Restless Legs Syndrome: A Disorder of Dopamine Neurotransmission

Abstract & Commentary

By Melissa Nirenberg, MD, Assistant Professor of Neurology, Weill Cornell College of Medicine; Associate Director, Weill Cornell Parkinson's, Disease & Movement Disorders Institute. Dr. Nirenberg reports no financial relationship relevant to this field of study.

Synopsis: PET scans using 2 different dopamine receptor ligands demonstrate abnormalities in dopaminergic transmission in subjects with restless legs syndrome, in the striatum and in extra-striatal regions including thalamus and anterior cingulate cortex.

Source: Cervenka S, et al. Support for Dopaminergic Hypoactivity in Restless Legs Syndrome: A PET Study on D2-Receptor Binding. Brain. 2006;129:2017-2028.

This case-control study examined 16 subjects with restless legs syndrome (RLS) and 16 age-matched control subjects. RLS subjects' mean age was 55 ± 7 years, and none had taken mediations for RLS. One had occasionally taken zolpidem for insomnia. Symptom duration was 27 ± 12 years, and 9/16 had a family history of RLS. Positron emission tomography (PET) data were obtained using the dopamine receptor ligands [11C] raclopride, in addition to [11C] FLB 457, which has sufficiently high dopamine D2 receptor affinity to allow analysis of regions outside the striatum, ie, where receptor density is low. Data obtained during evening hours revealed higher [11C] raclopride striatal binding potential (BP) in RLS subjects compared with controls (2.79 ± 0.22 vs 2.61 ± 0.17, P = 0.029). [11C] FLB 457 BP was higher in RLS subjects compared with controls in the thalamus (right medial and left posterior sub-regions), left insula, and rostral anterior cingulate cortex. A subgroup of 8 subjects and 8 matched controls were also examined in the morning. As in the evening, [11C] raclopride BP was higher in cases than controls, but neither regional nor sub-regional analysis of [11C] FLB 457 demonstrated statistically significant extra-striatal differences. There was no significant difference in PET data obtained in the morning compared with evening, despite documented differences in subjects' symptoms as expected from diurnal changes in RLS.

Commentary

RLS is a common neurological disorder affecting up to 10% of the population. It responds to treatment with dopaminergic agents, but the reasons for such a response, and its precise anatomic substrates, remain unclear. The present study re-investigates the controversial question of whether there exist dopamine neurotransmission abnormalities in RLS and, in contrast to previous investigations, finds increased striatal dopamine receptor BP. Prior studies have been conflicting, with reduced striatal dopamine receptor ligand binding in 2 studies, and normal BP in 2 studies. However, previous findings have been criticized due to timing of scans (RLS symptoms peak at night, and scans are routinely performed earlier in the day), and for lack of adequate controls for medication use and other variables. Cervenka and colleagues have directly addressed these concerns, and although a full explanation for differences in published results remains unclear, the present study has a number of advantages in its methodology that make its results compelling.

A further advantage of the present study is that it is the first use of [11C] FLB 457 in RLS, which allows measurements of dopamine binding outside of the striatum. In identifying involvement of sub-regions of the thalamus and anterior cingulate cortex, Cervenka et al suggest an explanation for the effect of dopaminergic agents upon the sensory symptoms and urge to move that are so disturbing to RLS patients. Finally, what do BP differences detected in RLS mean? As Cervenka et al point out, altered BP may result from a change in available receptor density or, less likely, a change in ligand binding affinity. Increased [11C] raclopride or [11C] FLB 457 BP, therefore, may reflect: 1) decreased intrasynaptic dopamine, or 2) increased dopamine receptor number, which could possibly be due to receptor hypostimulation. Intriguingly, receptor number is affected by dopamine agonist or antagonist exposure, as well as by opioid receptor agonists. This study, therefore, supports, although it does not directly demonstrate, dopaminergic hypoactivity in RLS. More importantly, it provides a springboard for further studies aimed at improving, understanding, and treatment of this common and debilitating condition.