editorials
Therapeutic Dilemma for Restless Legs Syndrome Sudhansu Chokroverty, M.D. Since the tantalizing description by Willis in 1672 and the modern exposition by Ekbom in 1945,1 we have enhanced our understanding of the common yet uncommonly recognized entity of restless legs syndrome (RLS). RLS is a sensori motor neurologic disorder with an unknown natural history that profoundly disturbs sleep and quality of life. The condition was not viewed as a true disease by some until 2011, when it was renamed Willis–Ekbom disease. Four essential diagnostic criteria have been established: the urge to move the legs (with or without uncomfortable leg sensations), beginning or worsening of symp toms during quiescence, relief on moving the legs, and occurrence largely in the evening.2 Later, a fifth criterion was added specifying that the four criteria could not be solely accounted for as symptoms of another medical or behav ioral condition (so-called RLS mimics).2 Epidemi ologic studies of the North American and Euro pean3 populations subsequently estimated the prevalence of moderate-to-severe RLS at 2.7% (with a prevalence of 7.2% when severity was not considered), with slightly lower rates estimated in some Asian countries,4 suggesting the possi bility that environment and race may influence susceptibility to disease. The incidence and nat ural history of RLS are not well described. Recent studies have reported a cumulative incidence of 8%5 and 6.6%6 and a persistence of symptoms of 40% during a 2-year period.7 The pathophysiologic features of RLS remain undetermined, which has made it difficult to develop an effective drug. The most popular theory suggests an iron–dopamine connection, with problems in iron acquisition in the basal ganglia, which in turn creates dopamine dys function.8 Controversy remains as to whether RLS results from a hyperdopaminergic state (as suggested by increased levels of dopamine transporters in the striatum, indicating an in crease in synaptic levels of dopamine) or a hypo dopaminergic state (as attested by an improve ment in symptoms in response to dopaminergic drugs and worsening in response to dopamine antagonists).8 Iron deficiency may play a role in a subset of patients with RLS, but not in all cases.
There is no convincing evidence of dysfunction in the diencephalospinal dopamine pathway. Other theories8 that suggest the involvement of an alternative neurotransmitter or neuronal path way include increased levels of thalamic gluta mate to account for hyperarousal and sleep dis ruption and the activation of hypoxic pathways in the brain, which may either contribute to or result from cellular iron deficiency. Opioid-path way dysfunction and reduced thalamocortical connectivity may explain the sensory symptoms of RLS. Genetic disposition to the condition plays a role in all these theories (genomewide studies have reported an association between RLS and the genes implicated in disease processes, periodic limb movements during sleep, and iron status). These multiple and inconsistent theories create challenges for researchers seeking to make advances in treatment, a difficulty compounded by the fact that the suggested causes of RLS are many and that it may occur as a primary or sec ondary condition. Since the serendipitous observation by Akpi nar9 in 1982 of the benefit of levodopa for RLS, dopamine agonists have remained the first-line therapy, and clinical trials have attested to their efficacy. However, dopamine agonists can be associated with augmentation, an iatrogenic ef fect in which symptoms worsen after treatment is started. Augmentation remains a vexing longterm problem in the management of RLS. In one study, treatment with pramipexole (a dopamine agonist) for 10 years was associated with an an nual rate of augmentation of 7%, which suggests that treatment may result in a slow progression of dopaminergic dysfunction.10 This finding fueled a search for an alternative drug. In this issue of the Journal, Allen et al.11 report the re sults of a large multicenter study including 719 patients with moderate-to-severe primary RLS. The trial showed that pregabalin, an α2δ ligand, was more efficacious than pramipexole. The trial provides compelling evidence for the efficacy of a nondopaminergic drug in the treatment of RLS, thus implicating a role for nondopaminergic pathways in the disease. The authors noted an augmentation rate of 6.6 to 9.0% with pramipex
n engl j med 370;7 nejm.org february 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at UTSA Libraries on September 8, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
667
editorials
ole but only 1.7% with pregabalin over a 52week period. This study, one of few head-to-head studies of two classes of medications in the treatment of RLS, showed long-term efficacy in a nondopaminergic drug and reported a new observation of augmentation with pregabalin. The study focused on a select group of patients who did not undergo an objective assessment of sleep. Despite its limitations, this carefully con ducted study, which included follow-up that in corporated clinically appropriate criteria for end points, should inspire further research. More in formation is needed about long-term efficacy and the adverse effects of pregabalin. The observation that augmentation can occur with different drugs (pramipexole or pregabalin in this study and tramadol in a prior study12) raises the question of whether augmentation is related to medication, is intrinsic to RLS, or is related to individual patient characteristics. Many other gaps exist in our knowledge of how to best treat patients with this condition. More head-to-head comparisons of treatments are needed, and future trials should include chil dren and elderly patients, those with secondary RLS, and those with mild-to-moderate RLS. Studies should also include an objective assess ment of sleep and an evaluation of the role of sleep disruption in morbidity. I hope that this latest progress in RLS research will spur the de velopment of an ideal drug for the treatment of this challenging condition. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
From the Department of Neurology, New Jersey Neuroscience Institute at JFK Medical Center, Edison, and Seton Hall University, South Orange — both in New Jersey. 1. Ekbom KA. Restless legs: a clinical study. Acta Med Scand
Suppl 1945;158:1-123.
