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Restless legs syndrome RLS is one of Assumptions about restless leg syndrome commonest movement disorders affecting sleep and also daytime Assumptions about restless leg syndrome. The diagnosis is simple and is based on a well-validated clinical questionnaire, yet misdiagnosis is common and the condition remains underdiagnosed and consequently inappropriately treated, often causing great distress to the sufferers.

This review addresses the diagnostic issues, the differential diagnosis, and the evidence base for treatment of the common condition.

The term restless legs syndrome was first introduced in by Karl-Axel Ekbom, a Swedish neurologist and surgeon, who described and systematically characterized the condition Ekbom RLS Assumptions about restless leg syndrome present in primary care and secondary Assumptions about restless leg syndrome, across a range of specialities, and in the UK, the condition remains under-recognized and is often regarded as a neurosis in spite of evidence that RLS adversely affects quality of life Chaudhuri et al; Kirsch ; Chaudhuri et al ; Abetz et al Although Assumptions about restless leg syndrome is effectively treatable, and there is a growing evidence base for drug treatment of RLS, the condition is generally poorly treated and investigated and often prescribed inappropriate drugs.

With such a broad, unusual spectrum of reported sensations, RLS is frequently misunderstood and misdiagnosed, and even classified as a psychogenic disorder Allen and Early ; Chaudhuri Ekbom distinguished between the sensory form of RLS asthenia crurum paraesthetica and the painful variant of RLS asthenia crurum dolorosa. More recently, abnormal involuntary movements during sleep such as nocturnal myoclonus subsequently termed periodic limb movements during sleep [PLMS] have been reported to have a strong association with RLS Symonds ; Lugaresi et al The diagnosis of Assumptions about restless leg syndrome had been difficult owing to lack of validated diagnostic criteria till Four essential criteria are all necessary for diagnosis Table 1.

The supportive and associated features help in uncertain cases. The diagnostic criteria for RLS Walters et al RLS needs to be Assumptions about restless leg syndrome from nocturnal leg cramps and positional discomfort and akathisia Table 2. Other differential diagnoses are noted in Table 3 Mrowka et al ; Assumptions about restless leg syndrome et al It is clear from the above criteria that any condition that causes legs to be restless or fidgety is not necessarily due to RLS.

The differences between akathisia, cramps, positional discomfort, and RLS Mrowka et al Increasing age and female sex are risk factors for the development of RLS. The three common associations of RLS are iron deficiency anaemia, renal failure—uraemia, and pregnancy Ondo ; Chaudhuri ; Jobges et al Other secondary causes of RLS are listed in Figure 1. PLM can occur in lower and upper limbs during quiet wakefulness as well. PLM occurs commonly with RLS and is defined as repetitive flexing Assumptions about restless leg syndrome lower limb joints hip, knee, or ankle and occasionally the upper limb and dorsiflexion or fanning of toes, for periods of 0.

Not all patients with RLS need pharmacological treatment. In many cases not severe enough to merit pharmacological treatment, self-help measures may enable a patient to cope with symptoms of RLS. Sleep hygiene is often used for management of sleep disorders and can be adapted for RLS Table 5.

It is important Assumptions about restless leg syndrome ensure that patients have not been given drugs that worsen RLS Table 6. Support groups such as the Ekbom Support Group, RLS: UK in the UK and websites are available to assist the patients with this distressing condition and to provide useful information and services Chaudhuri Primary and secondary RLS need to be differentiated and treated accordingly.

The commonest secondary causes Assumptions about restless leg syndrome RLS include iron deficiency anemia, and all RLS patients must have serum ferritin levels checked some believe transferrin receptor assays are better. However in many RLS patients, oral iron supplements may not be as efficacious as previously thought. Blood transfusions may also be considered an option for treatment in severely anemic patients with RLS. Despite the fact that RLS is a treatable condition, which generally responds well to various medications, the treatment options are limited by the fact that at present none of the treatment options are licensed in the UK.

It is envisaged that the situation will soon change and at least two or three products are likely to gain license for use in RLS soon. An established body of evidence is now gathered from double-blind, placebo-controlled trials providing level 1 evidence that dopamine agonists DAs are effective for treatment of RLS and currently should be considered the drug of first choice in most patients Chaudhuri ; DeKokker et al Before DAs were available, levodopa was considered effective for RLS, although high rates of augmentation and rebound-related complications have limited the role of levodopa in the treatment of RLS Allen and Earley ; Chaudhuri ; DeKokker et al Trials are being considered to look at the role of enhanced formulations of levodopa combined with entacapone in the treatment of variants of RLS.

