Restless legs syndrome

What every physician needs to know:

Restless legs syndrome (RLS) is a common neurological movement disorder that affects 5-10 percent of the general population. Sleep disturbances, such as insomnia, are a very common complaint of RLS patients.

RLS remains a clinical diagnosis made by patient history and physical examination. Four criteria are essential to make this diagnosis: an urge to move the legs in association with some paresthesias or disagreeable sensations, such as crawling, aching, or burning in the legs; relief of RLS sensations by movements; circadian rhythmicity of symptoms that are worse at night; symptoms are worse at rest.

RLS can be primary with an early onset or secondary with a late onset (>45 yo). Periodic leg movements in sleep are not necessary to make a diagnosis of RLS. The most common causes of secondary RLS include iron deficiency anemia, uremia, pregnancy, rheumatoid arthritis, and medications. RLS patients have brain iron deficiency despite a normal systemic iron status, which leads to dopamine dysfunction that produces the RLS symptoms. Some patients who have very infrequent symptoms can be candidates for solely non-pharmacologic therapy of RLS (decrease caffeine intake, mild exercise activity, hot baths).

Dopamine agonists, such as Pramipexole and Ropinirole, starting at 0.125 mg and 0.25 mg one hour before bedtime, respectively, are the first-line treatments for symptomatic patients. Side effects like nausea, headache, dizziness, augmentation, rebound, and even compulsive behaviors have been reported with these medications. Iron supplementation is beneficial if the serum ferritin level is less than 75 µg/liter, but its efficacy may take three to six months. Opioids and anti-epileptic agents may represent alternative therapeutic options.

Classification:

Primary RLS is hereditary, and more than half of RLS patients report a positive family history. The prevalence of RLS is three to five times higher among first-degree relatives than among those without RLS. Primary RLS is characterized by slowly progressing symptoms.

In contrast, secondary RLS is characterized by more rapid progression of symptoms and later age of onset. Secondary RLS can be associated with iron deficiency anemia in up to 43 percent of cases; renal failure, including patients on hemodialysis (21%) or peritoneal dialysis; pregnancy (19%), especially during the last trimester; peripheral or lumbosacral neuropathy; diabetes; Parkinson’s disease; rheumatoid arthritis; Sjogren syndrome; and chronic myelopathy. Medications that can worsen RLS are tricyclics (TCA), selective serotonin reuptake inhibitors (SSRI), lithium, antipsychotics, dopamine antagonists, antihistamines, and antiemetics.

Are you sure your patient has restless legs syndrome? What should you expect to find?

RLS patients usually present with sleep disturbance–that is, initiation and/or maintenance insomnia–since RLS is more common during the evening or night. Insomnia is the most common reason for consult among RLS patients. Some RLS patients can also present with complaint of disagreeable feeling in the legs, some leg pain, and/or the inability to stay still or get comfortable or with fatigue. RLS is usually triggered by long periods of inactivity, such as plane travel or car rides. The prevalence of RLS ranges around 5-10 percent in the general population and is more frequent among women and Caucasians than among men and members of other races. RLS remains a clinical diagnosis.

Primary RLS has an early onset (< 40 yo), tends to be familial and is less responsive to iron treatment, while secondary RLS has a late onset (>45 yo), is more rapidly progressive and sporadic, tends to be strongly affected by serum ferritin, and is associated with other medical conditions as listed above.

The International Restless Legs Syndrome Study Group developed essential diagnostic criteria for RLS:

• an irresistible urge to move the legs, caused by uncomfortable sensations (crawling, burning, pulling) that can affect both legs but can also be unilateral or involve the upper extremities in severe cases

• an urge to move or disagreeable sensations that are worsened by prolonged periods of rest or inactivity; increased intensity of the symptoms with the duration of rest

• an urge to move that is partially or totally (and immediately) improved by movement, such as walking or stretching

• an urge to move or disagreeable sensations that have a circadian rythmicity and are worse in the evening or at night than during the daytime; the circadian rhythmicity may disappear with time in severe cases of RLS

Some supportive criteria can also be helpful in the diagnosis of RLS: A positive family history of RLS, especially in patients with early onset RLS; the presence of increased periodic leg movements during sleep (PLMS) (rhythmic extension of the big toe during sleep occurring every 20-40 seconds) since the prevalence of PLMS can be higher than 80 percent in RLS patients; and improvement in symptoms with dopaminergic therapy, which is seen in more than 90 percent of RLS patients.

There is no need to order a polysomnography to diagnose RLS, as the diagnosis of RLS should be established based on the clinical criteria described above.

