Sacral neuromodulation for constipation and fecal incontinence in children and adolescents - study protocol of a prospective, randomized trial on the application of invasive vs. non-invasive technique.

BACKGROUND: A therapeutic effect of sacral neuromodulation (SNM) on fecal incontinence (FI) and quality of life has been proven in adults. SNM is, however, rarely used in pediatric cases. The aim of the study is to investigate effects of SNM in pediatric constipation in a prospective parallel-group trial. METHODS: A monocentric, randomized, unblinded, parallel-group trial is conducted. SNM is conducted in the invasive variant and in an innovative, external approach with adhesive electrodes (enteral neuromodulation, ENM). We include patients with constipation according to the ROME IV criteria and refractory to conventional options. Patients with functional constipation and Hirschsprung's disease are able to participate. Participants are allocated in a 1:1 ratio to either SNM or ENM group. Clinical data and quality of life is evaluated in regular check-ups. Neuromodulation is applied continuously for 3 months (end point of the study) with follow-up-points at 6 and 12 months. Findings are analyzed statistically considering a 5% significance level (p ≤ 0.05). Outcome variables are defined as change in (1) episodes of abdominal pain, (2) episodes of FI, (3) defecation frequency, (4) stool consistency. Improvement of proprioception, influence on urinary incontinence, quality of life and safety of treatment are assessed as secondary outcome variables. We expect a relevant improvement in both study groups. DISCUSSION: This is the first trial, evaluating effects of neuromodulation for constipation in children and adolescents and comparing effects of the invasive and non-invasive application (SNM vs. ENM). TRIAL REGISTRATION: The study is registered with clinicaltrials.gov, Identifier NCT04713085 (date of registration 01/14/2021).

Noninvasive Sacral Neuromodulation in Children and Adolescents: A Case-Control Study of Patients With Chronic Refractory Constipation.

OBJECTIVES: In adult patients with chronic refractory constipation, invasive sacral neuromodulation (SNM) has been applied successfully. There is a need for less invasive solutions while providing comparable therapeutic effects in children and adolescents. We present a prospective, interventional case-control study on the application of noninvasive SNM. MATERIALS AND METHODS: Patients with chronic constipation refractory to conservative treatment were prospectively included in the study from 2018 to 2021 and randomized to either SNM (SNM group: single current stimulation for 24 h/d, frequency 15 Hz, pulse width 210 µs, intensity 1-10 mA) or conventional treatment (controls: full range of pharmacologic and nonpharmacologic options). Treatment was conducted for 12 weeks. Treatment effects were collected with specialized questionnaires and quality-of-life analysis (KINDLR). Outcome variables were defecation frequency, stool consistency, fecal incontinence (FI) episodes, and abdominal pain. RESULTS: Analysis was conducted in 28 patients with SNM and 31 controls (median age 7.0, range 3-16 years). Overall responsiveness to treatment was 86% of the SNM group and 39% of the control group (p < 0.001). All outcome variables were positively influenced by SNM treatment. Defecation frequency improved in 46% of patients with SNM and in 19% of controls (p = 0.026), as did stool consistency in 57% of patients with SNM and in 26% of controls (p = 0.014). Fecal incontinence was significantly reduced in 76% of patients with SNM (n = 16/21 vs 42% of controls [n = 11/26], p = 0.042). Quality of life improved significantly during SNM treatment (71.32 [baseline] vs 85.00 [after 12 weeks], p < 0.001) and confirmed a positive influence of SNM treatment compared with the control group (85.00 [SNM after 12 weeks] vs 79.29 [controls after 12 weeks], p = 0.047). CONCLUSIONS: Outcome of noninvasive SNM treatment in patients with chronic refractory constipation is better than conventional treatment.

Reprogramming Sacral Neuromodulation for Sub-Optimal Outcomes: Evidence and Recommendations for Clinical Practice.

OBJECTIVES: In some patients treated for urinary or fecal incontinence with sacral neuromodulation (SNM) persistence of symptoms, a reduction in efficacy or adverse effects of stimulation can occur. In such situations, further programming of the SNM device can help resolve problems. Infrequently hardware failure is detected. This article aims to provide practical guidance to solve sub-optimal outcomes (troubleshooting) occurring in the course of SNM therapy. MATERIALS AND METHODS: A systematic literature review was performed. Collective clinical experience from an expert multidisciplinary group was used to form opinion where evidence was lacking. RESULTS: Circumstances in which reprogramming is required are described. Actions to undertake include changes of electrode configuration, stimulation amplitude, pulse frequency, and pulse width. Guidance in case of loss of efficacy and adverse effects of stimulation, developed by a group of European experts, is presented. In addition, various hardware failure scenarios and their management are described. CONCLUSIONS: Reprogramming aims to further improve patient symptoms or ensure a comfortable delivery of the therapy. Initial changes of electrode configuration and adjustment of stimulation parameters can be performed at home to avoid unnecessary hospital visits. A logical and stepwise approach to reprogramming can improve the outcome of therapy and restore patient satisfaction.

