Urinary symptoms are correlated with quality of life after deep brain stimulation in Parkinson's disease

Abstract Aims Deep brain stimulation (DBS) is known to dramatically improve motor complications in patients with Parkinson's disease (PD), but its effect on urinary symptoms and health‐related quality of life (HRQOL) remains unknown. We aimed to examine the relationship between urinary symptoms and HRQOL in patients with PD who underwent DBS. Methods The International Prostate Symptom Score (IPSS) and overactive bladder symptom score (OABSS) were determined to evaluate urinary symptoms in patients with PD who underwent DBS. Postoperative evaluations were performed at 3 months, 1 year, and 3 years postoperatively. We also performed a urodynamic study (UDS) in 13 patients with PD preoperatively and postoperatively. A follow‐up UDS was performed 2.0 ± 0.5 years postoperatively. Results The preoperative urinary symptoms questionnaire was completed by 28 patients, of whom 14 completed the postoperative urinary symptoms questionnaire after 3 months, 18 after 1 year, and 10 after 3 years. The mean OABSS and IPSS did not change significantly at any follow‐up periods postoperatively. When assessing the relationship between urinary symptoms and HRQOL and motor functions, the OABSS and IPSS showed significant positive correlations with HRQOL at 3 months postoperatively. The OABSS and IPSS showed significant positive correlations with activities of daily living (ADL) during the off‐phase at 3 years postoperatively. All urodynamic parameters remained unchanged postoperatively. Conclusions Deep brain stimulation did not significantly affect urinary dysfunctions in patients with PD. Urinary symptoms might partially contribute to HRQOL at 3 months postoperatively and ADL during the off‐phase at 3 years postoperatively.


| INTRODUC TI ON
Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus interna (GPi) is a standard therapy for patients with advanced stages of Parkinson's disease (PD) with motor complications such as dyskinesia and wearing-off (Okun, 2012). DBS improves motor complications in patients with PD. Furthermore, several non-motor symptoms including autonomic dysfunctions, dementia, and neuropsychiatric symptoms generally occur in advanced stages of PD (Kalia and Lang, 2015). Among autonomic dysfunctions, urinary dysfunctions are severe and prevalent in patients with PD (Sakakibara, Panicker, Finazzi-Agro, Iacovelli, & Bruschini, 2016). In particular, overactive bladder symptoms, including urinary urgency or urgent urinary incontinence, are common in advanced stages of PD (Sakakibara et al., 2016). Quality of life (QOL) in patients with PD is seriously deteriorated by the presence of urinary dysfunctions.
Drug therapies, such as anticholinergics and β3 adrenoceptor agonists, are only partially effective in patients with PD (Sakakibara et al., 2016). Although DBS might be an important treatment option for urinary dysfunctions, the effect of DBS on urinary dysfunctions in patients with PD remains controversial (Finazzi-Agrò et al., 2003;Seif et al., 2004;Winge et al., 2007;Witte et al., 2018).
We have previously reported that high-frequency electrical stimulation of the STN significantly inhibited bladder contractions in normal cats (Sakakibara et al., 2003). We have also revealed that many of the recorded neurons in the STN preferentially fired during the bladder storage phase in normal cats (Sakakibara et al., 2003), suggesting that STN-DBS might be effective for patients with PD with urinary dysfunctions. Seif, et al. (2004) reported that STN-DBS significantly increased the maximum capacity of the bladder in PD patients and concluded that STN-DBS has a urodynamically and significant recordable effect which result in normalization of pathologically increased bladder sensibility. Finazzi-Agrò, et al. (2003) reported that STN-DBS increased bladder capacity and decreased the amplitude at the detrusor overactivity. Herzog, et al. (2006Herzog, et al. ( , 2008 demonstrated that STN-DBS in patients with PD normalized the activity of the anterior cingulate cortex and prefrontal cortex, which are usually overactive, thereby improving lower urinary tract symptoms (urinary symptoms) in patients with PD. However, Winge, et al. (2007) reported that none of the primarily measured urodynamic parameters were significantly changed by STN-DBS. Although several other studies also revealed that urinary symptoms, such as urinary frequency or urgency, significantly improved after DBS, the degrees of their improvement were very slight and not clinically relevant; moreover, it is unknown whether DBS significantly improves urinary dysfunctions in patients with PD (Finazzi-Agrò et al., 2003;Seif et al., 2004;Winge et al., 2007;Witte et al., 2018). The effect of DBS on urinary symptoms in PD patients is controversial.
Furthermore, the detailed relationships between urinary symptoms and motor dysfunction and health-related QOL (HRQOL) are also unknown, which is important for the clinical examination of patients with PD after DBS. We have previously reported that HRQOL and motor symptoms were not necessarily correlated despite the significant improvement in motor functions, suggesting that nonmotor symptoms might affect HRQOL after DBS . Among several non-motor symptoms, urinary symptoms are known to be prevalent and severe in PD patients (Schapira, Chaudhuri, & Jenner, 2017). However, temporal changes in urinary symptoms and their relationship to HRQOL after DBS are unknown.
The present study aimed to clarify the effect of DBS on urinary symptoms in patients with PD and examine the relationship between urinary symptoms and motor functions and HRQOL.

