Few conditions are characterized by the difficulty people with restless legs have in explaining their problem: they complain often and bitterly about their condition but as there's often nothing to see, or feel, or measure they may be dismissed as neurotics or kooks. People report sensations that are not painful yet are bothersome and often lead to physical and emotional disability. Once diagnosed, restless legs syndrome can usually be effectively treated, and in some cases, where a cause can be found, restless legs can be cured.
In the mid-1940s, Swedish neurologist Karl A. Ekbom described a disorder characterized by sensory symptoms and motor disturbance of the limbs, mainly during rest. He named the condition restless legs syndrome. Although the syndrome affects about 5% to 10% of the US population, it is often unrecognized and misdiagnosed. Although it may affect up to 10% of the US population, in perhaps 10% of the 10% is restless legs sufficiently bothersome for patients to seek treatment. Nonetheless, if 1% of the US population is sufficiently bothered by restless legs this represents 3 million people, more people than PD, almost as many people as Alzheimer disease.
Restless legs may begin at any age, even as early as infancy, but most patients who are severely affected are middle-aged or older. Symptoms progress over time in about two thirds of patients and may be severe enough to be disabling, disrupting sleep and impacting on a patient's life and well-being.
In 1995, the newly formed International Restless Legs Syndrome Study Group developed criteria for diagnosing restless legs syndrome. Four basic elements must be present to make the diagnosis:
The desire to move the limbs may be associated with paraesthesia characterized by a peculiar sensations often described as burning, or creeping, or crawling, or numbness, or pins and needles, or tingling. Or the desire to move the limbs may be associated with dysesthesia characterized by a peculiar sensation when the limbs are stroked or touched. Patients often describe an unpleasant sensation in the calves and occasionally in the thighs, feet, or upper limbs. Many patients in addition to the symptoms described above may relate vague, nonpainful, poorly described bilateral (rarely unilateral) discomfort in the limbs, using, in addition to the terms above, terms such as aching, or itching, or irritating, or goose-bump like, or painful.
Symptoms are similar to those described by patients with akathesia a condition caused by certain tranquillizing drugs or by levodopa in which people have an controlled desire to move and keep moving, a general body restlessness as opposed to restlessness confined to the legs. In contrast to patients with restless legs syndrome, those with akathesia have an inner feeling of restlessness, gain the most relief by resting in a recumbent position, and do not experience parenthesis or nocturnal worsening of symptoms.
Symptoms of restless legs are increased by rest, relieved by activity. The unpleasant limb sensations of restless legs syndrome are precipitated by rest or inactivity such as lying in bed at night, riding in a car or airplane, sitting in a theater. The discomfort is usually relieved by motor activity such as moving the legs, walking.
Some patients describe a buildup of discomfort and involuntary limb jerking if they remain still. There is an urge to move the legs because they often gain relief after moving. Increased restless can result in a compulsion to toss and turn in bed, or to pace the floor, or to stretch or shake the legs, or a need to exercise. Limb movements in restless legs syndrome are partly voluntary, in that patients choose to move to relieve the discomfort, and partly involuntary, since some patients are compelled to move. Such partly voluntary, partly involuntary movements are sometimes referred to as "a compulsion to move and keep moving."
All patients notice worsening of symptoms at night usually as they lie in bed before sleep or when they are awakened in the middle of the night. Most but not all patients notice an improvement early in the morning. Nocturnal worsening is caused by lack of motor activity at night and is also thought to be due to a disruption of the normal circadian rhythm: where when you lie down at night your legs should be at rest. But because of the disruption in the normal circadian rhythm it is as though your brain is ready for sleep but your legs are awake and want to remain awake and keep moving. In severe cases, patients experience symptoms both day and night.
About 80% of patients with restless legs syndrome have unilateral or bilateral periodic limb movements of sleep, also called nocturnal myoclonus. These movements are stereotyped, repetitive, slow flexion of the limbs (legs alone or legs more than arms) during the early stages of sleep. They occur semirhythmically at intervals of 5 to 60 seconds and last about 1.5 to 2.5 seconds. In the lower limbs, repetitive dorsi flexion of the big toe (the big toe moves upward toward the head)with fanning of the small toes is seen, along with flexion of the ankles, knees, and thighs. Periodic limb movements can occur while patients are awake and are called, similar to those caused by levodopa, dyskinesia. Such dyskinesias while awake although uncommon may, nonetheless be seen in up to 50% of patients in some series with restless legs syndrome. They are similar to periodic limb movements of sleep but occur only during wakefulness. They can be fast or slow and periodic or nonperiodic.
Because of limb discomfort and jerking, most patients with restless legs syndrome have disturbances of sleep onset or maintenance. The result is excessive daytime sleepiness and fatigability, although not to the same degree as that caused by narcolepsy.
