Key Facts

RLS is common and frequently underdiagnosed. Iron deficiency must be corrected before starting other treatments. Augmentation (paradoxical worsening) with dopamine agonists is a major management challenge.

Epidemiology

Prevalence ~5-10% (clinically significant in ~2-3%). F:M 2:1. Increases with age. ~40-60% have positive family history (autosomal dominant with variable penetrance). Pregnancy prevalence up to 25% (usually resolves postpartum).

Aetiology

• Primary (idiopathic): genetic predisposition (BTBD9, MEIS1, MAP2K5 loci); ~60% have positive family history
• Secondary: iron deficiency (most important treatable cause — brain iron stores may be low even with 'normal' serum ferritin), CKD/ESRD (up to 30%), pregnancy, peripheral neuropathy (diabetic), Parkinson disease
• Drug-induced: SSRIs, SNRIs, mirtazapine, TCAs, antipsychotics (dopamine blockers), antihistamines, metoclopramide

Pathophysiology

Central dopaminergic dysfunction (A11 diencephalospinal pathway) + brain iron deficiency are the leading hypotheses. Iron is a cofactor for tyrosine hydroxylase (rate-limiting enzyme in dopamine synthesis) → low brain iron → reduced dopaminergic transmission. Circadian variation: dopamine levels are lowest in the evening → explains temporal pattern. Spinal cord hyperexcitability contributes to sensory symptoms and PLMS.

Essential Features (IRLSSG Criteria — All Required)

1. Urge to move the legs (usually accompanied by uncomfortable sensations — crawling, creeping, tingling, aching, pulling)
2. Worse at rest (sitting, lying down)
3. Relieved by movement (walking, stretching — returns on stopping)
4. Worse in evening/night (circadian pattern)
5. Not solely explained by another condition (leg cramps, positional discomfort, peripheral neuropathy)

Associated Features

• Sleep disturbance: difficulty falling asleep, sleep fragmentation → daytime fatigue, impaired concentration
• PLMS: repetitive dorsiflexion of the ankle/toes during sleep (every 20-40 seconds); may cause sleep disruption (patient may be unaware)
• Arms/body: can affect arms and trunk in severe cases

Red Flags

• Unilateral or asymmetric symptoms → consider neuropathy, radiculopathy
• Symptoms only during sleep (without wake symptoms) → PLMS disorder (different entity)
• Worsening despite dopamine agonist → augmentation

Bloods (Essential)

• Serum ferritin: threshold for RLS is <75 μg/L (even if within 'normal' lab range); also check transferrin saturation
• FBC: iron deficiency anaemia
• U&Es: renal impairment (CKD)
• HbA1c: diabetes (neuropathy)
• TFTs: thyroid dysfunction
• B12, folate: deficiency

Sleep Studies (If Diagnosis Uncertain)

• Polysomnography: demonstrates PLMS (>15 per hour = significant); not routinely required for RLS diagnosis
• Actigraphy: ambulatory monitoring of limb movements

Neurophysiology

• NCS: if peripheral neuropathy suspected (symptoms atypical for RLS)

Clinical Diagnosis

• RLS is a clinical diagnosis based on IRLSSG criteria; no specific confirmatory test

Non-Pharmacological (First-Line)

• Correct iron deficiency: oral ferrous sulphate 200mg OD-TDS (target ferritin >75 μg/L); IV iron (ferric carboxymaltose 500-1000mg) if oral not tolerated, CKD, or inadequate response
• Sleep hygiene: regular sleep-wake schedule
• Avoid aggravating factors: caffeine, alcohol, nicotine (evening)
• Review medications: stop/change SSRIs, antihistamines, metoclopramide if possible
• Exercise: moderate regular exercise (not excessive in evening)
• Leg massage, hot baths, distraction techniques

Pharmacological (If Non-Pharmacological Insufficient)

Alpha-2-delta ligands (preferred first-line — lower augmentation risk):

• Pregabalin 75-300mg ON: effective for RLS and improves sleep
• Gabapentin 300-2400mg ON: alternative
• Gabapentin enacarbil: extended-release formulation specifically for RLS (not widely available in UK)

Dopamine agonists (effective but augmentation risk):

• Ropinirole 0.25-4mg ON: start low, titrate slowly
• Pramipexole 0.088-0.54mg ON
• Rotigotine patch 1-3mg/24h
• Augmentation risk: ~10-15% per year; symptoms worsen, occur earlier in day, spread to arms

If augmentation develops:

• Reduce/stop dopamine agonist gradually
• Switch to alpha-2-delta ligand
• Ensure ferritin >75 μg/L
• Consider low-dose opioid (oxycodone 5-20mg) for severe refractory RLS

Severe/refractory:

• Sodium oxybate: for severe RLS with sleep disruption
• Low-dose opioids: oxycodone 5-20mg ON (short-term, under specialist supervision)

Pregnancy

• Correct iron/folate deficiency
• Non-pharmacological measures
• Avoid dopamine agonists and alpha-2-delta ligands in pregnancy
• Usually resolves postpartum

Referral Criteria

• Sleep medicine/neurology: diagnostic uncertainty, treatment resistance, suspected augmentation
• Renal: RLS in CKD/dialysis

Primary RLS is a chronic lifelong condition (in most). Symptoms fluctuate — may have periods of remission. Secondary RLS (iron deficiency, pregnancy): often improves/resolves when underlying cause treated. Augmentation is the main treatment challenge with dopamine agonists (~50% at 10 years). Alpha-2-delta ligands have better long-term tolerability. Quality of life is significantly impaired by sleep disruption. No increased mortality, but significant morbidity (depression, anxiety, impaired work performance).

RLS Severity Scale (IRLS)

Augmentation Diagnostic Features