Restless Legs Syndrome (RLS)

Bad medicine: restless legs syndrome

Restless Legs Syndrome (RLS) | Johns Hopkins Medicine

In response to the Views and Reviews column by Des Spence—“Bad Medicine: Restless Legs Syndrome” (January 3, 2014) (1), we are writing as the Medical Advisory Board of the Willis- Ekbom Disease (WED) Foundation, a patient-based organization in the U.S.A.

that serves individuals in North America and internationally who have restless legs syndrome (RLS, also known as Willis-Ekbom disease, or WED/RLS). We are medical professionals from various institutions and collectively have treated thousands of patients with moderate to severe WED/RLS over the years.

It is absolutely true, as pointed out by another responder to the article, that WED/RLS can be mild and not need treatment, but the literature also indicates that about 2.7% of the population reports symptoms as moderately or severely distressing.

The resultant quality of life of these more severely affected patients is as equally poor as that seen with other chronic medical conditions (2) and, in some cases, the condition is severe enough to warrant visits to the emergency room (3).

WED/RLS consists of 4 primary features, all of which are necessary for the diagnosis: (a) an urge to move the legs usually but not always accompanied by bothersome leg sensations; (b) worsening of symptoms later in the day or at night; (c) worsening of symptoms when lying or sitting with (d) resultant relief by activity such as walking;.

Most recently a 5th criterion has been added that excludes mimics of WED/RLS which superficially meet all the 4 primary criteria for WED/RLS but are not WED/ RLS, such as leg cramps and positional discomfort (4).

Do these criteria hold together as a biological whole? The clinical and basic science studies of WED/RLS would indicate that this is so, as there is robust objective data showing CNS abnormalities.

More than 80% of patients with WED/RLS have involuntary movements while asleep (periodic limb movements in sleep) that can be recorded on an overnight sleep study and are responsive to dopaminergic medications (5). About 1/3 to 2/3 of cases are familial and genetic linkage studies have revealed multiple gene loci (6).

Genetic allelic association studies have revealed several genes that predict WED/RLS, the BTBD9 and the MEIS-1 gene being the most studied of these (7,8).

Cerebrospinal fluid (CSF), neuro-imaging and autopsy studies show evidence of iron deficiency consistently, alterations in dopamine neurotransmitter levels, decreases in the endogenous opioids, (endorphins and enkephalins), and increases in glutamate in the brain (9-14).

Most recently, several specific proteins have been found to be altered in the CSF of WED/RLS patients compared to controls (15). In fact, autopsy studies have shown much more consistent pathology than other movement disorders, including essential tremor and dystonia. RLS/WED is a diagnosis officially recognized by the American Academy of Sleep Medicine, and expertise in RLS/WED diagnosis and treatment is required for board certification in Sleep Medicine by the American Board of Medical Specialties (16). Recently an increased co-morbidity of hypertension, heart disease and stroke has been suggested for RLS/WED as well as an increased mortality, although the literature is not entirely consistent in these regards and a causal link remains to be established (17, 18). The most common treatment for RLS is actually dopamine agonists, which robustly improve the condition in many highly controlled clinical trials and have a rather specific mechanism of action. Much is made of the 40% placebo response. This is high, but no higher than that seen in other pain/neurologic disorders, and the placebo responder rate is lower than that seen with Parkinson’s disease (19,20). Discussion of placebo mechanisms are beyond the scope of this letter but dopaminergic disease seem physiologically predisposed to higher placebo rates as placebo increases brain dopamine activity (21).

The Willis-Ekbom Disease Foundation is named in honor of Sir Thomas Willis and Dr. Karl Ekbom who did the pioneering descriptions of WED/RLS in the 1600s in England and the 1940s in Sweden, long before there was any interest in this disorder by the pharmaceutical industry (22, 23).

