Michael A. Kamm

Anal-Sphincter Disruption during Vaginal Delivery

Background Lacerations of the anal sphincter or injury to sphincter innervation during childbirth are major causes of fecal incontinence, but the incidence and importance of occult sphincter damage during routine vaginal delivery are unknown. We sought to determine the incidence of damage to the anal sphincter and the relation of injury to symptoms, anorectal physiologic function, and the mode of delivery. Methods We studied 202 consecutive women six weeks before delivery, 150 of them six weeks after delivery, and 32 with abnormal findings six months after delivery. Symptoms of anal incontinence and fecal urgency were assessed, and anal endosonography, manometry, perineometry, and measurement of the terminal motor latency of the pudendal nerves were performed. Results Ten of the 79 primiparous women (13 percent) and 11 of the 48 multiparous women (23 percent) who delivered vaginally had anal incontinence or fecal urgency when studied six weeks after delivery. Twenty-eight of the 79 primiparous women (35 p...

Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine

Background and aim: Evidence exists for the pathogenic role of the enteric flora in inflammatory bowel disease. Probiotics contain living microorganisms which exert health effects on the host. We compared the efficacy in maintaining remission of the probiotic preparation Escherichia coli Nissle 1917 and established therapy with mesalazine in patients with ulcerative colitis. Patients and methods: In total, 327 patients were recruited and assigned to a double blind, double dummy trial to receive either the probiotic drug 200 mg once daily (n = 162) or mesalazine 500 mg three times daily (n = 165). The study lasted for 12 months and patients were assessed by clinical and endoscopic activity indices (Rachmilewitz) as well as by histology. The primary aim of the study was to confirm equivalent efficacy of the two drugs in the prevention of relapses. Results: The per protocol analysis revealed relapses in 40/110 (36.4%) patients in the E coli Nissle 1917 group and 38/112 (33.9%) in the mesalazine group (significant equivalence p = 0.003). Subgroup analyses showed no differences between the treatment groups in terms of duration and localisation of disease or pretrial treatment. Safety profile and tolerability were very good for both groups and were not different. Conclusions: The probiotic drug E coli Nissle 1917 shows efficacy and safety in maintaining remission equivalent to the gold standard mesalazine in patients with ulcerative colitis. The effectiveness of probiotic treatment further underlines the pathogenetic significance of the enteric flora.

Prospective comparison of faecal incontinence grading systems

Background Existing scales for assessing faecal incontinence have not been validated against clinical assessment, or with regard to reproducibility. They also fail to take into account faecal urgency, and the use of antidiarrhoeal medications. Aims To establish the validity, and sensitivity to change, of existing scales and a newly designed incontinence scale. Methods (1) Twenty three patients (21 females, median age 57 years) were prospectively evaluated by two independent clinical observers, using three established scales (Pescatori, Wexner, American Medical Systems), a newly devised scale which also includes details about urgency and antidiarrhoeal drugs, and by a 28 day diary. (2) A further 10 female patients were assessed by the same scales before and after surgery for faecal incontinence. Results (1) Assessments by two independent clinicians correlated well. All four scales and a diary card correlated highly and significantly with the clinical impression, with the new scale reaching the highest correlation (r=0.79, p<0.001). (2) All except one score changed significantly in response to surgical treatment; the new scale showed the greatest change, at the highest level of significance (p=0.004), and correlated best with the clinicians’ assessment of change (r=0.94, p<0.001). Conclusions Existing scales for the assessment of faecal incontinence correlate well with careful clinical impression of severity, and serve as useful and reproducible measures for comparison of patients and treatments. A newly devised scale has shown high clinical validity and utility.

Once daily high dose probiotic therapy (VSL#3) for maintaining remission in recurrent or refractory pouchitis

Background: Ten to 15% of patients with pouchitis experience refractory or recurrent disease. The aim of this study was to evaluate the effectiveness of a single daily high dose probiotic preparation (VSL#3) in maintaining antibiotic induced remission, and quality of life (QOL), for one year in such patients. Methods: Patients with pouchitis at least twice in the previous year or requiring continuous antibiotics, associated with a pouchitis disease activity index (PDAI) ⩾7 (0 = perfect; 18 = worst), in whom remission was induced by four weeks of combined metronidazole and ciprofloxacin, were randomised to receive VSL#3 6 g or placebo once daily for one year or until relapse. Symptomatic, endoscopic, and histological evaluations were made before, and two and 12 months after randomisation or at the time of relapse. Remission was defined as a clinical PDAI ⩽2 and endoscopic PDAI ⩽1. Relapse was defined as an increased clinical PDAI score ⩾2 and increased endoscopic PDAI score ⩾3. QOL was assessed using the inflammatory bowel disease questionnaire (IBDQ). Results: Thirty six patients were randomised: 20 to VSL#3 and 16 to placebo. Remission was maintained at one year in 17 patients (85%) on VSL#3 and in one patient (6%) on placebo (p<0.0001). The IBDQ score remained high in the VSL#3 group (p = 0.3) but deteriorated in the placebo group (p = 0.0005). Conclusion: The once daily high dose probiotic VSL#3 is effective in maintaining antibiotic introduced remission for at least a year in patients with recurrent or refractory pouchitis. This is associated with a high level of quality of life.