The science behind programming algorithms for sacral neuromodulation.

AIM: Sacral neuromodulation (SNM) is a widely adopted treatment for overactive bladder, non-obstructive urinary retention and faecal incontinence. In the majority, it provides sustained clinical benefit. However, it is recognized that, even for these patients, stimulation parameters (such as amplitude, electrode configuration, frequency and pulse width) may vary at both initial device programming and at reprogramming, the latter often being required to optimize effectiveness. Although some recommendations exist for SNM programming, the scientific data to support them are understood by few clinicians. METHODS: This is a narrative review of the literature covering some of the science behind stimulating a mixed peripheral nerve and available preclinical data in the field of SNM. It covers electrode configuration, amplitude, frequency, pulse width and cycling considerations. The review is targeted at clinicians with an interest in the field and does not seek to provide exhaustive detail on basic neuroscience. RESULTS AND CONCLUSIONS: Knowledge of the science of neuromodulation provides some guiding principles for programming but these are broad. These principles are not refuted by preclinical data but specific parameters in clinical use are not strongly supported by animal data, even after the limitations of small and large animal models are considered. The review presents a shortlist of programming principles on a theoretical basis but acknowledges that current practice is as much derived from evolved experience as science.

Programming Algorithms for Sacral Neuromodulation: Clinical Practice and Evidence-Recommendations for Day-to-Day Practice.

BACKGROUND: In sacral neuromodulation (SNM), stimulation programming plays a key role to achieve success of the therapy. However to date, little attention has been given to the best ways to set and optimize SNM programming during the test and chronic stimulation phases of the procedure. OBJECTIVE: Standardize and make SNM programming easier and more efficient for the several conditions for which SNM is proposed. METHODS: Systematic literature review and collective clinical experience report. RESULTS: The basic principles of SNM programming are described. It covers choice of electrode configuration, stimulation amplitude, pulse frequency and pulse widths, while use of cycling is also briefly discussed. Step-by-step practical flow charts developed by a group of 13 European experts are presented. CONCLUSIONS: Programming of SNM therapy is not complex. There are few programming settings that seem beneficial or significantly impact patient outcomes. Only four basic electrode configurations could be identified according to four different options to define the cathode. In a majority of patients, the proposed stimulation parameters will allow a satisfactory improvement for long periods of time. A regular follow-up is, however, necessary to assess and eventually optimize results, as well as to reassure patients.

New Technologies and Applications in Sacral Neuromodulation: An Update.

Recently rechargeable devices have been introduced for sacral neuromodulation (SNM) with conditional safety for full-body magnetic resonance imaging (MRI). Currently a recharge-free SNM device represents the standard implant; however, it is only approved for MRI head scans. As further new technologies with broader MRI capabilities are emerging, the advantages as well as disadvantages of both rechargeable versus recharge-free devices will be briefly discussed in this commentary from the perspective of patients, healthcare professionals, and providers.

Chemoradiotherapy with and without deep regional hyperthermia for squamous cell carcinoma of the anus.

PURPOSE: To compare results after chemoradiotherapy with and without deep regional hyperthermia in patients with anal cancer. METHODS: Between 2000 and 2015, a total of 112 consecutive patients with UICC stage I-IV anal cancer received chemoradiotherapy with 5­fluororuracil and mitomycin C (CRT). In case of insufficient tumor response 4-6 weeks after chemoradiotherapy, patients received an interstitial pulsed-dose-rate brachytherapy boost. Additionally, 50/112 patients received hyperthermia treatments (HCRT). RESULTS: Median follow-up was 41 (2-165) months. After 5 years follow-up, overall (95.8 vs. 74.5%, P = 0.045), disease-free (89.1 vs. 70.4%, P = 0.027), local recurrence-free (97.7 vs. 78.7%, P = 0.006), and colostomy-free survival rates (87.7 vs. 69.0%, P = 0.016) were better for the HCRT group. Disease-specific, regional failure-free, and distant metastasis-free survival rates showed no significant differences. The adjusted hazard ratios for death were 0.25 (95% CI, 0.07 to 0.92; P = 0.036) and for local recurrence 0.14 (95% CI, 0.02 to 1.09; P = 0.06), respectively. Grades 3-4 early toxicities were comparable with the exception of hematotoxicity, which was higher in the HCRT group (66 vs. 43%, P = 0.032). Incidences of late side effects were similar with the exception of a higher telangiectasia rate in the HCRT group (38.0 vs. 16.1%, P = 0.009). CONCLUSION: Additional regional hyperthermia improved overall survival, local control, and colostomy rates. Its potential beneficial role has to be confirmed in a prospective randomized setting. Therefore, the HyCAN trial has already been established by our group and is currently recruiting patients (Clinicaltrials.gov identifier: NCT02369939).

