symptoms can involve other parts of the body as well, particularly among those with a longer course of the disease.¹ Other features of RLS include worsening of symptoms at night or with inactivity and development of complete or partial relief with movement.^2,3

Impact and Burden of RLS

The prevalence of moderate to severe RLS symptoms, occurring at least twice a week, is about 1.5% to 2.7%.^4,5 The symptoms of RLS often result in reduced quality of life and cause significant distress and impairment in social, occupational, educational or other important areas of daily function by the sheer impact on sleep, energy/vitality, cognition, or mood. For many patients, RLS can lead to depression and even increased risk of suicide.^6,7 In one case control study, the odds ratio of having a lifetime suicidal ideation or behavior was much higher in those individuals with RLS even after adjusting for underlying depression and other confounders.⁶

Diagnosis

Diagnosis of RLS is based on key clinical features in addition to differentiation from other similar conditions, and specification of clinical course and clinical significance of RLS according to the 2012 revised diagnostic criteria:²

1. An urge to move the legs often, but not always, accompanied by or felt to be caused by an uncomfortable and unpleasant sensations in the legs.
2. The urge to move or any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting.
3. The urge is partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues.
4. The urge often occurs or are worse in the evening or at night than during the daytime.
5. The occurrence of the above features cannot be solely accounted for as symptoms primary to another medical or a behavioral condition (e.g., myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping).

Specifiers for Clinical Course of RLS

1. Chronic-persistent RLS Symptoms defined by occurring at least twice a week on average for the past year when not treated.
2. Intermittent RLS Symptoms occur less than twice a week on average for the past year when not treated.

Association with Cardio-cerebral Vascular Diseases

Recent studies suggest the association of RLS and cardio-cerebral vascular diseases. A Canadian study, enrolled 30,097 participants, found that higher carotid intima-media thickness in patients with RLS, suggesting RLS is associated with atherosclerosis.³ Factors correlated with higher atherosclerotic risk include a chronic diagnosis of RLS over 3 years duration with frequent symptoms.⁸ Underlying mechanisms were thought to be due to a nocturnal increase in cardiac sympathetic surge and blood pressure. However, other studies showed conflicting results. A cross-sectional study among 22,786 participants of the US Physicians Health Studies I and II used age- and multivariable-adjusted logistic regression models to evaluate the association of cardiovascular disease, vascular risk factors, and RLS. The study reported an increase in the prevalence of stroke but decreased prevalence of myocardial infarction in patients with RLS.⁹ Women’s Health Study of 30,262 participants with similar design; however, demonstrated no association between prevalent cardiovascular disease (including major cardiovascular disease, myocardial infarction, and stroke) and RLS prevalence.¹⁰ The complex association of cardiovascular disease and RLS was thought to be confounded by the presence of comorbid conditions such as hypertension and other vascular risk factors such as obstructive sleep apnea, etc.¹¹ A retrospective cohort study within Kaiser Permanente Northern California (KPNC), including 7,621 primary RLS and 4,507 secondary RLS patients, found primary Restless Legs Syndrome (RLS) was associated with a slight increased risk of hypertension but not associated with new-onset cardiovascular disease or coronary artery disease. In contrast, secondary RLS was associated with an increased risk of CVD, CAD, and hypertension.¹² In summary, there isn’t enough data to confirm this complex association between cardiovascular disease and RLS. Further clinical trials that investigate the beneficial effect of RLS treatment on progression of cardiovascular disease may provide further insight for this complex relationship.

Treatments

Treatment discussion for RLS should include the consideration of non-pharmacological approach and pharmacotherapy, and this must be individualized and closely monitored by the provider due to variability with periods of exacerbation and remission.

