Restless Legs
Restless Legs Syndrome is a common sleep-related movement disorder.
Fact Sheet
Prevalence
Restless Legs Syndrome (RLS) of any severity occurs in 5 to 15% of adults
2 to 3% of people have a clinically significant syndrome.
Most common in Northern European countries
Females more likely than men
Occurs at any age
Cause
The overall cause is incompletely understood but we have identified several associated abnormalities in the nervous system
Central Nervous System (CNS) = Brain + Spine
Iron stores are low in the brain and cerebrospinal fluid.
Dopamine improves symptoms
Peripheral Nerves
Elevated pinprick pain ratings in legs (hyperalgesia)
Family History
Present in 40 to 60% of cases
High concordance in twins studies
No specific gene mutations identified
Risk Factors
Systemic iron deficiency
Kidney failure
Neuropathy
Spinal cord pathology
Pregnancy
Multiple Sclerosis
Possible Parkinson’s Disease
Low Iron
Low serum iron stores in the form of Ferritin (<45 to 50 ng/mL) correlates with RLS
More strongly associated with older-onset RLS and those without a family history of RLS
Frequent blood donors develop RLS due to depletion of iron stores
Ferritin is also an acute phase reactant and '“normal” levels increase with age, so a normal ferritin doesn’t always exclude iron deficiency
Kidney Failure
RLS is strongly associated with Uremia (build up of toxins in your blood) that happens in kidney failure.
RLS present in 20 to 73% of dialysis patients and is often more severe
Neuropathy
Seen at a higher frequency in RLS patients
Pregnancy
RLS affects up to 25% of women during pregnancy, peaking in the third trimester and remitting soon after delivery
Parkinson’s
RLS affects 15 to 20% of patients with Parkinson’s
Clinical Features
The characteristic feature is an often unpleasant or uncomfortable urge to move the legs (and sometimes arms).
The symptoms emerge during periods of inactivity.
Most prominent in the evening.
Transient relief with movement.
Usually felt deep in the legs, between the knees and ankle.
The sensation can be described as a need to move, crawling, tingling, restlessness, cramping, creeping, pulling electric, itching or soreness.
Exacerbating Factors
Antihistamines - particularly older first-generation sedating antihistamines.
Dopamine receptor antagonists - such as antipsychotic medication or anti-nausea medication like metoclopramide or prochlorperazine.
Antidepressants - including mirtazapine and possible TCAs, SSRIs and SNRIs.
Natural History
Early and moderate RLS symptoms tend to wax and wane
Severe RLS symptoms tend to be persistent
The spontaneous remission rate ranges from 30 to 60%.
Adverse Health Outcomes
Associated with multiple morbidities and general poor health
Some evidence that RLS is a risk factor for
Cardiovascular disease and mortality
Stroke
All-cause mortality
Increased risk of suicide
Depression
Periodic Limb Movement of Sleep
Periodic episodes of repetitive and highly stereotyped limb movements occur during sleep. Last 0.5 to 10 seconds with intervals of 20 to 40 seconds. These are found in 80% of patients with RLS. The relationship between the two is unclear.
Differential Diagnoses
Volitional Movements - Foot tapping, leg rocking
Akathisia - Sense of inner restlessness within the whole body, associated with drugs that block dopamine
Nocturnal leg cramps - A common disorder involving spasms of the muscles of the feet or calf.
Position discomfort - Movement due to discomfort from prolonged sitting or lying
Leg pain - Due to any reason, such as peripheral neuropathy or vascular problems
Physiological Movement - Sleep is associated with normal movements such as jerks when falling asleep
Diagnosis
Clinical diagnosis
Management
Iron Replacement
Early morning, fasting iron blood test checking Ferritin, Total Iron-binding capacity (TIBC) and Transferrin saturation (TSAT)
Consider iron replacement if the serum ferritin is ≤75 ng/mL
As ferritin is also an acute phase reactant, testing for a (TSAT) of <20% may be more accurate, particularly if there is a concurrent inflammatory condition. Don’t replace iron if TSAT >45% of evidence of iron overload disorders
If iron deficient (Ferritin <30) then look for and treat any causes
Oral iron is easy and safe, start with 1 tablet taken daily at night, such as Ferrous Sulfate 325mg. The response is slow and may take months.
Intravenous iron works faster and patients may respond within days to weeks. It is effective in approximately 40 to 60% of appropriate patients.
Recheck iron after 3 months and then every 3 to 6 months until ferritin is >100.
Behaviour Strategies
The use of the following interventions is supported primarily on the basis of clinical experience and, in some cases, small, randomized trials.
