Is ferroportin-hepcidin signaling altered in restless legs syndrome?

Restless legs syndrome (RLS) is a neurological disorder characterized by a strong urge to move the legs. Sufferers of RLS often experience chronic sleep deprivation, due to the characteristic worsening of symptoms both when at rest and during the night. MRI data, autopsy studies, and a consistent decrease in CSF ferritin all suggest that early-onset RLS is associated with insufficient iron in the brain. In this study, we examined the relationship between the iron regulatory hormone hepcidin and RLS. Hepcidin serves as a hormone that signals iron release from cells by interacting with ferroportin. We measured the expression and concentration of pro-hepcidin in the brain and cerebrospinal fluid of both RLS patients and control individuals. In CSF, we found that pro-hepcidin levels were significantly decreased in early-onset RLS patient samples, but not in late-onset RLS patients, when compared to controls. Conversely, in neuromelanin cells, substantia nigra, and putamen, the concentration of pro-hepcidin in RLS samples is significantly increased compared to controls. Functionally, hepcidin binds to ferroportin to limit iron movement from cells. Therefore, we provide immunocytochemical evidence that ferroportin is expressed by the epithelial cells of the choroid plexus and the ependymal cells lining the ventricles. These data suggest that sites of action for hepcidin include signaling the ventricular system for movement between brain and CSF. At this time, it cannot be determined if the lower levels of pro-hepcidin in the CSF represent a compensatory response to the decreased levels of iron in the brain or a defective signaling mechanism in RLS. Nonetheless, these data support the mounting evidence that there is a biological basis for RLS and the underlying mechanism involves iron management.     

Does domperidone potentiate mirtazapine-associated restless legs syndrome?

There is now evidence to suggest a central role for the dopaminergic system in restless legs syndrome (RLS). For example, the symptoms of RLS can be dramatically improved by levodopa and dopamine agonists, whereas central dopamine D2 receptor antagonists can induce or aggravate RLS symptoms. To our knowledge, there is no previous report regarding whether domperidone, a peripheral dopamine D2 receptor antagonist, can also induce or aggravate symptoms of RLS. Mirtazapine, the first noradrenergic and specific serotonergic antidepressant (NaSSA), has been associated with RLS in several recent publications. The authors report here a depressed patient comorbid with postprandial dyspepsia who developed RLS after mirtazapine had been added to his domperidone therapy. Our patient started to have symptoms of RLS only after he had been treated with mirtazapine, and his RLS symptoms resolved completely upon discontinuation of his mirtazapine. Such a temporal relationship between the use of mirtazapine and the symptoms of RLS in our patient did not support a potentiating effect of domperione on mirtazapine-associated RLS. However, physicians should be aware of the possibility that mirtazapine can be associated with RLS in some individuals, especially those receiving concomitant dopamine D2 receptor antagonists.     

DBS in restless legs syndrome: a new therapeutic approach?

ObjectiveRestless legs syndrome (RLS) is a sleep disorder characterized by an urge to move legs or arms, with a typical circadian rhythm. RLS can be treated with pharmacological and non-pharmacological therapies. Nevertheless, in some patients RLS can be refractory to all medical and non-medical treatments.Deep brain stimulation (DBS) of the globus pallidus internus (GPi) has been reported to improve RLS symptoms in Parkinson's disease (PD) patients with RLS. We describe the case of a patient suffering from refractory idiopathic RLS implanted with bilateral GPi DBS.MethodThe patient underwent DBS targeting the bilateral GPi. Follow up for three years involved clinical evaluation and polysomnography (PSG).ResultsThe patient reported subjective improvement, with reduction in the IRLS score. Furthermore, the polysomnography (PSG) showed an objective improvement of polysomnographic parameters, which remained stable during the follow-up.ConclusionDBS for RLS can be a new therapeutic approach for severe RLS, but further studies are needed.     

Is preeclampsia associated with restless legs syndrome?

