IN THE NAME OF GOD

Treatments of Restless Legs Syndrome Dr. maryam Dehghan

Case Scenario A 46 years old woman with discomfort in the legs that occurs only at rest and is immediately relieved by movement. Terms that patients use to describe the symptoms include crawling, itching and stretching, all localized to deep structures rather than the skin. Symptoms typically worsen towards the end of the day and are maximal at night. Which one of the treatments is more benefit for reduce this symptoms ?

PICO

Patient or Problem A 46 years old woman with restless legs syndrome

Intervention Treatment with: Acupuncture Levodopa Dopamine agonists Iron

Comparison Drugs with placebo

Outcomes Symptom improvement of RLS

Key words Restless legs syndrome Acupuncture Levodopa Dopamine agonists Iron

INTRODUCTION — Restless legs syndrome (RLS) refers to symptoms of spontaneous, continuous leg movements associated with unpleasant paresthesias.These sensations occur only at rest and are relieved by movement. Sleep disturbance and a frequent association with involuntary, jerking movements of the legs during sleep, known as periodic leg movements of sleep (PLMS), are common. EPIDEMIOLOGY — Mild symptoms of RLS occur in 5 to 15 percent of the population. PATHOGENESIS — In most cases RLS is a primary idiopathic disorder, but it also can be associated with a variety of underlying medical disorders. Primary RLS — The cause of primary (or idiopathic) RLS is unknown. However, a family history consistent with dominant inheritance is present in more than 40 percent of patients with idiopathic RLS.

Secondary RLS — RLS can occur secondary to a number of disorders including iron deficiency, uremia, diabetes mellitus, rheumatic disease, and venous insufficiency, among others. CLINICAL MANIFESTATIONS — The hallmark of RLS is a marked discomfort in the legs that occurs only at rest and is immediately relieved by movement. The abnormal feelings are typically deep seated and localized below the knees. Distribution is usually bilateral, but some asymmetry may occur and the arms can be affected in more severe cases.

DIAGNOSIS —The International Restless Legs Study Group proposed the following four features as essential criteria for the diagnosis of RLS: An urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs. Sometimes the urge to move is present without the uncomfortable sensations, and sometimes the arms or other body parts are involved in addition to the legs. The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying or sitting. 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. 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. When symptoms are severe, the worsening at night may not be noticeable but must have been previously present.

13

Acupuncture for restless legs syndrome Cui Y, Wang Y, Liu Z

Department of Acupuncture and Moxibustion, Guang An Men Hospital, The China Academy of Chinese Medicine Science, Beijing, China Editorial group: Cochrane Movement Disorders Group. Publication status and date: Edited (no change to conclusions), published in Issue 8, Review content assessed as up-to-date: 30 May Citation: Cui Y, Wang Y, Liu Z. Acupuncture for restless legs syndrome. Cochrane Database of Systematic Reviews 2008, Issue 4. Art.No.: CD DOI: / CD pub 2. Copy right © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Background Restless legs syndrome (RLS ) is a common movement disorder for which patients may seek treatment with acupuncture. However, the benefits of acupuncture in the treatment of RLS are unclear and have not been evaluated in a systematic review until now.

Objectives To evaluate the efficacy and safety of acupuncture therapy in patients with RLS.

Search methods We searched : Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007) MEDLINE( January 1950 to February 2007) EMBASE ( January 1980 to 2007 Week 8) Chinese Biomedical Database (CBM) (1978 to February 2007) China National Knowledge Infrastructure (CNKI) (1979 to February 2007) VIP Database (1989 to February 2007) Japana Centra Revuo Medicina (1983 to 2007) Korean Medical Database (1986 to 2007) Four Chinese journals, relevant academic conference proceedings and reference lists of articles were handsearched.

Selectioncriteria Selection criteria Randomized control led trials and quasi- randomized trials comparing acupuncture with no intervention, placebo acupuncture, sham acupuncture, pharmacological treatments, or other non-acupuncture interventions for primary RLS were included. Trials comparing acupuncture plus non-acupuncture treatment with the same non-acupuncture treatment were also included. Trials that only compared different forms of acupuncture or different acupoints were excluded.

