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Iron management is impaired in restless leg syndrome/Willis-Ekbom disease, leading to brain iron deficiency.
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Brain iron deficiency acting partly through hypoxic pathway activation produces increased presynaptic and synaptic dopamine. This produces postsynaptic down-regulation that overcorrects for the normal evening and nocturnal decrease in dopamine-producing restless leg syndrome/Willis-Ekbom disease symptoms. Increasing dopamine activation in the evening and night corrects this problem
Restless Leg Syndrome/Willis-Ekbom Disease Pathophysiology
Section snippets
Key points
Genetics and restless leg syndrome/Willis-Ekbom disease pathophysiology
The well-defined RLS/WED phenotype enabled successful genomewide association studies (GWAS) that have now identified RLS/WED risk alleles on 5 specific genomic regions for MEIS1, BTBD9, PTPRD, MAP2k/SKOR1, and TOX3/BC034767 and on an intergenic region on chromosome 2 (rs6747972).1, 2, 3 Most of these variants also seem to have some relation to the periodic leg movements (PLMS) motor sign of RLS/WED.4 An RLS/WED risk allele on BTBD9 is also strongly associated with both increased PLMS
Iron pathophysiology
RLS/WED has one major, well-defined primary environmental factor of iron deficiency. This deficiency was noted in the seminal RLS/WED studies of Ekbom10 and Nordlander.11 RLS/WED severity increases with decreased peripheral iron,12 and its prevalence is about 9 times greater in iron-deficient anemia than general populations.13 All conditions that compromise iron status have been associated with increased risk of RLS/WED (eg, pregnancy and end-stage renal disease). Moreover, in these cases,
Consequences of iron deficiency: hypoxic pathway activation and myelin loss
The 2 major expected pathophysiologic consequences of brain iron deficiency have been documented: hypoxia and myelin loss. Oxygen transport depends on iron, and decreased iron should signal potential hypoxia. The hypoxic inducible factor 1-alpha has been found increased in the RLS/WED substantia nigra. The hypoxic inducible factor 2-alpha and the vascular endothelial growth factor were increased in the microvessels.25 These differences occurred despite the lack of any significant indication of
Dopamine pathophysiology
The dramatic and immediate treatment benefits from levodopa led to a general view that RLS/WED has a significant brain dopamine deficiency. The search to document the dopamine abnormalities in RLS/WED turned out to be much more difficult than expected and produced surprising results. The initial CSF analyses showed no differences between RLS/WED and controls for the major proteins related to dopamine.36, 37 A repeat analysis of 3-orthymethyl dopamine (3-OMD) found significant increases in the
Dopamine pathophysiology: basis for restless leg syndrome/Willis-Ekbom disease treatment augmentation
The obvious problem arises: if in the RLS/WED brain dopamine is already abnormally increased, how does increasing this further by levodopa reduce the symptoms? Resolving this apparent contradiction requires appreciating the strong circadian aspect of both dopaminergic activity and RLS/WED symptoms. Increased dopaminergic stimulation will produce a postsynaptic down-regulation likely at both receptor and internal cellular function. The general pattern of decreased D2 receptors, especially for
Other pathophysiologic findings in restless leg syndrome
Studies have found a range of other possible biological abnormalities in RLS/WED that have somewhat limited scientific support. Cortical excitability is one major exception. Transcranial magnetic stimulation (TMS) of the motor cortex for control of hand muscles has consistently shown decreased thresholds for response and reduced paired-pulse inhibition.48, 49, 50, 51 The increased cortical excitability is partially reduced by dopamine treatment.52, 53, 54 The significance of these findings
Summary
RLS/WED pathophysiology occurs in a wide range of locations and systems. It seems to have largely metabolic abnormalities mostly involving iron and the consequences of iron deficiency including increased dopamine. The iron-related abnormalities have even been found in the lymphocytes.64 But iron is probably not the whole picture. RLS/WED like other common diseases may have multiple pathways to disease, some less common than others (eg, hypoxia without iron deficiency producing tyrosine
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Disclosures: Dr R.P. Allen in the last 2 years has served as a consultant for UCB pharma, Xenoport. Luipold pharmceuticals and has had research support from NIH (NINDS R01 NS075184, NIA PO1-AG21190), Pharmacosmos and UCB Pharma.