These are generally considered the first-line pharmacological agents for both RLS and PLM, and have been proven to be very effective in relieving both a symptoms experienced in the awake state, including the subjective feelings of discomfort and other associated movement abnormalities, and b problems relating to sleep and nocturnal arousals Earley et al ; Chaudhuri ; Tse et al Virtually all the DAs are effective to some degree.

In cases where a definitive diagnosis of RLS has been made, a dramatic response with the use of night-time DAs is expected and some recommend use of this strategy as a challenge test for Assumptions about restless leg syndrome Earley et al As a general guideline most DAs should be started well below the recommended dosage used for PD and gradually titrated upwards, in line with the clinical response.

Side-effects include nausea, nasal stuffiness, and hypotension and we routinely use domperidone prophylaxis for 2 weeks for preventing nausea. Nasal stuffiness or postural hypotension is rarely clinically serious. Newer DAs such as cabergoline 1—4 mg noctepramipexole 0. Several of these trials pergolide, cabergoline, ropinirole, rotigotine, pramipexole have all used randomized, double-blind, placebo-controlled design.

Some key DAs are discussed below. Bromocriptine Assumptions about restless leg syndrome pergolide Although bromocriptine 5—20 mg was one of the first DAs described in the treatment of RLS, to date pergolide has been most frequently studied Earley et al ; Stiasny et al Stiasny et al demonstrated lasting relief from symptoms throughout the night where pergolide 0.

These findings were also confirmed in a similar trial comparing the efficacy of pergolide 0. In comparison with levodopa, pergolide caused a statistically significant improvement in both PLMS and RLS, while bromocriptine, in a comparative analysis with levodopa, demonstrated similar therapeutic effects in terms of relieving RLS symptoms; however, levodopa did demonstrate better tolerability DeKokker et al Ropinirole The recently published TREAT-RLS study is the largest trial reported so far, including patients from 10 European countries, investigating the efficacy of ropinirole in a week, randomized, double-blind, placebo-controlled design followed by a month open-label extension Trenkwalder, Garcia-Borreguero, et al At 12 weeks, ropini-role at a mean dose of 1.

A high placebo response rate was a problem in Assumptions about restless leg syndrome trial, but the improvement in clinical global impression, measures of health-related quality of life, and sleep were significantly in favor of ropinirole treatment at 12 Skinny girl naked big coock. Pramipexole In a recent placebo-controlled, crossover, polysomnographic study involving patients, pramipexole given at dose range of 0.

A large multicenter European study has recently reported the efficacy of pramipexole in the treatment of RLS Oertel and Stiasny-Kolster Few sufficiently long-term follow-up studies have reported on the continued efficacy of DA treatment.

One study Montplaisir et al reported continued efficacy of pramipexole 0. Recent reports suggest that depression and low mood may be a problem in RLS and the proposed psychotropic action of pramipexole may be particularly useful in this regard Corrigan et al ; Goldberg et al Cabergoline Cabergoline, an ergot DA, has the longest half-life 65 hours of all the DAs and therefore has the added advantage of being active for up to 24 hours.

Work from our group and others has demonstrated the efficacy of cabergoline Assumptions about restless leg syndrome PD patients with RLS, and it has recently been proven to be well tolerated in both young and elderly patients, with acceptable side-effect profiles Appiah-Kubi et al Studies suggest that cabergoline is well tolerated in patients with severe RLS who have failed other therapies and also those experiencing augmentation Appiah-Kubi et al More recently, a double-blind, placebo-controlled trial in 85 patients randomized to placebo and 0.

Rotigotine and apomorphine Rotigotine is a nonergot agonist used as a cutaneous patch. In a randomized, double-blind, Assumptions about restless leg syndrome trial involving 63 patients with RLS, rotigotine significantly reduced RLS severity scores compared with placebo at 4. Further trials using rotigotine transdermal delivery system for RLS are underway. Apomorphine, a subcutaneously administered nonergot DA, has also been shown to be effective for symptoms of RLS used as an overnight infusion in severe cases Reuter et al Sumanirole, a dual-acting DA, has been evaluated in a double-blind manner for the treatment of RLS but has been withdrawn from clinical development.

Other dopaminergic drugs reported to be of benefit in RLS include orphenadrine, piribedil, dihydroergocriptine, and amantadine Henning et al ; Stiasny et al ; Chaudhuri ; DeKokker et al Ergot agonists have been linked to a small risk of cardio-pleuro-pulmonary fibrosis, while nonergot agonists seem to have a slightly increased risk of Assumptions about restless leg syndrome sudden sleep onset in susceptible patients. However, these observations were found only in PD patients and their relevance to RLS patients is unclear.

