Overview
Restless Legs Syndrome
1. Clinical Overview
Summary
Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensorimotor disorder characterised by an irresistible urge to move the legs, usually accompanied by uncomfortable sensations. Symptoms are worse at rest and in the evening, and are relieved by movement.
Key Facts
| Aspect | Detail |
|---|---|
| Classification | Primary (idiopathic) or Secondary |
| Peak Age | Two peaks: 20-30 years and >50 years |
| Gender | Slightly more common in women |
| Key Investigation | Serum Ferritin (treat if <75 μg/L) |
| First-Line Treatment | Iron replacement if deficient; Gabapentinoids preferred |
Clinical Pearls
- Ferritin Threshold: Standard ferritin "normal" is misleading - aim for >75 μg/L (or even >100) in RLS
- Ask the Right Question: "Do you have an urge to move your legs that's worse at night?"
- Augmentation Risk: Long-term dopamine agonist use can worsen symptoms (augmentation)
- Avoid Culprits: Antihistamines, antidepressants (especially SSRIs), and antiemetics can exacerbate RLS
2. Epidemiology
Prevalence & Demographics
| Population | Prevalence |
|---|---|
| General population | 5-15% |
| Pregnancy (third trimester) | Up to 25% |
| End-stage renal disease | 20-40% |
| Iron deficiency | Significantly increased |
Risk Factors
| Risk Factor | Notes |
|---|---|
| Family history | 50% of primary RLS have +ve family history |
| Iron deficiency | Even with normal Hb |
| Chronic kidney disease | Especially dialysis patients |
| Pregnancy | Usually resolves postpartum |
| Peripheral neuropathy | Comorbid condition |
| Medications | SSRIs, antihistamines, antiemetics |
3. Pathophysiology
Proposed Mechanisms
Iron Deficiency (Brain)
↓
Reduced Dopamine Synthesis
(Tyrosine Hydroxylase requires Iron)
↓
Dopaminergic Dysfunction
(A11 diencephalospinal pathway)
↓
Altered Sensorimotor Integration
↓
URGE TO MOVE + Dysaesthesias
↓
Circadian Variation (worse evening/night)
Key Points
| Factor | Role |
|---|---|
| Brain iron | Low brain iron even with normal serum ferritin |
| Dopamine | Central dopaminergic hypofunction |
| Genetics | BTBD9, MEIS1 genes identified |
| Circadian rhythm | Dopamine and iron levels fluctuate; lowest at night |
| Adenosine | May modulate dopaminergic activity |
Secondary Causes
| Cause | Mechanism |
|---|---|
| Iron deficiency | Impaired dopamine synthesis |
| CKD/haemodialysis | Uraemia, iron deficiency |
| Pregnancy | Iron deficiency, hormonal |
| Neuropathy | Sensory nerve dysfunction |
| Medications | Dopamine blockade (antiemetics, antipsychotics) |
4. Clinical Presentation
Diagnostic Criteria (IRLSSG)
All 5 must be present:
- Urge to move the legs, usually with uncomfortable sensations
- Begins or worsens during rest or inactivity
- Partially or totally relieved by movement
- Worse in the evening or night
- Not solely due to another condition (leg cramps, positional discomfort, myalgia)
Symptom Descriptions (Patient Words)
| Description | Notes |
|---|---|
| "Creepy-crawly" | Classic |
| "Itchy bones" | Deep, internal sensation |
| "Electric" | Tingling quality |
| "Like worms under the skin" | Common metaphor |
| "Can't keep still" | Motor component |
Associated Features
| Feature | Notes |
|---|---|
| Periodic limb movements (PLMs) | Present in 80-90% of RLS |
| Sleep disturbance | Difficulty initiating/maintaining sleep |
| Daytime fatigue | Due to sleep disruption |
| Impact on mood | Anxiety, depression common |
5. Clinical Examination
Examination Findings
| Finding | Notes |
|---|---|
| Usually normal | RLS is a clinical diagnosis |
| Peripheral neuropathy signs | May indicate secondary cause |
| Signs of iron deficiency | Pallor, koilonychia, angular stomatitis |
| Uraemic features | If CKD-related |
What to Look For
| System | Assessment |
|---|---|
| Neurological | Sensory examination, reflexes |
| Peripheral pulses | Exclude vascular claudication |
| Skin | Signs of anaemia |
| General | Thyroid, renal disease features |
6. Investigations
First-Line Investigations
| Test | Target | Notes |
|---|---|---|
| Serum Ferritin | >75 μg/L | Most important! |
| Transferrin saturation | >20% | Low may indicate iron deficiency |
| Full blood count | Normal Hb doesn't exclude ID | Check ferritin regardless |
| Renal function | eGFR | Exclude CKD |
| Blood glucose/HbA1c | Exclude diabetes/neuropathy | |
| Thyroid function | TSH | Exclude hypothyroidism |
Additional Investigations (if indicated)
| Test | Indication |
|---|---|
| Polysomnography | If sleep apnoea suspected or to document PLMs |
| Nerve conduction studies | If neuropathy suspected |
| B12, folate | If macrocytic or neuropathy |
7. Management
Management Algorithm
RLS Diagnosis Confirmed
↓
Check and Optimise Iron
(Ferritin >75, TSAT >20%)
↓
Review Medications
(Stop exacerbating drugs)
↓
┌────┴────┐
↓ ↓
Intermittent Daily
RLS RLS
↓ ↓
PRN treatment ┌────────────────┐
as needed ↓ ↓
Mild-Moderate Severe
↓ ↓
Gabapentinoids Gabapentinoids
(1st line) + Low-dose
dopamine agonist
(consider
opioids if
refractory)
Non-Pharmacological
| Intervention | Evidence |
|---|---|
| Moderate exercise | Beneficial |
| Leg stretches before bed | May help |
| Good sleep hygiene | Important adjunct |
| Avoid caffeine, alcohol | Can exacerbate |
| Hot/cold compresses | Symptomatic relief |
| Mental distraction | Can reduce perception |
Iron Supplementation
