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Postgraduate Education Corner: CONTEMPORARY REVIEWS IN SLEEP MEDICINE |

Restless Legs Syndrome*: A Clinical Update FREE TO VIEW

Charlene E. Gamaldo, MD; Christopher J. Earley, MB, BCh, PhD
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*From the Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD.

Correspondence to: Charlene E. Gamaldo, MD, Neurology and Sleep Medicine, Johns Hopkins University, Asthma and Allergy Bldg 1B75, 5501 Hopkins Bayview Circle, Baltimore, MD 21224; e-mail cgamald1@jhmi.edu



Chest. 2006;130(5):1596-1604. doi:10.1378/chest.130.5.1596
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Restless legs syndrome (RLS) is a common and often disabling sensorimotor disorder. Epidemiologic studies suggest that RLS is an underrecognized and undertreated disorder affecting both children and adults. The diagnosis is based primarily on the following four essential criteria: (1) an urge to move, usually associated with paresthesias, (2) onset or exacerbation of symptoms at rest, (3) relief of symptoms with movement, and (4) symptoms manifesting in a circadian pattern. Supplemental workup including polysomnography, iron profile, and/or neuropathy screen can provide support for the diagnosis and aid in the treatment strategy. Behavioral techniques, dopaminergic agents, opiates, benzodiazepines, and antiepileptics all have potential value in treating this disorder. Dopaminergic agents continue to be the most effective RLS treatment. However, due to their potential long-term side effects, these agents should not be considered the sole treatment of choice. In the end, the therapeutic plan should be individualized to suit each patient’s presentation and needs.

Figures in this Article

Restless legs syndrome (RLS) is a common and often disabling sensorimotor disorder. Epidemiologic studies14 suggest that 7 to 10% of the general population in the United States and Northern Europe have RLS. RLS prevalence and disease severity increase with age.5Individuals originating from the Mediterranean/Middle Eastern regions of the world have a 3% prevalence, whereas Eastern Asians have a 1 to 5% prevalence.68 Significantly fewer African Americans have RLS than whites, even within the hemodialysis group.910 The incidence in women is twice that of men.11A higher-than-normal prevalence (from 25 to 30%) of RLS is found in patients with iron deficiency, pregnancy, and end-stage renal disease.1216 Several neurologic conditions are linked with RLS, including spinal cerebellar atrophy, Charcot-Marie tooth disease type 2, spinal stenosis, lumbar sacral radiculopathy, and Parkinson disease (PD).1720

Idiopathic RLS appears to run in families,2122 suggesting a genetic basis for the syndrome. Separate chromosomal loci have been linked to the disease (12q, 14q, 9p) in three longitudinal family genetic studies2325; an autosomal recessive inheritance pattern was noted with 12q in one study, and a dominant pattern was demonstrated in the other two studies. A strong family history of RLS is more closely correlated with an early age of onset (< 45 years); however, RLS developing at an older age is associated more with neuropathy and faster disease progression.5,2627

Most of the RLS pathophysiology work has focused on the dopamine and iron systems. The > 90% efficacy rate with levodopa is the primary basis for the dopaminergic hypothesis. Several radiographic studies2832 have been conducted looking specifically at the dopamine system including positron emission tomography, MRI, and single-photon emission CT investigations. Although the results are mixed, there is some support implicating the nigrostriatal dopaminergic loop.

The role of iron in RLS has also been supported by demonstrated therapeutic benefit. Autopsy and MRI studies3335 have found lower iron levels in the substantia nigra of RLS patients. Other studies3637 have even found lower cerebral spinal fluid ferritin and iron concentrations in RLS patients with normal serum iron stores. The inability to store iron in the brain was more profound in patients with early onset RLS patients compared to patients with late onset RLS.36

Diagnosis

There are four essential clinical criteria necessary to establish the diagnosis of RLS, discussed below (Table 1 ).38

Urge To Move, Usually Associated With Paresthesias:

The core symptom of RLS is an uncontrollable urge to move the legs, which is often so overwhelming that the patient cannot keep his or her legs still. The patient often states that the sensation is “hard to describe.” Others characterize the sensations using such colorful descriptors as “creepy-crawly sensations,” “electrical currents”, or “cola in the veins.” In most instances, the feeling is deep and uncomfortable rather than painful. Pain, when reported, usually has a neuropathic characteristic.38 Although the legs are primarily affected and may affect the legs in total or in part, as the disease progresses, other body parts (shoulders, arms, and trunk) may be affected too.38

