Sleep Disorders
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Restless legs syndrome (RLS) …
- Updated 08.22.2024
- Released 04.05.1995
- Expires For CME 08.22.2027
Restless legs syndrome
Introduction
Overview
The sensory symptoms of restless legs syndrome are paresthesias and dysesthesias in the calves and legs. Descriptions of these phenomena include words such as aching, pulling, drawing, numbness, tingling, prickling, creeping, or crawling. The unpleasant sensations occur during rest and inactivity and are worse in the late evening and when attempting to sleep. In this article, the authors discuss the genetics, clinical features, diagnosis and differential diagnosis, etiology, pathophysiology, management, and prognosis of this common disorder. Management of special conditions, such as restless legs syndrome in pregnancy, is addressed as well. The current update includes recent literature on insights into the etiopathogenesis of restless legs syndrome and its impact on cardiovascular health.
Key points
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• Restless legs syndrome is an underdiagnosed and very common disorder, often with a positive family history. | |
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• Several genetic linkages have been identified. | |
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• Restless legs syndrome may be primary or secondary to other conditions. | |
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• Treatment is generally quite effective, though sometimes drugs are associated with side effects. | |
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• Several potential drugs are under investigation for treating restless legs syndrome. |
Historical note and terminology
The first clinical description of restless legs is attributed to Thomas Willis. He described the syndrome in 1672, and in the 1685 edition of his textbook wrote, "Wherefore to some, when being a Bed they betake themselves to sleep, presently in the Arms and Legs, Leapings and Contractions of the Tendons, and so great a Restlessness and Tossings of their Members ensue that the diseased are no more able to sleep than if they were in a Place of the greatest Torture" (335). In 1861 Wittmaack called the disorder "anxiety tibiarum" and wrote that it was a frequent symptom of hysteria (340). Oppenheim was the first to define the disease as a neurologic illness and the first to recognize the genetic component of the disease (241). The first significant clinical review of restless legs syndrome was written by Ekbom in 1945. His monograph described two forms of the disorder: one form presents with prominent paresthesia, "asthenia crurum paresthetica," and the other form presents with prominent pain, "asthenia crurum dolorosa" (82).
Clinical manifestations
Presentation and course
Diagnostic criteria for the diagnosis of restless legs syndrome include (1) an urge to move the legs usually accompanied or caused by uncomfortable and unpleasant sensations in the legs, (2) the urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity, such as lying or sitting, (3) 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, and (4) 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. The occurrence of the above features is not solely accounted for as symptoms primary to another medical or behavioral condition (eg, myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping) (18; 334).
Supportive clinical features include a positive family history, response to dopaminergic therapy, and periodic limb movements during wakefulness or sleep. Additional criteria have been defined for cognitively impaired elderly persons and for children (19). Restless legs syndrome is often considered to have a mean age of onset in the sixth decade; however, in a review of 133 patients studied with surveys and polysomnography, mean age at onset was 27.2 years, whereas onset was before 20 years of age in 38.3% of cases (214). In another study, as many as 33% of patients had onset before 10 years of age (329). The syndrome is rarely diagnosed before 20 years of age, although in some patients, the onset of restless legs symptoms may be traced to infancy. In one study of 23 children, 20 (87%) had a family history of restless legs compatible with an autosomal dominant inheritance pattern (220).
The sensory symptoms of restless legs syndrome are paresthesias and dysesthesias in the calves and legs. Descriptions of these phenomena include words such as aching, pulling, drawing, numbness, tingling, prickling, creeping, or crawling. The unpleasant sensations occur during rest and inactivity and are worse in the late evening and when attempting to sleep. They are relieved by moving the legs or walking; patients pace the room, toss and turn in bed, and rub their feet and legs (105).
Body rocking and marching in place may also be seen, particularly in elderly subjects with longstanding severe disease (327). Occasionally, rhythmic movement disorders consisting of stereotypic movements in sleep, such as body rocking, head banging, and head rolling, may be noted in severe restless legs syndrome (324). Although it would seem that the motor phenomena occur solely in response to the unpleasant sensations, recordings during forced immobilization suggest that muscle activity may occur independent of the unpleasant sensation (249). About one-half of patients with restless legs syndrome also complain of restlessness in the arms (203). Restless genitalia has been described in one patient with Parkinson disease and responds well to low-dose dopamine agonists (22).
Most patients with restless legs syndrome have other symptoms of sleep disorder. Most common are periodic leg movements of sleep, present in 80% of patients (218). In addition, over 55% of patients report daytime crises frequently associated with reduced daytime activity (319). Periodic leg movements of sleep are stereotyped movements of the legs occurring in long trains. The movements always include dorsiflexion of the big toe or foot. More intense movements include flexion of the knee and hip, and when fully developed, resemble the triple flexion withdrawal response of pyramidal disease. Periodic arm movements are also common (50). Although sometimes called nocturnal myoclonus, the movements do not look like other forms of myoclonus. Movements tend to recur every 20 seconds to 40 seconds and are often associated with a K-complex on EEG and increases in heart rate, blood pressure, and depth of respiration (190). The frequency of leg movements is related to sleep stage. Movement frequency and duration decrease with progression from wakefulness through stage 1 and stage 2 of non-REM sleep, and movements are dramatically suppressed during REM and slow wave sleep (224). The occurrence of periodic leg movements of sleep may be related to an underlying circadian rhythm, the sleep stages, and body position (310). For example, peak intensity of subjective discomfort and motor restlessness is on the falling phase of the core temperature cycle, suggesting that restless legs syndrome is partially controlled by a process that varies with the normal circadian rhythm (124). The circadian pattern of periodic limb movements in sleep was very similar to the circadian pattern previously reported in restless legs syndrome (79). Suppression of periodic limb movements of sleep with dopamine agonists such as pramipexole did not affect arousal or EEG instability in sleep, whereas the use of benzodiazepines lowered EEG instability and arousal in sleep without affecting periodic limb movements, suggesting that periodic limb movement disorder may not be directly related to arousal from sleep or sleep fragmentation (195). Glutamate/creatine ratio in the thalamus on MR spectroscopy was higher in patients with restless legs syndrome than in controls and correlated with wake time during sleep period but not with periodic limb movements of sleep, adding credence to the hypothesis that periodic limb movements themselves do not contribute to arousals in restless legs syndrome (11).
Despite the clinical similarity, some authors have termed this movement "resting dyskinesias while awake" (254). Variable levels of sleep disruption are reported by patients and especially by their bed partners. Patients with restless legs syndrome have increased sleep latency, decreased sleep efficiency, and frequent awakenings. Nocturnal eating and sleep-related eating disorders can also be seen in restless legs syndrome and may respond to dopaminergic therapy. Amnestic sleep-related eating disorders can occur in restless legs syndrome in the setting of sedative use (132). Headache, anxiety, social isolation, reduced libido, and mild depression have been reported. Some reports suggest significant deficits in cognitive tests sensitive to prefrontal cortex dysfunction (246). Subsequent studies have shown no effect on cognition but have found a strong correlation between untreated restless legs syndrome and depression (175). However, studies have shown that decision-making, problem-solving, and working memory performance seem to improve with dopaminergic therapy in restless legs syndrome (92; 147).
Reflection impulsivity, a function of cognitive impulsivity, is common in restless legs syndrome in drug naïve patients and those on dopaminergic treatment (121). Jumping to conclusions and irrational decision-making are more common in patients with restless legs syndrome on dopaminergic therapy with augmentation (122).
Patients with restless leg syndrome are more likely to show symptoms of depression and higher rates of neuroticism than controls (301). Restless legs syndrome was associated with a high risk of suicide and self-harm, and the risk was independent of associated conditions and comorbidities (349).
Primary restless legs syndrome sufferers had a mean productivity loss of 1 day/week, resulting in increased financial disease burden (13). In the workplace, restless legs syndrome has been noted as a highly prevalent sleep disorder contributing to worker absenteeism, decline in productivity, and employer costs (200).
The impact on partners of patients with restless leg syndrome has been noted concerning sleep, leisure time activity, and quality of relationship (234).
Physical and neurologic examinations of most sufferers of restless legs syndrome are normal (primary restless legs syndrome). However, in some cases, examination or diagnostic studies uncover evidence of systemic or neurologic disease (secondary restless legs syndrome) (237).
Prognosis and complications
Restless legs syndrome is generally a lifelong condition. Symptoms tend to progress with age. Brief remissions and variability over time are common. Restless legs syndrome and periodic limb movements in sleep are reported to be associated with an increased risk of hypertension, cardiovascular disease, and stroke (330). Men with restless legs syndrome have been reported to have a higher likelihood of concurrent erectile dysfunction because dopaminergic hypofunction contributes to both conditions (93).
Clinical vignette
A 73-year-old woman presented for evaluation of gait disorder. Two years before the present evaluation, she began to notice "slapping" of her feet. Evaluations by a podiatrist and a neurosurgeon revealed peripheral neuropathy. Shortly after this diagnosis, she noticed "twitching" in both feet and a sense of restlessness in the feet when resting in bed at night. The weight of the bedclothes seemed unbearable, and she repeatedly got out of bed and walked the floor of her room. The discomfort was relieved by walking, only to recur when she returned to bed. Her medical history was remarkable only for osteoarthritis, hypothyroidism treated with levothyroxine, and remote kidney stones. She was an ex-smoker and moderate alcohol drinker. The family history was negative. Examination revealed signs suggestive of a mild peripheral neuropathy. No involuntary movements were seen. Investigation revealed mild axonal neuropathy and cerebellar atrophy. She was prescribed carbidopa at 50 mg daily, carbidopa-levodopa at 50 mg carbidopa, and 200 mg levodopa at bedtime with good control of the symptoms.
Biological basis
Etiology and pathogenesis
Primary restless legs syndrome is hereditary in at least one third of cases; some authors suggest that 50% to 92% of such cases may be familial (237; 329). In these families, the inheritance pattern is autosomal dominant; however, variable penetrance and evidence of genetic anticipation in some families with restless legs syndrome suggest the disorder’s genetic basis may be heterogeneous (173). There was high concordance in a small study of monozygotic twin pairs in which one pair member had restless legs syndrome (238). However, due to variability in clinical manifestations, particularly symptom severity, family history may be falsely negative. In other cases, the disorder is idiopathic.
A review proposed a continuous spectrum in restless legs syndrome with major genetic contribution on one end and comorbid or environmental contributions on the other end rather than an idiopathic versus secondary classification (302).
Phenotypes.
(1) Early onset. Starts before 36 years of age; familial history is evident; symptoms are more severe; syndrome is highly genetically determined and highly dependent on brain iron levels.
(2) Delayed onset. Starts after 36 years of age; family history is not evident; symptoms are mostly secondary; syndrome is rapidly progressive over 2 to 3 years.
Secondary restless legs syndrome may be due to systemic or neurologic disease. Changes in iron status may be etiologic in at least some patients. Restless legs syndrome is associated with iron deficiency anemia, including frequent blood donation (282). The prevalence of clinically significant restless legs syndrome in iron deficiency anemia is nine times higher than in the general population (10). Another study interviewing 15 blood donors showed no increase in restless legs syndrome (24). Pathologic studies suggest decreased iron and ferritin staining in the substantia nigra of patients with restless legs syndrome (60; 103). Serum and cerebrospinal fluid ferritin levels are lower in patients with restless legs syndrome than controls, and symptoms may respond to ferrous sulfate in those patients with low ferritin (207). Iron deficiency in rodent models has been associated with increased extracellular striatal dopamine, reduced striatal dopamine uptake, and blunted D2 receptor feedback of dopaminergic uptake. An iron-deficient diet in mouse models with brain iron deficiency mutations has shown earlier onset of restless legs syndrome-like symptoms, supporting the possibility of a continuous spectrum in restless legs syndrome with genetic and environmental contributors (16). Iron infusion has been shown to reverse some of these changes, providing a causal link between iron deficiency and restless legs syndrome (321). Levels of serum hepcidin, a key regulator of iron metabolism, as well as hepcidin/ferritin ratio, were found to correlate with periodic limb movements in sleep severity and restless legs syndrome symptoms better than ferritin alone (67). Low ferritin has been associated with developing restless leg syndrome in patients with Parkinson disease (178).
Another common association is between restless legs syndrome and uremia associated with renal failure. Uremic patients appear to have a more rapidly progressive course with a less robust response to dopaminergic treatment (83). As many as 58.3% of dialysis patients have restless legs syndrome, and as many as 70.8% have periodic limb movement disorder (83). The presence of restless legs symptoms correlates to higher levels of urea nitrogen and creatinine and lower levels of intact parathyroid hormone and is associated with increased morbidity and mortality. Positive family history, low or absent residual urine, and presence of peripheral neuropathy were predictors of risk for restless legs syndrome in patients with end-stage renal disease undergoing hemodialysis (253). Renal transplantation appears to decrease the prevalence of symptoms in this population (210). Other patients have frank vitamin deficiency, diabetes mellitus (192), rheumatoid arthritis, gastric or pulmonary disease (226), peripheral arterial occlusive disease, or congestive heart failure (115). Longer duration of dialysis and greater number of dialysis sessions were associated with restless legs syndrome, but not adequacy of dialysis (320).
Restless legs syndrome may complicate singleton or multiple gestation pregnancy (232). Predictors for restless legs syndrome in pregnancy include a family history of restless legs syndrome and a personal history of restless legs syndrome in previous pregnancies (133). The prevalence of restless legs syndrome during pregnancy is two to three times the normal population, the mechanism is thought to be related to hormonal changes, and the iron and folate levels and incidence are influenced by the trimester and the number of parity (287). Pregnancies complicated by restless legs syndrome have a higher risk for preterm birth, suggesting a need for improved sleep health in pregnant women (201). Conversely, a history of pregnancy-induced hypertension was found to be twice as likely to be associated with restless legs syndrome in women (137). An increased prevalence of preeclampsia and cardiovascular disease has also been noted in pregnant women with restless legs syndrome (186). High estradiol, low iron, ferritin, and vitamin D deficiency may play a role in developing restless legs syndrome in pregnancy (110). Additionally, it has been found that magnesium and zinc levels are lower in pregnant women with restless legs syndrome, and the lower levels are correlated with higher rates of adverse perinatal outcomes, such as miscarriage, which suggests that zinc and magnesium may play a role in the etiology of restless legs syndrome in pregnancy (346).
A prospective study suggested transient restless legs syndrome developed in nearly 9% of patients following spinal anesthesia. Those with low mean corpuscular volume and mean corpuscular hemoglobin were most at risk. Restless legs syndrome in these patients was transient, with a mean duration of 33 days (127). Symptoms of restless legs syndrome have been said to complicate the use of certain medications, including second-generation antidepressants, especially mirtazapine (03; 262), zonisamide (54), venlafaxine (160), and olanzapine (154). On the other hand, bupropion may help with restless legs syndrome (160).
Acute restless leg has been described after pontine infarcts, often in the paralyzed limb contralateral to the stroke (316). In a study, the incidence of restless leg syndrome after acute lacunar infarction was 5.33%, with pons, centrum semiovale, and basal ganglia being the common locations. Poststroke restless leg syndrome appeared to be more often unilateral and involved the arm (317). Diagnosis of restless leg syndrome after acute ischemic stroke was found to be associated with increased arterial stiffness and poorer clinical outcome 3 months after stroke (113).
Peripheral neuropathy is the most commonly reported neurologic cause of secondary restless legs syndrome (237). Although most cases are apparent by history or examination, the condition is subclinical in some cases. In eight consecutive patients with restless legs syndrome and no symptoms of peripheral neuropathy, six had clinical or electrophysiological evidence of denervation. Sural nerve biopsies showed endoneurial fibrosis, acute axonal degeneration, and thinly myelinated fibers (135). In some patients with painful polyneuropathy, nociceptive deafferentation may trigger overactivity of spinal structures implicated in restless legs syndrome (99).
Several authors have suggested that the prevalence of restless legs syndrome is increased in patients with Parkinson disease. A large cohort of Parkinson disease cases revealed a similar prevalence of restless legs syndrome in the general population, but restless legs syndrome symptoms may have been masked in patients with Parkinson disease due to dopaminergic treatment for Parkinson disease. In this study, severity of restless legs syndrome was related to the severity of nondopaminergic Parkinson disease symptoms (323). Lang has suggested that restless legs syndrome can be confused with akathisia in this population (168). Restless legs syndrome in Parkinson disease appears to be influenced by a younger onset of Parkinson disease, male gender, higher Mini-Mental State Examination score, and less advanced Hoehn and Yahr stage (27).
A study demonstrated that patients experiencing restless legs syndrome symptoms more than 15 days a month were more likely to be diagnosed with Parkinson disease within 4 years of follow-up, suggesting that restless legs syndrome symptoms may be an early sign of Parkinson disease (341).
Subsequent studies have demonstrated a higher prevalence of restless legs syndrome in patients with Parkinson disease, with a greater impact on mood, nutritional status, and quality of life (87; 345). Patients with Parkinson disease and restless legs syndrome have an older age of onset of restless legs syndrome, shorter duration of symptoms unilaterality in accordance with Parkinson disease symptoms, and lower dosage as well as shorter duration of dopaminergic medication use compared to patients with Parkinson disease without leg restlessness (348). They have also been found to exhibit variants, including restlessness without the urge to move and leg motor restlessness, and the severity of restless legs syndrome has been associated with autonomic symptoms (199).
