What causes restless legs syndrome?

What Causes Restless Legs Syndrome

Restless legs syndrome is classified as either primary (idiopathic) with a genetic basis, or secondary to conditions that share iron deficiency as a common pathway, including iron-deficiency anemia, end-stage renal disease, and pregnancy. 1

Primary (Idiopathic) RLS

Primary RLS likely has a genetic basis and develops at an earlier age with no identifiable associated conditions. 1

• First and second-degree relatives of patients with idiopathic RLS have a significantly increased risk of developing RLS compared with relatives of matched controls 1
• Genetic variants on chromosome 6p21.2 have been identified as risk factors 1
• This form has no known predisposing factors and represents the intrinsic neurological disorder 1

Secondary RLS

Secondary RLS results from medical conditions that have iron deficiency as a common underlying mechanism. 1

The key secondary causes include:

• Iron-deficiency anemia 1
• End-stage renal disease 1
• Pregnancy 1
• Renal failure (increasing prevalence with age) 1

Core Pathophysiology

The impairment of dopamine transport in the substantia nigra due to reduced intracellular iron appears to play a critical role in most patients with RLS. 1

The pathophysiology involves:

• Central dopaminergic dysfunction related to brain iron deficiency 2, 3
• Involvement of the spinal cord, peripheral nerves, and central dopamine and narcotic receptors 1
• Altered homeostatic control of iron in the CNS, not simply insufficient iron entering the brain 4
• Dysfunction in nociceptive systems and altered adenosine and glutamatergic pathways 3

Exacerbating Factors and Risk Contributors

Several medications can worsen or trigger RLS symptoms, including tricyclic antidepressants, SSRIs, lithium, and dopamine antagonists (antipsychotics). 1

Lifestyle and social factors that contribute to RLS symptoms include:

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

Clinical Pitfall: Iron Assessment

Because iron deficiency states are often associated with secondary RLS, obtaining a serum ferritin is recommended, with values less than 50 ng/mL consistent with RLS diagnosis and suggesting need for iron supplementation. 1, 5

This is critical because:

• Iron measures should be checked at presentation and with worsened symptoms 2
• CNS iron deficiency occurs even when systemic iron stores appear adequate 4
• Treating iron deficiency may improve symptoms and potentially lower the risk of augmentation with dopaminergic therapy 6