Onset or Exacerbation of Symptoms at Rest:

RLS symptoms manifest when the individual is in a comfortable or resting position. In fact, the more comfortable the patient gets, the more likely the symptoms will occur. It should not, however, be associated with a specific body position, which is more suggestive of muscle stiffness or circulation etiology. As the patient remains in the resting position, the urge to move mounts in a crescendo pattern until the patient moves his or her leg. In many cases, the limb can even jump involuntarily.38

Relief of Symptoms With Movement:

Symptom amelioration usually commences immediately or soon after initiating movement. So, if the patient gets up and walks around, the symptoms should be completely gone. However, if they sit or lie down again, the symptoms may return. Counter stimuli such as leg rubbing and hot/cold baths can serve as alternatives to leg movements.38

Symptoms Manifest in a Circadian Pattern:

In most cases, patients initially have symptoms in the evening hours only. The morning hours should always represent a “protected time” associated with a reduction in symptoms. As the disease progresses, the symptoms can begin earlier in the day, sometimes leading to symptoms throughout the day. Even for the patients with 24-h symptoms, the symptom intensity should still take on a circadian pattern. This time-of-day component is independent of the quality or quantity of sleep the preceding night.39

Differential Diagnosis

Soliciting a thorough medical history is also important for ruling out common players in the differential diagnosis. Individuals with chronic pain often complain of uncomfortable sensations and restlessness; however, a circadian pattern is often absent and movement does not completely alleviate the symptoms. Leg cramps occurring at night that are relieved with stretching should be easily differentiated from RLS. Hypotensive akathisia is a rare but documented RLS pretender.40 These patients have leg discomfort that is brought on by sitting for extended periods of time, which is relieved with movement. Unlike RLS, this condition is usually associated with specific body positions, does not take on a circadian pattern, and is not associated with an uncontrollable urge to move. Disorders in the RLS differential can be excluded by keeping the diagnostic criteria and the phenomenology of the patient’s complaint in mind.

A thorough medication history allows for identification of exacerbating drugs (Table 2 ).5,11,4143 Any medication with antidopaminergic properties can aggravate or induce RLS symptoms, including the antiemetics and antipsychotics. Serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants are widely prescribed medications that can trigger or worsen RLS symptoms. Commonly used over-the-counter medications, such as the older antihistamines, can frequently worsen RLS symptoms too.

Supplemental Work-up

When the history or physical examination reveals a potential secondary cause for RLS, it should be appropriately evaluated. Any suspicion for a peripheral nerve or radiculopathy etiology warrants a routine neuropathy panel including thyroid, fasting glucose, B12, B6, folate, and electrophysiology assessment. Although RLS is a clinical diagnosis, additional tests can provide helpful diagnostic and therapeutic information.44

Polysomnography:

Sleep disturbance is one of the primary reasons that RLS patients seek medical attention. Those with severe disease may obtain as little as 4 to 5 h of sleep per night.26 Individuals with RLS exclusively, however, often deny daytime sleepiness despite their significant chronic sleep loss. Although polysomnography is not required to make the diagnosis of RLS, it should be utilized appropriately to rule out any concurrent sleep conditions.

Special attention to the patient’s leg activity can also be done with polysomnography. Periodic limb movements in sleep (PLMS) are rhythmic or semirhythmic movements of the legs that are found in 90% of RLS patients during sleep. PLMS are not restricted to the RLS population only and can also be seen in other sleep disorders, such as sleep apnea and narcolepsy. PLMS are also associated with several medications and medical disorders, and are present in up to 30% of individuals > 50 years of age (Table 3 ).41,4547 PLMS are not definitively linked with daytime sleepiness nor sleep quality; therefore, their clinical relevance remains controversial.46,4849 However, periodic limb movements during wakefulness have been recognized as a sensitive and specific RLS marker.5051 Evaluating periodic limb movements during wakefulness may help distinguish the relevance of RLS in patients with multiple comorbid sleep conditions.

