Restless legs syndrome

Restless Legs Syndrome

I. What every physician needs to know.

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a sensory disorder of the nervous system that affects both children and adults. Women are more commonly affected than men, as are those of northern European descent. Unless the symptoms are overwhelming, RLS is often undiagnosed until the patient sees a sleep physician.

RLS is characterized by an uncontrollable, unpleasant urge to move the legs while at rest, sitting or lying in bed. RLS can also affect the arms, face, trunk, and genitals, but this is less common. Symptoms have a circadian preference; they are usually worse in the evening or at night, but can occur at any time of the day in sedentary people. RLS can interfere with getting to sleep or, less likely, staying asleep which often causes excessive sleepiness the following day. Moving the legs (or affected areas), rubbing, massaging, pacing, jiggling, stretching, flexing, or even walking temporarily relieves the sensation. Tossing and turning in bed can also relieve symptoms.

II. Diagnostic Confirmation: Are you sure your patient has restless legs syndrome?

RLS is a clinical diagnosis. There are no specific diagnostic tests, but blood tests and other exams assist to rule out other conditions. Four diagnostic criteria must be met (URGE):

Urge to move the legs often associated with an unpleasant feeling: creepy crawly (bugs on skin), pulling, gnawing, itching, tingling, burning, aching, cramping, painful, or “just hard to describe” sensation.
Rest-induced or worsens: begins or worsens when sitting or lying down – sitting at work or when watching television or reading the paper in the evening.
Gets better with activity: partially or totally relieved by movement.
Evening-urge is worse or occurs exclusively in evening or night, circadian pattern.

A. History Part I: Pattern Recognition:

Key symptoms

Onset is gradual and often progressive over time; there may be periods of remission.
Can’t sit still – irresistible urge to move, may be constantly tapping foot or bouncing leg and may be unaware of it or think it is just a habit.
Have trouble settling when they get into bed, tossing or turning, shaking leg or foot.
Look at legs and slap non-existent “bugs”.
Complain of excessive sleepiness during daytime from unrefreshed sleep.
Difficulty falling asleep (prolonged) or unable to stay asleep.
Legs move or kick at night.
Worse in the evening or at night.
Worse on long car, train, or airplane rides.

The typical patient has difficulty sitting still during a history and physical examination session. They may be seen sitting in a chair with their legs or other body parts in motion. Some patients get in and out of bed several times late evening before they finally settle in. This is much like the child who needs another visit with the parents or a drink or food before settling down for the night. (Late night and nocturnal eating can also be a clue to RLS.)

B. History Part 2: Prevalence:

Prevalence of RLS is variable affecting between 4-29% of adults and about 2% of children. Overall, RLS affects about 10% of the population. RLS is more common in women than men and increases with age, especially after age 50. People of northern European descent are more likely to have RLS, but any race or ethnic group can be affected.

There are two types of RLS: primary (idiopathic) and secondary. In primary RLS, the cause is unknown and may have a familial tendency, but the genetic link is yet to be identified. People with variations of some genes (BBTBD9, MEIS1, MAP2K5/LBXCOR1, PTPRD, and TOX3) are at increased risk of RLS developing. Secondary RLS is caused by another disease, condition, or as a result of taking certain medications. The following commonly cause RLS:

Alcohol
Caffeine
Diabetes
Iron deficiency – with or without anemia
Chronic kidney failure
Medications (anti-seizure, anti-nausea, antidepressants, some cold and allergy medications)
Parkinson’s disease
Peripheral neuropathy – damage to nerves in hands and feet
Pregnancy – especially the last 3 months
Rheumatoid arthritis
Tobacco

Iron deficiency or iron insufficiency in the brain or tissues is commonly implicated in RLS. Only about 15% of patients with RLS have a ferritin level <50 mcg/l, but the brain may still have inadequate concentrations in the substantia nigra as demonstrated in MRI studies. Dopamine is produced in this area and may not be adequately transported to other tissues when iron levels are low. There is also some evidence that the number of dopamine receptors is lower in the brain of RLS patients even though production is normal or increased. Patients may have a family history of RLS which predisposes (3-7 times more likely) them to the condition as well.

