STN-DBS does not increase the risk of sialorrhea in patients with advanced Parkinson’s disease

The aims of this study were to assess the incidence rate and risk factors for sialorrhea in the long-term follow-up in a cohort of 132 patients with advanced Parkinson’s disease [88 with deep brain stimulation (DBS) and 44 on medical treatment]. The incidence rate of sialorrhea did not differ between the two groups; male sex, Hoehn and Yahr stage and dysphagia resulted risk factors for sialorrhea. These findings indicate that DBS does not increase the risk of developing sialorrhea.

observation in the DBS group and 43.7 (95% CI 17.5-90.2) per 1,000 person-years of observation in the control group (Fig. 1b).
Comparing DBS patients with and without new-onset sialorrhea during the follow-up, no difference was found for stimulation parameters (Supplementary Table 3).
In this retrospective case-control study, focused on the question if DBS-STN may increase the risk of developing sialorrhea in PD patients, the main finding is that the incidence rate of sialorrhea did not significantly differ between the groups of patients with and without DBS in the long-term follow up. To the best of our knowledge, this data has not been previously evaluated in the literature, whereas increased drooling has been reported as an adverse effect in cohorts of stimulated patients 11,12 . Indeed, in our study, the prevalence of sialorrhea at baseline was similar in the two groups of patients (19.3% in the DBS group and 11.4% in the control group). This value is in the lower range reported in PD literature (from 10% to 81%) 7 . This is probably due to selection criteria: in order to avoid selection biases, we included all patients fulfilling the eligibility criteria for DBS 13 , which means patients with advanced disease but without severe axial symptoms and cognitive impairment, which are strongly associated with sialorrhea 6,14 .
In our cohort, the risk factors for sialorrhea were male sex, Hoehn and Yahr stage, and dysphagia. All these variables are known risk factors of sialorrhea in general PD population, as previously described [14][15][16] . Male sex is a risk factor for PD 17 , and it has been associated with higher severity of PD motor and nonmotor symptoms, as sialorrhea 15,16 . Higher scores of Hoehn and Yahr scale represent a more severe disease, with disabling motor symptoms, which are often associated with oro-buccal symptoms as dysphagia, dysarthria and sialorrhea 14 . Dysphagia is a widely recognized causative factor of sialorrhea 18,19 . Interestingly, in our cohort, we have not found an increased or reduced risk deriving from STN-DBS in the long-term follow-up. Moreover, no stimulation parameter was specifically associated with sialorrhea development. All these findings support the hypothesis that sialorrhea is a consequence of the underlying neurodegenerative disease, regardless of DBS.
The main limitations of this study are the retrospective design and the lack of objective measures of sialorrhea. Another limitation is the use in this cohort of anticholinergics and tricyclic antidepressants, which could have an impact on sialorrhea, although these drugs did not significantly differ between the two groups of DBS and medically treated patients.
In conclusion, the present study shows that STN-DBS does not increase the risk of developing sialorrhea, which has a comparable incidence rate in DBS and medically treated patients with advanced PD. This is relevant information that expands our knowledge about the impact of DBS on non-motor symptoms. Indeed, recent evidence suggest the use of DBS in patients with early-stage PD 20 ; these are significant results to support the safety of neuromodulation about a disabling symptom such as sialorrhea.