| Patient evaluation
This study enrolled 28 patients undergoing DBS implantation (STN: Parkinson's Disease Society Brain Bank (Gibb & Lees, 1988). All participants had reported severe motor fluctuations and complications.
GPi-DBS was selected for patients who had markedly troublesome dyskinesia before surgery. Before enrollment in this study, the par- and the Frontal Assessment Battery (FAB). We evaluated HRQOL using the PDQ-39 because the PDQ-39 is the most widely used disease-specific, patient-completed scale assessing PD. The PDQ-39 comprises 39 items grouped into eight subscales, including mobility, activities of daily living (ADL), emotional well-being, stigma, social support, cognition, communication, and bodily discomforts. A higher score on the PDQ-39 also represents worse conditions. The PDQ -39 SI was assessed during stimulation after DBS, and the levodopa equivalent dose (LED) of anti-PD medication was calculated as described elsewhere (Tomlinson et al., 2010). We used overactive bladder symptom score (OABSS) and International Prostate Symptom Score (IPSS) to assess the urinary symptoms because both scales are widely used for the evaluation of urinary symptoms and are easily undertaken by patients. OABSS is used as the evaluation of storage dysfunctions (daytime and night-time urinary frequency, urinary urgency, and urgent urinary incontinence), whereas IPSS is used as the evaluation of both storage (urinary frequency, nocturia, and urgency) and voiding dysfunctions (incomplete emptying, intermittency, weak stream, and straining). The higher scores of OABSS and IPSS represent the worse condition. The OABSS and IPSS were determined to assess urinary symptoms in patients with PD (mean age: 65.5 ± 1.6 years, mean disease duration: 11.8 ± 1.0 years) who underwent DBS. The OABSS and IPSS were determined both before and after DBS. Postoperative evaluations were performed at 3 months, 1 year, and 3 years postoperatively. The temporal changes in urinary symptoms were examined in patients with PD after undergoing DBS.

| Urodynamic study (UDS)
Of the 28 patients, 13 agreed to be evaluated for urinary dysfunctions via a urodynamic study preoperatively and postoperatively.
The urodynamic evaluation was performed between April 2012 and December 2017. A follow-up UDS was performed at 2.0 ± 0.5 years postoperatively.
The UDS was performed by neurologists and urologist who were familiar with free-flowmetry and urodynamic findings. The neurologists evaluated urinary dysfunction associated with neurological dysfunction in detail. The average and maximum flow rates were acquired by performing free-flowmetry before conducting a pressure-flow study (PFS). Postvoid residual (PVR) (normal volume <50 ml) was measured via transurethral catheterization after the voided volume was measured. Cystometry and electromyography (EMG) was conducted using a urodynamic computer (Janus; Life-Tec, Houston, TX, USA) and an EMG computer (Neuropack Sigma; Nihon Kohden, Tokyo, Japan). During the cystometry and PFS, the EMG of the anal sphincter was recorded continuously by inserting a coaxial needle electrode into the EAS muscles. An 8-Fr double-lumen catheter was inserted transurethrally, and water (saline) cystometry was performed at an infusion rate of 50 ml/min while the patient remained seated. Rectal pressure was measured simultaneously with a balloon catheter. Rectal pressure was electronically subtracted from the intravesical pressure. PFS follows water cystometry. Both freeflowmetry and PFS were carried out with the patient in the sitting position in the same environment, and PVR was measured after PFS.
Tracings from each flow study were evaluated by the neurologists and the urologist.
Abnormal urodynamic findings during the voiding phase included impaired bladder contractile function. The degree of detrusor contractions was examined using Schäfer's nomogram, which categorizes detrusor contractility as strong, normal, weak, or very weak, depending on the flow rate and detrusor pressure. Abnormal urodynamic findings during the storage phase included detrusor overactivity (DO), which was defined as involuntary detrusor contractions during the filling phase. Quantitative parameters obtained during the storage phase included bladder volume at first desire to void (FDV) and strong desire to void (SDV); FDV <100 ml and SDV <300 ml values were considered abnormal findings. The maximum cystometric capacity was the volume at which the patient could no longer delay micturition. The methods, definitions, and units employed conformed to the standards recommended by the International Continence Society (Schäfer et al., 2002).