Leg motor restlessness, defined as an urge to move the legs but not meeting the four essential criteria for restless legs syndrome, was found to be more prevalent than restless legs syndrome in Parkinson disease than controls; however, it is unclear if leg motor restlessness is a distinct entity or a part of restless legs syndrome spectrum (292). Another condition that may resemble restless legs syndrome is leg stereotypy syndrome, which is manifested by repetitive, rhythmical, stereotypic leg movement, especially when sitting, but without the urge to move or diurnal variation, which is typical of restless legs syndrome (143). Similar to restless legs syndrome, leg stereotypy syndrome is almost always familiar, but it is even more common, occurring in 7% of the general population and even more frequently in patients with other movement disorders (189).
On the other hand, there may be evidence to suggest that idiopathic restless legs syndrome may be associated with delayed onset of Parkinson disease, less dyskinesias, and maybe even slower progression (76).
Moccia and colleagues conducted a longitudinal study on restless legs syndrome in Parkinson disease and demonstrated increasing prevalence over time, later onset of Parkinson disease, and worse sleep and cardiovascular measures (208). A prospective study of restless legs syndrome in de novo patients with Parkinson disease showed a higher cumulative incidence of restless legs syndrome than in the general population. Interestingly, at the end of 3-year follow-up, current restless legs syndrome was significantly more prevalent than previously seen in the drug naïve patients with Parkinson disease and controls, suggesting that restless legs syndrome emerging in the course of chronic dopaminergic therapy is a key determinant of the comorbid association with Parkinson disease (196). Restless leg syndrome has also been found to be an independent predictor of impulse control disorders in Parkinson disease (197).
A review raised questions on whether dopaminergic therapy in Parkinson disease may mask the true prevalence of restless legs syndrome, whether restlessness in Parkinson is different from idiopathic restless legs syndrome, and if restless leg symptoms may be an early manifestation rather than a risk factor for Parkinson disease (88).
Restless legs syndrome is more common in siblings of Parkinson disease with an onset age of less than 60 than in the general population, suggesting common pathogenic genetic factors and early living environment for neurodegeneration (187).
Restless legs syndrome appears to be more common than expected in essential tremor, and many of these patients have a positive family history of restless legs syndrome, suggesting some shared genetic factors (235).
Associations have also been reported between restless legs syndrome and startle disease (hyperekplexia), stiff person syndrome, Huntington chorea, spinocerebellar ataxia 3, amyotrophic lateral sclerosis, myasthenia gravis (280), polio and postpolio syndrome (164), brainstem strokes (265), ankylosing spondylitis (294), Tourette syndrome, multiple sclerosis (69; 38), neuromyelitis optica (134), attention deficit hyperactivity disorder (315; 263), migraine (277), Isaacs syndrome (25), obesity (183), chronic obstructive pulmonary disease (188; 23), fibromyalgia (289), diabetes mellitus (108), irritable bowel syndrome (32; 347), inflammatory bowel disease (08), epilepsy (100), endometriosis (295), and cardiovascular events (172).
Bidirectional association has been noted between migraines and restless legs syndrome, with the association being stronger and longer lasting for migraine-triggering restless legs syndrome (55).
A large prospective study did not reveal an association between restless legs syndrome and increased risk of cardiovascular events (339). A prospective study of restless legs syndrome and coronary heart disease in women suggested a marginal increase in risk for cardiovascular events with symptom duration greater than 3 years (180). Men with restless legs syndrome have been found to have higher mortality, even after excluding chronic conditions and adjusting for common risk factors. This association was more frequently seen in respiratory, endocrine, metabolic, and immunological disorders, suggesting the need for further studies to understand the pathophysiology of these associations (181). Diabetes and stroke appear to increase the odds of restless legs in males, whereas alcohol consumption and frequent exercise seemed to lower the odds (338). However, a United States veterans’ study showed a four-fold increase in coronary heart disease and stroke with incident restless legs syndrome compared to controls (211). Then a subsequent case-control study showed no significant association between primary restless legs syndrome and cardiovascular disease or hypertension after controlling for confounders (58). A systemic review also showed that after adjusting for confounders, restless legs syndrome was associated with increased all-cause mortality alone and not cerebrovascular events (150).
In a large, prospective study, obesity and high cholesterol, but not high blood pressure, were significantly associated with an increased risk of developing restless legs syndrome (72). Higher comorbidity of influencing conditions, such as diabetes, hypertension, myocardial infarction, obesity, stroke, cancer, renal disease, anemia, depression, thyroid disease, and migraine, was associated with a greater risk for restless legs syndrome (293).
Patients with restless legs syndrome exhibit a tendency toward hypertension and reduced amplitude of both sympathetic and parasympathetic responses as well as blunted parasympathetic drive to blood pressure changes in autonomic testing, suggesting autonomic nervous system involvement during wakefulness and consequently an enhanced cardiovascular risk in restless legs syndrome (142). Compromised cardiovagal tone and increased peripheral vascular resistance may mediate some of the cardiovascular effects (39). Significant correlations have been noted between periodic limb movements of sleep and nocturnal systolic, diastolic blood pressure elevations (48), restless legs syndrome, and nocturnal systolic blood pressure (281). Frequent restless leg syndrome, along with PLMS index scores of 26/hour or more, was associated with a higher risk of resistant hypertension (123).
Flow-mediated dilation, a measure of endothelial vascular function, has been noted to be affected in restless legs syndrome, suggesting a putative mechanism for vascular effects from restless legs syndrome (158). Poorer endothelial function has also been demonstrated on transcranial Doppler studies of cerebral blood flow in patients with restless legs syndrome (156).
A systematic review found limited evidence for restless legs syndrome as a prognostic factor for cardiovascular events or all-cause mortality; however, periodic limb movements in sleep may be an independent prognostic factor (152). A prospective study that included 57,147 women without cancer, cardiovascular disease, or renal failure at baseline found that restless leg syndrome was not associated with a higher risk of all-cause mortality, but it was significantly associated with cardiovascular disease mortality (182). However, a case-control longitudinal study that followed 235 patients, both men and women over 11 years, showed that age-standardized mortality rates and cardiovascular risk factors were not elevated in patients with restless leg syndrome (64).
Patients with restless legs syndrome exhibited an impairment of the long-term depression-like mechanisms induced by inhibitory repetitive transcranial magnetic stimulation, thus supporting the involvement of GABA in restless legs syndrome pathophysiology and impairment of short-term neural plasticity (170).
Pre-stroke restless legs syndrome was found to be a predictor for subcortical stroke (111), and silent small vessel disease was noted to be more common in patients with long-standing restless legs syndrome (more than 10 years) (90).
Multiple mechanisms may be involved regarding cardiovascular risk in restless legs syndrome, ranging from premenstrual syndrome-mediated vascular changes to the effect of iron deficiency on cardiovascular function and sleep deprivation or fragmentation and its effects on the oxidative, metabolic, and vascular systems (107).
The pathogenesis and pathophysiology of restless legs syndrome are not clear, although the association with peripheral neuropathy suggests that peripheral nervous system dysfunction may be important in the generation of the syndrome. Increased risk of restless legs syndrome in familial amyloid polyneuropathy supports the association between restless legs syndrome and polyneuropathy (296). The circadian rhythm of the movements and the periodicity of associated leg movements of sleep suggest the movements are organized at a higher level of the nervous system.
Electrophysiologic studies suggest that the movements are involuntary and are organized at the brainstem or spinal level (305; 57). Patients with periodic leg movements of sleep, with or without associated restless legs syndrome, may have abnormal blink reflexes, somatosensory-evoked responses, long latency responses, or H-reflexes, suggesting pontine or more rostral dysfunction (198). Functional magnetic resonance imaging studies suggest that the red nucleus and brainstem are generators for the abnormal movements of restless legs syndrome (44). Jerk-locked back averaging reveals no cortical precedent to the movements occurring during sleep (190). During wakefulness, no Bereitschaftspotential (cortical pre-movement) precedes the movements (306). Research subjects with restless legs syndrome have shortened cortical silent period compared to controls as assessed by transcranial magnetic stimulation with recording from the anterior tibialis muscle. Treatment with the dopamine agonist cabergoline normalized the cortical silent period in these subjects (106). Functional imaging studies have shown significantly increased connectivities in the sensory thalamic, ventral, and dorsal attention, basal ganglia-thalamic, and cingulate networks in patients with restless legs syndrome, suggesting that the pathophysiology of restless legs syndrome is beyond the sensorimotor regions (104).
MRI voxel-based morphometry showed increased gray matter volume in the pulvinar bilaterally in 51 subjects with idiopathic restless legs syndrome compared to 51 age-matched control subjects (84). Similarly, a decrease in gray matter volumes has been noted in the left hippocampal gyrus, bilateral parietal lobe, medial frontal areas, and cerebellum (51). Alterations in subcortical gray matter volume in putamen have been noted to correlate with disease duration in restless leg syndrome (179).
Average cortical thickness in the bilateral post-central gyrus and the corpus callosum posterior midbody was noted to be lower in patients with restless legs syndrome than in controls, suggesting altered white matter properties in the somatosensory pathway (174). White matter changes were detected in the left corticospinal tract and cingulum and in the right anterior thalamic radiation and inferior fronto-occipital fasciculus in patients with restless leg syndrome. Also, the number of periodic leg movements and movement arousal index were correlated with alterations in white matter in the corticospinal tract (242).
Neuropathological studies suggest that restless legs syndrome may result from impaired iron acquisition by neuromelanin cells, possibly because of impaired transferrin receptor regulation (60). Subjects with restless legs syndrome have lower serum and CSF iron and ferritin. There is a correlation between these measures in serum and cerebrospinal fluid, but the slope is lower in restless legs syndrome subjects than in normal controls, suggesting disordered transport of iron from the periphery to the central nervous system (207). A postmortem and imaging-based study revealed a decrease in myelin in patients with restless legs syndrome similar to that reported in animal models of iron deficiency (61). The presence of less myelin and loss of myelin integrity in the brains of patients with restless legs syndrome in combination with decreased ferritin and transferrin in the myelin fractions, presents a strong case of brain iron insufficiency in restless legs syndrome. A study also noted a continuum of substantia nigra echogenicity between patients with Parkinson disease (with and without restless legs) and those with SCA-3 (with and without restless legs) as well as controls, and restless legs syndrome severity inversely correlated with substantia nigra echogenicity, further supporting the role of brain iron metabolism in the pathogenesis of restless legs syndrome (247).
Phase analysis MRI has shown higher phase values in patients with restless legs syndrome at the level of the substantia nigra, thalamus, putamen, and pallidum, indicating reduced iron content in several regions of the brain of the patients and supporting the hypothesis of reduced brain iron content in patients with restless legs syndrome (260).
Patients with restless legs syndrome showed reduced thalamic connectivity with the right parahippocampal gyrus, right precuneus, right precentral gyrus, and bilateral lingual gyri, and restless legs syndrome severity was negatively correlated with connectivity between the thalamus and right parahippocampal gyrus, suggesting that patients with restless legs syndrome may have deficits in controlling and managing sensory information (161). Additionally, patients with restless legs syndrome showed alterations in salience network functional connectivity in the right pyramis, bilateral orbitofrontal gyri, and right postcentral gyrus, suggesting that sensory processing and inhibitory mechanisms could be disrupted (162).
A review on restless legs syndrome synthesizing the results from PET studies, functional MRI of white matter pathway, and brain iron content in restless legs syndrome hypothesized that the primary change could be the reduction of brain iron content, which leads to dysfunction of mesolimbic and nigrostriatal dopaminergic pathways, and in turn to dysregulation of limbic and sensorimotor networks (259).
A study involving quantification of advanced oxidation protein products and total thiol levels revealed that increased advanced oxidation protein products, malondialdehyde levels, and decreased thiol and nitric oxide levels may be indicative of patients with restless legs syndrome under oxidative stress (30). These factors may cause restless legs syndrome pathogenesis.
Dysregulation, instead of upregulation or downregulation, of central dopaminergic neurotransmission could be the underlying cause of the restless legs syndrome pathogenesis, as revealed by the assessment of dopamine transporter density using [(123) I]2β-carbomethoxy-3β-(4-iodophenyl)tropane single-photon emission computed tomography (SPECT) and [(123) I]iodobenzamide SPECT. A decreased dopaminergic neurotransmission may cause moderate to moderately severe restless legs syndrome in elderly patients (155).
Symptoms of restless legs syndrome improve when treated with dopaminergic medications and worsen with gamma-hydroxybutyrate, which blocks dopamine release (35), and pimozide (a dopamine receptor blocker) (06). In a single patient with familial restless legs syndrome, CSF-free dopamine and homovanillic acid levels were increased (217). Some authors have shown evidence of reduced 18-F-dopa uptake or reduced dopamine receptor binding in the caudate and putamen of patients with restless legs syndrome, suggesting a central dopaminergic deficit (264), but others have failed to confirm this (312). Single-photon emission computed tomography with the striatal dopamine transporter ligands [(123)I] N-(3-iodopropen-2-y1)-2beta-carbomethoxy-3beta-(chloro-phenyl) tropane and [(123)I]-2-beta-carboxymethoxy-3 beta-[4-iodophenyl] tropane showed no difference between subjects with restless legs syndrome and controls, compared to subjects with Parkinson disease, suggesting no presynaptic dopamine deficit in restless legs syndrome (184; 219). However, studies of striatal D2 receptor binding using iodobenzamide SPECT were suggestive of a post-synaptic dopaminergic disorder at this level, either a reduced number of D2 receptors or decreased affinity of the receptors for the ligand (205). The alterations in mesolimbic D2/3 receptor function reflect the pathophysiology of idiopathic restless legs syndrome, and the baseline availability of these receptors may predict the clinical outcome when patients are treated with D2/3 agonists (225). Preferential targeting of the dopamine D3 receptor subtype by agonists shows higher efficacy on restless legs syndrome than preferential targeting of the D2 receptor subtype (194). CSF studies showed large diurnal changes in tetrahydrobiopterin and serotonin and dopamine metabolites in subjects with restless legs syndrome compared to control subjects, suggesting greater than normal fluctuations in dopaminergic circadian rhythms (80). An animal model of restless legs syndrome produced by injecting the neurotoxin 6-hydroxy dopamine into A11 dopaminergic neurons in rats remains under development (236). The thymocyte differentiation antigen-1 (Thy-1) knockout mouse is a potential rodent model of restless legs syndrome based on clinical observations and the role of dopamine in the disease (46). Drosophila fly models with mutations in the homologue of human gene BTBD9 showed disruption in sleep architecture and motor restlessness, thus recapitulating key features of restless legs syndrome (278). They also showed lower brain dopamine levels. The abnormal sleep fragmentation was rescued by D2 receptor agonist pramipexole, thus supporting the evidence for BTBD9 as a risk factor for restless legs syndrome. Genetic studies have suggested that excess high-activity monoamine oxidase alleles contribute to the susceptibility to restless legs syndrome in women; however, this association is not particularly strong (70).
There has been evidence for adenosine pathway involvement and a complex interplay between adenosine, dopamine receptors, and cell adhesion molecules in the neural plasticity in restless legs syndrome and development of augmentation, suggesting possible new targets for treatment (81). Brain iron deficiency in rat models has been shown to downregulate adenosine A1 receptors, leading to hypersensitive striatal glutaminergic terminals and facilitation of striatal dopamine release (89). Striatal H3 receptor levels in mouse models were also found to positively correlate with periodic limb movements of sleep and negatively correlate with hematocrit, suggesting a role for H3 receptor blockers in restless leg syndrome (167).
Response of symptoms to opioids, and interference with this response by the opiate antagonist naloxone, suggests that restless legs syndrome may also relate to dysfunction of the endogenous opiate system (331). A theory that attempts to unite these pharmacologic observations with studies of abnormal iron metabolism in restless legs syndrome suggests that altered iron status affects both the opiate and dopaminergic systems because both the dopamine D2 receptor and the mu-opiate receptor are iron-dependent (288). Triple knockout mice lacking mu, kappa, and delta receptors showed hyperactivity and increased probability of waking during the rest period as well as decreased serum iron concentration and a significant dysfunction in dopamine metabolism, suggesting a role for the endogenous opioid system in iron metabolism (191). A small MRI study suggested reduced putaminal iron in patients with restless legs syndrome (12).
A study of hypocretin-1 (orexin A) levels in CSF obtained in the late evening in 16 patients with restless legs syndrome and eight control subjects suggested increased hypocretin that was especially marked in early-onset cases (17). It has been proposed that elevations in hypocretin might promote insomnia and increased motor activity.
Family history is positive in up to 92% of cases, which means that genetics plays a key role in the pathogenesis of restless legs syndrome. Most studies suggest autosomal dominant transmission with nearly complete penetrance (311). The phenomenon of genetic anticipation may be present, although ascertainment bias cannot be excluded in such studies (311). Family studies have suggested linkage to a number of genetic loci, including chromosome 12q (71), 13q (28), 14q (43), 19p13 (151; 284) and 20p13 (177). Genome-wide association studies have identified positive associations with protein tyrosine phosphatase receptor type delta (PTPRD) at 9p23-24 (275) and loci on chromosomes 9p22-24, 2q, 6p, and 15q (56; 252), loci on 2p14 and 16p12.1 (336) and 16p12.1 in a French Canadian pedigree (176). Restless legs syndrome and sensorimotor axonal polyneuropathy with fasciculations have been reported in a few patients with intermediate repeat lengths in the spinocerebellar ataxia-3 (Machado-Joseph disease) gene (322).
