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Restless Legs

Maladywise

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

References

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