Long-term durability of sacral nerve stimulation therapy for chronic fecal incontinence.

BACKGROUND: Limited data have been published regarding the long-term results of sacral nerve stimulation, or sacral neuromodulation, for severe fecal incontinence. OBJECTIVES: The aim was to assess the outcome of sacral nerve stimulation with the use of precise tools and data collection, focusing on the long-term durability of the therapy. Five-year data were analyzed. DESIGN: Patients entered in a multicenter, prospective study for fecal incontinence were followed at 3, 6, and 12 months and annually after device implantation. PATIENTS: Patients with chronic fecal incontinence in whom conservative treatments had failed or who were not candidates for more conservative treatments were selected. INTERVENTIONS: Patients with ≥ 50% improvement over baseline in fecal incontinence episodes per week during a 14-day test stimulation period received sacral nerve stimulation therapy. MAIN OUTCOME MEASURES: Patients were assessed with a 14-day bowel diary and Fecal Incontinence Quality of Life and Fecal Incontinence Severity Index questionnaires. Therapeutic success was defined as ≥ 50% improvement over baseline in fecal incontinence episodes per week. All adverse events were collected. RESULTS: A total of 120 patients (110 women; mean age, 60.5 years) underwent implantation. Seventy-six of these patients (63%) were followed a minimum of 5 years (maximum, longer than 8 years) and are the basis for this report. Fecal incontinence episodes per week decreased from a mean of 9.1 at baseline to 1.7 at 5 years, with 89% (n = 64/72) having ≥ 50% improvement (p < 0.0001) and 36% (n = 26/72) having complete continence. Fecal Incontinence Quality of Life scores also significantly improved for all 4 scales between baseline and 5 years (n = 70; p < 0.0001). Twenty-seven of the 76 (35.5%) patients required a device revision, replacement, or explant. CONCLUSIONS: The therapeutic effect and improved quality of life for fecal incontinence is maintained 5 years after sacral nerve stimulation implantation and beyond. Device revision, replacement, or explant rate was acceptable, but future efforts should be aimed at improvement.

Quality of life is markedly improved in patients with fecal incontinence after sacral nerve stimulation.

OBJECTIVE: The aim of the present analysis was to report on the relationship between long-term improvement in quality of life (QOL) and fecal incontinence (FI) severity and long-term reduction in FI episodes after sacral nerve stimulation (SNS) or sacral neuromodulation. METHODS: Patients who met inclusion/exclusion criteria, and initially had more than 2 FI episodes per week, were offered SNS therapy. Patients with 50% or higher reduction in FI during a 2-week test period were implanted with a neurostimulator (InterStim; Medtronic, Minneapolis, Minn). Assessments were completed by patients at baseline and at 3, 6, and 12 months after implant, and annually thereafter. The present report includes data from the 4-year postimplant follow-up. RESULTS: A total of 133 patients underwent test stimulation with a 90% success rate, and as a result, 120 (110 females) with a mean age of 60.5 years and a mean duration of FI of 6.8 years received long-term implantation. Of them, 78 patients completed all or part of the 4-year follow-up assessment. Fecal incontinence episodes decreased from a mean of 9.4 per week at baseline to 1.9 per week at 48 months (P < 0.001). The 4-year analyses showed that SNS had a positive and sustained impact on all 4 scales of the Fecal Incontinence Quality of Life questionnaire (P < 0.001), Fecal Incontinence Severity Index scores improved from a mean of 39.9 to 28 (P < 0.001), and self-rated bowel health scores improved from a mean of 3.5 to 6.9 (P < 0.001). CONCLUSIONS: Sacral nerve stimulation not only restores or improves continence in treated patients with chronic FI but also improves their quality of life and symptom severity.

The essential genome of a bacterium.

Caulobacter crescentus is a model organism for the integrated circuitry that runs a bacterial cell cycle. Full discovery of its essential genome, including non-coding, regulatory and coding elements, is a prerequisite for understanding the complete regulatory network of a bacterial cell. Using hyper-saturated transposon mutagenesis coupled with high-throughput sequencing, we determined the essential Caulobacter genome at 8 bp resolution, including 1012 essential genome features: 480 ORFs, 402 regulatory sequences and 130 non-coding elements, including 90 intergenic segments of unknown function. The essential transcriptional circuitry for growth on rich media includes 10 transcription factors, 2 RNA polymerase sigma factors and 1 anti-sigma factor. We identified all essential promoter elements for the cell cycle-regulated genes. The essential elements are preferentially positioned near the origin and terminus of the chromosome. The high-resolution strategy used here is applicable to high-throughput, full genome essentiality studies and large-scale genetic perturbation experiments in a broad class of bacterial species.

