User:Doc James/RLS

Mechanism
Although it is only partly understood, most researches on the pathophysiology of restless legs syndrome pointed at possible dopamine dysfunctions, iron system anomaly. There is also a commonly acknowledged circadian rhythm explanatory mechanism associated with it, clinically shown simply by markers of circadian rhythm like body temperature

These might be areas of particular interest since it is suggested that under normal circumstances, the brain does not respond to peripheral variations in iron concentrations.

Biochemical studies on the effect of brain iron levels suggested that several iron-containing proteins were implicated in oxidative phosphorylation, oxygen transportation, myelin production and the synthesis and metabolism of neurotransmitters. As such, iron deficiency can lead to cellular damage by oxidation and modification of cellular compounds. The interactions between impaired neuronal iron uptake and the functions of the neuromelanin-containing and dopamine-producing cells plays important roles in RLS development, indicating that iron deficiency might affect the brain dopaminergic transmissions in different ways.

Medial thalamic nuclei also seem to play an important role in RLS. They are part as the limbic system and as such modulated by dopaminergic afferent. A study found thalamic activity changes in the thalamocortical circuit. From this, it was suggested that the uncomfortable symptoms of RLS could be caused by a dopamine dysfunction resulting in impairment of the medial pain system.

Dopaminergic system dysfunctions have mainly been pointed out by substantial improvement of RLS symptoms in patients receiving low-dose dopamine agonists. As mentioned before, the absence of response from the brain to external changes of iron levels suggest that there is a need for the dopamine agonists to cross the blood-brain barrier in order to be effective. Tyrosine hydroxylase being a rate-limiting step enzyme with iron as a cofactor for the conversion of levodopa to dopamine, iron deficiency may once again alter the dopaminergic pathways in the brain.

However, it is also broadly understood that linked to iron deficiency is a decrease in dopamine functions which in turn mediates spinal hyperexcitability leading to the spontaneous sensory and motor movements of RLS. Inversely, it might also result from the decreasing supraspinal inhibition to the spinal cord. Periodic limb movements is common in people with spinal injuries indicating the importance of spinal projections in RLS pathophysiology and the excitatory/inhibitory role of dopamine in motor, sensory and autonomic regulations.