Iron Profile:

An iron profile including ferritin and percentage of transferrin saturation should be ordered on all RLS patients. Iron deficiency has been defined as a ferritin level ≤ 18 μg/L or a transferrin saturation percentage ≤ 16%. Ferritin levels of 50 μg/L have been correlated with increased symptom severity, decreased sleep efficiency, and increased PLMS associated with arousal.52As an acute-phase reactant, ferritin levels may misrepresent the true iron stores, so the transferrin saturation should be determined along with ferritin level. Transferrin saturation is the best initial screener for hemochromatosis (saturation > 50%), and cases of coexistent RLS and hemochromatosis have been reported.5354 If the patient is iron deficient, investigations into possible causes should also be pursued, including GI blood loss, menorrhagia, and blood donation.

The treatment strategy should be individualized for each patient based on the following: (1) iron status, (2) disease severity, (3) frequency/duration of symptoms, (4) presence of pain, and (5) drug side effect profile.

Iron Replacement

Supplementing iron in those with iron deficiency serves as the only potential cure for their RLS. The patient should receive 50 to 65 mg of elemental iron with each administration. Depending on the degree of deficiency, iron can be administered one to three times daily. To improve absorption, iron should be taken on an empty stomach (no calcium, antacids, or milk/dairy) with 200 mg of vitamin C. Constipation is the most common side effect. Motility agents should be administered prophylactically to potential at-risk patients. An iron panel (saturation percentage of ferritin) should be performed every 3 months. The goal is a ferritin level > 50 to 60 μg/L. To avoid exacerbation of underlying hemochromatosis, iron repletion should not be administered to anyone with a saturation > 45%.

In the case of the patient with severe iron deficiency (ferritin ≤ 10 μg/L) and oral iron intolerance, consider IV iron. Anaphylaxis has not been reported with the newer IV iron formulations (sodium ferric gluconate complex and iron sucrose). As a rule, 100 mg of iron administered IV will raise the serum ferritin level by 10 μg/L. Infusions of 100 to 125 mg each can be administered at least 2 days apart to reach the 60 μg/L ferritin goal. The physician should follow the Physicians Desk Reference for specific administration guidelines (www.pdr.net/Home/Home.aspx).

Behavioral Therapy

In mild or intermittent cases, behavioral techniques can be explored.38 Physical as well as mental activity (reading, card games, computer work) can ameliorate symptoms. Counter stimuli including massage and hot baths can also be helpful. Discontinue all other potential exacerbators including caffeine, alcohol, nicotine, and medications (Table 2) when possible.

Medical Therapy

Pharmacologic treatment options for RLS can be classified into four categories (Table 4 )45,5557: (1) dopaminergic agents, (2) opiates, (3) benzodiazepine receptor agonists (BRAs), and (4) antiepileptics.

Dopaminergic Agents:

The dopaminergic agents have shown a > 90% efficacy rate in randomized, placebo-controlled trials.45,55 Benefits were documented for relief of symptoms, improvement in sleep, and reduction in leg movements. Carbidopa/levodopa can provide relief within 20 min. Due to its short-half life (1 to 2 h), levodopa does not provide sustained relief for those with persistent symptoms. Therefore, levodopa is recommended only for intermittent treatment of bedtime symptoms or as a prophylaxis during infrequent sedentary activities such as long plane trips, car rides, or theater events.

For daily symptoms, the dopamine agonists (ropinirole, pergolide, and pramipexole) should be considered.45,5557 Ropinirole was approved by the Food and Drug Administration in May of 2005 for the treatment of RLS. However, there is no indication from the numerous studies45,55 done with the dopamine agonists to consider the efficacy of one to be better than another. The dopamine agonists are longer acting than levodopa (6 to 16 h), allowing for a more sustained response. The agents should be administered at least 2 h prior to the time of anticipated symptoms. All three agents require at least 2 h to reach peak dose effect when administered on an empty stomach.

Some of the common side effects related to the dopaminergic agents include nausea/vomiting, insomnia, hallucinations, nasal congestion, and fluid retention. Daytime sleepiness has been reported in 10 to 50% of PD patients and sudden sleep attacks in 4 to 9% of PD patients treated with dopaminergic agents.55,58 Sleepiness has been reported to a lesser extent in RLS patients treated with dopaminergic agents (20 to 30%).55 Sudden sleep attacks have been reported in only one RLS case report.59

A case report60 characterized a neuropsychological behavior disorder associated with levadopa use called hedonistic homeostatic dysregulation. These 15 PD patients displayed drug seeking and addictive behaviors in relation to levodopa. They also had mood instability, hypersexuality, and compulsive behaviors including shopping, gambling, and nocturnal eating. Similar cases have not been reported in RLS patients, although nocturnal eating binges have been anecdotally reported in our clinic population. The effective treatment dose in RLS is usually lower than in PD. Overall, RLS patients have a lower incidence of adverse events with these agents than do the PD patients, which may be a dose-response issue or a reflection of different disease pathophysiology.,55

