Restless legs syndrome (RLS) is the most common movement disorder and is characterized by the feeling of an urgent need to move the legs while lying down or resting. RLS worsens during the evening and at night and is relieved by leg movement.1,2 It is also known that RLS is commonly comorbid with Parkinson’s disease (PD).3 Although the exact pathological mechanism of RLS is unknown, dopaminergic medications for PD, such as levodopa and other dopamine agonists, symptomatically improve RLS as well.4 Istradefylline is a highly selective adenosine A2A receptor antagonist that is thought to modulate the overactivated striatopallidal pathway (indirect pathway) in PD,4 reducing the duration of the ‘‘off’’ state and extending the ‘‘on’’ state without inducing dyskinesia.5 Istradefylline has been recently approved in Japan for the treatment of PD, but, to date, there are no data on the effect of istradefylline on RLS in PD. Here we report the cases of three patients with RLS comorbid with PD who were treated with istradefylline

Hattori, Nobutaka

Kasemsuk, Chayut

Nuermaimaiti, Maierdanjiang

Oyama, Genko

Tremor and Other Hyperkinetic Movements

English

Maierdanjiang Nuermaimaiti

Genko Oyama

Chayut Kasemsuk

Nobutaka Hattori

Directory of Open Access Journals

Istradefylline for Restless Legs Syndrome Associated with Parkinson’s Disease

Columbia University Academic Commons

New Observations LettersIstradefylline for Restless Legs Syndrome Associated with Parkinson’s DiseaseMaierdanjiang Nuermaimaiti1, Genko Oyama1*, Chayut Kasemsuk1,2& Nobutaka Hattori11Department of Neurology, Juntendo University, Tokyo, Japan, 2Department of Neurology, Prasat Neurological Institute, Bangkok, ThailandKeywords: Parkinsonism, restless legs syndrome, adenosine A2A receptorCitation: Reyes AJ, Ramcharan K, Giddings SL, Aboh S, Rampersad F. Myoclonic jerks, exposure to many cats, and neurotoxoplasmosis in animmunocompetent man. Tremor Other Hyperkinet Mov. 2018; 8. doi: 10.7916/D8B86GQC* To whom correspondence should be addressed. E-mail: g_oyama@juntendo.ac.jpEditor: Elan D. Louis, Yale University, USAReceived: October 16, 2017 Accepted: December 14, 2017 Published: January 8, 2018Copyright: ’ 2018 Nuermaimaiti et al. This is an open-access article distributed under the terms of the Creative Commons Attribution–Noncommercial–No Derivatives License, whichpermits the user to copy, distribute, and transmit the work provided that the original authors and source are credited; that no commercial use is made of the work; and that the work is notaltered or transformed.Funding: None.Financial Disclosures: Dr. Oyama is funded by Grants from the Japan Society for the Promotion of Science; Grant-in-Aid for Young Scientists (B), and Novartis Pharma. Dr. Oyamahas received speaker honoraria from Medtronic, Boston Scientific, Novartis Pharma, MSD, Nihon Medi-Physics, Otsuka Pharmaceutical, and Kyowa Hakko Kirin, and Abbvie.Dr. Hattori is funded by the Japan Agency for Medical Research and Development (AMED), the Japan Society for the Promotion of Science; Grant-in-Aid for Scientific Research (B),Ministry of Education Culture, Sports, Science and Technology Japan (Grant-in-Aid for Scientific Research on Innovative Areas), Health and Labour Sciences Research Grants (Researchon Measures for Intractable Diseases), the Japan Society for the Promotion of Science and Sumitomo Dainippon Pharma Co., Ltd.; Consultancies: Hisamitsu Pharmaceutical, Dai-NipponSumitomo Pharma Co., Ltd; Expert Testimony: Ono Pharmaceutical Co., Ltd.; Advisory Boards: Otsuka Pharmaceutical, Co., Ltd., Novartis Pharma K.K, Takeda Pharmaceutical Co.,Ltd.; Donation: Astellas Pharma Inc., Eisai Co., Ltd., MSD K.K., Daiichi Sankyo Co., Ltd., Novartis Pharma K.K, Takeda Pharmaceutical Co., Ltd., Nihon Medi-physics Co., Ltd.,Dai-Nippon Sumitomo Pharma Co., Ltd., Pfizer Japan Inc., Bayer Yakuhin, Ltd.; Honoraria: GlaxoSmithKline K.K, Nippon Boehringer Ingelheim, Co., Ltd., FP PharmaceuticalCorporation, Dai-Nippon Sumitomo Pharma Co., Ltd., Eisai Co., Ltd., Kissei Pharmaceutical Company, NihonMedi-physics Co., Ltd., Kyowa Hakko-Kirin Co., Ltd., Novartis PharmaK.K, Biogen, Acorda Therapeutics, Inc.; Donation for the endowed research departments: GlaxoSmithKline K.K, Nippon Boehringer Ingelheim, Co., Ltd., Dai-Nippon SumitomoPharma Co., Ltd., Eisai Co., Ltd., Kissei Pharmaceutical Co., Janssen Pharmaceutical K.K, Nihon Medi-physics Co., Ltd., Kyowa Hakko-Kirin Co., Ltd., Medtronic Inc., NovartisPharma K.K, Ono Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Zaiho Co., Hydrogen Health Medical Labo Co., ABIST Co., Ltd., Melodian Co., Ltd., Daiwa Co., Ltd.,Biogen Idec Japan Ltd., Bayer Yakuhin, Ltd., Nihon