Restless Legs Syndrome

Restless legs syndrome is a common sensorimotor neurological disorder. It is characterised by an urge to move the legs, typically with uncomfortable sensations, occurring or worsening during rest or inactivity, particularly in the evening or at night, and relieved partially or completely by movement.

Causes and associations are broad. They include idiopathic disease (frequently with a genetic predisposition), iron deficiency (a particularly important, readily addressable secondary cause), pregnancy, chronic kidney disease, and certain medications (particularly antidepressants and antihistamines).

The closely related condition of periodic limb movements of sleep frequently coexists and contributes to the sleep disruption characteristic of this condition.

Pathophysiology

• The pathophysiology is believed to involve central nervous system dopaminergic dysfunction, together with an important relationship to brain iron status.
• Iron is a cofactor for tyrosine hydroxylase, the rate limiting enzyme in dopamine synthesis. This explains the association between peripheral iron deficiency and restless legs syndrome.
• It also explains the frequent improvement with iron replacement, even in patients with only borderline, rather than overtly deficient, peripheral iron studies.
• A strong genetic predisposition is recognised in a substantial proportion of patients with idiopathic disease, particularly those with earlier onset. Several genetic loci have been identified through genome wide association studies.
• The mechanism connecting these genetic variants to the clinical phenotype remains incompletely understood.
• Secondary restless legs syndrome occurs with iron deficiency, pregnancy, chronic kidney disease or certain medications. In pregnancy it is particularly common in the third trimester, likely reflecting relative iron deficiency and other pregnancy related physiological changes. In chronic kidney disease it is particularly relevant in the dialysis dependent population.
• Secondary disease generally reflects a similar, shared dopaminergic and iron related mechanism. Identifying and, where possible, correcting the underlying or contributing factor frequently produces meaningful symptomatic improvement.

• The core, defining diagnostic feature is an urge to move the legs, typically with uncomfortable sensations that are difficult to characterise precisely (variably described as crawling, creeping, pulling or aching).
• The urge occurs during rest or inactivity, is characteristically worse in the evening or at night, and is at least partially and temporarily relieved by movement.
• Symptoms characteristically interfere significantly with sleep onset, because they worsen with the inactivity and lying still of trying to fall asleep.
• This contributes to significant sleep disruption, daytime fatigue and impaired quality of life, a major component of the overall symptom burden and functional impact.
• Periodic limb movements of sleep are repetitive, stereotyped limb movements during sleep, typically involving dorsiflexion of the foot and, in some cases, flexion of the knee and hip. They frequently coexist with restless legs syndrome and can be identified on formal polysomnography where performed.
• They contribute further to sleep fragmentation and associated symptoms. In some individuals they occur in isolation, without the waking symptoms of restless legs syndrome.
• Explore specifically any history of iron deficiency, pregnancy, chronic kidney disease, or use of a potentially contributing medication (particularly certain antidepressants including selective serotonin reuptake inhibitors, and certain antihistamines), together with a family history in idiopathic disease. This identifies a cause that can be addressed where possible.

• Diagnosis is predominantly clinical, based on a symptom pattern meeting established diagnostic criteria: the urge to move with uncomfortable sensation, worsening with rest, relief with movement, and worsening in the evening or night.
• Formal polysomnography is not routinely needed in straightforward, typical presentations.
• Serum ferritin measurement is essential in every patient, given the important association with iron deficiency.
• A threshold somewhat higher than the standard laboratory reference range for iron deficiency (commonly a ferritin below 75 micrograms per litre, rather than the lower threshold typically used in other contexts) is generally used to guide the decision on iron replacement in this condition.
• This reflects evidence that symptomatic benefit can occur with iron replacement even at ferritin levels that would not otherwise be considered frankly deficient by standard haematological criteria.
• Renal function assessment, given the association with chronic kidney disease, and a full medication review to identify any contributing agent are important components of assessment.
• Polysomnography is reserved for diagnostic uncertainty, for suspected alternative or coexisting sleep disorders (including obstructive sleep apnoea), or where formal quantification of periodic limb movements of sleep is specifically required.

• Iron replacement is an important, frequently highly effective treatment where ferritin is below the higher threshold relevant to this condition. It may be oral iron supplementation or, where oral replacement is inadequate or poorly tolerated or more rapid repletion is desired, intravenous iron.
• Symptomatic improvement sometimes takes several weeks to become apparent after iron replacement starts.
• General, non-pharmacological measures are useful, low risk initial or adjunctive approaches. They include regular moderate exercise, avoidance of alcohol and caffeine (particularly in the evening), good general sleep hygiene and, where clinically feasible, discontinuation or switching of any identified contributing medication.
• Alpha-2-delta ligands (gabapentin or, particularly, gabapentin enacarbil and pregabalin) are first line pharmacological treatment when specific medication is needed beyond iron replacement and general measures.
• They have a generally favourable long term safety profile compared with the dopaminergic agents. They are particularly preferred with significant associated pain or anxiety symptoms, or where augmentation risk is a concern.
• Dopamine agonists (pramipexole or ropinirole, at doses substantially lower than those typically used in Parkinson disease) are an effective alternative and were historically first line. Their use has become more circumscribed because of the clinically significant risk of augmentation with longer term use.
• Augmentation is a paradoxical worsening of symptoms over time despite ongoing treatment. It is characterised by earlier onset of symptoms in the day, spread to previously unaffected body regions (including the arms), and a shorter latency to symptom onset with rest.
• Augmentation is generally managed by discontinuing the dopamine agonist, with a gradual taper to avoid withdrawal effects, and transitioning to an alternative, most commonly an alpha-2-delta ligand. Further dose escalation of the dopamine agonist would be expected to worsen it.
• Low dose opioid therapy (or, in some protocols, a specific low dose combination opioid preparation) is a further option, reserved for severe, refractory restless legs syndrome not adequately controlled with iron replacement, general measures and the other agents. Use it cautiously, given the general concerns of long term opioid therapy.
• Pregnancy related restless legs syndrome is generally managed with iron supplementation (where deficiency or low-normal ferritin is identified) and general non-pharmacological measures.
• Pharmacological treatment beyond this is generally avoided where possible, given limited safety data in pregnancy. Symptoms typically resolve after delivery in the great majority of affected women.
• Regular follow up underpins longitudinal management of this common, chronic condition. It includes monitoring for augmentation in patients treated with a dopamine agonist, periodic reassessment of iron status, and evaluation for the emergence or progression of any underlying or contributing condition.