Improving Sacral Neuromodulation for Lower Urinary Tract and Bowel Dysfunction:A Translational and Multidisciplinary Approach

Lower urinary tract and bowel dysfunction are associated with a decreased control of micturition and/or defecation. Sacral neuromodulation (SNM), using electrical stimulation of a nerve root in the lower back, is a treatment for these disorders and provides patients a better quality of life. In this thesis, two animal models, one for faecal incontinence and one for lower urinary tract dysfunction, were further optimized. These optimized models now allow future studies to investigate and improve interventions for lower urinary tract and bowel dysfunction, such as SNM. In addition, this thesis provides a systematic overview of the recent developments in the use and efficacy of SNM stimulation parameters in clinical and animal studies and revealed that the therapeutic effect of SNM can be improved by adjusting relevant stimulation parameters. Lastly, this thesis showed that a new form of SNM, called Burst-SNM, can modulate bladder and urethral responses in a distinctive way as compared to standard SNM stimulation parameters. These findings provide a new perspective to further optimize clinical outcome

Post-mortem diffusion MRI of the cervical spine and its nerve roots

Purpose: The aim of this work is to examine the architectural configuration and the microstructural substrate of the cervical spine and its nerve roots with post-mortem (PM) diffusion tensor imaging (DTI) in non-fixed subjects and to compare these findings with histology. Methods: Magnetic resonance imaging (MRI) data were acquired on a 1.5 T MRI scanner in five non-fixed non-trauma deaths. Two different areas were evaluated: 1) the cervical spinal cord and ventral and dorsal nerve roots with a "high in-plane" DTI and a multi-echo fast field echo protocol, and 2) the cervical peripheral nerves with an "isotropic" DTI and a 3D turbo spin echo protocol. Histology samples were obtained matching the anatomical level of the slices of the 'high in-plane' DTI protocol. Results: We were able to show detailed reconstructions of the dorsal and ventral nerve roots with the 'high in-plane' protocol and identified a low fractional anisotropy (FA = 0.30 ± 0.08) in the grey matter and a high FA (0.51 ± 0.13) in the white matter. Both grey and white matter configurations correlated with the anatomical MRI, the diffusion MRI, and with the histological sections. Using the 'isotropic' DTI protocol, it was feasible to reconstruct the spinal cord, cervical nerves, and nerve roots in all PM subjects. Conclusion: We were able to generate detailed architectural configurations of the ventral and dorsal nerve roots. Anatomical and diffusion MR scans showed good qualitative agreement with histology. We believe that PMDTI will be helpful in the assessment of head and neck injuries in a forensic setting

Replacement Adaptor 09106 for patients with a dynamic graciloplasty or patients with sacral neuromodulation and abdominal implantable pulse generators: a retrospective, single centre, Stage 2a/2b development IDEAL case series

AIM: Due to the introduction of a new implantable pulse generator (IPG), the Interstim II, patients with either a dynamic graciloplasty or an abdominally placed IPG for sacral neuromodulation could not undergo surgery to replace their IPG in case of end of battery life. For these patients, the Medtronic Replacement Adaptor 09106 was created. This retrospective case series aims to study safety and feasibility of the Medtronic Replacement Adaptor 09106 in patients with abdominally placed IPGs. METHODS: Seventeen patients (11 female, 6 male) received a replacement adaptor with a follow-up of 6 months. Outcome measures consisted of a bowel habit diary. Adverse events were classified using the Clavien-Dindo classification. RESULTS: Outcome measures in the bowel habit diaries after replacement (feasibility) did not differ significantly from outcome measures before replacement. Adverse events occurred in 4 out of 17 patients (24%): 2 patients initially showed pocket site pain (Clavien-Dindo level I), which resolved without intervention. One patient suffered from poor wound closure (Clavien-Dindo level II), and 1 patient had persisting pocket pain (Clavien-Dindo level IIIa), for which a pocket revision was performed. Statistical analyses were performed making paired comparisons using a Wilcoxon signed rank test. CONCLUSION: The Medtronic Replacement Adaptor 09106 is a valuable option for patients with dynamic graciloplasty or sacral neuromodulation and abdominal IPG and has complication rates similar to replacement of the Interstim without Replacement Adaptor 09106

Sacral Neuromodulation for Lower Urinary Tract and Bowel Dysfunction in Animal Models:A Systematic Review With Focus on Stimulation Parameter Selection

Objective Conventional sacral neuromodulation (SNM) has shown to be an effective treatment for lower urinary tract and bowel dysfunction, but improvements of clinical outcome are still feasible. Currently, in preclinical research, new stimulation parameters are being investigated to achieve better and longer effects. This systematic review summarizes the status of SNM stimulation parameters and its effect on urinary tract and bowel dysfunction in preclinical research. Materials and Methods The literature search was conducted using three databases: Ovid (Medline, Embase) and PubMed. Articles were included if they reported on stimulation parameters in animal studies for lower urinary tract or bowel dysfunction as a primary outcome. Methodological quality assessment was performed using the SYRCLE Risk of Bias (RoB) tool for animal studies. Results Twenty-two articles were eligible for this systematic review and various aspects of stimulation parameters were included: frequency, intensity, pulse width, stimulation signal, timing of stimulation, and unilateral vs. bilateral stimulation. In general, all experimental studies reported an acute effect of SNM on urinary tract or bowel dysfunction, whereas at the same time, various stimulation settings were used. Conclusions The results of this systematic review indicate that SNM has a positive therapeutic effect on lower urinary tract and bowel dysfunction. Using low-frequency-SNM, high-frequency-SNM, bilateral SNM, and higher pulse widths showed beneficial effects on storage and evacuation dysfunction in animal studies. An increased variability of stimulation parameters may serve as a basis for future improvement of the effect of SNM in patients suffering from urinary tract or bowel dysfunction

Vaginal Distention Rodent Model for Fecal Incontinence:A Pilot Study on the Effect on Defecation Behavior

Objectives Vaginal balloon inflation simulates the compressive forces on the pelvic floor during the second phase of natural delivery. The foremost use of this animal model of vaginal distention (VD) is to study the mechanisms underlying urinary incontinence. As damage to the pelvic floor during natural birth is a common cause of fecal incontinence, the present paper aimed to investigate the effect of VD on defecation behavior in adult rats. Methods Vaginal distention was performed in 8 rats for 2 hours, and in 3 rats for 4 hours, and sham inflation was performed in 4 rats. With the use of a latrine box in the rat home-cage and 24/7 video tracking, the defecation behavior was examined. The time spent in and outside the latrine was monitored for two weeks preoperatively and three weeks postoperatively, and a defecation behavior index (DBI; range: 0 [continent] to 1 [incontinent]) was defined. Pelvic floor tissue was collected postmortem and stained with hematoxylin and eosin. Results Vaginal balloon inflation for 2 hours resulted in fecal incontinence in 29% of the animals (responders) whereas the DBI scores of non-responders (71%) and control animals did not change in the postoperative phase compared with the baseline score. A 4-hour balloon inflation resulted in fecal incontinence in 1 animal and caused a humane endpoint in 2 animals with markedly more tissue damage in the 4-hour responder compared with the 2-hour responders. Conclusions Vaginal balloon inflation, with an optimum duration between 2 and 4 hours, can be used as a model to study changes in defecation behavior in rats induced by pelvic floor damage