Restless Legs Syndrome
Mathew M. Clark, MD, private practice
Patients with restless legs syndrome experience
an intensely uncomfortable sensation in their legs and
occasionally in other extremities that compels them to move.
This sensation has been described as "creepy crawly,
tingling, bubbly" and "like bugs tunneling."
While often quite distressing, the sensation is not normally
reported as painful. Symp toms typically appear at rest and are
at least temporarily relieved by moving the limbs.
Characteristically following a diurnal variation, the symptoms
worsen later in the afternoon and evenings, particularly at
Most patients with restless legs syndrome also
experience periodic limb movements of sleep. These
movements involve a periodic, stereotypical Babinski-like
flexion of the legs, with extension of the foot and toe, which
occurs during sleep. Periodic limb movements of sleep typically
occur in clusters throughout the night, with a periodicity of 20
to 40 seconds. Patients whose periodic limb movements of sleep
are associated with arousal and disrupted sleep sufficient to
cause daytime drowsiness are said to have periodic limb movement
Although mild in some patients, the symptoms
of restless legs syndrome and periodic limb movements of sleep
can cause intense suffering in others. A common source of
distress is insomnia. Affected patients might come to dread
bedtime, as the late hour and inactivity combine to produce
severe symptoms. Patients might report seeking relief by pacing
the floors in the middle of the night, only to have their
symptoms return as soon as they collapse, exhausted, back to
bed. Even after patients are able to achieve sleep, patients
with periodic limb movement disorder might find that sleep is
unrestorative and of poor quality.
Patients with restless legs syndrome are often
troubled by similar daytime symptoms as well. Sedentary
activities might be difficult. Travel by car or airplane can be
uncomfortable. Patients might be unable to sit through classes
or meetings or to work in a seated position for any length of
The cause of restless legs syndrome and periodic limb
movements of sleep is not known. A possible mechanism for the production
of symptoms involves disinhibition of normal central nervous system
pacemakers. Clinical and laboratory evidence supports a primary role of
the dopaminergic system in these disorders, with contributing influences
of opioid and other neurotransmitters. Despite shared
neurochemical features, however, current evidence does not support the
concept that patients with restless legs syndrome are at any increased
risk for developing Parkinson disease.
Both restless legs syndrome and periodic limb
movements of sleep are reported more frequently by patients with certain
medical conditions than they are in the general population. Iron
deficiency, even at levels insufficient to cause anemia, can be
associated with restless legs syndrome. Dialysis patients
are often affected, with studies reporting a prevalence of 20% to 57% in
this population. Restless legs syndrome symptoms appear
to be unaffected by dialysis but are often relieved after renal
transplantation. Symptoms are also more common during
pregnancy. One survey of 500 patients found that 19% reported restless
legs syndrome symptoms during pregnancy, that 7% described these
symptoms as "severe," and that resolution of symptoms occurred
in 96% of affected patients within 1 month of delivery.
Increased prevalence of restless legs syndrome symptoms has been
reported in patients with hypothyroidism and diabetes, although these
associations have not been extensively studied and might represent
coincidental comorbidities. Increased symptoms have also
been associated with decreased magnesium and folate
levels. A small case series found that patients with
prominent leg varicosities had an increased incidence of restless legs
syndrome symptoms, and that many patients experienced improvement after
Restless legs syndrome is diagnosed through a careful
history. Patients should describe symptoms that are worse in the
evening, are most pronounced at rest, and are at least temporarily
improved by moving the affected limbs.
Conditions that might mimic restless legs syndrome
should be excluded, including anxiety, drug-induced akathisia,
peripheral neuropathy, leg cramps, and tic disorders.
Periodic limb movements of sleep is a sleep phenomenon
and, like snoring, cannot be noticed by the sleeping patient. The
diagnosis can be suggested from the reports of a patient's bed partner
but can only be formally established by polysomnography. Reports of
periodic, abrupt leg movements should be differentiated from hypnic
jerks, which occur briefly just as a patient is falling asleep.
Although most cases of restless legs syndrome are
idiopathic, it is important to search for secondary causes or
exacerbating factors and address these causes, when possible. Intake of
alcohol, caffeine, and nicotine should be documented and minimized.