Non-pharmacological Management

Nonpharmacologic therapies may obviate the need for medications in mild cases of RLS and may even allow a reduction in dosage in patients with moderate or severe disease in some cases. Determine the patient’s iron status and replace iron as indicated. Consider the role of current medications in causing or exacerbating the underlying restless legs such as antidepressants, neuroleptic agents, dopamine-blocking antiemetics such as metoclopramide, or sedating antihistamines (including those found in nonprescription medications) may be contributing and whether discontinuation is possible without causing the patient harm.¹³ Recommend mental alerting activities, such as video games or crossword puzzles, which have been reported to be beneficial. Consider a trial of abstinence from caffeine and alcohol. Consider the possibility of other concomitant sleep disorders, most importantly obstructive sleep apnea.

Concurrent sleep disorders, sleep fragmentation, or insufficient sleep may exacerbate RLS. Clinicians should especially inquire about symptoms suggestive of obstructive sleep apnea and pursue appropriate testing as indicated; in some cases, sleep apnea treatment results in improvements in RLS, eliminating the need for medications. Patients with RLS may have other causes of insomnia, including underlying anxiety and depression, and these may need further psychological intervention.

A randomized controlled trial showed that aerobic and resistance exercise significantly reduced RLS symptom severity. The exercise and control groups did not differ significantly in either the total RLS severity total score or the 8-point rating at baseline. However, severity scores on the RLS Rating Scale for the control group decreased less than 8% over 6 weeks, whereas the exercise group severity scores dropped by 39% during the same time period. Scores for both groups remained relatively stable from six to twelve weeks, with symptom improvement from baseline only evident for the exercise group.¹⁴

Pooled data from two randomized, double-blind, prospective clinical trials were analyzed to determine if vibratory stimulation can safely treat patients with moderately severe Restless Legs Syndrome as compared to shams device. Patients that were randomized to the vibrating pads had significantly better outcomes than did patients randomized to the sham pads, after adjustment for multiplicity, on examination of IRLS scale and MOS-II scale, which is a validated medical outcome study scale (P <=0.03).¹⁵

Evidence suggests that RLS is associated with low intracerebral iron stores due to as yet unclear defects in iron homeostatic mechanisms and downregulation of striatal dopamine receptors.

An evidence-based consensus paper¹⁶ recommended that all RLS patients with serum ferritin concentration of 75 mg/L or less and transferrin saturation below 45% should receive a trial of oral iron therapy.

A cause for iron deficiency should also be pursued in those with serum iron levels below the lower limit of normal. Iron should not be prescribed empirically because it may result in iron overload, especially in patients with previously unsuspected hemochromatosis. Follow-up ferritin determinations are needed, initially after 3 months and then every 3 to 6 months until the serum ferritin level is greater than 100 mg/L. Intravenous administration of iron should be first-line iron therapy if moderate to severe chronic persistent or refractory RLS is present.

Intravenous iron therapy is also recommended if oral iron cannot be adequately absorbed because of disorders of the gastrointestinal system or bariatric surgery or if oral iron is not tolerated, and RLS symptoms do not improve despite an adequate (3-month) trial of oral intake of iron.

The majority of the class I well-designed clinical trials for intravenous iron therapy in RLS used ferric carboxymaltose, the clinical response to treatment is rarely immediate and may be delayed for 4 to 6 weeks or longer. Other intravenous iron preparations that can be considered are low-molecular-weight iron dextran and ferumoxytol, both as single infusions. Although low-molecular-weight iron dextran has a lower risk of life-threatening allergic reactions (estimated at 1 per 300,000 uses) compared with the older high-molecular weight iron dextran, a test dose (25 mg) should be given first. Pretreatment with diphenhydramine is unnecessary and may exacerbate restless legs. If there has been an adequate response to an intravenous iron infusion but symptoms recur, repeated infusions can be given in at least 12-week intervals as long as serum ferritin concentration is below 300 mg/L and transferrin saturation is less than 45%.¹³

Pharmacotherapy: Intermittent RLS

Carbidopa/levodopa, 25 mg/100 mg (1/2-1 tablet), can be used for RLS that occurs intermittently in the evening, at bedtime, or on waking during the night or for RLS associated with specific activities, such as airplane or lengthy car rides or theater attendance.

