Sacral Neural Crest-Independent Origin of the Enteric Nervous System in Mouse.

BACKGROUND & AIMS: The enteric nervous system (ENS), the gut's intrinsic nervous system critical for gastrointestinal function and gut-brain communication, is believed to mainly originate from vagal neural crest cells (vNCCs) and partially from sacral NCCs (sNCCs). Resolving the exact origins of the ENS is critical for understanding congenital ENS diseases but has been confounded by the inability to distinguish between both NCC populations in situ. Here, we aimed to resolve the exact origins of the mammalian ENS. METHODS: We genetically engineered mouse embryos facilitating comparative lineage-tracing of either all (pan-) NCCs including vNCCs or caudal trunk and sNCCs (s/tNCCs) excluding vNCCs. This was combined with dual-lineage tracing and 3-dimensional reconstruction of pelvic plexus and hindgut to precisely pinpoint sNCC and vNCC contributions. We further used coculture assays to determine the specificity of cell migration from different neural tissues into the hindgut. RESULTS: Both pan-NCCs and s/tNCCs contributed to established NCC derivatives but only pan-NCCs contributed to the ENS. Dual-lineage tracing combined with 3-dimensional reconstruction revealed that s/tNCCs settle in complex patterns in pelvic plexus and hindgut-surrounding tissues, explaining previous confusion regarding their contributions. Coculture experiments revealed unspecific cell migration from autonomic, sensory, and neural tube explants into the hindgut. Lineage tracing of ENS precursors lastly provided complimentary evidence for an exclusive vNCC origin of the murine ENS. CONCLUSIONS: sNCCs do not contribute to the murine ENS, suggesting that the mammalian ENS exclusively originates from vNCCs. These results have immediate implications for comprehending (and devising treatments for) congenital ENS disorders, including Hirschsprung's disease.

One-stage implant in sacral neuromodulation for faecal incontinence - short-term outcome from a prospective study.

AIM: Sacral neuromodulation (SNM) is approved for the treatment of faecal incontinence (FI) in a two-stage technique. With standardized implantation, approximately 90% of patients undergo successful Stage I operation and proceed to a permanent implant (Stage II). The aim of this work was to explore the feasibility of SNM as a one-stage procedure and report the 24-week efficacy. METHOD: This study included patients diagnosed with idiopathic FI or FI due to an external anal sphincter defect ≤160° and one or more episodes of FI per week despite maximal conservative therapy. Patients were offered a one-stage procedure if a motor response of the external anal sphincter was achieved in three or more poles with at least one at ≤1.5 mA at lead placement. Patients were followed for 24 weeks. Their evaluation included the Wexner/St Mark's Incontinence Score, Faecal Incontinence Quality of Life score (FIQoL), a visual analogue scale (VAS) for assessing patient satisfaction and a bowel habit diary. RESULTS: Seventy-three patients with a median age of 60 years (interquartile range 50-69 years) completed this prospective study. Episodes of FI were significantly reduced at the 24-week follow-up, from 13 (8-23) at baseline to 2 (0-5) (p-value = 0002). A ≥50% reduction in the number of FI episodes was achieved in 92% of participants. The Wexner score improved significantly from 16 (14-17) at baseline to 9 (5-13) (p-value < 0.001), and the St Mark's score improved significantly from 18 (16-20) to 11 (7-16) (p-value < 0.001). All domains in the FIQoL score and VAS for patient satisfaction improved significantly following the one-stage procedure. CONCLUSION: A one-stage implantation procedure is feasible in selected patients with FI, significantly improving continence, quality of life and patient satisfaction after 24 weeks of follow-up.

Sensing in Sacral Neuromodulation: A Feasibility Study in Subjects With Urinary Incontinence and Retention.