Mental alerting activities, such as working on a computer or doing crossword puzzles, at times of rest or boredom
Moderate regular exercise
A trial of abstinence from caffeine and alcohol
For symptomatic relief – walking, bicycling, soaking the affected limbs, and leg massage, including pneumatic compression
Short daily hemodialysis for patients with end-stage kidney disease
Yoga and acupuncture are low-risk strategies that may have some benefit
Avoidance of aggravating factors
Sleep deprivation is known to aggravate RLS
Consideration of withdrawal of possibly predisposing medications
Caffeine
Antidepressants
Centrally acting antihistamines
Dopamine blockers such as anti-nausea medication
Medications
Intermittent symptoms (Symptoms <2 per week)
Trial behavioural therapies above first
For intermittent use
Carbidopa-levodopa 25mg/100mg, one-half or one tablet, at night, as needed. Short-term therapy is well tolerated. Side effects include nausea, dizziness, sleepiness and rebound symptoms in the second half of the night.
Benzodiazepine can be useful in milder cases, particularly in younger patients, such as clonazepam 1mg daily. Side effects include drowsiness, cognitive impairment in the morning, impotence and exacerbation of sleep apnoea. This is complicated by tolerance and possible abuse.
Low-dose opioid options include
Codeine 30 mg (60 to 180 mg)
Tramadol (immediate release) 50 mg (50 to 100 mg)
Tramadol (extended-release) 100 mg (100 to 200 mg)
High-potency opioids:
Morphine controlled release 10 or 15 mg (15 to 45 mg)
Oxycodone (immediate or extended release) 5 mg (10 to 30 mg)
Hydrocodone (immediate or extended release) 10 mg (20 to 45 mg)
Methadone 2.5 mg (5 to 20 mg)
Chronic Persistent Symptoms
First-line is a Gabapentinoid agent
Pregabalin, start at 50 to 75mg at night, 1 to 2 hours before the usual onset of symptoms, and the usual effective dose is 150 to 450mg per day. Side effects include dizziness, somnolence, fatigue, headache, weight gain and feet swelling.
Gabapentin, start at 100 to 300mg at night, and slowly increase the dose, the usual effective dose is 900 to 2400mg daily. Side effects include somnolence, dizziness, and ataxia.
Second-line is a Dopamine agonist (can be used in patients with a high risk of side effects from Gabapentionoid such as obesity, history of moderate depression, and previous substance abuse.
Pramipexole, immediate release, 0.125mg once daily. Time to peak blood level 2 hours. The dose can be increased by 0.125mg every two to three days depending on response. Most patients need 0.5mg. Side effects include nausea, lightheadedness, fatigue, nasal stuffiness, constipation, insomnia, leg swelling and mental state changes.
Augmentation
Augmentation is when there is a worsening of RLS symptoms with increasing doses of medication, including earlier onset of symptoms, increased intensity of symptoms and shorter effectiveness of the medication. It should be considered when:
Maintained increase in severity despite appropriate treatment or a dose increase
Earlier onset of symptoms in the afternoon/evening
Spread to other body parts such as arms
Shorter duration of medication action
The risk of augmentation with dopamine agonists is:
3 to 9% after one year
30% of patients after two years
42 to 68% after 8 to 10 years of use
Treatment of Augmentation
Re-evaluate iron stores + check if iron deficiency is masked by other conditions such as inflammation, malignancy or acute illness
Review and enforce behavioural therapies
Check for new exacerbating factors such as other medications and sleep disorders
Adjust dosing in mild augmentation, trial split dosing into afternoon and evening doses
Rotate formulations e.g. pramipexole to ropinirole
Discontinue dopamine agonist and replace with gabapentinoid
Consider adding low-dose opioid
Other Medications
Vitamin D deficiency has been associated with an increased risk of RLS in several observational studies. It is not yet known, however, whether vitamin D supplementation improves symptoms.
Cannabis has been described as beneficial for RLS in case reports but has not been studied systematically
There is inadequate evidence to suggest that magnesium supplementation is an effective treatment for RLS
Special Cases
Pregnancy - Education, reassurance, iron supplementation if indicated and behavioural strategies.
End-stage kidney disease - Similar to normal management but medication doses may need to be adjusted.
Refractory RLS
Defined as RLS unresponsive to monotherapy with tolerable doses of a dopamine agonist. This should prompt referral to a RLS specialist. The main treatment is a combination of agents such as a dopamine agonist, +/- gabapentinoid +/- benzodiazepine or opioid.
Fact Sheet
Restless Legs Syndrome Fact Sheet [PDF]. This is the shortened version to be used as a patient handout. This is also the simplified version without medical jargon.
References
Clinical features and diagnosis of Restless Legs Syndrome - UpToDate
Management of Restless Legs Syndrome - UpToDate
Useful Links
Restless Legs Syndrome Foundation - Patient information and support