Restless Legs Syndrome: Diagnostic Workup and Treatment
Diagnosis
Restless legs syndrome is diagnosed clinically using the five essential IRLSSG criteria, with critical emphasis on excluding mimics through careful differential diagnosis. 1
Essential Diagnostic Criteria (All Five Must Be Met)
Urge to move the legs usually accompanied by uncomfortable and unpleasant sensations in the legs 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 1
Circadian pattern: symptoms occur or are worse in the evening or night than during the day 1
Exclusion of mimics: the symptoms are not solely accounted for by another medical or behavioral condition 1
Critical Diagnostic Pitfall
Without proper differential diagnosis, 16% of subjects who do not have RLS will be misclassified as having the condition if only the first four criteria are assessed. 1 This is the most common diagnostic error in RLS.
Specific Mimics to Exclude
The following conditions can superficially meet all four basic criteria and must be actively ruled out 1:
- Leg cramps
- Leg edema
- Venous stasis
- Positional discomfort
- Muscle aches (myalgia)
- Habitual foot tapping
- Arthritis
- Neuropathy 1
- Akathisia 1
- Spasticity 1
- Nocturnal leg cramps 1
Clinical Significance Specifier
Symptoms must cause significant distress or impairment in social, occupational, educational, or other important areas of functioning through their impact on sleep, energy/vitality, daily activities, behavior, cognition, or mood. 1
Diagnostic Workup: Iron Studies
Iron studies are mandatory in the diagnostic workup and should be obtained in the morning, avoiding all iron-containing supplements and foods for at least 24 hours prior to blood draw. 1
Required tests 1:
- Serum ferritin
- Transferrin saturation (or total iron binding capacity)
Treatment Algorithm
Step 1: Address Exacerbating Factors First
Before initiating pharmacologic therapy, address modifiable factors including alcohol, caffeine, antihistaminergic medications, serotonergic medications, antidopaminergic medications, and untreated obstructive sleep apnea. 1
Step 2: Iron Supplementation Based on Laboratory Values
For adults with serum ferritin ≤75 ng/mL or transferrin saturation <20%: Use oral or IV iron 1
For adults with serum ferritin between 75-100 ng/mL: Use IV iron only 1
For adults with RLS and end-stage renal disease (ESRD): The AASM suggests IV iron sucrose in patients with ferritin <200 ng/mL and transferrin saturation <20% 1
For children with serum ferritin <50 ng/mL: Use oral or IV iron formulations 1
These iron supplementation guidelines differ from those for the general population and are specific to RLS management. 1
Step 3: First-Line Pharmacologic Treatment
Dopamine receptor agonists are the first-line pharmacologic treatment for moderate-to-severe RLS. 2, 3, 4, 5 The American Academy of Sleep Medicine provides specific recommendations for various agents, though the 2025 guideline details are partially shown in the evidence provided. 1
Important Treatment Considerations
Levodopa carries significant risk of augmentation with long-term use. 1, 2 The AASM suggests against standard use of levodopa in adults with RLS and ESRD, noting it may only be used in patients who place higher value on short-term symptom reduction and lower value on long-term adverse effects, particularly augmentation. 1
Augmentation is a worsening of symptoms, usually manifesting as earlier onset of symptoms during the day, and represents a major treatment complication. 2, 4
Medications to Avoid
The AASM recommends against cabergoline (strong recommendation, moderate certainty of evidence) 1
The AASM suggests against valproic acid (conditional recommendation, low certainty of evidence) 1
The AASM suggests against valerian (conditional recommendation, very low certainty of evidence) 1
Second-Line Options
Alternative treatments include 2, 4:
- Gabapentin or similar antiepileptic drugs
- Opioids
For adults with RLS and ESRD, the AASM suggests gabapentin (conditional recommendation, very low certainty of evidence) 1
Pediatric Considerations
In children with RLS, the AASM suggests ferrous sulfate in patients with appropriate iron status (conditional recommendation, very low certainty of evidence) 1
Diagnosing RLS in children is challenging as they may have difficulty describing their symptoms; the description should be in the child's own words. 1 Growing pains, leg cramps, and behavioral issues are common mimics in the pediatric population. 1
Pregnancy Considerations
RLS is common in pregnancy; prescribers must consider the pregnancy-specific safety profile of each treatment being considered. 1
When to Refer
The American Academy of Sleep Medicine recommends appropriate specialist referral to neurologists when symptoms are severe. 6 RLS is classified as a neurological sensorimotor disease affecting the nervous system, not simply a sleep disorder. 6