OBJECTIVES: Sacral neuromodulation (SNM) therapy standard of care relies on visual-motor responses and patient-reported sensory responses in deciding optimized lead placement and programming. Automatic detection of stimulation responses could offer a simple, consistent indicator for optimizing SNM. The purpose of this study was to measure and characterize sacral evoked responses (SERs) resulting from sacral nerve stimulation using a commercial, tined SNM lead. MATERIALS AND METHODS: A custom external research system with stimulation and sensing hardware was connected to the percutaneous extension of an implanted lead during a staged (tined lead) evaluation for SNM. The system collected SER recordings across a range of prespecified stimulation settings (electrode configuration combinations for bipolar stimulation and bipolar sensing) during intraoperative and postoperative sessions in 21 subjects with overactive bladder (OAB) and nonobstructive urinary retention (NOUR). Motor and sensory thresholds were collected during the same sessions. RESULTS: SERs were detected in all 21 subjects. SER morphology (number of peaks, magnitude, and timing) varied across electrode configurations within and across subjects. Among subjects and electrode configurations tested, recordings contained SERs at motor threshold and/or sensory threshold in 75% to 80% of subjects. CONCLUSIONS: This study confirmed that implanted SNM leads can be used to directly record SERs elicited by stimulation in subjects with OAB and NOUR. SERs were readily detectable at typical SNM stimulation settings and procedural time points. Using these SERs as possible objective measures of SNM response has the capability to automate patient-specific SNM therapy, potentially providing consistent lead placement, programming, and/or closed-loop therapy.

Is sacral nerve modulation reprogramming effective after permanent implantation for faecal incontinence?

AIM: Sacral nerve modulation (SNM) is recommended as a first-line surgical therapy for patients with faecal incontinence (FI). During patient follow-up, it is recommended that stimulation settings be reprogrammed to optimize patient outcomes. The aim of the present study was to evaluate the efficacy of stimulator reprogramming in patients with an implanted SNM device to treat FI. METHOD: The data from patients who received a permanent SNM implant in a single centre from January 2008 to December 2019 were retrospectively analysed. Symptoms that occurred after implantation, the stimulator settings of the SNM device and changes made at each follow-up visit were noted. The efficacy of reprogramming was determined by assessing patient satisfaction. RESULTS: Of the 117 patients (male/female 4/113; mean age 59.5 ± 11.8 years) with a SNM implant for FI, 84 (72%) had at least one symptom requiring reprogramming of the stimulator, most often during the first year after implantation (p = 0.05). The most frequently reported symptoms were loss of efficacy (68.5%; p = 1 × 10-3 ) and pain (20.5%; p = 1 × 10-3 ). Reprogramming was effective 53% of the time when treating loss of efficacy and 76% of the time when treating pain. When the stimulation parameters were reprogrammed at least four consecutive times to correct a symptom, the reprogramming was less effective in treating the symptom (p = 0.02). CONCLUSION: Regular follow-up of patients with SNM device implants associated with reprogramming of stimulation parameters to improve the treatment of reported symptoms would optimize the efficacy of SNM.

Comparison of surgical techniques for optimal lead placement in sacral neuromodulation: a cadaver study.

BACKGROUND: Sacral neuromodulation (SNM) is a common treatment for patients with urinary and faecal incontinence. A close contact of the tined lead electrode with the targeted nerve is likely to improve functional outcome. The aim of this study was to compare the position of the SNM lead in relation to the sacral nerve by comparing different implantation techniques. METHODS: This cadaver study was conducted at the Division of Anatomy of Vienna's Medical University in October 2020. We dissected 10 cadavers after bilateral SNM lead implantation (n = 20), using two different standardized implantation techniques. The cadavers were categorized as group A (n = 10), representing the conventional guided implantation group and group B (n = 10), where SNM implantation was conducted with the novel fluoroscopy-guided "H"-technique. The primary goal was to assess the distance between the sacral nerve and the lead placement. RESULTS: The electrodes were inserted at a median angle of 58.5° (46-65°) in group A and 60° (50-65°) in group B, without reaching statistical significance. In 8 cadavers, the lead entered the S3 foramen successfully. The median distance of the lead to the nerve did not show a significant difference between both groups (E0: Group A: 0.0 mm vs. Group B: 0.0 mm, p = 0.969; E1: Group A: 0.0 mm vs. Group B: 0.5 mm p = 0.754; E2: Group A: 2.5 mm vs. Group B: 2.5 mm p = 1.000; E3: Group A: 3.5 mm vs. Group B: 4.0 mm p = 0.675). In 2 cases (20%) of the conventional group A, the lead was misplaced and located at the gluteal muscle. Perforation of the presacral fascia was observed in one lead placement in group A and in two placements in group B. CONCLUSIONS: Both standardized implantation techniques may ensure close electrode proximity to the targeted nerve. Misplacement of the electrode was more often observed with the conventional implantation technique.

