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Franco Gemignani,1 Andrea Melpignano,1,2 Giulia Milioli,1,2 Silvia Riccardi,1,2 Liborio Parrino1,2 1Neurology Unit, Department of Neurosciences, University of Parma, Parma, Italy; 2Sleep Disorders Center, Department of Neurosciences, University of Parma, Parma, Italy Abstract: Restless legs syndrome (RLS) is a disorder of sensorimotor integration characterized by an urge to move the legs when at rest, especially at night or in the evening, which is relieved by movement. Sensory symptoms may be prominent, often exhibiting features consistent with neuropathic pain. Iron deficiency and genetic factors are implicated in RLS causation in most patients. The pathogenetic model of impaired circadian dopaminergic modulation of sensorimotor integration circuitry at the spinal level is fitting with the co-occurrence of movement disorders, sensory symptoms, and sleep disruption in RLS. Accordingly, levodopa and dopamine agonists are effective for RLS symptoms, which compensate for the impaired descending control by diencephalo-spinal dopa(min)ergic pathway. Dopamine agonists are usually indicated as the first-line therapy, but their use in long-term treatment is often complicated by augmentation and impulse control disorder, thus alpha-2-delta ligands also are now considered the first line of treatment. It has been recognized that endogenous opioid system is also involved in the mechanisms generating RLS, possibly through an impaired modulation of pain pathways. Opioids can be considered as an alternative therapy, particularly in patients with augmentation and/or refractory to other treatments. Recently introduced prolonged-release oxycodone–naloxone was efficacious for short-term treatment of patients with severe RLS inadequately controlled with previous treatment. It will be important to assess whether opioids, as well as other drugs, are especially effective in definite RLS subtypes such as the painful phenotype. Keywords: small fiber neuropathy, allodynia, hyperalgesia

Francesca Brindani, Francesca Vitetta, Franco GemignaniDepartment of Neurosciences, University of Parma, ItalyAbstract: Restless legs syndrome (RLS) is a condition characterized by discomfort at rest and urge to move focused on the legs. RLS may occur as an idiopathic, often hereditary condition (primary RLS), or in association with medical conditions (secondary RLS) including iron deficiency, uremia, and polyneuropathy. Current understanding of the pathophysiology of RLS points to the involvement of three interrelated components: dopaminergic dysfunction, impaired iron homeostasis, and genetic mechanisms. The diagnosis of RLS is made according to the consensus criteria by a National Institutes of Health panel: 1) an urge to move the legs, usually accompanied by uncomfortable sensations; 2) beginning or worsening during rest; 3) relieved by movement; and 4) worse, or only occurring, in the evening or at night. The differential diagnosis of RLS aims to: 1) distinguish RLS from other disorders with RLS-like symptoms and 2) identify secondary forms, with investigation of underlying diseases. The treatment of RLS demands a clinical evaluation to rule out and cure causes of secondary RLS, including iron supplementation when deficient, and to eliminate the triggering factors. The presence of neuropathy should be especially investigated in nonhereditary, late-onset RLS, in view of a possible treatment of the underlying disease. The first line treatment for idiopathic RLS is represented by dopamine agonists, in particular nonergot-derived ropinirole and pramipexole, whereas ergot dopamine agonists (cabergoline and pergolide) are no longer in first-line use given the risks of cardiac valvulopathy. Although no comparative trials have been published, a meta-analysis of pramipexole versus ropinirole suggests differences in efficacy and tolerability favoring pramipexole.Keywords: restless legs syndrome, pramipexole, dopamine, agonists, small fiber neuropathy