Sincerely,

Medical Advisory Board of the Willis-Ekbom Disease (WED) FoundationArthur S. Walters, M.D.William Ondo, M.D.Philip Becker, M.D.Mark Buchfuhrer, M.D.Christopher Earley, M.D., PhD.Diego Garcia -Borreguero, M.DJennifer Hensley, Ed.D., C.N.M., R.N.Birgit Högl, M.D.Mauro Manconi, M.D., Ph.D.Abdul Q Rana, M.D.Daniel L. Picchietti, M.D.

Michael H. Silber, M.B.Ch.B.

References

(1) Spence D. Bad medicine: Restless Legs Syndrome. BMJ 2013; 347: 17615.

(2) Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, Ferini-Strambi L. Restless Legs Syndrome prevalence and impact; REST general population study. Arch Intern Med 2005; 165: 1286-92.

(3) Manconi M, Fulda S. Restless legs syndrome in the emergency room. Eur J Neurol. 2013 Feb;20(2):e36. doi: 10.1111/ene.12035. PubMed PMID: 23311509.

(4) International Restless Legs Syndrome Study Group, 2012 revised diagnostic
criteria. http://irlssg.org/diagnostic-criteria/ Accessed September 12, 2013.

(5) Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir J.

The participants in the Restless Legs Syndrome Diagnosis and Epidemiology workshop at the National Institutes of Health in collaboration with members of the International Restless Legs Syndrome Study Group.

Restless Legs Syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the Restless Legs Syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Medicine 2003; 4: 101-119.

(6) Trenkwalder C, Hogl B, Winkelmann J. Recent advances in the diagnosis, genetics and treatment of restless legs syndrome. J. Neurol 2009; 256: 539-53.

(7) Winkelmann J, Schormair B, Lichtner P, Ripke S, Xiong L, Jalilzadesh S et al. Genome-wed association study of Restless legs Syndrome identifies common variants in three genomic regions. Nat Genet 2007; 39: 1000-6.

(8) Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A, Thorgeirsson TE et al. A genetic rsik factor for periodic limb movements in sleep. N Engl J Med 2007; 357:639-47.

(9) Connor JR, Wang XS, Allen RP, Beard JL, Wiesinger JA, Felt BT et al. Altered dopaminergic profile in the putamen and substantia nigra in Restless Legs Syndrome. Brain 2009; 132: 2403-12.

(10) Early CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, Allen RP. Abnormalities in CSF concentrations of ferritin and transferring in Restless Legs Syndrome. Neurology 2000; 54: 1698-700.

(11) Allen RP, Barker PB, Wehrl F, Song HK, Earley CJ. MRI measurement of brain iron in patients with Restless Legs Syndrome. Neurology 2001; 56: 263-66.

(12) Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP Ondo WG et al. Neuropathological examination suggests impaired brain iron acquisition in Restless Legs Syndrome. Neurology 2003; 61: 304-9.

(13) Allen RP, Barker PB, Horska A, Earley CJ. Thalamic glutamate/glutamine in Restless Legs Syndrome: Increased and related to disturbed sleep. Neurology 2013; 80: 2028-34.

(14) Walters AS, Ondo WG, Zhu W, Le W. Does the endogenous opiate system play a role in the Restless Legs Syndrome? A pilot post-morten study. J Neurol Sci 2009; 279: 62-5.

(15) Patton SM, Cho YW, Clardy TW, Allen RP, Earley CJ, Connor JR. Proteomic analysis of the cerebrospinal fluid of patients with Restless Legs Syndrome/Will-Ekbom Disease. Fluids Barriers CNS 2013 Jun 7;10(1):20. doi: 10.1186/2045-8118-10-20.

(16) The International Classification of Sleep Disorders. Diagnostic and Coding Manual. Second Edition. The American Academy of Sleep Medicine. Westchester, Ill., pp. 1-297, 2005.

(17) Ferini-Strambi L, Walters AS, Sica D. The relationship among Restless Legs Syndrome (Willis Ekbom Disease), hypertension, cardiovascular disease, and cerebrovascular disease. J Neurol DOI 10:1007/s00415-013-7065-1 (Published Online August 21, 2013).

(18) Li Y, Wang W, Winkelman JW, Malhotra A, Ma J, Gao X. Prospective study of Restless Legs Syndrome and mortality among men. Neurology 2013; 81: 52-9.