Computed Tomography-Guided Placement of Sacral Electrodes.

BACKGROUND: The current approach to performing sacral neuromodulation consists of a two-stage procedure, the first of which includes insertion of the sacral electrode under fluoroscopic visualization of the S3 foramen. Alternatively, in certain situations computed tomography (CT)-guided insertion can be used. OBJECTIVES: To evaluate the use of CT in cases of reinsertion of the electrode due to infection, dislocation, or rupture. METHODS: Medical records of patients who underwent neuromodulation device reinsertion between 2005 and 2016 for fecal incontinence were reviewed. Study outcomes included procedure course, successful placement, and long-term treatment success. RESULTS: During the study period, we inserted a neuromodulation device in 67 patients. A CT-guided insertion of a sacral electrode was performed in 10 patients. In nine patients, the insertion and the final location of the electrode were successful. In one patient, the electrode migrated upward due to a malformation of the S3 foramen on both sides and had to be placed in S4. In a mean follow-up of 68.4 ± 30.0 months following the re-insertion, there was a significant reduction in the number of incontinence episodes per day (P < 0.001) and the number of pads used per day (P = 0.002). CONCLUSIONS: CT-guided insertion of a sacral electrode is a safe and promising option, especially in recurrent and or selected cases.

Global incidence of spinal perineural Tarlov's cysts and their morphological characteristics: a meta-analysis of 13,266 subjects.

BACKGROUND: Spinal perineural Tarlov's cysts (TCs) are considered incidental findings that occasionally might exert pressure upon nerve roots and correspond with patients' signs and symptoms. Purpose of this meta-analysis is to deliver global incidence and characteristics (location, size, and shape) of TCs. METHODS: Following PRISMA checklist, all major databases were searched by two authors for radiologic studies reporting incidence and morphologic features (location, size, and shape) of TCs. Anatomical Quality Assessment tool was applied for risk of bias evaluation. Meta-analysis of random-effects model was employed. Subgroup analysis for regional distribution, gender, sacral levels, age, correspondence with symptoms, and persistent genital arousal disorder (PGAD) were planned ahead. RESULTS: 22 radiologic studies of level 3 evidence involving 13,266 subjects were included. Global pooled prevalence of TCs was 4.18% (95% CI 2.47-6.30). Mean pooled sagittal diameter was 11.86 mm (95% CI 10.78-12.93). Sacral cysts strongly prevailed over the other segments. Of the sacral, S2 level was the most common (46.7% [95% CI 29.4-60.5]). Geographically, the highest incidence was found in Europe (6.07% [95% CI 1.49-13.00]), followed by North America (3.82% [95% CI 0.49-9.44]), and Asia (3.33% [95% CI 1.52-5.75]). TCs were more common in women than in men (5.84% vs 3.03%, p < 0.001, test of homogeneity, χ2). Subjects with PGAD had incidence of 37.87% (95% CI 2.45-81.75). TCs in pediatric population are rare-0.53% (95% CI 0.02-1.51). 15.59% of TCs corresponded with symptoms. CONCLUSIONS: Spinal perineural (Tarlov) cysts are found in a minority of population. S2 level of the sacral bone is affected most frequently. There is female predominance. Correspondence with symptoms is seen in less than one-fifth of TCs. Studies with stronger evidence level are needed to corroborate the results. The purported high incidence in PGAD requires confirmation in case-control studies for the risk-ratio calculation.

Anti-inflammatory effects of sacral nerve stimulation: a novel spinal afferent and vagal efferent pathway.

