What are the causes of restless leg syndrome?

Causes of Restless Legs Syndrome

Restless legs syndrome has both primary (idiopathic/genetic) and secondary causes, with iron deficiency and dopaminergic dysfunction being the central pathophysiological mechanisms across all forms. 1

Primary (Idiopathic) RLS

Primary RLS has a strong genetic basis and typically develops at earlier ages without identifiable associated conditions. 1

• First and second-degree relatives of patients with idiopathic RLS have significantly increased risk compared to matched controls, indicating familial clustering 1
• Genetic variants on chromosome 6p21.2 have been identified as specific risk factors 1
• This form generally presents earlier in life and progresses more slowly over decades 2

Secondary RLS Causes

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

Medical Conditions

• Iron-deficiency anemia is a major secondary cause, with serum ferritin <50 ng/mL consistent with RLS diagnosis 2
• End-stage renal disease causes RLS with increasing prevalence with age 1, 3
• Pregnancy is a well-established secondary cause 1, 4
• Peripheral neuropathy may trigger or be associated with RLS 2, 3
• Diabetes mellitus is associated with higher RLS rates 5, 6
• Rheumatologic disorders including rheumatoid arthritis, Sjögren's syndrome, and spondyloarthritis show increased RLS frequency 5

Medication-Induced RLS

Several medication classes can trigger or worsen RLS through dopamine antagonism or other mechanisms. 2

• Dopamine antagonists (antipsychotics) directly worsen RLS by blocking dopamine receptors 2, 1, 3
• Tricyclic antidepressants are reported to exacerbate symptoms 2, 1
• SSRIs can trigger or worsen RLS 2, 1
• Lithium has been associated with symptom exacerbation 2, 1

Core Pathophysiological Mechanisms

The impairment of dopamine transport in the substantia nigra due to reduced intracellular iron plays a critical role in most RLS patients. 2, 1

• Brain iron deficiency disrupts dopamine neurotransmission in the hypothalamic A11 dopaminergic circuit, leading to sensorimotor symptoms 7
• This brain iron deficiency can occur even with normal serum iron studies, affecting specific brain regions 7
• The spinal cord, peripheral nerves, and central dopamine and narcotic receptors are involved in the pathophysiology 2, 1

Lifestyle and Social Risk Factors

Multiple modifiable lifestyle factors contribute to RLS symptom development and severity. 2

• Increased body mass index (BMI) is associated with higher RLS risk 2, 1
• Caffeine intake contributes to symptom severity 2, 1
• Sedentary lifestyle increases RLS likelihood 2, 1
• Tobacco use is a contributing factor 2, 1
• Lower socioeconomic status correlates with increased RLS prevalence 2, 1

Clinical Pitfalls to Avoid

• Do not assume normal serum iron studies exclude iron deficiency in RLS—brain iron deficiency in specific regions drives dopamine dysfunction even with normal peripheral iron markers 7
• Always obtain serum ferritin in RLS evaluation, as values <50 ng/mL warrant iron supplementation regardless of other iron parameters 2
• Screen all RLS patients for medications that antagonize dopamine or otherwise worsen symptoms, as these can undermine treatment efficacy 7
• Perform thorough neurologic examination to identify secondary causes such as peripheral neuropathy or radiculopathy 2