What is restless legs syndrome?
Restless legs syndrome is a neurological disorder characterised by throbbing, pulling, creeping or other unpleasant
sensations in the legs and an uncontrollable, usually overwhelming, urge to move them. Symptoms occur primarily in the
evening when a person is relaxing, and can increase in severity throughout the night. Both legs may be affected or one
may be worse than the other. In more severe cases, the arms and lower trunk may also be affected.
Restless legs syndrome can be a primary condition or secondary to another disorder. It is known to have a genetic basis
and a positive family history is a strong risk factor. Despite this, the pathophysiology of restless legs syndrome remains
unclear; what is known about the function of the implicated genes does not yet explain the syndrome. Dopaminergic dysfunction
and iron deficiency are both thought to have a role in restless legs syndrome.1 The syndrome is also strongly
associated with depression and anxiety disorders, although whether these conditions are caused by restless legs syndrome
or are the result of lower sleep quality is not known.2
Restless legs syndrome is thought to affect between 7 - 15% of the population.3,4 It is twice as common
in females as in males and prevalence increases with age in most populations.2 Most people with restless legs
syndrome first report symptoms after middle-age, however, early onset is thought to be associated with increased severity
later in life.3
Approximately four in five people with restless legs syndrome also experience periodic limb movement of sleep (PLMS).
This is characterised by involuntary leg movement while the person is asleep. The condition can cause repeated waking
and poor sleep quality. The presence of PLMS in a person with restless legs syndrome is likely to increase the severity
of impact on the person's quality of life through the combination of delayed sleep onset from restless legs syndrome
and poor quality sleep from PLMS.
A diagnosis is made based on description of symptoms
There is no specific examination or test that will confirm a diagnosis of restless legs syndrome. The patient's description
of their symptoms, combined with a brief history, is sufficient to make a diagnosis.
The diagnostic criteria for restless legs syndrome is a history of:5
- A strong and often overwhelming urge to move the affected limbs, often associated with an uncomfortable or tingling
sensation (paraesthesia or dysaesthesia)
- Sensory symptoms that are triggered by rest, relaxation or sleep and relieved with movement
- Symptoms that are worse at night and are absent or negligible in the morning
- Symptoms that are partially or totally relieved by leg movement
The presence of sleep disruption or sleep onset problems, a positive family history and a history of response to dopaminergic
medicines (if previously taken), provide supportive evidence for the diagnosis.
The limb movements associated with restless legs syndrome are characteristic and repetitive - usually repeated dorsiflexing
of the big toe or flexion of the ankle, knee or hip, lasting between 5 - 90 seconds and occurring periodically.
Assess whether the cause is secondary to another condition
Restless legs syndrome can occur secondary to one of the following factors or conditions:6,7
- Iron deficiency
- Pregnancy, especially in the last trimester (prevalence of 11 - 26%), resolving after delivery
- Hypothyroidism or hyperthyroidism (can cause night-time restlessness)
- Rheumatoid arthritis
- Uraemia from chronic kidney disease
- Peripheral neuropathies, due to conditions such as diabetes and Charcot-Marie-Tooth disease
- Medicines, including anti-emetics (e.g. prochlorperazine), most antipsychotics (e.g. haloperidol, quetiapine and olanzapine),
anti-depressants (TCAs, SSRIs and SNRIs) and some over-the-counter cold and allergy remedies that contain sedating antihistamines
Further investigation is guided by the suspected secondary cause. Management of the cause, if identified, is likely
to eliminate or reduce the severity of restless legs syndrome in most people.
A serum ferritin test should be considered for patients with restless legs syndrome without an obvious secondary cause,
as iron deficiency is a common underlying cause.6 Although iron deficiency alone is not sufficient to cause
restless legs syndrome, serum ferritin correlates inversely with symptom severity.5 MRI, cerebrospinal fluid
and autopsy studies have shown that brain iron stores are reduced in patients with restless legs syndrome.5 Testing
is therefore a low cost, low harm way of potentially identifying a commonly implicated factor.