(19) [Goetz CG, Wu J, McDermott MP, Adler CH, Fahn S, Freed CR, et al. Placebo response in Parkinson's disease: comparisons among 11 trials covering medical and surgical interventions. Mov Disord 2008;23(5):690-9.

(20) Macedo A, Banos JE, Farre M. Placebo response in the prophylaxis of migraine: a meta-analysis. Eur J Pain. 2008;12(1):68-75]

(21) Lidstone SC, Schulzer M, Dinelle K, Mak E, Sossi V, Ruth TJ, et al. Effects of expectation on placebo-induced dopamine release in Parkinson disease. Archives of general psychiatry. 2010;67(8):857-65.

(22) Willis T. The London practice of physick. London,: Basset and Crook; 1685.

(23) Ekbom KA. Restless legs. Acta Med Scand. 1945;Suppl 158:1-123.

Source: https://www.bmj.com/content/347/bmj.f7615/rapid-responses

Restless Legs Syndrome Brain Stimulation Study Supports Motor Cortex ‘Excitability’ as A Cause

Restless Legs Syndrome (RLS) | Johns Hopkins Medicine

Johns Hopkins Medicine researchers say new experiments using magnetic pulse brain stimulation on people with moderate to severe restless legs syndrome (RLS) have added to evidence that the condition is due to excitability and hyperarousal in the part of the brain’s motor cortex responsible for leg movement.

The researchers say their findings, published online in Sleep Medicine on May 31, may help devise safer, more effective ways to treat RLS and the chronic sleep deprivation it causes, using electrical or magnetic pulses to calm or interrupt the hyperarousal.

Some 10 percent of adults in the U.S.

experience RLS at one time or another, and about 1 in 500 report that the condition is severe and chronic enough to interfere with their quality of life, work productivity or mental health, according to the National Sleep Foundation.

People with severe RLS describe symptoms of the condition as an overwhelming urge to move their legs when they are at rest.

They may feel pain, or the sensation of soda bubbles in their veins or worms crawling in their legs, with relief coming only when standing or deliberately moving their legs.

Long-term effects include fatigue, anxiety and depression, much of it linked to repeated interruption of sound sleep. Standard treatments, which may carry significant side effects, include medications that behave the neurotransmitter dopamine, opioids and anti-seizure drugs.

Although many conditions, such as kidney disease and diabetes, have been associated with RLS, the neurological roots of the condition have been subject to much debate.

The new study, the Johns Hopkins researchers say, supports the idea that the underlying mechanism for RLS rests in the brain’s “move my legs” center and makes even more sense of the relief those with RLS experience when they get up and move them.

“Essentially the brain sends the signal when it’s preparing to move a limb, even when you aren’t planning to move, so your body is ready and amped up,” says Richard Allen, Ph.D., professor of neurology at the Johns Hopkins University School of Medicine. “The only way to alleviate the feeling is to move.”

In the new study, the researchers identified 32 adults with a moderate to severe RLS diagnosis from patients and asked them to stop their treatments for 12 days. They recruited 31 adult matched controls with no history of RLS or other sleep disorders and healthy sleeping patterns as controls. Participants in both groups were an average age of 58, and 59 percent were women.

For the experiments, the researchers used transcranial magnetic stimulation (TMS) to apply safe pulses able to selectively stimulate various regions of the brain that control movement of the muscles in the hand or the leg. They then used electrodes attached to the hand or leg to measure muscle responses in that hand or leg during such stimulations in those with RLS and in the control group.

Pairing two pulses as a stimulus can either cause a reaction or suppress/inhibit a reaction in a muscle depending on the timing between the two pulses. The researchers looked at one type of excitatory paired pulses and two types of inhibitory pulses¾short- and long-interval ones.

For each analysis, the researchers took the ratio of the responses. The ratios were greater in the leg for those with RLS, at 0.36 compared with 0.07 for those people without RLS, when looking at the inhibitory long-interval pulses, but not with the short-interval pulses. They said they didn’t see a difference in excitatory pulses in the legs.