Long-term efficacy and safety of sacral nerve stimulation for fecal incontinence.

BACKGROUND AND OBJECTIVE: Sacral nerve stimulation is effective in the treatment of urinary incontinence and is currently under Food and Drug Administration review in the United States for fecal incontinence. Previous reports have focused primarily on short-term results of sacral nerve stimulation for fecal incontinence. The present study reports the long-term effectiveness and safety of sacral nerve stimulation for fecal incontinence in a large prospective multicenter study. DESIGN AND METHODS: Patients with fecal incontinent episodes more than twice per week were offered participation in this multicentered prospective trial. Patients showing ≥ 50% improvement during test stimulation were offered chronic implantation of the InterStim Therapy system (Medtronic; Minneapolis, MN). The aims of the current report were to provide 3-year follow-up data on patients from that study who underwent sacral nerve stimulation and were monitored under the rigors of an Food and Drug Administration-approved investigational protocol. RESULTS: One hundred thirty-three patients underwent test stimulation with a 90% success rate, of whom 120 (110 females) with a mean age of 60.5 years and a mean duration of fecal incontinence of 7 years received chronic implantation. Mean length of follow-up was 3.1 (range, 0.2-6.1) years, with 83 patients completing all or part of the 3-year follow-up assessment. At 3 years follow-up, 86% of patients (P < .0001) reported ≥ 50% reduction in the number of incontinent episodes per week compared with baseline and the number of incontinent episodes per week decreased from a mean of 9.4 at baseline to 1.7. Perfect continence was achieved in 40% of subjects. The therapy also improved the fecal incontinence severity index. Sacral nerve stimulation had a positive impact on the quality of life, as evidenced by significant improvements in all 4 scales of the Fecal Incontinence Quality of Life instrument at 12, 24, and 36 months of follow-up. The most common device- or therapy-related adverse events through the mean 36 months of follow-up included implant site pain (28%), paresthesia (15%), change in the sensation of stimulation (12%), and infection (10%). There were no reported unanticipated adverse device effects associated with sacral nerve stimulation therapy. CONCLUSIONS: Sacral nerve stimulation using InterStim Therapy is a safe and effective treatment for patients with fecal incontinence. These data support long-term safety and effectiveness to 36 months.

Infection rates in a large investigational trial of sacral nerve stimulation for fecal incontinence.

INTRODUCTION: Treatment options for patients with fecal incontinence (FI) are limited, and surgical treatments can be associated with high rates of infection and other complications. One treatment, sacral nerve stimulation (SNS), is approved for FI in Europe. A large multicenter trial was conducted in North America and Australia to assess the efficacy of SNS in patients with chronic fecal incontinence. The aim of this report was to analyze the infectious complication rates in that trial. METHODS: Adult patients with a history of chronic fecal incontinence were enrolled into this study. Those patients who fulfilled study inclusion/exclusion criteria and demonstrated greater than two FI episodes per week underwent a 2-week test phase of SNS. Patients who showed a > or = 50% reduction in incontinent episodes and/or days per week underwent chronic stimulator implantation. Adverse events were reported to the sponsor by investigators at each study site and then coded. All events coded as implant site infection were included in this analysis. RESULTS: One hundred twenty subjects (92% female, 60.5 +/- 12.5 years old) received a chronically implanted InterStim Therapy device (Medtronic, Minneapolis, MN, USA). Patients were followed for an average of 28 months (range 2.2-69.5). Thirteen of the 120 implanted subjects (10.8%) reported infection after the chronic system implant. One infection spontaneously resolved and five were successfully treated with antibiotics. Seven infections (5.8%) required surgical intervention, with infections in six patients requiring full permanent device explantation. The duration of the test stimulation implant procedure was similar between the infected group (74 min) and the non-infected group (74 min). The average duration of the chronic neurostimulator implant procedure was also similar between the infected (39 min) and non-infected group (37 min). Nine infections occurred within a month of chronic system implant and the remaining four infections occurred more than a year from implantation. While the majority (7/9) of the early infections was successfully treated with observation, antibiotics, or system replacement, all four of the late infections resulted in permanent system explantation. CONCLUSION: SNS for FI resulted in a relatively low infection rate. This finding is especially important because the only other Food and Drug Administration-approved treatment for end-stage FI, the artificial bowel sphincter, reports a much higher rate. Combined with its published high therapeutic success rate, this treatment has a positive risk/benefit profile.

