Restless legs syndrome (RLS) is a disorder characterized by an irresistible urge to move the legs during rest, usually accompanied by uncomfortable sensations in the affected extremity. When these symptoms are fully developed, the diagnosis is fairly straightforward. However when RLS is more subtle, or presents with nonmotor symptoms, the diagnosis is more challenging. An understanding of the expanded symptom spectrum and associated comorbidities will help healthcare providers diagnose and treat RLS. The negative effect of RLS symptoms on patients' quality of life and general health, as well as the likelihood for misdiagnosis, make it imperative for healthcare providers to know how to recognize, diagnose, and treat this condition.
The prevalence of RLS is 5% to 10% among adults, and increases with advancing age.1,2 RLS is more frequently reported in women, with multiparous women at increased risk.1,2 Primary and secondary RLS are phenotypically similar and can be difficult to differentiate upon initial presentation.
Primary idiopathic RLS
This form can manifest at any age. The prevalence is 2% in patients ages 8 to 17 years, 8% to 13% in patients younger than age 10 years, and 27% to 38% in patients younger than age 20 years.3 Patients may have a genetic predisposition for primary RLS.4
This form can be triggered by medications or can occur secondary to another condition such as renal failure.
Severe RLS, whether primary or secondary, is a chronic condition. Patients with milder RLS exhibit a variable pattern with long periods of remissions. Little is known about the course of the mild disorder because those with mild and/or intermittent RLS rarely seek treatment. About 40% of adults with primary RLS may have experienced symptoms as children or adolescents and gone into remission before symptoms reappeared between ages 30 and 40 years.3
In adults, RLS is a clinical diagnosis based on patient history because neurologic and physical examinations generally are normal. The International RLS Study Group lists five essential diagnostic criteria to help confirm or rule out RLS.5 Patients with either form of RLS must meet all five criteria, which follow the acronym “URGED”:
- Urge to move the legs, usually but not always accompanied by unpleasant or uncomfortable sensations described as crawling, tingling, cramping, creeping, pulling, painful, electric, tension, discomfort, or itching.
- Rest worsens symptoms when the position is more restful and the rest is of a longer duration.
- Gyration or movement partially or totally relieves symptoms, immediately or very soon after voluntary movement begins, but relief is not always complete. Patients with severe RLS may experience little or no relief of symptoms no matter the amount or degree of movement, although movement may have helped to alleviate the unpleasant sensations experienced earlier in the course of the disease.
- Evening/nighttime onset or worsening of symptoms with a peak immediately after midnight; symptoms decrease during late morning. In severe RLS, patients may have symptoms 24 hours a day with no variation, although earlier in the disease, symptoms may have worsened at evening or night.
- Denial of another primary cause of symptoms.5
The following features do not occur in all patients with RLS and are not necessary for diagnosis, but can be useful in diagnosing complicated or uncertain presentations.5
Family history. More than 50% of patients with primary RLS report a positive family history of RLS, and often present with symptoms at an earlier age. Patients with a family history of RLS tend to have a slower progression of the disease.4
Positive response to dopaminergic medications. Dopaminergic medications have been shown to improve sensory and motor symptoms of RLS. Agents that block dopamine receptors aggravate RLS symptoms. A meta-analysis revealed strong evidence that medications including escitalopram, fluoxetine, carbidopa, levothyroxine, mirtazapine, olanzapine, metoclopramide, and tramadol can exacerbate RLS. Take a thorough medication history for these agents.6
Periodic limb movements of sleep (PLMS). At least 80% of patients with RLS have PLMS, repetitive involuntary limb movements that also occur in patients with sleep disorders such as narcolepsy and sleep apnea.
This form of RLS often is related to iron deficiency, pregnancy, or end-stage renal disease. Secondary RLS during pregnancy often resolves postpartum.7 Medications that can cause or exacerbate RLS include antiemetics and motility drugs that block dopamine, antidepressants such as mirtazapine, tricyclic antidepressants, and serotonergic reuptake inhibitors (SSRIs).8
To gauge the severity of the disorder, ask patients about symptom intensity (mild, moderate, or severe) and frequency (1 to 2 times per week, 3 to 4 times per week, or daily).
RLS IN CHILDREN AND ADOLESCENTS
Diagnosing RLS in children and adolescents is more difficult than diagnosing the disorder in adults. The main difference between diagnosis in adults and children is that sleep disturbance, family history, and PLMS are included in the criteria for identifying RLS in children.
