A randomized double-blind pilot study to evaluate the efficacy, safety, and tolerability of intravenous iron versus oral iron for the treatment of restless legs syndrome in patients with iron deficiency anemia.

Restless legs syndrome (RLS) is a neurological disorder that can have a profound effect on sleep and quality of life. Idiopathic RLS is associated with brain iron insufficiency despite normal peripheral iron stores. There is, however, a five- to six-fold increase in prevalence of RLS in patients with iron deficiency anemia (IDA). Several open-label trials have demonstrated symptomatic improvement in RLS following treatment of IDA using oral or intravenous iron supplementation. To date, there have been no randomized double-blind controlled trials of intravenous iron compared with oral iron for the treatment of RLS patients with IDA. In the current study, oral ferrous sulfate and ferumoxytol were compared for efficacy and speed of response for treatment of RLS occurring in patients with IDA. The planned recruitment for this study was 70 patients with RLS and IDA, to be randomly assigned 1:1 to oral or intravenous iron, using double-blind, double-dummy procedures. At Week 6, the primary outcomes of Clinical Global Impression-Improvement score and change from baseline in the International Restless Legs Syndrome Study Group rating scale score were assessed. Due to challenges, performing the clinical trial during the COVID-19 pandemic, final-week data were found missing for 30 patients. As a result, in order to maintain the prespecified statistical analysis, an additional 30 patients were recruited. Both IV and oral iron were associated with a marked improvement in RLS symptoms, with no statistically significant difference between treatment groups. No serious adverse events were observed in either treatment group.

The Management of Restless Legs Syndrome: An Updated Algorithm.

Restless legs syndrome (RLS) is a common disorder. The population prevalence is 1.5% to 2.7% in a subgroup of patients having more severe RLS with symptoms occurring 2 or more times a week and causing at least moderate distress. It is important for primary care physicians to be familiar with the disorder and its management. Much has changed in the management of RLS since our previous revised algorithm was published in 2013. This updated algorithm was written by members of the Scientific and Medical Advisory Board of the RLS Foundation based on scientific evidence and expert opinion. A literature search was performed using PubMed identifying all articles on RLS from 2012 to 2020. The management of RLS is considered under the following headings: General Considerations; Intermittent RLS; Chronic Persistent RLS; Refractory RLS; Special Circumstances; and Alternative, Investigative, and Potential Future Therapies. Nonpharmacologic approaches, including mental alerting activities, avoidance of substances or medications that may exacerbate RLS, and oral and intravenous iron supplementation, are outlined. The choice of an alpha2-delta ligand as first-line therapy for chronic persistent RLS with dopamine agonists as a second-line option is explained. We discuss the available drugs, the factors determining which to use, and their adverse effects. We define refractory RLS and describe management approaches, including combination therapy and the use of high-potency opioids. Treatment of RLS in pregnancy and childhood is discussed.

Resting-state connectivity and the effects of treatment in restless legs syndrome.

OBJECTIVES: Resting-state brain connectivity has been shown to differ for Restless Legs Syndrome (RLS) compared to healthy control (CON) groups. This study evaluates the degree these RLS-CON differences are changed by concurrent treatment. METHODS: Resting-state functional MRIs were obtained from 32 idiopathic RLS patients during the morning asymptomatic period and 16 age and gender-matched CON subjects. Of the 32 RLS patients, 16 were drug-naïve (DN-RLS), and 16 were regularly drug-treated using a dopamine agonist (DT-RLS). Various assessments of disease characteristics were also performed. The primary purpose was to assess the replicability of prior results and the effects of treatment on these differences between controls and untreated RLS patients. Resting-state connectivity was analyzed by a seed-based method using the bilateral ventral-posterolateral nuclei (VPLN) in the thalamus. RESULTS: In the DN-RLS group, compared to the CON group, three areas (the bilateral lingual gyri and right middle temporal gyrus) were replicated. The three replicated areas did not significantly differ for DT-RLS compared to DN-RLS. DT-RLS compared to DN-RLS had significantly higher thalamic connectivity for the left uvula, right tuber, left anterior insula, and right declive. CONCLUSIONS: Thalamic connectivity to the bilateral lingual gyri and right middle temporal gyrus is a replicable finding in DN-RLS that was not affected by dopamine agonist treatments. Other changes in thalamic connectivity were altered by dopamine agonist treatment. These treatment effects may be pertinent to the known treatment benefits of a dopamine agonist on RLS symptoms.

Brain iron deficiency in idiopathic restless legs syndrome measured by quantitative magnetic susceptibility at 7 tesla.