A progressive symptomatic worsening of RLS symptoms after an initial improvement with dopaminergic medications should immediately raise the concern for RLS augmentation. Augmentation is the most common side effect seen with long-term use of all the dopaminergic agents.38,6162 The manifestation of symptoms earlier in the day with an increased intensity are some of the first symptoms seen with augmentation. For example, a patient initially presents only with bedtime symptoms that are successfully treated with a late-evening dose of a dopaminergic agent. Six to 18 months later, the symptoms become more intense and occur earlier in the evening compared to the patient’s initial presentation. The symptoms may also spread to other body parts such as shoulders, arms, pelvis, or trunk. Adding more medication to cover the period now associated with symptoms will initially bring about improvements. Despite immediate symptom improvement, augmentation progresses more rapidly with each incremental dose increase. Eventually the symptoms occur nonstop throughout the day. The patient is now unable to sit, let alone lie down, and obtains at best 3 to 4 h of sleep per night.

Levodopa has been associated with augmentation in up to 82% of patients.61 The risk of augmentation is markedly reduced when levodopa is used intermittently (less than three times a week). Augmentation has been reported in approximately 20 to 30% of those treated with the dopamine agonists.55 This figure may be an underestimate since most drug trials last only 4 to 6 weeks, while augmentation is seen after chronic use (> 3 months). More importantly, physicians should recognize augmentation and not treat it with further dose escalations. Once an augmentation pattern begins to develop, the dopaminergic agent should be withdrawn and alternative therapies considered. Changing from one dopaminergic agent to another does not eliminate augmentation. When the dopaminergic agent is withdrawn, the RLS symptoms will rebound severely, often resulting in 48 to 72 h of insomnia. Approximately 4 to 7 days after drug withdrawal, the symptoms should gradually return to the baseline/pretreatment state. The patient needs to be forewarned of this likely outcome when the drugs are withdrawn.

Pergolide, unlike pramipexole and ropinirole, is an ergot derivative and therefore carries the risk of inducing fibrosis of the pericardium, cardiac valves, and the pleural and retroperitoneal space. Twenty-seven total cases have been reported: the pleural space, (n = 10), the pericardium and cardiac valves (n = 10), the retroperitoneal space (n = 5), both the pleural and retroperitoneal space (n = 1), and both the pleural and pericardial space (n = 1).6364 Two of the patients were being treated for idiopathic RLS, with the remainder being PD patients. The duration of treatment ranged from 11 months to 11 years. Patient ages ranged from 42 to 83 years, with a higher incidence among men (59%). The total daily dose ranged from 1 to 8 mg/d, which is well above our maximum recommended dose in RLS (≤ 0.5 mg/d)57(Table 4). Dyspnea was the most common presenting complaint (54%); in most instances, the process was resolved on medication withdrawal. Pergolide should be considered an option in cases where there are unremitting side effects from the other dopaminergic agents. Patients should be informed about the rare association between pergolide and fibrosis and screened with echocardiography prior to initiation, then every 1 to 2 years thereafter. For further recommendations on counseling and management, refer to Agarwal et al.63

Opiates:

Double-blind, placebo-controlled studies65with opiates have documented significant improvement in RLS symptom severity, sleep quality, and nighttime leg activity. One long-term study66 showed that the efficacy of opiates was sustainable for ≥ 15 years with limited risk of addiction. However, patients should be followed up for the development or exacerbation of apnea.66 Augmentation has not been reported with the use of standard opiates, although tramadol use may be associated with augmentation.57 Opiates may be considered a first-line choice in RLS patients who present with neuropathy or painful dysesthesias. They also serve as a good second-line alternative to dopaminergic agents. Because hydrocodone, oxycodone, and codeine have 4-h half-lives, patients with more severe RLS often require frequent and higher doses. These short-acting agents can be useful for intermittent RLS symptoms as well as for nightly symptoms. Patients who have no benefit with one of the codeine-related drugs can sometimes have benefits from another.