A genome-wide association study identified a significant association of SNP rs1026732 in MAP2K5/SKOR1, in addition to variants in the MEIS1 and BTBD2 genes, and restless legs syndrome (344). The MEIS1 variant influences iron homeostasis (49) as well as altered sympathovagal balance in homozygotes for risk allele (298). MEIS1 variants have been confirmed to be the strongest genetic risk factor for restless legs syndrome (276); others include PTPRD and BTBD9 variants. MEIS1 ortholog in animal models has been linked to iron homeostasis and reduced MEIS1 expression in mouse models resulted in circadian hyperactivity phenotype similar to restless leg syndrome, suggesting a link to the restless leg biological pathway (271).
PCDHA3 has been suggested as a candidate gene for restless legs syndrome based on genome-wide linkage analysis and exome sequencing in a German family with autosomal dominant restless legs syndrome (333).
A study suggested an association between GABRR3rs832032 polymorphism and the risk for restless legs syndrome and a modifier effect of GABRA4 rs2229940 on the age of onset of restless legs syndrome (145).
Mutational load analysis identified 14 genes of significance with restless leg syndrome; nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) are in the vicinity of known restless legs syndrome loci, and 5 (BBS7, CADM1, CREB5, NRG3, SUN1) were not previously associated with restless legs syndrome (300).
A large genome-wide association identified three novel associations with restless leg syndrome: rs112716420-G, rs10068599-T, and rs10769894-A, which are associated with MICALL2 and UNCX, RANBP17 (Ran-binding protein 17), and LMO1 proteins, respectively. MICALL2 and UNCX are associated with hematocrit, hemoglobin, and glomerular filtration rates, but their role in iron homeostasis is unknown. RANBP17 (Ran-binding protein 17) is mainly expressed in the basal ganglia and cerebral cortex, and variants have been associated with visceral fat, body mass index, and high-density lipoprotein cholesterol. LMO1 encodes the protein rhombotin-1, and variants have been associated with neuroblastoma and T-cell leukemia because MEIS1 is also associated with leukemias and neuroblastomas (73). No animal model replicates all of the clinical features of resltess legs syndrome, but BTBD9 knockout mice showed motor restlessness, and striatal MEIS knockout mice demonstrated hyperactivity with a circadian trend (153).
Upregulation of the hypoxia pathway is demonstrated in multiple cell types in restless legs syndrome individuals. Increased nitric oxide synthase and nitrotyrosine suggest that nitric oxide is involved in hypoxia activation (244).
Reduced expression of mitochondrial iron genes as well as iron regulatory protein has been noted in restless leg patients, with improvement in mitochondrial respiratory capacity in patients on dopaminergic medications (118).
Epidemiology
No interventions have been shown to prevent the occurrence of restless legs syndrome.
Differential diagnosis
Akathisia is defined as an inner sense of restlessness relieved by voluntary leg movement. Although both restless legs syndrome and akathisia are typified by motor restlessness and sleep disorder, akathisia sufferers describe an inner sense of restlessness rather than the leg discomfort seen in restless legs syndrome. Also absent in akathisia is the striking predominance of evening and bedtime symptoms characteristic of restless legs syndrome. Neuroleptic use or exposure is a common feature in the history of those with akathisia. Polysomnography suggests that although both syndromes decrease sleep efficiency, the abnormalities are milder with akathisia (328).
Hypnic myoclonus, or sleep starts, occurs during the transition from wakefulness to sleep. Brief, massive body movements are synchronous on both sides and lack the periodicity of periodic leg movements of sleep. They are associated with sudden arousal and may be accompanied by a sensation of sinking or falling. No localized discomfort exists in the legs, nor is there inner restlessness (216).
"Vesper's curse" comprises lumbosacral and leg pain with calf cramps and fasciculations that arouse the patient from sleep. The pain and paresthesias are often accompanied by an inner urge to move the legs, similar to that seen in restless legs syndrome. The etiology of "Vesper's curse" is lumbar spinal stenosis with congestive heart failure. Increased right atrial filling pressure, secondary to the failure, is reflected in increased paraspinal venous volumes within the reduced confines of a stenotic lumbar spine. The symptoms may be relieved by assuming an erect or semi-reclining sleep position and are improved with adequate treatment of congestive heart failure (166).
Painful legs and moving toes syndrome may develop in the context of chronic or postsurgical back pain. Severe pain in one or both feet is associated with involuntary irregular wriggling and writhing movements of the toes, foot, or proximal muscles.
The patient cannot imitate the movements, which do not show preference for evening hours (285).
Diagnostic workup
Physical and neurologic examinations are usually normal in restless legs syndrome. The diagnosis rests on clinical criteria. The International Restless Legs Study Group (IRLS) rating scale has been shown to correlate significantly with polysomnographic measures of periodic leg movements during sleep and sleep efficiency as well as with results of the suggested immobilization test (07). Stiasny-Kolster has reported that a reduction in the severity of restless legs symptoms in the 2 hours following a single dose of carbidopa/levodopa 25/100 can diagnose the disorder with 88% sensitivity and 100% specificity (291).
No laboratory study reliably identifies restless legs syndrome. However, because of the association with systemic illness, especially with iron deficiency, it is wise to do screening serum chemistries and hematologic tests (including iron and ferritin) for systemic causes of the syndrome. Peripheral neuropathy may be ruled out using EMG and nerve conduction velocity studies. When clinically indicated, additional cardiac or pulmonary studies may be helpful to assess for the presence of underlying systemic illness.
Although all-night polysomnography may help quantify leg movements of wakefulness and confirm the presence of periodic leg movements of sleep, its utility in the diagnosis is debatable. One study suggested that two polysomnographic measures, the index of periodic leg movements during nocturnal wakefulness and the mean subjective leg discomfort score during the suggested immobilization test, correctly classified 88% of subjects, with a diagnostic sensitivity of 82% and specificity of 100% (204).
Management
There are many therapeutic strategies to achieve optimal outcomes in patients with restless legs syndrome (126). Several ways exist to assess treatment outcomes in restless legs syndrome. Many studies have relied on subjective reports of the presence and severity of paresthesia, leg movements, and sleep disruption. Polysomnographic recordings allow quantitation of leg movements when awake and demonstrate the number and amplitude of periodic leg movements of sleep (218).
Chronic renal failure and severe restless legs syndrome (polysomnogram)
Periodic leg movements during wakefulness in a 50-year-old woman with chronic renal failure and severe restless legs syndrome. The movements occur every 17 seconds to 18 seconds and are more vigorous in the right leg than the left...
In the forced immobilization test, the subject sits with the legs restrained and signals awareness of abnormal leg sensations when concurrent EMG recordings are made from the tibialis anterior muscles (218). The need for objective measures and placebo-controlled trials in this condition is underscored by a robust response to placebo in many trials (42). The magnitude of placebo response in restless legs syndrome is over the threshold for minimal clinically important difference, making it hard to interpret the response (283).
The International Restless Legs Scale correlates with objective signs of restless legs syndrome as measured by the frequency of and arousals associated with periodic limb movements of sleep and shows good psychometric properties for studying restless legs syndrome (343). The Restless Legs Syndrome Quality of Life questionnaire is a reliable, valid, and responsive tool in clinic-based populations and large-scale clinical trials (01).
The first aim of medical management of restless legs syndrome is to appropriately correct iron deficiency. Iron supplementation in patients with restless legs syndrome and low iron and ferritin levels improves motor and sensory symptoms and also may improve sleep, daytime sleepiness, depression, fatigue, and quality of life (65). Iron treatment could be useful in pediatric restless legs syndrome, as demonstrated in Japanese children (209). Studies have noted poor iron status in regular blood donors, and one study suggests iron supplementation with intravenous iron sucrose as more efficient than oral iron sulfate; this was shown as especially helpful in women to prevent the development of restless legs syndrome (40). Evaluating a new iron formulation, ferric carboxymaltose, with molecular properties that may make iron more available to the brain than iron sucrose, significantly improved primary and secondary restless legs syndrome symptoms (09). A single dose of intravenous ferric carboxymaltose led to significant improvement in restless legs symptoms in patients with iron deficiency or low normal ferritin, with responses noted within 1 week (130), though a randomized study suggested more delayed response by 12 weeks (313).
In one study, vitamin D supplementation was associated with improved restless legs syndrome severity in patients with vitamin D levels lower than 50 nmol/L; median levels in the study were around 21.7 nmol/l (326). Another study supplemented vitamin D-deficient patients with 50,000 units per week for 2 months and showed a positive impact on symptom severity, disease measures, and sleep (318).
The patient’s medication list should be reviewed for medications that are known to possibly exacerbate restless legs syndrome, which includes antihistaminergics, selective serotonin reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors, mirtazapine (anti-histaminergic, anti-adrenergic, anti-serotonergic), and lithium (222). The indication and dosing for these medications should be discussed with the prescribing provider, such as a consulting psychiatrist to understand if lower doses or alternatives could be tried.
The focus of management should then turn to symptom control. Symptomatic management of restless legs syndrome includes four major pharmacologic categories: (1) benzodiazepines, (2) opioids, (3) dopaminergics, and (4) some antiepileptics (112). Other medications used include clonidine, baclofen, carbamazepine, quinine, vitamin B12 and vitamin E, and folic acid (218). Vitamins C and E and their combination were shown to be effective in reducing restless legs syndrome severity in hemodialysis patients (266). According to an evidence-based review, the following drugs were considered efficacious for the treatment of restless legs syndrome: levodopa, ropinirole, pramipexole, cabergoline, pergolide, gabapentin, and a prodrug, gabapentin enacarbil; drugs considered likely efficacious are rotigotine, bromocriptine, oxycodone, carbamazepine, valproic acid, clonidine (309), and pregabalin (45).
Benzodiazepines. Benzodiazepines have been used in uncontrolled and a few controlled studies. Clonazepam is the most studied member of this class. A single nighttime dose of 0.5 to 2.0 mg has been shown to improve subjective measures of sleep efficiency as well as unpleasant leg sensations in short- and long-term uncontrolled trials (273; 218). In a controlled trial in six patients, clonazepam was found to be superior to placebo in improving sleep quality and leg discomfort (213). In contrast, Boghen found that clonazepam was not superior to placebo in improving subjective measures in six patients with restless legs syndrome (42). Studies of the effect of clonazepam on the movements of periodic leg movements of sleep are contradictory. In a double-blind, placebo-controlled parallel study of clonazepam in 20 patients with periodic leg movements of sleep, clonazepam decreased the number of leg movements and improved sleep parameters (248). Others have found that benzodiazepines improve the sleep of patients with periodic leg movements of sleep, but without significantly altering the number of leg jerks (269). Long-term (more than 6 months) therapy with clonazepam remains efficacious and is not associated with a high risk of dose tolerance, adverse effects, or abuse (274). Diazepam, alprazolam, nitrazepam, temazepam, and triazolam have also been used to treat restless legs syndrome and periodic leg movements of sleep. Short-acting benzodiazepines may be less effective than clonazepam in suppressing leg movement in these conditions, but they do effectively decrease nighttime arousals (75). A Cochrane review concluded that the effects of benzodiazepines on restless legs syndrome are unknown at this point (47). Effects of benzodiazepine therapy include excessive sedation, decreased libido, and nocturnal confusion or wandering.
Opioids. The history of opioid treatment of restless legs syndrome dates to Ekbom's 1945 manuscript. The effectiveness of opioids may relate to decreasing arousals without altering the frequency of leg movements (149). A retrospective review of 113 opioid-treated patients with restless legs syndrome suggested good long-term efficacy using clinical and polysomnographic measures (332). Concerns about the addictive potential of these treatments have led many authors to recommend them as treatments of last resort (216). Tramadol, a centrally acting analgesic that is better tolerated and has a lower addictive potential than classical opioids, has been shown effective in a small open-label trial (171). Methadone (15.5 ± 7.7 mg/day) reduced symptoms in an open trial in patients with refractory restless legs syndrome (233). An acute challenge with intravenous apomorphine (a combined opioidergic and dopaminergic agonist) was effective in a small trial (314). Two patients whose restless legs syndrome symptoms proved refractory to other medical interventions were safely and effectively treated with nocturnal subcutaneous apomorphine infusion (258). Refractory symptoms have been reported to improve with intrathecal morphine (261).
Prolonged release oxycodone/naloxone improved restless legs syndrome symptom severity and sleep quantity and adequacy, resulting in greater sleep satisfaction, less daytime tiredness, and improved quality of life, suggesting an alternative treatment option for severe restless legs syndrome that cannot be controlled by first-line dopaminergic medications (229).
Dopaminergics. Levodopa administered with a peripheral dopa decarboxylase inhibitor (carbidopa or benserazide) has been shown to be effective in treating restless legs syndrome and periodic leg movements of sleep in many studies (62). Although there is considerable evidence of short-term efficacy, long-term course has not been adequately studied. The drug’s short half-life is the main limitation of levodopa therapy for restless legs syndrome. Symptoms and polysomnographic abnormalities generally recur 4 to 6 hours following a bedtime dose of standard levodopa, which is consistent with the drug’s half-life. This phenomenon, called “augmentation,” has been approached by administration of a second levodopa dose 3 hours after bedtime or by combining controlled release levodopa with the standard preparation. The combination of immediate release and sustained release levodopa preparations leads to a significant improvement in measures of restless legs syndrome. Improvements in sleep efficiency and subjective sleep quality also improve, though the onset of improvement in these parameters may be somewhat delayed (268). However, long-term studies suggest that only 40% of patients continue to have good efficacy for 1 year or more (308). An evidence-based review found good evidence to support the use of short-term treatment with levodopa (particularly for treating periodic leg movements of sleep) but insufficient evidence of long-term safety and efficacy (62). In patients who have developed augmentation with more than one dopaminergic drug, treatment should be switched to nondopaminergics and opiates (98).
Direct-acting dopamine agonists have the advantage of longer half-lives than levodopa and have emerged as the preferred treatment for the disorder. Symptoms of restless legs syndrome can improve after the first dose of agonist. There have been two large randomized, double-blind, placebo-controlled clinical trials of ropinirole in restless legs syndrome. Both studies showed that ropinirole was safe, well-tolerated, and improved symptoms of restless legs syndrome, sleep quality, quality of life, and anxiety (41). A 6-week, randomized, double-blind study of pramipexole (median dose 0.35 mg/day) in subjects with severe restless legs syndrome showed significant improvement in the pramipexole arm. Overall, 63% of pramipexole-treated versus 32.5% of placebo-treated patients improved (230). In a long-term open-label study, 81% of pramipexole-treated subjects had a 50% or more reduction in International RLS Study Group Scale score at 26 weeks, and 90% rated themselves as much or very much improved. Headache and fatigue were the most common adverse effects (243). Long-term benefit and good long-term tolerability have been reported with pramipexole (215). A meta-analysis of published clinical trials of ropinirole and pramipexole found both treatments superior to placebo for treating restless legs syndrome. Pramipexole was felt to show superior efficacy and tolerability compared to ropinirole in this study (256). Both pramipexole and ropinirole have been FDA-approved for treating restless legs syndrome. In a Japanese study, primary restless legs syndrome sufferers of older age (55 years or older) and low IRLS score at baseline (less than 21.5 points) were significantly associated with early response to low-dose pramipexole therapy (139; 140). Pramipexole has also been reported to improve restless legs syndrome-related mood disturbances (212). Similar benefits have been demonstrated with 1 to 4 mg of cabergoline daily (227). A randomized, blinded clinical trial comparing cabergoline (2 to 3 mg daily) and levodopa and benserazide (200 to 300 mg levodopa) for 30 weeks in 361 research subjects with restless legs syndrome showed cabergoline was superior to, but somewhat less well tolerated than, levodopa (303). Randomized, double-blind, placebo-controlled studies of rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome showed good efficacy and tolerability for doses up to 3 mg/24 hours (230; 228; 231; 304; 125). A 2-year safety follow-up trial using a rotigotine patch in doses between 0.5 to 4 mg/24 hours demonstrated that it is efficacious and well-tolerated in moderate to severe restless legs syndrome (128). The rate of typical dopaminergic side effects, nausea, and fatigue was low; application site reactions declined over time (53). The safety profile of rotigotine is comparable to other non-ergolinic dopamine agonists. Nevertheless, the transdermal delivery may result in local, mild skin reactions leading to treatment discontinuation in a minority of patients (286). A rotigotine patch is now approved for use in moderate to severe restless legs syndrome, with the highest recommended dose being 3 mg per 24 hours. Extended-release pramipexole has been shown to treat augmentation induced by treatment with l-dopa, rotigotine, ropinirole, and immediate-release pramipexole, with treatment results sustained over mean follow-up periods of 13 months or more (193). Rotigotine has also been shown to reduce augmentation in severe restless legs syndrome on oral dopaminergic therapy (307). Additionally, rotigotine has been shown to reduce periodic limb movement-associated nocturnal systolic blood pressure elevations in moderate to severe restless legs syndrome (33).