METHODS
This retrospective case-control study was carried out on consecutive PD patients who underwent bilateral STN-DBS from 1993 to 2020 and followed up at the Fondazione Policlinico Universitario A. Gemelli IRCCS in Rome (Italy).
At the time of surgery, all patients fulfilled the criteria of idiopathic PD, according to the UK Brain Bank criteria 21 and the international inclusion and exclusion criteria for DBS 13 . Patients with previous neurosurgical interventions for PD or implantation of DBS electrodes in other deep brain nuclei were excluded from the study. A control group of medically managed patients with advanced PD, followed up at our Centre, was extracted from our databases 22,23 . The patients of the control group were age-and sexmatched with DBS patients with 1:2 ratio. At baseline, each patient included in the control group fulfilled the eligibility criteria for DBS but did not undergo surgery because of refusal by the patient itself or the absence of caregiver. The baseline was defined as the time of surgery for the DBS group and a comparable time-point, matched for disease duration, for the control group. Patients on treatment with infusion therapies for PD or with a follow-up less than six months from the baseline were excluded.
The main outcome of the study was to compare the incidence rate of sialorrhea after the baseline between the groups of STN-DBS and medically managed patients. For each patient, the development of sialorrhea was defined as a score ≥ 2 on item 6 of the Unified Parkinson's Disease Rating Scale (UPDRS) 24 . The development of sialorrhea was evaluated at each outpatient visit after the baseline (at least twice a year) until the last followup available for each patient.
Secondary outcomes included the evaluation of risk factors for sialorrhea and the assessment of post-operative stimulation parameters potentially associated with the development of sialorrhea during the follow-up. To assess the risk factors of sialorrhea, we evaluated at baseline: a) demographic data: sex, age, age at PD onset, disease duration; b) motor scores: Hoehn and Yahr stage 25 , score of part III of the UPDRS in off-and on-medication conditions, axial subscore of part III of the UPDRS (items 27-31) in off-and on-medication conditions; c) medications: mean levodopa equivalent daily dose (LEDD) 26 , therapy with anticholinergics, amantadine, antidepressants, antipsychotics, clozapine; d) stimulation: treatment with STN-DBS; e) motor and non-motor symptoms: presence or absence of dysphagia (score ≥ 2 of item 7 of the UDPRS), presence or absence of speech impairment (score ≥ 2 of item 5 of the UDPRS), psychosis (score ≥ 2 of the item 2 of the UDPRS), orthostatic hypotension (defined as fall in systolic blood pressure of at least 20 mm Hg and diastolic blood pressure of at least 10 mm Hg within 3 min of standing). To assess post-operative stimulation parameters potentially associated with the development of sialorrhea, at the time of development of sialorrhea or at the last follow-up visit for patients without sialorrhea, we evaluated the following variables in the group of DBS patients: stimulation current intensity, pulse width, frequency, setting (single monopolar, double monopolar, bipolar).
The study was approved by the local ethics committee.

Statistical analysis
Excluding from the analysis of the patients with sialorrhea at baseline, the incidence rate of sialorrhea of the two groups was calculated by dividing the number of new cases by the total number of person-years at risk during follow-up and compared using the χ 2 test. Fig. 1 Flowchart of the study and incidence rate of sialorrhea in the two groups of patients. a Flowchart of the study. b Incidence rate of sialorrhea in the groups of STN-DBS and medically managed patients. The incidence rate of sialorrhea was compared between the two groups using the χ 2 test. To assess the risk factors for sialorrhea, between-group (patients with and without sialorrhea) differences in baseline demographic and clinical variables were analyzed using the Mann-Whitney test for continuous variables and the χ 2 test or Fisher's exact test for categorical variables, as appropriate. Variables with p-value < 0.05 on univariate analysis were incorporated into a multivariate Cox regression model using a stepwise selection process, building the final regression model with the significant variables.
The between-group (patients with and without sialorrhea) postoperative differences in stimulation parameters were analyzed using the Mann-Whitney test for continuous variables and the χ 2 test or Fishers' exact test for categorical variables.
Continuous variables are presented as mean ± standard deviation (SD). All statistical computations were two-tailed, and a p-value < 0.05 was considered significant. The statistical analyses were performed using the XLSTAT software, version 2021.3.1 (Addinsoft, Inc., Brooklyn, NY, USA).

DATA AVAILABILITY
Anonymized data of this study will be available from the corresponding author on reasonable request from any qualified researcher, following the EU General Data Protection Regulation.