Reply to: Subthalamic Nucleus Deep Brain Stimulation as Rescue Therapy for Levodopa Carbidopa Intestinal Gel–Associated Biphasic‐Like Dyskinesias

We thank the authors for their interest in our case,¹ and for sharing their experience of subthalamic nucleus (STN) deep brain stimulation (DBS) in the treatment of levodopa‐carbidopa intestinal gel (LCIG) associated biphasic‐like dyskinesia.²

The benefits of STN DBS in treating biphasic dyskinesia were first unequivocally demonstrated by Krack et al. in 1999.³ In this study, 27 Parkinson's disease (PD) patients with motor complications underwent levodopa challenge before and after 6 months of chronic high‐frequency STN DBS—a 50% reduction in biphasic dyskinesia was observed. Most recently, Kim et al. reported outcomes from 66 patients with biphasic dyskinesia who had undergone STN DBS. In their cohort, biphasic events disappeared in 74% of patients, though in nearly half, this benefit took over 3 months to achieve.⁴

The improvements in dyskinesia following STN DBS are generally thought to result from levodopa dose reduction following the procedure. This is certainly part of the explanation, particularly in relation to peak‐dose dyskinesia, and there is a correlation between post‐operative levodopa dose reduction and improvements in dyskinesia.⁴ However, in some patients, such as the one presented here, benefit is obtained despite minimal changes in levodopa dose, suggesting an additional direct anti‐dyskinetic effect of STN stimulation.

In contrast to the anti‐akinetic effects of STN DBS, which are primarily mediated by suppression of beta‐band oscillatory activity in the dorso‐laterally located sensori‐motor STN,⁵ stimulation above the STN is best for controlling dyskinesia. This effect is likely mediated through influences on pallidofugal fibers in the sub‐thalamic region, interrupting pathological pallidal neuronal discharges from reaching the thalamus.⁶, ⁷

These cases yield a number of important learning points. First, patients being considered for LCIG therapy should be counseled about the fact that though motor OFF times are likely to improve, the effect of LCIG infusion on dyskinesia is more variable and indeed a significant minority may experience worsening or novel dyskinetic features.¹, ⁸, ⁹, ¹⁰ Second, both pallidal and STN DBS are effective treatments both for “classic” biphasic dyskinesia and as rescue therapy in patients with LCIG‐associated “biphasic‐like” dyskinesia. These interventions should be considered early for this debilitating condition, which is frequently refractory to medical management. Third, in those with pre‐existing, or at high‐risk of future biphasic phenomena (eg young‐onset PD, advanced disease), DBS may be the preferred advanced therapy in appropriate surgical candidates. Finally, in those undergoing STN DBS for dyskinesia management, it may be worthwhile during electrode placement to ensure coverage of the sub‐thalamic area.¹¹

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 Critique.

E.M.: 1A, 1B, 1C, 3A

V.L.: 1B, 1C, 3B

L.Z.: 1B, 1C, 3B

T.F.: 1B, 1C, 3B

K.R.C.: 1B, 1C, 3B

P.L.: 1B, 1C, 3B

Disclosures

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.

Funding Sources and Conflicts 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 support 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.