Serum ferritin levels should be obtained; levels less
than 50 ng/mL have been associated with restless legs syndrome, even in
the absence of decreased hemoglobin or serum iron levels.[21,22]
A study of cerebral spinal fluid in 16 patients with restless legs
syndrome found markedly lower ferritin levels than in those of healthy
age-matched controls. A recent randomized, double-blind,
placebo-controlled trial of iron supplementation involving 28 patients
with restless legs syndrome, only some of whom were iron-deficient, did
not show a measurable benefit. Both of the recent consensus statements
recommend a trial of iron replacement in patients with restless legs
syndrome in whom iron deficiency has been documented.[3,4]
Serum glucose and creatinine should be measured.[3,4]
Some evidence supports obtaining thyroid-stimulating hormone, magnesium,
and folate levels as well. Classical neuroleptic and many antidepressant
medications can exacerbate symptoms.[24-26] Affected patients
could benefit from medication changes, including a switch to
antipsychotic medications with fewer extrapyramidal side effects, and
trials of alternative antidepressants.
Not all patients with restless legs syndrome need
medication. Many patients will benefit from appropriate sleep hygiene
practices, including avoiding caffeine, nicotine, and alcohol.
Consistent, relaxing bedtime routines are helpful. Vigorous exercise and
stimulation, including sexual activity, can worsen symptoms if they
occur within 1 or 2 hours of bedtime. Because sleep deprivation can
worsen restless legs syndrome symptoms, which can in turn lead to
further sleep deprivation, patients should allow themselves adequate
opportunity for sleep in their daily schedules. Patients
might find it helpful to make adaptive changes, such as working at a
high desk with a stool, taking an aisle seat on trips or in meetings,
and shifting their sleep cycle to permit a later awakening time.
Several potentially important but not rigorously
tested nonpharmacologic therapies have been used in restless legs
syndrome, including massage, electroencephalographic biofeedback,
counterirritants, and acupuncture. Much of the information
regarding these and other modalities is disseminated informally, through
newsletters, support groups, and the Internet. Patients might find it
helpful to explore these resources to learn more about this chronic
disorder and how to cope with it.
Although medications used in restless legs syndrome
have been more extensively studied than have nondrug therapies, much of
the evidence base that supports current recommendations remains
relatively weak. Many published studies describe small case reports or
clinical trials that are not randomized, not blinded, or involve few
patients. Studies that have involved placebos often show a strong
placebo effect in this disorder. Nevertheless, a
combination of clinical experience and published
studies supports a number of evidence-based recommendations regarding
the use of medications to treat restless legs syndrome symptoms. A
decision to use medications should take into account the severity of the
patient's symptoms and functional impairment and a knowledge of the side
effects and difficulties associated with various pharmacologic agents.
Dopaminergic agents, as a rule, are highly effective in
treating the symptoms of restless legs syndrome and periodic limb
movement disorder. In fact, a lack of response to a moderate dose of a
dopaminergic agent might lead one to question seriously the diagnosis.
Unfortunately, these agents frequently cause challenging side effects.
Many dopaminergic agents have a rebound phenomenon, with a tendency for
symptoms to increase as a dose wears off, so that a patient experiences
disruptive symptoms during the night or early morning. A related
phenomenon, augmentation, involves an increase in symptom intensity,
earlier daily onset of symptoms, decrease in medication efficacy, or
expansion of symptoms to other parts of the body.
Increasing medication dosage typically leads to further worsening of
rebound and augmentation once they occur. These side effects usually
disappear once the offending agent is discontinued.
Carbidopa-levodopa (Sinemet) has been the most
frequently used agent for initial treatment of restless legs syndrome.
Therapy may be started with a very low dose, such as one half of a
25/100-mg tablet taken 1 hour before bedtime, and titrated upward until
the desired effect is reached. The patient might need to take a second
dose during the night. An alternative regimen involves combining the
usual bedtime dose with an additional low dose, typically 25/100 mg of
the long-acting formulation (Sinemet CR). Patients might need additional
doses to control daytime symptoms. Total daily dose of levodopa above
200 mg should be prescribed with caution to avoid augmentation, which
has been reported in more than 50% of patients with restless legs
syndrome who take this medication.