Third degree obstetric anal sphincter tears: risk factors and outcome of primary repair

Objectives To determine (i) risk factors in the development of third degree obstetric tears and (ii) the success of primary sphincter repair. Design (i) Retrospective analysis of obstetric variables in 50 women who had sustained a third degree tear, compared with the remaining 8553 vaginal deliveries during the same period. (ii) Women who had sustained a third degree tear and had primary sphincter repair and control subjects were interviewed and investigated with anal endosonography, anal manometry, and pudendal nerve terminal motor latency measurements Setting: Antenatal clinic in teaching hospital in inner London. Subjects (i) All women (n=8603) who delivered vaginally over a 31 month period. (ii) 34 women who sustained a third degree tear and 88 matched controls. Main outcome measures : Obstetric risk factors, defaecatory symptoms, sonographic sphincter defects, and pudendal nerve damage. Results - (i) Factors significantly associated with development of a third degree tear were: forceps delivery (50% v 7% in controls; P=0.00001), primiparous delivery (85% v 43%; P=0.00001), birth weight >4 kg (P=0.00002), and occipitoposterior position at delivery (P=0.003). No third degree tear occurred during 351 vacuum extractions. Eleven of 25 (44%) women who were delivered without instruments and had a third degree tear did so despite a posterolateral episiotomy. (ii) Anal incontinence or faecal urgency was present in 16 women with tears and 11 controls (47% v 13%;20P=0.00001). Sonographic sphincter defects were identified in 29 with tears and 29 controls (85% v 33%; P=0.00001). Every symptomatic patient had persistent combined internal and external sphincter defects, and these were associated with significantly lower anal pressures. Pudendal nerve terminal motor latency measurements were not significantly different. Conclusions Vacuum, extraction is associated with fewer third degree tears than forceps delivery. An episiotomy does not always prevent a third degree tear. Primary repair is inadequate in most women who sustain third degree tears, most having residual sphincter defects and about half experiencing anal incontinence, which is caused by persistent mechanical sphincter disruption rather than pudendal nerve damage. Attention should be directed towards preventive obstetric practice and surgical techniques of repair.

Modulation of human dendritic cell phenotype and function by probiotic bacteria

Background: “Probiotic” bacteria are effective in treating some inflammatory bowel diseases. However which bacteria confer benefit and mechanisms of action remain poorly defined. Dendritic cells, which are pivotal in early bacterial recognition, tolerance induction, and shaping of T cell responses, may be central in mediating the effects of these bacteria. Aims: To assess effects of different probiotic bacteria on dendritic cell function. Methods: Human intestinal lamina propria mononuclear cells, whole blood, or an enriched blood dendritic cell population were cultured with cell wall components of the eight bacterial strains in the probiotic preparation VSL#3 (four lactobacilli, three bifidobacteria, and one streptococcal strains). Dendritic cells were identified and changes in dendritic cell maturation/costimulatory markers and cytokine production in response to probiotic bacteria were analysed by multicolour flow cytometry, in addition to subsequent effects on T cell polarisation. Results: VSL#3 was a potent inducer of IL-10 by dendritic cells from blood and intestinal tissue, and inhibited generation of Th1 cells. Individual strains within VSL#3 displayed distinct immunomodulatory effects on dendritic cells; the most marked anti-inflammatory effects were produced by bifidobacteria strains which upregulated IL-10 production by dendritic cells, decreased expression of the costimulatory molecule CD80, and decreased interferon-γ production by T cells. VSL#3 diminished proinflammatory effects of LPS by decreasing LPS induced production of IL-12 while maintaining IL-10 production. Conclusions: Probiotic bacteria differ in their immunomodulatory activity and influence polarisation of immune responses at the earliest stage of antigen presentation by dendritic cells.

Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease

The incidence of various cancers, especially non-Hodgkin lymphoma (NHL), is higher among patients who receive azathioprine for immunosuppression after organ transplants than in the general population. We have studied the risk of neoplasia after azathioprine in 755 patients treated for inflammatory bowel disease. The patients received 2 mg/kg daily for a median of 12.5 months (range 2 days to 15 years) between 1962 and 1991; median follow-up was 9 years (range 2 weeks to 29 years). Overall there was no significant excess of cancer: 31 azathioprine-treated patients developed cancer before age 85 compared with 24.3 expected from rates in the general population (observed/expected ratio 1.27, p = 0.186). There was a difference in the frequency of colorectal (13) and anal (2) carcinomas (expected 2.27; ratio 6.7, p = 0.00001); these tumours are recognised complications of chronic inflammatory bowel disease. There were 2 cases of invasive cervical cancer (expected 0.5), but no case of NHL. Among patients with extensive chronic ulcerative colitis there was no difference in cancer frequency between 86 who had received azathioprine and 180 matched patients who had never received it. Thus, azathioprine treatment does not substantially increase the risk of cancer in inflammatory bowel disease.

Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience.