Levodopa Eight small-scale, double-blind and seven open-label studies have shown that levodopa in conjunction with a peripheral decarboxylase inhibitor mg levodopa with 25 mg carbidopa or benserazide is consistently effective for treatment of RLS symptoms Ondo ; Allen et al ; Jobges et al However, the benefits of levodopa treatment are complicated by the emergence of treatment-related side effects such as rebound and augmentation.

Rebound Atlas Task Force ; Chaudhuri represents re-emergence of RLS symptoms in the later part of the night or shortly after waking in the morning, and often necessitates the use of a second dose during the night, taken later at night, or alternatively the use of a slow-release formula. This phenomenon may occur due to the short half-life of levodopa. Augmentation Allen and Early; Chaudhuri is a paradoxical effect associated with levodopa and DAs to a lesser extentinvolving the loss of efficacy, the earlier onset of RLS symptoms before the scheduled dosage, a shorter latency to the onset of the RLS symptoms while at rest, involvement of other body parts ie, armsor an actual worsening in reported RLS symptoms.

DAs also appear Assumptions about restless leg syndrome be superior to levodopa based on a handful of comparative studies. Controlled-release levodopa prolongs the therapeutic effect into the second half of the night and may, therefore, be suitable for reducing rebound. The role of standard levodopa used with an additional catechol-O-methyltransferase COMT inhibitor such as entacapone, or Stalevo a combined preparation of levodopa with entacaponeis being investigated and this strategy may prove particularly beneficial for patients who need to take treatment in an intermittent basis, such as during long flights.

Augmentation with DAs and management Augmentation, although uncommon, has been occasionally reported with the use of other DAs. Augmentation is also rarely seen with the use of ropinirole. An additional early Assumptions about restless leg syndrome dose is helpful, but in some patients the dose of the agonist needs to be increased to the full dose.

If this fails, a switch to an alternative agonist or a nondopaminergic agent such as gabapentin needs to be considered. Gabapentin and carbamazepine have been most widely evaluated in open-label and double-blind studies. Recently, Garcia-Borreguero and colleagues reported the results of a double-blind, crossover, polysomnography-controlled study with gabapentin in 24 patients. At 6 weeks, no augmentation was observed.

In a Assumptions about restless leg syndrome, open, randomized trial, gabapentin was also compared with the DA ropinirole and was as effective as ropinirole in symptom reduction. A double-blind, randomized, controlled trial of carbamazepine showed effective reduction in the number of episodes of restless legs per week, but PLMS was not consistently reduced Assumptions about restless leg syndrome et al Levetiracetam and pregabaline have also been reported to be beneficial in RLS.

We feel that gabapentin seems to be beneficial particularly in cases of RLS associated with Assumptions about restless leg syndrome sensations, and studies have reported that gabapentin may be beneficial for RLS associated with uremia and hemodialysis Tse et al ; DeKokker et al One open trial has reported similar efficacy of gabapentin mg daily to ropinirole 0.

In the 17th century, opiates were actually used in the treatment of conditions that closely resembled RLS. In double-blind, placebo-controlled trials, several workers have reported the beneficial effects of drugs such as oxycodone and propoxyphone in providing symptomatic relief of both RLS and PLMS Allen et al ; Walters et al ; Henning et al Stronger opioids such as methadone, levorphanol, and sustained-release morphine should be reserved for the treatment of severe cases and for those not responding to dopaminergic treatment or in RLS associated with pain asthenia crurum dolorosa Tse et al A range of benzodiazepines has been used for RLS clonazepam [0.

Two double-blind, crossover studies involving only six patients reported contradictory results — either no or modest benefit in leg symptoms and sleep Tse et al Overall, studies suggest that clonazepam can Assumptions about restless leg syndrome helpful for treatment of RLS. An added benefit, relating specifically to clonazepam, is that it has also been successful in the treatment of related motor sleep disorders, such Assumptions about restless leg syndrome rapid eye Assumptions about restless leg syndrome REM behavior disorders, which may coexist in patients suffering from RLS Chaudhuri However, the confounding effect of benzodiazepines Assumptions about restless leg syndrome sleep architecture, respiratory depression, and dependence are concerns, although in a single study conducted with patients with nocturnal respiratory disturbances, benzodiazepines were well tolerated Stisany et al ; Tse Assumptions about restless leg syndrome al Additional to levodopa or DAs dosing of a benzodiazepine may help when insomnia is associated with RLS.

The role of modern sedatives such as zolpidem, zopiclone, and zaleplon in the treatment of RLS has not been established to date.

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