To be diagnosed with definite RLS, children ages 2 to 12 years must meet all essential adult criteria for RLS (U, R, G, and E of the URGED criteria) and one of the following two criteria:
- The child provides a description, in his or her own words, consistent with the leg discomfort.
- The child has two of the three supportive criteria: sleep disturbance for age, biologic parent or sibling with definite RLS, or five or more instances of PLMS per hour on polysomnography.
Adolescents ages 13 to 18 years have definite RLS if they meet all essential adult criteria for RLS.
As with adult RLS, symptoms must not be attributed to another ongoing sleep disorder, neurologic disorder such as ADHD, mental disorder such as depression, growing pains, medication or substance abuse. Clinical sleep disturbance can precede the full diagnostic manifestations of definite RLS by months or years in children and adolescents.3
Patients with suspected RLS do not need to be referred for further diagnostic tests; however, difficult cases can be referred to a neurologist or sleep specialist. For clinically classic RLS, patient history and normal physical examination usually suffice for diagnosis. In patients with suspected serum iron deficiency anemia, be sure to obtain iron studies, including serum ferritin and iron-binding saturation. For patients with renal failure, obtain electrolyte levels. Nerve conduction velocity and electromyograms (EMGs) may be necessary if the patient has peripheral neuropathy.
Polysomnographic studies can be performed in patients whose symptoms may be better explained by another disorder, such as PLMS.8 Polysomnographic studies have demonstrated that patients with RLS experience reduced sleep efficiency (the ratio of actual to attempted sleep time), increased arousals during sleep, and decreased total sleep duration.9
RLS has been deemed the fourth leading cause of insomnia.10 Patients may be unable to fall asleep or stay asleep, have multiple awakenings, awaken too early in the morning, feel unrefreshed after sleep, have daytime fatigue and impaired concentration.10 Sleep disturbances can cause significant distress, and often are the reason patients with RLS seek help. The diagnosis of RLS is supported if over-the-counter sleep medication containing antihistamines exacerbates RLS symptoms and worsens insomnia.11
Depression and anxiety
Patients with RLS have an increased prevalence of depression and anxiety, especially panic disorder, generalized anxiety disorder, and major depressive disorder.12,13 Causality between depression and RLS seems to be bidirectional, and one disease can exacerbate the other. Depression and RLS share common symptoms of sleep disturbance, fatigue, decreased concentration, and psychomotor agitation.13,14 As mentioned earlier, providers should note that antidepressants, especially mirtazapine, can exacerbate preexisting RLS symptoms.13 Bupropion, desipramine, trazodone, and nefazodone have lower rates of RLS symptom exacerbation, and should be considered for use in patients with comorbid depression.
RLS and PLMS are associated with hypertension, cardiovascular disease (CVD), and cerebrovascular disease.15-17 Sleep disturbances caused by RLS can increase patients' risk for hypertension and CVD.15
Both RLS and Parkinson disease are associated with CNS dopamine hypofunction, and both respond to dopaminergic medications.18,19 Several studies have found a 20% prevalence of RLS in patients with Parkinson disease, which may be underestimated.18,19
QUALITY OF LIFE
RLS is associated with lower future physical function, even when controlled for age, race, smoking status, weight, height, baseline physical activity, medication use, anxiety, and history of chronic diseases.20 Physical function scoring using the PF-10 questionnaire asks whether patients are restricted in the following 10 activities: vigorous activities such as running; moderate activities such as moving a table; lifting and carrying groceries; climbing several flights of stairs; climbing one flight of stairs; bending, kneeling, or stooping; walking more than 1 kilometer; walking several hundred meters; walking 100 meters; and bathing or dressing.20
As RLS symptoms increase in frequency, patients' physical function scores tend to fall. In a study of 12,000 participants over 6 years using the Physical Function-10 scale, patients with RLS symptoms had increased disability compared with patients without RLS.20 This increased disability is not accounted for by other covariates.20 Interestingly, the association between RLS and future physical function status remained, even among patients who were healthy without underlying CVD, obesity, diabetes, renal failure, or other conditions.20 Decreased sleep duration in general may increase the risk of weight gain.21 Taken together, these findings suggest that RLS may have an underlying effect on daily function and that these effects worsen as RLS symptoms progress.
