RLS Patients Research Articles

Serum ferritin measurements differ according to assay used: implications for iron therapy in restless legs syndrome.

Serum ferritin levels are used to determine the need for iron supplementation in patients with RLS. The purpose of the study was to determine whether immunoassay measurement of serum ferritin yields varying levels according to different manufacturer assays, with resultant variation in cut off values. We compared serum ferritin levels using 116 clinical samples assessed by the Beckman and Roche methods. While there was a high correlation between results obtained from the 2 methods (R2 = 0,99), the absolute values differed. The equivalent ferritin measures determined by Beckman, Roche were: 50 mcg/dL, 83 mcg/dL; 75 mcg/dL, 121 mcg/dL; 100 mcg/dL, 158 mcg/dL; and 300 mcg/dL, 457 mcg/dL. It is uncertain which assays were used to measure serum ferritin in the seminal studies on which current guidelines for iron therapy for RLS are based. In view of this uncertainty, as well as the limited data on which current recommendations are based, clinicians should be flexible in using recommended serum ferritin cut off values, also utilizing percentage transferrin saturation. Assuming that Beckman or equivalent assays were used, centers using the Roche method need to adjust the cut offs for administration of oral iron and intravenous iron recommended by current practice guidelines to avoid withholding treatment for RLS patients who might benefit from iron supplementation.

Effect of Blood Flow Restriction Training (BFRT) on Sleep Deprivation and Quality of Life in Restless Leg Syndrome – A Case Study

TITLE: Effect of blood flow restriction training (BFRT) on sleep deprivation and quality of life in restless leg syndrome – A case study BACKGROUND AND PURPOSE: To see the effect of blood flow restriction training (BFRT) on sleep deprivation and quality of life in restless leg syndrome. MATERIAL AND METHOD: A 22-year-old female was considered for this research purpose. The subject was taken for the study's conduction and given the intervention protocol. The protocol was 28 days long and the subject was asked to perform the exercises 6 times in a week, for about 2 times in a day. A total of 3 sets were performed for almost all the exercises with 20 repetitions in the first set, 15 repetitions in the second set, and 10 repetitions in the third set. Pre and Post results were recorded based on outcome measures such as RLS-QOL, PSQI, and SQS. DESIGN: A case study involving pre- and post-intervention readings. RESULT: The study found that blood flow restriction training (BFRT) can lessen RLS symptoms, enhance sleep quality, extend sleep duration, and enhance quality of life. CONCLUSION: Through this study, we can conclude that the effect of Blood flow restriction training (BFRT) on RLS patients can improve symptoms of RLS, better sleep quality, increase sleep timing, and improve quality of life. The Pre & Post reading value of RLSQOL on day 0 was 67, and on 28, it was 39. The pre- and post-reading value of PSQI on day 0 was 17 and on day 28 it was 07. And Pre & Post reading value of SQS on day 0 was 62 and on day 28 it was 44. As suggested by the study it would improve the symptoms of RLS along with better sleep quality, along with ease of living.

Ferric carboxymaltose effects on restless legs syndrome and on brain iron in patients with iron deficiency anemia

ObjectiveBrain iron status is fundamental in RLS pathogenesis. The aim of this study was to determine the clinical efficacy and brain iron concentration improvement in RLS patients with IDA, using 1500 mg FCM. MethodsThis is a randomized, double-blinded, placebo-controlled study. RLS patients with IDA were grouped into either 1500 mg FCM or placebo. The primary outcomes were the change from baseline on the International Restless Legs Syndrome Study Group scale (IRLS) and brain iron measured by QSM and R2∗. ResultsA total of 18 RLS patients with IDA were enrolled, 10 in the FCM group and 8 in the placebo. At the week 6 endpoint, the FCM group showed significant improvement in both IRLS (−13.60 ± 9.47 vs. −3.63 ± 5.40, p = 0.011) and VAS (−40.50 ± 28.81 vs. −0.63 ± 28.28, p = 0.004) from baseline. Change from baseline with R2∗ techniques showed a treatment effect for the thalamus and QSM technique for both the substantia nigra and pulvinar. A correlation was proved between the IRLS difference and the difference of QSM in thalamus (p = 0.028). ConclusionThis study demonstrates that 1500 mg FCM effectively treats RLS symptoms in IDA patients over six weeks, with MRI measurements of improved brain iron content serving as a potential biomarker for RLS patients.

