Based on the data collected from the RLS Epidemiology Symptoms Treatment (REST) general population study, the prevalence of restless legs syndrome (RLS) in the general population is 7.2%.1 This study evaluated more than 16,000 patients in the United States and across Europe for the presence of symptoms of RLS. Similar to previous studies, the prevalence of RLS was higher in women and older age groups. Women had approximately double the rate of RLS as compared to men, with a prevalence of 9% versus 5.4%, respectively. Moreover, there was an even higher prevalence of RLS symptoms in women who were pregnant.1 For these patients, RLS symptoms can cause sleep disturbance, discomfort, and disruption of daily activities, all of which can affect the quality of life. In a study performed by Abetz et al.,2 the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) was used to assess the quality of life in patients with RLS compared with other common medical comorbidities. The RLS cohort had significantly lower SF-36 scores than patients with hypertension, and lower scores than patients with cardiovascular disease or diabetes.2 Factors affecting quality of life that RLS patients commonly complain of include fatigue, sleep disturbance, diminished concentration, and psychomotor agitation, all of which can affect functionality.3
Four diagnostic criteria for RLS are defined by the International Restless Legs Syndrome Study Group (IRLSSG).4 These are (1) an urge to move usually associated with an abnormal sensation in the legs, (2) symptoms that occur at rest or are worsened by rest, (3) symptoms relieved by movement, and (4) symptoms that are more severe at night. The IRLSSG established a fifth criterion in 2012 that includes ruling out mimics of RLS (eg, leg cramps, arthritis, neuropathies, claudication, positional discomfort) that might confound the diagnosis.5 It is important to note that RLS is a clinical diagnosis that does not need confirmation with polysomnography.
Polysomnography may be indicated to rule out sleep apnea as a cause of leg movements during sleep. A study using the Icelandic Sleep Apnea Cohort assessed the prevalence of RLS symptoms in patients with obstructive sleep apnea (OSA) pre- and post-treatment with continuous positive airway pressure (CPAP).6 More than 800 patients with newly diagnosed moderate to severe OSA were included. Of the female patients with OSA, 35.8% reported RLS symptoms compared to controls, of which only 24.4% reported RLS symptoms. Upon reevaluation after initiation of CPAP, using the therapy had a reduced prevalence of RLS (from 25.7% to 13.8%).6 Therefore, sometimes, treatment with CPAP is adequate to control RLS symptoms in patients with comorbid OSA. Polysomnography can be useful to identify periodic limb movements (PLMs) of sleep. PLMs in sleep are a separate entity defined by brief limb movements in sleep that repeatedly occur over a short interval lasting seconds to minutes. In PLMs, the symptoms of leg movements are not noted by the patient; these may be noted by a bed partner or during polysomnogram studies. No associated urges to move prior to sleep onset are noted by the patient. These events occur most commonly in the first portion of the night. According to some studies, up to 80% to 90% of patients with RLS have PLMs.3 Of note, some patients may have PLM disorder, which is diagnosed in patients with an abnormally high incidence of PLMs and signs of sleep disturbance.3
RLS and Depression
Like RLS, major depression is a common psychiatric disorder and is more prevalent in women. The point prevalence in women is 5% to 9%, with a lifetime risk of major depression of 10% to 25%.3,7 Both disease states have common symptomatology, including sleep disturbance, fatigue, and psychomotor agitation.3 This can sometimes make it challenging to recognize RLS symptoms in patients with underlying depression. The fact that many medications used to treat depression exacerbate RLS symptoms further complicates this issue. A population-based survey by Sevim et al.8 looked to evaluate the incidence of depression and anxiety in patients with RLS. Patients with RLS were evaluated using the Hamilton Anxiety and Depression Scales to identify comorbid symptoms of anxiety and depression. Compared to controls, patients with RLS were found to have significantly higher rates of symptoms of depression and anxiety.8 A prospective study by Li et al.9 aimed to further stratify the risk of depression in patients with RLS. This study observed more than 56,000 women without baseline symptoms of depression from 2002 to 2008. They found that women with RLS were statistically more likely to develop depression. Moreover, they also had higher scores on the 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) and the 15-item Geriatric Depression Scale (GDS-15). When comparing women with RLS and those without RLS, there was a mean difference of 1 in the CESD-10 assessment and 0.47 for the GDS-15 score, which reached statistical significance of P <0.0001.9
RLS and Insomnia