“This basically means that inhibition is reduced or weakened in people with restless legs syndrome compared to people without the condition,” says Rachel Salas, M.D., associate professor of neurology at Johns Hopkins. “The reduced response means that the region of the brain controlling the legs shows increased cortical excitability in the motor cortex.”

In a separate set of experiments measuring the effect of paired pulses given to the brain in the region that controls the hand, they found no real differences in the ratios of either of the inhibitory pulses¾short- or long-interval ones¾between people with RLS and those without the condition.

But the researchers say they did find that the ratios picked up from the hand muscles using excitatory pulses were lower, at 1.01 compared with controls with a ratio of 1.85.

“The measurements from the hand muscles show that the activity in the brain is reduced in the region that controls the hand in people with restless legs syndrome compared to controls,” says Salas.

Salas says that previous research shows that inhibitory pulses are associated with the action of the neurotransmitter GABA, a brain chemical typically known for tamping down activity in the brain’s neurons. The researchers say that since there is hyperactivity in the leg-controlling portion of the brain, it’s possible that cells and tissues there are lacking enough GABA to prevent hyperactivity.

“Other studies with TMS have been done on people with RLS, but they didn’t look at people with severe forms of the condition or at the long-interval paired pulses in the leg,” says Salas. “We are fortunate to have access to such individuals because the Johns Hopkins Sleep Center attracts people worldwide and many who have exhausted treatment options available elsewhere,” she adds.

Salas notes that medications that act the neurotransmitter dopamine, such as ropinirole or pramipexole, work in the short term but can exacerbate the condition over time.

Opioids are effective, but not ideal due to their risk for dependency.

With the results of this new study, the researchers are hoping to use electrical stimulation to suppress the brain’s activity, and planning of these studies is in the works.

Additional authors on the study included Aadi Kalloo, Christopher Earley, Pablo Celnik, Tiana Cruz, Keyana Foster and Gabriela Cantarero of Johns Hopkins.

The study was funded by a National Institute of Neurological Disorders and Stroke grant (R01 NS075184).

COI: Earley received research funding from Luitpold Pharmaceuticals. Allen has received consulting fees from AMAG and Luitpold Pharmaceuticals.

Source: https://www.hopkinsmedicine.org/news/newsroom/news-releases/restless-legs-syndrome-brain-stimulation-study-supports-motor-cortex-excitability-as-a-cause

Treatment for Restless Legs Syndrome (RLS) | The Johns Hopkins Center for Restless Legs Syndrome

Restless Legs Syndrome (RLS) | Johns Hopkins Medicine

Unfortunately, there is no known cure for restless legs syndrome.

At present, there is no one drug which works for everybody, but most individuals with restless legs syndrome will find some benefit and relief with the currently available medications for treating this disorder, which can be divided into several categories: dopamine-related medications, opiates, benzodiazepines receptor agonists (BRAs), alpha-2 delta medications and iron supplementation.

Iron Status and Iron Treatment

Dr. Christopher Earley discusses the role of iron in the treatment of RLS.

Augmentation

Dr. Christopher Earley discusses augmentation in the drug treatment for RLS; what it is and how it's addressed.

Dopamine is a chemical that is produced by certain cells in the brain and this group of drugs functions to either increase the amount of dopamine made by the cell (levodopa) or increase the dopamine signal to other surrounding cells by mimicking dopamine in the brain. The dopamine-related drugs include levodopa, pramipexole, ropinirole and rotigotine.

These drugs are also used for Parkinson's disease. However, there is no indication that RLS is related to, or is a precursor of, Parkinson's disease.

These medications are ly to be effective in reducing symptoms in 90 percent of patients with restless legs syndrome.

Excessive sleepiness, increased compulsive behavior and more commonly, augmentation, a paradoxical worsening of symptoms, may occur with these medications after extended use. Learn more about dopamine drugs and possible side effects.

Opiates

Dr. Willis in his description of this disease in 1685 also reported on the benefits of opiates for treating the symptoms. Thus for over 300 years opiates remained the only truly effective treatment for this disease. This category of medications includes codeine, hydrocodone, oxycodone, morphine, hydromorphone, methadone, buprenorphine and pentazocine.