Restless leg syndrome and risk of all-cause dementia: a nationwide retrospective cohort study

BackgroundRestless leg syndrome (RLS) is associated with poor sleep quality, depression or anxiety, poor dietary patterns, microvasculopathy, and hypoxia, all of which are known risk factors for dementia. However, the relationship between RLS and incident dementia remains unclear. This retrospective cohort study aimed to explore the possibility that RLS could be deemed as a non-cognitive prodromal feature of dementia.MethodsThis was a retrospective cohort study using the Korean National Health Insurance Service-Elderly Cohort (aged ≥ 60). The subjects were observed for 12 years, from 2002 to 2013. Identifying patients with RLS and dementia was based on the 10th revised code of the International Classification of Diseases (ICD-10). We compared the risk of all-cause dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) in 2501 subjects with newly diagnosed RLS and 9977 matched controls based on age, sex, and index date. The association between RLS and the risk of dementia was assessed using Cox regression hazard regression models. The effect of dopamine agonists on the risk of dementia among RLS patients was also explored.ResultsThe baseline mean age was 73.4, and the subjects were predominantly females (63.4%). The incidence of all-cause dementia was higher in the RLS group than that in the control group (10.4% vs 6.2%). A baseline diagnosis of RLS was associated with an increased risk of incident all-cause dementia (adjusted hazard ratio [aHR] 1.46, 95% confidence interval [CI] 1.24–1.72). The risk of developing VaD (aHR 1.81, 95% CI 1.30–2.53) was higher than that of AD (aHR 1.38, 95% CI 1.11–1.72). The use of dopamine agonists was not associated with the risk of subsequent dementia among patients with RLS (aHR 1.00, 95% CI 0.76–1.32).ConclusionsThis retrospective cohort study suggests that RLS is associated with an increased risk of incident all-cause dementia in older adults, providing some evidence that requires confirmation through prospective studies in the future. Awareness of cognitive decline in patients with RLS may have clinical implications for the early detection of dementia.

Correlation between vitamin D and poor sleep status in restless legs syndrome.

BackgroundRestless Legs Syndrome (RLS) is closely related to poorer sleep quality. Vitamin D can regulate sleep regulation, cell proliferation, and differentiation. To measure whether vitamin D has predictive value for poor sleep quality in RLS was our aim in this study.MethodsTo analyze the serum levels of 25-hydroxyvitamin D [25(OH)D] in 95 RLS patients. We used the Pittsburgh Sleep Quality Index (PSQI) to measure sleep quality. Subjects had been divided into a normal and poor-sleeper groups according to the PSQI score. Using correlation and regression analysis to explore underlying etiologies that affect sleep disorder in RLS patients.ResultsPatients in the poor-sleeper group had significantly lower vitamin D levels in comparison to the normal group. The serum vitamin D levels were negative correlate with PSQI scores after adjusting for confounding factors. In addition, regression analysis showed that vitamin D could act as a predictor for sleep disorders in RLS patients (odds ratio [OR] = 0.008, p = 0.004). The area under the curve (AUC), cut-off value, sensitivity, and specificity of serum vitamin D was 0.967 (95% CI 0.935–0.998), 16.84 ng/ml, 87.5%, and 93.7% by receiver operating characteristic (ROC) analysis.ConclusionOur study confirmed the relationship between poorer sleep quality and vitamin D in RLS. However, the causal relationship between vitamin D deficiency and RLS is currently inconclusive. The effect of vitamin D supplementation is needed to confirm as the therapeutic strategies for sleep disorders in RLS patients in future work.

Association between thyroid function and disease severity in restless legs syndrome.