International Continence Society best practice statement for use of sacral neuromodulation.

AIMS: Sacral neuromodulation (SNM) is an accepted therapy for a variety of conditions. However, despite over 20 years of experience, it remains a specialized procedure with a number of subtleties. Here we present the recommendations issued from the International Continence Society (ICS) SNM Consensus Panel. METHODS: Under the auspices of the ICS, eight urologists, three colorectal surgeons and two urogynecologists, covering a wide breadth of geographic and specialty interest representation, met in January 2017 to discuss best practices for neuromodulation. Suggestions for statements were submitted in advance and specific topics were assigned to committee members, who prepared and presented supporting data to the group, at which time each topic was discussed in depth. Best practice statements were formulated based on available data. This document was then circulated to multiple external reviewers after which final edits were made and approved by the group. RESULTS: The present recommendations, based on the most relevant data available in the literature, as well as expert opinion, address a variety of specific and at times problematic issues associated with SNM. These include the use of SNM for a variety of underlying conditions, need for pre-procedural testing, use of staged versus single-stage procedures, screening for success during the trial phase, ideal anesthesia, device implantation, post-procedural management, trouble-shooting loss of device function, and future directions for research. CONCLUSIONS: These guidelines undoubtedly constitute a reference document, which will help urologists, gynecologists, and colorectal surgeons optimize their use of SNM for refractory urinary urgency and frequency, UUI, NOR, and FI.

Sacral Neuromodulation: Standardized Electrode Placement Technique.

INTRODUCTION: Sacral neuromodulation (SNM) (sacral nerve stimulation SNS) has become an established therapy for functional disorders of the pelvic organs. Despite its overall success, the therapy fails in a proportion of patients. This may be partially due to inadequate electrode placement with suboptimal coupling of the electrode and nerve. Based on these assumptions the technique of sacral spinal neuromodulation has been redefined. All descriptions relate to the only currently available system licensed for all pelvic indications (Medtronic Interstim® ). METHOD: An international multidisciplinary working party of ten individuals highly experienced in performing SNM convened two meetings (including live operating) to standardize the implant procedure. This report addresses the main steps to optimal electrode lead placement in temporal sequence. RESULTS: Key elements of the electrode placement are radiological marking, the use of a curved stylet, the entry of the electrode into the sacral foramen and its progression through the foramen, its placement guided by a combination of a typical appearance in fluoroscopy and achieving specific motor/sensory responses with stimulation. The report describes quadripolar electrode placement and then either insertion of a connecting percutaneous extension lead or permanent implantation of the programmable device. CONCLUSION: Standardization of electrode placement may ensure close electrode proximity to the target nerve providing a higher likelihood for optimal effect with less energy consumption (better battery longevity), more programming options with more electrode contacts close to the nerve and reduced likelihood of side-effects. The potentially better clinical outcome needs to be demonstrated.

Long-term outcome of sacral neuromodulation for chronic refractory constipation.

PURPOSE: Sacral neuromodulation has been reported as a treatment for severe idiopathic constipation. This study aimed to evaluate the long-term effects of sacral neuromodulation by following patients who participated in a prospective, open-label, multicentre study up to 5 years. METHODS: Patients were followed up at 1, 3, 6, 12, 24, 36, 48 and 60 months. Symptoms and quality of life were assessed using bowel diary, the Cleveland Clinic constipation score and the Short Form-36 quality-of-life scale. RESULTS: Sixty-two patients (7 male, median age 40 years) underwent test stimulation, and 45 proceeded to permanent implantation. Twenty-seven patients exited the study (7 withdrawn consent, 7 loss of efficacy, 6 site-specific reasons, 4 withdrew other reasons, 2 lost to follow-up, 1 prior to follow-up). Eighteen patients (29%) attended 60-month follow-up. In 10 patients who submitted bowel diary, their improvement of symptoms was sustained: the number of defecations per week (4.1 ± 3.7 vs 8.1 ± 3.4, mean ± standard deviation, p < 0.001, baseline vs 60 months) and sensation of incomplete emptying (0.8 ± 0.3 vs 0.2 ± 0.1, p = 0.002). In 14 patients (23%) with Cleveland Clinic constipation score, improvement was sustained at 60 months [17.9 ± 4.4 (baseline) to 10.4 ± 4.1, p < 0.001]. Some 103 device-related adverse events were reported in 27 (61%). CONCLUSION: Benefit from sacral neuromodulation in the long-term was observed in a small minority of patients with intractable constipation. The results should be interpreted with caution given the high dropout and complication rate during the follow-up period.

