Treatment of childhood-onset restless legs syndrome and periodic limb movement disorder using intravenous iron sucrose.

OBJECTIVE: An alternative treatment approach is needed for children who cannot tolerate oral iron preparations or when there is a need for rapid replenishment of iron stores. We report on the safety, adverse effects, and efficacy of intravenous iron sucrose in a retrospective sample of children with restless legs syndrome (RLS) or periodic limb movement disorder (PLMD). METHODS: Sixteen children with RLS/PLMD who received intravenous iron sucrose at our institution between 2005 and 2011 were identified. The diagnosis of RLS/PLMD was established after formal sleep consultation and nocturnal polysomnography (PSG). Serum ferritin was assayed in all 16 subjects prior to iron sucrose infusion and in 14 subjects after infusion. The medical records were reviewed for treatment-related details. RESULTS: The mean age of subjects was 6.6 years (range, 2-16 y; 5/16 girls). The mean periodic limb movement index (PLMI) was 18.2±12.8. Fifteen of the 16 subjects (93.7%) had systemic or neurologic comorbidities. Fourteen of 16 (87.5%) subjects had received prior oral iron supplementation for sleep-related concerns, with the majority of the subjects either having gastrointestinal (GI) side effects or insufficient benefits. Intravenous iron sucrose therefore was provided to these 16 subjects through our outpatient pediatric infusion therapy center. The average dose of intravenous iron sucrose of 3.6 mg/kg was infused over 2 h. The baseline mean serum ferritin was 16.4±6.6 ng/mL. After infusion with intravenous iron sucrose, the mean serum ferritin rose to 45.7±22.4 ng/mL (n=14; [95% confidence interval, 17.2-41.3]; P<.0001). Parental assessment of response to iron sucrose therapy was conducted on follow-up clinic visits or via telephone calls. There was improved sleep in 62.5% (n=10) of subjects and no improvement in 12.5% (n=2) of subjects. No follow-up information was available for 25% (n=4) of subjects. Minor adverse events occurred in 25% (n=4) of subjects--two subjects experienced difficulty with peripheral intravenous catheter placement, while two had transient GI symptoms, such as anorexia, nausea, and vomiting. None of the subjects had anaphylaxis. CONCLUSIONS: Intravenous iron sucrose appears to be a relatively effective therapy for patients with childhood-onset RLS/PLMD and iron deficiency who do not tolerate or respond to oral iron supplements. Side effects were transient. The most common adverse events were difficulty with intravenous line placement and GI disturbance. There is a need for systematic prospective studies on the safety and efficacy of intravenous iron sucrose in RLS/PLMD in children.

Dopamine transporter shown by SPECT in patients with periodic leg movement after acute physical exercise.

PURPOSE: This study aimed to evaluate dopamine transporter (DAT) density in patients with periodic leg movement (PLM) shown by [(99mt)Tc]TRODAT-1 single-photon emission computed tomography (SPECT) imaging and to determine the influence of acute physical exercise (maximal exercise test [MET]) on DAT densities. METHODS: Sixteen healthy male volunteers between 45 and 65 yr of age were selected to participate in the study. Each subject (eight subjects in the control group and eight subjects in the patients with PLM experimental group) underwent baseline polysomnography (PSG) to evaluate sleep patterns and PLM index values. After obtaining PSG baselines, SPECT baselines were determined using [(99mt)Tc]TRODAT-1, a selective DAT imaging ligand. Subsequently, the volunteers performed the MET in the morning, followed by a SPECT 2 h later and PSG that night to assess the effect of acute physical exercise on DAT and sleep patterns. RESULTS: The baseline SPECT results showed marginally significantly lower DAT densities in the striatal region of the experimental group. After the MET, no significant differences were observed between groups. The results also showed a significant reduction in the PLM index in the experimental group and a significantly increased percentage of stage 1 non-REM sleep in both groups after MET. CONCLUSIONS: Our results show that patients with PLM had a marginally lower DAT density in the left putamen region compared with the control group. Although the effect of acute physical exercise (MET) reduced PLM symptoms, the results suggest that this improvement was not due to DAT availability.

Normal striatal D2 receptor binding in idiopathic restless legs syndrome with periodic leg movements in sleep.

Dopaminergic treatment is very effective in restless legs syndrome (RLS) and periodic leg movements in sleep (PLMS). However, neuroreceptor imaging studies that addressed altered striatal dopaminergic function have given controversial results. In this present study, 14 patients with idiopathic RLS (iRLS) and PLMS with a good response to dopaminergic and non-dopaminergic treatment and ten healthy sex- and age-matched controls were investigated off-medication by using 123I-IBZM and SPECT. RLS symptoms and sleep disturbances were evaluated using three nights of polysomnography, the Pittsburgh Sleep Quality Index, and the International RLS Study Group (IRLSSG) rating scale. The patients presented with sleep disturbances, a high PLMS index (56.2 +/- 33.1 per h), and severe RLS symptoms during SPECT (IRLSSG rating scale 23.1 +/- 8.0), and showed no significant differences in striatal to frontal IBZM binding to D2 receptors compared to controls (ratio striatum/frontal cortex, right side 1.60 +/- 0.10 vs 1.63 +/- 0.08, P = 0.35, NS; left side 1.61 +/- 0.11 vs 1.63 +/- 0.08, P = 0.51, NS). These findings show normal function of striatal D2 receptors in successfully treated patients with iRLS and PLMS. Dopaminergic and non-dopaminergic pretreatment does not appear to change striatal D2 receptor binding as compared to healthy controls. Structures other than striatal D2 receptors are discussed as possible causes of the treatment effects in RLS.