BackgroundRestless Legs Syndrome (RLS) is a common neurological disorder. Growing evidence shows that dopaminergic dysfunction and iron deficiency are associated with the pathogenesis of RLS. Additionally, the dopaminergic system is linked with the hypothalamic-pituitary-thyroid (HPT) axis. Thus, the current study aimed to compare thyroid function between RLS patients and healthy subjects and investigate the associations with clinical characteristics of RLS.MethodsSerum levels of thyroid hormones were investigated in 102 first-episode drug-naïve RLS patients and 80 matched healthy controls (HCs). Baseline data and clinical characteristics were performed by professional personnel. In addition, multivariate regression was used to analyze the relationship between thyroid function and RLS.ResultsCompared with control group, RLS patients had significantly higher serum thyroid-stimulating hormone (TSH) levels (p < 0.001), and higher prevalence of subclinical hypothyroidism [Odds ratio (OR) 8.00; 95% confidence interval (CI) = 3.50–18.30; p < 0.001]. The Subclinical hypothyroidism rate (47.1 vs. 10%, p < 0.001) in RLS patients was higher than the HCs group. Regression analysis revealed that serum TSH (OR = 1.77; 95% CI = 1.41–2.23; p < 0.001) was independently associated with RLS. There was a statistically significant positive correlation between TSH and the Pittsburgh sleep quality index (PSQI) scores (r = 0.728, p < 0.001), and the International Restless Legs Scales (IRLS) points (r = 0.627, p < 0.001). Spearman correlation analysis showed that FT3 was positive correlated with HAMA14 score (r = 0.239, p = 0.015). In addition, compared with the good-sleeper group, poor-sleeper patients had significantly higher serum TSH levels (p < 0.001).ConclusionSerum levels of TSH and the prevalence of subclinical hypothyroidism were higher in RLS patients, indicating the imbalance between thyroid hormones (TH) and the dopaminergic system may contribute to the development of primary RLS. Additionally, the TH axis may influence the quality of sleep in RLS patients.

0549 Prevalence and Impact of Muscle Cramps in Patients with Restless Legs

Abstract Introduction Recent studies have shown alterations in Vitamin D binding protein in RLS, and Vitamin D is intimately related to calcium metabolism, while hypocalcemia is a well-known trigger for muscle cramps. The presence and consequences of muscle cramps in RLS has never been systematically studied. Therefore, the aim of this study was to determine the prevalence and impact of muscle cramps in RLS patients. Methods An email was sent to 4222 active members of the RLS foundation (RLSF) with a link to survey adult RLS patients. The survey included demographic information, questions on muscle cramps (including a visual analogue scale rating intensity), the Pittsburgh Sleep Quality Index assessing sleep disturbances, the 36-Item Short Form Survey Instrument (SF-36) evaluating health status, the 13-item short-form Cambridge-Hopkins diagnostic questionnaire (CH-RLSq13) for diagnosing RLS, and the International RLS Severity Scale measuring RLS severity. Patients who answered “yes” to the question “In the last 3 months have you experienced muscle cramps (defined as involuntary painful muscle contraction occurring at rest, not associated with exercise)?” were considered to have muscle cramps. Results A total of 509 RLSF members completed the whole electronic survey, while 317 participants (Age: 68.9±10.2; 73.1% Women; 97.8% White/Caucasian; BMI: 27.4±5.8) qualified as RLS patients and were included in further analysis. The prevalence of muscle cramps in RLS patients was 60.3%. RLS patients with (versus without) muscle cramps were more overweight (p=0.0119) and had lower scores (more disability) on several SF-36 health concepts including physical functioning (p=0.0093), role limitations due to emotional problems (p=0.0429), social functioning (p=0.0017), and more pain (p=0.0387). In addition, there was a weak (Spearman coefficient ρ=0.253) but significant positive correlation (p=0.0004) between intensity of muscle cramps and severity of RLS symptoms. Conclusion Muscle cramps were present in almost two-third of RLS patients and were associated with a negative impact on health status and severity of RLS. Therefore, from a clinical practice point of view, it seems warranted to screen for muscle cramps in RLS patients. RLS and leg cramps may theoretically be related to each other through calcium metabolism and/or through inflammatory mechanisms. Support (If Any) This study was not funded.