Problems with levodopa treatment include augmentation and rebound. Augmentation (drug-induced worsening of RLS) may occur in up to 70% of patients taking levodopa daily, and the risk increases with daily doses of 200 mg or more. As a result, levodopa should be prescribed only for intermittent use, such as 3 or fewer times a week, although a lower risk of augmentation with such use has not been firmly established. Rebound, the recurrence of RLS in the early morning, occurs in 20% to 35% of patients taking levodopa.

Low-potency opioids – Intermittent use of low-potency opioids usually before bed can be effective. Doses of 30 to 90 mg of codeine, in combined preparations with acetaminophen, or 50 to 100 mg of tramadol can be taken before bed or during the night. Constipation or nausea may occur. Tramadol can rarely induce seizures and is the only nondopaminergic drug associated occasionally with the development of augmentation.

Benzodiazepines – Intermittent use of benzodiazepines or benzodiazepine receptor agonists before sleep may be considered such as temazepam, zolpidem, zaleplon, or eszopiclone, especially if the patient has another cause of poor sleep efficiency in addition to RLS, such as insomnia associated with psychophysiological factors.¹³

Pharmacotherapy: Chronic Persistent RLS

Alpha2-delta ligand – Treatment should start with an alpha2-delta ligand (gabapentin, pregabalin, or gabapentin enacarbil) unless patient factors suggest that a non-ergot dopamine agonist (pramipexole, ropinirole, or rotigotine patch) would be safer.

A 12-week, multicenter, double-blind, placebo-controlled study that compared the efficacy and tolerability of gabapentin enacarbil with placebo in subjects with moderate-to-severe primary restless legs syndrome showed that gabapentin enacarbil significantly improved mean IRLS total score at Week 12 LOCF (baseline: 23.2; Week 12: 10.2) compared with placebo (baseline: 23.8; Week 12: 14.0). The study also showed that gabapentin enarcarbil significantly improved sleep outcomes when compared to placebo.¹⁷

Factors for considering a dopamine agonist, instead of alpha 2 delta ligands, as initial treatment include obesity and its complications, past or present moderate or severe depression, gait instability, disorders causing respiratory failure, and previous history of substance use disorder.

A double-blind, randomized, 12-week, multinational study compared the efficacy and safety of ropinirole and placebo in RLS, showed that improvements were significantly greater for ropinirole than placebo for change in IRLS score at week 12 with adjusted treatment difference of -2.5 (P = 0.0197).¹⁸

Dopamine agonists – When dopamine agonists are considered, nonergot agents like pramipexole, ropinirole, rotigotine patch should be prescribed because ergot agonists such as cabergoline and pergolide are associated with cardiac valvular fibrosis and other fibrotic reactions. Doses used are lower than approved for treatment of Parkinson disease because higher doses are associated with increased risk of augmentation. A second common adverse effect of long-term dopamine agonist use is impulse control disorder, with rate of occurrence estimated to be between 6% and 17%.¹⁹

Pharmacotherapy: Refractory RLS

Iron stores should be rechecked. If the serum ferritin level is less than 100 mg/L and symptoms are severe, intravenous iron therapy should be considered. Other exacerbating factors should be sought. These include the use of medications that can worsen restless legs; change in lifestyle, such as more sedentary behavior or shift work; and other causes of sleep disturbance, such as sleep apnea or chronic insufficient sleep. Consider combination therapy with drugs of different classes, taking into account the augmentation from dopamine agonists. Consider adding a second agent when trying to reduce the dose of the initial Dopamine agonist drug. Second agents may include an alpha2-delta ligand or a longer acting dopamine agonist and vice versa, a benzodiazepine (if RLS is present mainly at night with resulting insomnia), or a low- or high-potency opioid. Consider substituting an opioid such as oxycodone, hydrocodone, morphine, or methadone. In particular, consider low-dose methadone for severe refractory RLS resistant to other treatments.^{13, 20}