Data collection and analysis Two authors independently identified potential articles, assessed methodological quality and extracted data. Relative risk (RR) was used for binary outcomes and weighted mean difference for continuous variables. Results were combined only in the absence of clinical heterogeneity.

Main results Fourteen potentially relevant trials were identified initially, but twelve of them did not meet the selection criteria and were excluded. Only two trials with 170 patients met the inclusion criteria. No data could be combined due to clinical heterogeneity between trials. Both trials had methodological and/or reporting shortcomings. No significant difference was detected in remission of overall symptoms between acupuncture and medications in one trial (RR 0. 97, 95% CI to 1. 24).

Another trial found that dermal needle therapy used in combination with medications and massage was more effective than medications and massage alone, in terms of remission of unpleasant sensations in the legs (RR 1.36, 95% CI 1.06 to 1.75; WMD-0.61, 95% CI-0.96 to -0.26) and reduction of RLS frequency (WMD-3.44, 95% CI to -1.73).

Authors’ conclusions There is insufficient evidence to determine whether acupuncture is an efficacious and safe treatment for RLS. Further well-designed, large-scale clinical trials are needed.

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Levodopa for the treatment of restless legs syndrome Scholz H, Trenkwalder C, Kohnen R, Kriston L, Riemann D, Hornyak M

Interdisciplinary Pain Canter,UniversityMedical Center, Freiburg, Freiburg, Germany Editorial group: Cochrane Movement Disorders Group. Publication status and date: Edited (no change to conclusions), published in Issue 5, Review content assessed as up-to-date: 18 January Citation: Scholz H, Trenkwalder C, Kohnen R, Kriston L, Riemann D, Hornyak M. Levodopa for the treatment of restless legs syndrome. Cochrane Database of Systematic Reviews 2011, Issue 2. Art.No.: CD DOI: / CD pub2. Copyright © 2011 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd.

Background Levodopa plus dopamine decarboxylase inhibitor is a common treatment for restless legs syndrome (RLS).

Objectives To evaluate efficacy and safety of levodopa for RLS compared to placebo and other active agents.

Search methods We searched CENTRAL ( The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, PsycINFO and CINAHL, from January 1985 to December 2008, reference lists of articles, and contacted pharmaceutical companies.

Selectioncriteria Selection criteria We included double -blind randomised controlled trial s (RCT) investigating levodopa treatment versus placebo or other treatment for at least seven day s in patients with RLS (age ≥ 18 years). Outcomes included symptom severity, CGI-I, objective as well as self rated sleep parameters, quality of life, and safety parameters.

Data collection and analysis Two authors extracted data, assessed risk of bias, and contacted pharmaceutical companies and authors for additional information. We collected dropouts due to adverse events and patients experiencing adverse events.

Main results Six placebo controlled and three active controlled RCTs were included (521 participants). Symptom severity (11 point rating scale, 0 points indicating no symptoms, 10 points indicating maximally severe symptoms) was more reduced with levodopa than placebo in two studies (me an difference (MD) -1.34, 95% confidence interval (CI-2.18 to - 0.5, P=0.002). Periodic limb movements in sleep per hour of sleep (PLMS-Index; PLMSI) improved by /h compared to placebo (95% CI to , P< ). The CGI-I changed more with levodopa than placebo in two studies (MD-1.25, 95% CI-1.89 to -0.62, P=0.0001).

In two studies, sleep quality (sleep questionnaire, visual analogue scale) showed a large effect (standardised mean difference (S MD) 0.92, 95% CI 0.52 to 1.33, P< ) where as quality of life (50 mm Visual Analogue Scales) improved by 3.23 compared to placebo (95% CI 1.64 to 4.82, P< ). Few patients dropped out of treatment (3 of 218 patients) but more levodopa treated patients experienced adverse events than with placebo (odds ratio 2.61, 95% CI 1.35 to 5.04, P=0.004). Two dopamine agonist controlled studies showed smaller effects with levodopa than cabergoline and pramipexole on the IRLS (MD 5.25, 95% CI 2.10 to 8.40, P=0.001), CGI-I (MD 0.62, 95% CI 0.37 to 0.87, P< ), and quality of life (MD 5.54, 95% CI 2.65 to 8.43, P=0.0002).

Authors’ conclusions Levodopa is efficacious for the short-term treatment of RLS. Augmentation, the clinically most relevant adverse event, was not investigated sufficiently.