OBJECTIVES: Altered brain iron homeostasis with regional iron deficiency has been previously reported in several studies of restless legs syndrome (RLS) patients. Inconsistencies still exist, however, in the reported iron changes in different brain regions and different RLS phenotypes. The purpose of this study was to assess differences in brain iron concentrations between RLS patients and healthy controls and their relation to severity of disease and periodic limb movement during sleep (PLMS). METHODS: Assessment of brain iron was done using quantitative magnetic susceptibility measurement, which has been shown to correlate well with the tissue iron content in brain's gray matter. Thirty-nine RLS patients and 29 age-matched healthy controls were scanned at 7 T. Magnetic susceptibilities in substantia nigra (SN), thalamus, striatum, and several iron-rich gray matter regions were quantified and compared with related clinical measures. RESULTS: Compared with healthy controls, RLS patients showed significantly decreased magnetic susceptibility in the thalamus and dentate nucleus. No significant difference was found in the SN between RLS patients and healthy controls, but a significant correlation was observed between magnetic susceptibility in SN and the PLMS measure. CONCLUSIONS: Using quantitative magnetic susceptibility as an in vivo indicator of brain iron content, the present study supports the general hypothesis of brain iron deficiency in RLS and indicates its possible link to PLMS.

Functional connectivity alternation of the thalamus in restless legs syndrome patients during the asymptomatic period: a resting-state connectivity study using functional magnetic resonance imaging.

BACKGROUND: Restless legs syndrome (RLS) is a primary sensory disorder with a secondary motor component (e.g., urge to move), and the thalamus is known to play a central role in RLS. The purpose of our study was to explore the intrinsic changes in the thalamocortical circuit in RLS patients using a resting-state functional magnetic resonance imaging (fMRI) paradigm. METHODS: Resting-state fMRIs were obtained in the morning from 25 idiopathic RLS patients who were not using RLS medications and 25 controls. Resting-state connectivity was analyzed by a seed-based method using Analysis of Functional NeuroImages (AFNI) software with the bilateral thalami (ventroposterolateral nucleus [VPLN]). The connectivity characteristics of RLS patients were compared to those of the controls. RESULTS: We found that RLS patients showed reduced thalamic connectivity with the right parahippocampal gyrus, right precuneus, right precentral gyrus, and bilateral lingual gyri; however, the right superior temporal gyrus, bilateral middle temporal gyrus, and right medial frontal gyrus showed enhanced connectivity with the thalamus. RLS severity was negatively correlated with connectivity between the thalamus and right parahippocampal gyrus (r = -0.414; P = .040). CONCLUSIONS: Our results suggest that the characteristics of the connectivity changes may reflect the pathways involved in producing RLS symptoms and indicate that RLS patients may have deficits in controlling and managing sensory information, which supports the act of viewing RLS as a disorder disrupting somatosensory processing.

Thalamic glutamate/glutamine in restless legs syndrome: increased and related to disturbed sleep.

OBJECTIVE: To evaluate possible abnormal increase in thalamic glutamate/glutamine levels for restless legs syndrome (RLS) indicating increased glutamatergic activity producing arousal that at night disrupts and shortens sleep. METHODS: (1)H MRS of the right thalamus was performed using a 1.5 T GE MRI scanner and the PROBE-P (PRESS) on 28 patients with RLS and 20 matched controls. The Glx signal (combination of mostly glutamate [Glu] and glutamine [Gln]) was assessed as a ratio to the total creatine (Cr). This study tested 2 primary hypotheses: 1) higher thalamic Glx/Cr for patients with RLS than controls; 2) thalamic Glx/Cr correlates with increased wake during the sleep period. RESULTS: The Glx/Cr was higher for patients with RLS than controls (mean ± SD 1.20 ± 0.73 vs 0.80 ± 0.39, t = 2.2, p = 0.016) and correlated significantly with the wake time during the sleep period (r = 0.61, p = 0.007) and all other RLS-related polysomnographic sleep variables (p < 0.05) except for periodic leg movements during sleep (PLMS)/hour. CONCLUSIONS: The primary findings introduce 2 new related dimensions to RLS: abnormalities in a major nondopaminergic neurologic system and the arousal disturbance of sleep. The strong relation of the arousal sleep disturbance to glutamate and the lack of relation to the PLMS motor features of RLS contrasts with the reverse for dopamine of a limited relation to arousal sleep disturbance but strong relation to PLMS. Understanding this dichotomy and the interaction of these 2 differing systems may be important for understanding RLS neurobiology and developing better treatments for RLS.

Postmortem and imaging based analyses reveal CNS decreased myelination in restless legs syndrome.

BACKGROUND: Restless legs syndrome (RLS) is a neurological disorder characterized by a strong urge to move the legs and has been shown in many studies with abnormally low brain iron. Iron deficiency is associated with hypomyelination in brains of animals. Therefore we hypothesized that a myelin deficit should be present in the brains of patients with RLS. METHODS: We performed Western blot analysis on myelin isolated from RLS (n=11) and control (n=11) brain tissue obtained at autopsy for the expression of the integral myelin proteins, myelin basic protein (MBP), and proteolipid protein (PLP) and the oligodendrocyte specific enzyme 3'5'-cyclic nucleotide phosphohydrolase (CNPase). To expand the postmortem findings to in vivo, we analyzed the brains of RLS patients (n=23) and controls (n=23) using voxel-based morphometry (VBM). RESULTS: The expression of MBP, PLP and CNPase in the myelin from RLS was decreased by approximately 25% (p<0.05) compared to controls. The amounts of transferrin (Tf) and H-ferritin (H-Frt) in the myelin fraction were also significantly decreased in RLS compared to controls. The imaging analysis revealed significant small decreases in white matter volume in RLS patients compared to controls in the corpus callosum, anterior cingulum and precentral gyrus. CONCLUSION: A decrease in myelin similar to that reported in animal models of iron deficiency was found in the brains of individuals with RLS. The evidence for less myelin and loss of myelin integrity in RLS brains, coupled with decreased ferritin and transferrin in the myelin fractions, is a compelling argument for brain iron insufficiency in RLS. These data also indicate the need to look beyond the sensorimotor symptoms that typically define the syndrome and its assumed relation to the dopaminergic system. Understanding the full range of RLS pathology may help us better understand the complex, intermittent nature and diversity of the clinical features of RLS and expand our consideration of treatment options for RLS.