Symptomatic treatment of restless legs
Recommend lifestyle changes
Advice includes improving sleep hygiene (behaviours to enhance sleep), brief exercise, e.g. walking, before bedtime,
performing gentle leg stretches for five minutes prior to sleep and eating a healthy diet. Distracting activities, e.g.
reading a book, may also reduce the awareness of the discomfort.
Reassurance and support is also important, as many people believe that restless legs syndrome is a precursor condition
to Parkinson's disease. There is a large body of evidence showing no link between the two conditions.5,8
Best Practice Tip: Find out if there are any support groups within the
community that patients can be referred to for advice and education.
Medicines for severe symptoms
Pharmacological treatment should be limited to people with severe symptoms who are distressed by their condition and
whose daytime function is affected by poor sleep quality, despite lifestyle intervention and exclusion of secondary causes.
It is estimated that approximately 20% of people with restless legs syndrome have severe symptoms.5,9
Medicines are usually taken one to three hours prior to going to bed, as guided by symptom onset.8 Because
restless legs syndrome fluctuates over time, patients may require only intermittent medicine use.
The choice of medicine should be based on the patient's symptoms and requirements:
- Low-dose dopamine agonists, e.g. ropinirole, are first-line treatment for daily symptoms of restless leg syndrome8
- Dopamine precursors, e.g. levodopa, can be trialled if dopamine agonists are not tolerated or if medicine is only
- Anticonvulsants (particularly gabapentin) may be considered if treatment with dopaminergic medicines has failed or
is contraindicated, or where symptoms are painful
Dopaminergic medicines such as ropinirole and levodopa should never be abruptly stopped, as this can precipitate neuroleptic
malignant syndrome, particularly if the medicine has been used for a long time. If cessation is necessary, the dose should
be tapered gradually over at least one month. In addition, significant adverse effects, such as sleep attacks and impulse
control issues, are possible with dopaminergic medicines. These potential adverse effects should be discussed with patients,
and those with a history of addictive or compulsive behaviours should be monitored more closely while taking dopaminergic
Ropinirole has the most evidence of efficacy for restless legs syndrome (among dopamine agonists).8,9 In
New Zealand it is fully subsidised, but unapproved for this indication. Ropinirole can be started at 250 micrograms, daily,
taken two to three hours before bed, gradually titrated up to a maintenance dose of 0.5 - 3 mg /day.8
Pramipexole is subsidised and approved for use in restless legs syndrome.10 Pramipexole can be started at
125 micrograms, once daily, two to three hours before bed, doubled weekly as needed, to a maximum of 750 micrograms daily.8,11
Bromocriptine is often suggested as a treatment for restless leg syndrome, but there is limited evidence for its use.12
Augmentation is a common adverse effect of dopamine treatment
Augmentation is the worsening of restless leg symptoms over time, with symptoms occurring earlier in the day (than
before treatment) and may begin to involve the trunk and arms. It occurs in up to 70% of patients three to four weeks
after beginning treatment with a dopamine precursor, e.g. levodopa, but can occur with any dopaminergic medicine.14 Augmentation
may be less likely with intermittent treatment. If augmentation occurs, reduce the dose or stop the medicine for a short
time (low-dose opioids may be used as an adjunctive medicine, however, the evidence for their use is weak15).
Alternatively, switch to a longer acting formulation, or if using levodopa, switch to a dopamine agonist such as ropinirole.14
Levodopa was traditionally used first-line for the treatment of restless legs syndrome, however, adverse effects and
the high occurrence of augmentation with levodopa (see "Augmentation") mean that it is now considered second-line to dopamine
agonists. Levodopa is a short-acting medicine, therefore it is recommended in patients with intermittent symptoms or if
dopamine agonists are not tolerated.13 It is fully subsidised, but not approved for this indication.
Levodopa can be started at 50 mg, daily, one to two hours before bed, titrated to a maintenance dose of 100 - 200 mg/day.
It is formulated with either carbidopa or benserazide to prolong its actions in the central nervous system and reduce
rebound restless legs syndrome that can occur in the early morning.8 For some patients, symptoms may rebound
late at night. If rebound occurs regularly, switch to an alternative long-acting formulation.