Insomnia is a common disorder that manifests as difficulty falling and or staying asleep. It is often a comorbid disorder that occurs alongside psychiatric or medical conditions. Insomnia occurs more often in women, based on meta-analysis data.10 RLS is the most common sleep disorder associated with the occurrence of insomnia.11 One Swedish study looked at the prevalence of insomnia in patients with RLS.12 Of the patients surveyed, 18.8% had RLS symptoms, with 5.8% reporting frequent symptoms. In the subgroup of patients with moderate to severe RLS symptoms characterized by increased frequency of symptoms, there was a significantly longer reported sleep latency and shorter sleep duration compared to patients without RLS symptoms or infrequent RLS symptoms.12 Without addressing the RLS symptoms, insomnia can be challenging to treat in these patients. Several studies have demonstrated improvement in sleep quality and duration using dopamine agonists for the treatment of RLS.13,14
RLS and Antidepressant Use
RLS has been noted as a side effect of many drugs including cimetidine, carbamazepine, lithium, zonisamide, caffeine, olanzapine, promethazine, pimozide, risperidone, haloperidol, tricyclic antidepressants, and selective antidepressants. A prospective study by Rottach et al.15 demonstrated that RLS was found to be a side effect in 9% of patients taking a selective antidepressant such as fluoxetine. Mirtazapine had the most significant tendency to provoke or exacerbate symptoms of RLS symptoms, with adverse effects occurring in 28% of patients.15 These medications are commonly used to treat a variety of psychiatric diseases. Therefore, it is crucial to ensure that patients taking these medications are screened for RLS in the appropriate clinical settings. Moreover, efforts should be made to minimize or treat RLS symptoms in patients taking antidepressants.
Often patients with psychiatric comorbidities are treated with first-generation antipsychotic medications. This class of medications is considered a leading cause of akathisia, a movement disorder characterized by a self-reported inner feeling of restlessness and urge to move involving the whole body16 (not confined to the limbs as in RLS). It is important to note that akathisia and tardive dyskinesia are not the same as RLS, although these can result from the use of medications that also are known to exacerbate RLS symptoms. A history of exposure to medications that can cause akathisia should be obtained; withdrawal of these medications will result in resolution of symptoms. These movement disorders will present with repetitive movement of the body or body parts that persists throughout the day. Where as in RLS, there is a clear worsening or onset of symptoms at night.
Treatment of RLS
A variety of factors triggering RLS may influence the management of patients with this disorder. The goal of treatment is to prevent onset of symptoms to facilitate sleep initiation and to ameliorate sleep maintenance, thus improving associated daytime fatigue and tiredness. Patient education is important regarding avoidance of RLS triggers like smoking, nicotine, caffeine, selective serotonin reuptake inhibitors medications, and prolonged sitting. It is also helpful to reiterate the known worsening of symptoms in anticipation of travels and anxiety-provoking situations; being aware of this phenomenon improves management and reduces frustration for the patients. The treatment algorithm is depicted in Figure 1.
Treatment algorithm for restless legs syndrome (RLS). IRLSSG, International Restless Legs Syndrome Study Group; IV, intravenous.
Iron deficiency is more common in premenopausal and adolescent women due to regular loss through menstruation. Therefore, it is recommended to check ferritin levels in serum before initiation of treatment. In patients with ferritin levels <75 ng/mL, iron supplementation should be considered, preferably with oral or intravenous replacement if needed. Vitamin C should be used with oral iron therapy to help improve absorption. If iron replacement is not feasible or appropriate, first-line therapy for newly diagnosed RLS includes alpha-2-delta ligands such as gabapentin, gabapentin enacarbil, or pregabalin. This class of medications is also preferred in patients with chronic pain, anxiety, insomnia, or impulse control concerns. Dopamine agonists are another class of first-line medications commonly used for the treatment of RLS. This class is often preferred for patients with severe depression, obesity, increased risk for falls, or cognitive impairment.17 For moderate to severe disease, the 2016 RLS practice guidelines recommend treatment with pramipexole, rotigotine, or gabapentin enacarbil.18 These medications are approved by the US Food and Drug Administration for the treatment of RLS. In cases of refractory disease, intolerance to other therapy, or augmentation, additional therapies such as opioids may be needed.19 These medications should be used with caution in patients with altered mentation, cognitive deficits, or sleep-disordered breathing. Lower doses of these medications, particularly dopamine agonists, are recommended for elderly patients because they may be more susceptible to side effects. Longer-acting medications are preferred for patients with significant symptoms, usually due to movement disorders such as Parkinson's disease. The treatment for RLS should be customized according to comorbid conditions (eg, anemia, pregnancy, Parkinson's disease, anxiety, and depression). Otherwise, there is no significant difference in treatment among the genders.