An estimated 85 percent to 90 percent of patients with RLS will respond very well to opiates.

An analysis of drug responses in RLS over a 2 -10 year period showed that 85 percent of RLS patients who started on methadone were still on it compared to less than 20 percent of those started on a dopamine drug.

The median starting dose for methadone in this study was 10 mg per day with a range between 2.5 mg and 20 mg per day.

It is important to realize that RLS for a majority of patients is not about pain; it is an abnormal, uncomfortable sensation. Tolerance to the opiates when treating RLS seems to be less of a problem than that seen with treatment of chronic pain disorders.

Presented by Christopher J.Earley, MB, BCh, PhD of the RLS Foundation Quality Care Center Director at Johns Hopkins Center for Restless Legs Syndrome.

Benzodiazepines Receptor Agonists

This group of drugs is also known as sleeping pills and has valium- effects. The structure of the parent compound was designated as a benzodiazepine, and later research identified a benzodiazepine receptor. This receptor interacts with a larger GABA receptor. 

Benzodiazepine receptor agonists (BRAs) are newer drugs  that do not have the benzodiazepine structure of the previous parent compound, but still bind to the benzodiazepine receptor.

Clonazepam was the treatment of choice for RLS for many years but it is not clear that any one of this class of drugs is better than another for treating RLS.

 BRAs  such as zolpidem (Ambien®), eszopiclone (Lunesta®), and zaliplon (Sonata®) are shorter acting agents than clonazepam and may be equally effective. BRAs are most effective in those with mild symptoms.

Alpha-2 delta Drugs

These drugs interact with one of the calcium channel proteins, alpha-2 delta protein. Calcium channels allow the charged calcium ion to move into the nerve cell and are therefore important in activating, deactivating and stabilizing the electrical activity of the nerve cell.

The alpha-2 delta drugs are also used to treat patients with nerve-damage related pain even in those without RLS. There are currently three drugs that fall into the alpha-2 delta class of drugs: gabapentin (Neurontin®), pregabalin (Lyrica®), and gabapentin enacarbil (Horizant®).

 

Gabapentin enacarbil is the only one of these three drugs that has be approved by the FDA (June 2011) for specific use in RLS, although the other two drugs have been used in treatment trial of RLS.

Gabapentin enacarbil is a prodrug to gabapentin, which means the compound is converted into gabapentin and thus acts gabapentin in the brain. Its advantage over regular gabapentin is that it is more consistently absorbed and is much longer lasting.

A clinical trial of the effects of pregabalin versus pramipexole in RLS patients over 1 year showed pregabalin to be significantly better than pramipexole in improving the severity of RLS symptoms.

The alpha-2 delta drugs are an effective treatment option for many patients with RLS and should be considered one of the choices for first line treatment of RLS.

Iron Supplementation

The significance of low iron in causing RLS is outlined in the segment on Causes of Restless Legs Syndrome. 

Since the 1950s, it has been known that iron therapy, even without the presence of anemia has benefits for RLS symptoms.

Studies have shown a strong relation between body iron stores as determined by serum ferritin and the severity of the RLS symptoms.

A study has shown that in patients whose serum ferritin was < 75 µg/l, oral iron therapy (325 mg ferrous sulfate twice a day on an empty stomach) on average improved RLS symptom after 3 months.  

A recent study has shown that giving oral iron more than once a day or at a dose greater than 85 mg per day does not necessary lead to a greater increase in absorbable iron. Oral iron equivalent to 65-85 mg of elemental iron will be best absorbed if given once a day.  It should NOT be given with solid or liquid food/dietary supplements or with milk.

  It should be given on an empty stomach an hour before eating or two hours after eating along with 100-200 mg of vitamin C. An iron panel (early morning fasting blood to check iron, ferritin, TIBC, and percent iron saturation) should be done after three months to check on progress of the treatment. Oral iron should be stopped 2 days before the iron studies are done.

