Restless Legs Syndrome: Neurochemistry and Therapy

David Anguizola; Alba Garcia Aragón; Brian Moncada; Diego Garcia-Borreguero

doi:10.1055/a-2538-3300

Seminars in Neurology, Inhaltsverzeichnis

Semin Neurol
DOI: 10.1055/a-2538-3300

Review Article

Restless Legs Syndrome: Neurochemistry and Therapy

David Anguizola

¹Instituto Europeo del Sueño, Panamá, Panamá

,

Alba Garcia Aragón

²Sleep Research Institute, Madrid, Spain

,

Brian Moncada

²Sleep Research Institute, Madrid, Spain

,

Diego Garcia-Borreguero

²Sleep Research Institute, Madrid, Spain

› Institutsangaben

Abstract

Restless legs syndrome (RLS) is a complex sensorimotor disorder characterized by disturbances in key neurochemical pathways, including dopaminergic, glutamatergic, and adenosinergic systems. This review provides an overview of the current knowledge on RLS, including its clinical features and diagnosis, pathophysiology, and treatment (non-pharmacological and pharmacological). We examine the association between RLS and neurological disorders, genetic predispositions, and brain iron deficiency. Emerging therapies targeting glutamate and adenosine receptors, alongside established dopamine agonists and α2δ ligands, offer promising avenues for treatment.

