RESTELESS LEG SYNDROME

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SRC="Symb075c00b700f099006600.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">WEBLINKS </U></A></div> <div> <A HREF="#how_to_help_patients_with_restless_legs" TITLE="RESTELESS LEG SYNDROME"><U><IMG BORDER="0" SRC="Symb075c00b700f099006600.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">How to help patients with restless legs syndrome ARTICLE FROM POSTGRADUATE MEDICINE</U></A></div> <div> <IMG BORDER="0" SRC="Symb075c00b700f099006600.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">TREATMENTS</div> <div> <A HREF="#treatment_of_restless_leg_syndrome" TITLE="RESTELESS LEG SYNDROME"><U><IMG BORDER="0" SRC="Symb075c00b700f099006600.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">Treatment of restless leg syndrome</U></A></div> <div> <A HREF="#iron" TITLE="RESTELESS LEG SYNDROME"><U><IMG BORDER="0" SRC="Symb075c00b700f099006600.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">IRON</U></A></div> <div> <A HREF="http://www.requip.com/" TARGET="_top" TITLE="http://www.requip.com/"><U><IMG BORDER="0" SRC="Symb075c00b700f099006600.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">REQUIP WEB SITE </U></A></div> <div> <A HREF="http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/req1372.shtml" TARGET="_top" TITLE="http://www.pdrhealth.com/drug_info/rxdru"><U><IMG BORDER="0" SRC="Symb075c00b700f099006600.png" HEIGHT="16" WIDTH="24" ALIGN="bottom" HSPACE="0" VSPACE="0">PDR DRUG INFORMATION ON REQUIP </U></A></div> <bR> <bR> <bR> <div> <TABLE BORDER="2" CELLPADDING="2" CELLSPACING="1" WIDTH="787" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="BOX" RULES="ALL" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=TOP HEIGHT= 87 ><NOBR><div> <B> <A NAME="weblinks"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>Weblinks</B></div> <div> Restless Legs Syndrome Foundation <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>www.rls.org</U></FONT></div> <div> The National Institutes of Health RLS information <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>www.nlm.nih.gov/medlineplus/restlesslegs.html</U></FONT></div> <div> Sleep Foundation information about restless legs <FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>www.sleepfoundation.org/publications/fact_rls.cfm</U></FONT></div> </NOBR></tD> </tR> </TABLE></div> <bR> <bR> <div> <B> <A NAME="treatment_of_restless_leg_syndrome"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></B><B>TreatmentSof restless leg syndrome</B> is first directed toward any underlying illness, if known. For example, a search for iron deficiency by blood testing to reveal underlying iron deficiency anemia. Reduction or elimination of caffeine and alcohol can be very helpful. Stopping smoking can also diminish symptoms. Getting better sleep and  exercise can help some persons affected by restless legs.</div> <bR> <div> Medications used to treat restless leg syndrome include carbidopa- levodopa, opioids (such as propoxyphene) or tramadol (Ultram) for intermittent symptoms, carbamazepine, clonazepam, diazepam, triazolam, temazepam, baclofen, bromocriptine and clonidine. Also, recently, gabapentin (Neurontin) has been found helpful. The FDA has now approved ropinirole (Requip) for the treatment of restless leg syndrome. Other treatments that have been helpful for some patients include avoiding caffeine, warm/cold baths, electric nerve stimulation, oral magnesium, and acupuncture.</div> <div> <B><U> <A NAME="iron"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></U></B><B><U>IRON</U></B></div> <div> Current research suggests <B>correction of iron deficiency</B> may improve symptoms for some patients.</div> <div> Recent research has found that although there are no unique pathological changes in the brains of patients with RLS, it appears that cells in a portion of the mid-brain are not getting enough iron. (Penn State College of Medicine and Johns Hopkins University)</div> <bR> <div>  <A NAME="general_discussion"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A>GENERAL DISCUSSION:</div> <div> Washington -- A patient with restless legs syndrome is most definitely not someone whose boots are made for walking. In fact, a severe case of RLS would probably render someone too tired to walk very far.