Periodic limb movements in sleep and iron status in children.

STUDY OBJECTIVES: To assess potential relationships between serum iron and ferritin levels and the severity of periodic limb movement in sleep (PLMS) in a pediatric population, and to evaluate the response to supplemental iron therapy. DESIGN: A prospective study of all consecutively diagnosed children with PLMS (periodic limb movement index [periodic limb movements per hour of total sleep time, [PLMI] > 5) who underwent overnight polysomnographic evaluation. In all patients, complete blood count and serum iron and ferritin levels were obtained. Patients with serum ferritin concentrations less than 50 microg/L were prescribed iron sulfate at 3 mg/kg of elemental iron per day for 3 months. At the end of treatment, serum iron and ferritin levels and sleep studies were repeated. SETTING: Comprehensive Sleep Medicine Center, Tulane University Health Sciences Center, and Kosair Children's Hospital Sleep Medicine and Apnea Center. PATIENTS: Twenty boys and 19 girls with PLMS with a mean age of 7.5 +/- 3.1 years. INTERVENTION: Iron therapy. RESULTS: Twenty-eight (71.8%) patients had ferritin levels less than 50 microg/L. There was no significant correlation between serum ferritin concentration and PLMS severity as indicated by the PLMI (r = -0.19). The PLMI in patients with serum ferritin levels less than 50 microg/L (29.9 +/- 15.5 PLM/h) was higher than in patients with serum ferritin levels greater than 50 microg/L (21.9 +/- 11.8 PLM/h); however, the difference did not achieve statistical significance (P = 0.09). In contrast, serum iron was significantly correlated with PLMI (r = -0.43, P < 0.01). Indeed, patients with serum iron concentrations less than 50 microg/dL had a higher PLMI compared to patients with serum iron concentrations greater than 50 microg/dL (42.8 +/- 18.3 PLM/h and 23.1 +/- 10.1 PLM/h, respectively; P = 0.02). Twenty-five out of the 28 PLMS patients with serum ferritin levels less than 50 microg/L received treatment with iron sulfate, and 19 (76%) responded favorably. Among the responders to iron therapy, PLMI decreased from 27.6 +/- 14.9 PLM per hour to 12.6 +/- 5.3 PLM per hour after 3 months of iron supplements (P < 0.001) and coincided with increases in serum ferritin levels (pre: 40.8 +/- 27.4 microg/L vs post: 74.1 +/- 13.0 microg/L; P < 0.001). CONCLUSIONS: In children, the presence of PLMS is frequently associated with low serum iron and a tendency toward low serum ferritin levels. In addition, iron therapy is associated with clinical improvement in most of these patients.

Periodic leg movements in patients with Parkinson's disease are associated with reduced striatal dopamine transporter binding.

We used single photon emission computed tomography (SPECT) to study striatal [(123)I]beta-CIT binding and polysomnography to study periodic leg movements during sleep (PLMS) in eleven patients with idiopathic Parkinson's disease (PD). The reduced striatal [(123)I]beta-CIT binding was significantly correlated with the number of PLMS. We propose that striatal dopaminergic nerve cell loss is involved in the increased number of PLMS in PD patients.

[Pathophysiology of restless-legs syndrome. Review of current research]. / Pathophysiologie des Restless-legs-Syndroms. Aktueller Stand der Forschung.

The primary pathomechanism of restless legs syndrome is unclear. Neurophysiological, pharmacological, and imaging studies have demonstrated a complex interaction between central and peripheral structures. The degree of integration of central and peripheral mechanisms is not known. Altered excitability at a spinal level modulated by supraspinal rhythms of the brainstem possibly plays an important role. There is no anatomical structural lesion and it is more likely that circadian disturbances of dopaminergic and/or opioidergic neurotransmission are involved.

Dopaminergic therapy in children with restless legs/periodic limb movements in sleep and ADHD. Dopaminergic Therapy Study Group.

The long-term effects of monotherapy with levodopa or the dopamine agonist pergolide on the motor/sensory, behavioral, and cognitive variables in seven children with restless legs syndrome/periodic limb movements in sleep (RLS/PLMS) and attention-deficit-hyperactivity disorder (ADHD) were investigated. Five of the seven children had previously been treated with stimulants that had either been determined to be ineffective or to have intolerable side effects. Dopaminergic therapy improved the symptoms of RLS and reduced the number of PLMS per hour of sleep (P = 0.018) and associated arousals (P = 0.042) for the entire group. After treatment, three children no longer met the criteria for ADHD, and three reverted to normal on the Test of Variable Attention. ADHD improved in all seven as measured by the Connors parent rating scale (P<0.04) and the Child Behavior Checklist (P<0.05). A significant improvement also occurred in the visual, but not verbal, memory scores on the Wide Range Assessment of Memory and Learning (P<0.001). Five of seven children continue on dopaminergic therapy 3 years after treatment initiation, with good response. We postulate that the improvement in ADHD may be the result of the amelioration of RLS/PLMS and its associated sleep disturbance. Alternatively, ADHD and RLS/PLMS may share a common dopaminergic deficit.