What causes restless leg syndrome?

Causes of Restless Leg Syndrome (RLS)

Restless Leg Syndrome is primarily caused by brain iron deficiency and dopaminergic dysfunction, with genetic factors playing a significant role in primary RLS, while secondary RLS is commonly associated with conditions like iron deficiency anemia, pregnancy, and renal failure. 1, 2

Primary (Idiopathic) RLS

Primary RLS has several key contributing factors:

• Genetic predisposition:

  • Strong familial component with genetic linkages identified 1
  • Significant association with a common variant on chromosome 6p21.2 1
  • First-degree relatives of patients with idiopathic RLS have significantly increased risk compared to controls 1

• Dopaminergic dysfunction:

  • Central dopamine transport impairment in the substantia nigra 1, 2
  • Diurnal variations in dopamine activity explain why symptoms worsen in the evening and at night 2

Secondary RLS

Secondary RLS develops due to underlying medical conditions:

• Iron deficiency:

  • Reduced iron stores in the CNS is a critical pathophysiological factor 1, 2
  • Ferritin levels below 50 ng/mL are consistent with RLS diagnosis 1
  • The homeostatic control of iron appears altered in the brain 3

• Medical conditions associated with RLS:

  • End-stage renal disease/uremia 1
  • Pregnancy 1
  • Peripheral neuropathies 1
  • Venous stasis 1

Contributing Factors and Exacerbating Conditions

Several factors can contribute to or worsen RLS symptoms:

• Medications:

  • Tricyclic antidepressants
  • Selective serotonin reuptake inhibitors (SSRIs)
  • Lithium
  • Dopamine antagonists (antipsychotics) 1

• Lifestyle factors:

  • Increased body mass index (BMI)
  • Caffeine intake
  • Sedentary lifestyle
  • Tobacco use
  • Lower income 1

Pathophysiological Mechanisms

The exact pathophysiology remains incompletely understood but involves:

• Iron metabolism abnormalities:

  • Brain iron deficiency is a major contributing factor 2
  • Altered homeostatic control of iron rather than simply insufficient iron entering the brain 3

• Neurological involvement:

  • Spinal cord pathways
  • Peripheral nerves
  • Central dopamine and narcotic receptors 1
  • Calcium channel dysfunction (suggested by response to alpha2-delta calcium channel ligands) 2

Common Mimics and Differential Diagnosis

Several conditions can mimic RLS and must be excluded for proper diagnosis:

• Leg cramps
• Leg edema
• Venous stasis
• Positional discomfort
• Muscle aches
• Habitual foot tapping
• Arthritis
• Peripheral neuropathies
• Vascular disease (intermittent claudication)
• Neuroleptic-induced akathisia 1

Clinical Caveat

When evaluating patients with suspected RLS, it's essential to perform a thorough differential diagnosis, as approximately 16% of subjects who do not have RLS may be misclassified if only the four main diagnostic criteria are applied without proper exclusion of mimics 1.