A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome.

OBJECTIVE: The aim of this study was to ascertain whether high-dose intravenous (IV) iron sucrose could improve symptoms and change brain iron concentrations in idiopathic RLS. METHODS: The study was a randomized, parallel-group double-blind study of 1000mg iron sucrose given IV versus placebo. Primary measures of the clinical status were global rating scale (GRS) and periodic leg movements of sleep (PLMS). Primary measures of brain iron status were CSF ferritin and MRI-determined iron in the substantia nigra. RESULTS: At the time of the interim analysis there were 7 placebo and 11 iron-treated subjects. At 2-weeks post-treatment, iron treatment resulted in a small but significant increase in CSF ferritin and a decrease in RLS severity (GRS) but did not change PLMS or MRI iron index. None of the secondary outcomes changed with treatment. There was no single case of clear treatment benefit in any of the patients. This interim analysis revealed an effect size that was too small to allow for adequate power to find significant differences with the planed 36-subject enrollment for either the primary objective outcome of PLMS or any of the secondary outcomes. The study was stopped at this planned break-point given the lack of both adequate power and any indication for clinically significant benefit. CONCLUSIONS: High-dose IV iron failed to demonstrate the robust changes reported in three prior open-label studies. Differences in iron formulation, dosing regiment, and peripheral iron status may explain some of the discrepancies between this and previous IV iron treatment studies.

Restless legs syndrome: a clinical update.

Restless legs syndrome (RLS) is a common and often disabling sensorimotor disorder. Epidemiologic studies suggest that RLS is an underrecognized and undertreated disorder affecting both children and adults. The diagnosis is based primarily on the following four essential criteria: (1) an urge to move, usually associated with paresthesias, (2) onset or exacerbation of symptoms at rest, (3) relief of symptoms with movement, and (4) symptoms manifesting in a circadian pattern. Supplemental workup including polysomnography, iron profile, and/or neuropathy screen can provide support for the diagnosis and aid in the treatment strategy. Behavioral techniques, dopaminergic agents, opiates, benzodiazepines, and antiepileptics all have potential value in treating this disorder. Dopaminergic agents continue to be the most effective RLS treatment. However, due to their potential long-term side effects, these agents should not be considered the sole treatment of choice. In the end, the therapeutic plan should be individualized to suit each patient's presentation and needs.

Repeated IV doses of iron provides effective supplemental treatment of restless legs syndrome.

BACKGROUND AND PURPOSE: To evaluate in RLS patients the efficacy and safety of repeated infusions of iron in order to maintain symptomatic improvements achieved with a prior single 1000 mg infusion of iron. PATIENTS AND METHODS: Subjects who had demonstrated initial improvement in RLS symptoms after a single 1000 mg infusion of iron were evaluated monthly for serum ferritin and RLS severity. If symptoms returned at any time in the 2-year period after initial iron treatment, supplemental 450 mg iron gluconate infusions could be given, provided the ferritin was <300 mcg/l. The primary outcome measures were side effect profile, duration (weeks) of sustained improvement, and rate of change of serum ferritin. RESULTS: Ten subjects received the initial single 1000 mg dose of iron dextran, but only five subjects were eligible to receive supplemental iron infusions. RLS symptoms returned on average 6 months after the initial 1000 mg infusion. Because of noncompliance with monthly visits one subject was dropped after receiving three supplemental iron infusions. Because of a ferritin >300 mcg/l, a second subject was dropped after having received one supplemental treatment. Three subjects completed the 2-year period of the study, having received between two and four courses of supplemental iron. After the initial 1000 mg iron infusion, the ferritin declined on average 6.6 mcg/l/week, which was substantially higher than the predicted value of <1 mcg/l per week. The rate of ferritin decline decreased toward normal with repeated IV iron treatments: the average rate of decline in ferritin for the last treatment course was 2.3 mcg/l/wk. The slower the rate of ferritin decline the more prolonged the symptom improvements. CONCLUSIONS: Supplemental iron treatments can sustain previously achieved improvements with a single IV iron treatment, but achieving high ferritin levels was not in themselves a guarantee of sustained improvements. The most notable finding was the post-infusion changes in serum ferritin and its implication for altered iron excretion.