Original Articlel-Dopa improves Restless Legs Syndrome and periodic limb movements in sleep but not Attention-Deficit-Hyperactivity Disorder in a double-blind trial in children
Introduction
Recent literature has shown a higher prevalence of Restless Legs Syndrome (RLS) and Periodic Limb Movements in Sleep (PLMS) in both children and adults with Attention-Deficit-Hyperactivity Disorder (ADHD) [1], [2], [3], [4], [5], [6]. Although the relationship of PLMS to ADHD has been less consistently reported than that of RLS to ADHD [7], [8], a recent meta-analysis of polysomnographic studies verified that PLMS occur more commonly in children with ADHD than normal controls [9]. The reverse relationship is also true, i.e., there is a higher prevalence of ADHD in children and adults with RLS/PLMS [4], [5], [6], [10], [11], [12], [13], [14].
Links between ADHD and RLS/PLMS have been described elsewhere [4], [6]. There are reports [4], [6] that children diagnosed with RLS appear hyperactive because they cannot sit at their school desks as a result of leg discomfort and this leads directly to inattention. In addition, the sleep disruption from RLS/PLMS may lead to symptoms consistent with ADHD. Yet another possibility is that ADHD and RLS/PLMS share a dopaminergic deficit. There are abnormalities in the brain dopaminergic system in both disorders as determined by Positron Emission Tomography (PET), although the distribution is somewhat different [15], [16]. In addition, genetic studies have shown alterations in dopamine transporters and receptors in ADHD patients in comparison with normal controls [17]. An alternative possibility is that RLS/PLMS and ADHD may share a genetic link that is independent of dopaminergic function. Indeed this seems to be the case as the Protein Tyrosine Phosphatase Receptor type Delta (PTPRD) gene and the Nitric Oxide Synthase (NOS1) seem to be related to either condition [18], [19], [20]. Lastly, both RLS/PLMS and ADHD have been independently shown to be characterized by iron deficiency [21], [22], [23] and an interaction of symptomotology of both disorders has been postulated with iron deficiency as intermediary [24], [25].
Because of these observations and the effectiveness of dopaminergic therapy in adults with RLS/PLMS [26], we conducted an open-label study of l-DOPA in RLS children with ADHD [27]. The results indicated not only improvement in RLS/PLMS symptoms, but improvement in ADHD symptoms as well. Based upon the open-label study, we conducted the current double-blind placebo-controlled study of l-DOPA to determine if ADHD symptoms improve differentially in children with and without RLS/PLMS. Our primary hypothesis was that ADHD would improve more in children with RLS/PLMS because of allied improvement in sleep disruption. A secondary hypothesis was that l-DOPA would improve symptoms of RLS/PLMS in children under double-blind conditions. To our knowledge, this is the first double-blind placebo controlled study of a dopaminergic agent for the treatment of RLS/PLMS in children.
Section snippets
General study design, subject recruitment, and initial screening
In this double-blind study, children with ADHD who were on no ADHD medications were divided into two groups: ADHD only or ADHD with comorbid RLS/PLMS. After baseline measurements, they were randomized to receive either Carbidopa/l-DOPA or placebo for 8–13 weeks. Polysomnography, Conners’ rating scales and neuropsychometric testing were performed at baseline and endpoint. For most children with RLS, rating of severity of symptoms was also performed at baseline and endpoint.
This study was carried
Results
The demographic data of the analyzed patient groups are presented in Table 1. There were no significant age differences between groups as assessed by ANOVA (p = 0.15). As predicted based on the incidence of ADHD in children, a larger number of males were enrolled in the study. No patients experienced severe adverse side effects from the drug therapy and only one patient dropped out of the study due to side effects (drowsiness). The only other side effects reported were headache and nausea.
Discussion
The major finding of this double blind, placebo controlled trial is that l-DOPA improves RLS/PLMS in children under blinded conditions. This is consistent with the well-established response to dopaminergic therapy in adults with RLS/PLMS [26]. There have been several previous small open-label studies of l-DOPA in ADHD that showed only a modest benefit [41], [42], [43], [44], [45]. To our knowledge, however, this is the first double-blind trial of a dopaminergic agent for RLS/PLMS in children.
A
Conflicts of Interest
The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: doi:10.1016/j.sleep.2011.01.008.
Acknowledgments
Support was provided by funding from NIH R01 NS4 0829 and by a supplemental grant from Glaxo Smith Kline. Data analysis and writing of this article were done solely by the authors. Editorial comments were provided by Glaxo Smith Kline. We dedicate this paper to our dear, departed friend, colleague and co-author, Wayne Hening, M.D., Ph.D. His companionship and brilliant insights are sorely missed. We also want to acknowledge the assistance of Donna Underwood, Ph.D., Anny Wu, Katie Kumar, and
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