Other dopamine agonists suggested to be useful in open-label or small controlled trials include piribedil (85), alpha-dihydroergocryptine (297), and oral and transdermal lisuride (36). Because they are well-tolerated, highly effective, and associated with little, if any, symptom rebound, dopamine agonists have largely replaced levodopa in the treatment of restless legs syndrome (59).
Treatment with dopaminergic agents usually promotes wakefulness in patients with restless legs syndrome with daytime sleepiness but may infrequently cause daytime sleepiness (148). Tolerance and augmentation may occur with long-term use of dopamine agonists, but these problems tend to improve with dose adjustment (337). At baseline, patients with restless legs syndrome were found to have similar incidences of impulsivity, impulse control disorders, and addictive behavior as age- and sex-matched controls (34). Some agonist-treated patients with restless legs syndrome will develop impulse control disorders, such as pathological gambling, shopping, or hypersexuality. Patients with restless legs syndrome with mood and stress states may be at greater risk of impulse control disorders with dopamine agonists (255). Patients with restless legs syndrome and augmentation may have up to 6-fold increased risk for exhibiting impulse control disorder symptoms, suggesting a need to screen such patients for impulse control disorder symptoms (120).
Typically, stopping the agonists or lowering the dose results in improvement but, first, may lead to severe personal and financial distress (159). A survey of 261 patients with idiopathic restless legs syndrome revealed increased gambling behavior in about 7% and increased sexual desire in 5% (78). The mean duration of treatment before onset of impulse control disorders was 9.5 months (63).
Dopamine agonists frequently cause gastrointestinal side effects and are associated with excessive daytime sleepiness and peripheral edema. These agents have also infrequently been associated with serious complications such as pleuropulmonary or retroperitoneal fibrosis. Most such cases have been associated with longstanding treatment with ergot-derived agonists (pergolide, bromocriptine, cabergoline) in Parkinson disease, but there have been anecdotal reports in restless legs syndrome (342; 66). These effects are generally believed to be related to their ergot properties. There is accumulating evidence that fibrotic valvulopathy, such as is seen in carcinoid syndrome, may occur in association with pergolide or bromocriptine therapy in Parkinson disease (131). Pergolide has been withdrawn from the market due to the risk of cardiac valvulopathy. Although the risks of dopamine agonists in restless legs syndrome treatment need further study, the treating physician should exercise caution in their use. It would seem prudent to avoid ergot-derived dopamine agonists and to clinically monitor patients treated with non-ergoline agents for toxicity.
Gabapentin. A double-blind placebo-controlled crossover study of gabapentin in 24 patients with restless legs syndrome (22 idiopathic, two related to iron deficiency) showed improvements in clinical rating scales, reduced periodic leg movements during sleep, and improved sleep architecture during gabapentin treatment. The mean effective dose was just under 2000 mg daily. The duration of the study was short, with just 6 weeks of treatment in each arm of the study. A double-blind placebo-controlled crossover study in 16 hemodialysis patients with restless legs syndrome found gabapentin superior to placebo (299). A brief open trial in which treatment to ropinirole (0.25 to 1.5 mg) or gabapentin (300 to 1200 mg) was randomized showed the two agents were similarly effective and well-tolerated (116). Gabapentin has been shown to be safe and efficacious in low doses of 100 mg for uremic restless legs syndrome (52). Because gabapentin, in contrast to dopaminergic drugs, has a low risk of augmentation and gabapentin enacarbil is often not covered by third-party payers, generic gabapentin is now considered the drug of choice in restless legs syndrome (334).
Pregabalin. Pregabalin was found to be more effective than placebo for moderate to severe restless legs syndrome, with mild adverse effects of daytime somnolence, headache, and unsteadiness (45). A dose of 123.9 mg/day provided 90% efficacy at 6 weeks (15). It also improves sleep architecture and periodic limb movements in placebo-unresponsive patients (97).
Pregabalin provided significantly improved treatment outcomes compared to placebo, and augmentation rates were significantly lower with pregabalin than with 0.5 mg of pramipexole (14).
Gabapentin enacarbil. Gabapentin enacarbil is a GABA analogue, a precursor to gabapentin, and is better absorbed with sustained dose-dependent bioavailability. It has been approved by the U.S. Food and Drug Administration for the management of restless legs syndrome in adults. In clinical trials, it has demonstrated superiority over placebo for restless legs syndrome and is well tolerated and safe (165; 04; 136; 119). Doses from 1200 to 1800 mg/day appeared effective in treating restless legs syndrome with mild side effects of dizziness and somnolence (202). It has been shown that gabapentin enacarbil at 600 mg/day or lower doses may treat subjective restless legs syndrome symptoms, and 1200 mg/day or higher doses may help both subjective restless legs syndrome symptoms and associated problems, such as severe sleep disturbances (163).
Long-term treatment, up to 52 weeks, with gabapentin enacarbil improved restless legs syndrome symptoms in Japanese patients with an acceptable safety profile (141).
Interestingly, at least one study has demonstrated that prior dopaminergic use reduced the effectiveness of gabapentin enacarbil, suggesting that nondopaminergic options may be better as first-line treatment for restless legs syndrome (94).
Clonidine. In three small uncontrolled studies and two small controlled studies, clonidine was found effective in treating restless legs syndrome. Overall, 37 of 51 patients included in these studies benefited from clonidine treatment (114; 31; 290; 325). However, another study failed to confirm the usefulness of clonidine in this condition (29).
Baclofen. Baclofen has been shown in a single study to reduce sleep disturbance in patients with restless legs syndrome. Although the force and amplitude of periodic leg movements were reduced, their number was increased. The reported dose range was 20 to 40 mg at bedtime (109).
Other drugs. Amantadine (100 to 300 mg daily), a drug with putative dopaminergic and antiglutamatergic effects, improved symptoms of restless legs syndrome in 21 patients in an open-label trial (86). Two double-blind placebo trials using carbamazepine 200 to 1000 mg daily have shown improvements in subjective measures of restless legs symptoms. The effects of carbamazepine have not been studied using polysomnography. A few case reports outlined the benefit of oxcarbazepine, the keto derivative of carbamazepine (146). A double-blind placebo-controlled trial of iron in 27 patients with restless legs syndrome showed no benefit (68).
Preliminary results suggest significant effects on sensory and motor symptoms in restless legs syndrome with the AMPA antagonist perampanel, suggesting an alternative to dopaminergic agents (95).
A small study testing the adenosine hypothesis in restless legs syndrome has shown that nonselective equilibrative nucleoside transporter (ENT) 1/2 Inhibitor, dipyridamole, has significant therapeutic effects on both sensory and motor symptoms, as well as sleep with minimal side effects (96).
Two independent pilot trials of botulinum toxin A in restless legs syndrome showed no benefit (221; 101). However, in another pilot trial treatment with onabotulinum toxin A (Botox®) demonstrated a statistically significant improvement in restless legs syndrome during the first 4 weeks after the treatment (05). There has been some debate about intramuscular versus intradermal botulinum toxin administration, with the latter possibly enhancing the nociceptive effects of botulinum toxin on the sensory symptoms in restless legs syndrome (144). A trial of incobotulinumtoxin A injected into the tibialis anterior, gastrocnemius, and biceps femoris muscles showed a reduction in the severity of restless legs syndrome symptoms, pain score, and quality of life without any adverse effects (206).
An isolated case report mentions the use of intravenous physostigmine for perioperative restless leg exacerbation with good response (245).
Some patients with restless legs syndrome rapidly develop tolerance to medications. Current practice is to prescribe medication cycles, changing between medication classes every several weeks.
Nonpharmacologic treatments. Nonpharmacologic treatments may be useful in patients who rapidly become tolerant to medications. Transcutaneous electric nerve stimulation may be useful in some patients.
Some suggest that high-frequency repetitive transcranial magnetic stimulation delivered to the leg area of the primary motor cortex may raise functional activity in the sensorimotor regions, leading to improved restless legs syndrome symptoms (185). Low-frequency, repetitive transcranial magnetic stimulation to the primary somatosensory and motor areas has also been shown to alleviate sensory and motor symptoms in restless legs syndrome (169).
Parathyroidectomy can relieve some symptoms associated with restless legs syndrome in hemodialysis patients with severe secondary hyperparathyroidism and elevated serum phosphate (270).
A randomized trial in 28 subjects with restless legs syndrome showed a significant effect of aerobic and lower-body resistance training over 12 weeks (26). Intradialytic aerobic exercise has shown improvement in restless legs syndrome symptoms in hemodialysis patients (267).
An exploratory trial looking at 12 weeks of yoga in patients with moderate to severe restless legs syndrome showed improvements in the severity of restless legs syndrome, perceived stress, mood, and sleep quality (138).
A proof of concept study suggested a specific cognitive behavioral therapy (the RELEGS coping therapy program) may improve quality of life and mental health status in patients with restless legs syndrome, but this requires further study (129).
Acupuncture point injection markedly improved sensory symptoms and motor signs in two patients with restless legs syndrome (91). A randomized trial also showed acupuncture with gabapentin had an additive therapeutic effect over gabapentin alone (257).
A systemic review of 11 randomized controlled trials of nonpharmacological interventions for restless leg syndrome showed that repetitive transcranial magnetic stimulation, exercise, compression devices, counterstrain manipulation, infrared therapy, and standard acupuncture effectively controlled symptoms. Although vibration pads, cryotherapy, yoga, compression devices, and acupuncture significantly improved sleep-related outcomes, the quality of the evidence was not high and posed the question about the placebo effect in these studies (117).
Experimental therapies. In a group of six patients with Parkinson disease who underwent bilateral subthalamic nucleus deep brain stimulation for Parkinson disease, restless legs syndrome had excellent improvement, with IRLS scores improving by a mean of 84% even though their dopaminergic medications were lowered by 56% postoperatively (77). Subthalamic nucleus deep brain stimulation decreased restless legs syndrome symptoms in patients with Parkinson disease despite a decrease in dopaminergic therapy, and this was sustained for at least 2 years after implant (157).
Another group implanted bilateral ventralis intermedius nucleus deep brain stimulation stimulators in nine patients with essential tremor with coexistent restless legs syndrome; the patients reported no benefit in their restless legs syndrome symptoms (235). A case report suggested the potential role for deep brain stimulation to the posteroventral lateral globus pallidus in a patient with medication refractory restless legs syndrome with sustained benefits at 2 years postprocedure (239). The globus pallidus was chosen for stimulator implantation due to the hyperkinetic restless leg phenotype seen in the patient, which resembled dyskinesias seen in Parkinson disease.
A small case series looking into spinal cord stimulation for chronic low back or leg pain showed benefits with concomitant restless legs syndrome (02).
Special considerations
Pregnancy
Reported rates of restless legs symptoms in pregnancy range between 17% and 30% (272). In a series of 500 pregnant women, 97 had restless legs syndrome. In 16 patients, symptoms were present before pregnancy; in one-third, symptoms were exacerbated during the third trimester of pregnancy but returned to baseline following delivery. Patients without symptoms before pregnancy were nearly all normal by 10 days postpartum. In a French population study, one third of pregnant women in their third trimester were reported to have restless legs syndrome, which usually improved after delivery. There is no allowed treatment; typically, only counseling and iron status assessment should be provided (223). The teratogenic risks of dopamine agonists are unknown, so they are currently not recommended in pregnancy. In refractory cases after correction of iron status, some medications may be considered, such as opioids, antiepileptics (eg, carbamazepine and gabapentin), and some benzodiazepines, which have a more extensive safety record in pregnancy (74).
Anesthesia
Spinal anesthesia may be poorly tolerated in restless legs syndrome if dysesthetic sensations persist and leg movement is not possible. Shin reported excessive agitation due to an inability to move restless legs following epidural anesthesia in a woman about to undergo a Cesarean section (279). No other known anesthetic considerations exist.
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References
- 01
- Abetz L, Arbuckle R, Allen RP, Mavraki E, Kirsch J. The reliability, validity and responsiveness of the Restless Legs Syndrome Quality of Life questionnaire (RLSQoL) in a trial population. Health Qual Life Outcomes 2005;3:79. PMID 16329756
- 02
- Adil SM, Han JL, Parente BA, Hickey P, Lad SP. Spinal cord stimulation for restless legs syndrome: case series and mechanistic hypothesis. Stereotact Funct Neurosurg 2019;97(1):31-6. PMID 30947223
- 03
- Agargun MY, Kara H, Ozbek H, Tombul T, Ozer OA. Restless legs syndrome induced by mirtazapine. J Clin Psychiatry 2002;63(12):1179. PMID 12530413
- 04
- Agarwal P, Griffith A, Constantino HR, Vaish N. Gabapentin enacarbil-clinical efficacy in restless legs syndrome. Neuropscychiatr Dis Treat 2010;6:151-8. PMID 20505847
- 05
- Agarwal P, Sia C, Vaish N, Roy-Faderman I. Pilot trial of onabotulinumtoxina (Botox) in moderate to severe restless legs syndrome. Int J Neurosci 2011;121(11):622-5. PMID 21740308
- 06
- Akpinar S. Treatment of restless legs syndrome with levodopa plus benserazide. Arch Neurol 1982;39:739. PMID 7126008
- 07
- Aksu M, Demirici S, Bara-Jimenez W. Correlation between putative indicators of primary restless legs syndrome severity. Sleep Med 2007;8(1):84-9. PMID 16740410
- 08
- AlHarbi OR, Bahammam A, Olaish AH, et al. Prevalence, severity and associated factors of restless leg syndrome in inflammatory bowel disease patients. Saudi J Gastroenterol 2021;27(6):348-54. PMID 34596594
- 09
- Allen RP, Adler CH, Du W, Butcher A, Bregman DB, Earley CJ. Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centered, placebo-controlled preliminary clinical trial. Sleep Med 2011a;12(9):906-13. PMID 21978726
- 10
- Allen RP, Auerbach S, Bahrain H, Auerbach M, Earley CJ. The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 2013a;88(4):261-4. PMID 23494945
- 11
- Allen RP, Barker PB, Horská A, Earley CJ. Thalamic glutamate/glutamine in restless legs syndrome: increased and related to disturbed sleep. Neurology 2013b;80(22):2028-34. PMID 23624560
- 12
- Allen RP, Barker PB, Wehrl F, et al. MRI measurement of brain iron in patients with restless legs syndrome. Neurology 2001;56(2):263-5. PMID 11160969
- 13
- Allen RP, Bharmal M, Calloway M. Prevalence and disease burden of primary restless legs syndrome. Results of a general population survey in the United States. Mov Disorder 2011b;26(1):114-20. PMID 21322022
- 14
- Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014a;370(7):621-31. PMID 24521108
- 15