If daily symptoms extend beyond 8 h and require more than twice-daily dosing with the codeine-related products, then longer-acting opiates (oxycodone, methadone, or fentanyl patch) should then be considered. In a long-term, open-label trial,65 methadone was shown to be effective in treating severe RLS with minimal tolerance or dependence issues. Methadone has a 16- to 22-h half-life, so it can be taken in the evening as a single dose for treatment of evening and bedtime symptoms. It can also be administered twice daily for those with significant 24-h symptoms.

Antiepileptic Agents:

One double-blind, cross-over trial and three open-label trials6770 for gabapentin documented improvement in subjective symptoms as well as PLMS and sleep architecture. Common side effects include sleepiness, dizziness, fluid retention, and increased appetite. The dosing of gabapentin should be scheduled to cover the symptomatic period. Therefore, if symptoms are only at bedtime, then only a late evening dose is required. If symptoms occur throughout the day, dosing three times daily may be required.

Two small, open-label trials have reported symptomatic benefits and PLMS improvements with lamotrigine.7172 Common side effects of lamotrigine are similar to gabapentin; however, there is a higher risk of allergic skin reactions including the rare incidence of Steven-Johnson syndrome. Therefore, lamotrigine must be titrated slowly (increased by no more then 25 mg/wk) in order to reduce this risk. On the positive side, lamotrigine holds the convenience benefit of being a once-daily drug. Along with the opiates, antiepileptic agents should be considered first-line therapy in individuals with coexisting neuropathy or associated pain.57

BRAs:

Although the efficacy rate for these agents may not approach the dopaminergic agents or the opiates, they still have a viable role in the treatment of RLS in selected cases.45 In patients with intermittent nighttime symptoms, the newer short-acting BRAs may be a good first-line choice, as they offer a quick onset of action with only a short-lived period of pharmacologic action.57 Thus, a patient may be able to reach sleep quickly without the detrimental side effects of chronic changes in sleep or daytime sedation.

Similar to their adult counterparts, RLS in children commonly goes unrecognized. Studies7374 have associated RLS with behavioral, mood, cognitive, and sleep difficulties during childhood. In fact, links have been made between childhood iron deficiency and the manifestation of RLS, attention deficit/hyperactivity disorder, and periodic leg activity.7578 Because children may have difficulties articulating their complaints, the diagnostic criteria are somewhat different than for adults (Table 5 ).,38

Behavioral techniques and improved sleep hygiene should be the first-line strategy. In more severe cases, these techniques should be used in combination with medical management. Limited information exists regarding the efficacy of medical management beyond case reports79and one small open-label trial80of the dopaminergic agents. Nonetheless, the four classes of drugs have been used safely and effectively to treat other medical conditions in children.8184

RLS is a common sensorimotor disorder that often compromises the patient’s quality of life. With a solid understanding of the condition, a clinician can proficiently diagnose the syndrome and offer beneficial treatment options. Once a thorough evaluation and workup are completed, treatment should be individualized to suit each patient’s presentation and needs (Fig 1 ).

Abbreviations: BRA = benzodiazepine receptor agonist; PD = Parkinson disease; PLMS = periodic limb movements in sleep; RLS = restless legs syndrome; SSRI = serotonin reuptake inhibitor

The authors have no conflicts of interest to disclosure.

Table Graphic Jump Location
Table 1. Features of RLS
Table Graphic Jump Location
Table 2. RLS Aggravators
Table Graphic Jump Location
Table 3. Conditions Associated With PLMS
Table Graphic Jump Location
Table 4. Pharmacologic Treatment Options for RLS
Table Graphic Jump Location
Table 5. Diagnosis of RLS in Children
Figure Jump LinkFigure 1. Individualized treatment plan based on patient presentation and needs. Mod = moderate.Grahic Jump Location
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Allen, RP, Dean, T, Earley, CJ Effects of rest-duration, time-of-day and their interaction on periodic leg movements while awake in restless legs syndrome.Sleep Med2005;6,429-434. [CrossRef] [PubMed]
 
Sun, ER, Chen, CA, Ho, G, et al Iron and the restless legs syndrome.Sleep1998;21,371-377. [PubMed]
 
Haba-Rubio, J, Staner, L, Petiau, C, et al Restless legs syndrome and low brain iron levels in patients with haemochromatosis.J Neurol Neurosurg Psychiatry2005;76,1009-1010. [CrossRef] [PubMed]
 
Brandhagen, DJ, Fairbanks, VF, Baldus, W Recognition and management of hereditary hemochromatosis.Am Fam Physician2002;65,853-860. [PubMed]
 