Myelosuppression is an important and potentially lethal complication of azathioprine treatment. The blood count has been reviewed in all patients treated with azathioprine for inflammatory bowel disease over 27 years in one hospital. Altogether 739 patients (422 with Crohns disease, 284 with ulcerative colitis, and 33 with indeterminate colitis) were treated with 2 mg/kg/day azathioprine for a median of 12.5 months (range 0.5-132) between 1964 and 1991. Full blood counts were performed monthly for the duration of treatment. In 37 patients (5%) who developed bone marrow toxicity, the drug was withdrawn or the dose reduced. Thirty two of these patients were asymptomatic and five developed symptoms. Leucopenia (white blood count less than 3.0 x 10g/l) occurred in 28 (3.8%) patients, in nine of whom it was severe (white blood count < 2.0 x 10(9)/l). Of these nine patients, three were pancytopenic: two died from sepsis and the other had pneumonia but recovered. A further two patients with severe leucopenia developed a mild upper respiratory infection only. Thrombocytopenia (platelet count < 100,000 x 10(6)/l) in 15 patients was associated with leucopenia in six and developed in isolation in a further nine (total 2%). Isolated thrombocytopenia was never clinically severe. Myelotoxicity from azathioprine developed at any time during drug treatment (range 2 weeks-11 years after starting the drug) and occurred either suddenly or over several months. Bone marrow suppression as a result of azathioprine treatment is uncommon when a moderate dose is used, but is potentially severe. Leucopenia is the commonest and most important haematological complication. Regular monitoring of the full blood count is recommended during treatment.

Long-term results of overlapping anterior anal-sphincter repair for obstetric trauma

BACKGROUND Anterior structural damage to the anal sphincter occurs in up to a third of women at first vaginal delivery, and of these a third have new bowel symptoms. The standard treatment for such structural damage is anterior overlapping anal-sphincter repair. We aimed to assess the long-term results of this operation. METHODS We assessed the long-term results in 55 consecutive patients who had had repair a minimum of 5 years (median 77 months [range 60-96]) previously. Questionnaire and telephone interview assessed current bowel function and continence, restriction in activities related to bowel control, and overall satisfaction with the results of surgery. 42 of these patients had been continent of solid and liquid stool at a median of 15 months after the repair. FINDINGS We were able to contact 47 (86%) of the 55 patients. One of these patients had required a proctectomy and end ileostomy for Crohns disease. Of the remaining 46 patients, 27 reported improved bowel control without the need for further surgery, and 23 rated their symptom improvement as 50% or greater. Seven patients had undergone further surgery for incontinence and one patient had not had a covering stoma closed. Thus, the long-term functional outcome of the sphincter repair alone could be assessed in 38 patients. Of these patients, none was fully continent to both stool and flatus; only four were totally continent to solid and liquid stool; six had no faecal urgency; and eight had no passive soiling. Of the 38 patients, 20 still wore a pad for incontinence and 25 reported lifestyle restriction. 14 reported the onset of a new evacuation disorder after sphincter repair. 23 of the 46 patients contacted had a successful long-term outcome (defined as no further surgery and urge faecal incontinence monthly or less). INTERPRETATION The results of overlapping sphincter repair for obstetric anal-sphincter damage seem to deteriorate with time. Preoperative counselling should emphasise that although most patients will improve after the procedure, continence is rarely perfect, many have residual symptoms, and some may develop new evacuation disorders.

Randomised controlled trial of CDP571 antibody to tumour necrosis factor-α in Crohn's disease

Summary Background Tumour necrosis factor-α (TNFα) is thought to have a central role in the pathogenesis of Crohns disease. We tested the hypothesis that CDP571, a genetically engineered human antibody to TNFα, is effective in modifying disease activity in patients with moderately active Crohns disease. Methods In this double-blind, placebo-controlled study, 31 patients were randomly assigned to CDP571 (n=21) or placebo (n=10). The primary endpoint was change in Crohns disease activity index 2 weeks after a single infusion of CDP571 (5 mg/kg), or human albumin as placebo. One patient who attended no follow-up assessments was excluded from the analyses (CDP571 group). Findings The median Crohns disease activity index fell from 263 (IQR 186·5–323·5) at baseline to 167 (137·5–294·0) at 2 weeks in the CDP571-treated patients (p=0·0003); the change in the placebo group (253 [240–334] to 247 [183–256]) was not significant. In the treated group, there were also significant differences between baseline and 2 weeks in Harvey-Bradshaw score (p=0·0005), key symptom score (p=0·049), α1-glycoprotein concentration (p=0·012), and erythrocyte sedimentation rate (p=0·01); concentrations of C-reactive protein fell, but not significantly (p=0·067). Six patients achieved remission (Crohns disease activity index ≤150) and three others had activity indices of 156 or lower. There were no significant changes in the placebo group. Interpretation A single 5 mg/kg infusion of CDP571 reduced disease activity in Crohns disease at 2 weeks. These data suggest that antibody neutralisation of TNFα is a potentially effective strategy in the management of Crohns disease. The use of CDP571 in Crohns disease requires further study.