There is some evidence that gabapentin is an effective treatment for restless legs syndrome, and is useful where pain
is a significant s ymptom.5,8 It can be started at 300 mg, daily, although evidence suggests doses of 1300
- 1800 mg/day are needed for full effect.8
Gabapentin is not approved for use in restless legs syndrome and not subsidised for this use, therefore the cost of
the medicine should be discussed with the patient.
N.B. Gabapentin is fully subsidised under Special Authority for the treatment of neuropathic pain, where a tricyclic
antidepressant has previously been trialled and is not tolerated or not effective.
Iron supplementation should be considered for patients with a serum ferritin level below 50 micrograms/L.5,15 However,
there is a lack of quality evidence for the treatment of restless legs syndrome with iron supplementation in patients
without an iron deficiency.1 The underlying cause of anaemia should always be assessed.
Low-dose strong opioids may be used temporarily to permit a lowering of the dose of dopaminergic medicines when augmentation
occurs.6 However, the evidence base for this group of medicines for the treatment of restless legs syndrome
Clonazepam may be considered for patients who have significant sleep disturbance as a result of restless legs syndrome,
particularly difficulty falling asleep. There is modest evidence for the intermittent use of clonazepam for sleep disturbance
at 1 mg, daily, before bedtime.9
Pharmacological treatment in pregnancy
Reassurance and advice about lifestyle measures is usually sufficient for most women who are pregnant and experiencing
restless legs syndrome. Pharmacological treatment should be a last resort.
Restless legs syndrome in women who are pregnant may be associated with iron or folic acid deficiency. Supplementation
with iron and folic acid is a safe treatment option, and these supplements are commonly used by women during pregnancy.
Where supplementation is ineffective and symptoms are severe, gabapentin (pregnancy safety category B1) or benzodiazepines
(category C) may be used, with careful consideration of the risks to the foetus associated with these medicines during
pregnancy, such as cleft palate, and neonatal syndromes, e.g. hypotonia, hypothermia and respiratory depression.16
Burning feet syndrome
Burning feet syndrome is a condition resembling restless legs syndrome, caused by the dysfunction of peripheral neurons.17 It
is most commonly seen in people aged over 40 years. Symptoms are described as a burning sensation, heaviness, numbness
or dull ache in the feet that is worse at night.17 The sensation is usually limited to the soles of the feet,
but may be more widespread. The condition may be idiopathic or secondary to another condition, such as hyperthyroidism
or diabetes.17 An underlying vitamin B deficiency may be present in some people with burning feet.
Neurologic examination may reveal hypoaesthesia (reduced sense of touch), allodynia (the perception of non-painful
stimuli as painful) or hyperalgesia (exaggerated pain perception). Objective signs are typically absent: there should
be no muscle atrophy, and knee and ankle reflexes should be normal.
Physical deformities such as muscle loss, high medial arch or toe clawing rule out burning feet and suggest other conditions,
such as autonomic neuropathy or Charcot-Marie-Tooth disease. The presence of marked erythema and increased skin temperature
is characteristic of erythromelalgia, a neurovascular pain disorder in which blood vessels become periodically blocked,
rather than burning feet syndrome. Burning feet may rarely co-exist with these conditions, but would be the less significant
Investigation for burning feet syndrome is directed by the suspected secondary cause (Table 1).17
Treatment should include advice on symptom control and relief: avoid tight shoes/socks and exposure to excessive heat.
During an episode, soaking the feet in water for fifteen minutes may relieve symptoms. Where required, pharmacological
management is similar to the management of neuropathic pain; begin with paracetamol and an adjuvant treatment such as
capsaicin ointment.17 Tricyclic antidepressants, carbamazepine or gabapentin may be added if symptoms are
Table 1: Initial investigations for burning feet syndrome17
|Appropriate testing may include:
|Liver function test
|ESR, serum free light chain testing (or Bence Jones protein in urine) and serum protein electrophoresis
|Ferritin / B12 / folate
|HIV status in at-risk patients
ACKNOWLEDGEMENT: Thank you to Dr Alex Bartle, Sleep Physician, Director Sleep Well Clinics, New Zealand
for expert guidance in developing this article.