Pharmaceutical Co., Ltd., Asahi Kasei Medical Co., Ltd., MiZ Co., Ltd.Conflicts of interest: The authors report no conflicts of interest.Ethics Statement: This study was reviewed by the authors’ institutional ethics committee and was considered exempted from further review.IntroductionRestless legs syndrome (RLS) is the most common movementdisorder and is characterized by the feeling of an urgent need to movethe legs while lying down or resting. RLS worsens during the eveningand at night and is relieved by leg movement.1,2 It is also known thatRLS is commonly comorbid with Parkinson’s disease (PD).3 Althoughthe exact pathological mechanism of RLS is unknown, dopaminergicmedications for PD, such as levodopa and other dopamine agonists,symptomatically improve RLS as well.4Istradefylline is a highly selective adenosine A2A receptor antagonistthat is thought to modulate the overactivated striatopallidal pathway(indirect pathway) in PD,4 reducing the duration of the ‘‘off’’ state andextending the ‘‘on’’ state without inducing dyskinesia.5 Istradefyllinehas been recently approved in Japan for the treatment of PD, but, todate, there are no data on the effect of istradefylline on RLS in PD.Here we report the cases of three patients with RLS comorbid with PDwho were treated with istradefylline.Case reportsCase 1A 73-year-old right-handed male had developed a tremor inhis right lower limb at the age of 61 years. He began taking selegi-line 5 mg/day at the age of 62 years but experienced only mildimprovement and subsequently began taking pramipexole 1 mg/day.As wearing-off developed, and he found it difficult to work when in the‘‘off’’ state at the age of 70, he began taking istradefylline 20 mg/day,which improved his gait. After a while, as wearing-off got severe, healso started to feel discomfort at night. This discomfort led to an urgeto walk around, and the patient experienced relief after walking;his istradefylline was increased to 40 mg/day for his parkinsonism.Freely available onlineTremor and Other Hyperkinetic Movementshttp://www.tremorjournal.orgThe Center for Digital Research and ScholarshipColumbia University Libraries/Information Services1His parkinsonism improved, and his Unified Parkinson’s DiseaseRating Scale part 3 (UPDRS-III) score improved from 40 to 30. Theincreased istradefylline subsequently improved his RLS symptoms, andresulted in complete remission. The discomfort in his legs that made himfeel the need to move his legs disappeared. His score on the InternationalRLS Study Group RLS Severity Scale6 improved from 18 to 0 points.This improvement lasted at least 30 months without augmentation.Case 2A 65-year-old right-handed male had developed a resting tremor inhis right hand at the age of 54 years and was subsequently diagnosedwith PD. He began taking pramipexole extended release (2 mg/day),but development of gait disturbance required an increase in dosageto 3 mg/day; however, the dosage increase resulted in hypersexuality.His medication was then changed from pramipexole extended releaseto ropinirole controlled release, and he was started on levodopa/carbidopa (150 mg/day) at the age of 62 years. After a while, he beganto feel the urgency to walk around when he was resting, particularly inthe evening and at night. He was started on istradefylline (20 mg/day),and his RLS symptoms improved and almost disappeared, and resultedin an improvement in his sleep. The improvement lasted 5 monthsuntil he stopped taking istradefylline due to the initiation oflevodopa/carbidopa infusion gel therapy because of a wearing-offand dyskinesia.Case 3A 49-year-old right-handed male noted slowness in his left leg anddifficulty in using his left hand at the age of 44 years. He began to takepramipexole (up to 3.75 mg/day), which effectively improved the PDsymptoms. At the age of 46 years, he was prescribed selegiline 2.5 mg/day in addition because of wearing-off. His left leg began dragging atthe age of 47 years, and he started falling down occasionally. He alsoreported sleep disturbance and an urgency to move his legs at age49 years. Istradefylline (20 mg/day) was started, and the feelings ofurgently needing to move his legs diminished and his quality of sleepimproved remarkably. This effect lasted at least 17 months.DiscussionSummaries of the outcomes of the three cases are presented in Table 1.In all three cases, introducing or increasing istradefylline produced afavorable response to both RLS and PD symptoms. Patients in all threecases reported feeling the urgent need to move their legs when restingor lying in bed. The symptoms worsened in the evening and at night,leading to sleep disturbance in at least one