- Allen R, Chen C, Soaita A, et al. A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome. Sleep Med 2010;11(6):512-9. PMID 20466589
- 16
- Allen RP, Earley CJ, Jones BC, Unger EL. Iron-deficiency and dopaminergic treatment effects on RLS-Like behaviors of an animal model with the brain iron deficiency pattern of the restless legs syndrome. Sleep Med 2020;S1389-9457(20)30058-7. PMID 32094092
- 17
- Allen RP, Mignot E, Ripley B, Nishino S, Earley CJ. Increased CSF hypocretin-1 (orexin A) in restless legs syndrome. Neurology 2002;59(4):639-41. PMID 12196669
- 18
- Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria--history, rationale, description, and significance. Sleep Med 2014b;15(8):860-73. PMID 25023924
- 19
- Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003;4(2):101-19. PMID 14592341
- 20
- Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165(11):1286-92. PMID 15956009
- 21
- Ancoli-Israel S, Kripke D, Klauber MR, et al. Periodic limb movements in sleep in community-dwelling elderly. Sleep 1991;14:496-500. PMID 1798881
- 22
- Aquino CC, Mestre T, Lang AE. Restless genital syndrome in Parkinson disease. JAMA Neurol 2014;71(12):1559-61. PMID 25285600
- 23
- Aras G, Kadakal F, Purisa S, Kanmaz D, Aynaci A, Isik E. Are we aware of restless legs syndrome in COPD patients who are in an exacerbation period. Frequency and probable factors related to underlying mechanism. COPD 2011;8(6):437-43. PMID 22149404
- 24
- Arunthari V, Kaplan J, Fredrickson PA, Lin SC, Castillo PR, Heckman MG. Prevalence of restless legs syndrome in blood donors. Mov Disord 2010;25(10):1451-5. PMID 20629149
- 25
- Auger C, Montplaisir J, Duquette P. Increased frequency of restless legs syndrome in a French-Canadian population with multiple sclerosis. Neurology 2005;65(10):1652-3. PMID 16301499
- 26
- Aukerman MM, Aukerman D, Bayard M, Tudiver F, Thorp L, Bailey B. Exercise and restless legs syndrome: a randomized controlled trial. J Am Board Fam Med 2006;19(5)487-93. PMID 16951298
- 27
- Azmin S, Khairul Anuar AM, Nafisah WY, et al. Restless legs syndrome and its associated risk factors in Parkinson's disease. Parkinsons Dis 2013;2013:535613. PMID 24455416
- 28
- Balaban H, Bayrakli F, Kartal U, Pinarbasi E, Topaktas S, Kars HZ. A novel locus for restless legs syndrome on chromosome 13q. Eur Neurol 2012;68(2):111-6. PMID 22797413
- 29
- Bamford CR, Sandyk R, Gillman MA. Failure of clonidine to ameliorate the symptoms of restless legs syndrome. Sleep 1987;10:398-9. PMID 3659738
- 30
- Baskol G, Korkmaz S, Erdem F, Caniklioglu A, Kocyigit M, Aksu M. Assessment of nitric oxide, advanced oxidation protein products, malondialdehyde, and thiol levels in patients with restless legs syndrome. Sleep Med 2012;13(4):414-8. PMID 22469072
- 31
- Bastani B, Westervelt FB. Effectiveness of clonidine in alleviating the symptoms of "restless legs." Am J Kidney Dis 1987;10(4):326. PMID 3661556
- 32
- Basu PP, Shah NJ, Krishnaswamy N, Pacana T. Prevalence of restless legs syndrome in patients with irritable bowel syndrome. World J Gastroenterol 2011;17(39):4404-7. PMID 22110266
- 33
- Bauer A, Cassel W, Benes H, et al. Rotigotine's effect on PLM-associated blood pressure elevations in restless legs syndrome: an RCT. Neurology 2016;86(19):1785-93. PMID 27164714
- 34
- Bayard S, Yu H, Langenier MC. Decision making in restless legs syndrome. Mov Disord 2010;25(15):2634-40. PMID 20669306
- 35
- Bedard MA, Montplaisir J, Godbout R, Lapierre O. Nocturnal gamma-hydroxy butyrate effect on periodic leg movements and sleep organization of narcoleptic patients. Clin Neuropharmacol 1989;12:29-36. PMID 2713866
- 36
- Benes H. Transdermal lisuride: short-term efficacy and tolerability study in patients with severe restless legs syndrome. Sleep Med 2006;7(1):31-5. PMID 16194624
- 37
- Berger K, Luedemann, Trenkwalder C, John U, Kessler C. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med 2004;164(2):196-202. PMID 14744844
- 38
- Bernheimer JH. Restless legs syndrome presenting as an acute exacerbation of multiple sclerosis. Mult Scler Int 2011;2011:872948. PMID 22096645
- 39
- Bertisch SM, Muresan C, Schoerning L, Winkelman JW, Taylor JA. Impact of restless legs syndrome on cardiovascular autonomic control. Sleep 2016;39(3):565-71. PMID 26564128
- 40
- Birgegard G, Schneider K, Ulfberg J. High incidence of iron depletion and restless legs syndrome (RLS) in regular blood donors: intravenous iron sucrose substitution more effective than oral iron. Vox Sang 2010;99(4):354-61. PMID 20598107
- 41
- Bogan RK, Fry JM, Schmidt MH, Carson SW, Ritchie SY; TREAT RLS US Study Group. Ropinirole in the treatment of patients with restless legs syndrome: a US-based randomized, double-blind, placebo-controlled clinical trial. Mayo Clin Proc 2006;81(1):17-27. PMID 16438474
- 42
- Boghen D, Lamothe L, Elie R, Godbout R, Montplaisir J. The treatment of the restless legs syndrome with clonazepam: a prospective controlled study. Can J Neurol Sci 1986;13:245-7. PMID 3527387
- 43
- Bonati MT, Ferini-Strambi L, Aridon P, Oldani A, Zucconi M, Casari G. Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain 2003;126(Pt 6):1485-92. PMID 12764067
- 44
- Bucher SF, Seelos KC, Oertel WH, Reiser M, Trenkwalder C. Cerebral generators involved in the pathogenesis of the restless legs syndrome. Ann Neurol 1997;41(5):639-45. PMID 9153526
- 45
- Buchfuhrer MJ. Pregabalin is more effective than placebo for restless legs syndrome with mild adverse effects of daytime somnolence, headache and unsteadiness. Evid Based Med 2011;16(1):9-10. PMID 21081629
- 46
- Carkaci-Salli N, Battula S, Wang X, Connor JR, Vrana KE. Gender-specific regulation of tyrosine hydroxylase in thymocyte differentiation antigen-1 knockout mice. J Neurosci Res 2012;90(8):1583-8. PMID 22430860
- 47
- Carlos K, Prado GF, Teixeira CD, et al. Benzodiazepines for restless legs syndrome. Cochrane Database Syst Rev 2017;3:CD006939. PMID 28319266
- 48
- Cassel W, Kesper K, Bauer A, et al. Significant association between systolic and diastolic blood pressure elevations and periodic limb movements in patients with idiopathic restless legs syndrome. Sleep Med 2016;17:109-20. PMID 26847983
- 49
- Catoire H, Dion PA, Xiong L, et al. Restless legs syndrome-associated MEIS1 risk variant influences iron homeostasis. Ann Neurol 2011;70(1):170-5. PMID 21710629
- 50
- Chabli A, Michaud M, Montplaisir J. Periodic arm movements in patients with the restless legs syndrome. Eur Neurol 2000;44(3):133-8. PMID 11053959
- 51
- Chang Y, Chang HW, Song H, et al. Gray matter alteration in patients with restless legs syndrome: a voxel-based morphometry study. Clin Imaging 2015;39(1):20-5. PMID 25176196
- 52
- Cheikh Hassan HI, Brennan F, Collett G, Josland EA, Brown MA. Efficacy and safety of gabapentin for uremic pruritus and restless legs syndrome in conservatively managed patients with chronic kidney disease. J Pain Symptom Manage 2015;49(4):782-9. PMID 25220049
- 53
- Chen JJ, Swope DM, Dashtipour K, Lyons KE. Transdermal rotigotine: a clinically innovative dopamine-receptor agonist for the management of Parkinson’s disease. Pharmacotherapy 2009;29(12):1452-67. PMID 19947805
- 54
- Chen JT, Garcia PA, Alldredge BK. Zonisamide-induced restless legs syndrome. Neurology 2003;60(1):147. PMID 12525743
- 55
- Chen PK, Fuh JL, Wang SJ. Bidirectional triggering association between migraine and restless legs syndrome: a diary study. Cephalalgia 2016;36(5):431-06. PMID 26195587
- 56
- Chen S, Ondo WG, Rao S, Li L, Chen Q, Wang Q. Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p. Am J Hum Genet 2004;74(5):876-85. PMID 15077200
- 57
- Chokroverty S, Jankovic J. Restless legs syndrome. A disease in search of identity. Neurology 1999;52:907-10. PMID 10102404
- 58
- Cholley-Roulleau M, Chenini S, Béziat S, et al. Restless legs syndrome and cardiovascular diseases: a case-control study. PLoS One 2017;12(4):e0176552. PMID 28445539
- 59
- Comella CL. Restless legs syndrome: Treatment with dopaminergic agents. Neurology 2002;58(4 Suppl 1):S87-92. PMID 11909990
- 60
- Connor JR, Boyer PJ, Menzies SL, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 2003;61(3):304-9. PMID 12913188
- 61
- Connor JR, Ponnuru P, Lee BY, et al. Postmortem and imaging-based analyses reveal CNS decreased myelination in restless legs syndrome. Sleep Med 2011;12(6):614-9. PMID 21570342
- 62
- Conti CF, de Oliveira MM, Andriolo RB, et al. Levodopa for idiopathic restless legs syndrome: evidence-based review. Mov Disord 2007;22(13):1943-51. PMID 17659645
- 63
- Cornelius JR, Tippmann-Peikert M. Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: a case-control study. Sleep 2010:33(1):81-7. PMID 20120624
- 64
- Cubo E, Collazo RC, Gallego-Nieto C, et al. Mortality in restless leg syndrome: A 11 year-year follow up study. Neuroepidemiology 2020;54:375-82.
- 65
- Cuellar NG, Hanlon A, Ratcliffe SJ. The relationship with iron and health outcomes in persons with restless legs syndrome. Clin Nurs Res 2011;20(2):144-61. PMID 21041807
- 66
- Danoff SK, Grasso ME, Terry TB, Flynn JA. Pleuropulmonary disease due to pergolide use for restless legs syndrome. Chest 2001;120:313-6. PMID 11451859
- 67
- Dauvilliers Y, Chenini S, Vialaret J, et al. Association between serum hepcidin level and restless legs syndrome. Mov Disord 2018;33(4):618-27. PMID 29418021
- 68
- Davis BJ, Rajput A, Rajput ML, Aul EA, Eichhorn GR. A randomized, double-blind placebo-controlled trial of iron in restless legs syndrome. Eur Neurol 2000;43:70-5. PMID 10686463
- 69
- Deriu M, Cossu G, Molari A, et al. Restless legs syndrome in multiple sclerosis: a case control study. Mov Disord 2009;24(5):697-701. PMID 19117365
- 70
- Desautels A, Turecki G, Montplaisir J, et al. Evidence for a genetic association between monoamine oxidase A and restless legs syndrome. Neurology 2002;59(2):215-9. PMID 12136060
- 71
- Desautels A, Turecki G, Montplaisir J, et al. Restless legs syndrome. Confirmation of linkage to chromosome 12q, genetic heterogeneity, and evidence of complexity. Arch Neurol 2005;62:591-6. PMID 15824258
- 72
- De Vito K, Li Y, Batool-Anwar S, Ning Y, Han J, Gao X. Prospective study of obesity, hypertension, high cholesterol, and risk of restless legs syndrome. Mov Disord 2014;29(8):1044-52. PMID 24753235
- 73
- Didriksen M, Nawaz MS, Dowsett J, et al. Large genome-wide association study identifies three novel risk variants for restless legs syndrome. Commun Biol 2020;25:3(1):703. PMID 33239738
- 74
- Djokanovic N, Garcia-Bournissen F, Koren G. Medications for restless legs syndrome in pregnancy. J Obstet Gynaecol Can 2008;30(6):505-7. PMID 18611302
- 75
- Doghramji K, Browman CP, Gaddy JR, Walsh JK. Triazolam diminishes daytime sleepiness and sleep fragmentation in patients with periodic leg movements in sleep. J Clin Psychopharmacol 1991;11:284-90. PMID 1765571
- 76
- Dragan EM, Chen Z, Ondo WG. Does idiopathic restless legs syndrome delay onset and reduce severity of Parkinson's disease: a pilot study. Int J Neurosci 2015;125(7):526-30. PMID 25405536
- 77
- Driver-Dunckley E, Evidente VG, Adler CH, et al. Restless legs syndrome in Parkinson's disease patients may improve with subthalamic stimulation. Mov Disord 2006;21(8):1287-9. PMID 16671093
- 78
- Driver-Dunckley ED, Noble BN, Hentz JG, et al. Gambling and increased sexual desire with dopaminergic medications in restless legs syndrome. Clin Neuropharmacol 2007;30(5):249-55. PMID 17909302
- 79
- Duffy JF, Lowe AS, Silva EJ, Winkleman JW. Periodic limb movements in sleep exhibit a circadian rhythm that is maximal in the late evening/early night. Sleep Med 2011;12(1):83-8. PMID 21093364
- 80
- Earley CJ, Hyland K, Allen RP. Circadian changes in CSF dopaminergic measures in restless legs syndrome. Sleep Med 2006;7(3):263-8. PMID 16564215
- 81
- Earley CJ, Uhl GR, Clemens S, Ferré S. Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation. Sleep Med 2017;31:71-77. PMID 27539027
- 82
- Ekbom KA. Restless legs. Acta Med Scand Suppl 1945;158:5-123.
- 83
- Enomoto M, Inoue Y, Namba T, et al. Clinical characteristics of restless legs syndrome in end stage renal failure and idiopathic RLS patients. Mov Disord 2007;23(6):811-6. PMID 18074382
- 84
- Etgen T, Draganski B, Ilg C, et al. Bilateral thalamic gray matter changes in patients with restless legs syndrome. Neuroimage 2005;24:1242-7. PMID 15670702
- 85
- Evidente VG. Piribedil for restless legs syndrome: a pilot study. Mov Disord 2001;16(6):579-81. PMID 11391766
- 86
- Evidente VG, Adler CH, Caviness HN, Hentz JG, Gwinn-Hardy K. Amantadine is beneficial in restless legs syndrome. Mov Disord 2000;15:324-7. PMID 10752586
- 87
- Fereshtehnejad SM, Shafieesabet M, Shahidi GA, Delbari A, Lökk J. Restless legs syndrome in patients with Parkinson's disease: a comparative study on prevalence, clinical characteristics, quality of life and nutritional status. Acta Neurol Scand 2015;131(4):211-8. PMID 25263328
- 88
- Ferini-Strambi L, Carli G, Casoni F, Galbiati A. Restless legs syndrome and Parkinson disease: a causal relationship between the two disorders? Front Neurol 2018;9:551. PMID 30087647
- 89
- Ferre S, Quiroz C, Guitart X, et al. Pivotal role of adenosine neurotransmission in restless legs syndrome. Front Neurosci 2018;11:722. PMID 29358902
- 90
- Ferri R, Cosentino FI, Moussouttas M, Lanuzza B. Silent cerebral small vessel disease in restless legs syndrome. Sleep 2016;39(7):1371-7. PMID 27091527
- 91
- Fukutome T. Acupuncture point injection markedly improved sensory symptoms and motor signs in 2 patients with restless legs syndrome. Clin Case Rep 2018;6(7):1353-7. PMID 29988645
- 92
- Galbiati A, Marelli S, Giora E, Zucconi M, Oldani A, Ferini-Strambi L. Neurocognitive function in patients with idiopathic restless legs syndrome before and after treatment with dopamine-agonist. Int J Psychophysiol 2015;95(3):304-9. PMID 25514234
- 93
- Gao X, Schwarzschild MA, O'Reilly EJ, Wang H, Ascherio A. Restless legs syndrome and erectile dysfunction. Sleep 2010;33(1):75-9. PMID 20120623
- 94
- Garcia-Borreguero D, Cano-Pumarega I, Garcia Malo C, Cruz Velarde JA, Granizo JJ, Wanner V. Reduced response to gabapentin enacarbil in restless legs syndrome following long-term dopaminergic treatment. Sleep Med 2019;55:74-80. PMID 30772697
- 95
- Garcia-Borreguero D, Cano I, Granizo JJ. Treatment of restless legs syndrome with the selective AMPA receptor antagonist perampanel. Sleep Med 2017;34:105-8. PMID 28522077
- 96
- Garcia-Borreguero D, Guitart X, Garcia Malo C, et al. Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis. Sleep Med 2018;45:94-7. PMID 29680437
- 97
- Garcia-Borreguero D, Larrosa O, Williams AM, et al. Treatment of restless legs syndrome with pregabalin: a double-blind, placebo-controlled study. Neurology 2010a;74(23):1897-904. PMID 20427750
- 98
- Garcia-Borreguero D, Williams AM. Dopaminergic augmentation of restless legs syndrome. Sleep Med Rev 2010b;14(5):339-46. PMID 20219397
- 99
- Gemignani F, Brindani F, Vitetta F, Marbini A. Restless legs syndrome and painful neuropathy-retrospective study: a role for nociceptive deafferentation. Pain Med 2009;10(8):1481-6. PMID 20021603
- 100
- Geyer JD, Geyer EE, Fetterman Z, Carney PR. Epilepsy and restless legs syndrome. Epilepsy Behav 2017;68:41-4. PMID 28109988
- 101
- Ghorayeb I, Burbaud P. Failure of botulinum toxin A to relieve restless legs syndrome. Sleep Med 2009;10(3):394-5. PMID 18514023
- 102
- Ghorayeb I, Tison F. Restless legs syndrome epidemiology. Presse Med 2010;39(5):564-70. PMID 20334990
- 103
- Godau J, Klose U, Di Santo A, Schweitzer K, Berg D. Multiregional brain iron deficiency in restless legs syndrome. Mov Disord 2008;23:1184-7. PMID 18442125
- 104
- Gorges M, Rosskopf J, Müller HP, Lindemann K, Hornyak M, Kassubek J. Patterns of increased intrinsic functional connectivity in patients with restless legs syndrome are associated with attentional control of sensory inputs. Neurosci Lett 2016;617:264-9. PMID 26921454
- 105
- Gorman CA, Dyck PJ, Pearson JS. Symptom of restless legs. Arch Intern Med 1965;115:155-60. PMID 14331995
- 106
- Gorsler A, Liepert J. Influence of cabergoline on motor excitability in patients with restless legs syndrome. J Clin Neurophys 2007;24(6):456-60. PMID 18090527
- 107
- Gottlieb DJ, Somers VK, Punjabi NM, Winkelman JW. Restless legs syndrome and cardiovascular disease: a research roadmap. Sleep Med 2017;31:10-17. PMID 28065687
- 108
- Greco D. [Restless legs syndrome and diabetes mellitus: an accidental association.] [Article in Italian]. Recenti Prog Med 2011;102(5):212-6. PMID 21607006
- 109
- Guilleminault C, Flagg W. Effect of baclofen on sleep related periodic leg movements. Ann Neurol 1984;15:234-9. PMID 6721446
- 110
