Advances in managing RLS and PLMS

Effective therapeutic intervention is available through behavioral strategies and pharmacotherapy when treating restless legs syndrome and periodic leg movements in sleep

Restless legs syndrome (RLS) is a neurosensorimotor disorder of uncertain etiology that commonly disturbs sleep. Ekbom¹ first described the syndrome in 1945. The main feature of the disorder is paresthesia felt deep in the limbs that troubles the individual when he or she is at rest. In 1995, the International RLS Study Group² published primary and associated features of the disorder. The primary features of the idiopathic form of RLS provide the basis for diagnosis. RLS can be either idiopathic or secondary to other medical disorders. Table 1 lists the primary symptoms required for diagnosis and the secondary features that are commonly present. The patient’s history is normally enough to establish these features and the diagnosis of RLS.

PRIMARY FEATURES
Dysesthesias (uncomfortable sensations deep in the muscles of the legs and, less frequently, the arms or other body areas) are the hallmark symptom. The common descriptions of RLS sensations are tingling, burning, like water moving, like insects crawling, aching, nervous, grabbing, and (less often) painful.³ Some patients find it difficult to describe the sensation at all. The sensation is normally accompanied by a need or urge to move the affected limb; movement provides relief. The sensations are not generally painful, although up to 20% of patients may describe the sensation as being that of a painful limb. There are also patients who have neuropathy and RLS in combination.

The newsletter of the RLS Foundation, Rochester, NY, is called The Nightwalker. Walking at night is commonly used in an effort to relieve the sensation. To provide relief and satisfy the urge to move, patients use stretching, walking, shaking, marching in place, riding an exercise bicycle, or bending. Some will feel better upon standing. Severely affected patients are rarely capable of suppressing their restless movements for more than a brief period when they are symptomatic. The urge to move can vary from one night to the next.

Being at rest during either the day or the night causes the sensation to intensify. Both sensory and motor components may be worse. Being a passenger in the confined spaces of an airplane, train, or automobile will frequently worsen the sensation. Occasionally, dining, attending meetings or performances, or simply relaxing while reading or watching television may cause the sensation to worsen.

The paresthesias of RLS commonly increase during the evening or the early part of the night. The most common hours for RLS presentation are 4 pm to 4 am. Patients are commonly less bothered by symptoms in the morning, unless they are severely affected. Many find their relief arriving at 4 am, when they can finally enter consistent sleep.

ASSOCIATED FEATURES
Periodic leg movements in sleep (PLMS) are repetitive movements that typically occur as flexions of the foot, knee, and hip at intervals of 5 to 90 seconds. Most commonly, the interval is 20 to 40 seconds. The movements are present during non–rapid-eye-movement (REM) sleep and are less common during REM sleep. The flexion movement is also accompanied by an extension of the great toe in a manner similar to that seen in the Babinski reflex. Montplaisir et al⁴ in Montreal have determined that 80% to 88% of RLS patients will demonstrate PLMS during one or two nights of sleep study.
PLMS incidence increases after the age of 65 years. Ancoli-Israel et al⁵ described the finding that more than 30% of those over 65 have a significant presentation of PLMS. The clinical significance of this finding remains uncertain, although PLMS can contribute to the lightening of sleep and increased daytime sleepiness that is sometimes found in the elderly.

The delay of sleep onset can be very extended in patients with RLS. Some patients may discover that they are so fatigued that they can fall asleep, but will then awaken after 20 to 30 minutes and begin pacing for the next 1 to 2 hours. The repetitive movements that lead to arousal may also cause a subset of patients to become quite sleepy during the daytime. This sleepiness is usually not as severe as that found in patients with sleep apnea or narcolepsy. There are certainly patients who begin to have sufficient sleepiness to disturb their ability to drive.

Some patients with RLS report that they experience jerks while awake. These involuntary movements more typically occur in the evening. The sensation of RLS is often, but not always, present. The jerking is noted primarily as flexion at the hip, knee, and ankle. Montplaisir et al⁶ have designed a polygraphic test that is done prior to nocturnal polysomnography. The test can be done as either a fixed or suggested immobilization test as a means to identify these movements and better characterize the severity of RLS.