Hening, WA, Allen, RP, Earley, CJ, et al An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder.Sleep2004;27,560-583. [PubMed]
 
Silber, MH, Ehrenberg, BL, Allen, RP, et al An algorithm for the management of restless legs syndrome.Mayo Clin Proc2004;79,916-922. [CrossRef] [PubMed]
 
Earley, CJ Restless legs syndrome.N Engl J Med2003;348,2103-2109. [CrossRef] [PubMed]
 
Plowman, BK, Boggie, DT, Morreale, AP, et al Sleep attacks in patients receiving dopamine-receptor agonists.Am J Health Syst Pharm2005;62,537-540. [PubMed]
 
Bassetti, C, Clavadetscher, S, Gugger, M, et al Pergolide-associated ‘sleep attacks’ in a patient with restless legs syndrome.Sleep Med2002;3,275-277. [CrossRef] [PubMed]
 
Giovannoni, G, O’Sullivan, JD, Turner, K, et al Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies.J Neurol Neurosurg Psychiatry2000;68,423-428. [CrossRef] [PubMed]
 
Allen, RP, Earley, CJ Augmentation of the restless legs syndrome with carbidopa/levodopa.Sleep1996;19,205-213. [PubMed]
 
Garcia-Borreguero, D Augmentation: understanding a key feature of RLS.Sleep Med2004;5,5-6. [CrossRef] [PubMed]
 
Agarwal, P, Fahn, S, Frucht, SJ Diagnosis and management of pergolide-induced fibrosis.Mov Disord2004;19,699-704. [CrossRef] [PubMed]
 
Tintner, R, Manian, P, Gauthier, P, et al Pleuropulmonary fibrosis after long-term treatment with the dopamine agonist pergolide for Parkinson disease.Arch Neurol2005;62,1290-1295. [CrossRef] [PubMed]
 
Walters, AS Review of receptor agonist and antagonist studies relevant to the opiate system in restless legs syndrome.Sleep Med2002;3,301-304. [CrossRef] [PubMed]
 
Walters, AS, Winkelmann, J, Trenkwalder, C, et al Long-term follow-up on restless legs syndrome patients treated with opioids.Mov Disord2001;16,1105-1109. [CrossRef] [PubMed]
 
Happe, S, Klosch, G, Saletu, B, et al Treatment of idiopathic restless legs syndrome (RLS) with gabapentin.Neurology2001;57,1717-1719. [CrossRef] [PubMed]
 
Garcia-Borreguero, D, Larrosa, O, de la Llave, Y, et al Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study.Neurology2002;59,1573-1579. [CrossRef] [PubMed]
 
Adler, CH Treatment of restless legs syndrome with gabapentin.Clin Neuropharmacol1997;20,148-151. [CrossRef] [PubMed]
 
Mellick, GA, Mellick, LB Management of restless legs syndrome with gabapentin (neurontin).Sleep1996;19,224-226. [PubMed]
 
Staedt, J, Stoppe, G, Riemann, H, et al Lamotrigine in the treatment of nocturnal myoclonus syndrome (NMS): two case reports.J Neural Transm1996;103,355-361. [CrossRef] [PubMed]
 
Youssef, EA, Wagner, ML, Martinez, JO, et al Pilot trial of lamotrigine in the restless legs syndrome [letter]. Sleep Med. 2005;;6 ,.:89. [CrossRef] [PubMed]
 
Walters, A Is there a subpopulation of children with growing pains who really have restless legs syndrome? A review of the literature.Sleep Med2002;3,93-98. [CrossRef] [PubMed]
 
Rajaram, SS, Walters, AS, England, SJ, et al Some children with growing pains may actually have restless legs syndrome.Sleep2004;27,767-773. [PubMed]
 
Konofal, E, Lecendreux, M, Arnulf, I, et al Iron deficiency in children with attention-deficit/hyperactivity disorder.Arch Pediatr Adolesc Med2004;158,1113-1115. [CrossRef] [PubMed]
 
Konofal, E, Lecendreux, M, Arnulf, I, et al Restless legs syndrome and serum ferritin levels in ADHD children. Sleep. 2003;;26 ,.:A136
 
Konofal, E, Lecendreux, M, Bouvard, MP, et al High levels of nocturnal activity in children with attention-deficit hyperactivity disorder: a video analysis.Psychiatry Clin Neurosci2001;55,97-103. [CrossRef] [PubMed]
 
