Re: Bad medicine: Restless Legs Syndrome by the Medical Advisory Board

Re: Bad medicine: Restless Legs Syndrome      In response to the Views and Reviews column by Des Spence—“Bad Medicine: Restless Legs Sy...

Re: Bad medicine: Restless Legs Syndrome

     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.

       WED/RLS is a diagnosis officially recognized by the American Academy of Sleep Medicine, and expertise in WED/RLS 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 WED/RLS 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 WED/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). 


Medical Advisory Board of the Willis-Ekbom Disease (WED) Foundation
Arthur 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.D
Jennifer 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.


(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. 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.

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