Understanding Restless Legs Syndrome: Epidemiology, Pathophysiology, Diagnosis, and Treatment

Restless legs syndrome ( RLS) is a debilitating condition. In 1945 it was defined as a distinct clinical entity characterized by the uncontrollable urge to move the legs due to an uncomfortable or unpleasant sensation that worsens at night and at rest, and is temporarily relieved by movement. This disorder is now recognized as a common condition in general practice with evidence-based therapeutic options supported by large, well-conducted clinical trials.

Restless legs syndrome ( RLS) is a common sensorimotor disorder. Many epidemiological studies support a high prevalence. It is estimated that it affects up to 12% of adults. Clinically, significant RLS, defined as moderate to severe illness occurring at least 2 times/week, is also common and is seen in 2.7% of adults. However, this figure is not uniform in all countries. For example, studies agree that RLS is more common in Europe (especially Scandinavia) and North America than in Asia.

Furthermore, the reported prevalence differs between studies when a severity criterion is included. In Australia, the only epidemiological data come from the Raine study, in which 3.7% of men and 2.2% of women met the diagnostic criteria of the International Restless Legs Syndrome Study Group Diagnostic Criteria (2003) with symptoms that occur ≥5 times/month and involve moderate to severe discomfort.

Onset and severity increase with age, and the condition is 2 times more common in women, although risks are equivalent between men and nulliparous women, indicating that pregnancy contributes significantly.

Renal failure leading to dialysis is a significant risk factor for RLS, and the presence of RLS in patients on dialysis is associated with increased mortality in this population. Of note, although kidney transplants reverse RLS within days to weeks, dialysis has not been shown to significantly improve symptom burden.

The underlying pathophysiology of restless legs syndrome (RLS) is not yet fully understood, although, crucially for patients, they can be assured that it is not a neurodegenerative disease. RLS frequently occurs in families with concordance between monozygotic twins ranging from 54% to 83%.

The mode of inheritance is usually autosomal dominant, especially with an early age of onset. Genome-wide association studies have shown that more than 20 loci are involved .

A key feature in restless legs syndrome (RLS) is dopaminergic dysfunction although, contrary to popular belief, it is not simply a case of dopaminergic deficiency of the central nervous system, despite the improvement that patients report with the use of dopaminergic agents and dopamine agonists.

Restless legs syndrome (RLS) is associated with iron deficiency related to brain iron deficiency and not serum iron deficiency, and only occurs in 25-44% of these patients.

This is supported by the finding of low iron levels in neuropathological samples, on MRI and fMRI brain imaging (particularly in the substantia nigra and putamen) and in cerebrospinal fluid (ferritin). Other causes of anemia alone (non-iron deficiency anemias) are not commonly associated with RLS.

Pregnancy is often associated with transient RLS . Symptoms are most common in the third trimester and usually resolve around the time of delivery. Of note, more than half of pregnancy-related RLS cases had no history of RLS, although the development of pregnancy-associated RLS increases the risk of developing chronic persistent RLS.

The diagnosis of RLS is clinical and there are established diagnostic criteria that include 5 essential and supporting characteristics.

Polysomnography is not routinely used but, when performed, can show repetitive muscle contractions of the lower extremities, known as periodic leg movements (PLMs), in 70-80% of patients with RLS. However, MPPs are also common in the general population (especially the elderly), in other sleep disorders such as obstructive sleep apnea, narcolepsy, and REM behavior disorder; also in disorders not related to sleep, such as Parkinson’s disease and other synucleinopathies.

As a sensorimotor disorder, the characteristic symptom of RLS is the uncomfortable or unpleasant need to move the legs (and, in some circumstances, the arms).

It is important to note that this sensation is not always painful or uncomfortable and that patients may use different descriptors to explain the symptoms.

Common terms include "need to move," "crawling sensation," "restlessness," "nervousness," and "legs want to move on their own . " Questionnaire symptom scales such as the International RLS Study Group scale may be a useful adjunct in deciding when to treat and monitoring response to treatment.

There are many imitations of restless legs that constitute the differential diagnosis and must be carefully excluded before making the diagnosis of RLS. These mimics include leg cramps, positional discomfort, myalgia, venous stasis, leg edema, arthritis, and habitual foot tapping. Sleep disturbances are common and could be the only reason for consultation in primary care.

Up to 90% of RLS patients complain of disorders in the initiation and maintenance of sleep.

Although daytime fatigue and sleepiness are common complaints, the expected level of daytime sleepiness is lower than expected for the level of sleep disturbance, suggesting a degree of RLS hyperarousal.

The natural history of RLS has been established through cohort studies. Although mild, the symptoms of intermittent forms of RLS may wax and wane while the symptoms of severe RLS appear to be more persistent with less chance of spontaneous remission.

A careful review of medications should be performed . Commonly implicated drugs that could precipitate or exacerbate RLS are antihistamines (particularly sedatives), selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and dopamine antagonists such as metoclopramide. Of the antidepressants, mirtazapine appears to be most closely associated with RLS while bupropion appears to be much better tolerated. Case studies have suggested that lithium could be an inducer of RLS.

It is essential to order both a complete blood count and fasting iron studies (including ferritin and transferrin saturation), because iron deficiency can be associated without anemia itself. Electrolytes, urea, and creatinine should be ordered to exclude clinically significant kidney disease, as well as a pregnancy test in premenopausal women.

If the history and examination reveal neuropathy , then screening for a cause should be performed, including diabetes, hypothyroidism and vitamin (B12 and folate) deficiencies, autoimmune diseases, and alcohol abuse.

Both non-pharmacological and pharmacological approaches are essential in the treatment of RLS. The severity and frequency of RLS symptoms should be established because this helps guide the choice of therapy. Intermittent RLS is commonly described as symptoms that occur <2 times/week. In contrast, chronic persistent RLS occurs, on average, at least twice a week.

