Restless Leg Syndrome/Willis-Ekbom Disease Pathophysiology

Abstract

Restless leg syndrome/Willis-Ekbom disease has brain iron deficiency that produces excessive dopamine and known genetic risks, some of which contribute to the brain iron deficiency. Dopamine treatments work temporarily but may eventually produce further postsynaptic down-regulation and worse restless leg syndrome. This article includes sections focused on pathophysiologic findings from each of these areas: genetics, cortical-spinal excitability, and iron and dopamine.

Keywords: Dopamine; Iron; PLMS; RLS augmentation; RLS/WED.

Fig. 1

R2* images in a 70-year-old RLS patient and a 71-year-old control subject. Much lower R2* relaxation rates are apparent in the RLS case in both red nucleus and substantia nigra. (Adapted from Allen RP, Barker PB, Wehrl F, et al. MRI measurement of brain iron in patients with restless legs syndrome. Neurology 2001;56(2):263–5; with permission.)

Fig. 2

RLS CSF samples show 3-OMD is increased and correlated with increased HVA. Top right panel shows increase in 2 separate sets of RLS patients for samples from evening and morning. Left panel shows metabolic pathways for levodopa to 3-OMD and HVA. Bottom right panel shows correlation of these 2 metabolites of levodopa from different metabolic pathways. The values correlate for both metabolites indicating likely increased levodopa rather than abnormalities in the 2 different metabolic pathways. These data are compatible with the autopsy data showing increased tyrosine hydroxylase in the substantia nigra. (Adapted from Allen RP, Connor JR, Hyland K, et al. Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis. Sleep Med 2009;10(1):124, 127; with permission.)

Fig. 3

Conceptualized basis for RLS augmentation. The dotted line indicates the critical postsynaptic dopamine signal level, decreasing below this produces RLS symptoms. The light white line is the RLS before treatment with symptoms at night. The dark white line represents initial treatment success with no symptoms. The red line represents the adjustment to the increased evening dopamine producing earlier and more intense RLS symptoms lasting longer during the night. Note that the morning and day stay protected from RLS symptoms. (Adapted from Earley CJ, Allen RP, Connor JR, et al. The dopaminergic neurons of the A11 system in RLS/WED autopsy brains appear normal. Sleep Med 2009;10:1155–7; with permission.)