</div> <div> Described as both a sleep disorder and a neurologic movement disorder, patients with RLS have an irresistible urge to move their legs when what they most desire is to sit down and rest or just drop off to sleep. Such patients may spend the night tossing and turning, unable to settle into a comfortable sleeping position.</div> <div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="170" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 38 WIDTH="166"><div> With this article </div> <bR> </tD> </tR> </TABLE></div> <div> Still, patients don't tell and physicians don't ask about sleep disorders, so the syndrome often eludes diagnosis, said Clete Kushida, MD, PhD, director of Stanford University's Center for Human Sleep Research in Palo Alto, Calif.</div> <div> That's too bad, because RLS is easy to diagnose and to treat, said Dr. Kushida.</div> <div> But it's also easy to understand a hesitation to volunteer information about symptoms that one patient described as feeling as though ants are crawling over his legs. Patients also describe the sensations as creeping, crawling, itching, burning, aching, pulling or tugging.</div> <div> Patients wonder, crazy or normal?</div> <div> "Patients may be a little reluctant to tell their physicians about it because the primary symptoms are unusual, and they may fear that their physician will think they're crazy," said Dr. Kushida.</div> <div> "A lot of people have never heard of restless legs syndrome," said Deborah A. Nichols, Northwest Regional director of Stanford's Primary Care Sleep Education Project. "They knew that Grandma or Dad had these weird feelings so they think, 'It's alright that I have them.' "</div> <div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="95" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 134 WIDTH="91"><div> 10% to 15% of Americans have some degree of restless legs syndrome. </div> </tD> </tR> <tR> <tD VALIGN=CENTER HEIGHT= 19 WIDTH="91"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="19" ALIGN="bottom" WIDTH="91" HSPACE="0" VSPACE="0"></tD> </tR> </TABLE></div> <div> As many as 10% to 15% of the U.S. population has RLS to some degree, estimates Richard P. Allen, PhD, assistant professor of neurology at Johns Hopkins Medical Center in Baltimore. "In severe forms it's less common, dropping down to something like 2.5%."</div> <div> The prevalence was especially high among adults recently surveyed in rural Idaho by the Stanford and Johns Hopkins researchers. They found that 21% of more than 2,000 patients who visited a primary care clinic reported experiencing restless legs sensations at least once a month. Fifteen percent said they experienced RLS at least once a week. The findings were published in the Oct. 27 <I>Archives of Internal Medicine</I> and are now being validated in another study expected to be completed early next year, said Dr. Kushida.</div> <div> RLS, which was first recognized more than 300 years ago by British physician Thomas Willis, often runs in families and is diagnosed most frequently in middle-aged people, especially in women. However, some can trace their symptoms to childhood when they were said to be having "growing pains."</div> <div> Syndrome not exactly rare</div> <div> Syndrome not exactly rare</div> <div> RLS affects as many as 19% of women during pregnancy but symptoms usually subside within a few weeks postpartum. The syndrome also affects up to 50% of patients with end-stage renal failure and is particularly troubling during the confinement of dialysis. Improvements have been seen after kidney transplants.</div> <div> While there are no laboratory tests available to confirm a diagnosis, four criteria can generally pinpoint the syndrome.</div> <div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="95" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 134 WIDTH="91"><div> Patients say estless legs feel like itching, burning or ants crawling around. </div> </tD> </tR> </TABLE></div> <div> The minimum criteria include a compelling urge to move the limbs, generally the legs; restlessness that includes pacing the floor and tossing and turning in bed; symptoms that are worse when resting but relieved by moving; and symptoms that are worse in the evening and at night.