Between 30% and 50% of first-degree relatives of a patient with RLS may well experience some degree of RLS.⁷ Because RLS is frequently found in the offspring of RLS patients, it has been suggested that inheritance follows an autosomal-dominant pattern. Genetic studies continue in an effort to understand these features. The challenge in such studies is the high prevalence of the disorder. Large population samples are required to offer valid data for accurate analysis.

Most patients with RLS have the primary (idiopathic) form of the disorder. RLS can also manifest itself due to other medical illnesses. Anemia and iron deficiency can result in the development of RLS.^8-10 End-stage renal disease and its associated anemia result in up to 35% of patients complaining of RLS.^11,12 Patients who have undergone gastrectomy are also at increased risk for the development of RLS.^13,14

The idiopathic type of RLS can begin at any age, including childhood, but RLS problems increase with age. Recent studies^15,16 suggest that cognitive, behavioral, and affective disorders such as attention deficit hyperactivity disorder and oppositional defiant disorder may be more common in children who have RLS. In patients past the age of 60 years, the clinician should consider the possibility that the new presentation of RLS could be due to clinical or subclinical iron deficiency. Serum ferritin levels should be checked. Some patients experience remission and then return of the disorder; more commonly, though, it becomes progressive, particularly in patients who were affected at an early age.

PREVALENCE AND DIAGNOSIS
Pivotal epidemiologic studies have not yet been completed. Recent surveys^17-19 indicate that RLS occurs in 10% to 15% of the population. A larger Canadian study17 completed in 1994 indicated that 15% of respondents noted leg restlessness at bedtime. The 1996 Kentucky Behavioral Risk Factor Surveillance Survey18 showed that 5.9% of the population had symptoms similar to RLS that occurred very often, and an additional 4.1% reported them as happening often. The National Sleep Foundation completes surveys of the US population on an annual basis to determine sleep symptoms. Its 1998 survey19 revealed that 25% reported “unpleasant feelings in their legs such as creepy, crawly, or tingling sensations” a few nights or more per week; 8% experienced them almost every night. Subsequent surveys have been comparable.

Pregnancy sometimes results in the presentation of RLS. Various studies in pregnant women have indicated an RLS prevalence of 11% to 33%, most commonly in the third trimester. The most recent study was by Goodman et al,²⁰ who found that 19.4% of 500 women presented with RLS. Only approximately one fifth of these patients had any suggestion of symptoms prior to pregnancy. The reason for pregnancy-related RLS remains uncertain, but factors such as anemia, hormonal changes, and vascular congestion have been suggested.

RLS in renal disease occurs before and after the initiation of dialysis. Research has correlated various findings in patients with renal disease and RLS.²¹

RLS is primarily diagnosed through interviewing the patient. There are no specific tests in the sleep laboratory or the chemistry laboratory that will conclusively identify the disorder. There is certainly value in ensuring that no underlying primary medical disorders are present, however. It is important to rule out anemia and deficiencies of iron, vitamin B12, and folate before determining that a patient has idiopathic RLS. If there is any suggestion of a neuropathy, completion of an electromyogram and a nerve conduction study should be considered.

TREATMENT CONSIDERATIONS
Treatment should be focused on a set of target symptoms. The goal will be to produce the greatest reduction of symptoms for the patient while also minimizing the potential for side effects. Behavioral interventions should be included along with pharmacologic agents.

Reduction of the dysesthesias to the lowest potential level is important. This should occur around the clock. PLMS should be reduced to an asymptomatic level for both the patient and the bed partner. Sleep quality should be restored so that the patient experiences improved nocturnal sleep onset and continuity with good daytime alertness. Side effects should be minimized.

Table 2 provides a review of various strategies used to improve the symptoms of RLS. The goal should be to avoid anything that will overly stimulate the nervous system. Patients should be encouraged to use those methods that they have discovered to be helpful for themselves. These could include warming of the legs using a shower, a bath, or socks. Occasionally, cold application could be considered. Care must be taken to avoid neuropathy. Increased mental focus (for example, the playing of engrossing computer games) may prove helpful. Moderate exercise may help suppress symptoms, but overly active exercise or suddenly heightened exercise could cause problems.