C. History Part 3: Competing diagnoses that can mimic restless legs syndrome.

Differential diagnosis

Akathisia: Inner urges to move all or part of the body. There is no circadian variation and does not have a predilection for rest times. Akathisia may be caused by SSRIs, antipsychotic neuroleptics, and dopamine blocking agents.
Neuropathy: May have similar complaints of numbness, tingling, and pain, but movement does not improve the feeling as in RLS and there is no circadian pattern. But, RLS may occur in conjunction with neuropathies.
Nocturnal leg cramps: Occur at night and at rest like RLS, but are usually unilateral and caused by involuntary sudden tightening and hardness of the muscle not seen in RLS.
Periodic limb movement disorder (PLMD): Has very similar signs and symptoms to RLS. Up to 80% of people with RLS also have periodic limb movement disorder. The main difference is that RLS occurs when awake and PLMD occurs at night when sleeping. Often people are not aware that their legs are moving at night until a polysomnogram demonstrates presence of the movements and the arousals that come from them. Treatment is also similar.
Radiculopathy: Spinal cord injury can cause a variety of unilateral or bilateral symptoms in the lower extremities including painful legs and flexion/extension of the toes. Radiculopathy usually does not exhibit a circadian pattern and may not be focal like RLS.
Vascular disease: May cause unpleasant sensations, especially deep vein thrombosis and claudication with activity, not rest. Varicose veins and venous insufficiency are notorious for discomfort. RLS patients generally have intact pulses without edema or cool extremities.

Other disorders to consider include the following: semi-conscious leg jiggling, fidgeting, arthritis leg discomfort, and positional discomfort.

D. Physical Examination Findings.

The physical examination in RLS is usually normal unless co-morbid conditions are present or the examiner identifies a secondary cause of RLS. The physician may observe movement of the legs or other body parts while the patient is sitting still or lying in bed. Some patients have a generalized restlessness.

The physical examination should be targeted to rule out neuropathy, radiculopathy, vascular disease, and other possible causes of the leg movements. Look for signs of anemia, B12 deficiency, and renal failure.

Laboratory tests often demonstrate iron deficiency with or without anemia. RLS may be more common in patients with elevated hemoglobin A1C (diabetes), elevated BUN/creatinine (kidney failure), or peripheral neuropathy (low vitamin B12/folate or elevated methylmalonic acid).

E. What diagnostic tests should be performed?

There are no diagnostic tests exclusive to RLS. The physician may want to order nerve conduction studies for peripheral neuropathy or a polysomnogram for periodic limb movement disorder. Other diagnostic tests of the back, spinal cord, or vasculature may be warranted for radiculopathy or vascular disease. Patients with previously undocumented anemia may require upper and lower gastrointestinal examinations to identify the source of blood loss.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Anemia and iron (CBC with MCV, ferritin – falsely elevated in inflammatory states, total iron, transferrin, TIBC). Evaluate for anemia or iron deficiency. Patients with a ferritin <50 mcg/l or evidence of low total iron should begin replacement therapy.
Kidney function (BUN, creatinine). Renal failure may precipitate RLS.
Leg cramps (magnesium). Although fluid deficit is often the cause, leg cramps may also be caused by low magnesium or potassium and other electrolytes.
Metabolic disorders (diabetes – fasting glucose or HgA1C, thyroid – TSH). Diabetes and thyroid disorders may affect RLS.
Neuropathy (vitamin B12, folate, methylmalonic acid if B12 <400 pg/ml). Evaluate for low vitamin states.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

There are no required imaging studies. Consider tests to rule out differential diagnoses.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Serial testing of labs is not needed. Do not order ferritin if patient is in an inflammatory state. Choose instead another indicator of iron status such as total serum iron and transferrin (also measured as total iron binding capacity [TIBC]); iron deficiency is suggested with a low total serum iron and high transferrin (TIBC). Alternatively, delay measurement until the patient is stable. Be sure patient is not taking vitamin supplements for a couple of days before testing vitamin levels as levels may be falsely elevated.