</div> <div> Evidence is pointing to a connection between iron deficiency and RLS. A recently published autopsy study of the brains of people with the syndrome suggests that the disorder may result from insufficient processing of iron in some part of the brain.</div> <div> "Although restless legs syndrome should be considered a possible indicator of iron deficiency problems, that doesn't mean that all restless legs syndrome patients will have that, and it doesn't mean that all patients can be helped by oral iron," said Dr. Allen. "It could have something to do with the way iron is distributed in the brain."</div> <div> If no underlying iron or vitamin deficiency is found to be the cause of a patient's restless legs, then treatment is generally with dopaminergic agents, such as carbidopa/levodopa or ropinirole. Both are considered first-line treatments.</div> <div> The discovery 20 years ago that the same medication prescribed to people with Parkinson's disease works for those with RSL was serendipitous, said Dr. Allen.</div> <div> A Turkish physician, unaware that others were steering clear of dopamine treatments thinking they would only make restless legs worse, tried many treatments for a patient with severe RLS. Dopaminergic agents worked.</div> <div> Although such agents are used to treat Parkinson's disease, it doesn't mean that patients with RLS have Parkinson's or are more likely to develop it, Dr. Kushida notes.</div> <div> Sedatives, pain relievers and anticonvulsants also can be helpful in relieving symptoms and improving sleep, according to the Restless Legs Syndrome Foundation.</div> <div> The syndrome is attracting increased research attention, said Dr. Allen. The aging population is one big driver. "We live longer and we live healthier, and we demand more of life in our older years," Dr. Kushida said. "This is a disorder that can be very disabling when a person is young but is more commonly disabling for people who are over 50."</div> <div> The increased recognition of sleep disorders as medical problems and the discovery of a simple, effective treatment also have sparked interest, he said.</div> <bR> <div> Weblink</div> <div> Restless Legs Syndrome Foundation (<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>www.rls.org</U></FONT>)</div> <div> The National Institutes of Health RLS information (<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>www.nlm.nih.gov/medlineplus/restlesslegs.html</U></FONT>)</div> <div> Sleep Foundation information about restless legs (<FONT SIZE="3" COLOR="#0000FF" FACE="Arial" ><U>www.sleepfoundation.org/publications/fact_rls.cfm</U></FONT>)</div> <bR> <div>  <A NAME="_restless_leg_syndrome_tied_to_mental"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A></div> <div>  Restless leg syndrome tied to mental woes</div> <bR> <div> People who suffer from restless leg syndrome (RLS) often have debilitating psychiatric disorders, including depression and anxiety, investigators reported today at big medical convention in Montreal.</div> <bR> <div> At a news conference during the annual meeting of the American College of Chest Physicians, Dr. Barbara Phillips of the University of Kentucky at Lexington presented results of the annual sleep poll conducted by the National Sleep Foundation. Phillips is president of the Foundation.</div> <bR> <div> Researchers conducted a telephone survey of some 1,500 randomly selected adults aged 18 and older. Their average age was 49.</div> <bR> <div> Symptoms of RLS were reported by 9.7 percent of the participants - 8 percent of all men and 11 percent of all women.</div> <bR> <div> Residents of the Southern and Western US had a higher risk of RLS than those living in the Northeast US. Other risk factors were heavy smoking, unemployment status, hypertension, gastroesophageal reflux disease, arthritis, diabetes, depression and anxiety.</div> <bR> <div> Sleep apnea and insomnia appear to be other risk factors for RLS, along with difficulty falling asleep (taking more than 30 minutes), driving while drowsy and excessive daytime fatigue.