 The goal is to get the serum ferritin above 100 µg/l.

If the patient cannot tolerate the iron, or, if after three months there has been very little change in the iron stores, an iron infusion may be appropriate.

Delivering iron directly into the blood by vein allows the iron to bypass the gastrointestinal tract, which can limit absorption of iron when iron is given orally. Several different formulations of iron are designed for intravenous treatment and are used for the treatment of anemia.

Two formulations of iron dextran exist (Dexferrum and INFeD), with the low molecular weight (LMW) iron dextran (INFeD) demonstrating better safety profile than the older version of iron dextran, Dexferrum (Chertow et al. Nephrol Dial Transplant 2004:19,1571).

Other iron formulations currently available for intravenous use include: iron sucrose (Venofer®), iron gluconate (Ferrlicit®), ferumoxytol (Feraheme®) and ferric carboxymaltose (Ferinject®).

Two, randomized, double-blind, placebo-controlled clinical studies using 1000 mg of ferric carboxymaltose versus placebo (subjects just received the solution with no iron in it), have shown that RLS patients who received the iron had significantly greater improvement in RLS symptoms (Allen et al.

 Sleep Medicine 2011: 12, 906; Cho et al. Sleep Medicine 2016:25,16). None of these patients had an anemia and some of the subjects has serum ferritin values of greater than 100 ug/l before the iron infusion.

Approximately 35 percent of subjects who had received the iron treatment still remained off of all RLS medications even 6 months after the treatment. 

From clinical experience in using LMW iron dextran (INFeD) in RLS patients, we find that the maximum effect of the iron infusion may take as long as six weeks.

As part of our clinical practice, we will repeat an early-morning, fasting iron panel about 8 weeks after the infusion to establish the new iron status and may repeat another iron panel in about two months to make sure that the iron levels are stable and not dropping.  

Non-Drug Treatments

Several non-drug related treatments that most patients suffering with this disorder already appreciate include hot baths, massaging and rubbing the legs, applying hot or cold packs, restricting the amount of caffeine or alcohol and partaking in moderate physical exercise. Any of  these methods may bring about some level of relief from the symptoms, but in the end, many of these patients will still be unable to have a good night of sleep.

To make an appointment or request an evaluation, please call the Johns Hopkins Sleep Disorders Center at 410-550-0572

Source: https://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/restless-legs-syndrome/what-is-rls/treatment.html

Restless Legs Syndrome – NORD (National Organization for Rare Disorders)

Restless Legs Syndrome (RLS) | Johns Hopkins Medicine

TEXTBOOKS
Fauci AS, et al., eds. Harrison’s Principles of Internal Medicine. 17th ed. New York, NY: McGraw-Hill Companies, Inc.; 2008:156, 2362.

Bennett JC, et al., eds. Cecil Textbook of Medicine. 21st ed. Maryland, MO: Elsevier Health Sciences; 1999.

Ropper AH, Samuels MA. Adams and Victor’s Principles of Neurology. 9th ed. New York, NY: McGraw-Hill, Inc; 2009.

JOURNAL ARTICLES
Silber MH, Becker PM, Buchfuhrer MJ, Earley CJ, Ondo WG, Walters AS, Winkelman JW; Scientific and Medical Advisory Board, Restless Legs Syndrome Foundation.The appropriate use of opioids in the treatment of refractory restless legs syndrome. Mayo Clin Proc. 2018;93:59-67.

Garcia-Borreguero D, Silber MH, Winkelman JW, Högl B, Bainbridge J, Buchfuhrer M, Hadjigeorgiou G, Inoue Y, Manconi M, Oertel W, Ondo W, Winkelmann J, Allen RP guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016;21:1-11.

Winkelman JW, Armstrong MJ, Allen RP, Chaudhuri KR, Ondo W, Trenkwalder C, Zee PC, Gronseth GS, Gloss D, Zesiewicz T.Practice guideline summary: Treatment of restless legs syndrome in adults: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology 2016;87:2585-93.