Sacral nerve stimulation (SNS) was reported to improve 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. The aim of this study was to investigate whether the SNS anti-inflammatory effect is mediated via the local sacral splanchnic nerve or the spinal afferent-vagal efferent-colon pathway. Under general anesthesia, rats were administrated with TNBS intrarectally, and bipolar SNS electrodes were implanted unilaterally at S3. The sacral and vagal nerves were severed at different locations for the assessment of the neural pathway. SNS for 10 days improved colonic inflammation only in groups with intact afferent sacral nerve and vagus efferent nerve. SNS markedly increased acetylcholine and anti-inflammatory cytokines (IL-10) and decreased myeloperoxidase and proinflammatory cytokines (IL-2, IL-17A, and TNF-α) in colon tissues. SNS increased the number of c-fos-positive cells in the brain stem and normalized vagal activity measured by spectral analysis of heart rate variability. SNS exerts an anti-inflammatory effect on TNBS-induced colitis by enhancing vagal activity mediated mainly via the spinal afferent-brain stem-vagal efferent-colon pathway.NEW & NOTEWORTHY Our findings support that there is a possible sacral afferent-vagal efferent pathway that can transmit sacral nerve stimulation to the colon tissue. Sacral nerve stimulation can be carried out by spinal cord afferent to the brain stem and then by the vagal nerve (efferent) to the target organ.

Single Institutional Experience with Single Stage Sacral Neuromodulation: Cost Savings and Outcomes in a Contemporary Case Series.

PURPOSE: Sacral neuromodulation is traditionally performed in 2 stages. Studies have projected that 1-stage sacral neuromodulation is cost-effective if the conversion rate is 61.3% or greater. To our knowledge we present the first case series in the literature to evaluate the cost of 1-stage sacral neuromodulation. The objective of our study was to evaluate outcomes and analyze cost using our institutional experience with 1-stage sacral neuromodulation. MATERIALS AND METHODS: A total of 15 consecutive 1-stage sacral neuromodulation procedures were performed at a self-insured, integrated health care institution. Cost data were determined using 2019 Medicare reimbursement rates for CPT codes 64581, 64585, 64590 and 64595. Median operative time was derived from actual institutional data. RESULTS: One-stage sacral neuromodulation implantation was performed in 15 patients. Median followup was 14.6 months (IQR 6.9-22.5). Of the 15 cases 14 (93.3%) were successful, defined as a 50% or greater improvement from baseline. Total reimbursement for the 15 patients who underwent 1-stage implantation was $329,430. If these patients had undergone traditional 2-stage implantation with equivalent outcomes, the overall reimbursement was determined to be $414,796. Single-stage sacral neuromodulation implantation provided a calculated total cost savings of $85,366 (p <0.01). Moreover, a projected 233 minutes in operative time was saved by performing 1-stage sacral neuromodulation (p <0.01). CONCLUSIONS: This study demonstrates the potential health care savings of a 1-stage sacral neuromodulation procedure. Moreover, 1-stage sacral neuromodulation may have other added benefits, such as reduced infection rates, patient satisfaction and other indirect cost savings, including reduced time off from work.

Effect and mechanisms of sacral nerve stimulation on visceral hypersensitivity mediated by nerve growth factor.

To investigate the efficacy of sacral nerve stimulation (SNS) on nerve growth factor (NGF) mediated visceral sensitivity in normal rat and visceral hypersensitivity model rats. 120 male newborn rats were randomly divided into 6 groups: group A was normal model group; group B ~ F were all sensitized with acetic acid enema and grouped again. Group c2 was given NGF antagonist, d2 group was given NGF agonist, e2 group was given PI3K inhibitor, and f2 group was given PLC-γ inhibitor. After treatment, the expression of NGF, TrKA, PI3K, AKT, PLC-γ, NF-κB, TRPV1, pTRPV1 and intracellular Ca2+ content were detected. The expression of protein TRPV1 and pTRPV1 was increased, and Ca2+ was increased in the visceral hypersensitive group. NGF, TrKA in NGF antagonist group, PI3K, AKT, NF-κB in PI3K inhibitor group, PLC-γ in PLC-γ inhibitor group were all almost not expressed. The relative expression of NGF, TrKA, PI3K, AKT, PLC-γ and NF-κB in NGF antagonist group was lower than that in visceral hypersensitivity group and NGF activator group (P < .01). The relative expression of NGF, TrKA, PI3K and AKT mRNA in NGF antagonist group was lower than that in the normal model group (P < .01). There was no significant difference in the relative expression of PLC-γ and NF-κB mRNA (P > .05). The expression level of MAPK, ERK1 and ERK2 in visceral hypersensitivity group was higher than that in PI3K inhibitor group and PLC-γ inhibitor group. The normal group Ca2+ curve was flat, and the NGF agonist group had the highest Ca2+ curve peak. Calcium concentration in visceral hypersensitivity group was higher than that in PI3K inhibitor group and that in PLC-γ inhibitor group was higher than that in NGF antagonist group. The binding of TrkA receptor to NGF activates the MAPK/ERK pathway, the PI3K/Akt pathway and the PLC-γ pathway, causing changes in the fluidity of intracellular and extracellular Ca2+ , resulting in increased sensitivity of visceral tissues and organs.