0547 RLS Patient Odyssey Survey II

Abstract Introduction RLS affects 5%-10% of European and North American adults, with 2%-3% experiencing moderate to severe symptoms. RLS patients, often undiagnosed or improperly treated, experience significant depression in addition to loss of sleep. Methods ODYSSEY II, an online and in-print self-administered questionnaire (respondents primarily from the United States) included validated questions on RLS diagnosis and severity, associated medical conditions, RLS treatment responses, access to RLS care, and standardized PHQ-9 depression measures. RLS status was confirmed using the Cambridge-Hopkins Questionnaire. Analysis included linkage of PHQ-9 depression scores to EQ-5D Health-Related Quality-of-Life (HRQoL) scores using externally validated methods. Results Of 3,003 online or mail-in participants, 2,745 were RLS confirmed, 55% having severe symptoms (IRLS ≥ 21), 86% using medications and 73% reporting histories of dopaminergic augmentation (medication related worsening of symptoms).Of RLS-confirmed respondents, average PHQ-9 depression scores were 8.98 for women (US average 3.72) and 7.22 for men (US average 2.67). Among RLS patients, 29% of males and 40% of females (comparable US averages 11% and 6.5%) had PHQ-9 depression scores ≥ 10 (moderate, moderately severe or severe) a fourfold risk of important (≥ 10 score) depression. Suicidal ideation was reported by 15% of respondents (US average 4.0%). Associated EQ-5D scores show that 37% of all respondents had HRQoL scores below 50% of “full health.”Of six drug classes used to treat RLS, three drug classes had patient-reported efficacy above 60%, but all had patient-reported drawbacks, ranging from weaker efficacy for some patients (alpha-2-delta ligands) to augmentation (dopaminergics, almost three-quarters of patients) and difficulties in obtaining prescriptions (opioids) for others.Respondents reported decade-plus delays from time of symptom onset to diagnosis, and still may remain improperly diagnosed or inadequately treated. Respondents managed by RLSF certified providers reported better outcomes. Conclusion ODYSSEY II documents that depression, suicidal thinking and HRQoL losses are very significant among many RLS patients. Respondents report troubling delays from symptom onset to correct diagnosis. Survey results demonstrate that RLS related symptoms are best improved when patients use RLSF certified providers. Improved education to both primary care providers and patients may also lead to better patient outcomes. Support (If Any) Arbor Pharmaceuticals

0546 An Informatics Approach to Assessing Quality of Care Metrics for Restless Legs Syndrome/Willis-Ekbom Disease

Abstract Introduction Management of restless legs syndrome (RLS, aka Willis-Ekbom Disease) with dopaminergic agents is often complicated by development of augmentation. Clinical practice guidelines and stepwise algorithms suggest that prior to prescribing dopaminergic agents, clinicians should assess iron stores and consider alpha-2-delta agents (e.g. gabapentin). We developed an informatics approach to assess quality of care metrics for RLS management. Methods We used Veterans Affairs (VA) electronic health record data to identify a cohort of patients at a single tertiary care academic VA facility prescribed dopaminergic agents between 01 Jan 2018 to 31 Dec 2019. Patients with any prior codes for Parkinson’s disease were excluded. A random sample of charts were manually reviewed to determine if dopaminergic drugs were being prescribed for RLS or other indications. We then assessed for evidence of prior iron store assessments, iron repletion if appropriate, and alpha-2-delta agents (gabapentin, pregabalin). Results We identified 1160 patients treated with dopaminergic agents and no prior Parkinson’s codes. Chart reviews indicated 95% accuracy of this methodology to identify dopaminergic use for RLS. Evidence of pre-treatment iron storage assessment was missing in 30.2% for ferritin and 33.5% for transferrin saturation. Among those with iron studies present, lack of iron replacement was noted in 34% of those with ferritin &amp;lt;75 mcg/L and 33% of those with transferrin saturation &amp;lt;20%. Prior or concomitant prescriptions of alpha-2-delta agents was present in 59.7% of the cohort. Conclusion Our informatics approach provides an accurate and efficient means to quantify RLS care metrics. Results were most notable for a high proportion of dopaminergic-treated RLS patients without iron assessments and without iron repletion when stores were low. This methodology will inform future quality improvement initiatives to improve the delivery of guideline concordant RLS care. Support (If Any) This material is the result of work supported with resources and the use of facilities at the Minneapolis Veterans Affairs Health Care System, Minneapolis/USA.