In most cases, the cause of restless legs syndrome is unknown idiopathic. Such idiopathic disease can be familial (in 25% to 75% of cases) and, if so, is transmitted in an autosomal-dominant fashion from generation to generation not skipping a generation. Progressive decrease in age at onset with subsequent generations (ie, genetic anticipation) has been described in some families. Patients with familial restless legs syndrome tend to have an earlier age at onset and slower progression.
Restless legs syndrome can develop as a result of certain conditions including iron deficiency and peripheral neuropathy. These two conditions should be ruled out on clinical grounds before restless legs syndrome is labeled of unknown cause.
Table 1Factors and conditions that may contribute to restless legs (in order of frequency)
Restless legs syndrome can be the initial symptom of iron deficiency. A low serum ferritin level may precede a drop in serum iron level. Depletion of iron stores, in the absence of overt iron deficiency, can lead to restless legs syndrome. How this occurs in unknown. Treatment with ferrous sulfate may bring improvement. The evaluation of a person with a polyneuropathy is performed by a neurologist who in addition to an office examination may require additional tests called nerve conduction velocities and electromyography (the equivalent of an EKG of individual muscles). About 5% of patients with polyneuropathy especially those caused by uremia, rheumatoid arthritis, and diabetes have restless legs syndrome. Treatment of the underlying condition such as uremia, rheumatoid arthritis, diabetes may improve (decrease) the restless legs symptoms. Or treatment of the restless legs with drugs such as dopamine agonists may be tried while treatment of the underlying condition such as uremia, rheumatoid arthritis, diabetes) is proceeding. Other possibilities include: |
Ekbom originally proposed that it was mainly the result of accumulation of metabolites in the legs from venous congestion. Peripheral nerve abnormalities have also been proposed, but no structural changes in nerve endings have been seen. Many experts believe that the syndrome is generated centrally in the brain and not in the nerves outside the brain. Periodic limb movements of sleep, in particular, are thought to be caused by sleep-related disruption of descending inhibitory pathways that are normally active at the brain stem or spinal cord level.
On the basis of treatment response, restless legs syndrome has been linked to dopamine or opiate abnormalities. Dopamine blockers and opiate blockers reactivate symptoms when given to patients with the syndrome. Results of special imaging studies have suggested deficiency of dopamine D2 receptors. Sympathetic hyperactivity has also been implicated on the basis of observations that sympathetic nerve blockade relieves periodic limb movements of sleep and that alpha-adrenergic blockers improve symptoms of restless legs syndrome. Studies also have suggested possible underactivity of the serotonin and GABA neurotransmitter systems.
Diagnosis of restless legs syndrome is founded mainly on clinical history. If a secondary cause is suspected on the basis of history, abnormal findings on neurologic examination, or poor response to treatment, a laboratory work up should be done. Testing should measure levels of blood urea nitrogen, creatinine, fasting blood glucose, ferritin, magnesium, thyrotropin, and folate and should include a glucose tolerance test and a complete blood cell count.
Needle electromyography and nerve-conduction studies should be considered if Polyneuropathy is suspected on clinical grounds, even if results of neurologic examination are apparently normal. Evaluation in a sleep laboratory is sometimes required and may be used to quantify periodic limb movements of sleep or to characterize sleep architecture, especially in patients who continue to have significant sleep disturbance despite relief of sensory symptoms with treatment.
Patients with suspected restless legs syndrome who are sensitive to caffeine, alcohol, or nicotine should avoid these substances. Offending medications also should be discontinued. In general, physical measures are only partially or temporarily helpful. Some patients benefit from hot or cold baths, whirlpool baths, rubbing of the limbs, or vibratory or electrical stimulation of the feet and toes before bedtime.
Supplementation to correct deficiencies in vitamins (e.g., folate), electrolytes (e.g., magnesium), or iron may improve symptoms. Patients with prominent varicose veins in the legs may benefit from use of sclerosing agents . Those with uremia may have relief after kidney transplantation or correction of anemia with erythropoietin (Epogen, Procrit).
Drug therapy for primary restless legs syndrome is largely symptomatic, since cure is only possible in secondary disease. Medications should be initiated at a low dose and be taken an hour or two before bedtime to allow sufficient absorption and onset of action. Additional doses can be taken if symptoms cause awakening in the middle of the night. If tolerance to one drug develops, another class of drugs may be substituted. Monthly rotation of two or three agents found to be effective may help prevent tolerance. A combination of drugs may be beneficial in severe cases.
are less likely to produce augmentation or rebound and can be useful alone or along with levodopa in patients in whom one of these conditions develops. Side effects of dopamine agonists include nausea, light-headiness (related to a drop in blood pressure on standing) and drowsiness.
