From the Guidelines
Restless Leg Syndrome (RLS) is primarily caused by iron deficiency, genetic factors, and dysfunction in the brain's dopamine pathways, which control muscle movements, as suggested by the American Academy of Sleep Medicine in their 2025 clinical practice guideline 1. The most common causes of RLS include:
- Iron deficiency, with ferritin levels below 50 ng/mL often triggering symptoms
- Genetic factors, with about 60% of cases having a family history
- Certain medications, such as antidepressants, antihistamines, and antipsychotics, which can worsen RLS
- Pregnancy, which frequently triggers temporary RLS due to hormonal changes and iron demands, typically resolving after delivery
- Chronic conditions, such as kidney failure, diabetes, and peripheral neuropathy, which are associated with higher RLS rates
- Lifestyle factors, including caffeine, alcohol, and nicotine, which can exacerbate symptoms, as well as sleep deprivation According to the American Academy of Sleep Medicine guideline 1, the use of ferrous sulfate is suggested over no ferrous sulfate in patients with appropriate iron status, highlighting the importance of addressing iron deficiency in the management of RLS. Other potential causes and contributing factors to RLS include:
- Dopamine pathway dysfunction
- Hormonal changes
- Nutritional deficiencies
- Certain medical conditions, such as kidney disease and diabetes It is essential to note that the American Academy of Sleep Medicine guideline 1 provides conditional recommendations for various treatments, including ferrous sulfate, dipyridamole, and opioids, but the primary focus should be on addressing underlying causes, particularly iron deficiency, to improve symptoms and quality of life.
From the Research
Causes of Restless Leg Syndrome
The causes of restless leg syndrome (RLS) can be categorized into primary (idiopathic) and secondary forms.
- Primary RLS is often associated with a family history and genetic predisposition 2, 3, 4.
- Secondary RLS can be caused by various factors, including:
- Iron deficiency: Low iron levels in the brain have been linked to RLS, and iron supplementation may help alleviate symptoms 2, 3, 5, 4, 6.
- Chronic renal insufficiency: Patients with kidney disease are at a higher risk of developing RLS 2, 3, 5.
- Pregnancy: Pregnant women are more likely to experience RLS symptoms 2, 3, 6.
- Neurological diseases: Conditions affecting the central or peripheral nervous system can contribute to RLS 3, 5.
- Other comorbidities: RLS has been linked to various conditions, including cardiovascular diseases, diabetes mellitus, and respiratory disorders 5.
Pathophysiology of RLS
The exact pathophysiology of RLS is still not fully understood, but several mechanisms have been proposed, including:
- Dopaminergic dysfunction: Abnormalities in dopamine metabolism and signaling may contribute to RLS symptoms 2, 3, 5, 4, 6.
- Brain iron deficiency: Low iron levels in the brain may play a role in the development of RLS 2, 3, 5, 4, 6.
- Genetic factors: Genetic variants, such as MEIS1 and BTBD9, have been associated with RLS 4.
- Altered adenosine and glutamatergic pathways: These pathways may also be involved in the pathophysiology of RLS 5.