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

We read with interest the report by Mulroy et al about the patient with Parkinson's disease (PD) who developed troublesome dyskinesias while on levodopa carbidopa intestinal gel (LCIG) that were successfully treated by adding deep brain stimulation (DBS) of the globus pallidus pars interna (Gpi).1 “Biphasic-like” dyskinesias have been described by our group as a potential complication of LCIG therapy.2 We agree with Mulroy et al that such dyskinesias reflect the combination of disease progression and LCIG. Indeed, a significant amount of our patients had a previous history of typical biphasic dyskinesias while on oral therapy.2 The pathogenesis of biphasic dyskinesias is still not fully elucidated. In fact, although they might be associated with a low or end-of-dose levodopa plasmatic concentration—thus explaining the sustained presentation in patients on underdosed LCIG—not all cases can be explained in pharmacokinetic terms.2 Intriguingly, pharmacodynamic hypotheses—such as a more widespread dopaminergic degeneration also involving D1 receptors—have been advocated to explain the pathogenesis of biphasic dyskinesias.3 Herein we report a 59-year-old man with a 20-year history of PD who developed biphasic-like dyskinesias while on LCIG.2 This patient was successfully treated by adding DBS of the subthalamic nucleus (STN). Prior to LCIG, his levodopa equivalent daily dose was 1150 mg/day. Because of the presence of severe motor fluctuations, he received LCIG in 2017 (levodopa equivalent daily dose [LEDD] of 1326 mg/day). A few weeks after LCIG, he developed biphasic-like dyskinesias, which we tried to manage with multiple strategies for several months, unsuccessfully. Thus, STN DBS was added. In contrast with a similar case4 and similarly to Mulroy et al,1 LCIG therapy was continued with a slight LEDD reduction (1232 mg/day). The combination of STN DBS and LCIG led to the improvement of motor fluctuations and a sustained remission of dyskinesias (Video 1). LCIG should be the best strategy to treat biphasic dyskinesias, but all of the aforementioned clinical experiences would suggest a more careful selection of patients for LCIG infusion if biphasic dyskinesias are present because the pharmacological management has been demonstrated to be poorly effective, especially in the long term.2 In support of this observation and as previously discussed, similar dyskinesias have been already described in patients undergoing intravenous levodopa or lisuride infusion.2 In refractory biphasic dyskinesias, STN but also thalamic DBS can be effective. The study by Mulroy et al confirms that Gpi DBS is also effective on LCIG-related biphasic dyskinesias in keeping with a single case report in a patient not on LCIG.5 The use of STN-DBS as a rescue therapy after unsuccessful LCIG has been documented even in patients with disabling dyskinesias,4 although in this case, LCIG was discontinued. In contrast, both our patient and the Mulroy et al case retained both treatments, in keeping with our previous series of STN and Gpi DBS patients rescued by the addition of LCIG.6 These observations, together with further recent hints, might indicate that a patient undergoing LCIG should be informed about the possibility that LCIG could fail to completely control involuntary movements.7 We now have some evidence that adding DBS might avoid such discontinuation and guarantee a synergistic effect on the motor complications experienced by some patients with advanced PD. We are grateful to the patient and his family for their kind disposability. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. MM: 1A, 1B, 1C, 3A AF: 1C, 3B The authors confirm that the approval of an institutional review board was not required for this work. Informed consent from the patient was obtained 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. No specific funding was received for this work. M.M. declares that there are no conflicts of interest relevant to this work. A.F. received honoraria from Abbott, Abbvie, Boston Scientific, and Medtronic. M.M. received honoraria for participating in advisory boards from Abbvie, Zambon, Allergan, and Sanofi; speaker's honoraria from Abbvie; and research grants from the Alberto Sordi Foundation and Bial Pharmaceuticals. A.F. received honoraria for consultancies from Abbvie, Medtronic, Boston Scientific, Sunovion, Chiesi Farmaceutici, UCB pharma, and Ipsen; honoraria for participating in advisory boards from Abbvie, Boston Scientific, and Ipsen; speaker's honoraria from Abbvie, Medtronic, Boston Scientific, Sunovion, Chiesi Farmaceutici, UCB, and Ipsen; and research grants from University of Toronto, Weston Foundation, Abbvie, Medtronic, and Boston Scientific.

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