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

We 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 (10–20 min) after levodopa intake, abates at peak serum concentrations, and recurs during the subsequent decay in plasma drug levels before administration of the next levodopa dose. Such temporal patterns facilitate diagnosis, although 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 disease described by Růžička et al. in 2011) ⁴ means that misdiagnoses remain common. Continuous dopaminergic stimulation approaches have added an extra layer of complexity. Indeed, although 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 because of 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 , ⁸ , ⁹ Pallidal stimulation has superior efficacy and exerts a direct anti‐dyskinetic effect, whereas STN stimulation largely improves dyskinesia through permitting reductions in levodopa dosing. ⁷

In 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.

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 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

E.M. 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. V.L. reports grants from BRC, Parkinson's United Kingdom (UK), a travel and congress grant from Bial UK, speaker‐related activities fees from Britannia pharmaceuticals, and consultancy fees from Invisio Pharmaceuticals, outside the submitted work. L.Z. has received honoraria for educational activities and has acted as consultant for Boston Scientific and Medtronic. K.R.C. 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 Britannia 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. P.L. has received honoraria and travel expenses from Medtronic and Boston Scientific, and a grant from Boston Scientific.