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      Incidence of Augmentation in Primary Restless Legs Syndrome Patients May Not Be That High: Evidence From A Systematic Review and Meta-Analysis

      , Bachelor, , MD, , Master, , Master, , Master, , MD, PhD, , MD, PhD


      Wolters Kluwer Health

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          Augmentation is a common complication of primary restless legs syndrome (RLS) during treatment; however, its incidence rate remains unclear.

          The aim of this study is investigate the rate of augmentation during RLS treatment.

          We searched 6 databases, including PubMed, OVID, Embase, Wiley citations, Web of Science research platform (including SciELO Citation Index, Medline, KCI Korean Journal Database, the Web of Science™ Core Collection), and the Cochrane library, and screened the reference lists of the included trials and recently published reviews.

          Randomized controlled trials and observational studies that reported augmentation events during RLS treatment.

          Primary RLS patients older than 18 years.

          No restrictions regarding intervention types were applied.

          Three investigators independently extracted and pooled the data to analyze the augmentation rate of the total sample and of patient subgroups with different interventions, treatment durations and drug regimens and different geographic origins. Fixed-effects or random-effects model was used for pooled analysis.

          A total of 60 studies involving 11,543 participants suggested an overall augmentation rate of 5.6% (95% confidence intervals (CI), 4.0–7.7). The augmentation incidence was 6.1% (95% CI, 4.1–9.1) for long-term treatment and 3.3% (95% CI, 1.4–7.3) for short-term treatment. In addition, 27.1% (95% CI, 12.3–49.5) of the levodopa-treated patients, 6.0% (95% CI, 4.1–8.8) of the patients treated with dopamine agonists, and 0.9% (95% CI, 0.2–3.3) of the patients taking pregabalin or gabapentin developed augmentation. Augmentation occurred in 7.2% (95% CI, 5.0–10.3) of the patients taking immediate-release drugs and in 1.7% (95% CI, 0.6–5.0) of the patients taking transdermal application.

          The main limitations are that the augmentation rates were not evaluated according to drug dosage, gender, and age and symptom severity.

          Approximately 5 to 6 in 100 RLS patients developed augmentation during treatment.

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          Most cited references 74

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          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.

          Restless legs syndrome is a common yet frequently undiagnosed sensorimotor disorder. In 1995, the International Restless Legs Syndrome Study Group developed standardized criteria for the diagnosis of restless legs syndrome. Since that time, additional scientific scrutiny and clinical experience have led to a better understanding of the condition. Modification of the criteria is now necessary to better reflect that increased body of knowledge, as well as to clarify slight confusion with the wording of the original criteria. The restless legs syndrome diagnostic criteria and epidemiology workshop at the National Institutes of Health. Members of the International Restless Legs Syndrome Study Group and authorities on epidemiology and the design of questionnaires and scales. To modify the current criteria for the diagnosis of restless legs syndrome, to develop new criteria for the diagnosis of restless legs syndrome in the cognitively impaired elderly and in children, to create standardized criteria for the identification of augmentation, and to establish consistent questions for use in epidemiology studies. The essential diagnostic criteria for restless legs syndrome were developed and approved by workshop participants and the executive committee of the International Restless Legs Syndrome Study Group. Criteria were also developed and approved for the additional aforementioned groups.
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            Restless legs syndrome: pathophysiology, clinical presentation and management.

            Restless legs syndrome (RLS) is a somatosensory network disorder that is clinically diagnosed according to four main criteria: an urge to move the legs, usually associated with unpleasant leg sensations; induction or exacerbation of symptoms by rest; symptom relief on activity; and diurnal fluctuations in symptoms with worsening in the evening and at night. Genetic variants in four chromosomal regions have been identified that increase the risk of RLS. In addition, various different lesions, ranging from peripheral neuropathies to spinal cord lesions or alterations of brain metabolism, are implicated in RLS. In most cases, sleep disorders with frequent sleep fragmentation and characteristic periodic limb movements during sleep can be identified during a polysomnographic recording. The first-line drugs for RLS are dopaminergic agents, which are effective in low to moderate doses. Alternative or additional treatments include opioids and anticonvulsants. Augmentation-paradoxical worsening of symptoms by dopaminergic treatment-is the main problem encountered in difficult-to-treat patients. Iron deficiency must be identified and treated by supplementation, both to improve RLS symptoms and to potentially lower the risk of augmentation. Here, we review the latest studies pertaining to the pathophysiology, clinical presentation and management of RLS.
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              Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study.

              To assess the effects of gabapentin on sensory and motor symptoms in patients with restless legs syndrome (RLS). Patients with RLS (22 idiopathic, 2 secondary to iron deficiency) were randomized and treated for 6 weeks with either gabapentin or placebo. After a 1-week washout they crossed over to the alternative treatment for 6 weeks. Patients were rated at baseline and at scheduled intervals by the RLS Rating Scale, Clinical Global Impression, pain analogue scale, and Pittsburgh Sleep Quality Index. At the end of each treatment period, all-night polysomnography was performed. Compared to placebo, gabapentin was associated with reduced symptoms on all rating scales. In addition, sleep studies showed a significantly reduced periodic leg movements during sleep (PLMS) index and improved sleep architecture (increased total sleep time, sleep efficiency, and slow wave sleep, and decreased stage 1 sleep). Patients whose symptoms included pain benefited most from gabapentin. The mean effective dosage at the end of the 6-week treatment period was 1,855 mg, although therapeutic effects were already observed at the end of week 4 (1,391 mg). Gabapentin improves sensory and motor symptoms in RLS and also improves sleep architecture and PLMS.

                Author and article information

                Medicine (Baltimore)
                Medicine (Baltimore)
                Wolters Kluwer Health
                January 2016
                15 January 2016
                : 95
                : 2
                From the Department of Neurology, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan City, Hubei Province, China (GJL, SLW, LD, LLX, YFW); Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN (LW); Center for Clinical and Translational Science, Mayo Clinic, Rochester, MN (LW); and Department of Neurology, Xiangyang Center Hospital Affiliated to Hubei University of Arts and Science, Xiangyang City, Hubei Province, China (LYC).
                Author notes
                Correspondence: Guang Jian Liu, Department of Neurology, Taihe Hospital Affiliated to Hubei University of Medicine, Shiyan City, Hubei Province 442000, China (e-mail: liuguangjianaliyun.com). Li Ying Chang, Department of Neurology, Xiangyang Center Hospital Affiliated to Hubei University of Arts and Science, Xiangyang City, Hubei Province 441021, China (e-mail: liying_changxf@ 123456163.com ).
                Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

                This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0

                Research Article
                Systematic Review and Meta-Analysis
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