ObjectiveRestless legs syndrome (RLS) is a common neurologic disorder. Secondary RLS includes pregnancy and iron deficiency. Prevalence of RLS in pregnancy ranges from 11% to 27%. We aimed to assess the frequency and characteristics of RLS in pregnancy in a Peruvian population and to evaluate the possible pregnancy or delivery complications due to RLS.MethodsWe assessed 218 consecutive expectant mothers at the inpatient clinic of the Hospital San Bartolome in Lima, Peru. Assessment was performed by using the standard diagnostic criteria for RLS and by using a clinical and diagnostic interview. Questionnaires for RLS severity, idiopathic RLS (IRLS), and excessive daytime sleepiness (EDS) according to the Epworth sleepiness scale (ESS) were used. Blood examination was performed for hemoglobin and hematocrit. For comparison, RLS patients were matched for age and body mass index (BMI) with pregnant women without RLS.ResultsOut of 218 patients, 40 (18.4%) fulfilled diagnostic criteria for RLS. In RLS patients, prophylactic iron supplementation therapy during pregnancy was less frequently taken (P = .02). Pregnant women with RLS had a higher ESS score than pregnant controls (10.6 +/− 3.1 vs 7.6. +/− 3.6; P < .001). Preeclampsia was more frequent in RLS (7/40 vs 1/39; P = .03).ConclusionsIn our study, RLS was frequent in pregnant Peruvian women, especially in those without prophylactic iron supplementation. RLS patients described more EDS. Preeclampsia was more common in RLS. Our study is the first study to indicate a possible association between RLS and preeclampsia.     

Is there a polysomnographic signature of augmentation in restless legs syndrome?

Objective

Augmentation of restless legs syndrome (RLS) is a potentially severe side-effect of dopaminergic treatment. Data on objective motor characteristics in augmentation are scarce. The aim of this study was to investigate in detail different variables of leg movements (LM) in untreated, treated, and augmented RLS patients.

Methods

Forty-five patients with idiopathic RLS [15 untreated, 15 treated (non-augmented), 15 augmented] underwent RLS severity assessment, one night of video-polysomnography with extended electromyographic montage, and a suggested immobilization test (SIT).

Results

Standard LM parameters as well as periodicity index (PI) and muscle recruitment pattern did not differ between the three groups. The ultradian distribution of periodic leg movements (PLM) in sleep during the night revealed significant differences only during the second hour of sleep (P < 0.05). However, augmented patients scored highest on RLS severity scales (P < 0.05) and were the only group with a substantial number of PLM during the SIT.

Conclusion

This study demonstrates that polysomnography is of limited usefulness for the diagnosis and evaluation of RLS augmentation. In contrast, the SIT showed borderline differences in PLM, and differences on subjective scales were marked. According to these results, augmentation of RLS is a phenomenon that predominantly manifests in wakefulness.     

Is autonomic nervous system involved in restless legs syndrome during wakefulness?

ObjectiveTo investigate cardiovascular autonomic function in patients with restless leg syndrome (RLS) by means of cardiovascular reflexes and heart rate variability (HRV) during wakefulness.MethodsTwelve RLS patients and 14 controls underwent cardiovascular function tests including head-up tilt test (HUTT), Valsalva maneuver, deep breathing, hand grip, and cold face. HRV analysis was performed in the frequency domain using both autoregressive (AR) and fast Fourier transform algorithms in rest supine condition and during HUTT.ResultsThere was a significant increase in systolic blood pressure values in supine rest condition and a trend toward a lower Valsalva ratio in RLS patients with respect to controls. The significant and physiological changes of HRV at HUTT detected in healthy subjects were not found in RLS patients.ConclusionRLS patients exhibit a tendency toward hypertension, reduced amplitude of both sympathetic and parasympathetic responses at HUTT, as well as blunted parasympathetic drive to blood pressure changes. These findings, if confirmed by more controlled studies, might support the hypothesis of autonomic nervous system involvement during wakefulness and consequently an enhanced cardiovascular risk in RLS.     

Can changes in cortical excitability distinguish progressive from juvenile myoclonic epilepsy?