- Gupta R, Dhyani M, Kendzerska T, et al. Restless legs syndrome and pregnancy: prevalence, possible pathophysiological mechanisms and treatment. Acta Neurol Scand 2016;133(5):320-9. PMID 26482928
- 111
- Gupta A, Shukla G, Mohammed A, Goyal V, Behari M. Restless legs syndrome, a predictor of subcortical stroke: a prospective study in 346 stroke patients. Sleep Med 2017;29:61-7. PMID 26323645
- 112
- Haba-Rubio J, Krieger J. Management of restless legs syndrome. Presse Med 2010;39(5):571-8. PMID 20303704
- 113
- Han SH, Park KY, Kim JM, Youn YC, Shin HW. Restless legs syndrome is associated with arterial stiffness and clinical outcome in stroke patients. Sleep Med 2019;60:219-23. PMID 31186216
- 114
- Handwerker JV, Palmer RF. Clonidine in the treatment of restless leg syndrome. N Engl J Med 1985;313:1228-9. PMID 4058497
- 115
- Hanly P, Zuberi N. Periodic leg movements during sleep before and after heart transplantation. Sleep 1992;15:489-92. PMID 1475562
- 116
- Happe S, Trenkwalder C. Role of dopamine receptor agonists in the treatment of restless legs syndrome. CNS Drugs 2004;18(1):27-36. PMID 14731057
- 117
- Harrison EG, Keating JL, Morgan PE. Non-pharmacological interventions for restless legs syndrome: a systematic review of randomised controlled trials. Disabil Rehabil 2019;41(17):2006-14. PMID 29561180
- 118
- Haschka D, Volani C, Stefani A, et al. Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome. Mov Disord 2019;34(1):114-23. PMID 30311259
- 119
- Hayes WJ, Lemon MD, Farver DK. Gabapentin enacarbil for treatment of restless legs syndrome in adults. Ann Pharmacother 2012;46(2):229-39. PMID 22298601
- 120
- Heim B, Djamshidian A, Heidbreder A, et al. Augmentation and impulsive behaviors in restless legs syndrome: coexistence or association? Neurology 2016;87(1):36-40. PMID 27261093
- 121
- Heim B, Pertl MT, Stefani A, et al. Reflection impulsivity perceptual decision-making in patients with restless legs syndrome. Ann Clin Transl Neurol 2018;5(3):315-22. PMID 29560376
- 122
- Heim B, Pertl MT, Stefani A, et al. Haste makes waste: decision making in patients with restless legs syndrome with and without augmentation. PLoS One 2017;12(4):e0174793. PMID 28380045
- 123
- Hein M, Lanquart JP, Hubain P, Loas G. Risk of resistant hypertension associated with restless legs syndrome and periodic limb movements during sleep: a study on 673 treated hypertensive individuals. Sleep Med 2019;63:46-56. PMID 31606649
- 124
- Hening W, Allen R, Earley C, et al. The treatment of restless legs syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine Review. Sleep 1999;22:970-99. PMID 10566916
- 125
- Hening WA, Allen RP, Ondo WG, et al. Rotigotine improves restless legs syndrome: a 6 month randomized, double-blind, placebo-controlled trial in the United States. Mov Disord 2010;25(11):1675-83. PMID 20629075
- 126
- Hogl B, Comella C. Therapeutic advances in restless legs syndrome (RLS). Mov Disord 2015;30(11):1574-9. PMID 26371624
- 127
- Hogl B, Frauscher B, Seppi K, Ulmer H, Poewe W. Transient restless legs syndrome after spinal anesthesia: a prospective study. Neurology 2002;59(11):1705-7. PMID 12473756
- 128
- Hogl B, Oertel WH, Stiasny-Kolster K, et al. Treatment of moderate to severe restless legs syndrome: 2-year safety and efficacy of rotigotine transdermal patch. BMC Neurol 2010;10:86. PMID 20920156
- 129
- Hornyak M, Grossmann C, Kohnen R, et al. Cognitive behavioural group therapy to improve patients coping strategies with restless legs syndrome: a proof-of-concept trial. J Neurol Neurosurg Psychiatry 2008;79(7):823-5. PMID 18303103
- 130
- Hornyak M, Scholz H, Kiemen A, Kassubek J. Investigating the response to intravenous iron in restless legs syndrome: an observational study. Sleep Med 2012;13(6):732-5. PMID 22503006
- 131
- Horvath J, Fross RD, Kleiner-Fisman G, et al. Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists. Mov Disord 2004;19:656-62. PMID 15197703
- 132
- Howell MJ, Schenck CH. Restless nocturnal eating: a common feature of Willis-Ekbom Syndrome (RLS). J Clin Sleep Med 2012;8(4):413-9. PMID 22893772
- 133
- Hubner A, Krafft A, Gadient S, Werth E, Zimmermann R, Bassetti CL. Characteristics and determinants of restless legs syndrome in pregnancy: a prospective study. Neurology 2013;80(8):738-42. PMID 23390174
- 134
- Hyun JW, Kim SH, Jeong IH, et al. Increased frequency and severity of restless legs syndrome in patients with neuromyelitis optica spectrum disorder. Sleep Med 2016;17:121-3. PMID 26847984
- 135
- Iannaccone S, Zucconi M, Marchettini P, et al. Evidence of peripheral axonal neuropathy in primary restless legs syndrome. Mov Disord 1995;10:2-9. PMID 7885351
- 136
- Imamura S, Kushida C. Gabapentin enacarbil (XP13512/GSK1838262) as an alternative treatment to dopaminergic agents for restless legs syndrome. Expert Opin Pharmacother 2010;11(11):1925-32. PMID 20629607
- 137
- Innes KE, Kandati S, Flack KL, Agarwal P, Selfe TK. The relationship of restless legs syndrome to history of pregnancy-induced hypertension. J Womens Health (Larchmt) 2016;25(4):397-408. PMID 26913940
- 138
- Innes KE, Selfe TK, Montgomery C, et al. Effects of a 12-week yoga versus a 12-week educational film intervention on symptoms of restless legs syndrome and related outcomes: an exploratory randomized controlled trial. J Clin Sleep Med 2020;16(1):107-19. PMID 31957638
- 139
- Inoue Y, Kuroda K, Hirata K, Uchimura N, Kagimura T, Shimizu T. Long term open-label study of pramipexole in patients with primary restless legs syndrome. J Neurol Sci 2010;294(1-2):62-6. PMID 20451927
- 140
- Inoue Y, Kuroda K, Hirata K, Uchimura N, Kagimura T, Shimizu T. Efficacy, safety and dose-response of pramipexole in Japanese patients with primary restless legs syndrome: randomized trial. Neuropsychobiology 2011;63(1):35-42. PMID 21063131
- 141
- Inoue Y, Uchimura N, Kuroda K, Hirata K, Hattori N. Long-term efficacy and safety of gabapentin enacarbil in Japanese restless legs syndrome patients. Prog Neuropsychopharmacol Biol Psychiatry 2012;36(2):251-7. PMID 22036917
- 142
- Izzi F, Placidi F, Romigi A, et al. Is autonomic nervous system involved in restless legs syndrome during wakefulness? Sleep Med 2014;15(11):1392-7. PMID 25266501
- 143
- Jankovic J. Leg stereotypy disorder. J Neurol Neurosurg Psychiatry 2016;87(2):220-1. PMID 26209715
- 144
- Jankovic J. An update on new and unique uses of botulinum toxin in movement disorders. Toxicon 2018;147:84-8. PMID 28888928
- 145
- Jimenez-Jimenez FJ, Alonso-Navarro H, García-Martín E, Agundez JAG. Genetics of restless legs syndrome: an update. Sleep Med Rev 2018;39:108-21. PMID 29033051
- 146
- Jimenez-Trevino L. Oxcarbazepine treatment of restless legs syndrome: three case reports. Clin Neuropharmacol 2009;32(3):169-70. PMID 19483488
- 147
- Jung KY, Kim SM, Song JY, et al. Sternberg working memory performance following treatment with pramipexole in patients with moderate-to-severe restless legs syndrome. Sleep Med 2015;16(6):703-8. PMID 25934537
- 148
- Kallweit U, Khatami R, Pizza F, Mathis J, Bassetti CL. Dopaminergic treatment in idiopathic restless legs syndrome: effects on subjective sleepiness. Clin Neuropharmacol 2010;33(6):276-8. PMID 21060282
- 149
- Kaplan PW, Allen RP, Buchholz DW, Walters JK. A double-blind, placebo-controlled study of the treatment of periodic limb movements in sleep using carbidopa/levodopa and propoxyphene. Sleep 1993;16:717-23. PMID 8165385
- 150
- Katsanos AH, Kosmidou M, Konitsiotis S, et al. Restless legs syndrome and cerebrovascular/cardiovascular events: systematic review and meta-analysis. Acta Neurol Scand 2018;137(1):142-8. PMID 28948600
- 151
- Kemlink D, Plazzi G, Vetrugno R, et al. Suggestive evidence for linkage for restless legs syndrome on chromosome 19p13. Neurogenetics 2008;9(2):75-82. PMID 18193462
- 152
- Kendzerska T, Kamra M, Murray BJ, Boulos MI. Incident cardiovascular events and death in individuals with restless legs syndrome or periodic limb movements in sleep: a systematic review. Sleep 2017;40(3). PMID 28329227
- 153
- Khachatryan SG, Ferri R, Fulda S, et al. Restless legs syndrome: over 50 years of European contribution. J Sleep Res 2022; 31(4): e13632. PMID 35808955
- 154
- Khalid I, Rana L, Khalid TJ, Roehrs T. Refractory restless legs syndrome likely caused by olanzapine. J Clin Sleep Med 2009;5(1):68-9. PMID 19317385
- 155
- Kim KW, Jhoo JH, Lee SB, et al. Increased striatal dopamine transporter density in moderately severe old restless legs syndrome patients. Eur J Neurol 2012;19(9):1213-8. PMID 22435397
- 156
- Kim MS, Park DG, Yoon JH. Impaired endothelial function may predict treatment response in restless legs syndrome. J Neural Transm (Vienna) 2019;126(8):1051-9. PMID 31218470
- 157
- Klepitskaya O, Liu Y, Sharma S, Sillau SH, Tsai J, Walters AS. Deep brain stimulation improves restless legs syndrome in patients with Parkinson disease. Neurology 2018;91(11):e1013-21. PMID 30111549
- 158
- Koh SY, Kim MS, Lee SM, Hong JM, Yoon JH. Impaired vascular endothelial function in patients with restless legs syndrome: a new aspect of the vascular pathophysiology. J Neurol Sci 2015;359(1-2):207-10. PMID 26671114
- 159
- Kolla BP, Mansukhani MP, Barraza R, Bostwick JM. Impact of dopamine agonists on compulsive behaviors: a case series of pramipexole-induced pathological gambling. Psychosomatics 2010;51(3):271-3. PMID 20484726
- 160
- Kolla BP, Mansukhani MP, Bostwick JM. The influence of antidepressants on restless legs syndrome and periodic limb movements: a systematic review. Sleep Med Rev 2018;38:131-40. PMID 28822709
- 161
- Ku J, Cho YW, Lee YS, et al. Functional connectivity alternation of the thalamus in restless legs syndrome patients during the asymptomatic period: a resting-state connectivity study using functional magnetic resonance imaging. Sleep Med 2014;15(3):289-94. PMID 24555993
- 162
- Ku J, Lee YS, Kim KT, Chang H, Cho YW. Alterations in salience network functional connectivity in individuals with restless legs syndrome. Sci Rep 2020;10(1):7643. PMID 32377013
- 163
- Kume A. Gabapentin enacarbil for the treatment of moderate to severe primary restless legs syndrome (Willis-Ekbom disease): 600 or 1,200 mg dose? Neuropsychiatr Dis Treat 2014;10:249-62. PMID 24523590
- 164
- Kumru H, Portell E, Barrio M, Santamaria J. Restless legs syndrome in patients with sequelae of poliomyelitis. Parkinsonism Relat Disord 2014;20(10):1056-8. PMID 25042342
- 165
- Kushida CA, Becker PM, Ellenbogen Al, et al. Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS. Neurology 2009;72(5):439-46. PMID 19188575
- 166
- LaBan MM, Viola SL, Femminineo AF, Taylor RS. Restless legs syndrome associated with diminished cardiopulmonary compliance and lumbar spinal stenosis--a motor concomitant of "Vesper's curse." Arch Phys Med Rehabil 1990;71:384-8. PMID 2334280
- 167
- Lai YY, Hsieh KC, Cheng YH, et al. Striatal histamine mechanism in the pathogenesis of restless legs syndrome. Sleep 2020;43(2):zsz223. PMID 31671173
- 168
- Lang AE. Restless legs syndrome and Parkinson's disease: insights into pathophysiology. Clin Neuropharmacol 1987;10:476-8. PMID 3503686
- 169
- Lanza G, Cantone M, Aricò D, et al Clinical and electrophysiological impact of repetitive low-frequency transcranial magnetic stimulation on the sensory-motor network in patients with restless legs syndrome. Ther Adv Neurol Disord 2018a;11:1756286418759973. PMID 29511386
- 170
- Lanza G, Lanuzza D, Arico D, et al. Impaired short-term plasticity in restless legs syndrome: a pilot rTMS study. Sleep Med 2018b;46:1-4. PMID 29773202
- 171
- Lauerma H, Markkula J. Treatment of restless legs syndrome with tramadol: an open study. J Clin Psychiatry 1999;60:241-4. PMID 10221285
- 172
- La Manna G, Pizza F, Persici E, et al. Restless legs syndrome enhances cardiovascular risk and mortality in patients with end-stage kidney disease undergoing long-term haemodialysis treatment. Nephrol Dial Transplant 2011;26(6):1976-83. PMID 21056943
- 173
- Lazzarini A, Walters AS, Hickey K, et al. Studies of penetrance and anticipation in 5 autosomal-dominant restless legs syndrome pedigrees. Mov Disord 1999;14:111-6. PMID 9918352
- 174
- Lee BY, Kim J, Connor JR, Podskainy GD, Ryu Y, Yang QX. Involvement of the central somatosensory system in restless legs syndrome: a neuroimaging study. Neurology 2018;90(21):e1834-41. PMID 29695597
- 175
- Lee HB, Ramsey CM, Spira AP, Vachon J, Allen R, Munro CA. Comparison of cognitive functioning among individuals with treated restless legs syndrome (RLS), untreated RLS, and no RLS. J Neuropsychiatry Clin Neurosci 2014;26(1):87-91. PMID 24515680
- 176
- Levchenko A, Montplaisir JY, Asselin G, et al. Autosomal-dominant locus for restless legs syndrome in French-Canadians on chromosome 16p12.1. Mov Disord 2009;24(1):40-50. PMID 18946881
- 177
- Levchenko A, Provost S, Montplaisir JY, et al. A novel autosomal dominant restless legs syndrome locus maps to chromosome 20p13. Neurology 2006;67(5):900-1. PMID 16966564
- 178
- Li K, Liu B, Wang F, et al. Decreased serum ferritin may be associated with increased restless legs syndrome in Parkinson's disease (PD): a meta-analysis for the diagnosis of RLS in PD patients. Int J Neurosci 2019;129(10):995-1003. PMID 31092087
- 179
- Li T, Liu C, Lyu H, et al. Alterations of sub-cortical gray matter volume and their associations with disease duration in patients with restless legs syndrome. Front Neurol 2018a;9:1098. PMID 30619055
- 180
- Li Y, Walters AS, Chiuve SE, et al. Prospective study of restless legs syndrome and coronary heart disease among women. Circulation 2012;126(14):1689-94. PMID 22967852
- 181
- Li Y, Wang W, Winkelman JW, Malhotra A, Ma J, Gao X. Prospective study of restless legs syndrome and mortality among men. Neurology 2013;81(1):52-9. PMID 23761622
- 182
- Li Y, Li Y, Winkelman J, et al. Prospective study of restless legs syndrome and total and cardiovascular mortality among women. Neurology 2018b;90(2):e135-41. PMID 29247069
- 183
- Lin S, Zhang H, Gao T, et al. The association between obesity and restless legs syndrome: A systemic review and meta-analysis of observational studies. J Affect Disord 2018;235:384-91. PMID 29674254
- 184
- Linke R, Eisensehr I, Wetter TC, et al. Presynaptic dopaminergic function in patients with restless legs syndrome: are there common features with early Parkinson’s disease. Mov Disord 2004;19:1158-62. PMID 15390076
- 185
- Liu C, Dai Z, Zhang R, et al. Mapping intrinsic functional brain changes and repetitive transcranial magnetic stimulation neuromodulation in idiopathic restless legs syndrome: a resting-state functional magnetic resonance imaging study. Sleep Med 2015;16(6):785-91. PMID 25959094
- 186
- Liu G, Li L, Zhang J, et al. Restless legs syndrome and pregnancy or delivery complications in China: a representative survey. Sleep Med 2016;17:158-62. PMID 26847992
- 187
- Liu JB, Leng JL, Zhang XJ, et al. Investigation of non-motor symptoms in first-degree relatives of patients with Parkinson’s disease. Parkinsonism Relat Disor 2018;52:62-8. PMID 29606605
- 188
- Lo Coco D, Mattaliano A, Lo Coco A, Randisi B. Increased frequency of restless legs syndrome in chronic obstructive pulmonary disease patients. Sleep Med 2009;10(5):572-6. PMID 18996743
- 189
- Lotia M, York MK, Strutt AM, Jankovic J. Leg stereotypy syndrome: phenomenology and prevalence. J Neurol Neurosurg Psychiatry 2018;89(7):692-5. PMID 29332008
- 190
- Lugaresi E, Cirignotta F, Coccagna G, Montagna P. Nocturnal myoclonus and restless legs syndrome. Adv Neurol 1986;43:295-307. PMID 3946114
- 191
- Lyu S, DeAndrade MP, Mueller S, Oksche A, Walters AS, Li Y. Hyperactivity, dopaminergic abnormalities, iron deficiency and anemia in an in vivo opioid receptors knockout mouse: implications for the restless legs syndrome. Behav Brain Res 2019;374:112123. PMID 31376441
- 192
- Machtey I. Restless legs and latent diabetes. BR Med J 1971;1(751):726. PMID 5551253
- 193
- Maestri M, Fulda S, Ferini-Strambi L, et al. Polysomnographic record and successful management of augmentation in restless legs syndrome/Willis-Ekbom disease. Sleep Med 2014;15(5):570-5. PMID 24767724
- 194
- Manconi M, Ferri R, Zucconi M, et al. Preferential D2 or preferential D3 dopamine agonists in restless legs syndrome. Neurology 2011;77(2):110-7. PMID 21715702
- 195
- Manconi M, Ferri R, Zucconi M, et al. Dissociation of periodic leg movements from arousals in restless legs syndrome. Ann Neurol 2012;71(6):834-44. PMID 22718547
- 196
- Marchesi E, Negrotti A, Angelini M, Goldoni M, Abrignani G, Calzetti S. A prospective study of the cumulative incidence and course of restless legs syndrome in de novo patients with Parkinson's disease during chronic dopaminergic therapy. J Neurol 2016;263(3):441-7. PMID 26566909
