The Swedish physician Karl-Axel Ekbom provided the first comprehensive description in 1945, and emphasized several principal features including:

• a prevalence of at least 5%;
• proclivity to affect pregnant women;
• families with a dominant mode of inheritance; and
• a favorable response to iron supplementation.

A second advance was realised with the recognition that periodic limb movements in sleep (PLMS) are evident in the anterior tibialis in 85% to 95% of RLS subjects, making them a useful parameter for diagnosis and assessing treatment adequacy. The third major advance was realised with the discovery of treatments, most notably dopaminergics and opioids. The fourth and most recent advance is the discovery that delivery of iron to the brain appears critical to the pathophysiology of RLS, as evidenced by depressed iron acquistion in in vivo and post-mortem brains.

Definition and Epidemiology
Four concensus criteria comprise those necessary to establish a diagnosis of RLS, although 5% to 7% of subjects deny symptom alleviation with movement (see Table 1). High prevalences (5% to 12%) in the US and Europe contrast with low prevalences in individuals of African or Asian descent. Prevalence varies significantly by age and sex, affecting 3% of 30-year-olds and 20% aged 80 and older, and women more often than men in an approximate 6:4 ratio. Nearly one-third of patients experience symptoms before the age of 20, so it is important to query for this disorder in children and adolescents where it can mimic attention defecit hyperactivity disorder (ADHD).Variability in symptom expressivity is the rule rather than exception. Symptoms are mild and infrequent at onset (e.g. two to three nights per month), and together with symptom-free periods delay presentation to the fourth to sixth decades of life. Increasingly, PLMS in the absence of subjective symptoms are recognized as a forme fruste of RLS. A familial component to RLS exists given that 20% to 60% of first-degree relatives are affected, autosomal dominant transmission patterns occur in many families, and monozygotic twins exhibit at least 80% concordance. Operationally, RLS is divided into primary and secondary forms. The former is remarkable for age of onset less than 45 years old, 2:1 female to male ratio, a slow, fluctuating progressive course, limited relation to the status of iron in the body, exacerbation by pregnancy and alcohol, and a 25% risk in first degree relatives. Secondary RLS occurs less often in families, exhibits a 1:1 female–male ratio, is more rapidly progressive, amd is more often correlated with the status of iron in the body, or associated with identifiable factors such as neuropathy, radiculopathy, myelopathy, neurodegenerative diseases, arthritic conditions, cervical spondylosis, end-stage renal disease, and diabetes (see Table 2).

The underlying pathophysiology of RLS remains unknown. The final common pathway mediating RLS/PLMS are neural elements intrinsic to the spinal cord given their frequent unveiling below the level of brainstem infarction, or spinal cord pathology. The principal deficit manifests as spinal reflex ‘hyperexcitability’, which is state-dependent (i.e. a reduced threshold and segmental spread of the flexor-reflex during sleep).Waking electromyographic (EMG) activity, resting motoneuron excitability, simple reflexes, and sensory evoked potentials are usually normal. Diffuse peripheral nerve dysfunction is nonetheless common, and is likely to modify RLS/PLMS expression. The most powerful influences impacting upon RLS/PLMS originate from outside the spinal cord, in supraspinal, premotor circuits. Major susceptibility loci have been reported on chromosomes 12q, 14q, and 9p in several families from diverse ethnic backgrounds. RLS therefore appears to be a complex disorder influenced by several acquired and genetic factors.