Sacral nerve stimulation in slow-transit constipation: effectiveness at 5-year follow-up.

AIM: The aim of this study is to evaluate the short- and long-term efficacy of sacral nerve stimulation (SNS) for treating slow-transit constipation (STC). METHOD: This is a retrospective cohort analysis of the efficacy of SNS in treating patients affected by STC, who previously failed to respond to conservative therapies. Only patients free of concomitant diseases were enrolled in our study. A temporary stimulation lead was initially implanted; patients with a > 50% symptom reduction were eventually deemed eligible for a permanent implant. RESULTS: This study enrolled 25 patients who underwent a SNS test stimulation; 21 patients (13 women; median age 32 years) eventually got a permanent implant. The median preoperative Cleveland Clinic Constipation Score (CCCS) was 21 (16-25). Preoperative colorectal transit time recorded a median of 10 markers (7-19) retained in the colorectal tract. At 6-month postoperative follow-up, the total number of markers retained in the colorectal tract decreased to 3 (0-4). The CCCS score improved during the first postoperative year (P < 0.001), but progressively worsened over the longer term. The SF-36 questionnaire showed an improvement in all 8 scales measuring physical and psycho-emotional states; all parameters recorded into the bowel diary also improved. Overall, at 60-month follow up, the overall neuromodulator removal rate was 48%. CONCLUSIONS: The SNS is a minimally invasive surgical procedure that we tested for treating STC. The short-term outcome was promisingly after 6 months; however, there was a declining trend beyond this interval. Thus, the long-term efficacy of SNS needs to be further assessed.

Sacral nerve stimulation for bowel dysfunction following low anterior resection: a systematic review and meta-analysis.

AIM: Low anterior resection syndrome (LARS) can affect up to 70% of all patients with rectal cancer. In the last two decades, sacral nerve stimulation (SNS) has emerged as an effective treatment for faecal incontinence. There is some encouraging literature on the use of SNS in patients with LARS. The purpose of this review is to provide an up to date review on the utility of SNS on LARS. METHOD: A literature search was conducted using the MEDLINE, Embase and PubMed databases (January 1981-March 2019). Studies identified were appraised with standard selection criteria. Data points were extracted, and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: Ten studies met the inclusion criteria and were included in this study. All studies used the Cleveland Clinic Incontinence Score (CCIS), whereas the low anterior resection syndrome score (LARS score) was used in three studies. Overall median improvement in the scoring system was 67.0% (range 35.5%-88.2%) after SNS implantation. There was a significant reduction in CCIS after SNS implantation (mean difference 11.23, 95% confidence interval 9.38-13.07, Z = 11.90, P < 0.00001). The LARS score was also significantly reduced after using SNS in patients with LARS (mean difference 17.87, 95% confidence interval 10.15-25.59, Z = 4.54, P < 0.00001). CONCLUSION: Use of SNS may provide symptomatic benefits for patients with LARS refractory to medical therapy. However, the current level of evidence remains limited. A large multicentre study of SNS for LARS using the validated LARS score is warranted. In addition, the cost-effectiveness of SNS for patients with LARS needs further exploration.

Robot-assisted laparoscopic management of a vascular entrapment of the sacral nerve roots causing pelvic pain.