2. Allen RP, Walters AS, Chokroverty S. Restless legs syndrome
(Willis-Ekbom disease). In: Chokroverty S, Allen RP, Walters AS, Montagna P, eds. Sleep and movement disorders. 2nd ed. New York: Oxford University Press, 2013:598-611. 3. Allen RP, Walters AS, Montplaisir J, et al. Restless legs syn drome prevalence and impact: REST general population study. Arch Intern Med 2005;165:1286-92. 4. Tan EK, Seah A, See SJ, Lim E, Wong MC, Koh KK. Restless legs syndrome in an Asian population: a study in Singapore. Mov Disord 2001;16:577-9. 5. Szentkiralyi A, Fendrich K, Hoffmann W, Happe S, Berger K. Incidence of restless legs syndrome in two population-based cohort studies in Germany. Sleep Med 2011;12:815-20. 6. Budhiraja P, Budhiraja R, Goodwin JL, et al. Incidence of rest less legs syndrome and its correlates. J Clin Sleep Med 2012;8: 119-24. 7. Kagimura T, Nomura T, Kusumi M, Nakashima K, Inoue Y. Prospective survey on the natural course of restless legs syn drome over two years in a closed cohort. Sleep Med 2011;12: 821-6. 8. Allen RP. Pathophysiology: the biology of restless legs syn drome (Willis-Ekbom disease). In: Chokroverty S, Allen RP, Walters AS, Montagna P, eds. Sleep and movement disorders. 2nd ed. New York: Oxford University Press, 2013:585-97. 9. Akpinar S. Treatment of restless legs syndrome with levo dopa plus benserazide. Arch Neurol 1982;39:739. 10. Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longi tudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med 2011;12: 440-4. 11. Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014;370:621-31. 12. Earley CJ, Allen RP. Restless legs syndrome augmentation associated with tramadol. Sleep Med 2006;7:592-3. DOI: 10.1056/NEJMe1313155 Copyright © 2014 Massachusetts Medical Society.
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n engl j med 370;7 nejm.org february 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at UTSA Libraries on September 8, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
Therapeutic Dilemma for Restless Legs Syndrome Sudhansu Chokroverty, M.D. Since the tantalizing description by Willis in 1672 and the modern exposition by Ekbom in 1945,1 we have enhanced our understanding of the common yet uncommonly recognized entity of restless legs syndrome (RLS). RLS is a sensori motor neurologic disorder with an unknown natural history that profoundly disturbs sleep and quality of life. The condition was not viewed as a true disease by some until 2011, when it was renamed Willis–Ekbom disease. Four essential diagnostic criteria have been established: the urge to move the legs (with or without uncomfortable leg sensations), beginning or worsening of symp toms during quiescence, relief on moving the legs, and occurrence largely in the evening.2 Later, a fifth criterion was added specifying that the four criteria could not be solely accounted for as symptoms of another medical or behav ioral condition (so-called RLS mimics).2 Epidemi ologic studies of the North American and Euro pean3 populations subsequently estimated the prevalence of moderate-to-severe RLS at 2.7% (with a prevalence of 7.2% when severity was not considered), with slightly lower rates estimated in some Asian countries,4 suggesting the possi bility that environment and race may influence susceptibility to disease. The incidence and nat ural history of RLS are not well described. Recent studies have reported a cumulative incidence of 8%5 and 6.6%6 and a persistence of symptoms of 40% during a 2-year period.7 The pathophysiologic features of RLS remain undetermined, which has made it difficult to develop an effective drug. The most popular theory suggests an iron–dopamine connection, with problems in iron acquisition in the basal ganglia, which in turn creates dopamine dys function.8 Controversy remains as to whether RLS results from a hyperdopaminergic state (as suggested by increased levels of dopamine transporters in the striatum, indicating an in crease in synaptic levels of dopamine) or a hypo dopaminergic state (as attested by an improve ment in symptoms in response to dopaminergic drugs and worsening in response to dopamine antagonists).8 Iron deficiency may play a role in a subset of patients with RLS, but not in all cases.