</div> <bR> <div> Subjects with self-reported RLS also had a higher incidence of being late for work, missing work, making errors at work and missing social events because of fatigue more often than those without RLS.</div> <bR> <div> "There is definitely a circadian rhythm," Phillips told Reuters Health. Patients describe their symptoms as more of an urge to move rather than actual pain, Phillips said. Sleep labs are not actually necessary to make a diagnosis of RLS, she added.</div> <bR> <div> "No one really knows what causes RLS," Dr. Phillips said. "RLS is probably not a single thing...A lot of things look the same but aren't the same."</div> <bR> <div> "Primary RLS probably has some genetic basis," she said. "The brain content of iron is different in RLS...Iron and dopamine stores are low...Treating iron deficiency can correct the symptoms," she pointed out.</div> <bR> <div> This past summer, FDA approved the dopamine agonist ropinirole (Requip) as first-line therapy for RLS. Phillips predicts that other similar drugs will soon receive similar approval.</div> <bR> <div> She called for studies to better define the diagnosis of restless leg syndrome.</div> <bR> <div> Copyright © 2005 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content is e</div> <bR> <bR> <bR> <div>  <A NAME="how_to_help_patients_with_restless_legs"><IMG BORDER="0" SRC="1x1.gif" HEIGHT="1" ALIGN="bottom" WIDTH="1" HSPACE="0" VSPACE="0" ></A>How to help patients with restless legs syndrome</div> <bR> <div> Virgilio Gerald H. Evidente, MD Charles H. Adler, MD, PhD</div> <div> VOL 105 / NO 3 / MARCH 1999 / POSTGRADUATE MEDICINE</div> <bR> <div> CME learning objectives</div> <bR> <div>     * To familiarize primary care physicians with diagnostic criteria for restless legs syndrome</div> <div>     * To elucidate secondary, and often curable, causes of restless legs syndrome</div> <div>     * To describe current treatment options for restless legs syndrome </div> <bR> <bR> <bR> <div> Preview: Few conditions are characterized by the difficulty encountered in trying to depict their symptoms, but such is the case in restless legs syndrome. Patients report sensations that are not painful yet are distinctly bothersome and can lead to significant physical and emotional disability. Once correctly diagnosed, restless legs syndrome can usually be effectively treated symptomatically, and in some secondary cases, it can even be cured. In this article, the authors focus on clinical features that enable timely identification of the condition and on current management strategies.</div> <bR> <div> 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 (1). Although the syndrome affects about 10% to 15% of the US population (2), it is often unrecognized and misdiagnosed. It may begin at any age (1-3), 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.</div> <div> Diagnostic criteria and common features</div> <bR> <div> In 1995, the newly formed International Restless Legs Syndrome Study Group developed criteria for diagnosing restless legs syndrome (3). Four basic elements must be present to make the diagnosis: (1) a desire to move the limbs, often associated with paresthesia or dysesthesia, (2) symptoms exacerbated by rest and relieved by activity, (3) motor restlessness, and (4) nocturnal worsening of symptoms. These and several additional features commonly seen in restless legs syndrome are discussed in the following paragraphs.</div> <bR> <div>     * Desire to move the limbs, paresthesia, dysesthesia. Patients often describe an unpleasant sensation in the calves and occasionally in the thighs, feet, or upper limbs. Although the study group refers to dysesthesia or paresthesia (which implies abnormal sensations) (3), most patients simply relate vague, nonpainful, indescribable, bilateral (rarely unilateral) discomfort in the limbs, using such terms as crawling, creeping, tingling, burning, itching, and aching.</div> <bR> <div>       Symptoms are similar to those described by patients with akathisia (which is usually caused by use of neuroleptic drugs). However, in contrast to patients with restless legs syndrome, those with akathisia have an inner feeling of restlessness, gain the most relief by resting in a recumbent position, and do not experience paresthesia or nocturnal worsening of symptoms.