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Miscellaneous

Treating restless legs syndrome: current pathophysiological concepts and clinical trials

Bjorn Wito Walther Department of Neurology, Helios Klinikum Erfurt, PO Box 101263, 99012 Erfurt, Germany
Pages 501-514 | Published online: 24 Feb 2005

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  • •Interesting clinical study on circadian dependency of RLS using the suggested immobilisation test.
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  • ••Excellent survey about secondary RLS witha discussion of pathophysiological concepts.
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  • ••Presents basic data for the new concept ofRLS classification based on family history and the presence of neuropathy distinguishing an idiopathic and a neuropathic form.
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  • ••A basic report summarising the currentknowledge of all aspects of RLS.
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  • ••Represents the first mapping of a locusconferring susceptibility to RLS: lists findings of significant linkage to RLS on chromosome 12q in a large French-Canadian family.
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  • •This study summarises a new concept for RLS classification based on age of onset of the disease and family history.
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  • ••Presents findings which support the newconcept for RLS classification based on age of onset of the disease and family history.
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  • ••The most promising study of those suggesting that RLS may be related to peripheral factors and can be triggered by the painful dysaesthesias associated with a small-sensory-fibre loss in a subgroup of RLS patients. The authors postulate that this subgroup probably responds to neuropathic pain medications, such as carbarnazepine or gabapentin.
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  • •A collection of fundamental epidemiological data gathered by direct interview using specific RLS items in a large elderly population.
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  • •The first systematic examination of iron metabolism during pregnancy.
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  • •An important study indicating that RLS may be confused with ADHD.
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  • •A second important study indicating that RLS may be confused with ADHD.
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  • •Very first report of effectiveness of L-DOPA in RLS.
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  • •A study which shows that opioidergic substances probably mediate their effect via the dopaminergic system.
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  • ••The only study existing using high-resolution functional MRI to make brain areas involved in RLS visible.
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  • •Results indicated a reduced supraspinal inhibition in RLS subjects. The results are consistent with a subcortical dysfunction which alters the motor pathways. This study shows that L-DOPA could be responsible for the removal of impaired inhibition observed by TMS in RLS patients.
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  • •A study confirming the hypothesis of supraspinal origin of RLS.
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  • •A well-controlled study using pergolide in combination with the domperidone.
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  • •This study used matched control subjects to show substantially decreased fluor-dopa uptake in the putarnen and caudate of RLS patients.
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  • •Results presented here support the theory of subcortical dysfunction in RLS.
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  • •Pramipexole is thought to be the most potent and efficacious dopaminergic agent ever tested for RLS treatment due to this well-controlled study.
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  • ••An excellent compendium of RLS therapiesbased on evidence based medicine criteria.
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  • •A well-controlled study dealing with L-DOPA that shows the immediate onset of therapeutic effects of L-DOPA in RLS patients.
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  • •The best characterisation of this severe L-DOPA side effect thus far.
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  • •One of two well-controlled studies using pergolide in RLS treatment.
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  • •The first long-term follow-up study showing a persistent beneficial effect of pergolide on RLS symptoms for the duration of 1 year.
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  • •First of few studies comparing L-DOPA with dopamine agonists.
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  • •A follow-up study for mean 7.8 months showing a long-term benefical effect of pramipexole in RLS treatment.
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  • •The first report in the literature which pointed to the possible side effect of sleep attacks in therapy with dopamine agonists.