III. Default Management.

The management of RLS depends on its severity, presence of iron deficiency, and life disturbance. Repletion of vitamins and minerals is important and should be initiated as soon as possible. In very symptomatic patients, pharmacologic treatment of RLS should commence simultaneously. When vitamin and minerals levels are replete, evaluate ongoing need for other pharmacologic treatments.

A. Immediate management.

RLS is not an urgent issue. See ‘Long-term management’.

B. Physical Examination Tips to Guide Management.

After treatment is initiated, the patient should experience a decrease in limb activity at rest. The physician should observe for side effects such as drowsiness or unsteadiness, a common side effect of pharmacologic treatment that may place the patient at risk for falls or other adverse events.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

There are no specific follow-up laboratory tests for RLS. The primary care provider should re-evaluate abnormal laboratory tests associated with RLS in 3-6 months.

D. Long-term management.

Treatment for RLS targets symptomatic relief. The physician can consider both non-pharmacologic and pharmacologic options. Non-pharmacologic treatments should be tried first, before prescribing medications that often have unwanted side effects or drug interactions. Patients with intermittent or mild symptoms may not require pharmacologic therapy.

Non-pharmacologic options

Alcohol elimination
Caffeine elimination
Sequential compression stockings
Exercise late afternoon/early evening or stretching just before bed
Hot baths in most or cold baths in some
Heating pads or ice packs
Leg massages
Medication list examination and removal of offending ones, if able
Mental activity like puzzles and video games in evening
Tobacco elimination
Vibrating pad like Relaxis

Pharmacologic options

Vitamin and mineral repletion is important and can be curative of symptoms. Oral iron and possibly B12 are usually initiated, but patients with severe depletion or gastrointestinal intolerance may require intravenous iron or intramuscular vitamin B12.
Dopaminergic drugs are first-line therapeutic agents which act on the neurotransmitter dopamine in the brain. They include pramipexole, ropinirole, and rotigotine transdermal, but other dopaminergic precursor agents such as levodopa may also be used. Dosages are generally much lower than those used in Parkinson’s and are titrated to appropriate effect. The oral drugs are usually taken an hour or two before symptoms start in the late afternoon or evening, but some can be taken 2-3 times a day in severe cases.
Augmentation may occur with this class of drugs where symptoms start much earlier and are often more severe after a period of time taking the agent even with increased dosages of the drug. (The brain becomes more dependent on the dopamine drug and begins to produce less dopamine so more drug is needed for the same effect.) The physician often needs to discontinue the agent and choose another class of medication.

Other major side effects are edema, sleepiness soon after taking the medication or throughout the day, and compulsive behaviors. Compulsive behaviors may include new or increased gambling, drinking, shopping, smoking, spending money, etc. Compulsive behaviors may also include over-attention to thoroughness or tidiness, especially at work, which can be incapacitating.
Anticonvulsant medications are first-line in children and are often used in adults, especially when neuropathy is also present. The main agents are gabapentin, pregabalin, carbamazepine, and long-acting gabapentin enacarbil. Dosages are titrated to effect. Sedation, dizziness, hepatic disorders, and bone marrow suppression are the main adverse effects.
Benzodiazepines, like clonazepam, are sedating drugs that may help the patient get to sleep when symptoms invade bedtime. If used at other times of day, they may cause drowsiness, gait unsteadiness, and fall risk. Benzodiazepines may worsen obstructive sleep apnea.
Opioids are an effective alternative when patients cannot take dopaminergic agents, but the risk of tolerance and dependence is present. Opioids can be employed when RLS presents as pain when other agents are ineffective for the patient. Common side effects include constipation, sleepiness, or cognitive changes. Opioids may worsen obstructive sleep apnea or cause central sleep apnea.

