Restless leg syndrome

Synonym: Willis-Ekbom disease

What is restless legs syndrome?

The term restless legs syndrome (RLS) was first used in the mid-1940s by Swedish neurologist Karl Ekbom to describe a disorder characterised by sensory symptoms and motor disturbances of the limbs, mainly occurring during rest.

RLS is characterised by an urge to move, usually but not always affecting the legs. Abnormal sensations, including tingling, aching, or burning, are usually present in association with restless legs. There may be associated pain, which can be severe. The abnormal sensations tend to be worse in the evenings and are temporarily or partially relieved by movement.¹

This article is only relevant to adults aged 18 and over.

• Prevalence in the adult population is between 1.9% and 4.6% in Western Europe.

• The prevalence increases with age. Symptoms begin after 40 years of age in most patients but it can occur at any age.

• Over the age of 35 years, the prevalence in women is about double that of men. This is thought to be related to pregnancy. In younger adults, both sexes are equally affected.

RLS may be idiopathic or symptomatic of an underlying condition. In most people there is no apparent cause (idiopathic or primary RLS). 18.5-59.6% of patients with idiopathic RLS have a family history, suggesting a genetic component.¹

It is thought to be related in some way to dysfunction of the dopaminergic system. Iron is important to dopamine metabolism and iron deficiency is one of the causes of restless legs syndrome, so some research has been concentrated on the use of iron.

In the absence of iron deficiency, however, iron replacement has not been proven to be efficacious, and aetiology is clearly more complex.³

Causes of secondary RLS include:

• Pregnancy (RLS is estimated to affect one in five pregnant women), usually during the third trimester.⁴

• Stage 5 chronic kidney disease.

• Iron deficiency (RLS is estimated to be present in about 24% of people with iron-deficiency anaemia).⁵

• Adverse effects of medication. Causative agents include beta-blockers, neuroleptics, lithium, antihistamines, antipsychotics, antiepileptics, antidepressants, and dopamine receptor blocking agents such as metoclopramide and prochlorperazine.²

Associations have also been found with:

• Periodic limb movement disorder (PLMD).^{6 7}

  PLMD is a disorder characterised by periodic episodes of repetitive involuntary limb movements during sleep, usually in the lower limbs. It causes sleep disturbance and daytime sleepiness. It differs from RLS in that movements are involuntary. It is present in 85% of people with RLS.²

• Folate deficiency, B12 deficiency, magnesium deficiency and vitamin D deficiency.

• Endocrine: diabetes mellitus, hypothyroidism.

• A range of neurological disorders including Parkinson's disease, polyneuropathy and spinal disorders.

• Rheumatoid arthritis, Sjögren's syndrome.

• Excessive intake of caffeine, alcohol or chocolate (possibly) and sleep deprivation.

• Obesity.

• Patients have characteristic difficulty in trying to depict their symptoms of RLS. They may describe creeping, crawling or other uncomfortable feelings in the legs and arms, relieved by rubbing or moving the affected limb.

• It is usually the lower legs which are affected. They may report sensations such as an almost irresistible urge to move the affected limbs.

• Patients often complain of pain in the affected limbs, which can be severe.

• The sensations are usually worse during inactivity and often interfere with sleep, leading to chronic sleep deprivation and stress. Daytime sleepiness is usually less than expected however, given the sleep disruption.

• It can lead to significant physical and emotional difficulties.

Diagnostic criteria should be met as set out by the International Restless Legs Syndrome Study Group (IRLSSG). The latest version was released in 2014. All essential criteria must be met for a positive diagnosis.

• Essential criteria:

  • An urge to move the legs, usually (but not always) accompanied by uncomfortable or unpleasant (and difficult to describe) sensations in the legs.

  • The urge to move the legs and any accompanying unpleasant sensations:

    • begin or worsen during periods of rest or inactivity such as lying or sitting.

    • are partially or totally relieved by movement such as walking, bending, stretching, etc, at least for as long as the activity continues.

    • are worse in the evening or at night rather than during the day, or only occur in the evening or night.

  • The above symptoms cannot be accounted for as symptoms primary to another medical or a behavioural condition. Examples given in the criteria are myalgia, venous stasis, leg oedema, arthritis, leg cramps, positional discomfort, or habitual foot tapping.

• The IRLSSG added the following caveats to their diagnostic criteria:

  • sometimes the urge to move the legs is present without uncomfortable sensations.

  • Sometimes the symptoms are felt in the arms or other parts of the body in addition to the legs, but the legs are usually affected first and most severely.

  • When symptoms are very severe, relief by activity may not be noticeable but must have been previously present.

  • When symptoms are very severe, worsening in the evening or night may not be noticeable but must have been previously present.

• Supportive criteria:

  • Positive response to dopaminergic treatment.

  • Periodic limb movements during sleep.

  • Positive family history of RLS in first-degree relatives.

• Clinical course may be:

  • Chronic-persistent: untreated, symptoms have occurred at least twice per week for the past year.

  • Intermittent: untreated, symptoms have occurred on average less than twice per week for the past year, with at least five lifetime occurrences.

• RLS may be triggered by peripheral neuropathy or radiculopathy but a distinction should be made between these disorders. In pure peripheral neuropathy and radiculopathy, patients do not have the compelling need to move to relieve leg discomfort and the RLS symptoms are not consistently worse at rest or at night.

