Restless legs syndrome: pathophysiology, diagnosis and treatment

Abstract

Restless legs syndrome (RLS) is clinically defined by the presence of (i) an urge to move the legs with or without an actual paraesthesia; (ii) a worsening of symptoms with inactivity; (iii) improvement with activity; and (iv) a worsening of symptoms in the evening and at night. Patients may use a variety of semantic phrases to describe their symptoms but all must have an urge to move. Most people with RLS also have periodic limb movements during sleep, although this is not part of the clinical diagnostic criteria. RLS is very common. About 10% of all Caucasian populations have RLS, although it may be mild in the majority of cases. Women generally outnumber men by about 2:1. As a general rule, RLS severity worsens through the first seven to eight decades of life, but may actually lessen in old age. The aetiology of RLS is only partly understood. There is a strong genetic component, and several genetic linkages and three causative genes have been identified worldwide. Several medical conditions, including renal failure, systemic iron deficiency and pregnancy, and possibly neuropathy, essential tremor and some genetic ataxias, are also associated with high rates of RLS. In all cases to date, the actual CNS pathology of RLS demonstrates reduced iron stores, in a pattern that suggests that the homeostatic control of iron is altered, not just that there is not enough iron entering the brain. The relationship between reduced CNS iron levels and the clinical phenotype or treatment response to dopaminergics is not known but generates promising speculation. Treatment of RLS is usually rewarding. Most patients respond robustly to dopamine receptor agonists. Over time, response may lessen, or the patients may develop 'augmentation', whereby they have a worsening of symptoms, usually in the form of an earlier onset. Other treatment options include gabapentin, or similar antiepileptic drugs, and opioids. High-dose intravenous iron is a promising but still experimental approach.