The following just appeared on the Yahoo dialysis_support group group and may be of interest.
Concise Review for Primary-Care Physicians
Restless Leg Syndrome
Michael H. Silber, M.B.Ch.B.
Source: Mayo Clinic Proc., March 1997, Vol. 72
Restless legs syndrome (RLS) is a common condition characterized by
unpleasant limb sensations that are precipitated by rest and relieved by
activity. Symptoms are worse during the evening and may result in insomnia.
Most cases are idiopathic, although the condition is sometimes familial and
may be associated with a range of medical illnesses, including chronic renal
failure and iron deficiency anemia. RLS is responsive to several
medications, including levodopa, dopamine agonists, benzodiazepines, opiods,
and some anticonvulsants. A practical approach to management involves a
stepwise plan, commencing with intermittent therapy with less potent agents
for mild cases and progressing to medications with greater potency but a
higher potential for side effects.
PLMS=periodic limb movements of sleep; RLS= restless leg syndrome
RLS, a common condition, may afflict up to 10 to 15% of the population.1 It
is often misdiagnosed, and patients report a mean of 2 years’ delay in the
correct diagnosis after they have sought medical attention. Although the
condition can develop in patients of any age, about 40% of patients recall
symptoms before age 20 years.2 The symptoms tend to worsen with age but may
fluctuate with periods of relative remission and exacerbation.
RLS is a clinical diagnosis based on the history of the patient. The six
essential characteristics are as follows:
unpleasant limb sensations,
sensations precipitated by rest and relieved by activity
compelling motor restlessness
symptoms that are worse during the evening or later at night
resultant insomnia and
an association with periodic limb movements of sleep (PLMS)
Unpleasant Limb Sensations: Unpleasant limb sensations are most commonly
experienced in the lower extremities, especially in the calves, but
occasionally occur in the thighs, feet, or upper extremities. They are
usually (but not always) bilateral. The discomfort is often difficult to
characterize, and patients often indicate that it is not pain. It is often
described as a deep-seated, creeping, crawling, jittery, tingling, burning,
or aching sensation. Frequently, patients report the sensations as
Sensations Precipitated by Rest and Relieved by Activity:
The unpleasant sensations are exclusively present (or worsen in severity)
while the person is lying or sitting and are relieved, at least temporarily,
by activity. Lying in bed is the most common precipitant, but symptoms may
also occur while the patient is sitting, especially for prolonged periods
such as in a theater, automobile or airplane.
Compelling Motor Restlessness: Motor restlessness is associated with a
patient’s compelling desire to move the affected limbs. Forcing them to
remain still may be impossible and always results in worsening of the
discomfort and occasionally causes an involuntary limb jerk. Voluntary
activity that may be beneficial involves stretching or jiggling the legs,
pacing the floor, or exercising, such as a stationary bicycle. Massaging the
legs or taking hot baths may be effective alternative measures.
Worsening of Symptoms During the Early Evening or Later at Night: Symptoms
are most troublesome while the person is in bed before sleep or during the
night. When the person is sitting, symptoms are most prominent during the
evening and are least noticeable in the morning. This phenomenon is probably
due to a circadian factor and does not occur only because people tend to
rest later during the day.
Resultant Insomnia: Most patients with RLS have sleep onset or sleep
maintenance insomnia, which is clearly due to limb discomfort. In some
patients, the symptoms are worst before sleep, whereas in others, they may
be most severe later during the night.
Association with PLMS: PLMS are stereotyped, repetitive flexion movements of
the legs during sleep that last .5 to 5 seconds and occur semirythmically at
intervals of 20 to 40 seconds. PLMS are common, especially in elderly
people,4 and are usually not associated with RLS or any other clinical
consequence. Nevertheless, about 80% of patients with RLS will experience
PLMS, and often a sleeping partner will describe the movements. PLMS
associated with RLS may sometimes cause arousals that fragment sleep and
result in excessive daytime sleepiness; occasionally, PLMS without RLS may
produce similar effects.