Keywords

neurology - restless legs syndrome - sleep disorders - periodic limb movements

Volltext

Referenzen

References
1 Garcia-Malo C, Peralta SR, Garcia-Borreguero D. Restless legs syndrome and other common sleep-related movement disorders. Continuum (Minneap Minn) 2020; 26 (04) 963-987
2 Earley CJ, Silber MH. Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med 2010; 11 (09) 807-815
3 Hening W, Walters AS, Allen RP, Montplaisir J, Myers A, Ferini-Strambi L. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med 2004; 5 (03) 237-246
4 Broström A, Alimoradi Z, Lind J, Ulander M, Lundin F, Pakpour A. Worldwide estimation of restless legs syndrome: a systematic review and meta-analysis of prevalence in the general adult population. J Sleep Res 2023; 32 (03) e13783
5 Para KS, Chow CA, Nalamada K. et al. Suicidal thought and behavior in individuals with restless legs syndrome. Sleep Med 2019; 54: 1-7
6 Allen RP, Earley CJ. Defining the phenotype of the restless legs syndrome (RLS) using age-of-symptom-onset. Sleep Med 2000; 1 (01) 11-19
7 Allen RP, Picchietti DL, Garcia-Borreguero D. et al; International Restless Legs Syndrome Study Group. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria–history, rationale, description, and significance. Sleep Med 2014; 15 (08) 860-873
8 Gao X, Ba DM, Bagai K, Liu G, Ma C, Walters AS. Treating restless legs syndrome was associated with low risk of cardiovascular disease: a cohort study with 3.4 years of follow-up. J Am Heart Assoc 2021; 10 (04) e018674
9 Coccagna G, Vetrugno R, Lombardi C, Provini F. Restless legs syndrome: an historical note. Sleep Med 2004; 5 (03) 279-283
10 Kerr S, McKinon W, Bentley A. Descriptors of restless legs syndrome sensations. Sleep Med 2012; 13 (04) 409-413
11 Ruppert E. Restless arms syndrome: prevalence, impact, and management strategies. Neuropsychiatr Dis Treat 2019; 15: 1737-1750
12 Hochstrasser KJ, Rogers SC, Quyyumi A. et al. Restless legs syndrome, periodic limb movements of sleep, and subclinical cardiovascular disease. Sleep Biol Rhythms 2023; 22 (02) 259-267
13 Mansur A, Castillo PR, Rocha Cabrero F, Bokhari SRA. Restless Legs Syndrome. StatPearls; 2024
14 Walters AS, LeBrocq C, Dhar A. et al; International Restless Legs Syndrome Study Group. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003; 4 (02) 121-132
15 Mizuno S, Mihara T, Miyaoka T, Inagaki T, Horiguchi J. CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res 2005; 14 (01) 43-47
16 Chokroverty S. Differential diagnoses of restless legs syndrome/Willis-Ekbom disease: mimics and comorbidities. Sleep Med Clin 2015; 10 (03) 249-262 , xii
17 Garcia-Borreguero D, Larrosa O, de la Llave Y, Granizo JJ, Allen R. Correlation between rating scales and sleep laboratory measurements in restless legs syndrome. Sleep Med 2004; 5 (06) 561-565
18 Manconi M, Garcia-Borreguero D, Schormair B. et al. Restless legs syndrome. Nat Rev Dis Primers 2021; 7 (01) 80
19 Montplaisir J, Boucher S, Nicolas A. et al. Immobilization tests and periodic leg movements in sleep for the diagnosis of restless leg syndrome. Mov Disord 1998; 13 (02) 324-329
20 De Cock VC, Bayard S, Yu H. et al. Suggested immobilization test for diagnosis of restless legs syndrome in Parkinson's disease. Mov Disord 2012; 27 (06) 743-749
21 Garcia-Borreguero D, Kohnen R, Boothby L, Tzonova D, Larrosa O, Dunkl E. Validation of the Multiple Suggested Immobilization Test: a test for the assessment of severity of restless legs syndrome (Willis-Ekbom Disease). Sleep 2013; 36 (07) 1101-1109
22 Berg D, Godau J, Walter U. Transcranial sonography in movement disorders. Lancet Neurol 2008; 7 (11) 1044-1055
23 Garcia-Malo C, Novo-Ponte S, Castro-Villacañas Farzamnia A. et al. Correlation between systemic iron parameters and substantia nigra iron stores in restless legs syndrome. Sleep Med 2021; 85: 191-195
