What are the causes of Restless Legs Syndrome (RLS) in order of most likely?

From the Guidelines

Restless Legs Syndrome (RLS) is most commonly caused by iron deficiency, followed by genetic factors, chronic conditions, pregnancy, certain medications, and lifestyle factors, in order of most likely, as supported by the American Academy of Sleep Medicine clinical practice guideline 1. The causes of RLS can be broken down into the following categories:

• Iron deficiency: Iron is essential for dopamine production in the brain, which regulates movement, and its deficiency is a common cause of RLS, as suggested by the use of ferrous sulfate in patients with appropriate iron status 1.
• Genetic factors: While genetic factors are often cited as a common cause of RLS, the provided evidence does not explicitly support this, and iron deficiency is suggested as a more likely cause in the context of treatment 1.
• Chronic conditions: Kidney failure, diabetes, and peripheral neuropathy can damage nerves or affect circulation, leading to RLS, and the use of gabapentin and IV iron sucrose in patients with end-stage renal disease (ESRD) supports this 1.
• Pregnancy: Hormonal changes and potential iron deficiency during pregnancy, particularly in the third trimester, can contribute to RLS, although this is not explicitly stated in the provided evidence.
• Certain medications: Antidepressants, antipsychotics, antihistamines, and some anti-nausea drugs can interfere with dopamine function, leading to RLS, and the suggestion against the use of certain medications such as levodopa, pramipexole, and ropinirole supports this 1.
• Lifestyle factors: Alcohol use, caffeine consumption, and sleep deprivation can exacerbate RLS symptoms, although this is not explicitly stated in the provided evidence. It is essential to note that the provided evidence focuses on the treatment of RLS rather than its causes, and the suggested causes are inferred from the treatment recommendations. Therefore, the order of likelihood may vary depending on the specific context and population.

From the Research

Causes of Restless Legs Syndrome (RLS)

The causes of RLS can be primary (idiopathic) or secondary to various systemic disorders. The most likely causes of RLS, in order, are:

• Genetic predisposition with a family history, as 40% to 60% of RLS patients have a positive family history 2
• Iron deficiency, as brain iron insufficiency is supported by independently replicated cerebrospinal fluid and brain imaging studies for patients without iron deficiency anemia 3
• Central nervous system dopaminergic dysfunction, as RLS symptoms respond dramatically to dopaminergic therapy 4, 5, 2
• Chronic renal insufficiency, as RLS is associated with higher mortality rate in patients on hemodialysis 6
• Pregnancy, as RLS may occur as a secondary condition during pregnancy 4, 6
• Polyneuropathy, as some patients with sensory polyneuropathy may exhibit RLS symptoms 5, 2
• Uremia, as RLS may occur as a secondary condition in patients with uremia 5

Secondary Causes of RLS

Secondary causes of RLS include:

• Systemic disorders such as iron deficiency, chronic renal insufficiency, and polyneuropathy
• Pregnancy
• Certain medications
• Other medical conditions such as diabetes, rheumatoid arthritis, and peripheral neuropathy

Pathophysiology of RLS

The pathophysiology of RLS is not fully understood, but it is thought to involve:

• Central nervous system dopaminergic dysfunction
• Impaired iron homeostasis
• Genetic mechanisms
• Abnormal spinal sensorimotor integration at the spinal cord level
• Abnormal central somatosensory processing 2