Investigators at Johns Hopkins University, Baltimore, MD, studied glutaminergic activity and arousal in 28 adults with restless legs syndrome (RLS) and 20 matched controls, using proton magnetic resonance spectroscopy. The thalamic glutamate/glutamine/creatine ratio was higher in patients with RLS than controls (p=0.016) and correlated significantly with the wake time during the sleep period (p=0.007) and all other RLS-related polysomnographic sleep variables (p<0.05) except for periodic leg movements during sleep (PLMS/hour). Glutamate metabolism is strongly related to arousal sleep disturbance but not to PLMS motor features of RLS. This finding contrasts with the reverse for dopamine that shows a limited relation to arousal sleep disturbance but strong relation to PLMS. 
COMMENT. An increased glutaminergic activity in RLS demonstrated in this study represents a new RLS abnormality involving thalamocortical activation in a major nondopaminergic neurologic system. The authors (Allen RP, et al) conclude that the combination of glutaminergic (sleep disturbance) and dopaminergic (sensory symptoms, PLMS) abnormalities are involved in the full RLS symptomatology. The elevated glutamate levels are considered a reflection of “hyperarousal” of RLS, which leads to sleep disturbance at night.
In an editorial , Winkelman JW asks the question, is RLS a sleep disorder, a movement disorder, or a chronic pain disorder? He concludes that individual patients should be subtyped into biologically based phenotypes, with or without sleep disturbance, PLMS, or painful RLS. Although the current Hopkins study was confined to older subjects, RLS is also a pediatric problem and is closely associated with brain iron insufficiency and dopaminergic dysfunction. [3, 4]
Oral iron and RLS. Oral iron treatment is initiated for RLS if serum ferritin is below 50 ng/mL. In a study of 22 children referred because of sleep disturbances, median age at onset of RLS symptoms was 7.5 months (range, 0-40 months). In addition to kicking or hitting the legs, the most striking symptoms were awakening after 1-3 hours of sleep followed by screaming and crying. Oral iron supplementation had a positive ferritin-concentration-dependent clinical effect. A relation between high PLMS index and low ferritin levels was demonstrated. An increased awareness of RLS in early childhood is recommended.