Restless Legs Syndrome: Causes, Symptoms, and Management

Causes and Pathophysiology

RLS results from central dopaminergic dysfunction combined with brain iron deficiency, with genetic predisposition playing a major role in primary cases. 1

Primary (Idiopathic) RLS

Genetic variants in four chromosomal regions increase RLS risk, with family history commonly present 2, 3
Impaired dopamine transport in the substantia nigra due to reduced intracellular iron plays a critical role 1
The spinal cord, peripheral nerves, and central dopamine and narcotic receptors are involved in pathophysiology 1

Secondary RLS Causes

Iron deficiency (ferritin <50 ng/mL) is the most important treatable secondary cause 1
Chronic renal insufficiency and end-stage renal disease 2, 4
Pregnancy 1, 2
Peripheral neuropathy or radiculopathy 1

Exacerbating Medications and Factors

Dopamine antagonists (antipsychotics like lurasidone) directly worsen RLS through dopamine blockade 1, 5
Tricyclic antidepressants, SSRIs, and lithium 1
Antihistaminergic and serotonergic medications 1, 5
Lifestyle factors: increased BMI, caffeine intake, sedentary lifestyle, tobacco use 1
Untreated obstructive sleep apnea 1, 5

Clinical Symptoms and Diagnostic Criteria

RLS is diagnosed clinically using four essential criteria, with symptoms characteristically worsening at night and relieved by movement. 1

Four Essential Diagnostic Criteria

Urge to move the legs accompanied or caused by uncomfortable or unpleasant sensations in the legs 1
Symptoms begin or worsen during rest or inactivity, such as sitting or lying down 1
Symptoms are partially or totally relieved by movement, such as walking or stretching, for at least as long as the activity continues 1
Symptoms worsen or only occur in the evening or night 1

Associated Features

Sleep disorders with frequent sleep fragmentation 3
Periodic limb movements during sleep (PLMS) 1, 3
Insomnia is present in roughly 90% of patients and represents the primary morbidity 5
Physical examination is usually unremarkable in primary RLS 1

Assessment in Cognitively Impaired Patients

Signs of leg discomfort: rubbing or kneading the legs, groaning while holding lower extremities 1
Excessive motor activity: pacing, fidgeting, repetitive kicking, tossing and turning in bed, cycling movements 1
These signs must be exclusively present or worse during inactivity and diminished with activity 1
Symptoms occur only in evening/night or are worse at those times 1

Management Algorithm

Step 1: Initial Assessment and Iron Status

Check morning fasting serum ferritin and transferrin saturation in all patients before starting any medication, avoiding iron-containing supplements for 24 hours prior. 1, 5, 6

Iron supplementation is indicated if ferritin ≤75 ng/mL or transferrin saturation <20% (different thresholds than general population) 1, 5, 6
In children, supplement if ferritin <50 ng/mL 1, 5
Thorough neurologic exam to identify secondary causes like peripheral neuropathy 1

Step 2: Address Exacerbating Factors

Eliminate or reduce caffeine and alcohol, discontinue antihistaminergic and serotonergic medications, and screen for untreated obstructive sleep apnea. 1, 5, 6

Avoid caffeine, alcohol, and nicotine too close to bedtime 5
Avoid heavy meals or drinking within 3 hours of bedtime 5
Implement moderate exercise (morning/afternoon, not close to bedtime) 5, 6
Smoking cessation 6
Review and discontinue dopamine antagonists (antipsychotics), SSRIs, tricyclic antidepressants if possible 1, 5

Step 3: Iron Supplementation

For ferritin ≤75 ng/mL or transferrin saturation <20%, start with oral ferrous sulfate or proceed directly to IV iron if ferritin is between 75-100 ng/mL. 1, 5, 6

Oral Iron

Oral ferrous sulfate is conditionally recommended for appropriate iron parameters 1, 5, 6
Monitor for constipation, especially in pediatric patients 5

Intravenous Iron

IV ferric carboxymaltose is strongly recommended (strong recommendation, moderate certainty) for patients with appropriate iron parameters who don't respond to oral therapy 1, 5, 6
IV low molecular weight iron dextran is conditionally recommended 1, 5
IV ferumoxytol is conditionally recommended 1, 5
For end-stage renal disease patients: IV iron sucrose if ferritin <200 ng/mL and transferrin saturation <20% 5, 6

Duration and Monitoring

Continue iron therapy indefinitely with ongoing monitoring 5
Recheck iron studies every 6-12 months, even after symptom resolution, as brain iron deficiency may persist despite normal serum parameters 5, 7

Step 4: First-Line Pharmacological Treatment

Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are strongly recommended as first-line therapy over dopamine agonists. 1, 5, 6