Purpose: We used transcranial magnetic stimulation (TMS) to investigate whether there were any characteristic cortical excitability changes in progressive myoclonic epilepsy (PME) compared to juvenile myoclonic epilepsy (JME). Methods: Six patients with PME were studied. Motor threshold (MT) at rest and recovery curve analysis using paired‐pulse stimulation at a number of interstimulus intervals (ISIs) was determined. Results were compared to those of 9 patients with chronic refractory JME and 10 with chronic well‐controlled JME. Results: PME showed a marked increase in cortical excitability at all the long ISIs (p < 0.01), compared to refractory JME (effect sizes ranging from 1.4 to 1.9) and well‐controlled JME (effect sizes ranging from 2.0 to 2.4). Significant differences at the short ISIs 2–5 ms were seen only on comparison with the well‐controlled group (p < 0.05, effect size 0.6, 0.7). There were no significant differences in MTs of PME compared to either JME groups. Conclusion: Our findings demonstrate specific differences in cortical excitability using TMS between PME and those with JME, particularly at long latencies in the paired‐pulse paradigm, implicating a role for γ‐aminobutyric acid (GABA)_B‐mediated networks.     

Topography of sensory symptoms in patients with drug-naïve restless legs syndrome

ObjectivesWe aimed to describe the sensory topography of restless legs syndrome (RLS) sensory symptoms and to identify the relationship between topography and clinical variables.MethodsEighty adult patients with drug-naïve RLS who had symptoms for more than 1 year were consecutively recruited. During face-to-face interviews using a structured paper and pencil questionnaire with all participants, we obtained clinical information and also marked the topography of RLS sensory symptoms on a specified body template, all of which were subsequently inputted into our in-house software. The RLS sensory topography patterns were classified according to localization, lateralization, and symmetry. We investigated if these sensory topography patterns differed according to various clinical variables.ResultsThe lower extremities only (LE) were the most common location (72.5%), and 76.3% of participants exhibited symmetric sensory topography. Late-onset RLS showed more asymmetric sensory distribution compared with early-onset RLS (P = .024). Patients whose sensory symptoms involved the lower extremities in addition to other body parts (LE-PLUS) showed more severe RLS compared with those involving the LE (P = .037).ConclusionRLS sensory symptoms typically were symmetrically located in the lower extremities. LE-PLUS or an asymmetric distribution more often occurred in patients with more severe RLS symptoms or late-onset RLS.     

Default mode network disturbances in restless legs syndrome/Willis–Ekbom disease

BackgroundThe unusual sensations of restless legs syndrome/Willis–Ekbom disease (RLS/WED) are induced by rest or a low arousal state with a circadian variation in the threshold for induction. It has been suggested that the emergence of RLS/WED symptoms relates to abnormal brain functions dealing with internally generated stimuli. The purpose of this study was to investigate the changes in the default mode network (DMN) in RLS/WED subjects.MethodsSixteen drug-naïve, idiopathic, RLS/WED subjects, and 16 age-matched and gender-matched healthy subjects were scanned in an asymptomatic resting state. A comparison of the DMN was conducted between the two groups. Resting state functional magnetic resonance imaging (MRI), Korean versions of the International RLS scale, and other sleep questionnaires were used.ResultsThe results showed reductions in the DMN connectivity in the left posterior cingulate cortex, the right orbito-frontal gyrus, the left precuneus, and the right subcallosal gyrus of the RLS/WED subjects. The DMN connectivity was increased in sensory-motor-associated circuits, which included the right superior parietal lobule, the right supplementary motor area, and the left thalamus. In addition, the connectivity between the DMN and thalamus was negatively correlated with that in the orbito-frontal gyrus and the subcallosal gyrus in the subjects.ConclusionsThe results showed disturbances of the DMN in RLS/WED subjects that influence the thalamic relay sensory-motor-associated circuit. These findings may underscore the fact that RLS/WED subjects have disturbances in default mode network functions involving internal stimuli in the resting state. This may be related to compensatory changes to maintain resting.     

Is restless legs syndrome associated with chronic mountain sickness?

