Circadian changes in CSF dopaminergic measures in restless legs syndrome

Johns Hopkins University, Baltimore, Maryland, United States
Sleep Medicine (Impact Factor: 3.15). 05/2006; 7(3):263-8. DOI: 10.1016/j.sleep.2005.09.006
Source: PubMed


Restless legs syndrome (RLS) has a circadian component with symptoms being prominent at night. The dopaminergic (DAergic) system, which plays a role in RLS, entails circadian changes that parallel RLS symptom changes. The aim of this study was to look for relative and diurnal differences in DAergic activity.
All RLS subjects were treated prior to their enrollment in the study but were all drug-free for at least 2 weeks prior to evaluation. Cerebrospinal fluid (CSF) collected at 10 p.m. was used to determine DA-related co-factors and metabolites. These were compared to CSF values collected in a previous study at 10 a.m.
The only significant finding from the 10 p.m. samples (30 RLS; 22 control) was increased 3-ortho-methyldopa (3OMD) for RLS compared to controls. A comparison of the 10 p.m. to 10 a.m. values (16 RLS; 9 controls) showed small, non-significant diurnal changes for controls but large diurnal changes in tetrahydrobiopterin (BH4), HVA:5HIAA ratio and 3OMD for RLS, with the 10 a.m. sample showing increases in all three CSF factors compared to the 10 p.m. sample.
The greater diurnal changes in RLS suggest greater fluctuations than normal in DAergic circadian dynamics. The increased 3OMD concentration in the absence of concurrent exogenous levodopa (l-dopa) suggests changes in synthesis or metabolism of l-dopa in RLS.

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    • "The involvement of the dopaminergic system in RLS is supported by numerous lines of evidence, including lower concentrations of dopamine metabolites and homovanillic acid levels in nocturnal urinary excretion from subjects with PLMS,82 significant differences in CSF dopamine metabolite concentrations between morning and evening from RLS patients compared with healthy controls,83 and the dramatic improvement of RLS symptoms with dopaminergic agents. "
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    ABSTRACT: Restless legs syndrome (RLS) is a sensorimotor disorder, characterized by a circadian variation of symptoms involving an urge to move the limbs (usually the legs) as well as paresthesias. There is a primary (familial) and a secondary (acquired) form, which affects a wide variety of individuals, such as pregnant women, patients with end-stage renal disease, iron deficiency, rheumatic disease, and persons taking medications. The symptoms reflect a circadian fluctuation of dopamine in the substantia nigra. RLS patients have lower dopamine and iron levels in the substantia nigra and respond to both dopaminergic therapy and iron administration. Iron, as a cofactor of dopamine production and a regulator of the expression of dopamine type 2-receptor, has an important role in the RLS etiology. In the management of the disease, the first step is to investigate possible secondary causes and their treatment. Dopaminergic agents are considered as the first-line therapy for moderate to severe RLS. If dopaminergic drugs are contraindicated or not efficacious, or if symptoms are resistant and unremitting, gabapentin or other antiepileptic agents, benzodiazepines, or opioids can be used for RLS therapy. Undiagnosed, wrongly diagnosed, and untreated RLS is associated with a significant impairment of the quality of life.
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