- 197
- Marques A, Figorilli M, Pereira B, et al. Impulse control disorders in Parkinson's disease patients with RLS: a cross sectional-study. Sleep Med 2018;48:148-54. PMID 29913341
- 198
- Martinelli P, Coccagna G, Lugaresi E. Nocturnal myoclonus, restless legs syndrome, and a normal electrophysiological findings. Ann Neurol 1987;21:515. PMID 3592646
- 199
- Matsubara T, Suzuki K, Fujita H, et al. Restless legs syndrome, leg motor restlessness and their variants in patients with Parkinson's disease and related disorders. J Neurol Sci 2018;393:51-7. PMID 30103064
- 200
- McCullagh MC. Restless legs syndrome negatively impacts worker health and safety. Workplace Health Saf 2018;66(7):360. PMID 29897020
- 201
- Meharaban Z, Yahya S, Sadegniiat K. Restless legs syndrome during pregnancy and preterm birth in women referred to health centers of Ardabil. Iran Red Crescent Med J 2015;17(12):e24438. PMID 26756014
- 202
- Merlino G, Serafini A, Lorenzut S, Sommaro M, Gigli GL, Valente M. Gabapentin enacarbil in restless legs syndrome. Drugs Today (Barc) 2010;46(1):3-11. PMID 20200691
- 203
- Michaud M, Chabli A, Lavigne G, Montplaisir J. Arm restlessness in patients with restless legs syndrome. Mov Disord 2000;15:154-8. PMID 10752578
- 204
- Michaud M, Paquet J, Lavigne G. Desautels A, Montplaisir J. Sleep laboratory diagnosis of restless legs syndrome. Eur Neurol 2002a;48(2):108-13. PMID 12187001
- 205
- Michaud M, Soucy JP, Chabli A, Lavigne G, Montplaisir J. SPECT imaging of striatal pre- and postsynaptic dopaminergic status in restless legs syndrome with periodic leg movements in sleep. J Neurol 2002b;249(2):164-70. PMID 11985381
- 206
- Mittal SO, Machado D, Richardson D, Dubey D, Jabbari B. Botulinum toxin in restless legs syndrome-a randomized double-blind placebo-controlled crossover study. Toxins (Basel) 2018;10(10):401. PMID 30274305
- 207
- Mizuno S, Mihara T, Miyaoka T, Inagaki T, Horiguchi J. CSF iron, ferritin and transferring levels in restless legs syndrome. J Sleep Res 2005;14:43-7. PMID 15743333
- 208
- Moccia M, Erro R, Picillo M, et al. A four-year longitudinal study on restless legs syndrome in Parkinson disease. Sleep 2016;39(2):405-12. PMID 26564123
- 209
- Mohri I, Kato-Nishimura K, Kagitani-Shimono K, et al. Evaluation of oral iron treatment in pediatric restless legs syndrome (RLS). Sleep Med 2012;13(4):429-32. PMID 22341906
- 210
- Molnar MZ, Novak M, Ambrus C, et al I. Restless legs syndrome in patients after renal transplantation. Am J Kidney Dis 2005;45:388-96. PMID 15685518
- 211
- Molnar MZ, Lu JL, Kalantar-Zadeh K, Kovesdy CP. Association of incident restless legs syndrome with outcomes in a large cohort of US veterans. J Sleep Res 2016;25(1):47-56. PMID 26377112
- 212
- Montagna P, Hornyak M, Ulfberg J, et al. Randomized trial of pramipexole for patients with restless legs syndrome (RLS) and RLS-related impairment of mood. Sleep Med 2010;12(1):34-40. PMID 20965780
- 213
- Montagna P, Sassoli de Bianchi L, Zucconi M, Cirignotta G, Lugaresi E. Clonazepam and vibration in restless legs syndrome. Acta Neurol Scand 1984;69:428-30. PMID 6380197
- 214
- Montplaisir J, Boucher S, Poirier G, et al. Clinical polysomnographic and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord 1997;12:61-5. PMID 8990055
- 215
- Montplaisir J, Fantini ML, Desautels A, et al. Long-term treatment with pramipexole in restless legs syndrome. Eur J Neurol 2006;13(12):1306-11. PMID 17116213
- 216
- Montplaisir J, Godbout R. Restless legs syndrome and periodic movements during sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. Philadelphia: WB Saunders, 1989.
- 217
- Montplaisir J, Godbout R, Boghen D, DeChamplain J, Young SN, Lapierre G. Familial restless legs with periodic movements in sleep: electrophysiologic, biochemical, and pharmacologic study. Neurology 1985;35(1):130-4. PMID 3965987
- 218
- Montplaisir J, Lapierre O, Warnes H, Pelletier G. The treatment of the restless leg syndrome with or without periodic leg movements in sleep. Sleep 1992;15(5):391-5. PMID 1360697
- 219
- Mrowka M, Jobges M, Berding G, et al. Computerized movement analysis and beta-CIT-SPECT in patients with restless legs syndrome. J Neural Transm 2005;112:693-701. PMID 15517434
- 220
- Muhle H, Neumann A, Lohmann-Hedrich K, et al. Childhood-onset restless legs syndrome: clinical and genetic features of 22 families. Mov Disord 2008;23:1113-21. PMID 18381645
- 221
- Nahab FB, Peckham El, Hallett M. Double-blind, placebo-controlled, pilot trial of botulinum toxin A in restless legs syndrome. Neurology 2008;71(12):950-1. PMID 18794499
- 222
- Nanayakkara B, Di Michiel J, Yee JB. Restless legs syndrome. Aust J Gen Pract 2023;52(9):615-21. PMID 37666782
- 223
- Neau JP, Marion P, Mathis S, et al. Restless legs syndrome and pregnancy: follow-up of pregnant women before and after delivery. Eur Neurol 2010;64(6):361-6. PMID 21088424
- 224
- Nicolas A, Michaud M, Lavigne G, Montplaisir J. The influence of sex, age and sleep/wake state on characteristics of periodic leg movements in restless legs syndrome patients. Clin Neurophysiol 1999;110:1168-74. PMID 10423183
- 225
- Oboshi Y, Ouchi Y, Yagi S, et al. In vivo mesolimbic D2/3 receptor binding predicts posttherapeutic clinical responses in restless legs syndrome: a positron emission tomography study. J Cereb Blood Flow Metab 2012;32(4):654-62. PMID 22234337
- 226
- Odegaard K. Restless legs and pulmonary disease. R Med J 1971;1:670. PMID 5548851
- 227
- Oertel WH, Benes H, Bodenshatz R, et al. Efficacy of cabergoline in restless legs syndrome: a placebo-controlled study with polysomnography (CATOR). Neurology 2006;67(6):1040-6. PMID 16931508
- 228
- Oertel WH, Benes H, Garcia-Borreguero D, et al. Rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome: a randomized, placebo-controlled polysomnographic study. Sleep Med 2010;11(9):848-56. PMID 20813583
- 229
- Oertel WH, Hallström Y, Saletu-Zyhlarz GM, et al. Sleep and quality of life under prolonged release oxycodone/naloxone for severe restless legs syndrome: an analysis of secondary efficacy variables of a double-blind, randomized, placebo-controlled study with an open-label extension. CNS Drugs 2016;30(8):749-60. PMID 27401882
- 230
- Oertel WH, Stiasny-Kolster K, Bergtholdt B, et al. Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study (effect-RLS study). Mov Disord 2007;22(2):213-9. PMID 17133582
- 231
- Oertel W, Trenkwalder C, Beneš H, et al. Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study. Lancet Neurol 2011;10(8):710-20. PMID 21705273
- 232
- O'Keeffe ST. Restless legs syndrome. A review. Arch Intern Med 1996;156:243-8. PMID 8572833
- 233
- Ondo W. Methadone for refractory restless legs syndrome. Mov Disord 2005;20:345-8. PMID 15580610
- 234
- Ondo W. Restless legs syndrome "Patient Odyssey" survey of disease burden on patient and spouses/partners. Sleep Med 2018;47:51-3. PMID 29753925
- 235
- Ondo W. VIM deep brain stimulation does not improve pre-existing restless legs syndrome in patients with essential tremor. Parkinsonism Relat Disord 2006;12(2):113-4. PMID 16446110
- 236
- Ondo W, He Y, Rajasekaran S, Le WD. Clinical correlates of 6-hydroxydopamine injections int A11 dopaminergic neurons in rats: a possible model for restless legs syndrome. Mov Disord 2000a;15:154-8. PMID 10634257
- 237
- Ondo W, Jankovic J. Restless legs syndrome: clinicoetiologic correlates. Neurology 1996;47(6):1435-41. PMID 8960723
- 238
- Ondo W, Vuong KD, Wang Q. Restless legs syndrome in monozygotic twins: clinical correlates. Neurology 2000b;55(9):1404-6. PMID 11087794
- 239
- Ondo WG, Jankovic J, Simpson R, Jimenez-Shahed J. Globus pallidus deep brain stimulation for refractory idiopathic restless legs syndrome. Sleep Med 2012;13(9):1202-4. PMID 22995627
- 240
- Ondo WG, Lai D. Association between restless legs syndrome and essential tremor. Mov Disord 2006;21(4):515-8. PMID 16250022
- 241
- Oppenheim H. Lehrbuch der Nervenkrankheiten. 7th ed. Berlin, Germany: S Karger, 1923:1744.
- 242
- Park HR, Kim HR, Oh S, Seong JK, Joo EY. White matter tract-specific alterations in patients with primary restless legs syndrome. Sci Rep 2021;11(1):16116. PMID 34373482
- 243
- Partinen M, Hirvonen K, Jama L, et al. Open-label study of the long-term efficacy and safety of pramipexole in patients with restless legs syndrome (extension of the PRELUDE study. Sleep Med 2008;9(5):537-41. PMID 18276187
- 244
- Patton SM, Ponnuru P, Snyder AM, Podskalny GD, Connor JR. Hypoxia-inducible factor pathway activation in restless legs syndrome patients. Eur J Neurol 2011;18(11):1329-35. PMID 21985026
- 245
- Peacock J, Mishra G, Roy RC. Physostigmine and restless legs syndrome. Anesthesiology 2012;117(5):1144-5. PMID 23095549
- 246
- Pearson VE, Allen RP, Dean T, Gamaldo CE, Lesage SR, Earley CJ. Cognitive deficits associated with restless legs syndrome (RLS). Sleep Med 2006;7(1):25-30. PMID 16198145
- 247
- Pedroso JL, Bor-Seng-Shu E, Felicio AC, et al. Severity of restless legs syndrome is inversely correlated with echogenicity of the substantia nigra in different neurodegenerative movement disorders. a preliminary observation. J Neurol Sci 2012;319(1-2):59-62. PMID 22632781
- 248
- Peled R, Lavie P. Double-blind evaluation of clonazepam on periodic leg movements in sleep. J Neurol Neurosurg Psychiatry 1987;50:1679-81. PMID 3437302
- 249
- Pelletier G, Lorrain D, Montplaisir J. Sensory and motor components of the restless legs syndrome. Neurology 1992;42:1663-6. PMID 1513452
- 250
- Phillips B, Young T, Finn L, et al. Epidemiology of restless legs symptoms in adults. Arch Int Med 2000;160:2137-41. PMID 10904456
- 251
- Picchietti MA, Picchietti DL. Advances in pediatric restless legs syndrome: iron, genetics, diagnosis and treatment. Sleep Med 2010;11(7):643-51. PMID 20620105
- 252
- Pichler I, Hicks AA, Pramstaller PP. Restless legs syndrome: an update on genetics and future perspectives. Clin Genet 2008;73(4):291-305. PMID 18070136
- 253
- Pizza F, Persici E, La Manna G, et al. Family recurrence and oligo-anuria predict uremic restless legs syndrome. Acta Neurol Scand 2012;125(6):403-9. PMID 21824115
- 254
- Pollmacher T, Schulz H. Periodic leg movements (PLM): their relationship to sleep stages. Sleep 1993;16:572-7. PMID 8235243
- 255
- Pourcher E, Remillard S, Cohen H. Compulsive habits in restless legs syndrome patients under dopaminergic treatment. J Neurol Sci 2010;290(1-2):52-6. PMID 19969309
- 256
- Quilici S, Abrams KR, Nicolas A, et al. Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome. Sleep Med 2008;9(7):715-26. PMID 18226947
- 257
- Raissi GR, Forogh B, Ahadi T, Ghahramanpoori S, Ghaboussi P, Sajadi S. Evaluation of acupuncture in the treatment of restless legs syndrome: a randomized controlled trial. J Acupunct Meridian Stud 2017;10(5):346-50. PMID 29078970
- 258
- Reuter I, Ellis CM, Ray Chaudhuri K. Nocturnal subcutaneous apomorphine infusion in Parkinson’s disease and restless legs syndrome. Acta Neurol Scand 1999;100:163-7. PMID 10478579
- 259
- Rizzo G, Li X, Galantucci S, Filippi M, Cho YW. Brain imaging and networks in restless legs syndrome. Sleep Med 2017;31:39-48. PMID 27838239
- 260
- Rizzo G, Manners D, Testa C, et al. Low brain iron content in idiopathic restless legs syndrome patients detected by phase imaging. Mov Disord 2013;28(13):1886-90. PMID 23780623
- 261
- Ross DA, Narus MS, Nutt JG. Control of medically refractory restless legs syndrome with intrathecal morphine: case report. Neurosurgery 2008;62(1):E263. PMID 18300885
- 262
- Rottach KG, Schaner BM, Kirch MH, et al. Restless legs syndrome as side effect of second generation antidepressants. J Psychiatr Res 2008;43(1):70-5. PMID 18468624
- 263
- Roy M, de Zwaan M, Tuin I, Philipsen A, Brähler E, Müller A. Association between restless legs syndrome and adult ADHD in a German community-based sample. J Atten Disord 2018;22(3):300-8. PMID 25555628
- 264
- Ruottinen HM, Partinen M, Hublin C, et al. An FDOPA PET study in patients with periodic limb movement disorder and restless legs syndrome. Neurology 2000;54(2):502-4. PMID 10668725
- 265
- Ruppert E, Kilic-Huck U, Wolff V, et al. Brainstem stroke-related restless legs syndrome: frequency and anatomical considerations. Eur Neurol 2015;73(1-2):113-8. PMID 25428634
- 266
- Sagheb MM, Dormanesh B, Fallahzadeh MK, et al. Efficacy of vitamins C, E, and their combination for treatment of restless legs syndrome in hemodialysis patients: a randomized, double-blind, placebo-controlled trial. Sleep Med 2012;13(5):542-5. PMID 22317944
- 267
- Sakkas GK, Hadjigeorgiou GM, Karatzaferi C, et al. Intradialytic aerobic exercise training ameliorates symptoms of restless legs syndrome and improves functional capacity in patients on hemodialysis: a pilot study. ASAIO J 2008;54(2):185-90. PMID 18356653
- 268
- Saletu M, Anderer P, Hogl B, et al. Acute double-blind, placebo-controlled sleep laboratory and clinical follow-up studies with a combination treatment of rr-L-dopa and sr-L-dopa in restless legs syndrome. J Neural Transm 2003;110(6):611-26. PMID 12768357
- 269
- Saletu M, Anderer P, Saletu-Zyhlarz G, et al. Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD): acute placebo-controlled sleep laboratory studies with clonazepam. Eur Neuropsychopharmacol 2001;11(2):153-61. PMID 11313161
- 270
- Santos RS, Coelho FM, Silva BC, et al. Parathyroidectomy improves restless leg syndrome in patients on hemodialysis. PLoS One 2016;11(5):e0155835. PMID 27196740
- 271
- Sarayloo F, Dion PA, Rouleau GA. MEIS1 and restless legs syndrome: a comprehensive review. Front Neurol 2019;10:935. PMID 31551905
- 272
- Sarberg M, Josefsson A, Wirehn AB, Svanborg E. Restless legs syndrome during and after pregnancy and its relation to snoring. Acta Obstet Gynecol Scand 2012;91(7):850-5. PMID 22458961
- 273
- Scharf M, Brown L, Hirschowitz J. Possible efficacy of alprazolam in restless leg syndrome. Hillside J Clin Psychiatry 1986;8:214-23. PMID 3557297
- 274
- Schenck CH, Mahowald MW. Long-term, nightly benzodiazepine treatment of injurious parasomnias and other disorders of disrupted nocturnal sleep in 170 adults. Am J Med 1996;100:333-7. PMID 8629680
- 275
- Schormair B, Kemlink D, Roeske D, et al. PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet 2008;40(8):946-8. PMID 18660810
- 276
- Schormair B, Zhao C, Bell S, et al. Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis. Lancet Neurol 2017;16(11):898-907. PMID 29029846
- 277
- Schurks M, Winter AC, Berger K, Buring J, Kurth T. Migraine and restless legs syndrome in women. Cephalalgia 2012;32(5):382-9. PMID 22395798
- 278
- Shaw PJ, Duntley SP. Neurological disorders: towards a mechanistic understanding of restless legs syndrome. Curr Biol 2012;22(12):R485-6. PMID 22720681
- 279
- Shin YK. Restless leg syndrome: unusual cause of agitation under anesthesia. South Med J 1987;80:278-9. PMID 3810235
- 280
- Sieminski M, Bilińska M, Nyka WM. Increased frequency of restless legs syndrome in myasthenia gravis. Eur Neurol 2012;68(3):166-70. PMID 22906874
- 281
- Sieminski M, Chwojnicki K, Partinen M. Higher nocturnal systolic blood pressure in patients with restless legs syndrome compared with patients with insomnia. Sleep Med 2017;32:229-33. PMID 27908587
- 282
- Silber MH, Richardson JW. Multiple blood donations associated with iron deficiency in patients with restless legs syndrome. Mayo Clin Proc 2003;78(1):52-4. PMID 12528877
- 283
- Silva MA, Duarte GS, Camara R, et al. Placebo and nocebo responses in restless legs syndrome: a systematic review and meta-analysis. Neurology 2017;88(23):2216-24. PMID 28490647
- 284
- Skehan EB, Abdulrahim MM, Parfrey NA, Hand CK. A novel locus for restless legs syndrome maps to chromosome 19p in an Irish pedigree. Neurogenetics 2012;13(2):125-32. PMID 22411506
- 285
- Spillane JD, Nathan PW, Kelly RE, Marsden CD. Painful legs and moving toes. Brain 1971;94:541-56. PMID 4255783
- 286
- Sprenger FS, Seppi K, Poewe W. Drug safety evaluation of rotigotine. Expert Opin Drug Saf 2012;11(3):503-12. PMID 22468676
- 287
- Srivanitchapoom P, Pandey S, Hallett M. Restless legs syndrome and pregnancy: a review. Parkinsonism Relat Disord 2014;20(7):716-22. PMID 24768121
- 288
- Stefano G. Comparative aspects of opioid-dopamine interaction. Cell Mol Neurobiol 1982;2:167-78. PMID 6130844
- 289
- Stehlik R, Arvidsson L, Ulfberg J. Restless legs syndrome is common among female patients with fibromyalgia. Eur Neurol 2009;61(2):107-11. PMID 19065057
- 290
- Steiner JC. Clonidine helps restless legs syndrome. Neurology 1987;37(Suppl 1):278.