RLS in Pregnancy
In women who menstruate, RLS can be problematic due to monthly blood loss and subsequent iron deficiency. However, cessation of menstruation in pregnancy does not mitigate the risk of RLS in pregnancy. As mentioned above, the prevalence of RLS in pregnancy is significantly higher than in the general population. Some studies estimate a prevalence as high as 10% to 34% in women who are pregnant.20
Several risk factors for RLS in pregnancy have been identified, including ferritin and folate levels, history of prior RLS diagnosis in pregnancy, multiparity, maternal age, body mass index, tobacco use, caffeine use before pregnancy, and hormonal factors.20,21 Many antinausea drugs (trimethobenzamide, prochlorperazine, promethazine, hydroxyzine, meclizine, and metoclopramide) block the dopamine system and thus may worsen RLS.5 Alternatives for pregnancy-related nausea include the newer selective serotonin receptor antagonists (granisetron hydrochloride, ondansetron hydrochloride), which do not bind to the dopamine receptors, and the peripherally acting drug domperidone (not available in the US), which does not cross the blood-brain barrier and does not affect RLS.5
RLS in pregnancy has been associated with pregnancy complications such as preeclampsia and increased rates of depressed mood. Treatment is often focused on nonpharmacologic options, including counseling, stretching and massage, decreasing caffeine, avoiding other triggers, and avoiding heavy exercise. There is limited high-quality evidence with regard to the effectiveness of these treatments. However, these options should be considered based on existing evidence of safety and effectiveness as initial treatment options in pregnancy.22 Iron supplementation is the first-line treatment for RLS in pregnancy and can be helpful to replete deficiencies that may contribute to RLS symptoms. Other pharmacologic therapies such as dopamine agonists (ropinirole), alpha-2-delta ligands (gabapentin), benzodiazepines, and opioids should be used with caution, as these medications have a pregnancy category C safety rating. Besides iron and vitamin supplementation, other pharmacologic therapy is typically reserved for severe or refractory disease and should be discussed with a pharmacist before initiation.21
RLS is a relatively common neurologic sensorimotor disorder defined by four clinical features, including (1) an urge to move, typically associated with an abnormal sensation in the legs, (2) symptoms that occur at rest or are worsened by rest, (3) symptoms relieved by movement, and (4) symptoms that are more severe at night.4 Sleep disturbance due to RLS is commonly seen in patients with significant psychiatric illness, leading to poor quality sleep marked by recurrent arousals and difficulty falling asleep. Treatment options for RLS depend on the associated diseases and health states (eg, pregnancy), ranging from trigger point massage, avoidance of triggers (such as nicotine and caffeine), iron supplementation, dopaminergic drugs (ropinirole, pramipexole), alpha-2-delta ligands (gabapentin, pregabalin), benzodiazepines (clonazepam), and opioids if clinically appropriate. The goal of treatment is to improve the quality and possibly the quantity of sleep by reducing arousals triggered by these leg movements.
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- Abetz L, Allen R, Follet A, et al. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther. 2004;26(6):925–935. https://doi.org/10.1016/S0149-2918(04)90136-1 PMID: doi:10.1016/S0149-2918(04)90136-1 [CrossRef]15262463
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- Benediktsdottir B, Janson C, Lindberg E, et al. Prevalence of restless legs syndrome among adults in Iceland and Sweden: lung function, comorbidity, ferritin, biomarkers and quality of life. Sleep Med. 2010;11(10):1043–1048. doi:10.1016/j.sleep.2010.08.006 [CrossRef]20961808
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