Silber MH, Becker PM, Earley C, Garcia-Borreguero D, Ondo WG; Medical Advisory Board of the Willis-Ekbom Disease Foundation. Willis-Ekbom disease foundation revised consensus statement on the management of restless legs syndrome..Mayo Clin Proc. 2013;88:977-86.

Trenkwalder C, Beneš H, Grote L, García-Borreguero D, Högl B, Hopp M, Bosse B, Oksche A, Reimer K, Winkelmann J, Allen RP, Kohnen R; RELOXYN Study Group.. Prolonged release oxycodone-naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomied, placebo-controlled trial with an open-label extension. Lancet Neurol. 2013;12:1141-50.

Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med. 2011;12:440-4.

Allen RP, Stillman P, Myers AJ. Physician-diagnosed restless legs syndrome in a large sample of primary medical care patients in western Europe: prevalence and characteristics. Sleep Med. 2010;11:31-7.

Cornelius JR, Tippmann-Peikert M, Slocumb NL, Frerichs CF, Silber MH. Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: a case-control study. Sleep 2010;33:81-7.

Garcia-Borreguero D, Williams A. Dopaminergic augmentation of restless legs syndrome. Sleep Med Rev. 2010;14:339-46.

Earley C, Silber MH. Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med. 2010:11.

Garcia-Borreguero D, Larrosa O, Williams AM, et al. Treatment of restless legs syndrome with pregabalin: a double-blind, placebo-controlled study. Neurology 2010;74:1897-904.

Walters AS, Ondo WG, Kushida CA, et al. Gabapentin enacarbil in restless legs syndrome: a phase 2b, 2-week, randomized, double-blind, placebo-controlled trial. Clin Neuropharmacol. 2009;32:311-20.

Oertel WH, Stiasny-Kolster K, Bergtholdt B, et al. Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study (effect-RLS study). Mov Disord. 2007;22;213-9.

Winkelman JW, Sethi KD, Kushida CA, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology 2006;67:1034-9.
Hening W, Allen R, Earley C, et al. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine review. Sleep 2004;27:560-83.

Trenkwalder C, Garcia-Borreguero D, Montagna P, et al. Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry 2004;75:92-7.

Walters AS, Ondo W, Dreykluft T, Grunstein R, Lee D, Sethi K. Ropinirole is effective in the treatment of restless legs syndrome. TREAT RLS 2: a 12-week, double blind, randomized parallel-group, placebo-controlled study. Mov Disord. 2004;19:1414-23.

Silber M, Girish M, Izurieta R. Pramipexole in the mangement of restless legs syndrome: an extended study. Sleep 2003;26:819-21.

Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisir J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology.

A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of health. Sleep Med. 2003;4:101-19.
Garcia-Borreguero D, Larrosa E, De la Llave Y, Verger K, Masramon X, Hernandez G.

Treatment of restless legs syndrome with gabapentin. A double-blind, cross-over study. Neurology 2002;59:1573-9.

Trenkwalder C, et al. Positron emission tomographic studies in restless legs syndrome.
Trenkwalder C, et al. Circadian rhythm of periodic limb movements and sensory symptoms of restless legs syndrome. Mov Dis. 1999;14:102-10.

Montplaisir J, et al. Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology 1999;52:938-43.

Allen RP, et al. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep. 1996;19:205-13.

Earley CJ, et al. Pergolide and carbidopa/levodopa treatment of the restless legs syndrome and periodic leg movements in sleep in a consecutive series of patients. Sleep 1996;19:801-10.

Walters AS, et al. A questionnaire study of 138 patients with restless legs syndrome: the ‘night-walkers’ survey. Neurology 1996;46:92-95.

Montplaisir J, et al. The treatment of the restless leg syndrome with or without periodic leg movements in sleep. Sleep 1992;15:391-95.

Ekborn KA. Restless legs. Acta Med Scand. 1945;158:1-123.

INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Restless Legs Syndrome, Susceptibility to, 1; RLS1. Entry No: 102300. Last Edited 08/11/2016. Available at: http://omim.org/entry/102300 Accessed April 17, 2018.