- 291
- Stiasny-Kolster K, Kohnen R, Moller JC, Trenkwalder C, Oertel WH. Validation of the l-dopa test for diagnosis of restless legs syndrome. Mov Disord 2006;21(9):1333-9. PMID 16705685
- 292
- Suzuki K, Okuma Y, Uchiyama T, et al. Characterizing restless legs syndrome and leg motor restlessness in patients with Parkinson's disease: a multicenter case-controlled study. Parkinsonism Relat Disord 2017;44:18-22. PMID 28827009
- 293
- Szentkirályi A, Völzke H, Hoffmann W, Trenkwalder C, Berger K. Multimorbidity and the risk of restless legs syndrome in 2 prospective cohort studies. Neurology 2014;82(22):2026-33. PMID 24808014
- 294
- Tekatas A, Pamuk ON. Increased frequency of restless leg syndrome in patients with ankylosing spondylitis. Int J Rheum Dis 2015;18(1):58-62. PMID 24612586
- 295
- Tempest N, Boyers M, Carter A, Lane S, Hapangama DK. Premenopausal women with a diagnosis of endometriosis have a significantly higher prevalence of a diagnosis or symptoms suggestive of restless leg syndrome: a prospective cross-sectional questionnaire study. Front Endocrinol (Lausanne) 2021;12:599306. PMID 33854478
- 296
- Teodoro T, Viana P, Abreu D, Conceição I, Peralta R, Ferreira JJ. A peripheral pathway to restless legs syndrome? Clues from familial amyloid polyneuropathy. Parkinsonism Relat Disord 2015;21(12):1465-8. PMID 26508424
- 297
- Tergau F, Wischer S, Wolf C, et al. Treatment of restless legs syndrome with the dopamine agonist alpha-dihydroergocryptine. Mov Disord 2001;16(4):731-5. PMID 11481700
- 298
- Thireau J, Farah C, Molinari N, et al. MEIS1 variant as a determinant of autonomic imbalance in restless legs syndrome. Sci Rep 2017;7:46620. PMID 28425489
- 299
- Thorp ML, Morris CD, Bagby SP. A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients. Am J Kidney Dis 2001;38(1):104-8. PMID 11431189
- 300
- Tilch E, Schormair B, Zhao C, et al. Identification of restless legs syndrome genes by mutational load analysis. Ann Neurol 2020;87(2):184-93. PMID 31788832
- 301
- Trautmann E, Barke A, Frisch JU, et al. Restless legs syndrome: Psychiatric comorbidities are more important than neuroticism. Behav Sleep Med 2015;13(5):375-86. PMID 24945565
- 302
- Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J. Restless legs syndrome associated with major diseases: a systematic review and new concept. Neurology 2016;86(14):1336-43. PMID 26944272
- 303
- Trenkwalder C, Benes H, Grote L, et al. Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: results from a multi-center, randomized, active controlled trial. Mov Disord 2007;22(5):696-703. PMID 17274039
- 304
- Trenkwalder C, Benes H, Poewe W, et al. Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2008a;7:595-604. PMID 18515185
- 305
- Trenkwalder C, Bucher SF, Oertel WH. Electrophysiological pattern of involuntary limb movements in the restless legs syndrome. Muscle Nerve 1996a;19:155-62. PMID 8559163
- 306
- Trenkwalder C, Bucher SF, Oertel WH, et al. Bereitschaftspotential in idiopathic and symptomatic restless legs syndrome. Electroencephalogr Clin Neurophysiol 1993;89:95-103. PMID 7683607
- 307
- Trenkwalder C, Canelo M, Lang M, et al. Management of augmentation of restless legs syndrome with rotigotine: a 1-year observational study. Sleep Med 2017a;30:257-65. PMID 26896370
- 308
- Trenkwalder C, Garcia-Borreguero D, Montagna P, et al. Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry 2004b;75(1):92-7. PMID 14707315
- 309
- Trenkwalder C, Hening WA, Montagna P, et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord 2008b;23:2267-302. PMID 18925578
- 310
- Trenkwalder C, Henning WA, Walters AS, et al. Circadian rhythm of periodic limb movements and sensory symptoms of restless legs syndrome. Mov Disord 1999a;14:102-10. PMID 9918351
- 311
- Trenkwalder C, Seidel VC, Gasser T, Oertel WH. Clinical symptoms and possible anticipation in a large kindred of familial restless legs syndrome. Mov Disord 1996b;11:389-94. PMID 8813218
- 312
- Trenkwalder C, Walters AS, Hening WA, et al. Positron emission tomographic studies in restless legs syndrome. Mov Disord 1999b;14:141-5. PMID 9918358
- 313
- Trenkwalder C, Winkelmann J, Oertel W, et al. Ferric carboxymaltose in patients with restless legs syndrome and nonanemic iron deficiency: a randomized trial. Mov Disord 2017b;32(10):1478-82. PMID 28643901
- 314
- Tribl GG, Sycha T, Kotzailias N, Zeitlhofer J, Auff E. Apomorphine in idiopathic restless legs syndrome: an exploratory study. J Neurol Neurosurg Psych 2005;76:181-5. PMID 15654028
- 315
- Tsai MH, Huang YS. Attention-deficit/hyperactivity disorder and sleep disorders in children. Med Clin North Am 2010;94(3):615-32. PMID 20451036
- 316
- Tuo HZ, Tian ZL, Cui YN, et al. Restless legs syndrome secondary to pontine infarction: Clinical analysis of five cases. Chronic Dis Transl Med 2017;3(3):186-90. PMID 29063076
- 317
- Tuo H, Tian Z, Ma X, et al. Clinical and radiological characteristics of restless legs syndrome following acute lacunar infarction. Sleep Med 2019;53:81-7. PMID 30458382
- 318
- Tutuncu M, Tutuncu M. The effect of vitamin D on restless legs syndrome: prospective self-controlled case study. Sleep Breath 2020;24(3):1101-6. PMID 32078093
- 319
- Tzonova D, Larrosa O, Calvo E, et al. Breakthrough symptoms during the daytime in patients with restless legs syndrome (Willis-Ekbom disease). Sleep Med 2012;13(2):151-5. PMID 22281003
- 320
- UI Abideen Z, Mahmud SN, Mushtaq F, et al. Association of hemodialysis inadequacy and duration with restless legs syndrome: a cross-sectional study. Cureus 2018;10(5):e2570. PMID 29974025
- 321
- Unger EL, Bianco LE, Jones BC, Allen RP, Earley CJ. Low brain iron effects and reversibility on striatal dopamine dynamics. Exp Neurol 2014;261:462-8. PMID 24999026
- 322
- van Alfen N, Sinke RJ, Zwarts MJ, et al. Intermediate CAG repeat lengths (53, 54) for MJD/SCA3 are associated with an abnormal phenotype. Ann Neurol 2001;49(6):805-7. PMID 11409435
- 323
- Verbaan D, van Rooden SM, van Hilten JJ, Rijsman RM. Prevalence and clinical profile of restless legs syndrome in Parkinson’s disease. Mov Disord 2010;25(13):2142-7. PMID 20737549
- 324
- Vitello N, Bayard S, Lopez R, et al. Rhythmic movement disorder associated with restless leg syndrome. Sleep Med 2012;13(10):1324-5. PMID 23063300
- 325
- Wagner ML, Walters AS, Coleman RG, et al. Randomized, double-blind, placebo-controlled study of clonidine in restless legs syndrome. Sleep 1996;19:52-8. PMID 8650464
- 326
- Wali S, Shukr A, Boudal A, Alsaiari A, Krayem A. The effect of vitamin D supplements on the severity of restless legs syndrome. Sleep Breath 2015;19(2):579-83. PMID 25148866
- 327
- Walters AS, Hening W, Chokroverty S. Frequent occurrence of myoclonus while awake and at rest, body rocking and marching in place in a subpopulation of patients with restless legs syndrome. Acta Neurol Scand 1988a;77:418-21. PMID 3414379
- 328
- Walters AS, Hening W, Rubinstein M, Chokroverty S. A clinical and polysomnographic comparison of neuroleptic-induced akathisia and the idiopathic restless legs syndrome. Sleep 1991;1:339-45. PMID 1682986
- 329
- Walters AS, Hickey K, Maltzman J, et al. A questionnaire study of 138 patients with restless legs syndrome: the 'night-walkers' survey. Neurology 1996;46(1):92-5. PMID 8559428
- 330
- Walters AS, Rye DB. Evidence continues to mount on the relationship of restless legs syndrome/periodic limb movements in sleep to hypertension, cardiovascular disease, and stroke. Sleep 2010;33(3):287. PMID 20337185
- 331
- Walters AS, Wagner ML, Hening WA, et al. Successful treatment of the idiopathic restless legs syndrome in a randomized double blind trial of oxycodone versus placebo. Sleep 1993;16:327-32. PMID 8341893
- 332
- Walters AS, Winkelmann J, Trenkwalder C, et al. Long-term follow-up on restless legs syndrome patients treated with opioids. Mov Disord 2001;16(6):1105-9. PMID 11748742
- 333
- Weissbach A, Siegesmund K, Brüggemann N, et al. Exome sequencing in a family with restless legs syndrome. Mov Disord 2012;27(13):1686-9. PMID 23192925
- 334
- Wijemanne S, Jankovic J. Restless legs syndrome: clinical presentation diagnosis and treatment. Sleep Med 2015;16(6):678-90. PMID 25979181
- 335
- Willis T. The London practice of physick. 1st ed. London: Thomas Bassett and William Crooke, 1685:404.
- 336
- Winkelmann J, Czamara D, Schormair B, et al. Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1. PLoS Genet 2011;7(7):e1002171. PMID 21779176
- 337
- Winkelman JW, Johnston L. Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome (RLS). Sleep Med 2004;5(1):9-14. PMID 14725821
- 338
- Winter AC, Berger K, Glynn RJ, et al. Vascular risk factors, cardiovascular disease, and restless legs syndrome in men. Am J Med 2013;126(3):228-35. PMID 23410563
- 339
- Winter AC, Schurks M, Glynn RJ, et al. Restless legs syndrome and risk of incident cardiovascular disease in women and men: prospective cohort study. BMJ Open 2012;2(2):e000866. PMID 22447047
- 340
- Wittmaack T. Pathologie und therapie der sensibilitat-neurosen. Leipzig: E. Schafer, 1861:459.
- 341
- Wong JC, Li Y, Schwarzschild MA, Ascherio A, Gao X. Restless legs syndrome: an early clinical feature of Parkinson disease in men. Sleep 2014;37(2):369-72. PMID 24497665
- 342
- Worthington A, Thomas L. Valvular heart disease associated with taking low-dose pergolide for restless legs syndrome. Eur J Echocardiogr 2008;9(6):828-30. PMID 18579494
- 343
- Wunderlich GR, Evans KR, Sills T, et al. An item response analysis of the international restless legs syndrome study group rating scale for restless legs syndrome. Sleep Med 2005;6:131-9. PMID 15799121
- 344
- Yang Q, Li L, Chen Q, Foldvary-Schaefer N, Ondo WG, Wang QK. Association studies of variants in MEIS1, BTBD9, and MAP2K5/SKOR1 with restless legs syndrome in a US population. Sleep Med 2011;12(8):800-4. PMID 21925394
- 345
- Yang X, Liu B, Shen H, et al. Prevalence of restless legs syndrome in Parkinson's disease: a systematic review and meta-analysis of observational studies. Sleep Med 2018;43:40-6. PMID 29482811
- 346
- Yildirim E, Apaydin H. Zinc and magnesium levels of pregnant women with restless leg syndrome and their relationship with anxiety: a case-control study. Biol Trace Elem Res 2021;199(5):1674-85. PMID 32676936
- 347
- Yun CH, Lee SK, Kim H, et al. Association between irritable bowel syndrome and restless legs syndrome in the general population. J Sleep Res 2012;21(5):569-76. PMID 22463600
- 348
- Zhu XY, Liu Y, Zhang XJ, et al. Clinical characteristics of leg restlessness in Parkinson's disease compared with idiopathic restless legs syndrome. J Neurol Sci 2015;357(1-2):109-14. PMID 26189051
- 349
- Zhuang S, Na M, Winkelman JW, et al. Association of restless legs syndrome with risk of suicide and self-harm. JAMA Netw Open 2019;2(8):e199966. PMID 31441941
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Robert Fekete MD
Dr. Fekete of New York Medical College received consultation fees from Acadia Pharmaceutical, Acorda, Adamas/Supernus Pharmaceuticals, Amneal/Impax, Kyowa Kirin, Lundbeck Inc., Neurocrine Inc., and Teva Pharmaceutical, Inc.
See Profile
Former Authors
- Kathleen M Shannon MD
- Narendra Vaish PhD
- Pinky Agarwal MD
- Sindhu R Srivatsal MD MPH
- Bridget Nolan MD
Patient Profile
- Age range of presentation
-
- 19 to 65+ years
- Sex preponderance
-
- male=female
- Heredity
-
- heredity may be a factor
- autosomal dominant
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Sporadic restless legs syndrome: G25.82
- Familial restless legs syndrome with or without periodic movements: G25.83
- ICC-11
-
- Restless legs syndrome: 7A80
- Sleep-related movement disorder due to a medical condition: 7A87
- OMIM
-
- Restless legs syndrome, susceptibility to, 1: %102300
- Restless legs syndrome, susceptibility to, 2: %608831
- Restless legs syndrome, susceptibility to, 3: %610438
- Restless legs syndrome, susceptibility to, 4: %610439
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