</div> <bR> <div>     * Symptoms exacerbated by rest, relieved by activity. The unpleasant limb sensations of restless legs syndrome are precipitated by rest or inactivity (eg, lying in bed at night, riding in a car or airplane, sitting in a theater). The discomfort is usually relieved by motor activity (eg, moving the legs, walking).</div> <bR> <div>     * Motor restlessness. Patients describe a buildup of discomfort and involuntary limb jerking if they remain still. There is an urge to move the legs and relief after moving (much like the sensation of tics). Compelling motor restlessness can manifest as tossing and turning in bed, needing to pace the floor, stretching or shaking the legs, or needing to exercise (3). Limb movements in restless legs syndrome are partly voluntary, in that patients choose to move to relieve the discomfort, and partly involuntary, since patients are compelled to move. Such partly voluntary, partly involuntary movements are sometimes referred to as "unvoluntary" or "semivoluntary."</div> <bR> <div>     * Nocturnal worsening of symptoms. 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) and improve-ment early in the morning. Nocturnal worsening is caused by lack of motor activity at night and is also thought to be due to an independent circadian rhythm (3). In severe cases, patients experience symptoms both day and night.</div> <bR> <div>     * Periodic limb movements of sleep. About 80% of patients with restless legs syndrome have unilateral or bilateral periodic limb movements of sleep, also called nocturnal myoclonus (1,3). These movements are stereotyped, repetitive, slow flexion of the limbs (legs alone or legs more than arms) during stage 1 or 2 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 dorsiflexion of the big toe with fanning of the small toes is seen, along with flexion of the ankles, knees, and thighs.</div> <bR> <div>     * Dyskinesias while awake. These motions, also called periodic limb movements while awake, are seen in 30% to 50% of patients with restless legs syndrome (3). They are similar to periodic limb movements of sleep but occur only during wakefulness. They can be fast or slow and periodic or nonperiodic.</div> <bR> <div>     * Sleep disturbance. Because of limb discomfort and jerking, most patients with restless legs syndrome have disturbances of sleep onset or maintenance (1,3). The result is excessive daytime sleepiness and fatigability, although not to the same degree as that caused by narcolepsy. </div> <bR> <div> Primary disease</div> <bR> <div> In most cases, restless legs syndrome is idiopathic. Such idiopathic disease can be familial (in 25% to 75% of cases) and, if so, is transmitted in an autosomal-dominant fashion (1,3,4). 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 (5).</div> <div> Secondary disease</div> <bR> <div> Restless legs syndrome can develop as a result of certain conditions or factors (table 1), particularly iron deficiency and peripheral neuropathy (6-12). These two conditions should be ruled out on clinical grounds before restless legs syndrome is labeled primary (13). Because of the prevalence of these conditions in the general population, their association with restless legs syndrome needs to be interpreted with considerable caution.</div> <bR> <div> Table 1. Factors and conditions that may contribute to secondary restless legs syndrome (in order of frequency)</div> <div> Deficiency of iron, folate, or magnesium</div> <bR> <div> Polyneuropathy caused by alcohol abuse, amyloidosis, diabetes mellitus, idiopathic polyneuropathy, lumbosacral radiculopathy, Lyme disease, monoclonal gammopathy of undetermined significance, rheumatoid arthritis, Sjögren's syndrome, uremia, or vitamin B12 deficiency</div> <bR> <div> Pregnancy</div> <bR> <div> Anemia</div> <bR> <div> Parkinson's disease</div> <bR> <div> Gastric surgery</div> <bR> <div> Chronic obstructive pulmonary disease</div> <bR> <div> Carcinoma</div> <bR> <div> Chronic venous insufficiency or varicose veins</div> <bR> <div> Intake of certain substances or drugs: alcohol, caffeine, anticonvulsants (eg, methsuximide [Celontin Kapseals], phenytoin [Dilantin]), antidepressants (eg, amitriptyline HCl [Elavil], paroxetine HCl [Paxil]), beta blockers, histamine2 antagonists, lithium, neuroleptics</div> <bR> <div> Withdrawal from vasodilators, sedatives, or imipramine HCl (Tofranil)</div> <bR> <div> Cigarette smoking</div> <bR> <div> Myelopathy or myelitis</div> <bR> <div> Hypothyroidism or hyperthyroidism</div> <bR> <div> Acute intermittent porphyria</div> <bR> <div> Fibromyalgia syndrome</div> <bR> <div> Arborizing telangiectasia of the lower limbs</div> <bR> <div> Peripheral microemboli made of cholesterol</div> <bR> <div> Restless legs syndrome can be the initial manifestation of iron deficiency (1,14). 