24 Godau J, Manz A, Wevers AK, Gaenslen A, Berg D. Sonographic substantia nigra hypoechogenicity in polyneuropathy and restless legs syndrome. Mov Disord 2009; 24 (01) 133-137
25 Garcia-Malo C, Wanner V, Miranda C. et al. Quantitative transcranial sonography of the substantia nigra as a predictor of therapeutic response to intravenous iron therapy in restless legs syndrome. Sleep Med 2020; 66: 123-129
26 Maggi G, Barone A, Mastromarino C, Santangelo G, Vitale C. Prevalence and clinical profile of patients with restless legs syndrome in Parkinson's disease: a meta-analysis. Sleep Med 2024; 121: 275-286
27 Fereshtehnejad SM, Shafieesabet M, Shahidi GA, Delbari A, Lökk J. Restless legs syndrome in patients with Parkinson's disease: a comparative study on prevalence, clinical characteristics, quality of life and nutritional status. Acta Neurol Scand 2015; 131 (04) 211-218
28 Alonso-Navarro H, García-Martín E, Agúndez JAG, Jiménez-Jiménez FJ. Association between restless legs syndrome and other movement disorders. Neurology 2019; 92 (20) 948-964
29 Jiménez-Jiménez FJ, Alonso-Navarro H, García-Martín E, Agúndez JAG. Association between restless legs syndrome and peripheral neuropathy: a systematic review and meta-analysis. Eur J Neurol 2021; 28 (07) 2423-2442
30 Polydefkis M, Allen RP, Hauer P, Earley CJ, Griffin JW, McArthur JC. Subclinical sensory neuropathy in late-onset restless legs syndrome. Neurology 2000; 55 (08) 1115-1121
31 Terai H, Toyoda H, Hoshino M. et al. Prevalence of restless legs syndrome and its symptoms among patients with spinal disorders. J Clin Med 2021; 10 (21) 5001
32 Kocabicak E, Terzi M, Akpinar K, Paksoy K, Cebeci I, Iyigun O. Restless leg syndrome and sleep quality in lumbar radiculopathy patients. Behav Neurol 2014; 2014: 245358
33 Kalampokini S, Poyiadjis S, Vavougios GD. et al. Restless legs syndrome due to brainstem stroke: a systematic review. Acta Neurol Scand 2022; 146 (05) 440-447
34 Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J. Restless legs syndrome associated with major diseases: a systematic review and new concept. Neurology 2016; 86 (14) 1336-1343
35 Rye DB. The molecular genetics of restless legs syndrome. Sleep Med Clin 2015; 10 (03) 227-233 , xii
36 Salminen AV, Lam DD, Winkelmann J. Role of MEIS1 in restless legs syndrome: from GWAS to functional studies in mice. Adv Pharmacol 2019; 84: 175-184
37 Salminen AV, Garrett L, Schormair B. et al; German Mouse Clinic Consortium. Meis1: effects on motor phenotypes and the sensorimotor system in mice. Dis Model Mech 2017; 10 (08) 981-991
38 Allen RP, Auerbach S, Bahrain H, Auerbach M, Earley CJ. The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 2013; 88 (04) 261-264
39 Pedroso JL, Bor-Seng-Shu E, Felicio AC. et al. Severity of restless legs syndrome is inversely correlated with echogenicity of the substantia nigra in different neurodegenerative movement disorders. a preliminary observation. J Neurol Sci 2012; 319 (1-2): 59-62
40 Godau J, Sojer M. Transcranial sonography in restless legs syndrome. Int Rev Neurobiol 2010; 90: 199-215
41 Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, Allen RP. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 2000; 54 (08) 1698-1700
42 Kapoor PM, Mavaddat N, Choudhury PP. et al; ABCTB Investigators, kConFab/AOCS Investigators. Combined associations of a polygenic risk score and classical risk factors with breast cancer risk. J Natl Cancer Inst 2021; 113 (03) 329-337
43 Connor JR, Ponnuru P, Wang XS, Patton SM, Allen RP, Earley CJ. Profile of altered brain iron acquisition in restless legs syndrome. Brain 2011; 134 (Pt 4): 959-968
44 Dauvilliers Y, Chenini S, Vialaret J. et al. Association between serum hepcidin level and restless legs syndrome. Mov Disord 2018; 33 (04) 618-627