The differential diagnosis and interdisciplinary treatment of anal carcinoma.

BACKGROUND: Anal carcinoma accounts for 2-4% of all cases of colorectal and anorectal carcinoma. Its peak incidence is from age 58 to age 64; women are affected somewhat more commonly than men. Its incidence has risen markedly in the past three decades. METHODS: This article is based on a selective review of the literature, including the guidelines of the National Comprehensive Cancer Network and the European Society of Medical Oncology. RESULTS: Anal carcinoma is often an incidental finding. About 85% of newly diagnosed cases are associated with an HPV infection with strain 16, 18, or 33. Radiochemotherapy with 5-fluorouracil and mitomycin C is the treatment of choice. The 5-year survival rate is 80-90%. Primary surgery with curative intent is indicated only for well-differentiated carcinoma of the anal margin (T1, N0). 10-30% of patients now undergo radical resection. The utility of endosonography and positron emission tomography for staging is debated and needs further study. CONCLUSION: The treatment of patients with anal carcinoma requires a specialized multidisciplinary approach in accordance with the current evidence-based guidelines. The potential role of prophylactic vaccination against oncogenic types of HPV in the prevention of anal carcinoma merits further investigation.

How does neuromodulation work.

Although sacral neuromodulation (SNM) is approved and successfully used for different urological and proctologic functional diseases for the long-term treatment, less is known about the working mechanisms underlying SNM. This review highlights SNM clinical application, the current data of LUT neuroanatomy and neurophysiology, SNM techniques and its prospective working mechanisms. Functional imaging techniques have facilitated a more detailed insight into the neural network between the central nervous system (CNS) and the lower urinary tract (LUT). In addition to the well-known factors of the spinal micturition pathway, several pontine (e.g. pontine micturition centre) and suprapontine (e.g. cingulate cortex) regions and their interactions have been identified. An attribution of CNS activity levels to different LUT conditions is possible for the first time. Based on this information, different SNM actions could also have been allocated to different ascending/descending pathways and supraspinal regions, whereas acute SNM especially affects regions of learning activity, chronic SNM might result in CNS plasticity even though clinical effectiveness fades after SNM deactivation. Studies to treat fecal incontinence or to prevent detrusor overactivity in complete spinal cord injured patients support the importance of sympathetic pathways for the action of SNM. Despite increasing knowledge about SNM influence on the CNS, the complexity of its underlying working mechanisms is not understood at all. Further investigations with improved functional imaging techniques will enhance our SNM background.

Sacral nerve stimulation for faecal incontinence following a rectosigmoid resection for colorectal cancer.

INTRODUCTION: Following recto-sigmoid resection some patients may become faecally incontinent and remain so despite conservative treatment. This multicentre prospective study assessed the use of sacral nerve stimulation (SNS) in this group. METHODS: All patients had more than or equal to 4 days of faecal incontinence for solid or liquid stools over a 21-day period following recto-sigmoid resection for colorectal carcinoma. The operation had to have been deemed curative. They had to have failed pharmacological and biofeedback treatment. RESULTS: Three male patients met these criteria. One had had a colo-anal and two a colo-rectal anastomosis for rectal carcinoma. All patients had intact internal and external anal sphincters. Two patients had a successful temporary stimulation period and proceeded to permanent implantation. Pre-operative symptom duration was 1 year in the permanently implanted patients. They were followed up for 12 months. SNS improved the number of faecally incontinent episodes in both patients. Ability to defer was improved in both patients from 0--5 min to 5--15 min. The faecal incontinence-specific ASCRS quality of life assessment improved in all four subcategories. CONCLUSION: This study demonstrates that SNS may be effective in the treatment of patients with faecal incontinence following recto-sigmoid resection if conservative treatment has failed.

Sacral nerve stimulation for fecal incontinence following surgery for rectal prolapse repair: a multicenter study.