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.</div> <bR> <div> About 5% of patients with sensory neuropathy (especially caused by uremia, rheumatoid arthritis, and diabetes) have restless legs syndrome (8). Treatment of the polyneuropathy may improve symptoms.</div> <div> Diagnosis</div> <bR> <div> 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 workup 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.</div> <bR> <div> 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 (13). Polysomnography is rarely necessary but 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.</div> <div> Nonpharmacologic management</div> <bR> <div> Patients with suspected restless legs syndrome who are sensitive to caffeine, alcohol, or nicotine should avoid these substances (1,6). Offending medications (table 1) 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.</div> <bR> <div> Supplementation to correct deficiencies in vitamins (eg, folate) (15), electrolytes (eg, magnesium) (7), or iron may improve symptoms. Patients with prominent varicose veins in the legs may benefit from use of sclerosing agents (9). Those with uremia may have relief after kidney transplantation or correction of anemia with erythropoietin (Epogen, Procrit) (6).</div> <div> Pharmacologic management</div> <bR> <div> 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.</div> <bR> <div> Levodopa with carbidopaLevodopa with carbidopa (Sinemet) can improve sensory symptoms and periodic limb movements of sleep in primary restless legs syndrome and that associated with uremia (1-3,16). For symptoms that start before sleep, one 25/100-mg carbidopa/levodopa tablet can be taken 1 to 2 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. Nausea and constipation are the most common side effects of levodopa.</div> <bR> <div> The major drawback in prescribing levodopa for restless legs syndrome is that in about 80% of patients, augmentation of symptoms occurs as early as a few months after initiation of therapy (17). 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 is more likely in patients with severe pretreatment symptoms and in those taking 200 mg or more of levodopa daily. If augmentation or rebound develops, adjunctive therapy with reduction of the levodopa dose or discontinuation of levodopa and substitution of another drug may help.</div> <bR> <div> Dopamine agonistsDopamine agonists 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 (2,17,18). Side effects of dopamine agonists include nausea, light-headedness, drowsiness, and postural hypotension.</div> <bR> <div> Pergolide mesylate (Permax) is a potent, long-acting dopamine D1 and D2 receptor agonist that has been shown to be effective in restless legs syndrome (1-3,16), even in patients who are unresponsive to levodopa (18). 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.</div> <bR> <div> Bromocriptine mesylate (Parlodel), a dopamine D2 receptor agonist, also has been found to be effective in restless legs syndrome (1-3,18). Bromocriptine can be started at a dose of 1.25 mg at bedtime and increased by 1.25 mg every few days until benefits or side effects are noted. The effective daily dose ranges from 5 to 15 mg.</div> <bR> <div> Pramipexole (Mirapex), a dopamine D2 and D3 receptor agonist, and ropinirole hydrochloride (Requip), a dopamine D2 receptor agonist, were recently approved by the Food and Drug Administration for treating Parkinson's disease. Pramipexole is started at 0.125 mg at bedtime and gradually increased to a maximum of 1.5 mg three times daily. Ropinirole is started at 0.25 mg and increased to 3 to 8 mg three times daily (19,20).