Restless Legs Syndrome
Medicine Central™ is a quick-consult mobile and web resource that includes diagnosis, treatment, medications, and follow-up information on over 700 diseases and disorders, providing fast answers—anytime, anywhere. Explore these free sample topics:
-- The first section of this topic is shown below --
- Sensorimotor disorder consisting of a strong, nearly irresistible urge to move the limbs (1)[A]
- The urge usually affects the legs at least initially but may involve arms or other body parts (2)[C].
- The urge might be accompanied by uncomfortable and unpleasant sensations.
- The symptoms:
- Begin or worsen during rest or inactivity
- Are relieved by movement but recur with inactivity. Relief by movement may not be noticeable but has been previously reported.
- Occur preferentially in the evening/night. Circadian aspect may not be noticeable but must have been previously reported.
- Are not solely accounted for by “mimics” or another medical or behavioral condition
- Mimics include leg cramps, positional discomfort, habitual foot tapping, arthralgias/arthritis, myalgias, leg edema, peripheral neuropathy, radiculopathy; even though some may coexist
- Cause concern, distress, sleep disturbance
- Patient may also report involuntary leg jerks during wake or sleep (1)[A].
- System(s) affected: nervous; musculoskeletal
- Early, <45 years versus late >45 years onset (1)[A]
- Early onset phenotype: 40–92% familial, stable, slow progression of symptoms
- Late onset phenotype: more aggravating factors; rapid progression is common.
- Synonym(s): Willis-Ekbom disease
- 0.8–2.2% annually
- Onset at any age
- Predominant sex: male = female (nulliparous); parous females are twice more affected than males.
- Temperature (cold weather) and other environmental factors may increase incidence or trigger symptoms.
- 4–15% in Caucasian adults, underdiagnosed
- 2–3% are clinically significant.
- 1–3% in children and adolescents
- Increases with age up to 70s
- Lower in non-Caucasians (except Koreans)
Etiology and Pathophysiology
- Brain iron deficiency, impaired into brain iron transport
- Iron deficiency and associated conditions
- CNS dopamine regulation:
- Fast dopamine turnover consistent with increased dopamine production
- Circadian changes in dopamine (increases in the evening)
- Decreased dopamine transporter
- Genetics: heterogeneous
- Susceptibility loci: 2p14, 2q, 6p21.2, 9p, 12q, 14q, 15q23, and 20p
- Genes: MEIS1, MAP2K5/LBXCOR1, BTBD9
- Changes in substantia nigra, striatum, putamen (reduced iron, less myelin, less D2 receptors)
- Sensorimotor pathways abnormalities:
- Bilateral activation of the cerebellum and contralateral activation of the thalamus
- Increased activation of the prefrontal and anterior cingulate cortex
- Decreased gray matter volume which correlates with disease severity and duration
- Cortical excitability: increased thalamic glutamate
- Increased endogenous opioids, possibly
- Triggering and exacerbating factors:
- Prolonged immobility, such hospitalizations
- Most antidepressants (except bupropion)
- Dopamine-blocking antiemetics (e.g., metoclopramide, prochlorperazine)
- Some antiepileptic agents (e.g., phenytoin)
- Phenothiazine antipsychotics (risperidone, clozapine, olanzapine, quetiapine) possible exception: aripiprazole (partial D2 agonist)
- Cognition-enhancing medication: donepezil
- Theophylline and other xanthines
- Antihistamines/over-the-counter (OTC) cold preparations (e.g., pseudoephedrine)
- Adrenergics, stimulants
- Anti-inflammatory medications
- Iron deficiency
- Family history
- Increased with every pregnancy
- Chronic renal failure—11–58% affecting dialysis compliance
- Sleep deprivation, alcohol, caffeine—limited data
Commonly Associated Conditions
- Periodic limb movements during sleep (PLMS), insomnia, sleep walking, delayed sleep phase
- Iron deficiency, renal disease/uremia/dialysis, gastric surgery, IBS, liver disease
- Parkinson disease, multiple sclerosis, peripheral neuropathy, Machado-Joseph disease, migraine
- Anxiety, depression, ADHD
- Cardiovascular disease, including coronary artery disease and stroke
- Venous insufficiency/peripheral vascular disease
- Pulmonary hypertension, lung transplantation, chronic obstructive pulmonary disease (COPD)
- Orthopedic problems, arthritis, fibromyalgia