Review ArticleRestless legs syndrome: clinical presentation diagnosis and treatment
Introduction
Restless legs syndrome (RLS), also referred to as Willis-Ekbom disease (WED), is a chronic neurological disorder that may require lifelong treatment [1]. Majority of patients with RLS respond well to currently available medications. One of the most challenging aspects of treating RLS is the occurrence of medication-related complication, namely augmentation (discussed in more detail below) and its management. A subset of patients may also progress to severe or refractory RLS (“malignant RLS”), which can be very disabling. This article summarizes different clinical presentations and discusses diagnosis of RLS with an emphasis on management of RLS.
RLS is a circadian disorder of sensory-motor integration manifested by an urge or a need to move the limbs to stop unpleasant sensations in the evening or while at rest [1], [2], [3], [4]. First described by Thomas Willis in 1685, it was Ekbom, in 1945, who described essentially all the cardinal clinical features of the syndrome and coined the name “restless legs syndrome” [5]. In recognition of the contributions by these two pioneers, the nonprofit Restless Legs Syndrome Foundation was recently renamed as the Willis-Ekbom Disease Foundation [6].
The diagnosis of RLS is based on the 2012 revised International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria [7], [8]. Compared to the 2003 criteria, the 2012 version includes criteria to rule out RLS mimickers [9] and, in addition, all the essential diagnostic criteria have to be met: (1) The urge to move the legs, usually but not always accompanied by or felt to be caused by uncomfortable and unpleasant sensations in the legs; (2) the urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting; (3) the urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues; (4) the urge to move and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day; (5) the above features are not solely accounted for by other medical or behavioral conditions, such as myalgias, venous stasis, leg edema, arthritis, leg cramps [10], positional discomfort, habitual foot tapping, and other nocturnal sensory-motor symptoms.
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Clinical manifestations
Descriptions of the uncomfortable sensation (in descending order of frequency) include “need to move,” “crawling,” “tingling,” “restless,” “cramping,” “creeping,” “pulling,” “painful,” “electric,” “tension,” “itching,” “burning,” “prickly,” but unique, culturally determined, terms such as “heebie jeebies,” “wriggling maggots,” “elvis legs,” “the shpilke,” and others [11], [12]. Typical RLS sensations are felt deep inside the muscles and bones of the legs but some patients describe sensations
Epidemiology
Based on well-conducted epidemiological studies, the overall prevalence of RLS has been reported to range from 7% for any RLS to 2.7% for clinically apparent RLS [29]. For primary RLS (excluding secondary causes), the overall prevalence in the USA was estimated to be 2.4% and 1.5% for primary and clinically significant RLS, respectively [23]. RLS seems to be an age-related disorder, although symptoms can begin in childhood, and 38% of adults have reported the onset of symptoms before the age of
Genetics
The presence of family history in RLS is common and, when present, supports the diagnosis of RLS. Primary RLS is characterized by high familial aggregation suggesting a genetic component. Approximately 63% of patients report having at least one first-degree relative with the condition [16]. Despite intensive efforts, a monogenic cause for RLS has not been detected to date [39], [40]. Independent genome-wide association studies in diverse populations of Northern European origin have found six
Imaging studies
Conventional brain magnetic resonance imaging (MRI) does not show any structural abnormalities in idiopathic RLS patients. Studies of structural brain images using voxel-based morphometry (VBM) and diffusion tensor imaging have reported contrasting results [46], [47], [48], [49]. Multiple studies using iron-sensitive sequences of MRI have shown reduced iron content in several regions of the brain [49], [50], [51]. A single study using phase imaging showed significantly higher phase values in
Pathogenesis
It has long been observed that iron deficiency exacerbates RLS and iron replacement improves symptoms [55], and brain iron dysregulation is considered to play a key role in the pathogenesis of RLS [56], [57]. Various studies based on analysis of cerebrospinal fluid (CSF) [58], [59], brain MRI [51], and autopsy examinations [60] have shown low levels of iron in the brain of RLS patients. Indeed, dysregulation of iron transport across blood-brain barrier is thought to be the chief mechanism of
Assessment
