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Restless Legs Syndrome (RLS) / Willis-Ekbom Disease

BASICS

  • Definition: Sensorimotor disorder with strong urge to move limbs (usually legs), especially during rest/inactivity and in the evening/night. Symptoms relieved by movement.
  • Phenotypes:
  • Early onset: Familial, slow progression, stable
  • Late onset: More aggravating factors, rapid progression
  • Synonyms: Willis-Ekbom disease

EPIDEMIOLOGY

  • Incidence: 0.8–2.2% annually; onset at any age
  • Gender: Parous females ~2Γ— prevalence of males
  • Pregnancy: 10–30% prevalence (peaks in 3rd trimester; most resolve 1 month postpartum)
  • Triggers: Cold, environmental factors, pregnancy, iron deficiency

ETIOLOGY & PATHOPHYSIOLOGY

  • Iron deficiency in brain (BID): Low serum iron or impaired transport β†’ CNS dopamine dysregulation
  • Neurochemistry: Morning ↑ DA β†’ D2 downregulation; night ↓ DA; ↑ glutamate, ↓ adenosine β†’ hyperarousal, insomnia
  • Medication-induced: Antidepressants (except bupropion), DA-blocking antiemetics, antipsychotics (except aripiprazole), PPIs, H2 blockers, theophylline, sedating antihistamines
  • Genetics: Multiple loci (MEIS1, BTBD9, PTPRD, TOX3, etc.)
  • Triggers: Prolonged immobility (e.g., hospitalization)

RISK FACTORS

  • Iron deficiency (ID), vitamin D deficiency
  • Family history
  • Chronic renal failure
  • Pregnancy
  • Medications (see above)

PREVENTION

  • Regular daytime activity/exercise; low-impact activity/stretching at night
  • Adequate sleep hygiene
  • Avoid caffeine, alcohol, nicotine (especially evening)
  • Avoid/limit meds that can trigger/exacerbate RLS

ASSOCIATED CONDITIONS

  • Insomnia, sleepwalking, delayed sleep phase
  • Renal disease/uremia/dialysis, GI surgery, IBS
  • Parkinson disease, multiple sclerosis, neuropathy, migraine
  • Psychiatric: anxiety, depression, ADHD
  • Cardiovascular disease, stroke, venous insufficiency
  • Pulmonary hypertension, COPD, lung transplantation
  • Arthritis, fibromyalgia, orthopedic problems

DIAGNOSIS

Clinical Criteria (all must be met):

  1. Urge to move legs, usually with uncomfortable sensations
  2. Symptoms begin or worsen during periods of rest/inactivity
  3. Symptoms relieved by movement (even if only previously reported)
  4. Occur predominantly in evening/night (circadian aspect)

  5. Not explained by β€œmimics” (e.g., leg cramps, neuropathy, claudication, arthritis)

  6. Symptoms: Painful in ~35% ("antsy," burning, aching, itching), urge to move, insomnia, fatigue, anxiety, depression

  7. PLMS: Present in ~80% (periodic limb movements in sleep)
  8. Severity: Ranges from minor to severe QOL impact
  9. Pediatrics: Sleep disturbance, immediate family history, PLMS

Physical Exam

  • Usually normal

Differential Diagnosis

  • Vascular compression, claudication, motor neuron disease, peripheral neuropathy, dermatitis, sleep-related leg cramps, PLMD, growing pains

Diagnostic Tests

  • Iron studies: Ferritin, transferrin saturation, iron-binding capacity, serum iron
  • Optional: Sleep study (PSG) for PLMS, SIT/m-SIT for movement quantification

TREATMENT

General Measures

  • Iron supplementation if ferritin <75 ng/mL or TSAT <16%
  • FeSOβ‚„ 325 mg + vitamin C 100 mg QHS; IV iron for refractory cases
  • Regular exercise; avoid aggravating factors
  • Sleep hygiene
  • Hot baths, massage, warm socks, weighted blanket
  • Treat OSA if present
  • Cognitive/mental engagement before sleep

Medications

  • First Line: Ξ±2Ξ΄ ligands (gabapentinoids)
  • Gabapentin enacarbil (Horizant): 300–1200 mg QD (5pm)
  • Pregabalin (Lyrica): 50–450 mg/day (off-label)
  • Gabapentin (Neurontin): 100–2400 mg/day (off-label)
  • Second Line: Dopamine agonists (monitor for augmentation/impulse disorders)
  • Pramipexole (Mirapex): 0.125–0.5 mg 1–2h before Sx (ER/IR)
  • Ropinirole (Requip): 0.25–4.0 mg 0.5–1h before Sx (XL/IR)
  • Rotigotine (Neupro) patch: 1–3 mg/24h
  • Carbidopa/levodopa: PRN, up to 2Γ—/week
  • Other: Opiates (buprenorphine/naloxone, methadone, oxycodone), benzodiazepines (clonazepam, temazepam), hypnotics (zolpidem), for refractory or sleep/anxiety cases

Pregnancy

  • Prefer nonpharmacologic therapies
  • Correct iron, vitamin D, folate
  • Severe cases (2nd/3rd trimester): low-dose clonazepam, clonidine, carbidopa/levodopa, or opioids

Pediatrics

  • Nonpharmacologic first, healthy sleep, correct ID
  • Low-dose gabapentin, clonidine, melatonin if needed

Geriatrics

  • Avoid meds causing sedation/dizziness
  • Monitor for polypharmacy triggers

Adjuncts & Alternative

  • Compression stockings, pneumatic devices
  • Nerve stimulators, vitamin/Mg/D/folate supplements
  • Referral for severe/intractable symptoms
  • Consider vascular/orthopedic interventions if indicated

MONITORING & ONGOING CARE

  • Assess severity at every visit (sIRLS, IRLS, JHRLSS scales)
  • Recheck iron stores as indicated
  • Monitor for augmentation and impulse control disorders (especially with DAs)
  • Educate: Avoid evening caffeine/alcohol; maintain regular sleep; RLS Foundation and sleep resources

PROGNOSIS

  • Early onset: lifelong, usually manageable
  • Late onset/secondary: may resolve if precipitant treated; otherwise chronic/progressive
  • Most therapies control symptoms; augmentation (DA-induced worsening) must be monitored

COMPLICATIONS

  • Augmentation: Symptoms worsen/advance in time/intensity/body distribution, especially with higher DA doses and shorter-acting agents
  • Impulse-control disorders (ICD)
  • Iatrogenic RLS after blood loss/donation

ICD-10

  • G25.81 Restless legs syndrome

CLINICAL PEARLS

  • Iron repletion is well-tolerated and often effective.
  • Ξ±2Ξ΄ ligands (gabapentinoids) are first-line.
  • Dopamine agonists: Use minimum dose, watch for augmentation.
  • Many psychiatric/GI drugs can trigger or worsen RLS.
  • Monitor with a standardized severity scale.
  • Insomnia is a frequent presenting symptom.

RESOURCES