45 Earley CJ, Uhl GR, Clemens S, Ferré S. Connectome and molecular pharmacological differences in the dopaminergic system in restless legs syndrome (RLS): plastic changes and neuroadaptations that may contribute to augmentation. Sleep Med 2017; 31: 71-77
46 Earley CJ, Connor J, Garcia-Borreguero D. et al. Altered brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease). Sleep Med 2014; 15 (11) 1288-1301
47 Connor JR, Wang X-S, Allen RP. et al. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain 2009; 132: 2403-2412
48 Yepes G, Guitart X, Rea W. et al. Targeting hypersensitive corticostriatal terminals in restless legs syndrome. Ann Neurol 2017; 82 (06) 951-960
49 Clemens S, Rye D, Hochman S. Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 2006; 67 (01) 125-130
50 Qu S, Le W, Zhang X, Xie W, Zhang A, Ondo WG. Locomotion is increased in a11-lesioned mice with iron deprivation: a possible animal model for restless legs syndrome. J Neuropathol Exp Neurol 2007; 66 (05) 383-388
51 Earley CJ, Allen RP, Connor JR, Ferrucci L, Troncoso J. The dopaminergic neurons of the A11 system in RLS autopsy brains appear normal. Sleep Med 2009; 10 (10) 1155-1157
52 Unger EL, Bianco LE, Jones BC, Allen RP, Earley CJ. Low brain iron effects and reversibility on striatal dopamine dynamics. Exp Neurol 2014; 261: 462-468
53 Allen RP, Barker PB, Horská A, Earley CJ. Thalamic glutamate/glutamine in restless legs syndrome: increased and related to disturbed sleep. Neurology 2013; 80 (22) 2028-2034
54 Garcia-Borreguero D, Patrick J, DuBrava S. et al. Pregabalin versus pramipexole: effects on sleep disturbance in restless legs syndrome. Sleep 2014; 37 (04) 635-643
55 Kapur N, Friedman R. Oral ketamine: a promising treatment for restless legs syndrome. Anesth Analg 2002; 94 (06) 1558-1559
56 Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med 2011; 12 (05) 440-444
57 Garcia-Borreguero D, Cano I, Granizo JJ. Treatment of restless legs syndrome with the selective AMPA receptor antagonist perampanel. Sleep Med 2017; 34: 105-108
58 Inoue Y, Hirata K, Kuroda K. et al. Efficacy and safety of pramipexole in Japanese patients with primary restless legs syndrome: a polysomnographic randomized, double-blind, placebo-controlled study. Sleep Med 2010; 11 (01) 11-16
59 Oertel WH, Benes H, Garcia-Borreguero D. et al. Rotigotine transdermal patch in moderate to severe idiopathic restless legs syndrome: a randomized, placebo-controlled polysomnographic study. Sleep Med 2010; 11 (09) 848-856
60 McGahan MC, Harned J, Mukunnemkeril M, Goralska M, Fleisher L, Ferrell JB. Iron alters glutamate secretion by regulating cytosolic aconitase activity. Am J Physiol Cell Physiol 2005; 288 (05) C1117-C1124
61 Quiroz C, Gulyani S, Ruiqian W. et al. Adenosine receptors as markers of brain iron deficiency: implications for restless legs syndrome. Neuropharmacology 2016; 111: 160-168
62 Ferré S, Quiroz C, Guitart X. et al. Pivotal role of adenosine neurotransmission in restless legs syndrome. Front Neurosci 2018; 11: 722
63 Ciruela F, Ferré S, Casadó V. et al. Heterodimeric adenosine receptors: a device to regulate neurotransmitter release. Cell Mol Life Sci 2006; 63 (21) 2427-2431
64 Ferré S, Bonaventura J, Zhu W. et al. Essential control of the function of the striatopallidal neuron by pre-coupled complexes of adenosine a_2a-dopamine D₂ receptor heterotetramers and adenylyl cyclase. Front Pharmacol 2018; 9: 243
65 Ferré S, Sarasola LI, Quiroz C, Ciruela F. Presynaptic adenosine receptor heteromers as key modulators of glutamatergic and dopaminergic neurotransmission in the striatum. Neuropharmacology 2023; 223: 109329
66 Garcia-Borreguero D, Guitart X, Garcia Malo C, Cano-Pumarega I, Granizo JJ, Ferré S. Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis. Sleep Med 2018; 45: 94-97
67 Garcia-Borreguero D, Garcia-Malo C, Granizo JJ, Ferré S. A randomized, placebo-controlled crossover study with dipyridamole for restless legs syndrome. Mov Disord 2021; 36 (10) 2387-2392