| Indication | Approach |
|---|---|
| Ferritin <75 μg/L | Oral iron (325mg ferrous sulfate TDS) |
| Ferritin 75-100 in refractory RLS | Trial oral iron |
| Malabsorption/intolerance | IV iron (ferric carboxymaltose) |
First-Line Pharmacotherapy: Gabapentinoids
| Drug | Dose | Notes |
|---|---|---|
| Pregabalin | 75-300mg at night | Preferred; less augmentation |
| Gabapentin | 300-2400mg at night | Alternative |
| Gabapentin enacarbil | 600mg at 5pm | Extended release |
Second-Line: Dopamine Agonists (Use with Caution)
| Drug | Dose | Key Risk |
|---|---|---|
| Ropinirole | 0.25-4mg at night | Augmentation (20-30% at 5 years) |
| Pramipexole | 0.125-0.5mg at night | Impulse control disorders |
| Rotigotine patch | 1-3mg/24hrs | Lower augmentation risk |
Augmentation
| Feature | Description |
|---|---|
| Definition | Worsening of RLS symptoms with dopamine agonist treatment |
| Signs | Earlier onset in day, spread to arms, shorter relief with medication |
| Management | Reduce/stop dopamine agonist, ensure iron replete, switch to gabapentinoid |
Refractory RLS
| Option | Notes |
|---|---|
| Low-dose opioids | Oxycodone, tramadol - effective but dependency risk |
| Combination therapy | Gabapentinoid + low-dose dopamine agonist |
8. Complications
Complications of RLS
| Complication | Impact |
|---|---|
| Chronic insomnia | Major impact on quality of life |
| Depression/anxiety | Common comorbidity |
| Impaired concentration | Due to sleep deprivation |
| Cardiovascular risk | Association with HTN, CVD (debated) |
Treatment Complications
| Treatment | Complication |
|---|---|
| Dopamine agonists | Augmentation, impulse control disorders, daytime sleepiness |
| Gabapentinoids | Sedation, dizziness, weight gain |
| Opioids | Dependency, constipation, sedation |
9. Prognosis & Outcomes
Natural History
| Type | Course |
|---|---|
| Primary/idiopathic | Chronic, often progressive, lifelong |
| Secondary | May resolve with treatment of underlying cause |
| Pregnancy-related | Usually resolves within 4 weeks postpartum |
Quality of Life Impact
- Comparable QoL impairment to other chronic diseases (diabetes, depression)
- Significant impact on sleep quality and daytime functioning
Factors Affecting Prognosis
| Favourable | Unfavourable |
|---|---|
| Secondary cause identified and treated | Primary/genetic RLS |
| Iron deficiency corrected | Augmentation from dopamine agonists |
| Good treatment response | Comorbid depression |
10. Evidence & Guidelines
Key Guidelines
| Organisation | Guideline | Key Points |
|---|---|---|
| AASM | Treatment of RLS (2012, 2022 update) | Gabapentinoids as first-line |
| IRLSSG | Consensus guidelines (2022) | Iron status essential; augmentation awareness |
| NICE | CKS RLS | Practical primary care guidance |
Evidence Summary
| Topic | Evidence |
|---|---|
| Iron supplementation | IV iron more effective than oral in some patients |
| Gabapentinoids vs dopamine agonists | Similar efficacy initially, but less augmentation with gabapentinoids |
| Augmentation | Major limitation of long-term dopamine agonist use |
11. Patient / Layperson Explanation
For Patients
What is Restless Legs Syndrome? It's a condition where you feel an uncomfortable urge to move your legs, especially when sitting still or lying down at night. The sensations are often described as "creepy-crawly," "tingling," or like "itchy bones."
What causes it?
- In some people: It runs in families and is related to how the brain handles a chemical called dopamine
- Low iron levels: Even if you're not anaemic, low iron stores can cause or worsen RLS
- Other conditions: Kidney disease, pregnancy, and some medications can trigger it
What makes it worse?
- Sitting still for long periods (flights, cinema, meetings)
- Evening and nighttime
- Certain medications: antihistamines (allergies/sleep aids), some antidepressants, anti-sickness tablets
- Caffeine and alcohol
How is it diagnosed? There's no specific test - diagnosis is based on your symptoms. However, blood tests are important to check your iron levels and kidney function.
How is it treated?
- Iron supplements if your levels are low (even "normal" levels may need boosting)
- Medications: Tablets that affect brain chemistry can be very effective
- Lifestyle changes: Regular exercise, avoiding caffeine, good sleep habits
- Movement: When symptoms occur, walking or stretching helps immediately
What should I avoid?
- Over-the-counter sleep aids containing antihistamines
- Too much caffeine or alcohol
- Prolonged sitting without breaks
Will it go away?
- If caused by low iron or pregnancy, it often improves significantly with treatment or after delivery
- If it's genetic/primary RLS, it's usually lifelong but very manageable with treatment
12. References
- Allen RP, et al. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated IRLSSG consensus. Sleep Med. 2014;15(8):860-873.
- Winkelman JW, et al. Practice guideline summary: Treatment of restless legs syndrome in adults. Neurology. 2016;87(24):2585-2593.
- Trenkwalder C, et al. Restless legs syndrome: pathophysiology, clinical presentation, and management. Nat Rev Neurol. 2021;17:423-438.
- Garcia-Borreguero D, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease. Sleep Med. 2016;21:1-11.
- NICE CKS. Restless Legs Syndrome. https://cks.nice.org.uk/topics/restless-legs-syndrome/