BackgroundRestless legs syndrome (RLS) and chronic mountain sickness (CMS) share physiological traits. Our objective was to explore a possible association between RLS and CMS.MethodsWe carried a cross-sectional study with male subjects living between 4100 and 4300 m above sea level. Participants underwent a clinical interview, physical examination, electrocardiographic (EKG) recording, and spirometry. We classified subjects into CMS, Limbo, and healthy high-altitude dwellers (hHAD), according to their Quinghai score and hematocrit levels. We applied the “Paradigm of questions for epidemiological studies of RLS,” The International Restless Leg Syndrome Study Group Scale, and the Pittsburgh Sleep Quality Index. Logistic regression analysis was used to determine the association between variables.ResultsSeventy-eight male subjects were included. Forty subjects were hHAD, 23 were CMS patients, and 15 participants were considered as Limbo. CMS and Limbo subjects had a higher frequency of RLS (p <0.05). Limbo subjects had the highest severity score for RLS. There were no differences in age, body mass index (BMI), or tobacco use between RLS patients and non-sufferers. In the multivariate analysis, CMS was not associated with RLS diagnosis. Oxygen saturation (p = 0.019), poor sleep quality (p <0.01), and Quinghai score of ≥6 (p = 0.026) were independently associated with RLS diagnosis.ConclusionsOur results did not show a direct association between RLS and CMS; however, RLS was associated with reduced oxygen saturation. Hence, RLS could represent an early clinical manifestation of hypoxia, or, in CMS natural history, an early sign of maladaptation to high altitude.     

Small fiber function in drug naïve patients with idiopathic restless legs syndrome

To assess whether idiopathic restless legs syndrome (RLS) is associated with small fiber abnormalities, we evaluated somatic and autonomic small fiber function in 56 patients with idiopathic RLS and 36 age-matched and sex-matched healthy controls using quantitative sensory testing and quantitative sudomotor axon reflex tests. The warm detection thresholds (WDT) of the hands (p=0.017) and feet (p=0.008) were higher in patients with RLS than in controls. Cooling detection thresholds (CDT) were higher in the feet of patients with RLS than controls (p<0.001), but CDT in the hands did not differ between groups (p=0.161). There were no significant between-group differences in total sweat volume and sweat production in the forearms, proximal legs, distal legs, and feet (p>0.1 each). These findings suggest that abnormal sensory perception in patients with idiopathic RLS may result from impairment of central somatosensory processing rather than small fiber neuropathy.     

Daytime symptoms of restless legs syndrome – clinical characteristics and rotigotine effectiveness

ObjectiveTo elucidate the prevalence and clinical characteristics of daytime restless legs syndrome (RLS) among patients with idiopathic RLS and investigate the effectiveness of rotigotine for daytime RLS.MethodsIn 256 enrolled RLS patients, we investigated factors associated with the presence of RLS symptoms throughout the day. We also assessed the duration of daytime RLS symptoms at hourly intervals, time of initial symptom onset during the day, and associations between duration of daytime and nighttime RLS symptoms. In addition, we compared changes in duration and frequency of RLS symptoms during daytime and nighttime after randomly assigning patients to a 13-week treatment with rotigotine, a dopamine agonist patch with 24-hour action, or placebo.ResultsEighty-one (31.6%) patients had daytime RLS symptoms. Only the International Restless Legs Syndrome Study Group rating scale total score was significantly associated with the presence of daytime RLS symptoms (p < 0.01) on multiple logistic regression analysis. Daytime RLS symptom onset was at 6 a.m. in 44.4% of patients; symptom duration increased significantly toward nighttime. There was a significant positive association between duration of daytime and nighttime RLS symptoms (p < 0.0001) and a greater statistically significant reduction of daytime RLS symptom duration with rotigotine treatment than with placebo (p = 0.03).ConclusionsDaytime symptoms are frequent in patients with RLS and may be associated with increased severity of the disorder and prolonged nighttime RLS symptoms. Rotigotine could become an important treatment choice for daytime symptoms.