Fesoterodine normalizes the brain function in overactive bladder patients due to central nervous system lesion: A real‐time measure of oxyhemoglobin concentration changes during urodynamics

Abstract

DOI: 10.1111/iju.14072 Anticholinergics ameliorate OAB mostly by acting at the periphery. In addition, anticholinergics might change the brain function in OAB patients. However, limited literature is available. In order to answer this question, we carried out a real-time NIRS-urodynamic study in OAB patients before and after administration of fesoterodine, which does not easily penetrate the BBB. The inclusion criteria were: patients who had OAB and gave their informed consent before participating in the study. The exclusion criteria were: patients who took another anticholinergics within 2 weeks of entry; those with post-void residuals >100 mL; and those with disease for which anticholinergics were contraindicated. We recruited 43 OAB patients, 28 men and 15 women with a mean age of 73 years (range 60–85 years). Underlying diseases included WMI (n = 28), Parkinson’s disease (n = 10), idiopathic OAB and so on. All were righthanded. Before and after 3-month administration of 4 mg/day fesoterodine, all underwent a validated questionnaire (OABSS, mean 8.5) and a real-time NIRS-urodynamics according to the International Continence Society standards. Cerebral changes in the oxyhemoglobin concentration were sampled (OMM-3000; Shimazu, Kyoto, Japan; 58 channels being measured simultaneously). The probe array covered the frontal cortex according to Talairach’s brain atlas (a wider area than we reported previously). We also divided the frontal area into nine parts for analysis. Statistical analysis was carried out using the Wilcoxon signed-rank test. Significance was accepted at P < 0.05. This study was approved by the local review board. Fesoterodine administration ameliorated frequency and urgency (P < 0.05), and increased bladder capacity (258–319 mL, P < 0.05). The number of patients with DO did not lessen (25 to 24). A representative recording of NIRS is shown in Figure 1a. The NIRS-urodynamic study showed that fesoterodine changed brain activity (P < 0.05); for example, increasing activation in the left prefrontal area (Brodmann’s area 44,46 and the more anterior parts, reaching levels akin to normal brain activation; Fig. 1b, FLD), lessening activation in the right prefrontral area (FRD), and lessening activation in the paramedian paracentral lobule (Brodmann’s area 6,8, motor area; MM, FM). There was no difference in brain activation changes in terms of underlying diseases or sex. In the present study, fesoterodine ameliorated patients’ OAB symptoms without marked disappearance of DO. Therefore, the above findings might well reflect fesoterodine’s suppression of bladder afferent signals. Although oxybutynin has high lipophilicity and might penetrate the BBB, the newer anticholinergics, including fesoterodine, do not easily penetrate the BBB. Along with the amelioration of OAB measures, fesoterodine modulated the brain function, which might be a secondary phenomenon after normalization of bladder sensory function and enlarged bladder capacity. In the present study using fesoterodine (the active metabolite of tolterodine), increased activation was marked in the left prefrontal area, the side of which was different from that obtained in our previous study (right) using tolterodine. However, we did not know the exact reason for the discrepancy. In addition, to the best of our knowledge, this is the first study to show that fesoterodine lessens activation in the sphincter motor cortex. In healthy volunteers, bladder behavior depends on wide brain area including the prefrontal cortex whereas sphincter behavior primarily depends on the motor cortex. Therefore, amelioration of OAB might well have led to relative relaxation of the sphincter/pelvic floor, which further lessened the activation of the motor cortex. Also, fesoterodine decreased activation in the right prefrontal area. We do not know the exact reason for this. However, previous studies suggest rightside dominancy in the central control of micturition, and each hemisphere has mutual connections. Another explanation might be that the present study included brain disease of age-related WMI. Even though minimal, previous neuroimaging studies (gadolinium-enhanced brain MRI, etc.) showed disruption of the BBB in WMI. In such an event, fesoterodine might have penetrated the BBB and might have central effects to some extent.