Restless Legs Syndrome

Pathophysiology

Though not fully elucidated, the pathophysiology of RLS is linked to

• Dopaminergic dysregulation in the central nervous system

• Iron deficiency in the brain (e.g. low ferritin or low iron stores even if peripheral iron levels appear normal)

• Possible genetic predisposition, with some familial cases described

Causes and risk factors

RLS may be

• Idiopathic (primary) – no identifiable secondary cause

• Secondary, related to

  • Iron deficiency or low ferritin (<50 micrograms/L is considered contributory)

  • Pregnancy (especially in the third trimester)

  • End-stage kidney disease

  • Neuropathy or certain chronic conditions (e.g. diabetes)

  • Medication-induced or exacerbated by antidepressants (especially SSRIs, SNRIs), antihistamines, certain antipsychotics, and antiemetics

Clinical features & diagnostic criteria

The hallmark feature is an uncomfortable sensation in the legs with an irresistible urge to move. Patients typically describe sensations as

• Creeping, crawling, itching, searing, tugging, or electrical-like

• Occurring predominantly at rest (lying or sitting still)

• Worsening in the evening or night-time, often disturbing sleep

• Temporarily relieved by movement (e.g. walking, stretching, rubbing the legs, or placing the limbs on something cold/hot)

Formal Diagnostic Criteria include

1. An urge to move the legs, usually accompanied by uncomfortable sensations

2. Symptoms begin or worsen during periods of rest or inactivity

3. Symptoms are partially or totally relieved by movement

4. Symptoms are worse in the evening or night than during the day (or only occur in the evening/night)

5. The above features are not solely accounted for by another medical or behavioural condition

A sleep study (polysomnography) is not routinely required for diagnosis if classic symptoms are present

Differential diagnoses

• Peripheral neuropathy (e.g. diabetic neuropathy)

• Nocturnal leg cramps

• Joint or muscle pain disorders (e.g. osteoarthritis, fibromyalgia)

• Positional discomfort or vascular claudication

• Anxiety or agitation with motor restlessness

Investigations

• Full blood count and ferritin to assess iron status (RACGP and Therapeutic Guidelines recommend maintaining ferritin ≥50 micrograms/L in RLS)

• Renal function tests if suspecting or monitoring for chronic kidney disease

• Fasting glucose/HbA1c if diabetic neuropathy is suspected

• Thyroid function tests in some cases (thyroid disorders may exacerbate RLS)

• B12 and folate levels may be checked if there is a suspicion of deficiency contributing to neuropathic sensations

In practice, the most critical and high-yield investigation is checking ferritin levels. Correcting even borderline low ferritin can significantly improve RLS symptoms

Management

Non-Pharmacological Measures

• Ensure good sleep hygiene (regular bedtimes, avoiding caffeine/alcohol before bed)

• Moderate exercise, particularly earlier in the day, but avoid strenuous exercise before bedtime

• Brief walking or stretching breaks when sitting still for long periods

• Correct underlying conditions (e.g. replete iron stores, optimise comorbidity management)

• Identify and reduce exacerbating medications such as antihistamines, certain antidepressants, and dopamine antagonists

Pharmacological Treatment

Therapeutic Guidelines recommend starting at the lowest effective dose and titrating cautiously to avoid side effects and augmentation (worsening or earlier onset of symptoms due to medication)

• Intermittent or mild RLS

  • Occasional use of low-dose levodopa+benserazide (100+25 mg to 200+50 mg) or levodopa+carbidopa (100+25 mg to 200+50 mg) at bedtime if needed

  • Note: Levodopa use is often limited to infrequent dosing because of the higher risk of augmentation with continuous or higher-dose use

• Moderate to severe RLS

  • Alpha-2 delta ligands (calcium channel modulators)

    • Gabapentin: Begin 100–300 mg at night; can be slowly titrated up (maximum ~2400 mg/day in divided doses)

    • Pregabalin: Begin 75 mg at night; can be slowly increased to a maximum of 450 mg/day if needed

  • Dopamine agonists

    • Pramipexole: Start 0.125 mg once daily 2–3 hours before bedtime. If needed, titrate to 0.25 mg after 4–7 days, with a usual maximum of 0.75 mg nightly

    • Ropinirole: Start 0.25 mg once daily 1–3 hours before bedtime. Can be cautiously increased to a usual range of 2 mg (max 4 mg) over weeks

    • Rotigotine patches: 1 mg transdermal daily, can titrate up to 3 mg daily in resistant cases (available via Special Access Scheme in some forms)

Long-term Complications of Dopaminergic Therapy

• Augmentation: A paradoxical worsening of RLS symptoms over time (earlier onset in the day, increased severity, or spread to arms). More common with levodopa and at higher doses (>200 mg daily). Management includes dose reduction, drug holidays, switching to an alternative class, or referral to a specialist

• Rebound phenomenon: A re-emergence of symptoms in the early morning when the medication effect wears off (similar to “wearing off” in Parkinson’s disease). Management includes using longer-acting agents (e.g. rotigotine, or splitting levodopa doses)

Special populations

• Pregnancy: RLS may worsen in late pregnancy. Focus on non-pharmacological measures and checking ferritin. Pharmacological choices are very limited in pregnancy; specialist advice may be needed for severe cases

• End-stage kidney disease: RLS can be pronounced in haemodialysis patients. Optimise dialysis and correct iron deficiency. Specialist consultation may be required for medication choice and dosing