There is no convincing evidence of dysfunction in the diencephalospinal dopamine pathway. Other theories8 that suggest the involvement of an alternative neurotransmitter or neuronal path way include increased levels of thalamic gluta mate to account for hyperarousal and sleep dis ruption and the activation of hypoxic pathways in the brain, which may either contribute to or result from cellular iron deficiency. Opioid-path way dysfunction and reduced thalamocortical connectivity may explain the sensory symptoms of RLS. Genetic disposition to the condition plays a role in all these theories (genomewide studies have reported an association between RLS and the genes implicated in disease processes, periodic limb movements during sleep, and iron status). These multiple and inconsistent theories create challenges for researchers seeking to make advances in treatment, a difficulty compounded by the fact that the suggested causes of RLS are many and that it may occur as a primary or sec ondary condition. Since the serendipitous observation by Akpi nar9 in 1982 of the benefit of levodopa for RLS, dopamine agonists have remained the first-line therapy, and clinical trials have attested to their efficacy. However, dopamine agonists can be associated with augmentation, an iatrogenic ef fect in which symptoms worsen after treatment is started. Augmentation remains a vexing longterm problem in the management of RLS. In one study, treatment with pramipexole (a dopamine agonist) for 10 years was associated with an an nual rate of augmentation of 7%, which suggests that treatment may result in a slow progression of dopaminergic dysfunction.10 This finding fueled a search for an alternative drug. In this issue of the Journal, Allen et al.11 report the re sults of a large multicenter study including 719 patients with moderate-to-severe primary RLS. The trial showed that pregabalin, an α2δ ligand, was more efficacious than pramipexole. The trial provides compelling evidence for the efficacy of a nondopaminergic drug in the treatment of RLS, thus implicating a role for nondopaminergic pathways in the disease. The authors noted an augmentation rate of 6.6 to 9.0% with pramipex
n engl j med 370;7 nejm.org february 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at UTSA Libraries on September 8, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
667
editorials
ole but only 1.7% with pregabalin over a 52week period. This study, one of few head-to-head studies of two classes of medications in the treatment of RLS, showed long-term efficacy in a nondopaminergic drug and reported a new observation of augmentation with pregabalin. The study focused on a select group of patients who did not undergo an objective assessment of sleep. Despite its limitations, this carefully con ducted study, which included follow-up that in corporated clinically appropriate criteria for end points, should inspire further research. More in formation is needed about long-term efficacy and the adverse effects of pregabalin. The observation that augmentation can occur with different drugs (pramipexole or pregabalin in this study and tramadol in a prior study12) raises the question of whether augmentation is related to medication, is intrinsic to RLS, or is related to individual patient characteristics. Many other gaps exist in our knowledge of how to best treat patients with this condition. More head-to-head comparisons of treatments are needed, and future trials should include chil dren and elderly patients, those with secondary RLS, and those with mild-to-moderate RLS. Studies should also include an objective assess ment of sleep and an evaluation of the role of sleep disruption in morbidity. I hope that this latest progress in RLS research will spur the de velopment of an ideal drug for the treatment of this challenging condition. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
From the Department of Neurology, New Jersey Neuroscience Institute at JFK Medical Center, Edison, and Seton Hall University, South Orange — both in New Jersey. 1. Ekbom KA. Restless legs: a clinical study. Acta Med Scand
Suppl 1945;158:1-123.
2. Allen RP, Walters AS, Chokroverty S. Restless legs syndrome
(Willis-Ekbom disease). In: Chokroverty S, Allen RP, Walters AS, Montagna P, eds. Sleep and movement disorders. 2nd ed. New York: Oxford University Press, 2013:598-611. 3. Allen RP, Walters AS, Montplaisir J, et al. Restless legs syn drome prevalence and impact: REST general population study. Arch Intern Med 2005;165:1286-92. 4. Tan EK, Seah A, See SJ, Lim E, Wong MC, Koh KK. Restless legs syndrome in an Asian population: a study in Singapore. Mov Disord 2001;16:577-9. 5. Szentkiralyi A, Fendrich K, Hoffmann W, Happe S, Berger K. Incidence of restless legs syndrome in two population-based cohort studies in Germany. Sleep Med 2011;12:815-20. 6. Budhiraja P, Budhiraja R, Goodwin JL, et al. Incidence of rest less legs syndrome and its correlates. J Clin Sleep Med 2012;8: 119-24. 7. Kagimura T, Nomura T, Kusumi M, Nakashima K, Inoue Y. Prospective survey on the natural course of restless legs syn drome over two years in a closed cohort. Sleep Med 2011;12: 821-6. 8. Allen RP. Pathophysiology: the biology of restless legs syn drome (Willis-Ekbom disease). In: Chokroverty S, Allen RP, Walters AS, Montagna P, eds. Sleep and movement disorders. 2nd ed. New York: Oxford University Press, 2013:585-97. 9. Akpinar S. Treatment of restless legs syndrome with levo dopa plus benserazide. Arch Neurol 1982;39:739. 10. Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longi tudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med 2011;12: 440-4. 11. Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014;370:621-31. 12. Earley CJ, Allen RP. Restless legs syndrome augmentation associated with tramadol. Sleep Med 2006;7:592-3. DOI: 10.1056/NEJMe1313155 Copyright © 2014 Massachusetts Medical Society.
early job alert service available at the nejm careercenter
Register to receive weekly e-mail messages with the latest job openings that match your specialty, as well as preferred geographic region, practice setting, call schedule, and more. Visit the NEJM CareerCenter at NEJMjobs.org for more information.
668
n engl j med 370;7 nejm.org february 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at UTSA Libraries on September 8, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