68 Lanza G, Lanuzza B, Aricò D. et al. Impaired short-term plasticity in restless legs syndrome: a pilot rTMS study. Sleep Med 2018; 46: 1-4
69 Lanza G, Ferri R. The neurophysiology of hyperarousal in restless legs syndrome: hints for a role of glutamate/GABA. Adv Pharmacol 2019; 84: 101-119
70 Ferri R, Manconi M, Aricò D. et al. Acute dopamine-agonist treatment in restless legs syndrome: effects on sleep architecture and NREM sleep instability. Sleep 2010; 33 (06) 793-800
71 Walters AS, Paueksakon P, Adler CH. et al. Restless legs syndrome shows increased silent postmortem cerebral microvascular disease with gliosis. J Am Heart Assoc 2021; 10 (11) e019627
72 de Paiva JPQ, Magalhães SC, Moura LM. et al. Sensorimotor white matter projections and disease severity in primary Restless Legs Syndrome/Willis-Ekbom disease: a multimodal DTI analysis. Sleep Med 2020; 73: 106-116
73 Kocar TD, Müller HP, Kassubek J. Differential functional connectivity in thalamic and dopaminergic pathways in restless legs syndrome: a meta-analysis. Ther Adv Neurol Disord 2020; 13: 1756286420941670
74 Stefani A, Mitterling T, Heidbreder A. et al. Multimodal Magnetic Resonance Imaging reveals alterations of sensorimotor circuits in restless legs syndrome. Sleep 2019; 42 (12) zsz171
75 Tuovinen N, Stefani A, Mitterling T. et al. Functional connectivity and topology in patients with restless legs syndrome: a case-control resting-state functional magnetic resonance imaging study. Eur J Neurol 2021; 28 (02) 448-458
76 Salminen AV, Rimpilä V, Polo O. Pramipexole alters thermoregulation in restless legs syndrome. J Clin Sleep Med 2014; 10 (12) 1325-1329
77 Larsson BW, Kadi F, Ulfberg J, Aulin KP. Skeletal muscle morphology in patients with restless legs syndrome. Eur Neurol 2007; 58 (03) 133-137
78 Allen RP. Restless leg syndrome/Willis-Ekbom disease pathophysiology. Sleep Med Clin 2015; 10 (03) 207-214 , x
79 Wåhlin-Larsson B, Ulfberg J, Aulin KP, Kadi F. The expression of vascular endothelial growth factor in skeletal muscle of patients with sleep disorders. Muscle Nerve 2009; 40 (04) 556-561
80 Yeh WL, Lu DY, Lin CJ, Liou HC, Fu WM. Inhibition of hypoxia-induced increase of blood-brain barrier permeability by YC-1 through the antagonism of HIF-1α accumulation and VEGF expression. Mol Pharmacol 2007; 72 (02) 440-449
81 Salminen AV, Rimpilä V, Polo O. Peripheral hypoxia in restless legs syndrome (Willis-Ekbom disease). Neurology 2014; 82 (21) 1856-1861
82 Sharon D. Nonpharmacologic management of restless legs syndrome (Willis-Ekbom disease): myths or science. Sleep Med Clin 2015; 10 (03) 263-278 , xiii
83 Silber MH, Buchfuhrer MJ, Earley CJ, Koo BB, Manconi M, Winkelman JW. Scientific and Medical Advisory Board of the Restless Legs Syndrome Foundation. The management of restless legs syndrome: an updated algorithm. Mayo Clin Proc 2021; 96 (07) 1921-1937
84 Klingelhoefer L, Cova I, Gupta S, Chaudhuri KR. A review of current treatment strategies for restless legs syndrome (Willis-Ekbom disease). Clin Med (Lond) 2014; 14 (05) 520-524
85 Akbaş P, Yaman Sözbir Ş. Non-pharmacological methods used in coping with restless leg syndrome (RLS): a systematic review. Sleep Biol Rhythms 2021; 19: 215-225
86 Singh H, Baker FC, Ojile J. et al. Efficacy and safety of TOMAC for treatment of medication-naïve and medication-refractory restless legs syndrome: a randomized clinical trial and meta-analysis. Sleep Med 2024; 122: 141-148
87 Oroz R, Kung S, Croarkin PE, Cheung J. Transcranial magnetic stimulation therapeutic applications on sleep and insomnia: a review. Sleep Sci Pract 2021; 5: 3
88 Park KM, Kim KT, Kang KW. et al; RLS Subcommittee of the Korean Sleep Research Society. Alterations of functional connectivity in patients with restless legs syndrome. J Clin Neurol 2022; 18 (03) 290-297