F wave in restless legs syndrome, as an electrophysiological response of clinical relief

ABSTRACT Objective The study aimed to evaluate the impact of postural changes on the F wave-related parameters and whether those changes were associated with clinical relaxation, which was achieved in restless legs syndrome patients with standing up. Methods F wave duration (FWD), compound muscle action potential duration (CMAPD), and FWD/CMAPD ratio were evaluated in supine and upward positions in 18 restless legs syndrome patients and compared with 18 age and gender-matched healthy volunteers. Results FWD/CMAPD was significantly higher for the tibial nerve at supine position (p = 0.043) but not at upright position (p = 0.206) and for ulnar nerve, both at supine (p = 0.007) and upright positions (p = 0.023) in RLS patients compared to controls. Ulnar FWD decreased significantly at the upright position in both control and RLS patients (p = 0.035, p = 0.028, respectively). CMAPD decreased only in the control group with standing up for both ulnar and tibial nerves (p = 0.048, p = 0.017, respectively). Discussion Ulnar and tibial FWD/CMAPD ratios increased in RLS patients compared to controls. However, FWD/CMAPD was not affected by the posture within the groups. Postural change seems to be a factor that decreased ulnar FWD both in RLS patients and the control group. Ulnar and tibial CMAPD reduced only in healthy controls with an upright position. Tibial and ulnar FWD/CMAPD ratios are favorable electrophysiological parameters diagnosing RLS. The tibial FWD/CMAPD ratio loses its significance only when the patient stands up, reflecting the clinical relief achieved with the postural change.

Serum Trace Elements Concentrations in Patients with Restless Legs Syndrome.

Increased brain and serum zinc levels in patients with idiopathic restless legs syndrome (idiopathic RLS or iRLS) were described when compared with controls, suggesting a possible role of zinc in the pathogenesis of this disease. However, serum magnesium, calcium, manganese, iron, and copper levels of RLS patients were similar to controls, suggesting a specific impairment of zinc-dependent metabolism in RLS. The aim of this study is to assess the serum concentrations of trace elements involved in oxidative stress or causing peripheral nerve toxicity in a large series of patients with iRLS and controls. We determined serum levels of iron, copper, manganese, zinc, magnesium, selenium, calcium, aluminium, lead, cadmium, arsenic and mercury in 100 patients diagnosed with iRLS and in 110 age- and sex-matched controls using Inductively Coupled Plasma Mass Spectrometry. Serum copper, magnesium, selenium, and calcium concentrations were significantly higher in RLS patients than in controls. These differences were observed both in men and women. There were no major correlations between serum trace metal concentrations and age at onset of RLS or RLS severity, nor was there any association with a family history of RLS or drug response. This study shows an association between increased serum concentrations of copper, magnesium, selenium, and calcium with RLS in a Spanish Caucasian population and does not confirm the previously reported increase in serum zinc concentrations in patients suffering from this disease, suggesting that the different accuracy of the analytical methods used could have influenced the inconsistent results found in the literature.

Searching for Novel Candidate Biomarkers of RLS in Blood by Proteomic Analysis.

PurposeWe performed comparative proteomic analyses of blood of patients with RLS and healthy individuals aiming to identify potential biomarker and therapeutic target candidate for RLS.Patients and MethodsBlood serum samples from 12 patients with a clinical diagnosis of RLS (8 females and 4 males, with a mean age of 68.52 years) and 10 healthy controls (5 females and 5 males, with a mean age of 67.61 years) underwent proteomic profiling by liquid chromatography coupled with tandem mass spectrometry. Pathway analysis incorporating protein–protein interaction networks was carried out to identify pathological processes linked to the differentially expressed proteins.ResultsWe quantified 272 proteins in patients with RLS and healthy controls, of which 243 were shared. Five proteins – apolipoprotein C-II, leucine-rich alpha-2-glycoprotein 1, FLJ92374, extracellular matrix protein 1, and FLJ93143 – were substantially increased in RLS patients, whereas nine proteins – vitamin D-binding protein, FLJ78071, alpha-1-antitrypsin, CD5 antigen-like, haptoglobin, fibrinogen alpha chain, complement factor H-related protein 1, platelet factor 4, and plasma protease C1 inhibitor – were decreased. Bioinformatics analyses revealed that these proteins were linked to 1) inflammatory and immune response, and complement activation, 2) brain-related development, cell aging, and memory disorders, 3) pregnancy and associated complications, 4) myocardial infarction, and 5) reactive oxygen species generation and subsequent diabetes mellitus.ConclusionOur findings shed light on the multifactorial nature of RLS and identified a set of circulating proteins that may have clinical importance as biomarkers and therapeutic targets.

