Diagnosis

Patients develop an urge to move their legs, often accompanied by or felt to be caused by uncomfortable and unpleasant sensations in the legs

The urge to move and unpleasant sensations begin, or worsen, during periods of rest or inactivity, such as lying down or sitting

These sensations are often relieved by movement, such as walking or stretching, at least as long as the activity continues

These symptoms occur or are worse in the evening or night compared to the day

Etiology

60% of RLS patients report a positive family history for RLS

Genetic association studies have now identified five genes and 10 different risk alleles for RLS

One of the allelic variations associated with increased risk of RLS is also associated with decreased serum ferritin, indicating relative reduction in body iron stores

Theoretically, brain iron deficiency may produce dopaminergic pathology producing RLS symptoms. This iron–DA hypothesis may best explain the pathology of RLS

Initial cerebrospinal fluid (CSF), autopsy, and brain imaging studies showed expected brain iron deficiency particularly affecting the DA-producing cells in the substantia nigra

Animal and cellular iron deficiency studies have suggested that tyrosine hydroxylase activity in the substantia nigra, decreased D2 receptors in the striatum, decreased DAT functioning, and increased extracellular DA, with larger increases in the amplitude of the circadian variation of extracellular DA exist in RLS models

These same findings have largely been replicated in RLS patients, revealing the iron–DA link

Specifically, brain iron deficiency affects dopaminergic function

First, by increasing tyrosine hydroxylase, which then increases extracellular DA

This results in a decrease in DAT (reuptake pumps) on the cell surface (DAT downregulation)

In extreme cases, it also causes a decrease in the number of D2 receptors on neuronal surfaces (receptor downregulation)

In these cases, RLS is a hyperdopaminergic condition with an apparent postsynaptic dopaminergic desensitization that overcompensates during the circadian low point of dopaminergic activity in the evening and night

Counterintuitively, this leads to the RLS symptoms that can be easily corrected by adding D2 receptor agonist medications at night

Essentially, more DA activity is added to overcome the desensitization

This D2 receptor agonist prescription-induced excess activity is very effective at calming RLS symptoms

However, this sometimes leads to RLS augmentation where RLS may actually worsen in a select few patients over longer-term treatment because this creates a further imbalance of greater DA activity in the face of even more downregulation of receptors

RLS may also be related to cortical sensorimotor dysfunction

This would be consistent with the disruptions in the adenosine and dopaminergic systems regulating sensorimotor responses that have been reported for iron deficiencies noted here

RLS often is comorbid with MDD, which is also known to have DLPFC hypoactivity

In this manner, MDD and RLS may share overlapping dysfunctional frontocortical DA neurocircuits