Dopamine agonists for the treatment of restless legs syndrome Scholz H, Trenkwalder C, Kohnen R, Kriston L, Riemann D, Hornyak M

Magdolna Hornyak, Interdisciplinary Pain Canter, University Medical Center. Editorial group: Cochrane Movement Disorders Group. Publication status and date: Edited (no change to conclusions), published in Issue 5, Review content assessed as up-to-date: 18 January Citation: Scholz H, Trenkwalder C, Kohnen R, Kriston L, Riemann D, Hornyak M. Dopamine agonists for the treatment of restless legs syndrome. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No. : CD DO I: / CD pub 2. Copy right © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd

Background According to clinical guidelines, dopamine agonists are the first-line treatment of restless legs syndrome (RLS ).

Objectives To evaluate efficacy and safety of dopamine agonists for RLS.

Search methods We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library 2008, Issue 4), MEDLINE, EMBASE, PsycINFO and CINAHL, from January 1985 to December 2008, plus reference lists of articles. We contacted pharmaceutical companies.

Selection criteria We included double -blind randomized controlled trials (RCTs) of dopamine agonist treatment versus placebo or other treatment for a period of at least seven days in patients with RLS ( ≥ 18 years). Outcomes included the International RLS Severity Rating Scale (IRLS ), Clinical Global Impressions (CGI-I), poly somnography and self rated sleep quality, quality of life, day time functioning, and safety parameters.

Data collection and analysis Two reviewers extracted data separately ; assessed risk of bias; and contacted pharmaceutical companies and authors for additional information. We collected dropout rates due to adverse events and experience of adverse events.

Main results We included 35 placebo controlled and three active controlled RCTs (N=7365). The mean reduction on the IRLS was −5.7 points lower in dopamine agonist treatment compared to placebo (95% confidence interval (CI)−6.7 to −4.7). Periodic limb movements in sleep per hour of sleep (PLMS -Index; PLMSI) were −22.4/ h lower than in placebo (95% CI −27.8 to −16.9). Self rated quality of sleep and disease specific quality of life were improved by a standardized mean difference (SMD) of 0.40 (95% CI 0.33 to 0.47) and % CI 0.23 to 0. 44), respectively. Patients were more likely to drop out (odds ratio (OR) 1.82, 95% CI 1.35 to 2.45) and experienced more adverse events under dopamine agonist treatment than with placebo (OR 1.82, 95% CI 1.59 to 2.08).

Authors’ conclusions The meta-analyses show the superiority of dopamine agonists over placebo. Cabergoline and pramipexole showed larger efficacy compared to levodopa in some but not all outcomes.

Forest plot of comparison: 1 Dopamine agonists versus placebo, outcome: 1.2 Medication subgroups: change on IRLS.

Forest plot of comparison: 1 Dopamine agonists versus placebo, outcome: 1.4 Medication subgroups: change in periodic limb movements in sleep.

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Iron for restless legs syndrome Trotti LM, Bhadriraju S, Becker LA

Department of Neurology, Emory University School of Medicine, Atlanta, USA. Editorial group: Cochrane Movement Disorders Group. Publication status and date: New, published in Issue 5, Review content assessed as up-to-date: 25 April Citation: Trotti LM, Bhadriraju S, Becker LA. Iron for restless legs syndrome. Cochrane Database of Systematic Reviews 2012, Issue 5. Art. No.: CD DOI: / CD pub2. Copyright © 2012 The Cochrane Collaboration. Published by JohnWiley & Sons, Ltd.

Background Restless legs syndrome (RLS) is a common neurologic syndrome and is associated with iron deficiency in many patients. It is unclear whether iron therapy is effective treatment for RLS.

Objectives The objective of this review was to assess the effects of iron supplementation (oral or intravenous) for patients with RLS.

Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Jan 1995 to April 2011); EMBASE (Jan 1995 to April 2011); PsycINFO (Jan 1995 to April 2011); and CINAHL (Jan 1995 to April 2011). Corresponding authors of included trials and additional members of the International Restless Legs Syndrome Study Group were contacted to locate additional published or unpublished trials.