, a dopamine D2 and D3 receptor agonist, and ropinirole de (Requip), a dopamine D2 receptor agonist are effective in the treatment of Parkinson disease (PD) and restless legs (secondary to PD and unrelated to PD). Pramipexole (Mirapex) is started at 0.125 mg at bedtime and gradually increased to a maximum of 1.5 mg three times daily for PD. In restless legs unrelated to PD a dose of 1.5 mg at bedtime may be sufficient. Ropinirole is started at 0.25 mg and increased to 3 to 8 mg three times daily for PD. In restless legs unrelated to PD a dose of 3 to 8 mg at bedtime may be sufficient.
is a long-acting dopamine D1 and D2 receptor agonist that is effective in restless legs syndrome, even in patients who are unresponsive to levodopa. The dose is 0.05 mg before bedtime initially, and it can be increased by 0.05 mg every 3 to 5 days until relief is obtained or side effects develop. The usual effective daily total is 0.1 to 0.75 mg, given in divided doses; some patients may need up to 1.5 mg. In some people the dose can be given at night. The dopamine agonists are preferred both for the treatment of restless legs not associated with PD and for restless legs associated with PD. The dopamine agonists : pramipexole, ropinerole, and pergolide are non addicting and non habit forming.
can improve symptoms and periodic limb movements of sleep in restless legs syndrome of unknown cause as well as in restless legs associated with uremia. Although a formal study has not been done similar relief are obtained with the dopamine agonists: pramipexole, ropinerole, and pergolide. As pramipexole is excreted solely by the kidney it must be used cautiously (and at lower doses) in people with restless legs secondary to kidney failure. And in people with restless legs related to liver failure ropinerole and pergolide which are metabolized by the liver must be used cautiously and at lower doses.
For restless legs symptoms that start before sleep, one 25/100-mg carbidopa/levodopa tablet can be taken 1 hours before bedtime. If symptoms occur during the night, one 25/100-mg controlled-release carbidopa/levodopa (Sinemet CR) tablet can be used. In patients who have symptoms both before sleep and during the night, a combination of short-acting and controlled-release tablets can be given. Most patients experience benefits when the levodopa portion of carbidopa/levodopa totals 100 to 500 mg daily, although some may need 1,000 to 1,500 mg (which are high doses). Nausea and constipation are the most common side effects of levodopa.
The major drawback in prescribing levodopa for restless legs syndrome related to PD and not related to PD is that in about 80% of patients, augmentation (worsening) of symptoms occurs as early as a few months after starting levodopa. It can manifest as earlier onset during the evening or after assuming a restful position, as increased intensity in the morning (ie, rebound), or as extension of symptoms to the upper body. Augmentation (worsening) is more likely in patients with severe pretreatment symptoms and in those taking 200 mg or more of levodopa daily. If augmentation (worsening) or rebound develops, discontinuation of levodopa and substitution of a dopamine agonist is helpful.
- Double-blind studies have shown that carbamazepine (Tegretol), at a dose of 200 to 400 mg daily, is effective in reducing symptoms of of restless legs syndrome, especially among young patients with recent onset of symptoms. Subsequent experience with carbamazepine has been less convincing. Open-label studies have found gabapentin (Neurontin) to be effective in relieving symptoms and even lessening periodic limb movements. The drug is started at a dose of 100 to 300 mg at bedtime and increased by 100 to 300 mg every 3 days to a maximum of 2,400 mg daily in divided doses. Gabapentin is usually well tolerated but may cause transient or mild side effects, such as drowsiness, dizziness, imbalance, and fatigue.
is a pre-synaptic alpha2-adrenergic agonist used to lower blood pressure. It may be effective in restless legs syndrome of unknown cause and in that associated with uremia. The drug should be started at 0.1 mg at bedtime and can be increased every week by 0.1 mg to a maximum of 1 mg daily (average effective daily dose, 0.5 mg). Among the common side effects are dry mouth, decreased memory, light-headiness, drowsiness and constipation.
may be used alone in patients with mild or intermittent symptoms or as add-on therapy in severe cases. Clonazepam (Klonopin) has been shown to ease the painful symptoms and periodic limb movements of sleep in restless legs syndrome. Clonazepam can be started at 0.25 mg at bedtime and increased by 0.25 mg every week to a maximum of 3 to 4 mg daily in divided doses. Anecdotal reports indicate that other benzodiazepines, such as temazepam (Restoril) and alprazolam (Xanax), are also effective. The major side effects of benzodiazepines include daytime drowsiness, confusion, memory, loss, unsteadiness, falls, and aggravation of sleep apnea. The benzodiazepines are addictive and their use, as initial treatment is discouraged.
such as codeine can benefit patients with mild and intermittent symptoms, and higher-potency agents may have a role in refractory cases. However, most physicians are hesitant to use opioids in restless legs syndrome because of the risk of addiction.