522 Reduced sympatho-vagal responses to orthostatic stress in drug-naïve idiopathic restless legs syndrome

Abstract Introduction Restless legs syndrome (RLS) is a risk factor for cardiovascular disease (CVD). However, there are no electrophysiological biomarkers to assess this risk. This study aimed to evaluate the heart rate variability (HRV) and autonomic control of cardiovascular reflexes in the supine and standing positions in patients with RLS during wakefulness. Methods Fourteen drug-naïve RLS patients (12 women, 2 men; mean age: 42.14 ± 7.81 years) and 10 healthy controls underwent tests for blood pressure, heart rate when in the supine-rest and standing positions, deep breathing, and handgrip in controlled laboratory conditions. Five-minute R-R intervals in each position were collected and analyzed for HRV. Results Cardiovascular changes during deep breathing and isometric handgrip maneuvers were normal and similar between the two groups. The normalized unit of the low frequency component and low frequency/high frequency (LH/HF) ratio during standing were lower in the RLS patients than in the controls. LF/HF ratio responses during positional change from supine-rest to standing were significantly reduced in the RLS patients (RLS patients: mean ± SD, 2.94 ± 3.11; controls: 7.51 ± 5.58; P = 0.042). In Spearman’s rank correlation, ISI and PSQI were associated with HRV parameters. Conclusion The RLS patients showed reduced sympatho-vagal responses during positional change from supine-rest to standing during wakefulness, and RLS-related sleep disturbance was an important contributing factor for autonomic nervous system dysfunction. Reduced HRV responses during wakefulness might be a good predictor for CVD risk. Support (if any):

526 Characteristics of Augmented RLS Patients on Dopamine Agonists at a Tertiary Referral Center: Where Do We Go From Here?

Abstract Introduction Augmentation is a management dilemma in RLS patients on dopaminergic therapy. Understanding the clinical characteristics of such patients may assist in better management strategies. Methods Consecutive new consultations for RLS from 4/2016-6/2020 were identified from a single tertiary referral center in Boston, USA. Patients were included in this analysis if they had augmentation and current treatment with a dopamine agonist. Clinical information from initial consultation was collected. RLS severity at time of consultation was determined retrospectively with a modified IRLSSG severity score (0–12), assessing RLS symptom frequency (0–4), duration (0–4), and severity (0–4). Results Out of 209 referrals with RLS, 105 patients had augmentation, of whom 88 were on dopamine agonists at initial evaluation. Average age was 67 years (SD 11 years, range 39–88); 62 were female (59%). Mean duration of RLS symptoms was 27 years (SD 20), and 91% had symptoms &amp;gt; 10 years. Mean duration of dopamine agonist therapy was 11 years; 72% had previously been treated with pramipexole, 65% with ropinirole, 73% with rotigotine, and 16% with levodopa; 72% of patients had been treated with alpha-2-delta ligands, and 28% with opioids. Common comorbidities included obstructive sleep apnea (47%), obesity (49%), and depression (44%). Serotonergic medications were currently used by 25%. Of the 88 augmented patients on dopamine agonist therapy, 97% had earlier onset of symptoms and 33% had symptoms in both morning and afternoon; 53% reported anatomical extension. The mean modified IRLSSG score was 8.4 (SD 3.2). 66% of patients had either ferritin &amp;lt;75 mcg/L or transferrin saturation &amp;lt;20%. At the time of initial assessment, 49% were on pramipexole, 47% on rotigotine, 5% on rotigotine and 7% on levodopa: mean daily dopamine agonist dose was 1.23 mg (SD 1.20) of pramipexole equivalent. 37% were on alpha-2-delta ligands: mean daily dose 1014 mg (SD 830, median 700 mg) of gabapentin equivalent. Conclusion Higher than FDA-recommended dopamine agonist dosing and high prevalence of iron deficiency in patients with augmented RLS represent a treatment gap in the care of RLS patients in the community. Controlled studies of guideline-based therapy are indicated to determine optimal management of augmented RLS. Support (if any) Baszucki Brain Research Fund

Treating Restless Legs Syndrome Was Associated With Low Risk of Cardiovascular Disease: A Cohort Study With 3.4Years of Follow-Up.