The most profound effects on patient quality of life appear to be in overall vitality, energy, and physical problems, leading to limitations in work and daily activities. Data suggest that RLS affects quality of life as much as or worse than other major chronic medical disorders.22
Nonpharmacologic therapies are the foundation of RLS therapy. Patients with mild RLS may be able to reduce symptoms with lifestyle changes and self-help measures that can help them cope with and alleviate their symptoms without medications.23,24
- Sleep hygiene. Patients should avoid eating or drinking anything containing caffeine or alcohol within 6 hours of bedtime. They should avoid smoking and avoid taking long naps during the day.
- Exercise. Mild exercise such as yoga, straight-leg raise stretching maneuvers, low-intensity leg strength training, treadmill walking, and cycling can improve RLS symptoms. However, extreme exercise may cause fatigue, which can exacerbate symptoms.25
- Distraction techniques. Patients should establish relaxing presleep rituals such as a warm bath, stretching, a massage, or reading, to distract from RLS symptoms.
- Cognitive behavioral therapy (CBT). This type of therapy can improve patients' coping strategies, quality of life, mental health, and subjective ratings of symptoms.23
Alternative therapies. Therapies such as acupuncture and vibration therapy have not been found to be helpful in patients with RLS.
Patients should consider pharmacologic treatment if they have symptoms three or more times a week (Table 1).
- Iron. Oral iron can cause or worsen constipation, and may not be tolerated by all patients. IV iron is better-tolerated and causes fewer gastrointestinal adverse reactions but has limited evidence of efficacy and sustained improvement of symptoms.26-28
- Dopaminergic drugs. For patients who have moderate-to-severe RLS with disturbances in daily activities, quality of life, or sleep, dopaminergic drugs are the treatment of choice because RLS appears to involve dopaminergic dysregulation in the CNS.1 Ropinirole, a nonergot dopamine receptor agonist, is the most commonly used dopaminergic drug for moderate-to-severe RLS, significantly reducing motor symptoms of RLS compared with placebo.29 Pramipexole has shown significant improvements in RLS symptoms, sleep, and quality of life.30,31 Rotigotine is available as an oral or transdermal preparation and also is indicated for treatment of RLS. Although all three medications have been deemed effective in treating RLS for 6 months, the main difference between ropinirole and pramipexole versus rotigotine is that ropinirole and pramipexole appear to be effective for up to 1 year but rotigotine appears to be effective for up to 5 years.32
The main complication of long-term dopaminergic therapy is augmentation, or treatment-induced exacerbation of RLS symptoms. Augmentation is characterized by increased symptom intensity, onset of symptoms earlier in the day, a shorter time to symptom onset during rest, spread of symptoms to previously unaffected parts of the body, and a shorter period of relief after medication administration. The mechanisms behind augmentation are unknown. However, to reduce the risk of augmentation, dopaminergic therapy should be maintained at the lowest dose possible.33
- Other medications. Opioids can successfully treat RLS and are considered second-line therapy for patients who do not respond to dopamine agonists. Methadone can benefit most patients with refractory RLS.3 Gabapentin enacarbil is the only nondopaminergic therapeutic agent approved by the FDA to treat moderate-to-severe RLS. This drug is recommended for patients whose sleep disturbances are worse than their sensorimotor symptoms, and who have comorbid insomnia, anxiety, or pain disorders.24,32 Benzodiazepines do not give adequate control of RLS symptoms, but can help induce and improve the quality of sleep.33 Patients requiring opioids or secondary forms of pharmacology should be managed or comanaged by a neurologist or a pain specialist.
Treating RLS in children
The FDA has not approved any medications to treat RLS in children. However, frequently used and accepted medications for childhood RLS include clonidine, clonazepam, and gabapentin prescribed off-label. Although dopaminergic agonists have been used in children, their effects have not been extensively studied.34 Children with RLS are best cared for by a pediatric neurologist.
Because 5% to 10% of the general population is estimated to have RLS, healthcare providers must recognize and appropriately treat RLS. Symptoms can cause significant negative mental and physical health effects, often going undiagnosed for many years. Using the URGED criteria can help clinicians diagnose patients early and establish a treatment regimen, minimizing the negative effect of RLS on patients' quality of life.
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Keywords:Copyright © 2016 American Academy of Physician Assistants
restless legs syndrome; movement disorder; URGED criteria; dopaminergics; periodic limb movements; involuntary