</div> <bR> <div> BenzodiazepinesBenzodiazepines may be used as monotherapy in patients with mild or intermittent symptoms or as add-on therapy in severe cases. Clonazepam (Klonopin) has been shown to ease the sensory symptoms and periodic limb movements of sleep in restless legs syndrome (1-3,16). The agent 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 and confusion, unsteadiness and falls, and aggravation of sleep apnea.</div> <bR> <div> OpioidsLow-potency opioids, such as codeine and propoxyphene (Darvon, Dolene), can benefit patients with mild and intermittent symptoms, and higher-potency agents, such as oxycodone hydrochloride (Roxicodone), methadone (Dolophine) hydrochloride, and levorphanol tartrate (Levo-Dromoran), may have a role in refractory cases (1-3,16). In a double-blind, placebo-controlled study, oxycodone (mean daily dose, 15.9 mg) was found to be more effective than placebo (21). However, most physicians are hesitant to use opioids in restless legs syndrome because of the perceived risk of addiction and do so only in refractory cases.</div> <bR> <div> AnticonvulsantsDouble-blind studies have shown that carbamazepine (Tegretol), at a dose of 200 to 400 mg daily, is effective in reducing sensory manifestations of restless legs syndrome (1-3,16), especially among young patients with recent onset of disease and severe symptoms. Unfortunately, subsequent clinical experience has not shown convincing efficacy of carbamazepine.</div> <bR> <div> Open-label studies have found gabapentin (Neurontin) to be effective in relieving sensory symptoms (22) and periodic limb movements of sleep, even in refractory cases. The drug can be initiated 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 somnolence, dizziness, ataxia, and fatigue.</div> <bR> <div> Presynaptic alpha2-adrenergic agonistClonidine hydrochloride (Catapres) may be effective in primary restless legs syndrome and that associated with uremia (1-3,16). 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 cognition, light-headedness, sleepiness, and constipation.</div> <div> Summary</div> <bR> <div> Restless legs syndrome is a common, potentially disabling condition that affects about 10% to 15% of the general population and yet is often unrecognized and misdiagnosed. It is mainly diagnosed clinically and only rarely requires polysomnography. The condition is usually primary and treatable. First, however, secondary causes should be sought, especially iron deficiency and peripheral neuropathy, because when the source is an accompanying factor or condition, the syndrome may be curable. The most effective drugs are dopaminergic agents, clonazepam, opioids, gabapentin, and clonidine. Additional agents are available that may be beneficial as add-on or alternative therapy.</div> <div> References</div> <bR> <div>    1. Trenkwalder C, Walters AS, Hening W. Periodic limb movements and restless legs syndrome. Neurol Clin 1996;14(3):629-50</div> <div>    2. Silber MH. Restless legs syndrome. Mayo Clin Proc 1997;72(3):261-4</div> <div>    3. Walters AS, for the International Restless Legs Syndrome Study Group. Toward a better definition of the restless legs syndrome. Mov Disord 1995;10(5):634-42</div> <div>    4. Trenkwalder C, Seidel VC, Gasser T, et al. Clinical symptoms and possible anticipation in a large kindred of familial restless legs syndrome. Mov Disord 1996;11(4):389-94</div> <div>    5. Ondo W, Jankovic J. Restless legs syndrome: clinicoetiologic correlates. Neurology 1996;47(6):1435-41</div> <div>    6. O'Keeffe ST. Restless legs syndrome: a review. Arch Intern Med 1996;156(3):243-8</div> <div>    7. Popoviciu L, Asgian B, Delast-Popoviciu D, et al. Clinical, EEG, electromyographic and polysomnographic studies in restless legs syndrome caused by magnesium deficiency. Rom J Neurol Psychiatry 1993;31(1):55-61</div> <div>    8. Rutkove SB, Matheson JK, Logigian EL. Restless legs syndrome in patients with polyneuropathy. Muscle Nerve 1996;19(5):670-2</div> <div>    9. Kanter AH. The effect of sclerotherapy on restless legs syndrome. Dermatol Surg 1995;21(4):328-32</div> <div>   10. Sanz-Fuentenebro FJ, Huidobro A, Tejadas-Rivas A, et al. Restless legs syndrome and