Beware: there are other diseases that can mimic restless legs syndrome:

Other conditions can mimic RLS. Peripheral neuropathy can present with burning sensations or pain and numbness; however, there is no urge to move, no relief with movement, and no circadian rhythmicity. Nocturnal leg cramps usually manifest with sudden muscular tightness/contraction that can be palpable and relieved by walking, but there is no urge to move. In neuroleptic-induced akathasia, there is an urge to move the entire body because of restlessness but no sensory discomfort and no circadian rhythmicity. Akathasia is not worse at rest.

With painful legs and moving toes, there is an urge to move the feet with repetitive movement of the toes but no circadian pattern. Hypnic jerks or sleep starts are sudden onsets of jerks at sleep onset that affect the legs; these can be associated with a sensation of falling. Finally, complex quiescegenic nocturnal dyskinesia consists of abnormal involuntary periodic movement with a circadian pattern but no discomfort or urge to move the legs.

How and/or why did the patient develop restless legs syndrome?

Familial studies have suggested that early onset primary RLS might follow an autosomal dominant pattern. Linkage analyses have discovered some common loci for RLS, but no causally related sequence variant or protein have been found.

In RLS, there are some iron and dopamine abnormalities in the brain. Iron-deficient patients are more likely to develop RLS than are controls. RLS patients have been found to have a lower brain iron concentration in the substantia nigra and the red nucleus, as quantified by MRI, compared to controls. Reduced ferritin was also found in the cerebrospinal fluid of the RLS patients. Dopamine and iron levels fall at night, indicating a circadian pattern.

Since iron is a cofactor for an enzyme involved in dopamine synthesis, the brain iron deficiency in RLS patients is likely to produce dopaminergic dysfunction. The evidence for the involvement of dopamine in the physiopathology of RLS comes from several observations:

• The dopaminergic system is involved in movement control.

• Dopamine levels are lower at night and have a wider diurnal variation compared to normal subjects without restless leg syndrome.

• Dopamine agonists relieve RLS symptoms.

• Dopamine antagonists exacerbate RLS symptoms.

• Animal iron deficiency studies show a decrease in dopamine transporter functioning on the cell surface.

• Autopsy studies in the brain of RLS patients have found a decrease in Dopamine-2 receptors that correlates directly to RLS severity.

These findings support the notions that alteration of the dopaminergic system in the brain can contribute to the symptoms of RLS and that iron and dopamine have a strong connection.

Some medications can worsen RLS. Selective serotonin reuptake inhibitors increase serotonin transmission, which lead to inhibition of the function of dopaminergic neurons; neuroleptics are dopamine-blocking agents; and lithium has been shown to decrease dopamine release.

Which individuals are at greatest risk of developing restless legs syndrome?

RLS is more common in women and older individuals than in men and younger people. More than 40 percent of RLS cases are hereditary.

Secondary RLS is most commonly found in patients with iron deficiency. RLS has been described in patients who were iron-deficient as a result of malignancy, partial gastrectomy, or blood donation. RLS patients also have decreased ferritin levels compared to controls, even when they have the same hemoglobin levels as controls. Patients with serum ferritin less than 50µg/L experience more severe RLS. Iron therapy has a beneficial impact on RLS symptoms.

RLS has been found in about 26 percent of pregnant women when stringent criteria from the International Restless Legs Syndrome Study Group were applied, and RLS symptoms increase from preconception to the third trimester. Pregnant women are two to three times more likely to develop RLS than are non-pregnant women. When compared to a pregnant control group, pregnant women with RLS have lower ferritin and folate levels. RLS remits post-partum in most women but might be persistent in some, which suggests that pregnancy is a risk factor for developing RLS.

RLS is common in patients with end-stage renal disease. RLS can occur before or after installation of dialysis treatment, whether hemodialysis or peritoneal dialysis. In those patients, an association was found between RLS and anemia with a positive response to epoetin alpha. RLS can improve or even resolve after successful renal transplantation.

RLS can occur in patients with neuropathy or radiculopathy, especially in patients with type 2 diabetes who also have myelopathies. Small-fiber sensory neuropathy is commonly associated with RLS.

RLS is also associated with rheumatoid arthritis; it can affect up to 25 percent of rheumatoid arthritis patients, especially women. RLS may be linked to the presence of neuropathy in this patient population, as the likelihood of developing RLS seems to correlate with the severity of the rheumatoid arthritis.

RLS is also associated with fibromyalgia and Sjogren syndrome. Whether RLS is associated with Parkinson’s disease is subject to debate since some authors have not found a higher prevalence of RLS among Parkinson’s patients, while others have found a high prevalence of Parkinson’s disease in RLS patients.

Medications and substances that can worsen or trigger RLS include the selective serotonin reuptake inhibitors, venlafaxine, mirtazapine, mianserin, bupropion, the tricyclic antidepressants, antipsychotics, antihistamines, lithium, dopamine antagonists, and even caffeine.