BackgroundRestless legs syndrome (RLS) is associated with higher cardiovascular disease (CVD) risk. However, it remains unknown whether treatment of RLS lowers the cardiovascular risk associated with RLS.Methods and ResultsAll data were collected retrospectively, but subjects were prospectively followed forward in time to determine outcomes of interest. We used the Truven Health MarketScan Commercial Claims and Encounters database from January 1, 2006, through December 31, 2014. Participants were 169 393 individuals, which included 24 199 nonpregnant participants with an RLS diagnosis (16 694 receiving treatments for RLS and 7505 without treatment) during 2006 to 2008 and 145 194 age‐ and sex‐matched participants without RLS. All participants were free of CVD before January 1, 2009 (analysis baseline). Incident CVD cases (myocardial infarction, angina, stroke, atrial fibrillation, and heart failure) were identified. We adjusted for potential confounders, such as presence of chronic conditions and medication use. We identified 16 574 incident CVD cases during 2009 to 2014. Relative to the non‐RLS group, the adjusted hazard ratio (HR) for future CVD was 1.26 (95% CI, 1.20–1.32) (P<0.001) for the RLS with treatment group, and 1.53 (95% CI, 1.42–1.65) (P<0.001) for the RLS without treatment group. Significant lower CVD risk was observed for all different RLS treatments, including dopaminergics, anticonvulsants, benzodiazepines, and opiates (adjusted HRs range, 0.71‐0.84; P<0.001 for all), except for ergot‐dopamine use.ConclusionsRLS was associated with higher future CVD risk. However, RLS was associated with statistically significantly less future cardiovascular risk in RLS patients with treatment than in those without treatment.

The Frontal Assessment Battery in RLS patients with and without augmentation

ObjectiveWe assessed frontal executive functions in patients with RLS/WED with and without augmentation and compared the results to healthy controls. MethodsWe recruited 38 patients with RLS/WED. A total of 23 patients were treated with dopaminergic therapy and showed no signs of augmentation and 15 patients had a history of augmentation (AUG). Results were compared to 21 healthy controls. All individuals were assessed by the Frontal Assessment Battery (FAB) and the MMSE. Furthermore, impulsivity was assessed during a semi-structured interview. ResultsPatients with AUG performed worse in the FAB than healthy controls and RLS/WED patients without AUG (p = 0.001, η2 = 0.201). When we assessed the subtests of the FAB separately, we found a significant difference in the subtest assessing inhibitory control (p = 0.008, η2 = 0.138). ConclusionsOur findings suggest an impaired executive function in RLS/WED patients with augmentation compared to RLS/WED patients without augmentation and healthy controls. Long term neuroplastic changes within the prefrontal cortex may be the underlying cause for these results. However, further studies in a larger sample size and with a more extensive neuropsychological test battery are needed to confirm our preliminary results.

Statistical shape analysis of corpus callosum in restless leg syndrome

ABSTRACT Objectives In this study we aimed to investigate corpus callosum shape differences between restless leg syndrome patients and healthy controls, and to determine whether disease severity and duration are indicators for corpus callosum deformation in RLS patients. Methods This study was conducted using the magnetic resonance imaging scans of 33 restless leg syndrome patients and 33 control subjects. Landmarks were marked on the digital images and callosal landmark coordinate data were used to assess shape difference by performing Generalized Procrustes analysis. The shape deformation from controls to the patients was evaluated performing the Thin Plate Spline approach. Results There was a statistically significant shape difference between the groups. Highest deformation was determined at the posterior midbody of the corpus callosum. Growth curve analyses showed that with the increase in disease duration and severity, the CC size decreased. Discussion The present study demonstrated callosal shape differences in restless leg syndrome using a landmark-based geometric morphometric approach, considering the topographic distribution of corpus callosum for the first time.