paroxetine. Acta Psychiatr Scand 1996;94(6):482-4</div> <div>   11. Drake ME. Restless legs with anti-epileptic drug therapy. Clin Neurol Neurosurg 1988;90(2):151-4</div> <div>   12. Metcalfe RA, MacDermott N, Chalmers RJ. Restless red legs: an association of the restless legs syndrome with arborizing telangiectasia of the lower limbs. J Neurol Neurosurg Psychiatry 1986;49(7):820-3</div> <div>   13. Iannaccone S, Zucconi M, Marchettini P, et al. Evidence of peripheral axonal neuropathy in primary restless legs syndrome. Mov Disord 1995;10(1):2-9</div> <div>   14. O'Keeffe ST, Gavin K, Lavan JN. Iron status and restless legs syndrome in the elderly. Age Ageing 1994;23(3):200-3</div> <div>   15. Botez MI, Lambert B. Folate deficiency and restless-legs syndrome in pregnancy. N Engl J Med 1977;297(12):670</div> <div>   16. Krueger BR. Restless legs syndrome and periodic movements of sleep. Mayo Clin Proc 1990;65(7):999-1006</div> <div>   17. Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep 1996;19(3):205-13</div> <div>   18. Earley CJ, Allen RP. Pergolide and carbidopa/levodopa treatment of the restless legs syndrome and periodic leg movements in sleep in a consecutive series of patients. Sleep 1996;19(10):801-10</div> <div>   19. Ondo W. Ropinirole for restless legs syndrome. Mov Disord 1999;14(1):138-40</div> <div>   20. Lin SC, Kaplan J, Burger CD, et al. Effect of pramipexole in treatment of resistant restless legs syndrome. Mayo Clin Proc 1998;73(6):497-500</div> <div>   21. Walters AS, Wagner ML, Hening WA, et al. Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep 1993;16(4):327-32</div> <div>   22. Adler CH. Treatment of restless legs syndrome with gabapentin. Clin Neuropharmacol 1997;20(2):148-51 </div> <bR> <div> What are the mechanisms that cause restless legs syndrome?</div> <bR> <div> Pathogenesis of the syndrome is unclear. Karl A. Ekbom originally proposed that it was mainly the result of accumulation of metabolites in the legs from venous congestion (1-3). Peripheral nerve abnormalities have also been proposed, but no structural changes in nerve endings have been seen (4). Many experts believe that the syndrome is generated centrally (1,3,5). Periodic limb movements of sleep, in particular, are thought to be caused by sleep-related disruption of descending inhibitory reticulospinal pathways that are normally active at the brain stem or spinal cord level.</div> <bR> <div> On the basis of treatment response, restless legs syndrome has been linked to dopaminergic or opiate abnormalities (3). Dopamine blockers and opiate blockers reactivate symptoms when given to patients with the syndrome. Results of single-photon emission computed tomography have suggested deficiency of dopamine D2 receptors (6). Sympathetic hyperactivity has also been implicated (5) 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 gamma-aminobutyric acid neurotransmitter systems.</div> <div> References</div> <bR> <div>    1. Trenkwalder C, Walters AS, Hening W. Periodic limb movements and restless legs syndrome. Neurol Clin 1996;14(3):629-50</div> <div>    2. Silber MH. Restless legs syndrome. Mayo Clin Proc 1997;72(3):261-4</div> <div>    3. Walters AS, for the International Restless Legs Syndrome Study Group. Toward a better definition of the restless legs syndrome. Mov Disord 1995;10(5):634-42</div> <div>    4. Rutkove SB, Matheson JK, Logigian EL. Restless legs syndrome in patients with polyneuropathy. Muscle Nerve 1996;19(5):670-2</div> <div>    5. O'Keeffe ST. Restless legs syndrome: a review. Arch Intern Med 1996;156(3):243-8</div> <div>    6. Staedt J, Stoppe G, Kogler A, et al. Dopamine D2 receptor alteration in patients with periodic movements in sleep (nocturnal myoclonus). J Neural Transm Gen Sect 1993;93(1):71-4 </div> <bR> <div> Dr Evidente was a fellow in movement disorders and Dr Adler is associate professor of neurology, Parkinson's Disease and Movement Disorders Center, Mayo Clinic Scottsdale, Scottsdale, Arizona. Dr Evidente is now at St Lukes Medical Center, Quezon City, Philippines. Correspondence: Charles H. Adler, MD, PhD, Parkinson's Disease and Movement Disorders Center, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ 85259. </div> </td> </tr></table> </body>