Restless Legs Syndrome Causes and Pathophysiology

Primary (Idiopathic) RLS

The American Geriatrics Society suggests that 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 for primary RLS 1

The American Geriatrics Society states that secondary RLS results from medical conditions that have iron deficiency as a common underlying mechanism, including iron-deficiency anemia, end-stage renal disease, and pregnancy 1
Renal failure is a secondary cause of RLS, with increasing prevalence with age 2

The American Geriatrics Society indicates that 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
Involvement of the spinal cord, peripheral nerves, and central dopamine and narcotic receptors is part of the pathophysiology of RLS 1

The American Geriatrics Society recommends that several medications can worsen or trigger RLS symptoms, including tricyclic antidepressants, SSRIs, lithium, and dopamine antagonists (antipsychotics) 1
Increased body mass index (BMI), caffeine intake, sedentary lifestyle, tobacco use, and lower income are lifestyle and social factors that contribute to RLS symptoms 1

The American Geriatrics Society suggests that obtaining a serum ferritin is recommended, with values less than 50 ng/mL consistent with RLS diagnosis and suggesting need for iron supplementation 3

Vitamin B12 deficiency causes extensive demyelination in both the central and peripheral nervous systems, with axonal degeneration particularly affecting distal afferent fibers of dorsal root ganglion neurons, producing a range of neuromuscular symptoms including paresthesias, numbness, muscle weakness, abnormal reflexes, and gait disturbances, which overlap substantially with RLS presentations 4, 5

Secondary RLS typically presents later in life, usually in the fifth to seventh decade, without family history, and approximately 80% of patients with only neurological symptoms from B12 deficiency don't present until between ages 50-70 years 6, 7

Neurological symptoms from B12 deficiency can present without hematological abnormalities, with approximately one-third of B12 deficiency cases lacking macrocytic anemia, and severe neurological symptoms often occurring with absent hematological findings, making it unreliable to rely on CBC findings alone to exclude B12 deficiency as a contributor to RLS symptoms 7

The American Geriatrics Society recommends iron supplementation for patients with serum ferritin levels below 50 ng/mL, as reduced intracellular iron in the substantia nigra impairs dopamine transport, with a strength of evidence based on studies from 2009 8
Medications such as dopamine antagonists, SSRIs, tricyclic antidepressants, and lithium can worsen RLS symptoms through dopaminergic blockade, according to the American Geriatrics Society, with a strength of evidence based on studies from 2009 8
Lifestyle factors, including increased caffeine intake, tobacco use, alcohol consumption within 3 hours of bedtime, elevated BMI, and sedentary lifestyle, contribute to symptom severity, as reported by the American Geriatrics Society, with a strength of evidence based on studies from 2009 8

In hospitalized or critically ill patients, hypophosphatemia, hypokalemia, and hypomagnesemia can cause muscle weakness, peripheral neuropathy risk, and neuromuscular dysfunction, according to Clinical Nutrition, with a strength of evidence based on studies from 2019, 2021, and 2021 9, 10, 11
Electrolyte disturbances, including hypophosphatemia, hypokalemia, and hypomagnesemia, occur commonly in patients receiving kidney replacement therapy, with a prevalence of 60-80%, 25%, and 60-65%, respectively, as reported by Clinical Nutrition, with a strength of evidence based on studies from 2021 and 2024 10, 11, 12
Refeeding syndrome, involving severe electrolyte disruptions, can cause muscle weakness and peripheral edema in malnourished patients, according to Clinical Nutrition, with a strength of evidence based on a study from 2017 13

The American Geriatrics Society recommends checking serum ferritin first and supplementing iron if levels are below 50 ng/mL, with a strength of evidence based on studies from 2009 8
A review of all medications for dopamine antagonists, antidepressants, and lithium is necessary, as these can worsen RLS symptoms, according to the American Geriatrics Society, with a strength of evidence based on studies from 2009 8
Electrolytes should be checked in RLS patients with concurrent end-stage renal disease or those receiving dialysis, as well as in malnourished or critically ill patients, according to Clinical Nutrition, with a strength of evidence based on studies from 2019, 2021, and 2024 9, 10, 11, 12, 13