The aim of this case report is to demonstrate the robot-assisted laparoscopic decompression approach to treat the aberrant vessels entrapping the sacral nerves causing pelvic pain. A 34-year-old female patient had been complaining about pelvic pain on the left perineal region which was radiating to the sacral 1-2 nerves dermatome for 3 years. Decompression of sacral nerve roots and sciatic nerve was performed via robot-assisted and a four-arm Da Vinci Si Surgical System laparoscopic approach. This case report is the first presentation of robot-assisted laparoscopic management of a vascular entrapment of the sacral nerve roots. The robotic technique offers, three-dimensional vision, improved maneuverability and enhanced ergonomics in the deepest area in the pelvis and could be a valid alternative to laparoscopy in the treatment of intrapelvic neurovascular entrapments.

Sacral nerve stimulation for constipation: long-term outcomes.

BACKGROUND: There has been some controversy regarding the efficacy of sacral nerve stimulation (SNS) for the treatment of chronic constipation, due to less positive outcomes and concerns about cost-effectiveness in the long term. The aim of the present study was to evaluate the long-term outcomes of SNS in patients with chronic constipation. METHODS: A retrospective study was conducted on patients who had SNS for chronic constipation in 2008-2017 at our institution. Clinical factors, profile of constipation, physiology studies, and patient satisfaction with SNS therapy were investigated during a follow-up period up to 10 years after the implantation. RESULTS: Twenty-nine patients [86% female, median age 49 years (range 17-86)] were tested for SNS, and 24 received implants after a positive test phase [median 47 days (range 21-56 days)]. There were 27 bilateral and 2 unilateral implants, in S3 or S4 depending on best response. Mean follow-up was 59 months. Efficacy was considered as a score > 5 (on a scale of 1-10) in general symptom improvement. Nine (37.9%) implanted patients had a satisfaction score > 5. In 6 cases (25%), patient satisfaction was higher than 9. Due to the small sample size, there were no statistically significant variables considered as predictors of response. CONCLUSIONS: Our results agree with current studies which describe around a 30% response of SNS for refractory constipation. However, there is a small group of patients highly satisfied with SNS therapy. More studies are needed to better understand this profile and optimize outcomes.

Sacral neuromodulation for fecal incontinence in Latin America: initial results of a multicenter study.

BACKGROUND: Sacral neuromodulation (SNM) is a widely used therapeutic option for fecal incontinence (FI). Larger series are mainly from Western countries, while few reports address the results of SNM in less developed or less wealthy countries. The aim of the present study was to evaluate the efficacy of SNM in patients with FI in Latin America. METHODS: A retrospective study was conducted on patients with FI who had SNM between 2009 and 2016 at 15 specialized colorectal surgery centers in Latin America. Main outcomes measures were functional outcomes, postoperative complications, requirement of revisional surgery, and requirement of device removal. All patients had failed conservative management and had clinical assessment including recording of the validated Cleveland Clinic Florida Fecal Incontinence Score (CCF-FIS) and, when available, anal manometry and endoanal ultrasound. Patients were followed up for a median of 36.7 (1-84) months. RESULTS: One hundred and thirty-one patients [119 females, median age of 62.2 (range 19-87) years] were included. The most common etiology of FI was obstetric injury (n = 60; 45.8%). After successful test lead implantation, the stimulator was permanently placed in 129 patients (98.5%). One patient failed to respond in the test phase and one patient did not proceed to permanent implantation for insurance reasons. Nineteen patients (14.7%) had 19 complications including infection (n = 5, 3.8%), persistent implant site pain (n = 5, 3.8%), generator/lead dislodgment (n = 5, 3.8%), malfunctioning device (n = 3, 2.3%), and hematoma (n = 1, 0.7%). Reimplantation after the first and second stages was necessary in 2 (1.5%) and 3 patients (2.3%), respectively. The device removal rate was 2.2%. At a median follow-up of 36.7 (range 1-84) months, the CCF-FIS significantly improved from a preoperative baseline of 15.9 ± 2.98 to 5.2 ± 3.92 (95%CI: 15.46 vs 4.43; p < 0.0001). Overall, 90% of patients rated their improvement as "significant". CONCLUSIONS: Sacral nerve stimulation for FI is safe and efficient, even in less wealthy or less developed countries.

Systematic review: sacral nerve stimulation in the treatment of constipation and fecal incontinence in children with emphasis in anorectal malformation.