PURPOSE: A proportion of patients have fecal incontinence secondary to a full-thickness rectal prolapse that fails to resolve following prolapse repair. This multicenter, prospective study assessed the use of sacral nerve stimulation for this indication. METHODS: Patients had to have more than or equal to four days with fecal incontinence per 21-day period more than one year after surgery. They had to have failed conservative treatment and have an intact external anal sphincter. RESULTS: Four female patients aged 42, 54, 68, and 65 years met the inclusion criteria. Three of the four patients had had more than one operation for recurrent full-thickness rectal prolapse before sacral nerve stimulation, one of whom had undergone a further operation for recurrence following stimulation. One patient had undergone one operation for prolapse repair. The preoperative duration of symptoms was ten, eight, three, and nine years, respectively. Although patients had an intact external anal sphincter, one patient had a fragmented internal anal sphincter. The frequency of fecal incontinent episodes changed from 11, 24.7, 5, and 8 per week at baseline to 0, 1.5, 5.5, and 1 per week at latest follow-up. Ability to defer defecation was also improved in two of three patients who had this documented. Fecal incontinence-specific quality of life assessment showed an improvement in all four domains. CONCLUSION: Sacral nerve stimulation should be considered for patients with ongoing fecal incontinence following full-thickness rectal prolapse repair if they prove resistant to conservative treatment.

P27 does not predict histopathological response to radiochemotherapy in rectal cancer.

BACKGROUND: Tumor response to radiochemotherapy (RCT) varies considerably, even among patients treated in accordance with the same protocol. The aim of the present study was to test the predictive value of the cell-cycle inhibitor p27kip1 with regard to neoadjuvant RCT response in rectal cancer. MATERIALS AND METHODS: P27kip1 was evaluated by immunohistochemistry in pretreatment biopsy material obtained from 42 patients with rectal cancer treated uniformly in accordance with an identical prospective neoadjuvant RCT protocol (CAO/AIO/ARO-94). Four expression patterns (staining intensity [-,+,++,+++] and the percentage of positive cells, evaluated separately for nuclei and cytoplasm) of p27kip1 were investigated for correlation with tumor response, which was assessed in the resected surgical specimen using a histopathological five-point grading system. Additionally, p27(kip1) expression was investigated for correlation with several pathological features, overall survival, and disease-free survival. RESULTS: p27kip1 expression was as follows: nuclear intensity: -: 8, +: 19, ++: 11, +++: 4 cases, median percentage of positive cells: 18.75%; cytoplasmic intensity: -: 0, +: 25, ++: 12, +++: 3 cases, median percentage of positive cells: 70%. Histopathological tumor regression was acceptable in 30 patients (3 complete; 27 good) and inadequate in 12 patients (7 moderate; 5 minimal). No tumor failed to show some regression. No significant correlation was found between any of the p27kip1 expression patterns and RCT response, tumor differentiation (low grade versus high grade), cT- and ypT-category, UICC stage, overall survival, and disease-free survival. CONCLUSIONS: p27kip1 cannot aid the individualization of multimodal treatment strategies in rectal cancer, nor can it serve as a predictor of survival.

Bilateral sacral spinal nerve stimulation for fecal incontinence after low anterior rectum resection.

BACKGROUND AND AIMS: The somatomotor innervation pattern has been shown to differ in patients undergoing percutaneous nerve evaluation for sacral nerve stimulation. In some patients bilateral stimulation might improve clinical outcome; however, only single-channel pulse generators have until now been available. We report a patient with fecal incontinence after surgery for rectal carcinoma in whom a dual-channel, individually programmable, pulse generator permitted implantation of neurostimulation electrodes bilaterally. PATIENTS AND METHODS: Intractable fecal incontinence developed in a 48-year-old man who underwent low anterior rectum resection, owing mainly to reduced internal anal sphincter function. The morphology of the anal sphincter was without defect. Based on the findings of unilateral and bilateral temporary sacral nerve stimulation the patient underwent placement of foramen electrodes on S4 bilaterally. Both electrodes were connected to a dual-channel impulse generator for permanent low-frequency stimulation. RESULTS: The percentage of incontinent bowel movements decreased during unilateral test stimulation from 37% to 11%, during bilateral test stimulation to 4%, and with chronic bilateral stimulation to 0%. The Wexner continence score improved from 17 preoperatively to 2, and quality of life (ASCRS score) was notably enhanced. Anorectal manometry revealed improved striated anal sphincter function; the internal anal sphincter remained unaffected. CONCLUSION: Sacral nerve stimulation can effectively treat incontinence after rectal resection, and bilateral stimulation can improve the therapeutic effect.