| Ethical considerations
This study was approved by the Chiba University Hospital Institutional Review Board. All participants provided written informed consents that were obtained during their on-time. None of the participants had a compromised capacity/ability to consent in this study.

| Statistical analysis
All data were expressed as mean ± standard error of mean. All

| RE SULTS
Twenty-eight patients (mean age: 65.5 ± 1.6 years, mean disease duration: 11.8 ± 1.0 years) completed the preoperative urinary Additionally, to treat urinary symptoms, three patients used anticholinergics both pre-and postoperatively. One patient used α-blocker only preoperatively and quitted taking α blocker postoperatively due to the appearance of orthostatic hypotension.
Postoperatively, three patients started to use β3 adrenoceptor agonist which was commercially available after surgery.

| D ISCUSS I ON
The present study showed that DBS did not significantly improve urinary symptoms in PD patients. DBS also did not significantly change the urodynamic parameters. However, the OABSS and IPSS  higher OABSS and IPSS score represents worse urinary symptoms, the significant positive correlations between the PDQ-39 and urinary symptoms (OABSS and IPSS) score indicated that the severity of urinary symptoms partially contributes to HRQOL.
Recent findings have suggested that non-motor symptoms are prevalent and severe in patients with PD (Schapira et al., 2017).
Although drug therapy is common for urinary symptoms in patients with PD, the responsiveness of drug therapy is not sufficient (Sakakibara et al., 2016). Therefore, DBS might be another treatment  2006, 2008Sakakibara et al., 2003;Seif et al., 2004;Winge et al., 2007;Witte et al., 2018).
The results of our study revealed that urinary symptoms did not significantly improve following DBS, and none of the urodynamic parameters changed postoperatively. Our UDS results reported a decreased bladder capacity and high prevalence of detrusor overactivity (84.6%), which indicates the presence of severe storage dysfunction preoperatively and postoperatively. The PVR was relatively small compared with that of multiple system atrophy, and bladder contractility assessed by Schäfer's nomogram was preserved, suggesting that voiding dysfunction was mild in this study  storage dysfunction such as low maximal capacity and high prevalence of detrusor overactivity. These points should be examined in the future. It is also important to discuss the effect of drug therapy for urinary symptoms before and after DBS. Three patients started to use β3 adrenoceptor agonist because β3 adrenoceptor agonist was commercially available only after DBS surgery in some patients, which made the interpretation of the present result complicated. Although the effect of β3 adrenoceptor agonist on the urinary symptoms in PD is not fully understood, recent retrospective study suggested that 50% of PD patients reported improvement in OAB after administration of β3 adrenoceptor agonist (Peyronnet et al., 2018). Because only three patients started to use β3 adrenoceptor agonist after DBS, the administration of β3 adrenoceptor agonist might have only subtle effects on overall results of this study.
In addition, we could not examine the effect of difference between STN and GPi-DBS on urinary dysfunction, because only six patients underwent GPi-DBS.

| CON CLUS IONS
Deep brain stimulation did not significantly change urinary dysfunctions in patients with PD. Urinary symptoms might partially contribute to HRQOL at 3 months postoperatively and to ADL during the off-phase at 3 years postoperatively.