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
). To our knowledge, however, this is the first double-blind trial of a dopaminergic agent for RLS/PLMS in children.
A second major finding of this study is that, as opposed to previous studies, ADHD was worse in children without RLS/PLMS than in children with RLS/PLMS (3
). One hypothesis to explain this result is that RLS/PLMS produces secondary ADHD symptoms that are milder in nature and degree than primary ADHD symptoms. This is comparable to the results in one study of ADHD where overnight polysomnography indicated that obstructive sleep apnea was present in 5% of those with significant ADHD symptoms, 26% of those with mild ADHD symptoms, and 5% of those with no ADHD symptoms. A similar explanation was put forth by the authors suggesting that sleep apnea leads to milder ADHD symptoms that mimic primary ADHD (46
). But if mild ADHD symptoms in RLS/PLMS are truly secondary to the symptomatology of RLS/PLMS, improvement in ADHD would have been expected to occur in parallel with the improvement in RLS/PLMS and this was not the case in our study.
It is also possible that more severe pure ADHD cases and more mild RLS/PLMS associated ADHD cases were recruited for the study because of referral bias. We do not believe that this is the case but cannot exclude this possibility. It should be noted, in any case, that baseline differences in ADHD severity were corrected by ANCOVA as part of the process of analyzing therapeutic response.
In this study, we did not find any significant improvement of ADHD symptoms, sleep parameters, or neuropsychometric measures in ADHD patients treated with L-DOPA as compared to those given placebo. We were also unable to show a greater improvement in those parameters in those patients with ADHD and RLS/PLMS compared to those with ADHD only as we originally hypothesized. These negative results may be attributable to small sample size. But given that there were no discernible trends for the Conners' rating scales, a larger sample size may not have yielded significant results. It also is possible that a longer follow-up period might have been necessary to identify a decrease in ADHD symptoms. Another possibility is that given the relatively low severity of ADHD symptoms in the RLS/PLMS group at baseline, large changes in T scores may not have occurred, limiting our ability to detect statistically significant differences.
Yet another possibility is that bona fide idiopathic ADHD and bona fide RLS occur together because of a non-dopaminergic genetic link. RLS and ADHD, for example, both show abnormalities in the PTPRD and NOS1 genes (18
). In this case improvement in RLS symptoms would not necessarily lead to improvement in ADHD symptoms.
L-DOPA was chosen over one of the dopamine agonists for this study because of our pilot data showing benefit in an open-label study (27
), greater experience with L-DOPA in children for other disorders (47
), and limited data at the time of study proposal for dopamine agonists in RLS. In addition, L-DOPA is the prototypical dopaminergic agent with impact on all dopamine receptor subtypes, and we therefore considered it the ideal agent to probe the putative ADHD-RLS-dopaminergic link. Whether a dopamine agonist with longer half-life might produce better results for pediatric RLS and ADHD is a currently unresolved issue.
One weakness of the current study was that we did not directly test the impact of improvement of RLS symptoms on quality of life. Such improvements would be likely, however, based upon the close link between RLS severity and quality of life and the close link between improvement in RLS severity and quality of life with treatment (48
). In addition, the RLS severity scale used in the current study did show improvement. In this scale 4 out of the 10 items directly probe quality of life issues including sleep, mood and ability to carry on a satisfactory school and family life. The small sample size, however, precluded any meaningful analysis of these items. This factor should be included in future studies.
In summary, further research is warranted to elucidate the relationship between dopamine, RLS/PLMS and ADHD. In the meantime, we suggest that patients with ADHD should be evaluated for RLS/PLMS as they may benefit from dopaminergic, iron, or nonpharmacologic therapies on an individual basis. In addition, children with RLS should be evaluated for symptoms of ADHD which may require stimulant or behavioral therapies.