Restless Legs Syndrome: Diagnosis and Treatment
Diagnosis
Restless legs syndrome (RLS) is diagnosed clinically using five essential criteria, with the critical fifth criterion requiring exclusion of mimics that can falsely appear to meet the first four criteria. 1
Essential Diagnostic Criteria (All Must Be Met)
An urge to move the legs usually accompanied by uncomfortable and unpleasant sensations in the legs (sometimes the urge exists without uncomfortable sensations, and occasionally arms or other body parts are involved) 1
Symptoms begin or worsen during rest or inactivity such as lying down or sitting 1
Symptoms are partially or totally relieved by movement such as walking or stretching, at least as long as the activity continues (when symptoms are very severe, relief may not be noticeable but must have been previously present) 1
Symptoms occur or worsen in the evening or night compared to during the day (when symptoms are very severe, this worsening may not be noticeable but must have been previously present) 1
The symptoms are not solely accounted for by another medical or behavioral condition 1
Critical Differential Diagnosis: RLS Mimics
Failure to properly exclude mimics leads to 16% misdiagnosis rates when only the first four criteria are assessed. 1 The most common conditions that superficially meet RLS criteria include:
- Leg cramps (painful tightening relieved specifically by stretching the affected muscle, not general movement) 2, 3
- Leg edema 1
- Venous stasis 1
- Positional discomfort 1
- Muscle aches 1
- Habitual foot tapping 1
- Arthritis 1
- Peripheral neuropathy 3
Ask these specific questions to differentiate RLS from nocturnal leg cramps: "What does it feel like?" (RLS: urge to move with dysesthesias vs. cramps: painful tightening), "Is it relieved by movement?" (RLS: any movement provides relief but symptoms return when movement stops vs. cramps: only stretching the specific muscle provides relief), and "When does it occur?" (RLS: worsens in evening/night vs. cramps: variable timing) 2, 3
Clinical Significance Specifier
Symptoms must cause significant distress or impairment in social, occupational, educational, or other important areas of functioning by their impact on sleep, energy/vitality, daily activities, behavior, cognition, or mood. 1
Treatment Algorithm
Step 1: Initial Assessment and Iron Status
Check serum ferritin and transferrin saturation in ALL patients with clinically significant RLS, ideally in the morning after avoiding iron-containing supplements for at least 24 hours. 4
If ferritin ≤75 ng/mL or transferrin saturation <20%, initiate iron supplementation before or concurrent with other pharmacological treatments. 4
- Oral ferrous sulfate is conditionally recommended with moderate certainty 4
- IV ferric carboxymaltose is strongly recommended with moderate certainty for patients with appropriate iron parameters, particularly if oral iron is not tolerated or ineffective 4
Address exacerbating factors: alcohol, caffeine, antihistaminergic medications (including over-the-counter sleep aids), serotonergic medications (SSRIs, SNRIs), antidopaminergic medications (antipsychotics, metoclopramide), and untreated obstructive sleep apnea. 4
Step 2: First-Line Pharmacological Treatment
Alpha-2-delta ligands (gabapentin, gabapentin enacarbil, or pregabalin) are the first-line pharmacological treatment for RLS, with strong recommendations and moderate certainty of evidence. 4
Gabapentin dosing: Start at 300 mg three times daily (900 mg/day total) and titrate up to 1800-2400 mg/day divided three times daily based on response. 4 If symptoms persist after 3-7 days, increase by 300 mg/day every few days until reaching the recommended maintenance dose. 4 Maximum doses up to 3600 mg/day are well-tolerated in clinical studies. 4
Pregabalin allows twice-daily dosing and may have superior bioavailability compared to gabapentin. 4
Gabapentin enacarbil is a prodrug of gabapentin that is also strongly recommended. 4
Common side effects include somnolence and dizziness, which are typically transient and mild. 4 Monitor for misuse potential, as there is increasing evidence these agents may be misused in certain populations. 4
Step 3: Medications to AVOID
The American Academy of Sleep Medicine suggests AGAINST the standard use of dopamine agonists (pramipexole, ropinirole, rotigotine) due to the high risk of augmentation—a paradoxical worsening of symptoms with earlier onset, increased intensity, and anatomic spread. 4
The American Academy of Sleep Medicine strongly recommends AGAINST cabergoline with strong recommendation and moderate certainty. 4
The American Academy of Sleep Medicine recommends AGAINST: bupropion, carbamazepine, clonazepam, valproic acid, and valerian for treating RLS. 4
Levodopa is suggested against for standard use with conditional recommendation and very low certainty due to high augmentation risk. 4
Step 4: Second-Line Options for Refractory Cases
Extended-release oxycodone and other low-dose opioids (methadone, buprenorphine) are conditionally recommended for refractory cases or when treating augmentation from dopaminergic agents. 4 Evidence suggests relatively low risks of abuse and overdose in appropriately screened patients, with long-term studies showing only small dose increases over 2-10 years. 4
Caution: Use opioids carefully due to risk of respiratory depression and central sleep apnea, especially in patients with untreated obstructive sleep apnea or chronic obstructive pulmonary disease. 4
Bilateral high-frequency peroneal nerve stimulation is conditionally recommended as a non-pharmacological option with moderate certainty of evidence. 4
Dipyridamole is conditionally recommended with low certainty of evidence. 4
Special Populations
End-Stage Renal Disease
Gabapentin is conditionally recommended with very low certainty, starting with 100 mg post-dialysis or 100 mg at bedtime, with maximum doses of 200-300 mg daily. 4 Caution: Gabapentinoids are associated with 50-68% higher hazard for altered mental status and falls in dialysis patients. 4
IV iron sucrose is conditionally recommended if ferritin <200 ng/mL and transferrin saturation <20% with moderate certainty. 4
Vitamin C is conditionally recommended with low certainty. 4
Pediatric RLS
Oral iron supplementation is recommended for serum ferritin <50 ng/mL in children with RLS, with monitoring for constipation. 4
Pregnancy
Special consideration of medication safety profiles is required for RLS in pregnancy, with iron supplementation particularly important given pregnancy-specific RLS prevalence. 4
Managing Augmentation
Augmentation is characterized by: worsening and earlier onset of symptoms in patients initially controlled on medication, increased symptom intensity, and spread of symptoms to other body parts. 4
Management strategy:
- Add an alpha-2-delta ligand or opioid to the current dopamine agonist regimen first 4
- Once adequate symptom relief is achieved with the second agent, initiate very slow down-titration of the dopamine agonist 5
- Do not abruptly discontinue the dopamine agonist, as this causes profound rebound RLS and insomnia 5
Monitoring and Follow-Up
Reassess iron studies every 6-12 months and monitor for side effects of alpha-2-delta ligands. 4 Evaluate for improvement in both nighttime RLS symptoms and daytime functioning (alertness, concentration, mood). 4
Continue iron supplementation indefinitely with ongoing monitoring, as RLS symptoms may recur if iron stores decline below therapeutic thresholds. 4
Critical Pitfalls to Avoid
- Do not diagnose RLS without excluding mimics—16% misdiagnosis rate occurs when differential diagnosis is not performed 1
- Do not use dopamine agonists as first-line therapy—they cause augmentation in long-term use despite FDA approval 4
- Do not use single nighttime dosing of gabapentin—this fails to address daytime RLS symptoms and provides suboptimal coverage 4
- Do not assume normal ferritin levels are adequate—brain iron deficiency plays a key role in RLS pathophysiology even when serum iron appears normal, requiring ferritin targets ≥75 ng/mL 4
- Do not abruptly stop dopamine agonists if augmentation occurs—add alternative treatment first, then slowly taper 5