ETIOLOGIC FACTORS AND PATHOGENESIS
Most cases of RLS are idiopathic, but certain associated factors have been
reported. These factors include pregnancy; neurologic conditions such as
peripheral neuropathy, lumbosacral radiculopathsies, myelopathies, and
Parkinson’s disease; hematologic conditions, of which iron deficient anemia5
is the most important; chronic renal failure; folate and vitamin B
deficiency; rheumatoid arthritis; hypothyroidism; and medications such as
tricyclic antidepressants. A family history of RLS is common, and an
autosomal dominant pattern of inheritance has been suggested in several
The pathogenesis of RLS and PLMS is uncertain. Various lines of evidence6
suggest that a disturbance of inhibitory subcortal pathways, such as the
reticulospinal tract, may allow expression of a normally suppressed neural
generator at the spinal cord level. Thus process may be modulated by
abnormal periphery sensory input from, for instance, a peripheral
RLS may occur at any age. The condition may remain static, but about
two-thirds of patients report progression of symptoms in time. At least 16%
of patients describe remission of symptoms for a month or more.2 RLS does
not seem to predict other neurologic disease that is not evident at the time
RLS is usually diagnosed on the basis of the patient’s history, although
sleep studies are occasionally undertaken to identify the presence of PLMS.
In selected patients, the suggested immobilization test can be used to
measure leg movements while the patient is awake during the day. The most
common mimickers of RLS have different clinical features and are usually
readily distinguished by elicitation of a thorough history. These mimickers
include symptoms of peripheral neuropathy such as paresthesias (different
from RLS as a complication of peripheral neuropathy), nocturnal leg cramps,
fibromyalgia, and akathisia, the need to move is more often generated by an
inner sense of restlessness than by limb discomfort and is often not worse
at night or at rest.8
A limited search for a secondary cause of RLS should be undertaken,
especially if the symptoms are brief in duration or have recently worsened.
Symptoms of peripheral neuropathy, radiculopathies, or blood loss should be
elicited. A brief neurological examination of the legs should be performed.
Electromyography is not usually indicated if findings from a history or
examination do not suggest neurologic disease. In patients in whom RLS has
only recently began or has worsened substantially, serum iron, ferritin,
folate, vitamin B12, creatinine, and thyroid-stimulating hormone
concentrations should be determined.
Nonpharmological management includes reduction in caffeine and alcohol
intake and cessation of smoking.
Medications that have been shown to be effective in RLS are as follows:
carbidopa-levodopa, dopamine agonists, opiods, benzodiazepines,
anticonvulsants, and clonidine hydrochloride.
Carbidopa-Levodopa: In controlled studies carbidopa-levodopa has been shown
to diminish the symptoms of RLS and reduce the frequency of PLMS. For
symptoms that are especially troublesome before onset of sleep, the usual
initial dosage of carbidopa-levadopa is one-half to one 25-100 mg tablet
(25mg of carbidopa and 100 mg of levadopa) before bed. If the main problem
is waking with symptoms later during the night, one 25-100 mg tablet of
controlled-release carbidopa-levadopa is preferable. In some patients, a
combination of the short-acting and controlled-release formulations may be
needed; others may require an additional dose of medication during the early
evening or later during the night. Levadopa should always be taken on an
empty stomach to enhance absorption. Minor side effects such as nausea and
insomnia occur occasionally, but long-term studies have shown that
dyskinesia do not generally develop.
The main complication of levadopa therapy for RLS is the development of
worsening symptoms during the afternoon or early evening, despite adequate
control later at night.9 This phenomenon, which has been termed “restless
legs augmentation,” may occur in 50 to 80% of patients, sometimes within
months after therapy has been instituted. In the past, it is often confused
with the development of tolerance to the medication, an outcome that is
considerably rarer. A recent study9 showed that the development of restless
legs augmentation correlates with two factors: pretreatment restless legs
symptoms commencing earlier than 6 p.m. and administration of a total daily
dosage of levadopa of 200 mg or more. Some physicians believe that a risk of
daytime augmentation may be decreased by administering levadopa five nights
a week and using other agents on the other two nights, but this approach has
not been tested scientifically. Once augmentation has occurred, levadopa
therapy should be discontinued, and a different agent such as pergolide
mesylate should be used. Administering additional doses of levadopa earlier
during the day usually results in further exacerbation of the augmentation
Dopamine Agonists: Peroglide is a potent long-acting dopamine agonist that
clinically has proved to be effective for treating RLS.10 Because of a
relatively high frequency of minor side-effects. I do not advise it as a
first-line agent. It is especially helpful in patients who experience
levadopa-induced daytime augmentation of symptoms. Efficacious doses are
usually considerably lower than those needed for the treatment of Parkinson’
s disease. Treatment should commence with 0.05 mg before sleep, and this
dose can be increased by 0.05 mg every two nights until relief is obtained,
side-effects develop, or a dose of 0.6 to 0.8 is attained. The average
effective dose is 0.15 to 0.20 mg. Occasionally, an additional dose is
needed during the early evening. Side-effects include nausea (often
controllable with a snack), insomnia (well controlled with the addition of a
benzodiazepine), light headedness, and nasal congestion. Daytime
augmentation is considerably milder and less frequent with peroglide than
with levadopa therapy, but it may occur in 25% of patients.
