Chronic inflammation markers and cytokine-specific autoantibodies in Danish blood donors with restless legs syndrome.

Restless Legs Syndrome (RLS) is a neurological sensorimotor disorder negatively impacting sufferers' quality of sleep and health-related quality of life. The pathophysiology of RLS is poorly understood and research focusing on the link between RLS and inflammation has been limited. Our study aimed to investigate whether chronic inflammation markers C-reactive protein (CRP) and soluble urokinase-type plasminogen activator receptor (suPAR), as well plasma levels of five different cytokine-specific autoantibodies (c-aAb), i.e. modulators of inflammation, associate with RLS in otherwise healthy individuals. CRP, suPAR and c-aAb were measured in plasma samples of participants from the Danish Blood Donor Study in 2010. Returning donors between 2015 and 2018 completed the validated Cambridge-Hopkins RLS-questionnaire for RLS assessment, resulting in datasets with RLS assessment and values for CRP (N = 3564), suPAR (N = 2546) and c-aAb (N = 1478). We performed logistic regression models using the CRP, suPAR or c-aAb as the independent variable and RLS status as the dependent variable, adjusted for appropriate covariates. Our study indicates that a high concentration of CRP is associated with RLS, while an increased probability of experiencing frequent RLS symptoms in those with an elevated plasma suPAR level appears to be mediated through lifestyle factors. We additionally report that a high titer of autoantibodies specific against the cytokine interferon-alpha was associated with RLS. Our results support the existence of links between systemic inflammation and RLS, though further RLS studies on CRP, suPAR and c-aAb in larger cohorts are warranted to confirm our findings and further reveal the hitherto underexplored links between RLS and inflammation.

Genetic and immunologic aspects of sleep and sleep disorders.

The study of genetics is providing new and exciting insights into the pathogenesis, diagnosis, and treatment of disease. Both normal sleep and several types of sleep disturbances have been found to have significant genetic influences, as have traits of normal sleep, such as those evident in EEG patterns and the circadian sleep-wake cycle. The circadian sleep-wake cycle is based on a complex feedback loop of genetic transcription over a 24-h cycle. Restless legs syndrome (RLS) and periodic limb movements in sleep (PLMS) have familial aggregation, and several genes have a strong association with them. Recent genome-wide association studies have identified single nucleotide polymorphisms linked to RLS/PLMS, although none has a definite functional correlation. Narcolepsy/cataplexy are associated with HLA DQB1*0602 and a T-cell receptor α locus, although functional correlations have not been evident. Obstructive sleep apnea is a complex disorder involving multiple traits, such as anatomy of the oropharynx, ventilatory control, and traits associated with obesity. Although there is clear evidence of familial aggregation in the obstructive sleep apnea syndrome, no specific gene or locus has been identified for it. Angiotensin-converting enzyme has been proposed as a risk variant, but evidence is weak. Fatal familial insomnia and advanced sleep phase syndrome are sleep disorders with a definite genetic basis.

Restless legs syndrome--theoretical roles of inflammatory and immune mechanisms.

Theories for restless legs syndrome (RLS) pathogenesis include iron deficiency, dopamine dysregulation and peripheral neuropathy. Increased prevalence of small intestinal bacterial overgrowth (SIBO) in controlled studies in RLS and case reports of post-infectious RLS suggest potential roles for inflammation and immunological alterations. A literature search for all conditions associated with RLS was performed. These included secondary RLS disorders and factors that may exacerbate RLS. All of these conditions were reviewed with respect to potential pathogenesis including reports of iron deficiency, neuropathy, SIBO, inflammation and immune changes. A condition was defined as highly-associated if there was a prevalence study that utilized an appropriate control group. Small case reports were recorded but not included as definite RLS-associated conditions. Fifty four diseases, syndromes and conditions have been reported to cause and/or exacerbate RLS. Of these, 38 have been reported to have a higher prevalence than age-matched controls, 9 have adequate sized reports and have general acceptance as RLS-associated conditions and 7 have been reported in case report form. Overall, 42 of the 47 RLS-associated conditions (89%) have also been associated with inflammatory and/or immune changes. In addition, 43% have been associated with peripheral iron deficiency, 40% with peripheral neuropathy and 32% with SIBO. Most of the remaining conditions have yet to be studied for these factors. The fact that 95% of the 38 highly-associated RLS conditions are also associated with inflammatory/immune changes suggests the possibility that RLS may be mediated or affected through these mechanisms. Inflammation can be responsible for iron deficiency and hypothetically could cause central nervous system iron deficiency-induced RLS. Alternatively, an immune reaction to gastrointestinal bacteria or other antigens may hypothetically cause RLS by a direct immunological attack on the central or peripheral nervous system.