Secondary RLS most often remits once the associated disease process has been successfully treated.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

The patient should be screened for iron deficiency; a ferritin level <75µg/L is a good indicator of low iron stores and warrants iron supplementation. The blood work should also include renal function and a screen for diabetes with HgA1C, B12, and folate deficiency.

What imaging studies will be helpful in making or excluding the diagnosis of restless legs syndrome?

Spinal MRI might be helpful if spinal cord disease is suspected as a secondary cause of RLS.

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of restless legs syndrome?

Pulmonary diagnostic studies are not indicated.

What diagnostic procedures will be helpful in making or excluding the diagnosis of restless legs syndrome?

If the diagnosis of RLS is uncertain, a full polysomnography might be useful to evaluate for the presence of increased numbers of periodic leg movements during sleep, which would be a supportive criteria. The number of periodic leg movements usually correlates with RLS severity. Nerve conduction studies may be indicated if there is doubt about the presence of a neuropathy.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of restless legs syndrome?

Pathology/cytology/genetic studies are not indicated

If you decide the patient has restless legs syndrome, how should the patient be managed?

The degree of impairment and the frequency of the symptoms dictate the need for therapy. In patients with intermittent symptoms, mild exercise or the elimination of caffeine may be beneficial. Other measures include hot or cold baths, leg massages, relaxation exercises, and withholding offending medications under a physician’s supervision. While mild exercise can be beneficial, strenuous exercise should be avoided since it can worsen RLS symptoms.

Intermittent symptoms can justify the use of medications before a planned prolonged period of immobility, such as that the patient is likely to experience on a plane. This strategy has been anecdotally reported to be successful.

Long-term pharmacological therapy is indicated in patients with daily or very frequent symptoms that impair their quality of life and sleep.

Four classes of medications–dopamine agonists, anti-convulsants, opioids, and iron therapy–can be used to treat RLS.

Dopamine agonists

The dopaminergic agonists, which target the D2 and D3 receptor-subtype, are the first-line treatment for RLS. They have been widely studied for the treatment of RLS and are FDA-approved for this use. Dopaminergic agents relieve RLS symptoms in up to 90 percent of patients. Pramipexole and Ropirinole are the newest non-ergotamine derivatives.

Pramipexole binds the D2-D3 receptor sub-types. The starting dose of 0.125 mg can be increased by 0.125 mg weekly to the efficacious dose of 0.25-0.70 mg. Pramipexole should be administered as a single dose one or two hours before bedtime since its half-life is eight to twelve hours. A six-month double-blind trial showed that Pramipexole is an effective and well tolerated medication that significantly decreases the symptoms of RLS, as assessed by the International RLS Study Group Rating Scale. Pramipexole also decreases the number of periodic leg movements during sleep and sleep latency. The most common side effects were mild morning nausea, headache, insomnia, somnolence, dizziness, and fatigue.

Ropinirole is another dopaminergic agonist with high affinity to the D2 and D3 receptor. The initial dose of 0.25 mg can be increased weekly by 0.25 mg to reach the efficacious dose of 0.5-4 mg/day. Ropinirole has an onset of action of approximately one hour and a half-life of six hours, so it should be given one hour before bedtime. The most common side effects are nausea, headache, fatigue, dizziness, and vomiting. Ropinirole significantly improves RLS symptoms within one week of treatment and also has a beneficial effect on sleep disturbances and quality of life. Ropinirole can also be used as needed for the treatment of mild/ and or intermittent RLS.

Anti-convulsants

Gabapentin is an analogue of the amino acid GABA. Although its mode of action is not completely understood, it may promote the release of dopamine. Gabapentin is efficacious in the treatment of RLS, especially among patients with painful symptoms, and it is also effective in primary and uremic RLS, although it is not FDA-approved for RLS.There is some clinical suggestion that Gabapentin may be useful when combined with a dopaminergic medication. The starting dose of 300 mg before bedtime should be increased by 300 mg every three days until the symptoms are controlled or a maximum dose of 1800 mg per day is reached. Side effects may include dizziness, somnolence, and peripheral edema. Gabapentin might be used as a second line therapy for patients who are not adequately controlled with dopaminergic therapy.

Opioids

Opioid therapy is not FDA-approved for RLS, but it is used as monotherapy or combination therapy with dopaminergic agents. A controlled trial showed that oxycodone at a mean daily dose of 15.9 mg is efficacious because it can decrease the number of periodic leg movements in sleep and improve sleep efficiency. Opioid therapy can be considered in patients who fail dopaminergic therapy or who present with neuropathy or painful dysthesias. Opioid use is limited by its risk for dependency and its potential to worsen sleep-disordered breathing.