E. Common Pitfalls and Side-Effects of Management

Remember to evaluate for iron deficiency, metabolic disease, and renal disease.
Most pharmacologic therapies, other than vitamins, can be associated with drowsiness, unsteadiness, or confusion.
Elderly patients may be more prone to side effects of the various medications and should start with the lowest dosage and proceed more slowly with increasing dosages.
There is conflicting evidence on whether antidepressants can cause or exacerbate RLS.
Primary RLS medications are traditionally taken within 1-2 hours of bedtime unless otherwise stated. Some patients need an afternoon/early evening dose, which can be smaller, of shorter-acting medications. Use the smallest dose to achieve control.
Clinicians generally reserve pregabalin and especially opioids until failure of the medications below. Other Parkinson’s medications like carbidopa-levodopa 25/100 mg can also be used at low doses. Pergolide, a dopamine agonist, should not be used; it was voluntarily withdrawn from the United States due to the risk of heart valve damage.

The following medications are more commonly used and should be started at the lowest dose and titrated to effect:

Pramipexole 0.125-1.5 mg
Ropinirole 0.25-4 mg
Rotigotine 1-3 mg/d patch
Gabapentin enacarbil 300-600 mg at 5 pm
Gabapentin 100-1800 mg
Clonazepam 0.25-2 mg (most common benzodiazepine used, but not exclusive)

IV. Management with Co-Morbidities

Renal impairment (if severe)

Maximum dose of pramipexole 1.5 mg/d
Maximum dose of ropinirole 3 mg/d
Maximum dose of gabapentin enacarbil is 300 mg every day to every other day
Maximum dose of gabapentin is 300 mg/d

Liver impairment

Pramipexole, ropinirole, rotigotine, gabapentin enacarbil, gabapentin – no adjustment, but use caution

Opioid medications may promote central apneas.

A. Renal Insufficiency.

Gabapentin is excreted through the renal system.

B. Liver Insufficiency.

None.

C. Systolic and Diastolic Heart Failure

Watch for inadequate drug clearance.

D. Coronary Artery Disease or Peripheral Vascular Disease

None.

E. Diabetes or other Endocrine issues

None.

F. Malignancy

None.

G. Immunosuppression (HIV, chronic steroids, etc).

None.

H. Primary Lung Disease (COPD, Asthma, ILD)

Watch for oversedation from agents.

I. Gastrointestinal or Nutrition Issues

Iron supplementation may cause constipation and require laxative therapy. Patients with previous bariatric surgery or removal of a significant portion of the small intestine may not absorb sufficient dietary or supplemental vitamins and iron. In these patients, parenteral therapy may be a better choice.

J. Hematologic or Coagulation Issues

None.

K. Dementia or Psychiatric Illness/Treatment

None.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Note initiation of new medications and possible fall risk. If patient has RLS and is anemic without cause, consider getting a colonoscopy as soon as feasible.

B. Anticipated Length of Stay.

This will be an incidental diagnosis and not an extended length of stay.

C. When is the Patient Ready for Discharge.

The patient is ready for discharge when the primary reason for admission is resolved. RLS is not a typical admitting diagnosis.

D. Arranging for Clinic Follow-up

1. When should clinic follow up be arranged and with whom.

The patient should have a follow-up appointment with the primary care provider in 3 months for evaluation of treatment.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

Patients should have a repeat test for abnormal vitamin or mineral studies at 3-6 months. This can also be decided by the primary care physician.

E. Placement Considerations.

None.

F. Prognosis and Patient Counseling.

Provide the patient with healthy dietary guidelines for iron (and vitamin B12 for neuropathy) if implicated in the cause of RLS. Caution the patient about medication side effects and to contact the primary care physician if augmentation or compulsive behaviors occur.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

None.

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

RLS does not generally require admission or readmission, but side effects from the medications may cause problems like falls that will precipitate an admission. Advise patients and families to avoid overdose and driving while sleepy.

What’s the Evidence?/References

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