Search

Background and purpose: The coexistence of peripheral neuropathy (PN) and restless legs syndrome (RLS) or Willis–Ekbom disease is relatively frequent, but its prevalence has shown a high variability across studies. In addition, several reports have shown data suggesting the presence of PN in patients with idiopathic RLS. Methods: A search was undertaken using the PubMed, Embase and Web of Science Databases, from 1966 to 6 December 2020, crossing the search term 'restless legs syndrome' with 'neuropathy', 'polyneuropathy' (PNP) and 'peripheral neuropathy', and the references of interest for this topic were identified; a meta‐analysis was performed, according to PRISMA guidelines, and a calculation of pooled prevalences, where appropriate, was made using standard methods. Results: Restless legs syndrome has been reported in 5.2%–53.7% of patients with PN (average 21.5%; 95% confidence interval 18.6%–24.5%), and PN has been reported in 0%–87.5% of patients with RLS (average 41.8%; 95% confidence interval 39.9%–43.6%), both being significantly more frequent than in controls. The heterogeneity across studies could be due to differences in the diagnostic criteria used for both RLS and PN. RLS is a frequent clinical complaint in patients with PN of different aetiologies, mainly diabetic PN, uraemic PNP, familial amyloid PNP, Charcot–Marie–Tooth disease and chronic dysimmune inflammatory PNP. Recent neurophysiological findings suggest the presence of small sensory fibre loss in patients diagnosed with idiopathic RLS, but it remains to be determined whether RLS associated with small sensory fibre loss and idiopathic RLS are different clinical entities. Conclusions: Future studies including clinical and neurophysiological assessment and skin biopsy involving a large series of patients with PN and RLS are needed for a better understanding of the association between these two entities. [ABSTRACT FROM AUTHOR]

The most important traditional hypotheses of the pathogenesis of idiopathic restless legs syndrome (iRLS) involve dopaminergic dysfunction and iron deficiency. However, a possible role of other neurotransmitter or neuromodulators, mainly glutamate, gamma-hydroxybutyric acid (GABA), and adenosine have been suggested in recent reports. Moreover, iron deficiency in experimental models (which causes sensorimotor symptoms resembling those of RLS) is able to induce changes in dopaminergic, glutamatergic and adenosinergic neurotransmission, thus suggesting its crucial role in the pathogenesis of this disease. Relationship between iRLS and opiates, oxidative stress and nitric oxide, and with vitamin D deficiency has also been reported, although data regarding these variables should be considered as preliminary. In this review, we focus on studies relating to neurochemical findings in iRLS. [ABSTRACT FROM AUTHOR]

A major role of genetic factors in the risk of developing restless legs syndrome (RLS) is supported by the high frequency of positive family history of RLS in patients affected with this disease, and the higher concordance rates in monozygotic twins compared with dizygotic ones in twin studies. In this review we have focused on those reports describing inheritance patterns of RLS, genetic anticipation, the results of studies performed on positivity of family history of RLS, twin studies, linkage studies in familial RLS, genome-wide association studies (GWAS), exome sequencing studies, and case-control association studies on candidate genes in RLS. Although to date the causative gene(s) has(ve) not been definitively identified, a number of variants of several genes, most of them through GWAS, have been associated with RLS risk, the strongest candidates being variants of PTPRD, BTBD9, and MEIS1 genes. Despite results of several recent case-control association studies which have suggested a possible contribution of heme-oxygenase 1 (HMOX1) rs2071746 and vitamin D3 receptor (VDR) rs731236 variants, or the presence of allele 2 of the complex microsatellite repeat Rep1 within the alpha-synuclein (SNCA) gene promoter in modifying the risk for RLS, these studies need to be replicated in further studies involving different populations. [ABSTRACT FROM AUTHOR]

The possible role of inflammatory factors in the pathogenesis of restless legs syndrome (RLS) is not well understood. Because several inflammatory diseases have shown an association with the risk for RLS, the measurement of serum/plasma levels of inflammatory factors has been a matter of a scarce number of studies. We performed a systematic review and a meta-analysis to assess the possible association of serum/plasma levels of inflammatory markers with the risk for RLS. Our results showed a significant trend towards higher serum/plasma C reactive protein (CRP) levels and higher neutrophil-to-lymphocyte (NLR) ratio in patients diagnosed with RLS than in controls, although statistical significance disappeared after applying the random-effects model. Further studies are needed to confirm the suggested possible role of inflammatory factors in the pathogenesis of RLS. [ABSTRACT FROM AUTHOR]

Abstract: Objective: A glutamatergic dysfunction has been postulated to play a role in restless legs syndrome (RLS) pathophysiology, as glutamate concentrations have been found to increase in the thalamus of RLS patients. The aim of our study was to investigate the possible association between the single nucleotide polymorphism (SNP) rs3794087 in the solute carrier family 1 (glial high affinity glutamate transporter), member 2 gene, SLC1A2, related with glutamate transport and the risk for RLS. Methods: We studied the allelic and genotype frequencies of the SNP rs3794087 in 205 patients with RLS and 328 healthy controls using TaqMan genotyping. Results: The rs3794087 genotype and allelic frequencies did not significantly differ between patients with RLS and controls and were unrelated with the age at onset of RLS, gender, and family history of RLS. Conclusions: The results of our study suggest that the rs3794087 polymorphism is not related to the risk for RLS. [Copyright &y& Elsevier]