Currently, there is no highly specific or sensitive objective biomarker of RLS and there is a need for an instrument that reliably measures and objectively assesses its severity. The overwhelmingly subjective nature of the disorder poses a challenge in documenting change in response to therapeutic interventions. There is also a very high placebo response in RLS [63], [64], [65]. Multiple scales and questionnaires have been used, but the most commonly used scales to assess severity of RLS
Non-pharmacological measures
Only few studies have examined the effects of non-pharmacological therapies, such as exercise and good sleep hygiene (e.g., avoiding daytime naps and maintaining regular bedtimes). Participating in aerobic and resistance training exercises has been shown to reduce RLS symptoms [71]. One randomized controlled trial showed that by engaging in lower body resistance training and walking on a treadmill for 30 min three times a week improved RLS symptoms [71]. Although controlled studies are lacking,
Dopamine agonists
Among the different pharmacological agents, dopamine agonists (DAs) are the most widely used [17], [77]. These drugs reduce not only the primary symptoms of RLS but also PLMS. A Cochrane meta-analysis concluded that non-ergot DAs, such as pramipexole, ropinirole, and rotigotine, are effective in treating various aspects of RLS [78]. However, there are no head-to-head studies comparing the three DAs. DAs also markedly improved PLMS compared with placebo and reduced the autonomic activation that
Augmentation
First described in 1996 by Allen and Early [113], augmentation is a severe and potentially disabling exacerbation of RLS, sometimes leading to continuous persistence of symptoms, even for 24 h a day. It is an important therapy-related complication of RLS. Augmentation is relatively common and is seen in patients chronically treated with dopaminergic drugs, such as DAs and carbidopa/levodopa [113], which limits the use of these medications. Augmentation is characterized by progressively earlier
Evaluation
The examination is essentially normal in primary RLS and may help to detect secondary causes of RLS. A comprehensive drug history including over-the-counter medications will help to identify medications that can potentially worsen RLS. Selective serotonin reuptake inhibitors (SSRIs) [163], [164], [165] and serotonin–norepinephrine reuptake inhibitors (SNRIs) [166] are known to exacerbate RLS. These drugs have been reported to have a risk of about 5% for triggering RLS. In one survey,
Guideline to the management of RLS
The choice of therapeutic strategy depends largely on the severity of the RLS-related symptoms (Fig. 1). If symptoms are mild and intermittent, pharmacological therapy may not be needed and non-pharmacological measures can be sufficient. Once the decision is made to treat, the first-line medication may include a non-dopaminergic drug such as gabapentin, gabapentin enacarbil, or pregabalin in order to avoid augmentation. There is no evidence to suggest that gabapentin enacarbil or pregabalin is
Pregnancy and RLS
RLS is the most common movement disorder related to pregnancy affecting 2.9–32% of pregnant women [32], [200]. In general, pharmacologic treatment should be avoided for RLS symptoms during pregnancy including both DAs and gabapentin. Consideration should be given to fully replenishing iron stores prior to pregnancy and maximizing non-pharmacological treatment, as significant correlation has been demonstrated between low iron and the risk of developing RLS during pregnancy [201]. There is some
Childhood RLS
The diagnosis of RLS in children can be quite challenging due to their inability to recognize or verbalize the classic RLS symptoms. The IRLSSG has recently revised the criteria for diagnosis of RLS and PLMS in pediatric populations [9], [203]. RLS occurs in about 1.9% in school-age children and 2% in adolescents, but the disorder is likely under-diagnosed in this age group or wrongly attributed to other disorders, including “growing pains” [204]. The poor recognition of RLS in pediatric
Conclusion
Management of severe or refractory RLS can be challenging. It is important to correctly identify the underlying reasons for worsening of symptoms, such as augmentation, tolerance, rebound, iron deficiency, secondary causes, or natural progression of the disease, among others, to be able to correctly apply appropriate management strategies. Non-pharmacological treatments may be helpful in mild cases or as an ancillary therapy. Augmentation is a major therapy-related complication and therefore
Future therapeutic strategies
Listed below are some of the clinical trials that are actively recruiting as well as studies that have been completed in RLS (https://clinicaltrials.gov/ct2/home):
- 1.
Clinical Evaluation of Ropinirole CR-RLS Tablets in Restless Legs Syndrome-Open-Label, Uncontrolled Study. Phase II trial. ClinicalTrials.gov Identifier: NCT00530790. Status: Completed.
- 2.
A 4-Week Randomized, Double-Blind, Cohort Study to Evaluate the Safety and Tolerability of Converting From Ropinirole Immediate Release (IR) to
Conflict of interest
The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2015.03.002.
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