Various dietary agents and medications have been described3 that worsen the symptoms of RLS and/or PLMS. Caffeine and chocolate are common offenders. Alcohol, particularly as it withdraws from the system, worsens RLS. Patients commonly describe problems caused by antidepressants. Newer agents that are selective serotonin reuptake inhibitors appear to worsen RLS in a significant portion of patients. Agents that block dopamine, such as the neuroleptics and antiemetic agents, may cause an abrupt worsening of the symptoms of RLS. For this reason (and also to treat some of the side effects of dopamine agonists) a physician might use domperidone, a dopaminergic antagonist that does not cross the blood-brain barrier. This antiemetic agent is not currently available in the United States, but can be obtained using a compassionate-use request from some Canadian suppliers.

Pharmacotherapy includes a variety of therapeutic agents. Dopaminergic agents have become the most common subjects of therapeutic trial by experienced clinicians. At times, the other therapeutic classes may be initial therapy, depending on the symptoms other than RLS that may be present in a particular patient. If patients have significant anxiety and other reasons for poor sleep, benzodiazepines might be considered. If pain is a prominent feature to the patient’s presentation, opiates may be offered. If the pain has a neuropathic quality, anticonvulsants, primarily gabapentin, would be an appropriate initial therapy.

Dopamine agents are divided into precursors and agonists. Studies21-24 have indicated that RLS and PLMS are both reduced by dopaminergic agents. The most common dopamine precursor in the United States is carbidopa/levodopa. It is available in both immediate-release and sustained-release preparations. Dosages for levodopa range from 100 mg to 300 mg, but patients have been treated at much higher dosages. Although these agents are most commonly used in Parkinson’s disease, therapeutic dosages for RLS have generally been noted to be lower than those required for more severe forms of Parkinson’s disease. The limitation in the use of levodopa is primarily the development of rebound or augmentation.25 Rebound involves the presentation of restlessness of greater intensity as the blood level of levodopa is falling. Augmentation is the presence of RLS at unexpected times of the day and at heightened levels of severity. This appears to be more common when the dosage reaches 300 mg or more and in patients who have a severe form of the disorder.

Various studies,^22-24,26-28 including open and double-blind trials, have described the benefits of dosages. These dosages vary in each patient, but benefits occur at dosages lower than the standard amounts used to treat Parkinson’s disease.

Pergolide requires careful dosing, beginning with a dose of 0.05 mg per day that is increased every 3 to 5 days until the symptoms are relieved. Side effects could include hypotension, nasal congestion, nausea, and constipation. As nausea can occur, domperidone can be offered during the first 2 to 4 weeks of therapy to lessen the peripheral dopaminergic side effects.22,23,26

Pramipexole has been used in an open-label trial27 and in a double-blind randomized trial24 with good efficacy. Significant improvement was noted in more than 70% of subjects treated with pramipexole at dosages ranging from 0.375 mg to 0.75 mg.24,27 The adjustment of dosage commonly proceeds at intervals of 2 to 3 days. Timing of doses is important, with the medication being taken 1 to 2 hours before bedtime or prior to the development of restlessness during the day.

Ropinirole has been reported efficacious by Ondo28 in an open trial with 16 patients. Overall, it was well tolerated and was considered generally as effective as the other dopaminergic agonists. Dosages ranged from 0.5 mg to 12 mg, with the mean daily dose being 2.8 mg (2.3 mg).

The dopaminergic agents are summarized in Table 3, which provides the dosages that might be considered for any of these agents. The keys to dosing are understanding the pharmacological properties of drugs and ensuring that therapeutic levels of medication are available when the RLS patient needs relief.

Opioid medications have a long, significant history of benefit in the treatment of RLS. The first report of their use in the medical literature was by Willis, made in the 1670s and concerning laudanum. Subsequently, Ekbom1 reported the benefits of codeine in 1945. More recently, Walters et al²⁹ described the benefits of oxycodone at 15.9 mg per day. Agents such as codeine (at 15 mg to 240 mg per day), propoxyphene (at 130 mg to 520 mg per day), oxycodone (at 0.2 mg to 20 mg per day), and methadone (at 5 mg to 30 mg per day) have all been described29 as beneficial. Side effects can sometimes be a problem; these include constipation, sedation, nausea, and vomiting that can sometimes limit therapeutic benefit. There is little evidence to suggest that addiction develops in the vast majority of patients with RLS. The stigma attached to the use of these agents may be an issue, however, particularly regarding a physician’s comfort in offering them.