Sacral nerve stimulation for fecal incontinence: results of a 120-patient prospective multicenter study.

BACKGROUND: Sacral nerve stimulation has been approved for use in treating urinary incontinence in the United States since 1997, and in Europe for both urinary and fecal incontinence (FI) since 1994. The purpose of this study was to determine the safety and efficacy of sacral nerve stimulation in a large population under the rigors of Food and Drug Administration-approved investigational protocol. METHODS: Candidates for SNS who provided informed consent were enrolled in this Institutional Review Board-approved multicentered prospective trial. Patients showing > or =50% improvement during test stimulation received chronic implantation of the InterStim Therapy (Medtronic; Minneapolis, MN). The primary efficacy objective was to demonstrate that > or =50% of subjects would achieve therapeutic success, defined as > or =50% reduction of incontinent episodes per week at 12 months compared with baseline. RESULTS: A total of 133 patients underwent test stimulation with a 90% success rate, and 120 (110 females) of a mean age of 60.5 years and a mean duration of FI of 6.8 years received chronic implantation. Mean follow-up was 28 (range, 2.2-69.5) months. At 12 months, 83% of subjects achieved therapeutic success (95% confidence interval: 74%-90%; P < 0.0001), and 41% achieved 100% continence. Therapeutic success was 85% at 24 months. Incontinent episodes decreased from a mean of 9.4 per week at baseline to 1.9 at 12 months and 2.9 at 2 years. There were no reported unanticipated adverse device effects associated with InterStim Therapy. CONCLUSION: Sacral nerve stimulation using InterStim Therapy is a safe and effective treatment for patients with FI.

Genomic DNA microarray comparison of gene expression patterns in Paracoccidioides brasiliensis mycelia and yeasts in vitro.

Paracoccidioides brasiliensis is a thermally dimorphic fungus, and causes the most prevalent systemic mycosis in Latin America. Infection is initiated by inhalation of conidia or mycelial fragments by the host, followed by further differentiation into the yeast form. Information regarding gene expression by either form has rarely been addressed with respect to multiple time points of growth in culture. Here, we report on the construction of a genomic DNA microarray, covering approximately 25 % of the genome of the organism, and its utilization in identifying genes and gene expression patterns during growth in vitro. Cloned, amplified inserts from randomly sheared genomic DNA (gDNA) and known control genes were printed onto glass slides to generate a microarray of over 12,000 elements. To examine gene expression, mRNA was extracted and amplified from mycelial or yeast cultures grown in semi-defined medium for 5, 8 and 14 days. Principal components analysis and hierarchical clustering indicated that yeast gene expression profiles differed greatly from those of mycelia, especially at earlier time points, and that mycelial gene expression changed less than gene expression in yeasts over time. Genes upregulated in yeasts were found to encode proteins shown to be involved in methionine/cysteine metabolism, respiratory and metabolic processes (of sugars, amino acids, proteins and lipids), transporters (small peptides, sugars, ions and toxins), regulatory proteins and transcription factors. Mycelial genes involved in processes such as cell division, protein catabolism, nucleotide biosynthesis and toxin and sugar transport showed differential expression. Sequenced clones were compared with Histoplasma capsulatum and Coccidioides posadasii genome sequences to assess potentially common pathways across species, such as sulfur and lipid metabolism, amino acid transporters, transcription factors and genes possibly related to virulence. We also analysed gene expression with time in culture and found that while transposable elements and components of respiratory pathways tended to increase in expression with time, genes encoding ribosomal structural proteins and protein catabolism tended to sharply decrease in expression over time, particularly in yeast. These findings expand our knowledge of the different morphological forms of P. brasiliensis during growth in culture.

The fate of the ileal pouch in patients developing Crohn's disease.

