This review presents a detailed summary of the current literature regarding RLS and vitamin D deficiency. To our knowledge it is the first review of its kind. We review the prevalence of vitamin D deficiency in RLS as well as the evidence for the use of vitamin D supplementation in RLS management. We further examine the literature for proteomic and genetic evidence of a role for vitamin D in the pathogenesis of RLS. An alteration in vitamin D binding protein in RLS is one of the most consistent findings in the proteomic studies. Furthermore, we examine the interaction of vitamin D with calcium, phosphorus, and parathyroid hormone and the possible role of these connections in RLS. We also explore the possible nexus between RLS and vitamin D in renal disease, cardiovascular and cerebrovascular disease as well as inflammation. In addition, we review the potential interaction between vitamin D and RLS with iron, dopamine and other neurotransmitter systems including the endogenous opiate, serotoninergic, glutamatergic and adenosinergic systems. We also explore the role of vitamin D in RLS Augmentation (i.e., the paradoxical worsening of RLS symptoms when dopaminergic agents are used as a therapy for RLS). Although the literature is not entirely consistent in affirming vitamin D deficiency in RLS or the amelioration of RLS symptoms with vitamin D therapy, the collective studies overall indicate that vitamin D deficiency is common enough in RLS patients to suggest that RLS patients should have their vitamin D levels checked and any deficiency corrected as a standard of care. Highlights Patients with Restless Legs Syndrome (RLS) may be deficient in vitamin D and therapy with vitamin D may ameliorate RLS. We present the first review dedicated solely to evaluating the relationship between RLS and vitamin D and present a case for the role of vitamin D in RLS pathogenesis.

Summary: This study aimed to investigate sex‐related differences in the response to ropinirole and pramipexole in patients with restless legs syndrome (RLS). By analysing clinical parameters and polysomnographic (PSG) findings, we sought to elucidate the potential factors related to sex disparities modulating treatment responses and sleep quality in RLS. A total of 41 drug‐free patients with RLS, aged ≥18 years, underwent two consecutive nocturnal PSG recordings, without medication at baseline; before the second night, 26 patients received an oral dose of 0.25 mg pramipexole whereas 15 received 0.5 mg ropinirole. After each PSG recording, patients self‐evaluated the severity of their previous night symptoms by means of an ad hoc visual analogue scale (VAS). At baseline, sleep efficiency and percentage of Stage N2 tended to be higher in females while wakefulness after sleep onset was significantly higher in males. After treatment, total leg movements during sleep (LMS), periodic LMS (PLMS), and periodicity indexes were significantly lower in females than in males. The VAS score was lower after treatment in all patients, without differences between the two sexes. This study demonstrates a higher acute responsiveness of PLMS to dopamine agonists (pramipexole and ropinirole) in females than in males with RLS. These findings might be explained by differential sex‐related expression of dopamine receptors, especially D₃, within the central nervous system. In addition, our findings provide translational hints toward a better tailored and sex‐specific approach to the treatment of RLS associated with PLMS, with dopamine agonist possibly associated with a better outcome in females than in males.

In behavioral medicine, sleep disorders, insomnia in particular, may be considered comorbidities and precipitating factors to intellectual or developmental disabilities (IDD). Nevertheless, sleep alterations have often been neglected in favor of daytime features and symptoms, albeit simple behavioral nighttime observations may disclose hypermotor features that characterize restless sleep. The root of most hypermotor restlessness is linked to central iron deficiency. The latter is often exacerbated by vitamin D deficiency (VDD), which interferes with both dopaminergic and serotonergic mechanisms. In this way, an imbalance affecting daytime behavior and mood is created. Several sleep-related motor disorders such as bruxism, periodic and aperiodic leg movements, Restless Legs Syndrome (RLS), and Restless Sleep Disorder (RSD) are commonly seen in Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorders (ASD). However, they are rarely diagnosed and often overlooked in affected children and adolescents. As a result, not only are these disorders not adequately addressed therapeutically, but their symptoms may be worsened by the side-effects of drugs used to contain disruptive daytime behavior, such as antipsychotics and antidepressants. In children with IDDs, obesity, inactivity and metabolic effects of antipsychotics often lead to Sleep Disordered Breathing (SDB), which is currently understood as an inflammatory state leading to “hyperactive” lethargy and further alterations of the hypoxic chain and vitamin D levels. Endorsing simple routine blood tests, including inflammatory markers such as C-reactive protein, ferritin, transferrin, and vitamin D levels, may favorably complement caregiver observations and ambulatory sleep recordings, leading to a sleep disorder diagnosis and consequent therapy. In fact, the treatment of SDB, RLS, and RSD has been copiously demonstrated to favorably impact vigilance, behavior, social competence, and academic skills in healthy and, to a greater extent, in IDD children. Thus, consulting and deliberating the root causes of functional and categorical diagnoses within a clinical framework may engender a more precise diagnosis and further benefit pediatric daytime and nighttime management of hyperactive behaviors.