Restless Legs Syndrome — Risk Factors, Diagnostic Criteria and Management

Restless Legs Syndrome — Risk Factors, Diagnostic Criteria and Management Fifteen–Twenty High-Yield Points Definition and epidemiology

Restless legs syndrome (RLS, Willis-Ekbom disease) is a sensorimotor disorder characterised by motor restlessness brought on by rest, usually or only present in the evening or early night, with an urge to move typically accompanied by an unpleasant sensation in the legs.

Periodic limb movements (PLMs) are discrete, repetitive, stereotyped movements — rhythmic extension of the big toe and ankle dorsiflexion, sometimes with knee and hip flexion — each lasting 0.5–5 seconds and recurring every 20–40 seconds. They are present in 90% of RLS patients but can occur independently.

Prevalence varies geographically: 10–20% in northern Europe, 3–10% in southern Europe, 0.7–12.1% in Asia, and under 1% in Africa. In India, prevalence is at the lower end of the Asian range but rises sharply in dialysis populations.

RLS is more common in women, but the prevalence in nulliparous women equals that in men — the difference is driven by pregnancy, during which prevalence rises to about 21%.

RLS commonly causes insomnia and excessive daytime sleepiness, and in older people this translates into falls, cognitive complaints and depression.

Genetic: about 60% of patients have a positive family history; at least eight major susceptibility loci are known, mostly autosomal dominant.

The three most commonly associated conditions are end-stage renal disease, pregnancy and iron deficiency anaemia (present in 25–35% of affected patients).

Other associations: stroke and migraine, mood disorders, cardiovascular disease, thyroid disorders and diabetes. Prevalence increases significantly when three or more comorbidities coexist.

Drug-induced/aggravated RLS: antidepressants, antihistamines and dopamine antagonists (including antipsychotics and metoclopramide); also withdrawal from opioids.

Brain iron deficiency is central: patients have lower CSF ferritin, higher transferrin, and reduced iron concentration in the basal ganglia and thalamus, even when peripheral iron stores appear adequate.

Dopamine dysfunction: there is a presynaptic hyperdopaminergic state with circadian fluctuation and downregulation of postsynaptic dopamine receptors. Dopamine production falls towards nightfall, producing a functional hypodopaminergic state — which explains both the circadian pattern and the response to dopaminergic drugs.

Brain iron deficiency and dopaminergic dysfunction interact by altering the glutamate and adenosine systems. Endogenous opioid deficiency in the central sensory system also contributes, causing abnormal processing of noxious stimuli and the characteristic urge to move.

RLS is a clinical diagnosis requiring all five criteria: (i) an urge to move the legs, usually accompanied or caused by uncomfortable, unpleasant sensations; (ii) the urge begins or worsens during rest or inactivity; (iii) the urge is relieved by movement, such as walking or stretching; (iv) the urge is worse in the evening or at night; (v) other conditions that mimic RLS have been excluded.

Supportive features: positive family history, positive response to dopaminergic therapy, and the presence of periodic limb movements during sleep or wakefulness.

Mimics to exclude: akathisia, positional discomfort, arthralgia, myalgia, peripheral venous insufficiency, painful peripheral neuropathy, nocturnal leg cramps and lumbar radiculopathy.

Investigations: iron studies must be obtained in every patient in whom RLS is suspected or diagnosed; renal function tests if uraemia is a concern. Polysomnography is not necessary but can objectify severity. A high PLMS rate on polysomnography is not sufficiently specific, as it occurs in many conditions and increases with age. Severity is quantified with the International RLS Severity Scale (IRLS).

First step: review the medication list and stop or reduce any drug that causes or exacerbates RLS. Non-pharmacological measures — sleep hygiene, hot and cold baths, lower limb massage, moderate exercise, avoidance of caffeine and alcohol — should be optimised before drugs.

Iron replacement: if deficient, give oral iron with vitamin C, or intravenous iron with a carbohydrate bond, especially ferric carboxymaltose. High-molecular-weight iron dextran must not be used because of severe anaphylactic reactions. Ferritin below 20 ng/mL warrants oral supplementation; between 20 and 50 ng/mL the decision is individualised; some evidence supports raising the threshold to 70 ng/mL in elderly patients with chronic renal failure or pro-inflammatory conditions. If iron studies are strictly normal, iron therapy is not effective.

Pharmacological options: dopamine agonists and levodopa are approved and widely used; only ropinirole has been shown to improve sleep efficacy on polysomnography. α2δ ligands (gabapentin, pregabalin) can be used as first-line agents. Second-line agents for severe refractory disease are opioids (oxycodone-naloxone, methadone), limited by side effects. Treatment starts as monotherapy at the lowest dose and is titrated slowly.

Augmentation is the feared complication of dopaminergic therapy — iatrogenic worsening with symptoms emerging progressively earlier in the day. An estimated 76% of patients on dopaminergic drugs need a dose increase or develop augmentation. To minimise risk: use long-acting agonists at the lowest effective dose, start only when quality of life is clearly affected, and never use carbidopa/levodopa as the initial agent because of its short half-life. Cross-titration to a different class is needed if augmentation develops. Consequently, α2δ ligands are increasingly favoured as initial therapy.