0790 The Clinical Significance of Hepcidin as a Predictive Value for Treatment Responses in Restless Legs Syndrome

Abstract Introduction Restless legs syndrome (RLS) is a common sensory motor neurological disorder that is related to iron-dopamine dysregulation and immune system alteration. Hepcidin is the key regulatory hormone of systemic iron homeostasis and is related to inflammatory processes. We aimed to evaluate the clinical utility of hepcidin as a diagnostic biomarker and index of therapeutic responses in RLS patients after dopaminergic treatment. Methods Non-anemic and drug-naive RLS patients (n=18) and healthy controls (n=15) were enrolled. Hepcidin (pre-prohepcidin) and iron-related values in serum were measured upon the first visit in both groups and 12 weeks later after dopaminergic treatment in 12 RLS patients. Information about sociodemographic characteristics, sleep-related profiles, mood, and anxiety was obtained upon the first visit in all participants as well as after treatment in RLS patients. Results Hepcidin levels exhibited no significant differences between patients with drug-naïve RLS and healthy controls at a diagnosis (7.1 ± 2.4 vs. 7.0 ± 3.2 ng/ml, p = 0.978). Decreased hepcidin levels were significantly associated with decreased RLS severity (β = 0.002, 95% CI = 0.00−0.00, p = 0.005) and improved quality of life (β = 0.002, 95% CI = 0.00−7.01, p = 0.044) in a dose-dependent manner after 12 weeks of treatment with a dopamine agonist. This association was independent of age, sex, inflammatory markers, sleep quality, insomnia, daytime sleepiness, depression, and anxiety. Conclusion This study demonstrates a role of hepcidin as a predictor of therapeutic responses in RLS patients. Support This work was supported by the Korea Health technology R&amp;D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health &amp; Welfare, South Korea [grant number HI17C2072].

0802 To Examine the Effect of Gabapentin Enacarbil in Primary Restless Legs Syndrome Patients Who are on Dopaminergic Agents and Exhibiting Augmentation

Abstract Introduction Augmentation is defined as worsening of the symptoms of Restless Legs Syndrome after a brief period of initial improvement with dopaminergic agents resulting in either an earlier onset, increase in severity, quicker onset, spread to other body parts. The exact prevalence of this phenomenon is not known and in patients experiencing augmentation, it can pose a difficult diagnostic and therapeutic challenge to the clinician. In our study, we found extended-release gabapentin to be an effective intervention in patients experiencing dopaminergic augmentation Methods This is an open-label single-arm study done in patients exhibiting augmentation while on dopaminergic agents. Patients who were enrolled in the study were initiated on oral extended-release gabapentin(Horizont) 600 mg at 5 pm at the beginning of the study. At day 90, attempts were made to reduce or discontinue dopaminergic agents. International Restless Legs Syndrome-Rating Scale (IRLS) and Augmentation Severity Rating Scale(ASRS) were recorded at each visit. Results A total of 10 patients were enrolled in the study while only 8 patients completed it. Compared to the baseline (visit 2), there is a significant improvement in both the augmentation severity(p= 0.0131) and the IRLS (p=0.0497). Wilcoxon matched-pairs signed rank test was used for statistical analysis. Conclusion Extended-release Gabapentin is an effective treatment option in primary RLS patients experiencing augmentation secondary to dopaminergic medication usage. Support The study is funded and medication is provided by Arbor Pharmaceuticals.

Clinical characteristics of Korean pediatric patients with restless legs syndrome

ObjectivesRestless legs syndrome (RLS) is a common neurological disorder but it is not sufficiently recognized in children and adolescents. It often overlaps with growing pains in children, and as a result the clinical characteristics of pediatric RLS are not well studied, especially in Asia. The purpose of this study is to investigate the clinical characteristics of pediatric RLS patients in Korea and compare it to those of adult RLS patients. MethodsWe retrospectively reviewed the medical records of all pediatric RLS patients (≤18 years) from January 2015 to December 2018 in a regional tertiary hospital sleep center. We randomly selected adult primary RLS patients without comorbid medical disorders from our sleep center's dataset as controls. The number of controls was determined to be twice the number of pediatric RLS patients according to sample size calculation. The clinical and polysomnographic (PSG) characteristics of both groups were compared. The independent t-test, chi-squared test, and Fisher's exact test were used for analyzing quantitative data between the two groups and p < 0.05 was considered statistically significant. ResultsTwenty-nine primary pediatric RLS patients and 57 adult RLS patients were enrolled. Pediatric RLS patients showed equal prevalence between sexes, as opposed to adults where there is female predominance. Ferritin level was significantly lower in pediatric patients, although it remained within the normal range. Also, pediatric RLS patients showed less severe RLS symptoms and had better sleep quality than adults did in both objective and subjective measures. In addition, PLMS was shown to be less common in pediatric RLS patients compared to adults. ConclusionsPediatric RLS patients showed relatively mild to moderate RLS symptoms and a smaller likelihood of experiencing PLMS than adult patients, which is comparable to similar western studies. Long-term evaluation of a patient's clinical course through multicenter clinical studies is strongly suggested for the future.