Selection criteria Controlled trials comparing any formulation of iron with placebo, other medications, or no treatment in adults diagnosed with RLS according to expert clinical interview or explicit diagnostic criteria.

Data collection and analysis Two review authors extracted data and at least two authors assessed trial quality. We contacted trial authors for missing data.

Main results Six studies (192 total subjects) were identified and included in this analysis. The quality of trials was variable. Our primary outcome was restlessness or uncomfortable leg sensations, which was quantified using the IRLS severity scale in four trials and another RLS symptom scale in a fifth trial. Combining data from the four trials using the IRLS severity scale, there was no clear benefit from iron therapy (mean difference in IRLS severity scores of -3.79, 95% CI: to 0.10, p = 0.06). However, the fifth trial did find iron therapy to be beneficial (median decrease of 3 points in the iron group and no change in the placebo group on a 10 point scale of RLS symptoms, p=0.01). Quality of life was improved in the iron group relative to placebo in some studies but not others.

Changes in periodic limb movements were not different between groups (measured in two studies). Objective sleep quality, subjective sleep quality and daytime functioning were not different between treatment groups in the studies that assessed them. The single study of subjects with end stage renal disease did show a benefit of therapy.The single study that was limited to iron deficient subjects did not show clear benefit of iron supplementation on RLS symptoms. There was no clear superiority of oral or intravenous delivery of iron. Iron therapy did not result in significantly more side effects than placebo (RR 1.39, 95% CI 0.85 to 2.27).

Authors’ conclusions There is insufficient evidence to determine whether iron therapy is beneficial for the treatment of RLS. Further research to determine whether some or all types of RLS patients may benefit from iron therapy, as well as the best route of iron administration, is needed.

SUMMARY Article 1 There is insufficient evidence to support the use of acupuncture for the symptomatic treatment of restless legs syndrome. This review investigated the efficacy and adverse effects of acupuncture in treating RLS. There view did not find consistent evidence to determine whether acupuncture is effective and safe in the treatment of RLS, based on the two trials identified.

Article 2 Levodopa is recommended for the treatment of RLS. We could include nine trials in the meta-analysis which compared levodopa treatment to placebo or to other active treatments in RLS. Levodopa reduced symptom severity to a larger extent than placebo. Periodic limb movements in sleep, monitored during polysomnography, were reduced more in levodopa treatment compared to placebo; however, total sleep time was not changed. quality of sleep and quality of life were markedly improved. Only a very low number of patients discontinued treatment due to adverse events but a larger number of patients on levodopa treatment reported adverse events compared to placebo. Evidence of three active controlled trials comparing levodopa to cabergoline, pergolide, and pramipexole was in favour of dopamine agonists regarding reduction of RLS severity, symptom improvement, and quality of life.

Article 3 Dopamine agonists are recommended as first-line treatment for RLS. We could include 38 trials in the meta-analyses which investigated the efficacy and safety of dopamine agonist treatment compared to placebo or to other treatments for RLS. Treatment durations varied from one week to seven months, but most treatments had durations of one to 12 weeks. Patients suffered from moderate to severe RLS and were treated with the dopamine agonists cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine, and sumanirole.

Dopamine agonists lead to a larger improvement on the International RLS Severity Rating Scale (IRLS) compared to placebo. Also periodic limb movements in sleep were significantly reduced by dopamine agonists compared to placebo. Sleep efficiency was also slightly improved. Patients rated their quality of sleep and quality of life as markedly improved. Patients were, however, more likely to discontinue dopamine agonist treatment and experienced more adverse events when treated with dopamine agonists compared to placebo. All dopamine agonists were superior to placebo except sumanirole. Indirect descriptive comparisons revealed the highest efficacy for the ergoline dopamine agonists cabergoline and pergolide. The non-ergoline dopamine agonists lisuride, pramipexole, rotigotine, and ropinirole showed adequate efficacy.

Article 4 Low blood levels of iron are frequently seen in people who have RLS and the lack of iron may be part of the cause of RLS. Iron can be supplemented either in pill form or through injections into the bloodstream. This review was performed to see if iron supplements are effective in reducing the symptoms of RLS. Six studies of iron were included, which together involved only 192 subjects. Results from the studies were conflicting, with some studies showing that iron was not effective but others showing some help for patients’ feelings of restlessness or discomfort.

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