What are the causes of restless leg syndrome?

Causes of Restless Leg Syndrome

Brain iron deficiency is the primary underlying cause of restless legs syndrome (RLS), with both primary (genetic) and secondary forms related to various medical conditions including iron deficiency, pregnancy, end-stage renal disease (ESRD), and neurological disorders. 1, 2

Primary (Idiopathic) Causes

• Genetic factors:
  • Strong genetic component with family history present in approximately 42% of primary RLS cases 3
  • Multiple genetic variants identified that increase RLS risk 4, 5
  • Genetic predisposition may affect brain iron metabolism and dopaminergic function 6

Secondary Causes

Iron Deficiency

• Brain iron deficiency is the most well-established pathophysiological mechanism 1, 2
  • Occurs even in patients with normal serum iron studies 1
  • Affects specific brain regions involved in RLS pathophysiology 1
  • May lead to dopaminergic dysfunction 7, 5

Medical Conditions

• End-stage renal disease (ESRD) 1, 7

  • High prevalence of RLS in dialysis patients
  • May be related to uremic toxins and altered iron metabolism

• Pregnancy 3, 5

  • Affects approximately 25% of pregnant women
  • Most severe during third trimester
  • Usually resolves within months after delivery

• Neurological conditions:

  • Peripheral neuropathies 7, 4
  • Parkinson's disease 3, 5
  • Essential tremor 7
  • Certain genetic ataxias 7

• Other associated conditions:

  • Diabetes mellitus (particularly diabetic neuropathy) 3, 5
  • Rheumatological disorders 5
  • Respiratory disorders 5
  • Cardiovascular diseases 5

Medication-Induced RLS

• Serotonergic reuptake inhibitors can worsen RLS symptoms 1
• Other medications that may trigger or exacerbate RLS include:
  • Certain antidepressants
  • Antihistamines
  • Dopamine antagonists (antipsychotics)

Pathophysiological Mechanisms

1. Dopaminergic dysfunction:

   • Central nervous system dopamine dysregulation 6, 7
   • Closely linked to brain iron deficiency 1, 5
   • Explains therapeutic response to dopaminergic agents

2. Altered iron metabolism:

   • Disrupted iron homeostasis in the central nervous system 7
   • Reduced iron stores in specific brain regions 1
   • May occur despite normal peripheral iron levels

3. Other neurotransmitter systems:

   • Altered glutamatergic pathways 5
   • Adenosine pathway dysfunction 5
   • Nociceptive system abnormalities 5

Clinical Implications

• Iron studies (ferritin and transferrin saturation) should be checked in all patients with RLS 2
• Morning testing is recommended, avoiding iron supplements for 24 hours prior 2
• Brain iron deficiency may respond to iron supplementation even with normal serum iron studies 1
• Treatment approach has shifted from dopamine agonists to alpha-2-delta ligands and iron therapy due to risk of augmentation 1, 2

Important Pitfalls to Avoid

• Not checking iron status: Always assess iron parameters in RLS patients, as iron deficiency is a major treatable cause 2
• Overlooking secondary causes: Thoroughly evaluate for underlying conditions that may cause or exacerbate RLS
• Misdiagnosis: Ensure proper diagnosis using the four essential clinical criteria (urge to move legs, worsening at rest, improvement with movement, evening/night exacerbation) 4, 3
• Starting with dopamine agonists: Despite being FDA-approved, these are no longer first-line due to risk of augmentation 1, 2

Understanding the underlying causes of RLS is crucial for proper management, with brain iron deficiency emerging as the central pathophysiological mechanism in both primary and many secondary forms of the condition.