BACKGROUND: Sacral nerve stimulation (SNS) is frequently used for constipation and fecal incontinence in the adult literature. The purpose of this study is to perform a systemic review of the literature for SNS for constipation and fecal incontinence in children with emphasis in anorectal malformations. METHODS: Systematic literature review was conducted to include all SNS studies in patients < 19 years of age. Studies were separated into those for (1) constipation, (2) bowel and bladder dysfunction, and (3) anorectal malformations. RESULTS: 28 articles were included in the review: (1) 12 constipation (269 patients) and (2) 16 bowel and bladder dysfunction (441 patients). Some studies overlapped groups, as they included some patients with anorectal malformations (4 articles and 29 patients). Constipation studies included slow transit and retention constipation and showed varying degrees of improvement. For bowel and bladder dysfunction, studies also reported varying degrees of improvement using different measures (number of bowel movements per day, transit times, and soiling improvement). There was no specific description of the results in anorectal malformation (ARM) cases and also information regarding specific ARM type, sacral ratio, or presence of tethered cord. CONCLUSIONS: SNS for constipation and urinary problems seems to be promising. Data are limited and heterogeneous, and SNS cannot be definitively encouraged or discouraged in patients with ARM, based on current studies. Future studies should include more objective measurements of bowel outcomes and specify outcomes related to patients with anorectal malformations including information regarding their specific malformation, sacral ratio, and presence of tethered cord. Complications' rate is considerable high.

Electromyographic Responses Across Different Pulse-Widths of Sacral Neuromodulation in Sheep.

OBJECTIVES: In rodents, we reported that short pulse-width (PW) neuromodulation might provide more efficient therapy delivery than traditional 0.21 msec PW. Using fully implanted, commercialized systems in the sheep, the goal of this study was to characterize the relationship of electromyographic (EMG) responses of the external anal sphincter (EAS) to different PWs of sacral neuromodulation (SNM). MATERIALS AND METHODS: In seven sheep, InterStim® quadripolar tined leads were implanted adjacent to the S3 nerve root bilaterally to deliver SNM and two pairs of intramuscular leads were placed on either side of the EAS for EMG sensing. The EMG responses to SNM with different PWs were examined using variable intensities in both anesthetized and conscious conditions. RESULTS: The EMG responses from ipsilateral EAS (IEAS ) and contralateral EAS (CEAS ) were compared. The area under the curve of EMG responses from IEAS were significantly stronger than that from CEAS. The late component EMGs were more sensitive to nerve stimulation with a higher response amplitude in awake sheep. The response threshold-PW relationship from the IEAS as ascertained visually and with EMG in anesthetized and awake sheep were fitted with a monoexponential nonlinear regression; the resulting chronaxies were of 0.05 msec (n = 6), and 0.04 msec (n = 6), and 0.04 msec (n = 8), respectively. CONCLUSIONS: In both anesthetized and awake conditions, a similar motor response may be evoked in the EAS at PWs much shorter (0.04-0.05 msec) than the 0.21 msec typically used with SNM. Potential battery savings manifested by shorter PW would provide more efficient therapy delivery and increased longevity of the stimulator.

Suppression of Urinary Voiding "on Demand" by High-Frequency Stimulation of the S1 Sacral Nerve Root in Anesthetized Rats.

OBJECTIVES: High-frequency (kHz) stimulation of preganglionic pelvic nerve afferents can inhibit voiding in both anesthetized and conscious rats. The afferents travel via the S1 sacral nerve root, which is easier to access than the distal pelvic nerve fibers within the abdominal cavity. We therefore investigated whether voiding could be inhibited by high-frequency stimulation at S1 and how this compared to distal pelvic nerve stimulation. METHODS: Urethane-anesthetized rats were instrumented to record bladder pressure and abdominal wall electromyogram and to stimulate the distal preganglionic pelvic nerve bundle and S1 sacral root. Saline was infused continuously into the bladder to evoke repeated voiding. Stimulation was initiated within 1-2 sec of the onset of the steep rise in bladder pressure signaling an imminent void. RESULTS: In six rats, stimulation of the distal pelvic nerve bundle (1-3 kHz sinusoidal waveform 1 mA, 60 sec) supressed the occurrence of an imminent void. Voiding resumed within 70 ± 13.0 sec (mean ± SEM) of stopping stimulation. Stimulation (using the same parameters) of the S1 root at the level of the sacral foramen suppressed voiding for the entire stimulation period in three rats and deferred voiding for 35-56 sec (mean 44.0 ± 3.2 sec) in the remaining three. Stimulation at either site when the bladder was approximately half full, as estimated from previous intervoid intervals, had no effect on voiding. CONCLUSIONS: This preliminary study provides proof-of-concept for the sacral root as an accessible target for high-frequency stimulation that may be developed as an "on demand" neuromodulation paradigm to suppress unwanted urinary voids. CONFLICT OF INTEREST: The authors reported no conflict of interest.

