Restless Legs Syndrome; Periodic leg movements during sleep; Autonomic nervous system; Cardiovascular disorders; Animal model
Ferri Raffaele, Manconi Mauro, Rundo Francesco, Zucconi Marco, Bruni Oliviero, Arico' Debora, Bruni Oliviero, Ferini-Strambi Luigi, Fulda Stephany (2016), A Data-Driven Analysis of the Rules Defining Bilateral Leg Movements during sleep, in
Sleep, 39(2), 413-421.
Ferri Raffaele, Rundo Francesco, Zucconi Marco, Manconi Mauro, Bruni Oliviero, Ferini-Strambi Luigi, Fulda Stephany (2015), An Evidence-based Analysis of the Association between Periodic Leg during Sleep and Arousal in Restless Legs Syndrome, in
Sleep, 38(6), 919-924.
Silvani Alessandro, Martire Viviana LO, Salvadè Agnese, Bastianini Stefano, Ferri Raffaele, Berteotti Chiara, Baracchi Francesca, Pace Marta, Bassetti Claudio L, Zoccoli Giovanna, Manconi Mauro (2015), Physiological time structure of the tibialis anterior motor activity during sleep in mice, rats and humans., in
Journal of Sleep Research, 24(6), 695-701.
Ferri Raffaele, Rundo Francesco, Zucconi Marco, Manconi Mauro, Arico' Debora, Bruni Oliviero, Ferini-Strambi Luigi, Fulda Stephany (2015), Putting the periodicity back into the periodic leg movement index: an alternative data-driven algorithm for the computation of this index during sleep and wakefulness, in
Sleep Medicine, 16, 1229-1235.
Ferri Raffaele, Rundo Francesco, Zucconi Marco, Manconi Mauro, Arico' Debora, Bruni Oliviero, Ferini-Strambi Luigi, Fulda Stephany, Diagnostic accuracy of the standard and alternative periodic leg movement during sleep indices for restless legs syndrome, in
Sleep Medicine.
Background: Restless legs syndrome (RLS) is one of the most frequent neurological disorders, a sleep-related movement disorder, affecting 3 to 10% of the general population in various degrees of severity. The majority of RLS patients present with insomnia, and around 90% of them with periodic leg movements during sleep (PLMS). PLMS are repetitive, stereotyped leg jerks which arise from sleep. Many hundreds of such leg movements may occur during a single night. In addition to its severe effects on sensory and motor functions, large-scale epidemiological studies have consistently identified RLS as an independent risk factor for cardiovascular disease. The candidate mechanisms associated with this autonomic dysfunction involve repetitive, nocturnal sympathetic system activations associated with PLMS in RLS. The critical question is whether PLMS are the cause, the consequence, or a correlate of nocturnal sympathetic hyperactivation in RLS. Several lines of evidence including the spinal dopaminergic hypothesis of RLS place the autonomic system at the core of RLS, yielding the question whether RLS is in fact an autonomic disorder. We will address this question by combininga translational approach which will combine a case control study with a double-blind treatment trial in patients with RLS and a basic research project focussed on creating an animal model for RLS. Results of these projects are expected to answer the question whether there is a generalized autonomic dysfunction in RLS, how this relates to the specific cardiovascular risk profile of patients, and whether treatment of RLS affects autonomic function and cardiovascular risk. The animal experiments will be performed to directly explore the link between RLS and autonomic dysfunction. Objectives: 1) to characterise autonomic functioning and cardiovascular risk in patients with RLS and to explore whether autonomic function is related to other markers of cardiovascular risk in these patients; 2) to investigate the effects of treatment of RLS and PLMS on autonomic function and selected markers of cardiovascular risk; 3) to establish a pharmacological rodent model for RLS and periodic limb movements during sleep (PLMS) to decipher the underlying pathophysiology of RLS and PLMS and directly to test the primary involvement of the autonomic system in RLS.Experimental design/Methods: In a prospective case-control study 50 patients with RLS and 50 age- and sex-matched controls will be included. Autonomic function (such as heart rate variability, blood pressure, tilt table test performance), cardiovascular risk markers and polysomnography will be assessed in all subjects. Subsequently, patients with RLS will participate in a double-blind, randomised treatment study comparing the effect of 4 week treatment with a previously-established dopamine agonist versus placebo on autonomic function and the above-mentioned markers of cardiovascular risk. In addition, we will establish a pharmacological animal model of RLS that will enable us to test the assumption that autonomic dysfunction is critically involved in the pathophysiology of RLS. Expected Value of the proposed Project: This project will answer the question whether RLS/PLMS is associated with autonomic dysfunction that increases cardiovascular risk, and if its treatment normalizes these autonomic abnormalities which will contribute towards feasible prevention strategies of cardiovascular diseases in RLS patients. Moreover, this project will establish the first animal model for RLS in order to improve our knowledge on the pathophysiology of RLS and particularly the role of the autonomic system in this disease. Since effective treatments are now available for RLS and PLMS the expected results of this study will have important implications not the least of which is whether treating RLS symptoms and PLMS will reduce cardiovascular risk in RLS.