89 Avni T, Reich S, Lev N, Gafter-Gvili A. Iron supplementation for restless legs syndrome - a systematic review and meta-analysis. Eur J Intern Med 2019; 63: 34-41
90 Earley CJ, García-Borreguero D, Falone M, Winkelman JW. Clinical efficacy and safety of intravenous ferric carboxymaltose for treatment of restless legs syndrome: a multicenter, randomized, placebo-controlled clinical trial. Sleep 2024; 47 (07) zsae095
91 Ferré S, Earley C, Gulyani S, Garcia-Borreguero D. In search of alternatives to dopaminergic ligands for the treatment of restless legs syndrome: iron, glutamate, and adenosine. Sleep Med 2017; 31: 86-92
92 Trotti LM, Becker LA. Iron for the treatment of restless legs syndrome. Cochrane Database Syst Rev 2019; 1 (01) CD007834
93 Salminen AV, Winkelmann J. Restless legs syndrome and other movement disorders of sleep-treatment update. Curr Treat Options Neurol 2018; 20 (12) 55
94 Wijemanne S, Ondo W. Restless Legs Syndrome: clinical features, diagnosis and a practical approach to management. Pract Neurol 2017; 17 (06) 444-452
95 Allen RP, Picchietti DL, Auerbach M. et al; International Restless Legs Syndrome Study Group (IRLSSG). Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report. Sleep Med 2018; 41: 27-44
96 Jadidi A, Rezaei Ashtiani A, Khanmohamadi Hezaveh A, Aghaepour SM. Therapeutic effects of magnesium and vitamin B6 in alleviating the symptoms of restless legs syndrome: a randomized controlled clinical trial. BMC Complement Med Ther 2022; 23 (01) 1
97 Garcia-Borreguero D, Cano-Pumarega I, Marulanda R. Management of treatment failure in restless legs syndrome (Willis-Ekbom disease). Sleep Med Rev 2018; 41: 50-60
98 Winkelmann J, Allen RP, Högl B. et al. Treatment of restless legs syndrome: Evidence-based review and implications for clinical practice (Revised 2017)^§ . Mov Disord 2018; 33 (07) 1077-1091
99 Scholz H, Trenkwalder C, Kohnen R, Riemann D, Kriston L, Hornyak M. Dopamine agonists for restless legs syndrome. Cochrane Database Syst Rev 2011; 2011 (03) CD006009
100 Lipford MC, Silber MH. Long-term use of pramipexole in the management of restless legs syndrome. Sleep Med 2012; 13 (10) 1280-1285
101 Garcia-Borreguero D, Silber MH, Winkelman JW. et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med 2016; 21: 1-11
102 Li YS, Yeh WC, Hsu CY. Association of low serum ferritin levels with augmentation in patients with restless legs syndrome: a systematic review and meta-analysis. Sleep Med 2023; 112: 173-180
103 Garcia-Borreguero D, Kohnen R, Silber MH. et al. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med 2013; 14 (07) 675-684
104 Winkelman JW, Berkowski JA, DelRosso LM. et al. Treatment of restless legs syndrome and periodic limb movement disorder: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med 2025; 21 (01) 137-152
105 Trenkwalder C, Allen R, Högl B. et al. Comorbidities, treatment, and pathophysiology in restless legs syndrome. Lancet Neurol 2018; 17 (11) 994-1005
106 Trenkwalder C, Winkelmann J, Inoue Y, Paulus W. Restless legs syndrome-current therapies and management of augmentation. Nat Rev Neurol 2015; 11 (08) 434-445
107 P LMB, e SSA, Castro-Villacañas A, Garcia-Borreguero D. Restless legs syndrome: challenges to treatment. Sleep Med Clin 2021; 16 (02) 269-277
108 Silber MH, Becker PM, Buchfuhrer MJ. et al; Scientific and Medical Advisory Board, Restless Legs Syndrome Foundation. The appropriate use of opioids in the treatment of refractory restless legs syndrome. Mayo Clin Proc 2018; 93 (01) 59-67
109 Winkelman JW, Purks J, Wipper B. Baseline and 1-year longitudinal data from the National Restless Legs Syndrome Opioid Registry. Sleep 2021; 44 (02) zsaa183
110 Ferré S, García-Borreguero D, Allen RP, Earley CJ. New insights into the neurobiology of restless legs syndrome. Neuroscientist 2019; 25 (02) 113-125