Development of a Remote-Controlled Implantable Rat Sacral Nerve Stimulation System.

OBJECTIVES: Sacral nerve stimulation (SNS) is a surgical treatment of urinary and fecal incontinence. Despite its clinical efficacy, the mechanisms of action of SNS are still poorly known. This may be related to the use of acute stimulation models. Up to date, no rodent model of chronic SNS implants has been developed. Therefore, the aim of this study was to create a fully implantable and remotely controllable stimulating device to establish an animal model of chronic SNS. MATERIALS AND METHODS: The stimulating device consisted of an implantable pulse generator linked to a platinum electrode. The communication with the device was made through an inductive link which allowed to adjust the stimulation parameters; that is, to turn the device on and off or check the battery status remotely. Rats underwent two surgical procedures. In the first procedure, we achieved chronic sacral stimulation but the implanted electrode was not fixated. In the second procedure, the electrode was fixated in the sacral foramen using dental resin. In both cases, the correct positioning of the electrode was evaluated by computed tomography (CT) imaging and the presence of tail tremor in response to high intensity stimulation. We only tested the function of implanted electrode with fixation using micturition frequency assessment following bipolar or unipolar SNS for three days after recovery. RESULTS: CT imaging showed that implantation of the electrode required fixation as we found that the second surgical procedure yielded a more precise placement of the implanted electrode. The correct placement of implanted electrode observed with imaging was always correlated with a successful tail tremor response in rats, therefore we pursued our next experiments with the second surgical procedure and only assessed the tail tremor response. We found that both bipolar and unipolar SNS reduced micturition frequency. CONCLUSION: This stimulating device provides an efficient method to perform chronic SNS studies in rats.

Results of Sacral Neuromodulation Therapy for Urinary Voiding Dysfunction: Five-Year Experience of a Retrospective, Multicenter Study in China.

PURPOSE: This five-year, retrospective, multicenter study evaluated the long-term safety and efficiency of sacral neuromodulation (SNM) in Chinese patients with urinary voiding dysfunction. PATIENTS AND METHODS: This is a Chinese national, multicenter, retrospective study that included 247 patients (51.2% female) who received an implantable pulse generator (IPG) (InterStim, Medtronic, Minneapolis, MN, USA) between 2012 and 2016. Success was considered if the initial ≥50% improvement in any of primary voiding diary variables persisted compared with baseline. The results were further stratified by identifying patients who showed >50% improvement and those although showed <50% improvement but still wanted to receive IPG; these data were collected and analyzed for general improvement. RESULTS: Following test stimulation, 187 patients (43%) declined implantation and 247 (57%) underwent implantation using InterStim®. Among 247 patients, 34 (13.7%) had overactive bladder (OAB), 59 (23.8%) had interstitial cystitis/bladder pain syndrome (IC/BPS), 47 (19%) had idiopathic urinary retention (IUR), and 107 (44.1%) had neurogenic bladder (NB). IPG efficiency rate for OAB, interstitial cystitis/bladder pain syndrome, idiopathic urinary retention, and neurogenic bladder were 42.5, 72.4, 51.6, and 58.8%, respectively. The mean duration of follow-up was 20.1 ± 12.8 months. CONCLUSIONS: SNM appears effective in the long term, with a total IPG implantation rate of approximately 57% (ranging between 42.5 and 72.4% depending on indication). Interstitial cystitis/bladder pain syndrome appear to be the best indication for stage I testing. Chinese neurogenic bladder patients are most inclined to choose SNM. SNM is relatively safe, with low postoperation adverse events of 16.1% and reoperation rate of 3.2% during the follow-up period.