• Neuroleptic-induced akathisia: motor restlessness induced by antipsychotic agents that block dopamine receptors. Patients feel compelled to move because of an inner sense of restlessness rather than a need specifically to move the legs.

• Positional discomfort: if the only movement needed is a small brief positional change to relieve pressure - for example, on an arthritic hip.

• Myalgia.

• Peripheral arterial disease: intermittent claudication is usually worse on exercise and improves with rest..

• Nocturnal leg cramps. Usually these are unilateral and require stretching of the muscle to ease the pain, rather than nonspecific movements.

• Parkinsonism.

• Venous insufficiency. Oedema or venous stasis.

• Attention deficit hyperactivity disorder (ADHD) in children.

• Serum ferritin: RLS is frequently associated with iron deficiency. Iron studies should be performed in the morning after fasting.

• Renal function: RLS may be associated with end-stage chronic kidney disease.

• Other investigations for underlying possible cause include fasting blood glucose, magnesium, TSH, vitamin B12 and folate. There is evidence suggesting low vitamin D may be associated with RLS and should be checked during the diagnostic process.⁹

• If the neurological examination suggests an associated peripheral neuropathy or radiculopathy, electromyography and nerve conduction studies should be undertaken.

Restless legs syndrome treatment and management ²

• Treat any underlying cause, including supplementation to correct vitamin, electrolyte or iron deficiency. Give iron supplementation according to guideline recommendations given below. If the cause is pregnancy, reassure that this should settle spontaneously usually a month or so after delivery. Medication is not recommended in pregnancy.

• Consider medications which may be aggravating the situation and stop where possible.

• Reassurance.

Self-help advice

• Sleep hygiene advice.

• Advice on reducing alcohol and caffeine consumption where relevant.

• Regular moderate exercise.

• Stop smoking if a smoker.

• Warm baths before bedtime.

• Measures during an episode of RLS:

  • Stretching affected limbs.

  • Walking about.

  • Relaxation exercises.

  • Massaging affected limbs.

  • Distraction techniques.

RLS medication^{2 10}

¹¹

The guidelines from the IRLSSG on iron replacement differ from the American Academy of Sleep Medicine. The National Institute for Health and Care Excellence (NICE) CKS has recommended oral iron but does not comment on the use of IV iron.

• RLS treatment is needed only in the moderate-to-severe forms of the disorder and where symptoms are having a significant negative impact on quality of life. Medication doses should be kept to a minimum to reduce side effects and the risk of augmentation. Patients should understand medications are to control symptoms and are likely to be lifelong if no primary cause for RLS is found. Annual medication holidays should be undertaken to assess current symptoms.

• Iron replacement. Patients with RLS demonstrate lower ferritin levels in cerebrospinal fluid than controls. Oral ferrous sulphate 325mg twice daily with 100mg vitamin C may be effective at treating RLS in patients with ferritin <75micrograms/l. IV iron should be considered for patients with higher ferritin levels. For further details refer to the updated IRLSSG and AASM guidelines above.

• The alpha-2-delta ligands gabapentin and pregabalin are recommended as first line medications for RLS. Evidence suggests they are more effective than dopamine agonists with less risk of augmentation and impulse control disorders. They are used off-licence in this context.

• Alternative options include a weak opioid such as codeine if pain is predominant. Intermittent use of hypnotics such as a benzodiazepine or Z-drug may be suggested if sleep disturbance is the main issue; however, consider the risk of dependence in both cases.

• Dopamine agonists may be considered in certain circumstances or for patient groups. They have a higher risk of augmentation and impulse control disorders. Patients should be monitored for these side effects and counselled not to abruptly stop the medication, which can lead to severe rebound RLS.

• One article suggests there is evidence to replace low vitamin D. ⁹

• Management options which have been investigated but NOT found to be conclusively effective, and which are not currently advised, include:

  • Folate, B12 or magnesium therapy.

  • Acupuncture.¹²

  • Aerobic exercise.

  • Physiotherapy.

  • Infrared light

Long-term therapy¹³

Long-term therapy may be a problem due to loss of efficacy and augmentation. Loss of efficacy over time is an issue encountered with all medication used in the treatment of RLS. Doses may need to be gradually increased, or a change made to a different class of medication.

Augmentation is a problem with dopaminergic treatments and is characterised by a worsening of symptoms some length of time (months or years) into successful therapy. In this scenario, symptoms become more severe, or start earlier in the day, or spread to other parts of the body which were previously unaffected. The higher the dose and the longer the duration of treatment, the higher the risk of augmentation.

Refer to a neurologist or sleep specialist if:

• There is diagnostic uncertainty.

• There is insufficient initial response despite adequate duration and dose of treatment.

• Response to treatment becomes insufficient despite an increased dose.

• Side-effects are intolerable.

• The maximum recommended dosage is no longer effective.

• Clinicians are considering the use of dopamine agonists or require medication advice.

• Augmentation develops (onset of symptoms earlier in the day, increased severity of symptoms, or the spread of symptoms to different parts of the body, such as the arms, trunk or face).

Children with RLS should not be treated in primary care.

• Insomnia.

• Significant negative effect on quality of life.¹

• Anxiety and depression. (People with RLS have a higher risk of anxiety and depression than the general population).¹⁴

• Prognosis depends on if a cause is identified. RLS may worsen over time, stabilise, improve, or remit.

• Periods of remission are common, especially in younger adults.

• If RLS is secondary to another condition, it may resolve once that condition is treated.