Iron therapy

Iron therapy is efficacious in RLS patients with low-normal serum ferritin levels (15-75 µg/L), but efficacy can take three to six months. Iron therapy has been shown to decrease RLS symptoms significantly based on the International Restless Leg Scale scores. RLS patients should take ferrous sulfate 325 mg twice a day on an empty stomach with vitamin C 100 mg orally twice a day to increase iron absorption. Patients should be supplemented with iron until the ferritin level reaches at least 50µg/L. Ferritin levels and transferrin saturation should be followed every three months to avoid hematochomatosis. Concomitant pharmacotherapy for RLS should be considered while waiting for the ferritin level to normalize.

Benzodiazepines

The benzodiazepines bind to the alpha-subunit of the GABA-A receptor, promoting sedation. They are commonly used to treat insomnia but are not FDA-approved to treat RLS. Benzodiazepines work mainly by improving sleep.

Early case reports suggested that Clonazepam was effective for the treatment of RLS and that it could reduce periodic leg movements in sleep. However, a recent review of the literature concluded that there is no consistent evidence of clinical benefit for Clonazepam in the treatment of RLS. Clonazepam has a long half life and can cause daytime somnolence and dependence.

What is the prognosis for patients managed in the recommended ways?

Loss of efficacy can be seen in up to 46 percent of patients during long-term treatment of RLS with dopaminergic agents, perhaps because of down regulation of the dopamine receptors. Tolerance does not lead to an increase or extension of symptoms to other body parts, compared to baseline.

RLS can progress, especially if the onset of disease happens in patients older than age forty-five, but the disease progression is usually slow. A reduction in dopaminergic therapy will worsen the symptoms, in contrast to RLS patients who experience augmentation. Augmentation is a complication that can arise during long-term dopaminergic administration, probably because of intense dopaminergic stimulation of D1 receptors compared to D2 receptors. Augmentation may be difficult to differentiate from fluctuation of RLS symptoms. Duration of treatment, iron deficiency, and sleep deprivation are risk factors for augmentation.

This complication is usually seen after at least three months of treatment with increasing doses of medication. Therefore, it is preferable to keep patients on the lowest effective dose possible. Augmentation is clinically characterized by RLS symptoms that paradoxically increase in severity, occur earlier in the day, that have a shorter latency at rest, and that can occasionally spread to the upper extremities. Augmentation, which is more frequent with Pramipexole (9%) than with Ropinirole (2.3%), can be treated by giving additional doses of dopaminergic agonist earlier in the day, reducing the dose of the dopaminergic agonist, or switching from one dopamine agonist to another or to an alternative class of medication.

Rebound is the reappearance of RLS symptoms after the medication has worn off such that the RLS symptoms occur late at night or early in the morning after the evening dose is no longer effective. Switching to another dopaminergic medication with a longer half life, such as Pergolide or Cabergoline (27 hours, 63-68 hours, respectively) will be efficacious. However, high cumulative doses and long-term therapy with Cabergoline in patients with Parkinsons disease has been associated with cardiac vavulopathy.

Impulse control disorders have been described in RLS patients on dopaminergic therapy. These have taken the form of pathological gambling, compulsive shopping or eating, kleptomania, and impulsive driving. No relationship between the duration of dopamine agonist exposure and the risk of impulse control disorders has been found, but impulse control disorders can develop in 7-17 percent of RLS patients on dopaminergic treatment.

What other considerations exist for patients with restless legs syndrome?

A family history should always be obtained in patients with primary RLS since the disease may start earlier with each new generation.

What’s the evidence?

Allen, RP, Picchietti, D, Hening, WA, Trenkwalder, C, Walters, AS, Montplaisir, J. “Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the Restless Legs Syndrome Diagnosis and Epidemiology Workshop at the National Institutes of Health”. Sleep Medicine. vol. 4. 2003. pp. 101-19. (This workshop report provides the most comprehensive review of the nature of restless legs syndrome.)

Trenkwalder, C, Hogl, B, Winkelman, J. “Recent advances in the diagnosis, genetics and treatment of restless legs syndrome”. J Neurol. vol. 256. 2008. pp. 539-53. (The inheritable nature of restless legs syndrome and the genetic foundation for therapy are reviewed here.)

Winkelman, J. “Genetics of restless legs syndrome”. Curr Neurol Neurosci Rep. vol. 8. 2008. pp. 211-16.

Trotti, L, Bhadriraju, S, Rye, DB. “An update on the pathophysiology and genetics of restless legs syndrome”. Curr Neurol Neurosci Rep. vol. 8. 2008. pp. 281-87.

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Trenkwalder, C, Hening, WA, Montagna, P, Oertel, WH, Allen, RP, Walters, AS. “Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice”. Mov Disord. vol. 23. 2008. pp. 2267-2302.

Wang, J, O’ Reilly, B, Venkataraman, R, Mysliwiec, V, Mysliwiec, A. “Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: a randomized, double-blind, placebo-controlled study”. Sleep Med. vol. 10. 2009. pp. 973-75.

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