  • FEIRREIRA JJ, GALITZKY M, MONTASTRUC JL, RASCOL 0: Sleep attacks and Parkinson's disease treatment. Lancet (2000) 355:1333–1334.
  • •This report suggests that all dopamine agonists can induce sleep attacks.
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  • RYAN M, SLEVIN JT, WELLS A: Non-ergot dopamine agonist-induced sleep attacks. Phannacotherapy (2000) 20:724–726.
  • SCHAPIRA AH: Sleep attacks (sleep episodes) with pergolide. Lancet (2000) 355:1332–1333.
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  • 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) 16:327–332.
  • KAPLAN PW, ALLEN RP, BUCHHOLZ DW, WALTERS JK: A double-blind, placebo-controlled study of the treatment of periodic limb movements in sleep using carbidopa/levodopa and propoxyphene. Sleep (1993) 16:717–723.
  • LAUERMA H, MARKKULA J: Treatment of restless legs syndrome with tramadol: an open study. Clin. Psychiatry (1999) 60:241–244.
  • •One of rare studies in recent literature to use an opioid in RLS treatment with an efficacy, comparable to dopamine agonists.
  • WALTERS AS, WINKELMANN J, FRY Jet al.: Longterm-treatment with opioids in the restless legs syndrome. Mov. Disord. (2001) 15:1105–1109.
  • VAHEDI H, KUCHLE M, TRENKWALDER C, KRENZ CJ: Peridurale morphiumanwendung bei restless-legs-status. Andsthesiol Intensivmed. Notfallmed. Schrnerzth. (1994) 29.
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  • MONTAGNA P, DE BIANCHI LS, SUCCONI M, CIRIGNOTTA F, LUGARESI E: Clonazepam and vibration in restless legs syndrome. Acta Neurol Scand. (1984) 69:428–430.
  • SALETU M, ANDERER P, SALETU-ZYLHARZ G et al.: Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) : acute placebo-controlled sleep laboratory studies with clonazepam. Ear.Neuropsychphartnacol (2001) 11:153–161.
  • LUNDVAL 0, ABOM PE, HOLM R: Carbamazepine in restless legs: a controlled pilot study. Eur. Clin. Phartnacol (1983) 25:323–324.
  • TELSTAD W, SORENSEN 0, LARSEN S, LILLEVOLD PE, STENSRUD P, NYBERG-HANSEN R: Treatment of the restless legs syndrome with carbamazepine: a double blind study. BMJ(1984) 288:444–446.
  • EHRENBERG BL, EISENSEHR I, CORBETT KE, CROWLEY PF, WALTERS AS: Valproate for sleep consolidation in periodic limb movement disorder. Clin. Psychophannacol(2000) 20:574–578.
  • ADLER CH: Treatment of restless legs syndrome with gabapentin. Clin. Neurophartnacol (1997) 20:148–151.
  • HAPPE S, KLOSCH G, SALETU B, ZEITLHOFER J: Treatment of idiopathic restless legs syndrome (RLS) with gabapentin. Neurology (2001) 57:1717–1719.
  • •An open therapy study using gabapentin in patients of various background and origin.
  • MELLICK GA, MELLICK LB: Management of restless legs syndrome with gabapentin. Sleep (1996) 19:224–226.
  • O'KEEFFE ST, GAVIN K, LAVAN JN: Iron status and restless legs syndrome in the elderly. Age Ageing (1994) 23:200–203.
  • EARLEY CJ, CONNOR JR, BEARD JL, MALECKI EA, EPSTEIN DK, ALLEN RP: Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology (2000) 54:1698–1700.
  • •This study demonstrates that there is a marked reduction in ferritin and marked increase in transferrin levels in CSF, despite normal serum ferritin and transferrin levels in patients with idiopathic RLS. This may implicate a circumscribed brain iron storage dysfunction in patients with idiopathic RLS.
  • ALLEN RP, BARKER PB, WEHR F, SONG HK, EARLEY CJ: MRI measurement of brain iron in patients with restless legs syndrome. Neurology (2001) 56:263–265.
  • •The first study showing that iron concentrations in the substantia nigra and putamen correlates with symptom severity in a small group of idiopathic RLS patients.
  • DAVIS BJ, RAJPUT A, RAJPUT ML, AUL EA, EICHHORN GR: A randomized, double-blind placebo-controlled trial of iron in restless legs syndrome. Ear. Neurol (2000) 43:70–75.
  • •The only well-controlled study of orally-administered iron treatment of RLS patients showing no significant improvement of symptoms.
  • EARLEY CJ, ALLEN RP, BEARD JL, CONNOR JR: Insight into pathophysiology of restless legs syndrome. J. Neurosci. Res. (2000) 62:623–628.
  • ••An excellent summary on the currentpathophysiological knowledge of RLS, the connection of iron and doparnine metabolism and RLS. It presents elegant arguments on CNS iron-regulation and possible relationship to RLS.
  • EARLEY CJ, HECKLER D, ALLEN RP: IV iron treatment for RLS [abstract]. Sleep (2001) 24:359.
  • ••A most promising study which aims clarifythe role of intravenous iron therapy in RLS.
  • BARTON JC, WOOTEN VD, ACTON RT: Hemochromatosis and iron therapy of restless legs syndrome. Sleep Med. (2001) 2:249–251.
  • EARLEY CJ: Editorial: hemochromatosis and iron therapy of restless legs syndrome. Sleep Med. (2001) 2:181–183.
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  • WAGNER ML, WALTERS AS, COLEMAN RG, HENING WA, GRASING K, CHOKROVERTY S: Randomized, double-blind, placebo-controlled study of clonidine in restless legs syndrome. Sleep (1996) 19:52–58.
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Websites

  • www.rls.org
  • www.sleepfoundation.org/publications/2001 poll.html National Sleep Foundation. Omnibus sleep in America poll (2000).

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