Chaudhuri, KR

Foltynie, T

Leta, V

Limousin, P

Mulroy, E

Zrinzo, L

English

UCL Discovery

Reply to Comment on: Successful Treatment of Levodopa/Carbidopa Intestinal Gel Associated “Biphasic-like” Dyskinesia with Pallidal Deep Brain StimulationEoin Mulroy FRACP1, Valentina Leta MD2, Ludvic Zrinzo PhD1, Thomas Foltynie PhD1, K Ray Chaudhuri MD PhD2, Patricia Limousin PhD11 Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK2 Parkinson's Foundation Centre of Excellence and NIHR Biomedical Research Centre, King's College Hospital and Kings College, London, United KingdomCorresponding Author:Eoin MulroyDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UKe-mail: e.mulroy@ucl.ac.ukWord count: 314Running title: Biphasic-like dyskinesia treated with DBSKey words:  Parkinson disease; Hyperkinesis; Deep brain stimulationPage 1 of 5 Movement Disorders Clinical PracticeWe thank the authors for their interest in our clinical vignette, and for highlighting potential difficulties in the diagnosis of ‘biphasic-like’ dyskinesia(1,2). Of the three classically described variants of levodopa-induced dyskinesia, biphasic dyskinesia is arguably the least understood, most debilitating, and hardest to treat(3). Typical biphasic dyskinesia occurs early (10-20min) after levodopa intake, abates at peak serum concentrations, and recurs during the subsequent decay in plasma drug levels prior to administration of the next levodopa dose. Such temporal patterns facilitate diagnosis, though co-existence with peak-dose and end-of-dose dyskinesia within individual patients as well as bizarre phenomenology (an excellent example being the ‘silly walks’ of Parkinson’s described by Růžička et al. in 2011)(4) means that mis-diagnoses remain common. Continuous dopaminergic stimulation approaches have added an extra layer of complexity. Indeed, while they are effective treatments for many motor complications (including dyskinesia), both levodopa-carbidopa intestinal gel and subcutaneous apomorphine have occasionally been associated with the emergence of ‘biphasic-like’ phenomena, likely due to continuous stimulation at a sub-therapeutic level(5,6). The pathophysiologic basis of biphasic dyskinesia is complex and incompletely understood. Intuitively, increasing dopaminergic stimulation beyond the ‘biphasic’ level should ameliorate symptoms, and indeed this is the most commonly adopted strategy. However, it is not always effective and the benefits may be lost over time. In such cases, deep brain stimulation (DBS) should be considered. Both the subthalamic nucleus (STN) and internal portion of the globus pallidus (GPi) have proven efficacy as targets for treating levodopa-induced dyskinesia, including biphasic dyskinesia(7–9). Pallidal stimulation has superior efficacy, and exerts a direct anti-dyskinetic effect, while STN stimulation largely improves dyskinesia through permitting reductions in levodopa dosing7.Page 2 of 5Movement Disorders Clinical PracticeIn our vignette, we illustrated the life-changing effects of successful GPi DBS for levodopa-carbidopa intestinal gel-associated biphasic-like dyskinesia. This management strategy should be considered for biphasic and ‘biphasic-like’ dyskinesia refractory to medical management, even in those with mild pre-existing cognitive symptoms or gait imbalance.Acknowledgement:We wish to acknowledge Miriam Parry, Parkinson’s disease nurse specialist, for her expert care of patients with intrajejunal levodopa infusions.Author roles:1 Research project: A. Conception, B. Organization, C. Execution;2 Statistical Analysis: A. Design, B. Execution, C. Review and Critique;3. Manuscript Preparation: A. Writing of the first draft, B. Review and CritiqueEM: 1A, 1B, 1C, 3AVL: 1B, 1C, 3BLZ: 1B, 1C, 3BTF: 1B, 1C, 3BKRC: 1B, 1C, 3BPL: 1B, 1C, 3BDisclosures:Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work.Financial Disclosures