Kotagal, S, Silber, MH Childhood-onset restless legs syndrome.Ann Neurol2004;56,803-807. [CrossRef] [PubMed]
 
Walters, AS, Mandelbaum, DE, Lewin, DS, et al Dopaminergic therapy in children with restless legs/periodic limb movements in sleep and ADHD.Pediatr Neurol2000;22,182-186. [CrossRef] [PubMed]
 
Konofal, E, Arnulf, I, Lecendreux, M, et al Ropinirole in a child with attention-deficit hyperactivity disorder and restless legs syndrome.Pediatr Neurol2005;32,350-351. [CrossRef] [PubMed]
 
Crawford, TO, Mitchell, WG, Snodgrass, SR Lorazepam in childhood status epilepticus and serial seizures: effectiveness and tachyphylaxis.Neurology1987;37,190-195. [CrossRef] [PubMed]
 
Hain, RD, Miser, A, Devins, M, et al Strong opioids in pediatric palliative medicine.Paediatr Drugs2005;7,1-9. [CrossRef] [PubMed]
 
Nygaard, T, Marsden, D, Fahn, S Dop-responsive dystonia: long-term treatment response and prognosis.Neurol1991;41,174-181. [CrossRef]
 
Pellock, JM, Watemberg, N New antiepileptic drugs in children: present and future.Semin Pediatr Neurol1997;4,9-18. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Individualized treatment plan based on patient presentation and needs. Mod = moderate.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Features of RLS
Table Graphic Jump Location
Table 2. RLS Aggravators
Table Graphic Jump Location
Table 3. Conditions Associated With PLMS
Table Graphic Jump Location
Table 4. Pharmacologic Treatment Options for RLS
Table Graphic Jump Location
Table 5. Diagnosis of RLS in Children

References

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Haba-Rubio, J, Staner, L, Krieger, J, et al Periodic limb movements and sleepiness in obstructive sleep apnea patients.Sleep Med2005;6,225-229. [CrossRef] [PubMed]
 
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Allen, RP, Dean, T, Earley, CJ Effects of rest-duration, time-of-day and their interaction on periodic leg movements while awake in restless legs syndrome.Sleep Med2005;6,429-434. [CrossRef] [PubMed]
 
Sun, ER, Chen, CA, Ho, G, et al Iron and the restless legs syndrome.Sleep1998;21,371-377. [PubMed]
 
Haba-Rubio, J, Staner, L, Petiau, C, et al Restless legs syndrome and low brain iron levels in patients with haemochromatosis.J Neurol Neurosurg Psychiatry2005;76,1009-1010. [CrossRef] [PubMed]
 
Brandhagen, DJ, Fairbanks, VF, Baldus, W Recognition and management of hereditary hemochromatosis.Am Fam Physician2002;65,853-860. [PubMed]
 
Hening, WA, Allen, RP, Earley, CJ, et al An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder.Sleep2004;27,560-583. [PubMed]
 
Silber, MH, Ehrenberg, BL, Allen, RP, et al An algorithm for the management of restless legs syndrome.Mayo Clin Proc2004;79,916-922. [CrossRef] [PubMed]
 
Earley, CJ Restless legs syndrome.N Engl J Med2003;348,2103-2109. [CrossRef] [PubMed]
 
Plowman, BK, Boggie, DT, Morreale, AP, et al Sleep attacks in patients receiving dopamine-receptor agonists.Am J Health Syst Pharm2005;62,537-540. [PubMed]
 
Bassetti, C, Clavadetscher, S, Gugger, M, et al Pergolide-associated ‘sleep attacks’ in a patient with restless legs syndrome.Sleep Med2002;3,275-277. [CrossRef] [PubMed]
 
Giovannoni, G, O’Sullivan, JD, Turner, K, et al Hedonistic homeostatic dysregulation in patients with Parkinson’s disease on dopamine replacement therapies.J Neurol Neurosurg Psychiatry2000;68,423-428. [CrossRef] [PubMed]
 
Allen, RP, Earley, CJ Augmentation of the restless legs syndrome with carbidopa/levodopa.Sleep1996;19,205-213. [PubMed]
 
Garcia-Borreguero, D Augmentation: understanding a key feature of RLS.Sleep Med2004;5,5-6. [CrossRef] [PubMed]
 