Source: https://rarediseases.org/rare-diseases/restless-legs-syndrome/

Restless Legs Syndrome (RLS)

Restless Legs Syndrome (RLS) | Johns Hopkins Medicine

Linkedin Pinterest

Restless legs syndrome, or RLS, is a neurological disorder characterized by unpleasant sensations in the legs and an uncontrollable urge to move when at rest in an effort to relieve these feelings. RLS sensations are often described as burning, creeping or tugging, or insects crawling inside the legs.

You usually have these sensations in the calf, but they may be felt anywhere from the thigh to the ankle. One or both of your legs may be affected. Some people may have the sensations in the arms. With RLS, you have an irresistible urge to move the affected limb when the sensations occur. Moving often briefly relieves the limb discomfort.

Sleep problems are common with RLS because of the difficulty it causes in getting to sleep. Severe daytime fatigue can also be a big problem.

What causes RLS?

The cause of RLS is still unknown. Some cases are believed to be inherited. Some cases have been linked with nerve damage in the legs due to diabetes, kidney problems, or alcoholism.

As many as one in 10 people in the U.S. may have RLS. RLS occurs in both genders, but the incidence may be slightly higher in women.

Although the syndrome may begin at any age, even as early as infancy, most patients who are severely affected are middle aged or older. In addition, the severity of the disorder appears to increase with age.

Older patients experience symptoms more frequently and for longer periods of time.

What are the symptoms of RLS?

Sensations occur when you lie down or sit for a prolonged time. This causes:

  • The need to move the legs for temporary relief of symptoms by:

    • Stretching or bending

    • Rubbing the legs

    • Tossing or turning in bed

    • Getting up and pacing

  • Worsening symptoms when lying down, especially when trying to fall asleep at night, or during other forms of inactivity, including just sitting

  • A tendency to feel the most discomfort late in the day and at night

How is RLS diagnosed?

Your doctor can diagnose RLS your signs and symptoms, a complete medical history, and a physical exam. In addition, tests, such as lab tests or a sleep study, may be done. Currently, there is not a definitive test to diagnose restless legs syndrome.

The diagnosis is especially difficult with children because the physician relies heavily on the patient's explanations of symptoms, and given the nature of the symptoms of RLS, can be difficult for a child to describe.

The syndrome can sometimes be misdiagnosed as “growing pains” or attention deficit disorder.

How is RLS treated?

Your doctor will consider your age, overall health and other factors when advising treatment for you.

Treatment options for restless legs syndrome may include:

  • Trying good sleep habits

  • Stopping activities that worsen symptoms

  • Avoiding caffeine, alcohol, and tobacco, which may worsen symptoms

  • Regular, moderate exercise

  • Maintaining a well-balanced diet

  • Treating underlying chronic conditions

Medications, including:

  • Dopaminergic agents (drugs that increase dopamine) which are largely used to treat Parkinson's disease

  • Benzodiazepines such as clonazepam and diazepam

  • Opioids such as codeine, propoxyphene, or oxycodone

  • Anticonvulsants such as gabapentin and pregabalin

Consult your doctor for more information regarding the treatment of restless legs syndrome.

Key Points

  • Restless legs syndrome is a sleep disorder that causes unpleasant sensations in the legs. The cause of RLS is still unknown.

  • With RLS, you have an irresistible urge to move the affected limb when the sensations occur.

  • Your doctor can diagnose RLS your signs and symptoms, a complete medical history, and a physical exam, but there is no definitive test to diagnose RLS.

  • Medications and lifestyle changes can help relieve RSL symptoms.

Next steps

Tips to help you get the most from a visit to your health care provider:

  • Before your visit, write down questions you want answered.

  • Bring someone with you to help you ask questions and remember what your provider tells you.

  • At the visit, write down the names of new medicines, treatments, or tests, and any new instructions your provider gives you.

  • If you have a follow-up appointment, write down the date, time, and purpose for that visit.

  • Know how you can contact your provider if you have questions.

Source: https://www.hopkinsmedicine.org/health/conditions-and-diseases/restless-legs-syndrome-rls