PURPOSE: Recent studies have suggested that a subset of patients with Crohn's colitis may have a favorable outcome after ileal pouch-anal anastomosis and have advocated elective ileal pouch-anal anastomosis in selected patients with Crohn's disease. We have not offered ileal pouch-anal anastomosis to patients with known Crohn's disease, but because of the overlap in clinical presentation of ulcerative colitis and indeterminate colitis, some patients receiving an ileal pouch-anal anastomosis are subsequently found to have Crohn's disease. We review our experience with these patients to identify potential preoperative predictors of ultimate pouch failure. METHODS: Patients with a final diagnosis of Crohn's disease were identified from an ileal pouch-anal anastomosis registry. These patients are followed prospectively. Preoperative and postoperative clinical and pathologic characteristics were evaluated as predictors of outcome. Median (range) values are listed. RESULTS: Thirty-two (18 females) patients (4.1 percent) with a final diagnosis of Crohn's disease were identified from a registry of 790 ileal pouch-anal anastomosis patients (1980-2002). Patients underwent ileal pouch-anal anastomosis in two stages (11 patients) or three stages (21 patients). The preoperative diagnosis was ulcerative colitis in 24 patients and indeterminate colitis in 8 patients. Median follow-up was 153 (range, 13-231) months. The median time from ileal pouch-anal anastomosis to diagnosis of Crohn's disease was 19 (range, 0-188) months. Complications occurred in 93 percent, including perineal abscess/fistula (63 percent), pouchitis (50 percent), and anal stricture (38 percent). Pouch failure (excision or current diversion) occurred in nine patients (29 percent) at a median of 66 (range, 6-187) months. Two of these 9 patients had preoperative anal disease (not significant). Comparing patients with failed pouches (n = 9) to patients with functioning pouches (n = 23), post-ileal pouch-anal anastomosis perineal abscess (67 vs. 26 percent, P = 0.05) and pouch fistula (89 vs. 30 percent, P = 0.01) were more commonly associated with pouch failure. Preoperative clinical, endoscopic, and pathologic features were not predictive of pouch failure or patient outcome. For those with a functional pouch, 50 percent have been or are currently on medication to treat active Crohn's disease. This group had six bowel movements in 24 (range, 3-10) hours, with leakage in 60 percent and pad usage in 45 percent. CONCLUSIONS: Patients who undergo ileal pouch-anal anastomosis and are subsequently found to have Crohn's disease experience significant morbidity. Preoperative characteristics, including the presence of anal disease, were not predictive of subsequent pouch failure. We choose not to recommend the routine application of ileal pouch-anal anastomosis in any subset of patients with known Crohn's disease.

Benefits of hand-assisted laparoscopic restorative proctocolectomy: a comparative study.

PURPOSE: Hand-assisted laparoscopic colectomy is thought to facilitate colonic mobilization while maintaining the benefits of laparoscopic surgery. Although previous studies of hand-assisted colectomy have focused on segmental colonic resection, the use of hand-assisted laparoscopic restorative proctocolectomy has not been investigated. This study evaluated the effectiveness of hand-assisted laparoscopic approach compared with a conventional laparoscopic method in patients undergoing restorative proctocolectomy. METHODS: From a prospective database, a consecutive series of patients were identified undergoing conventional and hand-assisted laparoscopic restorative proctocolectomy and results were compared. Twenty-three patients, comprising 10 hand-assisted and 13 conventional laparoscopic patients, were identified. Patient characteristics, perioperative parameters, and outcomes were assessed. RESULTS: Both groups were well matched with no differences in age, gender, body mass index, operative indication, diagnosis, comorbidity, or steroid usage. There were no differences among incision size between the hand-assisted (8 (range, 8-20) cm) and conventional laparoscopic cases (8 (range, 5-10) cm). The median operative time was significantly shorter in the hand-assisted group (247 (range, 210-390) minutes) compared with the conventional laparoscopic group (300 (range, 240-400) minutes; P < 0.01). The length of stay was similar between groups (hand-assisted: 4 (range, 3-13) days vs. conventional: 6 (range, 4-17) days). Complications occurred in four hand-assisted patients (40 percent; 2 ileus, mechanical obstruction, and dehydration) and in four patients undergoing conventional laparoscopic method (31 percent; 2 anastomotic leak, ileus, and mechanical obstruction). CONCLUSIONS: Compared with conventional laparoscopic restorative proctocolectomy, the hand-assisted method resulted in a significant reduction in operative time without detriment to bowel function, length of stay, or patient outcome. The hand-assisted approach to restorative proctocolectomy is likely to replace conventional laparoscopic methods as the preferred laparoscopic approach for this technically challenging procedure.

Is routine pouch surveillance for dysplasia indicated for ileoanal pouches?

