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      Restless Legs Syndrome: From Pathophysiology to Clinical Diagnosis and Management

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          Abstract

          Restless legs syndrome (RLS), a common neurological sensorimotor disorder in western countries, has gained more and more attention in Asian countries. The prevalence of RLS is higher in older people and females. RLS is most commonly related to iron deficiency, pregnancy and uremia. The RLS symptoms show a significant circadian rhythm and a close relationship to periodic limb movements (PLMs) in clinical observations, while the pathophysiological pathways are still unknown. The diagnostic criteria have been revised in 2012 to improve the validity of RLS diagnosis. Recent studies have suggested an important role of iron decrease of brain in RLS pathophysiology. Dopaminergic (DA) system dysfunction in A11 cell groups has been recognized long ago from clinical treatment and autopsy. Nowadays, it is believed that iron dysfunction can affect DA system from different pathways and opioids have a protective effect on DA system. Several susceptible single nucleotide polymorphisms such as BTBD9 and MEIS1, which are thought to be involved in embryonic neuronal development, have been reported to be associated with RLS. Several pharmacological and non-pharmacological treatment are discussed in this review. First-line treatments of RLS include DA agents and α2δ agonists. Augmentation is very common in long-term treatment of RLS which makes prevention and management of augmentation very important for RLS patients. A combination of different types of medication is effective in preventing and treating augmentation. The knowledge on RLS is still limited, the pathophysiology and better management of RLS remain to be discovered.

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          Most cited references 148

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          Brain dopamine and obesity.

          The cerebral mechanisms underlying the behaviours that lead to pathological overeating and obesity are poorly understood. Dopamine, a neurotransmitter that modulates rewarding properties of food, is likely to be involved. To test the hypothesis that obese individuals have abnormalities in brain dopamine activity we measured the availability of dopamine D2 receptors in brain. Brain dopamine D2 receptor availability was measured with positron emission tomography (PET) and [C-11]raclopride (a radioligand for the dopamine D2 receptor). Bmax/Kd (ratio of the distribution volumes in striatum to that in cerebellum minus 1) was used as a measure of dopamine D2 receptor availability. Brain glucose metabolism was also assessed with 2-deoxy-2[18F]fluoro-D-glucose (FDG). Striatal dopamine D2 receptor availability was significantly lower in the ten obese individuals (2.47 [SD 0.36]) than in controls (2.99 [0.41]; p < or = 0.0075). In the obese individuals body mass index (BMI) correlated negatively with the measures of D2 receptors (r=0.84; p < or = 0.002); the individuals with the lowest D2 values had the largest BMI. By contrast, neither whole brain nor striatal metabolism differed between obese individuals and controls, indicating that striatal reductions in D2 receptors were not due to a systematic reduction in radiotracer delivery. The availability of dopamine D2 receptor was decreased in obese individuals in proportion to their BMI. Dopamine modulates motivation and reward circuits and hence dopamine deficiency in obese individuals may perpetuate pathological eating as a means to compensate for decreased activation of these circuits. Strategies aimed at improving dopamine function may be beneficial in the treatment of obese individuals.
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            Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions.

            Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.
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              Prevalence of restless legs syndrome and periodic limb movement disorder in the general population.

              Periodic limb movement disorder (PLMD) and restless legs syndrome (RLS) are two sleep disorders characterized by abnormal leg movements and are responsible for deterioration in sleep quality. However, the prevalence of these disorders is not well known in the general population. This study aims to document the prevalence of RLS and PLMD in the general population and to identify factors associated with these conditions. Cross-sectional studies were performed in the UK, Germany, Italy, Portugal and Spain. Overall, 18,980 subjects aged 15 to 100 years old representative of the general population of these five European countries underwent telephone interviews with the Sleep-EVAL system. A section of the questionnaire assessed leg symptoms during sleep. The diagnoses of PLMD and RLS were based on the minimal criteria provided by the International Classification of Sleep Disorders. The prevalence of PLMD was 3.9% and RLS was 5.5%. RLS and PLMD were higher in women than in men. The prevalence of RLS significantly increased with age. In multivariate models, being a woman, the presence of musculoskeletal disease, heart disease, obstructive sleep apnea syndrome, cataplexy, doing physical activities close to bedtime and the presence of a mental disorder were significantly associated with both disorders. Factors specific to PLMD were: being a shift or night worker, snoring, daily coffee intake, use of hypnotics and stress. Factors solely associated with RLS were: advanced age, obesity, hypertension, loud snoring, drinking at least three alcoholic beverages per day, smoking more than 20 cigarettes per day and use of SSRI. PLMD and RLS are prevalent in the general population. Both conditions are associated with several physical and mental disorders and may negatively impact sleep. Greater recognition of these sleep disorders is needed.
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                Author and article information

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                02 June 2017
                2017
                : 9
                Affiliations
                1Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
                2Department of Psychiatry, Harvard Medical School, Belmont MA, United States
                3Division of Alcohol and Drug Abuse, Mailman Neuroscience Research Center, McLean Hospital, Belmont MA, United States
                Author notes

                Edited by: Aurel Popa-Wagner, University of Rostock, Germany

                Reviewed by: Antón Barreiro-Iglesias, Universidade de Santiago de Compostela, Spain; Jun Chang Su, Fourth Military Medical University, China; Shuqin Zhan, Xuan Wu Hospital of the Capital Medical University, China

                *Correspondence: Tao Wang, wangtaowh@ 123456hust.edu.cn

                These authors have contributed equally to this work.

                Article
                10.3389/fnagi.2017.00171
                5454050
                Copyright © 2017 Guo, Huang, Jiang, Han, Li, Xu, Zhang, Lin, Xiong and Wang.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 0, Tables: 5, Equations: 0, References: 158, Pages: 14, Words: 0
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 31171211
                Award ID: 81471305
                Award ID: 81200983
                Award ID: 81301082
                Categories
                Neuroscience
                Review

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