Bromocriptine mesylate has also been shown to be effective in a controlled
study. Effective dosages range from 5 to 15 mg daily.
Opiods: Opiods have been shown to be effective in many patients,12 but their
use is somewhat limited because of side effects and concerns about potential
addiction. Low-potency agents such as codeine (initial dose, 30 mg) may be
useful in mild cases with intermittent symptoms. Higher potency agents such
as oxycodone hydrochloride (initial dose 4.5 to 5 mg) or methadone (initial
dose, 5 to 10 mg) have a definite role in the treatment of patients with
resistant symptoms in whom other therapies have failed.
Benzodiazepines: Benzodiazepines such as clonazepam (.5 to 2 mg), temazepam
(7.5 to 30 mg), and triazolam (.125 to .25 mg) may be effective in relieving
RLS.13 Most studies have shown that these drugs seem to reduce arousals from
PLMS rather than eliminate the movements. Concerns about their use include
theoretic potential to exacerbate coexisting obstructive sleep apnea
syndrome; daytime sedation, especially with longer acting agents such as
clonazepam; and in elderly patients, risks of falls at night. These drugs
are often useful in patients with mild or intermittent symptoms and are
occasionally beneficial in combination with levadopa or a dopamine agonist
in patients with more severe symptoms.
Anticonvulsants: Carbamazepine was found to be superior to placebo in
relieving RLS in a double-blind study,14 but subsequent clinical experience
has not suggested a high degree of efficacy.
In a recently published abstract,15 investigators suggested that gabapentin
(9300 to 2,700 mg daily in divided doses) may be effective in some patients.
A controlled trial is needed, however, to assess its efficacy more
Clonidine: In a recent controlled study,16 clonidine (mean dose, .5 mg)
provided some relief from RLS symptoms but did not affect PLMS. Frequent
side effects were noted, including dry mouth, decreased cogitation, and
lightheadedness. Treatment should be initiated with .1 mg daily.
Practical management of RLS can be challenging and must be adapted to the
individual patient. No single method is correct. The following suggested
approach is based on personal experience at the Mayo Sleep Disorders Center.
Dosage schedules are those discussed in the preceding sections on the
specific medication. Associated disorders should be excluded, as discussed
in the preceding section on Diagnosis.
Step One: For mild RLS (symptoms are intermittent or only mildly disruptive
to onset or maintenance of sleep), consider the use of either
benzodiazepine, such as temazepam, clonazepam, or triazolam, or a
low-potency opiod, such as codeine or propoxyphene. Often, these medications
can be taken intermittently, at least initially.
Step Two: For moderate or severs RLS (symptoms are continuous, moderately to
severely disruptive to onset or maintenance of sleep or unresponsive to
medications listed in Step One), carbidopa-levadopa is the drug of choice.
Step Three: If levadopa is ineffective, use is limited by side effects, or
daytime augmentation develops, discontinue use and institute peroglide.
Step Four: If peroglide is ineffective, use is limited by side effects, or
daytime augmentation develops, consider use of higher potency opiods such as
oxycodone or methadone, bromocriptine, clonidine, or gabapentin. Some
patients respond to combination therapy, such as benzodiazepine and
levadopa. In some patients, levadopa or peroglide can be reintroduced at a
later time after a period free of the drug.
Lavigne, GJ, Montplaisir, JY “Restless legs syndrome and sleep bruxism:
prevalence and association among Canadians,” Sleep 1994;17:739-743
Walters, AS, Hickey, K Maltzman J, Verrico, T, Joseph, D, Hening, W, et
al. "A questionnaire study of 138 patients with restless leg syndrome: the
Night Walker’ survey. Neurology 1996; 46:92-95