Effect of the antiplatelet agent cilostazol on endovascular inflammatory biochemical parameters and the clinical symptoms of peripheral artery disease and restless legs syndrome in hemodialysis patients.

BACKGROUND: Peripheral artery disease (PAD) is a common complication in patients receiving hemodialysis (HD). Cilostazol is used for the treatment of ischemic symptoms in patients with PAD, based on its antiplatelet and vasodilating effects. In addition to these beneficial effects on clinical symptoms in PAD patients, cilostazol has been proposed to have additional effects on clinical symptoms in patients with restless legs syndrome (RLS) via the upregulation of dopamine. We performed an observational, prospective study to evaluate the effect of cilostazol on several clinical and biochemical parameters in HD patients with PAD and RLS. METHODS: All the study patients received cilostazol treatment for 12 months. During the study period, several biochemical parameters, such as high-sensitivity CRP, von Willebrand antigen (VW-Ag), triglyceride (TG), high-density lipoprotein (HDL) and malondialdehyde-modified low-density lipoprotein, were monitored. A questionnaire on the physical status of PAD and RLS was also completed. 45 HD patients who received cilostazol were compared with a control group of 22 patients. RESULTS: The patients who continued cilostazol treatment exhibited a improvement in their serum inflammatory and biochemical parameters (VW-Ag, TG, HDL). Although PAD and RLS scores were not improved by multivariate analysis, several patients showed improvement of signs and symptoms which were included in the PAD or RLS scores. CONCLUSION: The treatment of HD patients with cilostazol improved some of the lipid-related and endovascular inflammatory biochemical parameters associated with PAD, and relieved the clinical symptoms and physical status of PAD in some cases.

Restless legs syndrome is associated with irritable bowel syndrome and small intestinal bacterial overgrowth.

BACKGROUND: Restless legs syndrome (RLS) is linked to gastrointestinal disorders. The prevalence of irritable bowel syndrome (IBS) and small intestinal bacterial overgrowth (SIBO) in RLS patients was determined. METHODS: RLS subjects were recruited from unbiased ads that did not mention gastrointestinal symptoms. RLS diagnosis was confirmed by a neurologist and utilized the International RLS Study Group criteria. General population controls (GPC) were spouses of gastrointestinal clinic patients and were excluded for RLS. Completely healthy controls (CHC) were excluded for RLS and gastrointestinal symptoms. IBS was diagnosed by Rome II criteria. SIBO was diagnosed by the lactulose breath test (LBT). RESULTS: There were 32 RLS subjects (23F/9M; 57 yo), 25 GPC (13F/12M; 58 yo) and 30 CHC (19F/11M; 44 yo). Twenty-nine had RLS unassociated with other GI diseases, one had celiac disease, and two had gastric resections. IBS was diagnosed in 28% of RLS subjects compared to 4% GPC (p=0.0317). SIBO was diagnosed in 69% of RLS subjects compared to 28% of GPC (p=0.0033) and 10% of CHC. Using a false positive rate of 10%, 59% of positive LBT results are associated with RLS. CONCLUSIONS: IBS and SIBO are common in RLS. Three hypotheses developed are (a) RLS patients are selectively immunocompromised or genetically predisposed and thus more subject to SIBO; (b) SIBO leads to autoimmune changes, and subsequent auto-antibodies attack brain and/or peripheral nerves and (c) SIBO inflammation leads to increased hepcidin and CNS iron deficiency which, in turn, leads to RLS. These hypotheses bear further investigation.

Iron status and chronic kidney disease predict restless legs syndrome in an older hospital population.

BACKGROUND: Iron deficiency is important in the pathogenesis of restless legs syndrome (RLS), and serum ferritin measurement, using a cutoff of 45-50ng/ml, is widely recommended as the optimal screening test for iron deficiency in RLS. Serum ferritin often increases with inflammation, and a higher cutoff may be better in those with acute and chronic inflammatory conditions, including those with chronic kidney disease (CKD). METHODS: The relationships between RLS and potential secondary causes were examined in hospital patients aged 50years or more. Diagnosis of RLS was based on a clinician interview. RESULTS: Of 301 patients, 55 (18.3%) had RLS. Ferritin levels less than 40ng/ml and between 40 and 69ng/ml and Stage 4 CKD (estimated glomerular filtration rate [eGFR] between 15 and 29ml/min and not on dialysis) were associated with significantly higher odds for RLS in univariate and multivariate analyses. CONCLUSION: Iron deficiency and chronic kidney disease are the strongest predictors of RLS in older hospital patients. Ferritin less than 70ng/ml is the best cutoff for identifying possible iron deficiency in RLS patients with inflammatory conditions. Independent of iron status, RLS is strongly associated with chronic kidney disease that is not severe enough to require dialysis, and the results of this study suggest that eGFR values and stages of CKD should be reported in future studies of RLS.