The dopamine agonists bromocriptine (Parlodel) and
pergolide (Permax) are also effective in treating restless legs
syndrome. Pergolide, the more commonly used of the two drugs, appears to
cause less augmentation than is observed with levodopa, particularly
when higher doses are required.[31,32]An open-label trial of
pergolide in 15 patients with severe restless legs syndrome who had
previously experienced augmentation of symptoms while on levodopa found
that all patients experienced some degree of improvement while taking an
average of 0.4 mg of pergolide per day. None of these patients reported
serious augmentation during the 6-month period of observation.
A randomized, double-blind, placebo-controlled study of 16 patients with
restless legs syndrome who took an average 0.35 mg of pergolide per day
found a 61% global improvement in the treatment group compared with 19%
in those patients taking placebo. No rebound or
augmentation of restless legs syndrome symptoms was reported, but the
3-week duration of the trial limits the importance of this observation.
Another study started with patients taking levodopa and successfully
switched many patients who experienced augmentation to pergolide.
Because of side effects - gastrointestinal distress, hypotension, and
nasal stuffiness - pergolide needs to be started at a low dose and
slowly adjusted upward.
Two newer dopamine agonists, pramipexole (Mirapex) and
ropinirole (Requip), have also been found helpful in treating restless
legs syndrome,[34,35] although there are less experience and
fewer clinical trials involving these medications to date. Although the
dopamine agonists are currently considered to be second-line agents
after failure of carbidopa-levodopa therapy, as experience with and
knowledge of these promising drugs increases, they could become
medications of first choice.
The benzodiazepines have nonspecific sleep-promoting
properties. Whether they also have a specific effect on restless legs
syndrome and periodic limb movement disorder is unclear.
Clonazepam (Klonopin) is the best-studied benzodiazepine for this
disorder, but other medications in this class have been used as well.
Benzodiazepines could be a satisfactory choice in treating restless legs
syndrome symptoms that are relatively mild and primarily sleep related.
Side effects of daytime drowsiness, confusion, and unsteadiness might be
problematic, particularly in elderly patients. Prescribers and patients
also need to be aware of the potential for habituation and dependence
with all benzodiazepines.
Opioid agents have been shown to be helpful in both
restless legs syndrome and periodic limb movement disorder.[36,37]
In addition to their analgesic and sedative properties, they might work
through a specific interaction between the opioid and dopaminergic
systems. Direct comparisons between various opioids and between opioids
and other medications, are lacking. Because of concerns about their
addictive potential, these agents are generally reserved for use in more
severely affected patients, in patients who have failed other
medications, or in the uncommon patient with pain as a prominent
Anticonvulsant medications have been used with some
success in restless legs syndrome. A 1984 double-blind,
placebo-controlled study of carbamazepine (Tegretol) in 174 patients
showed significant improvement in both the treatment and placebo groups,
although there was a demonstrable treatment effect. Since
then, only two very small open-label trials have been undertaken using
carbamazepine in restless legs syndrome that have showed modest
benefits. More recently, gabapentin (Neurontin) has been found to have
some benefit in treating restless legs syndrome. In an open-label study
involving only 8 patients, gabapentin was given in doses ranging from
300 to 2,400 mg/d (mean 1,163 mg/d). Three patients had 76% to 100%
improvement in restless legs syndrome symptoms, 1 had 0% to 25%
improvement, and the remaining 4 patients experienced no benefit.
A second open-label series involved 16 consecutive patients who took
gabapentin at doses ranging from 300 mg at bedtime to 400 mg given 5
times a day. All patients reported at least a 50% improvement in
restless legs syndrome symptoms.
Although these anticonvulsants might have a role in
treating undifferentiated patients with restless legs syndrome, they
might be particularly well-suited for those with neuropathy or
considerable pain. Small trials have suggested some improvement of
restless legs syndrome symptoms with clonidine (Catapres),
which might be appropriately tried in a patient with both restless legs
syndrome and hypertension.
Restless legs syndrome is common and can be particularly
important in geriatric patients. Effective management involves excluding
or treating secondary causes, consistent sleep hygiene, and judicious
use of medications.
Restless Legs Syndrome
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