for the previous 12 months:EM is funded by the Edmond J. Safra Foundation. He also receives research Page 3 of 5 Movement Disorders Clinical Practicesupport from the National Institute for Health Research University College London Hospitals Biomedical Research Centre. VL reports grants from BRC, Parkinson’s UK, a travel and congress grant from Bial UK Ltd, speaker-related activities fees from Britannia pharmaceuticals, and consultancy fees from Invisio Pharmaceuticals, outside the submitted work. LZ has received honoraria for educational activities and has acted as consultant for Boston Scientific and Medtronic. KRC has served on the advisory board of AbbVie, UCB , GKC, Bial, Cynapsus, Novartis, Lobsor, Stada, Medtronic, Zambon, Profile, Sunovion, Roche, Therevance, Scion and Britannia, has received honoraria for lectures from AbbVie ,Britannia, UCB, Mundipharma, Zambon, Novartis and Boeringer Ingelheim has received Investigator Initiated grants from Britania Pharmaceuticals, AbbVie, UCB, GKC and Bial and academic grants from EU, IMI EU, Horizon 2020, Parkinson's UK, NIHR, PDNMG, EU (Horizon 2020), Kirby Laing Foundation, NPF, MRC and Wellcome Trust. PL has received honoraria and travel expenses from Medtronic and Boston Scientific we well as a grant from Boston Scientific.Ethical compliance statement: The authors confirm that the approval of an institutional review board was not required for this work. Written informed consent was obtained from all patients for publication of this work. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.ReferencesPage 4 of 5Movement Disorders Clinical Practice1. Gupta H et al. Comment on: Successful Treatment of Levodopa/Carbidopa Intestinal Gel Associated “Biphasic-like” Dyskinesia with Pallidal Deep Brain Stimulation. Mov Disord Clin Pract 2021; in press. 2. Mulroy E, Leta V, Zrinzo L, Foltynie T, Chaudhuri KR, Limousin P. Successful Treatment of Levodopa/Carbidopa Intestinal Gel Associated “Biphasic-like” Dyskinesia with Pallidal Deep Brain Stimulation. Mov Disord Clin Pract. 2021 Feb 5;8(2):273–4. 3. Chapuis S, Ouchchane L, Metz O, Gerbaud L, Durif F. Impact of the motor complications of Parkinson’s disease on the quality of life. Mov Disord. 2005 Feb;20(2):224–30. 4. Růžička E, Zárubová K, Nutt JG, Bloem BR. “Silly Walks” in Parkinson’s disease: Unusual presentation of dopaminergic-induced dyskinesias. Mov Disord. 2011 Aug 1;26(9):1783–4. 5. Durif F, Deffond D, Dordain G, Tournilhac M. Apomorphine and diphasic dyskinesia. Clin Neuropharmacol. 1994; 6. Olanow CW, Kieburtz K, Odin P, Espay AJ, Standaert DG, Fernandez HH, et al. Continuous intrajejunal infusion of levodopa-carbidopa intestinal gel for patients with advanced Parkinson’s disease: a randomised, controlled, double-blind, double-dummy study. Lancet Neurol. 2014 Feb;13(2):141–9. 7. Krack P. From off-period dystonia to peak-dose chorea: The clinical spectrum of varying subthalamic nucleus activity. Brain. 1999 Jun 1;122(6):1133–46. 8. Apetauerova D, Ryan RK, Ro SI, Arle J, Shils J, Papavassiliou E, et al. End of day dyskinesia in advanced Parkinson’s disease can be eliminated by bilateral subthalamic nucleus or globus pallidus deep brain stimulation. Mov Disord. 2006 Aug;21(8):1277–9. 9. Fan S, Wang K, Hu W, Eisinger RS, Han A, Han C, et al. Pallidal versus subthalamic nucleus deep brain stimulation for levodopa-induced dyskinesia. Ann Clin Transl Neurol. 2020 Jan 8;7(1):59–68. Page 5 of 5 Movement Disorders Clinical Practice

Reply to Comment on: Successful Treatment of Levodopa/Carbidopa Intestinal Gel Associated "Biphasic‐Like" Dyskinesia with Pallidal Deep Brain Stimulation

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Reply to Comment on: Successful Treatment of Levodopa/Carbidopa Intestinal Gel Associated "Biphasic‐Like" Dyskinesia with Pallidal Deep Brain Stimulation

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