For mild to moderate symptoms, non-pharmacological approaches may be sufficient and limit the need for dose escalation in patients with moderate to severe RLS, although the overall quality of the evidence is low.

Magnesium is highly regarded by the public as an essential treatment for RLS, but a recent, well-conducted systematic review found no conclusive evidence supporting its widespread use by the public.

Furthermore, although there appears to be a potential relationship between the presence and severity of RLS and vitamin D deficiency , evidence shows that vitamin D supplementation to control RLS appears to be contradictory; however, it must be considered.

Iron replacement is essential in the treatment of restless legs syndrome (RLS).

By consensus, it is suggested to aim for ferritin levels >75 g/l and/or transferrin saturation >20%. It is important to measure the latter because ferritin could be artificially elevated in the context of an acute phase response.

A common oral iron regimen is 325 mg ferrous sulfate (65 mg elemental iron) combined with 100 to 200 mg vitamin C to improve absorption. If ferritin is close to 75 g/l, intravenous iron is recommended due to the inverse correlation between oral iron absorption and ferritin levels. It is worth noting that the response to oral and intravenous iron is not immediate and clinical improvement may take 1 to 3 months to arrive.

Levodopa plus a DOPA decarboxylase inhibitor (either carbidopa or benserazide) is a reasonable option to treat intermittent RLS symptoms but is not recommended as chronic treatment due to the high risk of tolerance and worsening of drug-induced RLS . Early morning symptom rebound occurs in 20 to 35% of patients taking levodopa agents, which could be mitigated, in part, by the addition of controlled-release formulations.

Benzodiazepines could be used in patients with intermittent symptoms, particularly in patients who experience insomnia upon sleep onset . Clonazepam is the most studied of all agents, although its long-lasting hypnotic and sedative effects may limit its use.

Dopamine agonists are effective for the treatment of persistent chronic RLS to severe discomfort, warranting consideration of daily treatment. Once the first-line therapy has been chosen, it is suggested to try alpha-2-delta ligands first, unless there are significant contraindications. This recommendation stems from increased recognition of impulse control and enhancement disorders that could complicate dopamine agonist use.

In Australia, pramipexole is the only agent included in the Pharmaceutical Benefits Scheme while ropinirole and rotigotine patch are included in the Therapeutic Goods Administration (TGA). The doses (of pramipexole, rotigotine, and ropirinole) used for RLS are typically lower than those needed for the treatment of Parkinson’s disease because higher doses are associated with a greater risk of escalation.

Common side effects are nausea and dizziness, which usually disappear after 10 to 14 days. With higher doses, daytime drowsiness and sleep attacks may occur. Impulse control augmentation and impairment are two important side effects that have led to guidelines shifting away from dopamine agonists as first-line therapy.

Escalation is defined as a worsening of RLS symptoms after an initial positive response, with symptoms becoming more severe, often occurring earlier in the day, and sometimes extending to the arms/trunk in progressive cases. With pramipexole and ropinirole, the rate of increase is 40% to 70% over a 10-year period. If the rotigotine patch is used, it is reduced to 36%.

Because the increase is a dose-dependent effect, the maximum recommended doses should not be exceeded. If an increase occurs, consultation with a specialist is recommended. Various management strategies include switching to a nondopaminergic agonist agent, dividing doses, or using controlled-release formulations. If dopamine agonists are discontinued, they should be tapered off gradually because otherwise serious withdrawal effects could occur.

Impulse control disorder manifests as pathological gambling, hypersexuality or compulsive shopping, with an occurrence rate of 6% and 17%, starting on average 9 months after the start of dopamine agonist.

Alpha-2-delta ligands ( pregabalin, gabapentin, and gabapentin enacarbil ) are recognized as first-line treatments for chronic persistent RLS due to their comparable clinical efficacy along with lack of augmentation and impulse control disorder.

In Australia, none of these agents are listed on the PBS or approved by the TGA for this indication, so their use is off-label. The gabapentin enacarbil dose should be administered 1-2 hours before the usual onset of symptoms. Common adverse effects include dizziness, drowsiness, unsteadiness and cognitive disturbances, more common in older patients.

Special care should be taken when prescribing these agents in patients at increased risk of side effects, such as excessive weight, comorbid severe depression, dependence problems, and compromised respiratory reserve, particularly in combination with opioids. However, these agents are now preferred as first medications. Online therapy could be particularly advantageous for patients with comorbid insomnia, peripheral neuropathy, or anxiety.

Opioids may be useful for refractory RLS, defined as persistent symptoms despite treatment. This could occur due to the natural history of the condition, with a reduction in the effectiveness of first-line agents, increases, or medication side effects. The potential for abuse is low in patients without a history of substance abuse, although due to the known side effect profile of these high-potency agents, opioids should only be used in treatment-refractory cases.

Low potency agents should be tried first, but most patients will eventually require higher potency agents such as oxycodone/naloxone, which have the most evidence supported by randomized controlled trial data. Before starting any opioid, patients should be referred to a sleep doctor or neurologist.

Restless legs syndrome is a very common and debilitating disorder, characterized by an overwhelming need to move the legs, often associated with unpleasant sensations. Known risk factors are: pregnancy, end-stage renal failure on dialysis, iron deficiency, and certain exacerbating medications. Although the underlying pathophysiology is not yet fully understood, there is strong evidence for the role of iron and the need for supplementation aimed at achieving ferritin levels ≥75 g/l and/or transferrin saturations ≥20%.

Recent evidence supports a move away from dopamine agonists (pramipexole, ropinirole) as first-line agents due to the significant risk of augmentation as well as impulse control disorders. Alpha-2-delta ligands have been shown to be equally effective, although careful patient selection is required.