PURPOSE: Isolated accounts of neoplastic pouch transformation suggest the need to perform routine ileoanal pouch surveillance with biopsy. These reports imply a model of dysplasia to cancer transformation of the pouch mucosa. More recent reports studying "high risk" ulcerative colitis patients concluded that the development of pouch dysplasia is indeed a rare event. This study was designed to evaluate our institutional incidence of dysplasia in ileoanal pouch during long-term follow-up. METHODS: A prospective database of all patients undergoing ileoanal pouch construction (n = 767) was queried for all patients undergoing pouch biopsy between 1983 and 2001. All patients with ulcerative colitis who underwent pouch biopsy were included. This excluded patients with Crohn's disease, indeterminate colitis, and familial adenomatous polyposis. Pathology reports were reviewed for histologic evidence of inflammation, atypia, metaplasia, dysplasia, or cancer. Patient age at biopsy, pouch age at time of biopsy, and pathology were analyzed. RESULTS: The ileoanal pouches of 160 patients were surveyed with biopsies a total of 222 times. The average length of follow-up from pouch construction to time of surveillance and biopsy was 8.4 +/- 4.6 years. There were 83 patients (52 percent) whose pouches were older than 10 years (mean, 12.7 +/- 2) at time of surveillance. With over 1,800 pouch-years of surveillance, only 1 patient had focal, low-grade dysplasia in the pouch. This patient demonstrated no evidence of dysplasia on further surveillance. CONCLUSION: Even with long-term follow-up of ileoanal pouch patients, there is little evidence to support routine biopsy of the ileal mucosa in ulcerative colitis patients.

Linear pressure profiles and symmetric findings in the stimulated gracilis muscle.

PURPOSE: This is the first report of linear pressure profiles and symmetric findings in preoperative and postoperative (after gracilis muscle retraining) patients. Length of the anal canal and symmetry have been well documented in the literature as significant parameters in the maintenance of anal incontinence. Significant improvement of these parameters should play a critical role in the functional outcome of the stimulated gracilis. METHODS: Six patients underwent preoperative and postoperative anorectal manometry using an eight-channel radial catheter. Pressures were collected at 8 Hz using an automated continuous pullout technique (1 mm/sec). Preoperative and posttraining resting and squeeze pressures, pressure volumes, anal canal length, and linear and cross-sectional images were compared. RESULTS: Resting pressures significantly improved from 13.7 mmHg to 26.8 mmHg (P < 0.02). The squeeze pressure significantly improved from 28.67 mmHg to 62.9 mmHg (P < 0.02). The pressure volume increased from 10,429 mmHg to 26,162 mmHg. Anal canal length increased from an abnormal length of 2.95 cm to normal length of 3.55 cm (P < 0.04). The percentage of sphincter asymmetry decreased from 28.6 percent to 23.5 percent (P < 0.01). The most striking observation was the impact the gracilis muscle had on correcting the geographic cross sections as it wrapped more than 360 degrees from the proximal to distal anal canal. Patients were significantly improved, with four of the six patients completely continent to solid stool. Two of the six patients had minor episodes of seepage. Preoperatively, all patients were grossly incontinent to solid stool. CONCLUSIONS: Significant improvement in resting pressure, pressure volume, anal canal length, and cross-sectional symmetry has led to a significant improvement in anal incontinence after dynamic myoplasty.

Pudendal nerve terminal motor latency testing: assessing the educational learning curve: can we teach our own?

PURPOSE: Pudendal nerve terminal motor latency testing is useful as a diagnostic tool in fecal incontinence. It has also been used as a predictive factor in sphincteroplasty repairs. The technique is seldom taught and mastered in colorectal training programs. The purpose of this study was to assess a learning curve for teaching this procedure. METHODS: The student was a formally trained colorectal surgeon with no pudendal nerve terminal motor latency experience; the instructor has performed more than 3,000 pudendal nerve terminal motor latency studies. Fifty consecutive patients had manometry and pudendal nerve terminal motor latency testing. Both the student and instructor performed pudendal nerve terminal motor latency in a sequential fashion. Variables collected included pudendal nerve terminal motor latency, completion of test, time to complete test, and accuracy of the test. Variables were analyzed with paired t-test and chi-squared analysis. RESULTS: The study group included 41 female and 9 male patients. The average age of the patients was 53 years. Bowel complaints included constipation in 16 and incontinence in 34 patients. Data were analyzed in their entirety and at ten-patient intervals. The student tended to record longer latencies (P < 0.001). This led to false-positive rates of 23 and 21 percent, respectively, for left and right pudendal nerve terminal motor latency. On average, the time to complete the procedure was three times longer for the student than for the instructor (P < 0.001). At ten-patient intervals, the pudendal nerve terminal motor latency difference between the two groups disappeared at the 41-to-50-patient mark. CONCLUSION: Given the proper learning environment, pudendal nerve terminal motor latency testing can be mastered in a relatively short period. On the basis of this study, our estimation is 40 patients are required for a student to master this technique. The novice examiner can expect false-positive results early in the learning curve, and these should be validated accordingly.