Although publication on this topic is pending, significant benefits have been seen for levorphanol tartrate in severely affected patients. Levorphanol at 1 mg to 6 mg per day has been particularly effective, in view of its half life of 8 to 15 hours and its rapid onset of action. Tolerance does not appear to be a significant issue.

Clonazepam has been standard therapy for the past 30 years. Other benzodiazepines, such as lorazepam and triazolam, have also been offered. Open-label published reports^30,31 demonstrate that a dosage of 0.5 mg to 4 mg of clonazepam offers benefits. The primary side effects include carry-over sedation, memory disturbance, and imbalance. Dependency appears to be a small but potential problem, and issues of withdrawal may present themselves when these agents must be discontinued.

Anticonvulsant agents such as carbamazepine³² and gabapentin^33,34 have been used in the treatment of RLS patients who have mild to moderate symptoms. The benefits noted have included a reduction in restlessness and, perhaps, a reduction of pain. Sleep latency and sleep efficiency have also been reported32 as improved when carbamazepine was offered. For more severely affected patients, these agents may not be of sufficient benefit to be used as monotherapy. They are most beneficial in special cases or as second-line therapy.

Other RLS treatments have included bromocriptine, clonidine, centrally active a-adrenergic antagonists, and baclofen. Sedative hypnotic agents, b-blockers, tryptophan, over-the-counter analgesics, antidepressants, and vasodilators have also been described as helpful in clinical and case lore. In addition to the supplementation called for in iron deficiency, various forms of dietary supplements (such as magnesium, calcium, and vitamins B12, C, and E) have also been discussed as potential therapeutic agents. To date, these agents have generally produced consistent improvement only during times of deficiency. An exception, however, may be iron supplementation in RLS patients with low-normal ferritin levels.

Two recent trials9,10 revealed the benefit of supplemental iron. The current recommendation is that 65 mg of elemental iron (325 mg of iron sulfate or gluconate) plus vitamin C be added to the daily diet in an attempt to bring the ferritin level above 60 mg/dL (normal ferritin levels are 18 to 300 mg/dL). Ferritin should be monitored at 3-month to 6-month intervals to avoid iron accumulation. Absorption of iron is often difficult. Intravenous administration was used by Nordlander8 in 1953, and a trial is in progress to investigate its role in RLS.

ALGORITHM FOR TREATMENT
The first task of the clinician is to determine the severity of the RLS symptomatology. The algorithm relies upon the concepts of Allen and Earley.25 The mildly affected patient has symptoms only at bedtime, the moderately affected patient has them between 6 pm and an hour before bedtime, and the severely affected patient has symptoms that develop before 6 pm.

In the mildly affected patient, behavioral strategies should be emphasized. For breakthrough nights of increasing severity, levodopa/carbidopa would be offered at 25/100. If more frequent symptoms of mild RLS are occurring at bedtime on four or more nights per week, more consistent use of either levodopa or a dopamine agonist would be considered. For severe sleep disturbances, clonazepam or another hypnotic agent would be considered.

For the more moderately affected patient, dosing would occur at the time of the evening meal if symptoms occur in the early evening. The dopamine agonist would be offered 1 to 2 hours before bedtime if the symptoms occur primarily at bedtime.

For the severely affected patient, the goal of therapy is to offer treatment before symptoms begin to intensify. If the symptoms occur in the middle of the afternoon, a noon dose of pramipexole or pergolide would be considered. Dosing might occur up to three times per day. If therapeutic intervention does not prove effective, the use of an opiate would then be considered, with levorphanol tartrate preferred. If nausea becomes a problem for users of a dopamine agonist, the use of domperidone would be appropriate.

CONCLUSION
RLS is a remarkably common disorder that can be a misery to patients. Its consequences (lost sleep and reduced daytime function) result in a worsening quality of life. Effective therapeutic intervention is available through behavioral strategies and pharmacotherapy. Determination of primary versus secondary causes is important. Iron deficiency, even if it is only mild, should be treated. Specific target symptoms should be reduced, with the goal being effective relief at the lowest incidence of side effects. Dopamine agonists have been seeing increasing use, and they appear to be safe. Ongoing research is occurring, and the underlying pathophysiology of RLS may well be described over the next 5 to 10 years.

Philip M. Becker, MD, is medical director, Sleep Medicine Institute, Presbyterian Hospital, Dallas, and clinical associate professor, Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas.

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