Gabapentin

Start at 300 mg three times daily (900 mg/day total) 5
Titrate by 300 mg/day every 3-7 days until reaching maintenance dose of 1800-2400 mg/day divided three times daily 5, 6
Doses up to 3600 mg/day are well-tolerated 5
Common side effects: somnolence and dizziness (typically transient and mild) 5

Gabapentin Enacarbil

Strongly recommended (strong recommendation, moderate certainty) 1, 5, 6
Prodrug of gabapentin with potentially better bioavailability 5

Pregabalin

Strongly recommended (strong recommendation, moderate certainty) 1, 5, 6
Allows twice-daily dosing with potentially superior bioavailability compared to gabapentin 5, 6

Special Population: End-Stage Renal Disease

Gabapentin is conditionally recommended (very low certainty) 5, 6
Start with 100 mg post-dialysis or 100 mg at bedtime, maximum 200-300 mg daily 5
Caution: Gabapentinoids carry 50-68% higher hazard for altered mental status and falls in dialysis patients 5

Step 5: Medications to Avoid or Use with Extreme Caution

Dopamine agonists are no longer recommended for standard use due to high risk of augmentation—a paradoxical worsening of symptoms with long-term use. 1, 5, 6

Strongly Recommended AGAINST

Cabergoline (strong recommendation against, moderate certainty) 1, 5
Levodopa (conditional recommendation against, very low certainty) 1, 5
Pramipexole (conditional recommendation against, moderate certainty) 1, 5
Ropinirole (conditional recommendation against, moderate certainty) 5
Transdermal rotigotine (conditional recommendation against, low certainty) 5

Other Medications to Avoid

Bupropion (conditional recommendation against, moderate certainty) 5
Carbamazepine (conditional recommendation against, low certainty) 5
Clonazepam (conditional recommendation against, very low certainty) - does not reduce periodic limb movement index and has insufficient efficacy evidence 5
Valproic acid (conditional recommendation against, low certainty) 5
Valerian (conditional recommendation against, very low certainty) 5

Understanding Augmentation

Augmentation is characterized by earlier symptom onset during the day, increased symptom intensity, and spread to other body parts (arms, trunk) 5, 8
Occurs with dopaminergic medications including ropinirole, pramipexole, and levodopa 5, 8
This is why alpha-2-delta ligands are now first-line—they avoid augmentation entirely 5, 6

Step 6: Second-Line and Refractory RLS Treatment

For refractory cases or augmentation from dopamine agonists, consider low-dose opioids or bilateral high-frequency peroneal nerve stimulation. 1, 5

Opioids

Extended-release oxycodone is conditionally recommended for moderate to severe refractory cases 1, 5, 6
Methadone and buprenorphine show relatively low risks of abuse and overdose in appropriately screened patients 5
Long-term studies show only small dose increases over 2-10 years 5
Caution: Risk of respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea 5
Effective for treating augmentation when decreasing or eliminating dopamine agonists 5

Non-Pharmacological Options

Bilateral high-frequency peroneal nerve stimulation is conditionally recommended (moderate certainty) 1, 5, 6
Dipyridamole is conditionally recommended (low certainty) 5

For End-Stage Renal Disease

Vitamin C is conditionally recommended 5, 6

Special Considerations

Pregnancy

RLS is common in pregnancy 1, 2
Consider pregnancy-specific safety profile of each treatment 1, 5
Iron supplementation is particularly important, with oral formulations favored throughout gestation 5

Pediatric RLS

Oral ferrous sulfate is conditionally recommended if ferritin <50 ng/mL 1, 5
Monitor for constipation with iron supplementation 5

Differential Diagnosis

Peripheral neuropathies 1
Vascular disease (intermittent claudication) 1
Neuroleptic-induced akathisia 1, 5
Arthritides and venous varicosities 1
Positional discomfort and nocturnal leg cramps 5
A careful history is usually sufficient to distinguish RLS from these conditions 1

Critical Pitfalls to Avoid

Never start dopamine agonists as first-line therapy—they cause augmentation in long-term use, making RLS worse 1, 5, 6
Never use clonazepam as monotherapy—insufficient efficacy evidence and does not reduce objective disease markers 5
Never skip iron studies—iron deficiency is the most important treatable cause and influences all treatment decisions 1, 5, 6
Never use magnesium as monotherapy for clinically significant RLS without first addressing iron status and considering guideline-recommended treatments 5
Never assume "normal" ferritin is adequate—RLS requires ferritin >75 ng/mL, higher than general population thresholds 1, 5, 6
Never abruptly discontinue dopamine agonists—taper gradually to avoid withdrawal-emergent hyperpyrexia, confusion, and severe withdrawal symptoms (insomnia, apathy, anxiety, depression, fatigue, sweating, pain) 8
Never ignore medication-induced RLS—antipsychotics, SSRIs, and antihistamines commonly worsen symptoms 1, 5
Monitor for impulse control disorders (gambling, hypersexuality, compulsive spending, binge eating) if dopamine agonists are used 8

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