Agarwal, P, Fahn, S, Frucht, SJ Diagnosis and management of pergolide-induced fibrosis.Mov Disord2004;19,699-704. [CrossRef] [PubMed]
 
Tintner, R, Manian, P, Gauthier, P, et al Pleuropulmonary fibrosis after long-term treatment with the dopamine agonist pergolide for Parkinson disease.Arch Neurol2005;62,1290-1295. [CrossRef] [PubMed]
 
Walters, AS Review of receptor agonist and antagonist studies relevant to the opiate system in restless legs syndrome.Sleep Med2002;3,301-304. [CrossRef] [PubMed]
 
Walters, AS, Winkelmann, J, Trenkwalder, C, et al Long-term follow-up on restless legs syndrome patients treated with opioids.Mov Disord2001;16,1105-1109. [CrossRef] [PubMed]
 
Happe, S, Klosch, G, Saletu, B, et al Treatment of idiopathic restless legs syndrome (RLS) with gabapentin.Neurology2001;57,1717-1719. [CrossRef] [PubMed]
 
Garcia-Borreguero, D, Larrosa, O, de la Llave, Y, et al Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study.Neurology2002;59,1573-1579. [CrossRef] [PubMed]
 
Adler, CH Treatment of restless legs syndrome with gabapentin.Clin Neuropharmacol1997;20,148-151. [CrossRef] [PubMed]
 
Mellick, GA, Mellick, LB Management of restless legs syndrome with gabapentin (neurontin).Sleep1996;19,224-226. [PubMed]
 
Staedt, J, Stoppe, G, Riemann, H, et al Lamotrigine in the treatment of nocturnal myoclonus syndrome (NMS): two case reports.J Neural Transm1996;103,355-361. [CrossRef] [PubMed]
 
Youssef, EA, Wagner, ML, Martinez, JO, et al Pilot trial of lamotrigine in the restless legs syndrome [letter]. Sleep Med. 2005;;6 ,.:89. [CrossRef] [PubMed]
 
Walters, A Is there a subpopulation of children with growing pains who really have restless legs syndrome? A review of the literature.Sleep Med2002;3,93-98. [CrossRef] [PubMed]
 
Rajaram, SS, Walters, AS, England, SJ, et al Some children with growing pains may actually have restless legs syndrome.Sleep2004;27,767-773. [PubMed]
 
Konofal, E, Lecendreux, M, Arnulf, I, et al Iron deficiency in children with attention-deficit/hyperactivity disorder.Arch Pediatr Adolesc Med2004;158,1113-1115. [CrossRef] [PubMed]
 
Konofal, E, Lecendreux, M, Arnulf, I, et al Restless legs syndrome and serum ferritin levels in ADHD children. Sleep. 2003;;26 ,.:A136
 
Konofal, E, Lecendreux, M, Bouvard, MP, et al High levels of nocturnal activity in children with attention-deficit hyperactivity disorder: a video analysis.Psychiatry Clin Neurosci2001;55,97-103. [CrossRef] [PubMed]
 
Kotagal, S, Silber, MH Childhood-onset restless legs syndrome.Ann Neurol2004;56,803-807. [CrossRef] [PubMed]
 
Walters, AS, Mandelbaum, DE, Lewin, DS, et al Dopaminergic therapy in children with restless legs/periodic limb movements in sleep and ADHD.Pediatr Neurol2000;22,182-186. [CrossRef] [PubMed]
 
Konofal, E, Arnulf, I, Lecendreux, M, et al Ropinirole in a child with attention-deficit hyperactivity disorder and restless legs syndrome.Pediatr Neurol2005;32,350-351. [CrossRef] [PubMed]
 
Crawford, TO, Mitchell, WG, Snodgrass, SR Lorazepam in childhood status epilepticus and serial seizures: effectiveness and tachyphylaxis.Neurology1987;37,190-195. [CrossRef] [PubMed]
 
Hain, RD, Miser, A, Devins, M, et al Strong opioids in pediatric palliative medicine.Paediatr Drugs2005;7,1-9. [CrossRef] [PubMed]
 
Nygaard, T, Marsden, D, Fahn, S Dop-responsive dystonia: long-term treatment response and prognosis.Neurol1991;41,174-181. [CrossRef]
 
Pellock, JM, Watemberg, N New antiepileptic drugs in children: present and future.Semin Pediatr Neurol1997;4,9-18. [CrossRef] [PubMed]
 
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