Restless legs syndrome
Authors: P Medcalf, K P Bhatia
Journal: BMJ (2006)

Restless legs syndrome has probably been known for over three centuries but remains underdiagnosed. Recent advances in pathophysiology and new treatment options for the symptoms may not be widely appreciated. The syndrome has a prevalence of 10-15% in white adults, with some preponderance in women.1 Although it is widely believed to occur in middle aged or elderly people, it also affects children and adolescents.2 In over a third of patients symptoms start before the age of 10 years, although in most the disorder is not diagnosed until middle or late adult life.w1 One study has even asked whether “growing pains”—in a subgroup of children—may be a manifestation of this syndrome.3

The syndrome is characterised by unpleasant, “creepy crawly” sensations in the lower limbs, which occur at rest, mainly in the evenings when the person is seated or at night in bed, and are temporarily relieved by moving the legs. These cause the patient to move the legs relentlessly usually by pacing about in an attempt to gain relief. The International Restless Legs Syndrome Study Group has suggested four criteria for diagnosis: the desire to move the extremities, often associated with paraesthesiae or dysaesthesiae; motor restlessness; aggravation of symptoms by rest and at least temporary relief by activity; and worsening of symptoms in the evening or night.4

Restless legs syndrome is commonly associated with periodic leg movements of sleep (limb jerking) and even involuntary leg movements when awake. Such a complex of symptoms may be idiopathic or it may indicate a diverse range of underlying neurological and non-neurological disorders such as peripheral neuropathy, Parkinson's disease, uraemia, iron deficiency, varicose veins, and rheumatoid arthritis, or it may occur after gastrectomy. Restless legs may develop in or be aggravated by pregnancy.

Iron deficiency deserves a special mention as it is present in about a quarter of patients with restless legs syndrome, particularly in older people. In this group serum ferritin concentrations are inversely correlated with the severity of the symptoms in the legs.5 Reduced ferritin in the cerebrospinal fluid suggests that iron may have a role in the pathophysiology of the disorder. Reduction of iron has also been shown by magnetic resonance imaging in certain areas of the brain, notably the substantia nigra and the putamen.w2 The reduction in iron is proportionate to the severity of symptoms.

About 40% of patients with restless legs syndrome have a family history. In these patients it is inherited as an autosomal dominant disorder with variable penetrance and clinical expressivity. In the hereditary syndrome symptoms begin at a younger age, progression is slower, and the relation to serum iron status is less robust than in the idiopathic syndrome, which has a late onset (over age 45).

No anatomical pathology in the central nervous system is known to be associated with restless legs syndrome. Specialised neurophysiological studies indicate changes in excitability in the circuitry of the motor cortex in that the motor cortex is disinhibited. Some studies support a subcortical abnormality with impairment of the supraspinal inhibitory system.6 w3 Positron emission tomography has shown either normal or mildly reduced uptake of 18F-deoxyphenylalanine with a mild but significant reduction of D2 receptor binding in the striatum, suggesting post-synaptic dopaminergic dysfunction.7 w4 w5

Recognition of the disorder is an important first step in its management. Iron deficiency needs to be looked for, investigated, and treated, aiming for a ferritin concentration above 45 μg/l. Such treatment may itself reduce the symptoms. If symptoms are mild reassurance may be all that is needed. Caffeine may worsen the symptoms and is best avoided, especially at night, but there are no randomised controlled trials or systematic reviews to support this.

Drug treatment is offered to people with particularly troublesome symptoms or lack of sleep. Dopamine agonist receptor stimulating drugs are the first line treatment for restless legs syndrome.8 Levodopa is effective,9 but due to its short half life its use is limited by the insidious development of augmentation (earlier onset of symptoms during the day, increased severity of symptoms, spread of symptoms to the arms) and rebound (recurrence of restless legs symptoms early in the morning). This often necessitates increasing the size and frequency of doses of levodopa.

Studies show that all dopamine agonists are effective and well tolerated in restless legs syndrome, with pergolide, ropinirole, pramipexole, and cabergoline alleviating symptoms in 70-90% of patients.w6 A new transdermal patch, rotigotine, also looks promising.8 Ropinirole is now approved by the Food and Drug Administration for use for restless legs syndrome in the United States; pramipexole and ropinirole have similarly been licensed in the United Kingdom recently. Daytime sleepiness is a theoretical risk with all dopamine agonists, and patients need to be counselled about it. A slow titration period is recommended with all the agonists, with possible concomitant prescription of domperidone for the first few weeks to prevent nausea. Augmentation may occur (and may require an extra dose of dopamine agonist earlier in the day), but to a much lesser extent than with levodopa.



Wherefore to some, when being abed they betake themselves to sleep, presently in the arms and legs, leapings and contractions of the tendons, and so great a restlessness and tossing of their members ensue, if they were in a place of the greatest torture.

Thomas Willis, The London Practice of Physick (1685)



Specific studies show that pramipexole produced a 98% decrease in symptoms in 10 patients enrolled in a randomised double blind placebo controlled crossover trial.10 Ropinirole produced significant improvement over placebo in the symptoms of restless legs syndrome in a trial comprising 286 patients randomly assigned to 12 weeks of treatment or placebo.11

A significant reduction of symptoms was also seen in a placebo controlled trial of pergolide in 100 patients.12 w7 However, some patients taking pergolide for Parkinson's disease have been shown to develop valvular heart disease, although usually with higher doses than those used in restless legs syndrome.w7 Cabergoline, with the longest half life of 65 hours and therefore potentially the dopamine agonist least likely to cause augmentation, significantly reduced symptoms of restless legs syndrome in 85 patients in a placebo controlled trial.w8 Whether cabergoline can cause cardiac valve fibrosis (like the other ergot derivative, pergolide) is not known.

If dopamine agonists are not tolerated, second line options include opioids, clonazepam, carbamazepine, and gabapentin. Gabapentin may be particularly useful in patients with restless legs syndrome who are receiving dialysis. A Cochrane review on this is awaited. Little information is available about treating restless legs syndrome in pregnancy, so all drugs are best avoided. Symptoms almost always improve after delivery.w9