Causes of Restless Legs Syndrome
Restless Legs Syndrome has both primary (genetic/idiopathic) and secondary causes, with brain iron deficiency and dopamine dysfunction being the central pathophysiological mechanisms regardless of etiology. 1
Primary/Idiopathic Causes
Genetic Factors
- Strong genetic component exists with several identified gene loci on chromosomes 12,14, and 9, accounting for many cases of primary RLS 2
- Genetic variants in four chromosomal regions have been identified that increase RLS risk 3
- Family history is common, with hereditary forms representing a substantial proportion of cases 2
Dopamine Dysfunction
- The hypothalamic A11 dopaminergic circuit dysfunction is central to RLS pathophysiology, with brain iron deficiency disrupting dopamine neurotransmission and producing sensorimotor symptoms 1
- Impaired dopamine transport in the substantia nigra due to reduced intracellular iron plays a critical role in most RLS patients 1
- This dopamine-iron interaction occurs even when serum iron studies appear normal, as the deficiency is localized to specific brain regions 1
Brain Iron Deficiency
- Altered homeostatic control of brain iron is present in all RLS cases studied to date, not simply insufficient iron entering the brain 4
- Brain iron deficiency interacts with dopamine systems to produce RLS symptoms, affecting specific brain regions independently of peripheral iron markers 1
Secondary Causes
Metabolic and Systemic Conditions
- End-stage renal disease/uremia is strongly associated with high rates of RLS 4, 2
- Systemic iron deficiency (ferritin ≤75 ng/mL or transferrin saturation <20%) is a major reversible cause 5
- Pregnancy is associated with increased RLS prevalence, with pregnancy-specific mechanisms 5, 2
Neurological Conditions
- Peripheral neuropathy is associated with RLS, though the exact relationship remains under investigation 4, 2
- Spinal cord lesions ranging from various etiologies can trigger RLS symptoms 3
- Essential tremor and some genetic ataxias show associations with higher RLS rates 4
- Rheumatoid arthritis has been linked to symptomatic RLS 2
Medication-Induced Causes
- Dopamine antagonists (antipsychotics like lurasidone) can trigger or worsen RLS through dopamine receptor blockade 5, 1
- Serotonergic medications (SSRIs, tricyclic antidepressants) are well-documented RLS exacerbators 5, 1
- Antihistaminergic medications can worsen symptoms 5
- Lithium has been reported to exacerbate RLS 1
- Antidopaminergic medications of any class should be avoided 5
Lifestyle and Environmental Factors
- Alcohol consumption can exacerbate RLS symptoms 5
- Caffeine intake is a known trigger for symptom worsening 5
- Untreated obstructive sleep apnea can worsen RLS and must be addressed 5
Critical Diagnostic Pitfalls
- 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 markers 1
- Screen all RLS patients for medications that antagonize dopamine or otherwise worsen symptoms, as these can completely undermine treatment efficacy 1
- Remember that RLS prevalence is approximately 10% in Caucasian populations, with women outnumbering men 2:1, and severity typically worsening through the first seven to eight decades of life 4