case. Starting or increasingistradefylline subjectively improved the RLS symptoms in all three cases.To the best of our knowledge, this is the first report that notes thatistradefylline improves RLS that is comorbid with PD.One of the hypothesized mechanisms suggests that istradefyllineimproved the ‘‘hidden’’ RLS that became unmasked in the ‘‘off’’ stateof PD. Improving parkinsonism may subsequently improve the under-lying RLS in PD. In fact, RLS is thought to occur in up to 50% ofpatients with PD,3 but the symptoms of RLS may be masked by anti-PD dopaminergic treatment.7 Undertreatment of PD can unmaskRLS. In addition, there are reports indicating that the motor symp-toms of PD improved as expected after subthalamic deep brain stimu-lation but that reducing dopaminergic medication led to unmaskingof RLS.8It is also possible that istradefylline directly improves RLS. Onesuggested pathogenetic mechanism of RLS is brain iron deficiency.1Current studies have indicated that adenosine receptors play a sig-nificant role in both brain iron deficiency and sleep disorders in RLS.1One study demonstrated a significant downregulation of adenosineA1 receptors and upregulation of adenosine A2A receptors in RLS.1Thus, inhibiting adenosine A2A receptors may directly improve RLS,although this hypothesis remains speculative.A third hypothesis suggests that the improvement in dopamineagonist-induced daytime somnolence upon administration of istrade-fylline could improve RLS at night. Istradefylline is an analog of thestimulant caffeine, and it is known to be anti-somnogenic.4 However,the extent of these potential interactions is still unknown.In conclusion, istradefylline may be efficacious against RLS that iscomorbid with PD. Further prospective studies are needed to confirmour observations.Table 1. Patient Characteristics of the Three Presented CasesCase 1 Case 2 Case 3Age/sex 73/M 65/M 52/MParkinson’s disease duration (years) 12 11 5Dosage of istradefylline 20 mg 40 mg 20 mgL-dopa + + +Dopamine agonist + + +Follow-up 30 months 5 months 17 monthsAugmentation – – –Nuermaimaiti M, Oyama G, Kasemsuk C, et al Istradefylline for RLS in PDTremor and Other Hyperkinetic Movementshttp://www.tremorjournal.orgThe Center for Digital Research and ScholarshipColumbia University Libraries/Information Services2References1. Quiroz C, Gulyani S, Ruiqian W, Bonaventura J, Cutler R, Pearson V,et al. Adenosine receptors as markers of brain iron deficiency: implications forrestless legs syndrome. Neuropharmacology 2016;111:160–168. doi: 10.1016/j.neuropharm.2016.09.0022. Zhu XY, Liu Y, Zhang XJ, Yang WH, Feng Y, Ondo WG, et al. Clinicalcharacteristics of leg restlessness in Parkinson’s disease compared with idiopathicrestless legs syndrome. J Neurol Sci 2015;357:109–114. doi: 10.1016/j.jns.2015.07.0083. Moller JC, Unger M, Stiasny-Kolster K, Oertel WH. Restless legssyndrome (RLS) and Parkinson’s disease (PD)-related disorders or differententities? J Neurol Sci 2010;289:135–137. doi: 10.1016/j.jns.2009.08.0354. DeCerce J, Smith LF, Gonzalez W, Sussman NM. Effectiveness andtolerability of istradefylline for the treatment of restless legs syndrome: anexploratory study in five female patients. Curr Ther Res Clin Exp 2007;68:349–359.doi: 10.1016/j.curtheres.2007.11.0015. Mizuno Y, Kondo K, and the Japanese Istradefylline Study Group.Adenosine A2A receptor antagonist Istradefylline reduces daily OFF Time inParkinson’s disease. Mov Disord 2013;28:1138–41. doi: 10.1002/mds.254186. Walters AS, LeBrocq C, Dhar A, Hening W, Rosen R, Allen RP, et al.Validation of the International Restless Legs Syndrome Study Group ratingscale for restless legs syndrome. Sleep Med 2003;4:121–132. doi: 10.1016/S1389-9457(02)00258-77. Iranzo A, Comella CL, Santamaria J, Oertel W. Restless legs syndrome inParkinson’s disease and other neurodegenerative diseases of the central nervoussystem. Mov Disord 2007;22:S424–430.1. doi: 10.1002/mds.216008. Marques A, Fantini ML, Morand D, Pereira B, Derost P, Ulla M, et al.Emergence of restless legs syndrome after subthalamic stimulation in Parkinson’sdisease: a dopaminergic overstimulation? Sleep Med 2015;16:583–588. doi: 10.1016/j.sleep.2014.11.020Istradefylline for RLS in PD Nuermaimaiti M, Oyama G, Kasemsuk C, et alTremor and Other Hyperkinetic Movementshttp://www.tremorjournal.orgThe Center for Digital Research and ScholarshipColumbia University Libraries/Information Services3

https://academiccommons.columbia.edu/doi/10.7916/D8QJ90DV/download

Istradefylline for Restless Legs Syndrome Associated with Parkinson’s Disease

Abstract

Similar works

Full text

Available Versions

Directory of Open Access Journals

Columbia University Academic Commons