Deep Brain Stimulation as an Exclusion Criterion in Parkinson's Disease Studies: Time to Rethink?

Abstract

Deep brain stimulation (DBS) has been part of the Parkinson's Disease (PD) toolkit for more than 20 years.1 Since then, an increasing number of patients have received DBS for management of PD motor fluctuations, parkinsonian tremor, and dyskinesias.2 As clinical experience with DBS for PD has deepened and more results such as the 2013 publication of the EARLYSTIM trial have supported earlier use of DBS, patients who develop motor complications have been referred for DBS at earlier stages of PD.3 Despite the growing number, DBS patients are underrepresented in PD research. Strong evidence supports the positive effects of DBS on cardinal signs of PD and motor complications; notwithstanding, several gaps remain to be filled in the understanding and management of PD, particularly concerning axial and non-motor symptoms, as well as disease modification.4 Clinical trials addressing these and other PD issues are essential, but will the findings be applicable to patients with DBS if this population is not represented in studies?5 We have some concerns with the lack of clarity on eligibility of patients with DBS in PD research. Patients with DBS generally are considered more complex than those without DBS. It is possible that by excluding these patients, clinical studies are incurring a selection bias, in which only candidates with greater potential for favorable outcomes are eligible.6 In addition, PD patients may feel discouraged from undergoing DBS if they have an interest in participating in PD research. Finally, Parkinson's clinical trials have difficulty meeting enrollment goals and so exclusion criteria should be carefully evaluated.5 The Parkinson Study Group (PSG) Functional Neurosurgery Working Group explored this issue. We reviewed the clinical trials registered on clinicaltrials.gov to investigate the eligibility of DBS patients. We also surveyed PSG members on their views of the enrollment of DBS patients in PD research and how these individuals might be managed in the setting of a non-DBS clinical trial. This viewpoint discusses our findings and the potential challenges and solutions for improving access to PD research for DBS patients. DBS neurologists are often asked the following questions by patients: Will I be able to participate in clinical trials after DBS? Or, in other cases: I have DBS, can I participate in research? The answers to these questions can be challenging and are rarely supported by evidence to help in the decision-making process. Using the search criteria detailed in Table 1, we identified PD studies completed between 2016 and 2020. A total of 251 were identified, of which 28 were DBS studies. Among the 223 non-DBS studies, 60 (26.9%), including 11 observational and 49 interventional studies, specified DBS as an exclusion criterion (Fig. 1). In most studies, the rationale for excluding DBS patients was not provided. From 92 drug trials, 28 (30.4%) expressed the exclusion of subjects with previous DBS surgery, ablation surgery, or prior intracranial procedures. Considering all types of non-DBS studies, in the majority (n = 147, 65.9%) of the studies the eligibility of subjects with DBS was not defined in the inclusion and exclusion criteria available on clinicaltrials.gov. It is concerning that more than half of recent PD studies do not mention the eligibility of patients with DBS. It is even more concerning that only 8 (3.6%) studies specifically mentioned that patients with DBS were eligible for participation. We conducted a web-based survey with quantitative and qualitative questions among all PSG members. The survey contained questions about participants' roles in PD clinical trials and in clinical care of DBS patients, and asked whether, in the respondent's opinion, DBS patients should be excluded from different types of PD research. Additional questions exploring their opinion regarding the most appropriate time interval between DBS implantation and trial enrollment, as well as stability of DBS s