• Generally most scientists consider restless legs syndrome(RLS) as a central nervous system (CNS)-related disorder, but no specific lesion has been found to be associated with the syndrome.^[1]

• It is thought that RLS is the result of central nervous system anatomic lesions.^[1]
• Findings in imaging of CNS witch suggest the relation between the anatomic lesions in CNS and RLS include:^[1][2][3][4]
  • Presence of morphologic changes in the somatosensory cortex, motor cortex and thalamic gray matter in MRI
  • Abnormal bilateral cerebellar and thalamic activation during the manifestation of sensory symptoms, with additional red nucleus and reticular formation activity during periodic leg movements (PLMS), in functional MRI study
  • Evidences of the role of the limbic and opioid systems in SPECT and PET studies
  • Low brain iron concentrations and dysfunction of iron metabolism and intracellular iron
    • The “iron-dopamine model” explains that iron deficiency in the brain causes an abnormality in the dopaminergic system leading to manifestation of RLS.

• RLS symptoms seem to depend on abnormal spinal sensorimotor integration at the spinal cord level and abnormal central somatosensory processing
• In animal models, studies suggest that the All dopaminergic system and the D3 receptor participates in RLS symptoms

• Genes involved in the pathogenesis of RLS include: RLS 1: 12q and RLS 2: 14q and RLS 3: 9p and RLS 4: 2q and RLS 5: 20p.^[1]
• 40% of cases of RLS are familial and are inherited in an autosomal dominant fashion with variable penetrance.

Conditions which may be associated with RLS include:^[5][6][7]

• Hypertension
• Cardiovascular diseases
• Anxiety
• Depression
• Iron deficiency
• Anemia
• Kidney diseases
• Stroke
• Parkinson disease
• Polyneuropathy
• Multiple sclerosis

• The exact neuroanatomical substrate imbalance which causes restless legs syndrome (RLS) is unknown.^[8]
• Chronic ischemic changes were found in some brain tissue samples of patients whit RLS.^[8]